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Handbook ofPharmaceuticalGranulationTechnology DRUGS AND THE PHARMACEUTICAL SCIENCES A Series of Textbooks and Monographs Executive Editor James Swarbrick PharmaceuTech, Inc.Pinehurst, North Carolina Advisory Board Larry L. Augsburger University of Maryland Baltimore, Maryland Jennifer B. Dressman University of Frankfurt Institute of Pharmaceutical Technology Frankfurt, Germany Anthony J. Hickey University of North CarolinaSchool of Pharmacy Chapel Hill, North Carolina Ajaz Hussain Sandoz Princeton, New Jersey Joseph W. Polli GlaxoSmithKline Research Triangle Park North Carolina Stephen G. Schulman University of FloridaGainesville, Florida Yuichi Sugiyama University of Tokyo, Tokyo, Japan Geoffrey T. Tucker University of Sheffield Royal Hallamshire Hospital Sheffield, United Kingdom Harry G. Brittain Center for Pharmaceutical Physics Milford,New Jersey Robert Gurny Universite de Geneve Geneve, Switzerland Jeffrey A. Hughes University of Florida College of Pharmacy Gainesville, Florida Vincent H. L. Lee US FDA Center for Drug Evaluation and Research Los Angeles, California Kinam Park Purdue University West Lafayette, Indiana Jerome P. Skelly Alexandria, Virginia Elizabeth M. Topp University of Kansas Lawrence, Kansas Peter York University of Bradford School of Pharmacy Bradford, United Kingdom For information on volumes 1151 in the Drugs and Pharmaceutical Science Series, please visit www.informahealthcare.com 152. Preclinical Drug Development, edited by Mark C. Rogge and David R. Taft 153. Pharmaceutical Stress Testing: Predicting Drug Degradation, edited by Steven W. Baertschi 154. Handbook of Pharmaceutical Granulation Technology: Second Edition, edited by Dilip M. Parikh 155. Percutaneous Absorption: DrugsCosmeticsMechanismsMethodology,Fourth Edition, edited by Robert L. Bronaugh and Howard I. Maibach 156. Pharmacogenomics: Second Edition, edited by Werner Kalow, Urs A. Meyer and Rachel F. Tyndale 157. Pharmaceutical Process Scale-Up, Second Edition, edited by Michael Levin 158. Microencapsulation: Methods and Industrial Applications, Second Edition, edited by Simon Benita 159. Nanoparticle Technology for Drug Delivery, e d i t e d b y R a m B . G u p t a a n d Uday B. Kompella 160. Spectroscopy of Pharmaceutical Solids, edited by Harry G. Brittain

161. Dose Optimization in Drug Development, edited by Rajesh Krishna 162. Herbal Supplements-Drug Interactions: Scientific and Regulatory Perspectives, edited by Y. W. Francis Lam, Shiew-Mei Huang, and Stephen D. Hall 163. Pharmaceutical Photostability and Stabilization Technology, edited by Joseph T. Piechocki and Karl Thoma 164. Environmental Monitoring for Cleanrooms and Controlled Environments, edited by Anne Marie Dixon 165. Pharmaceutical Product Development: In Vitro-In Vivo Correlation, edited by Dakshina Murthy Chilukuri, Gangadhar Sunkara, and David Young 166. Nanoparticulate Drug Delivery Systems, edited by Deepak Thassu, Michel Deleers, and Yashwant Pathak 167. Endotoxins: Pyrogens, LAL Testing and Depyrogenation, Third Edition, edited by Kevin L. Williams 168. Good Laboratory Practice Regulations, Fourth Edition, edited by Anne Sandy Weinberg 169. Good Manufacturing Practices for Pharmaceuticals, Sixth Edition, edited by Joseph D. Nally 170. Oral-Lipid Based Formulations: Enhancing the Bioavailability of PoorlyWater-soluble Drugs, edited by David J. Hauss 171. Handbook of Bioequivalence Testing, edited by Sarfaraz K. Niazi 172. Advanced Drug Formulation Design to Optimize Therapeutic Outcomes, edited by Robert O. Williams III, David R. Taft, and Jason T. McConville 173. Clean-in-Place for Biopharmaceutical Processes, edited by Dale A. Seiberling 174. Filtration and Purification in the Biopharmaceutical Industry, Second Edition, edited by Maik W. Jornitz and Theodore H. Meltzer 175. Protein Formulation and Delivery, Second Edition, edited by Eugene J. McNally and Jayne E. Hastedt 176. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, ThirdEdition, edited by James McGinity and Linda A. Felton 177. Dermal Absorption and Toxicity Assessment, Second Edition, edited by Michael S. Roberts and Kenneth A. Walters 178. Preformulation Solid Dosage Form Development, edited by Moji C. Adeyeye and Harry G. Brittain 179. Drug-Drug Interactions, Second Edition, edited by A. David Rodrigues 180. Generic Drug Product Development: Bioequivalence Issues, edited by Isadore Kanfer and Leon Shargel 181. Pharmaceutical Pre-Approval Inspections: A Guide to Regulatory Success,Second Edition, edited by Martin D. Hynes III 182. Pharmaceutical Project Management, Second Edition, edited by Anthony Kennedy 183. Modified Release Drug Delivery Technology, Second Edition, Volume 1, edited by Michael J. Rathbone, Jonathan Hadgraft, Michael S. Roberts,and Majella E. Lane 184. Modified-Release Drug Delivery Technology, Second Edition, Volume 2, edited by Michael J. Rathbone, Jonathan Hadgraft, Michael S. Roberts, and Majella E. Lane 185. The Pharmaceutical Regulatory Process, Second Edition, edited by Ira R. Berry and Robert P. Martin 186. Handbook of Drug Metabolism, Second Edition, e d i t e d b y P a u l G . P e a r s o n a n d Larry C. Wienkers 187. Preclinical Drug Development, Second Edition, edited by Mark Rogge and David R. Taft 188. Modern Pharmaceutics, Fifth Edition, Volume 1: Basic Principles and Systems, edited by Alexander T. Florence and Ju rgen Siepmann 189. Modern Pharmaceutics, Fifth Edition, Volume 2: Applications and Advances,

edited by Alexander T. Florence and Ju rgen Siepmann 190. New Drug Approval Process, Fifth Edition, edited by Richard A.Guarino 191. Drug Delivery Nanoparticulate Formulation and Characterization, edited by Yashwant Pathak and Deepak Thassu 192. Polymorphism of Pharmaceutical Solids, Second Edition, edited by Harry G. Brittain 193. Oral Drug Absorption: Prediction and Assessment, Second Edition, edited by Jennifer J. Dressman, Hans Lennernas, and Christos Reppas 194. Biodrug Delivery Systems: Fundamentals, Applications, and Clinical Development, edited by Mariko Morishita and Kinam Park 195. Pharmaceutical Process Engineering, Second Edition, edited by Anthony J. Hickey and David Ganderton 196. Handbook of Drug Screening, Second Edition, edited by Ramakrishna Seethala and Litao Zhang 197. Pharmaceutical Powder Compaction Technology, Second Edition, edited by Metin Celik 198. Handbook of Pharmaceutical Granulation Technology, Third Edition, edited by Dilip M. Parikh edited by Dilip M. Parikh DPharma Group Inc.Ellicott City, Maryland, USA Handbook ofPharmaceuticalGranulationTechnology T H I R D E D

PART III: PRODUCT ORIENTED GRANULATIONS 14. Effervescent Granulation 323 Guia Bertuzzi 15. Granulation Approaches in Biotech Industry 338 Tuo Jin, Weien Yuan, and Hui Li 16. Granulation of Plant Products and Nutraceuticals 349 Dilip M. Parikh 17. Granulation Approaches for Modified Release Products 364 Neelima Phadnis and Sree Nadkarni 18. Granulation of Poorly Water-Soluble Drugs 381 Albert W. Brzeczko, Firas El Saleh, and Jiao Yang 19. Granulation Approaches for Orally Disintegrating Formulations 401 Gopi Venkatesh 2 0 . M e l t G r a n u l a t i o n 4 3 5 Chris Vervaet and Jean Paul Remon PART IV: CHARACTERIZATION AND SCALE-UP

21. Sizing of Granulation 449 Gurvinder Singh Rekhi and Richard Sidwell 22. Granulation Characterization 469 Cecil W. Propst 23. Bioavailability and Granule Properties 487 Sunil S. Jambhekar 24. Granulation Process Modeling 498 Ian T. Cameron and Fu Y. Wang 25. Scale-Up Considerations in Granulation 538 Yinghe He, Lian X. Liu, James D. Litster, and Defne Kayrak-Talay 26. Advances in Process Controls and End-Point Determination 567 Kevin A. Macias and M. Teresa Carvajal PART V: OPTIMIZATION STRATEGIES, TOOLS AND REGULATORY CONSIDERATIONS 27. Expert Systems and Their Use in Pharmaceutical Applications 578 Metin Celik and Susan C. Wendell 28. Regulatory Issues in Granulation: The Pharmaceutical Qualityf o r t h e 2 1 s t CenturyA Risk-Based Approach 597 Prasad Kanneganti 29. Quality by Design and Process Analytical Technology in Granulation 617 Gopi Vudathala, Stanley Rodgers, and John E. Simmons I n d e x 6 3 7 xiv Contents Contributors Guia Bertuzzi IMA SPA ACTIVE Division, Bologna, Italy Albert W. Brzeczko Acura Pharmaceuticals, Inc., Baltimore, Maryland, U.S.A. Ian T. Cameron School of Chemical Engineering, The University of Queensland,Queensland, Australia M. Teresa Carvajal Department of Industrial and Physical Pharmacy, School of Pharmacy andPharmaceutical Sciences, Purdue University, West Lafayette, Indiana, U.S.A. MetinCelik Pharmaceutical Technologies International, Inc., Belle Mead, New Jersey, U.S.A. andSchool of Pharmacy, Near East University, Nicosia, Turkish Republic of Northern Cyprus Lai Wah Chan Department of Pharmacy, National University of Singapore, Singapore Thomas Du rig Ashland Aqualon Functional Ingredients, Ashland Inc., Wilmington, Delaware, U.S.A. Michel Deleers Global Pharmaceutical Technology and Analytical Development, UCB, BrainelAlleud, Belgium Bryan J. Ennis E&G Associates, Inc., Nashville, Tennessee, U.S.A. David F. Erkoboni Cedar Consulting Corporation, Pennington, New Jersey, U.S.A. Rajeev Gokhale Abbott, Abbott Park, Illinois, U.S.A. Yinghe He School of Engineering and Physical Sciences, James Cook University, Queensland,Australia Paul W. S. Heng Department of Pharmacy, National University of Singapore, Singapore Sunil S. Jambhekar Department of Pharmaceutical Sciences, Lecom-Bradenton School of Pharmacy, Bradenton, Florida, U.S.A. Tuo Jin School of Pharmacy, Shanghai Jiaotong University, Shanghai, P.R. China

David M. Jones OWI Consulting Inc., Ramsey, New Jersey, U.S.A. Prasad Kanneganti Genentech Singapore Pte Ltd., Tuas Baylink, Singapore Defne Kayrak-Talay School of Chemical Engineering, Purdue University, West Lafayette, Indiana,U.S.A. Xiang Kou Department of Pharmacy, National University of Singapore, Singapore Hui Li School of Pharmacy, Shanghai Jiaotong University, Shanghai, P.R. China

James D. Litster School of Chemical Engineering and Department of Industrial and PhysicalPharmacy, Purdue University, West Lafayette, Indiana, U.S.A. Lian X. Liu Particle & Systems Design Centre, School of Chemical Engineering, The University of Queensland, Queensland, Australia Kevin A. Macias Department of Industrial and Physical Pharmacy, School of Pharmacy andPharmaceutical Sciences, Purdue University, West Lafayette, Indiana, U.S.A. Ronald W. Miller Miller Pharmaceutical Technology Consulting, Travelers Rest,South Carolina, U.S.A. Sree Nadkarni FibroGen Inc., San Francisco, California, U.S.A. Dilip M. Parikh DPharma Group Inc., Ellicott City, Maryland, U.S.A. Yashwant Pathak Sullivan University, Louisville, Kentucky, U.S.A. Neelima Phadnis Independent Pharma Consultant, Brisbane, California, U.S.A. Cecil W. Propst SPI Pharma, Grand Haven, Michigan, U.S.A. Gurvinder Singh Rekhi Elan Drug Technologies, Gainesville, Georgia, U.S.A. Stanley Rodgers Sanofi-Aventis US LLC, Bridgewater, New Jersey, U.S.A. Jean Paul Remon Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium Firas El Saleh ISP Global Technologies Deutschland GmbH, Cologne, Germany Richard Sidwell Elan Drug Technologies, Gainesville, Georgia, U.S.A. John E. Simmons Simmons FDA Consulting, Chapin, South Carolina, U.S.A. Harald Stahl GEA Pharma Systems, Hurth, Germany Deepak Thassu PharmaNova Inc., Victor, New York, U.S.A. Namrata R. Trivedi Covidien, Webster Groves, Missouri, U.S.A. Griet Van Vaerenbergh GEA Pharma Systems nv - Collette TM

, Wommelgem, Belgium Gopi Venkatesh Eurand, Inc., Vandalia, Ohio, U.S.A. Chris Vervaet Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium Gopi Vudathala Sanofi-Aventis US LLC, Malvern, Pennsylvania, U.S.A. Martin A. Wahl Pharmaceutical Technology and Biopharmacy, Institute of PharmaceuticalSciences, Eberhard-Karls-University Tubingen, Tubingen, Germany Fu Y. Wang School of Chemical Engineering, The University of Queensland, Queensland, Australia Susan C. Wendell Johnson & Johnson, Raritan, New Jersey, U.S.A. Jiao Yang ISP Pharma Technologies, Inc., Columbia, Maryland, U.S.A. Weien Yuan School of Pharmacy, Shanghai Jiaotong University, Shanghai, P.R. China xvi Contributors 1 Introduction Dilip M. Parikh DPharma Group Inc., Ellicott City, Maryland, U.S.A. BACKGROUND The term granulated material is derived from the Latin word granulatum, meaninggrained. The practice of delivering medicinal powder by hand r o l l i n g i n t o a p i l l b y u s i n g honey or sugar has been used for centuries. It is still the practice to deliver the botanical andherbal extracts in homeopathic and ayurvedic branches of medicine, which are still practicedin India along with allopathic medicine.T h o m a s S k i n n e r , a p h y s i c i a n i n h i s a r t i c l e i n 1 8 6 2 ( 1 ) , d e s c r i b e s e a r l i e r m e n t i o n o f granulating medicine cited in 1773 in Duncans Elements of Therapeutics , as follows: by theapplication of art, it is intended that medicines should b e r e n d e r e d m o r e a g r e e a b l e , m o r e convenient, more safe and more efficacious than they are in their natural state. To obtain theseends is the intention of pharmacy. Skinner further describes the earlier method of makinggranules by French pharmacists who had a form of medication that they call poudres granules .The process of preparing these granules consisted in enveloping the particles of medicines insyrup by means of heat and constant stirring, as in the art of making comfits. This method wasfurther modified to make granules with very little heat or moisture, which can be placed on thetongue and washed over with water, which was a modification of the method of granulatinggunpowder.Perrys Chemical Engineers Handbook (2) defines the granulation process as any processw h e r e b y s m a l l p a r t i c l e s a r e gathered into larger, permanent masses in which the originalparticles can still be identified. This definition is, of course, particularly appropriate to apharmaceutical granulation where the rapid breakdown of agglomerates is important tomaximize the available surface area and aid in solution of the a c t i v e d r u g . T h e g r a n u l a t e d material can be obtained by direct size enlargement of primary particles or size reduction fromdry, compacted material.I n m o d e r n t i m e s , g r a n u l a t i o n technology has been widely used by a wide range of industries, such as chemical, coal, mining, metallurgy, ceramic, and agrochemical. T h e s e industries employ agglomeration techniques to reduce dust, provide ease of handling, andenhance the materials ultimate utility.The development of pharmaceutical granulation was driven by the invention of the tabletpressbyW.Brockedon in1843.Subsequent improvements inthe tabletmachinerywerepatentedin the United States by J. A. McFerran (1874), T. J. Young (1874), and J. Dunton (1876). Thedemands on the granulation properties were further enhanced in the 1970s as high-speed tableta n d c a p s u l e filling machines with automated controls were introduced. The

continuousrefinements in the regulatory requirements such as low-dose p r o d u c t s r e q u i r i n g b l e n d uniformity/content uniformity necessitated knowledge and technology to produce the requiredgranule characteristics. The high-speed compression and capsulefilling machines require auniform flow of material to the dies or filling stations that produce pharmaceutical dosage form. Direct Compression The processing of drug substance with the excipients can be achieved without employing thep r o c e s s o f g r a n u l a t i o n . B y s i m p l y m i x i n g i n a b l e n d e r , a directlycompressibleformulationcan beprocessed and compressed in tablets o r f i l l e d i n t h e h a r d g e l a t i n c a p s u l e s . I n t h e 1 9 7 0 s , microcrystalline cellulose, as a directly compressible vehicle, was introduced. The compressibleformulation containing microcrystalline cellulose is suitable for a number of products. This hasseveral obvious advantages, such as lower equipment cost, faster process time, and efficientoperationinvolvingonly two processsteps. Sometimes, excipient costsmay havetobecomparedagainst the savings in the processing steps and equipment by using alternate methods.

There are, however, a number of products that cannot be directly compressed because of low dosage, or flow properties of the drug and excipient mixture. Blend uniformity and thecontent uniformity in the drug product are critical attributes with low dose drug formulation.Other than content uniformity of a low-dose drug substance, there are a number of reasonswhy direct compression may not be suitable for a wide array of products. These include therequired flow properties; the amount of drug substance in a dosage form may require it to bed e n s i f i e d t o r e d u c e t h e s i z e o f t h e d r u g p r o d u c t , o b t a i n t h e r e q u i r e d h a r d n e s s , f r i a b i l i t y , disintegration/dissolution, and other attributes. Current Granulation Techniques and Research The classical granulation process using either wet or dry methods is employed in the processi n d u s t r i e s . P h a r m a c e u t i c a l g r a n u l a t i o n p r o c e s s i s u s e d f o r t a b l e t , c a p s u l e , a n d s p h e r i c a l granules for the modified-release indications or to prepare granules as sprinkles to be used bypediatric patients. In some countries like Japan, having granulated product in a sachet isacceptable where a large dose of the drug product is not suitable for swallowing. The reasonsfor granulating a pharmaceutical compound are well documented in the literature.M a n y r e s e a r c h e r s s t u d i e d t h e i n f l u e n c e o f m a t e r i a l p r o p e r t i e s o f t h e g r a n u l a t i n g powders and process conditions on the granulation process in a rather empirical way. In the1 9 9 0 s , f u n d a m e n t a l a p p r o a c h t o r e s e a r c h w a s s t a r t e d o n v a r i o u s t o p i c s i n t h e g r a n u l a t i o n process, looking into more detailed aspects of particle wetting, mechanism of granulation,material properties, and influence of mixing apparatus on the product. The overall hypothesiss u g g e s t e d that the granulation can be predicted from the raw material properties and t h e processing conditions of the granulation process. One of the major difficulties encountered ingranulation technology is the incomplete description of the behavior of powders in general.The ongoing fundamental research on mixing, segregation mechanisms of powder, surfacec h e m i s t r y , a n d m a t e r i a l s c i e n c e i s n e c e s s a r y t o d e v e l o p t h e t h e o r e t i c a l f r a m e w o r k o f granulation technology. An excellent review of the wet granulation process was presentedby Iveson et al. (3). The authors have advanced the understanding of the granulation processb y stating that there are three fundamental sets of rate processes, which are i m p o r t a n t i n determining wet granulation behavior. These are wetting and nucleation, consolidation andgrowth; and breakage and attrition. Once these processes are sufficiently understood, then itwill be possible to predict the effect of formulation properties, equipment type, and operatingconditions of granulation behavior, provided these can be adequately characterized accordingto the reviewers.Five primary methods exist to form an agglomerated granule. They are formation of solidbridges, sintering, chemical reaction, crystallization, and deposition of colloidal particles.Binding can also be achieved through adhesion and cohesion forces in highly viscous binders.Successful processing for the agglomeration of primary particles depends on propercontrol of the adhesional forces between particles, which encourage

agglomerate formation andgrowth and provide adequate mechanical strength in the product. Furthermore, the rheology of the particulate system can be critical to the rearrangement of particles necessary to permitdensification of the agglomerate and the development of an agglomerate structure appropriatefor the end-use requirements. If the particles are close enough, then the surface forces such asv a n d e r W a a l s f o r c e s ( s h o r t r a n g e ) a n d e l e c t r o s t a t i c f o r c e s c a n i n t e r a c t t o b o n d p a r t i c l e s . Decreasing particle size increases surfacemass ratio and favors the bonding. van der Waalsforces are sevenfold stronger than electrostatic forces and increase substantially when thed i s t a n c e b e t w e e n t h e m i s r e d u c e d , w h i c h c a n b e a c h i e v e d b y a p p l y i n g p r e s s u r e a s i n d r y granulation method. The cohesive forces that operate during the moist agglomerates are mainlydue to the liquid bridges that develop between the solid particles. Electrostatic forces keepparticles in contact long enough for another mechanism to govern the agglomeration process.Dry compaction technique like roller compaction is experiencing renewed interest in theindustry. There are a number of drug substances that are moisture sensitive and cannot bed i r e c t l y compressed. The roller compaction provides suitable alternative technology f o r processing these products. Early stages of wet granulation technology development employedl o w - s h e a r m i x e r s o r t h e m i x e r s / b l e n d e r s n o r m a l l y u s e d f o r d r y blending such as ribbonmixers. There are a number of products currently manufactured using these low-shear 2 Parikh granulators. The process control and efficiency have increased over the years; however, thei n d u s t r y h a s e m b r a c e d h i g h - s h e a r g r a n u l a t o r s f o r w e t g r a n u l a t i o n b e c a u s e o f i t s e f f i c i e n t process reproducibility and modern process control capabilities. The high-shear mixers havealso facilitated new technologies, such as one-pot processing, that use the mixer to granulateand then dry using vacuum, gas stripping/vacuum, or microwave assist vacuum drying.Fluid-bed processors have been used in the pharmaceutical industry for the last 40 years,i n i t i a l l y o n l y a s a d r y e r a n d n o w a s a m u l t i p r o c e s s o r t o g r a n u l a t e , d r y , p e l l e t i z e , a n d c o a t particles. The most preferred method of granulation is to use the high-shear mixer to granulateand use the fluid bed as a dryer in an integrated equipment setup. This provides the best of both technologies: efficient controllable dense wet granules and a fast-drying cycle using fluid-bed dryer. Here again, the choice of this approach will be dependent on the product beingp r o c e s s e d a n d i t s desired properties at the end of the granulation process. E x t r u s i o n / spheronization is used to produce granulation for the tabletting or pelletizing, which involvesmixing, extruding, spheronizing, and drying unit operations. These pellets can be produceda s m a t r i x p e l l e t s w i t h t h e a p p r o p r i a t e p o l y m e r o r a r e c o a t e d i n f l u i d - b e d u n i t t o p r o d u c e modified-release dosage forms. Other techniques have been used by researchers such as steamg r a n u l a t i o n , u s i n g f o a m b i n d e r i n p l a c e o f l i q u i d b i n d e r s o r m o i s t u r e - a c t i v a t e d d r y granulation (MADG) where a s m a l l a m o u n t o f m o i s t u r e i s a d d e d t o t h e b l e n d c o n t a i n i n g certain binders under constant mixing in high-shear mixer. This process eliminates the needfor processing of the granulation however, essentially suffers from the same shortcomings asw o u l d b e e n c o u n t e r e d w i t h d i r e c t c o m p r e s s i o n b l e n d . T a b l e 1 l i s t s t h e m o s t c o m m o n techniques to granulate a pharmaceutical compound in the industry. Granulation and Particle Design Granulation is an example of particle design. The desired attributes o f t h e g r a n u l e a r e controlled by a combination of the formulation and the process.Spray drying technique is now routinely used to prepare particles for inhalation dosageforms or to create solid dispersions of poorly soluble drugs. Recent interest in nanotechnologyresearch has opened up a number of avenues for creating newer drugs. Various developmentg r o u p s a r e w o r k i n g t o e n h a n c e t r a d i t i o n a l o r a l d e l i v e r y s y s t e m s w i t h n a n o - e n g i n e e r e d improvements. There are some areas where nano-enhanced drugs could make a big differencei n i n c r e a s i n g o r a l b i o a v a i l a b i l i t y a n d reducing undesirable side effects. By increasingb i o a v a i l a b i l i t y , nanoparticles can increase the yield in drug development a n d , m o r e importantly, may help treat previously untreatable conditions. Another approach in the1990s was to use supercritical fluid technology to p r o d u c e u n i f o r m p a r t i c l e s t o r e p l a c e crystallization. Even though supercritical fluids were discovered over 100 years ago and thec o m m e r c i a l p l a n t w a s b u i l t o v e r

2 0 y e a r s a g o i n t h e U n i t e d S t a t e s , i t i s o n l y n o w t h a t t h e technology is used for a number of pharmaceutical applications (47) so as to produce aspirin,caffeine, ibuprofen, acetaminophen, etc. One of the major areas on which the research and Table 1 Frequently Used Granulation Techniques and Subsequent ProcessingP r o c e s s S u b s e q u e n t p r o c e s s i n g D r y g r a n u l a t i o n D i r e c t c o m p r e s s i o n B l e n d p r o c e s s f u r t h e r Slugging (double compression) Mill slugs/recompress/mill/ blendprocess furtherR o l l e r c o m p a c t i o n M i l l / b l e n d p r o c e s s f u r t h e r W e t g r a n u l a t i o n L o w - s h e a r m i x e r T r a y o r f l u i d - b e d d r y , m i l l , b l e n d p r o c e s s f u r t h e r H i g h - s h e a r m i x e r T r a y o r f l u i d - b e d d r y , m i l l , b l e n d p r o c e s s f u r t h e r H i g h - s h e a r m i x e r V a c u u m / g a s s t r i p p i n g / m i c r o w a v e a s s i s t m i l l , blendprocess furtherF l u i d - b e d g r a n u l a t o r d r y e r A f t e r d r y i n g mill, blendprocess furtherExtrusion/spheronization Tray or fluid-bed dryermill, blendprocess furtherS p r a y d r y e r S p r a y d r y e r p r o c e s s f u r t h e r Continuous mixer granulatormechanicalContinuous fluid bedmill, blend process furtherContinuous fluid-bed granulator/dryer Dried productmill, blendprocess further Introduction 3

development of supercritical fluids is focused is particle design. There are different conceptssuch as rapid expansion of supercritical solution, gas antisolvent recrystallization, andsupercritical antisolvent to generate particles, microspheres, microcapsules, liposomes, oro t h e r d i s p e r s e d m a t e r i a l s . W h e n t h e s u p e r c r i t i c a l fluid and drug solution make contact, avolume expansion occurs, leading to a r e d u c t i o n i n s o l v e n t c a p a c i t y , i n c r e a s e i n s o l u t e saturation, and then supersaturation with associated nucleation and particle formation. An u m b e r o f advantages are claimed by using this platform technology such as p a r t i c l e formation from nanometers to tens of micrometers, low residual solvent levels in products,preparation of polymorphic forms of drug, etc. (8). Attempts to make solid dosage forms of large molecules are under way even though there are numerous challenges. Current Industry Status and Challenges Efficient and cost-effective manufacturing of pharmaceutical products is being evaluated bythe scientists, engineers, and operational managers of pharmaceutical companies worldwide.I n t h e U n i t e d S t a t e s , w h e r e 4 9 % o f t h e w o r l d p h a r m a c e u t i c a l m a r k e t i s , p h a r m a c e u t i c a l companies are under tremendous pressure from the managed care organizations, politicians,and consumers. The pharmaceutical industry, worldwide in general and in the United States inp a r t i c u l a r , f a c e s a u n i q u e p a r a d o x t o d r i v e f u t u r e innovation through substantial R&Dinvestments and return competitive m a r g i n t o s h a r e h o l d e r s w h i l e p r o v i d i n g a c c e s s t o pharmaceutical products at low cost. The industry has reached a critical juncture in its 100+years of history. The industry is impacted simultaneously by growing competition, decliningmarket performance, increasing regulation, escalating pricing pressures, and rapidly evolvinginnovations for improving peoples health and quality of life. Recently published reports (9,1 0 ) i n t o pharmaceutical R&D and pharmaceutical manufacturing questioned the existingindustry business model and has identified an emerging trend f a v o r i n g o u t s o u r c i n g o f discovery, research, clinical trials, and manufacturing of dosage forms, providing relief fromthe consistent, high-growth financial return expectations faced by the majority of pharmaceu-tical companies. Outsourcing allows these companies to pursue

potential new revenue streamso u t s i d e o f t h e i r c o r e f o c u s a r e a s a n d t o b e n e f i t f r o m i m p r o v e d p r o d u c t i v i t y , e m e r g i n g technologies, in-licensing opportunities, and increased growth. Consumers and local govern-m e n t s i n t h e U n i t e d S t a t e s a r e p r e s s u r i n g t h e F D A a u t h o r i t i e s a n d p o l i t i c i a n s t o a l l o w importation of the drugs from other countries where costs are generally lower than in theU n i t e d S t a t e s . D e m a n d s f o r p r i c e c o n t r o l a l s o e x t e n d t o E u r o p e ; g o v e r n m e n t - b a c k e d pharmaceutical payment plans in Germany and Italy, for example, have cut back reimburse-ments. Other European countries have controls on the drug prices. As a result of these pricingpressures and to enhance the drugs in the pipeline, mergers and acquisitions have accelerated.Acquisitions remain the preferred route to quickly enhance a product portfolio.T h i s t r e n d o f m e r g i n g o f e q u a l s o r t a k e o v e r o f t h e s i g n i f i c a n t b i o t e c h n o l o g i c a l a n d technological companies will continue. Major pharmaceutical companies are witnessing thee n d o f t r a d i t i o n a l r e s e a r c h a n d d e v e l o p m e n t . T h i s h a s c r e a t e d e m e r g e n c e o f s m a l l n i c h e technology companies as well. Drug delivery companies are becoming potential targets formergers or strategic alliances.B e c a u s e b i o l o g i c s a r e l e s s s u s c e p t i b l e t o g e n e r i c c o m p e t i t i o n , b i g p h a r m a c e u t i c a l companies are acquiring biotech companies as well.Table 2 lists the 12 biggest mergers that have taken place in 20082009 alone which showshow the industry is accelerating the acquisition approach.During all of the upheaval that the industry is going through, it is becoming obvious thatthe cost of development, production, and goods must be controlled. The efficiencies in ther e s e a r c h , d e v e l o p m e n t , a n d m a n u f a c t u r i n g , w h i c h w e r e n o t n e c e s s a r i l y s o u g h t a f t e r , a r e becoming the first priority of the pharmaceutical companies however small they may be incomparison to the final cost of the product to the consumer. The manufacturing of solid dosageproduct is no exception.T h e significant advances that have taken place in the pharmaceutical g r a n u l a t i o n technology are presented in this book to provide the readers with choices that are available.T h e v a r i o u s t e c h n i q u e s p r e s e n t e d i n t h i s b o o k w i l l further help the scientists in theirunderstanding and selection of t h e g r a n u l a t i o n p r o c e s s m o s t a p p r o p r i a t e f o r t h e d r u g substance. There is no substitute for good science. The characterization of the drug substance 4 Parikh along with the knowledge of granulation theory, identifying the critical process parameters,process modeling capability, in-line or on-line process analytical tools (PAT), process scale-upa p p r o a c h e s , a n d a g o o d d e f i n i t i o n o f t h e e n d p r o d u c t r e q u i r e d w i l l prepare the reader toexplore the various options presented in this book. E a c h d r u g s u b s t a n c e p o s e s a u n i q u e challenge that must be taken into consideration at the process selection stage by the scientists.The optimization techniques due to availability of state of the art computers, process control,and mathematical techniques to model the granulation process will advance the traditionalgranulation technology.For production engineering, validation, and quality professionals in the industry, thisbook is intended to provide the fundamental understanding of the technique of granulationand the rationale behind the selection of each particular technique. This will further enhancet h e a b i l i t y t o d e s i g n t h e p r o d u c t i o n p l a n t , c a r r y o u t t h e t e c h n o l o g y t r a n s f e r , s c a l e u p , troubleshoot, and maintain the p h a r m a c e u t i c a l g r a n u l a t i o n o p e r a t i o n i n a c c o r d a n c e w i t h regulatory compliance. REFERENCES 1. Skinner T. The Granulation of medicines. Br Med J 1862; 1(59):172175.2. Ennis BJ, Litster JD. Particle enlargement. In: Perry RH, Greens D, eds. Perrys Chemical EngineersHandbook. 7th ed. New York:McGraw Hill, 1997:20-5620-89.3. Iveson SM, Litster JD, Hopgood K, et al. Nucleation, growth, and breakage phenomenon in agitatedwet granulation process: a review. Powder Technol 2001; 117:339.4. Charoenchaitrakool M, Dehghani F, Foster NR. Micronization by RESS to enhance the dissolutionrates of poorly water soluble pharmaceuticals. Proceedings of the 5th International Symposium onSupercritical Fluids, Atlanta, GA, April 812, 2000.5. Matson DW, Fulton JL, Petersen RC, et al. Rapid expansion of supercritical fluid solutions: soluteformation of powders, thin films, and fibers. Ind Eng Chem Res 1987; 26:22982306.6. Subra P, Boissinot P, Benzaghou S. Precipitation of pure and mixed caffeine and anthracene by rapidexpansion of supercritical solutions. Proceedings of the 5th Meeting on Supercritical Fluids, Tome I,Nice, France, March 2325, 1998.7. Gilbert DJ, Palakodaty S, Sloan R, et al. Particle engineering for pharmaceutical applicationsaprocess scale up. Proceedings of the 5th International

Symposium on Supercritical Fluids, Atlanta,GA, April 812, 2000.8. Baldyga J, Henczka M, Shekunov BY. Fluid dynamics, mass transfer and particle formation in supercritical fluids. In: York P, Kompella UB, Shekunov BY, eds. Super Critical Fluid Technology for DrugProduct Development. Marcel Dekker, 2004; 91158.9. Cambridge Healthcare Advisors (CHA) Report. Report identifies increasing outsourcing by pharma.September 29, 2004. Available at: http://www.outsourcing-pharma.com/Clinical-Development/Report-identifies-increasingoutsourcing-by-pharma.1 0 . P r i c e W a t e r h o u s e C o o p e r s . P h a r m a 2 0 2 0 : V i r t u a l R & D W h i c h P a t h w i l l y o u t a k e ? A v a i l a b l e a t : http://www.pwc.com/gx/en/pharma-lifesciences/index.jhtml11. Top 10 Deals of 2008. Available at: http://www.fiercebiotech.com/specialreports/top-10-deals-2008.12. Pfizer to pay $60 billion for Wyeth-Wall Street Journal, January 26, 2009.13. Merck to buy rival for $41 Billion-Wall street Journal, March 10, 2009. Table 2 Top Twelve mergers in 20082009N u m b e r M e r g e r / a c q u i s i t i o n p a r t n e r s V a l u e i n b i l l i o n d o l l a r s 1 N o v a r t i s a n d A l c o n 392 T a k e d a a n d M i l l e n i u m 8.83 T e v a a n d B a r r 7.464 E l i L i l l y a n d I m c l o n e 6.55 D a i i c h i a n d R a n b a x y 4.66 R o c h e a n d V a t a n a 3.47 G S K a n d A c t e l i o n 3.28 S a n o f i a n d Z e n t i v a 2.69 G e n z y m e a n d I s i s 1.91 0 L i i l y a n d C o v a n c e 1.61 1 P f i z e r a n d W y e t h ( 2 0 0 9 ) $68.01 2 M e r c k a n d S c h e r i n g - P l o u g h ( 2 0 0 9 ) $41.0 Source : From Refs. 1113. Introduction 5

2 Theory of Granulation: An EngineeringPerspective Bryan J. Ennis E&G Associates, Inc., Nashville, Tennessee, U.S.A. INTRODUCTIONOverview Wet granulation is a subset of size enlargement (16), which involves any process wherebysmall particles are agglomerated, compacted, or otherwise brought together into larger,relatively permanent structures in which the original p a r t i c l e s c a n s t i l l b e d i s t i n g u i s h e d . Granulation technology and size enlargement processes have been used by a wide range of industries, ranging from the pharmaceutical industry to fertilizer or detergent production tothe mineral processing industries. Size enlargement generally encompasses a variety of unitoperations or processing techniques dedicated to particle agglomeration. These processes canbe loosely broken down into agitation and compression methods.Although terminology is industry specific, agglomeration by agitation will be referred to as granulation

. A particulate feed is introduced to a process vessel and is agglomerated, eitherbatchwise and continuously, to form a granulated product. Agitative processes include fluidb e d , p a n ( o r d i s k ) , d r u m , a n d m i x e r g r a n u l a t o r s . S u c h p r o c e s s e s a r e also used as coatingoperations for controlled release, taste masking, and c a s e s w h e r e s o l i d c o r e s m a y a c t a s a carrier for a drug coating. The feed typically consists of a mixture of solid ingredients, referredto as a formulation, which includes an active or key ingredient, binders, diluents, flow aids,surfactants, wetting agents, lubricants, fillers, or end-use aids (e.g., sintering aids, colors ord y e s , t a s t e m o d i f i e r s ) . A closely related process of spray drying is also included here, butdiscussed in detail elsewhere (See Ref. 7 and chap. 5). Product forms generally i n c l u d e agglomerated or layered granules, coated carrier cores, or spray dried product consisting of agglomerated solidified drops.A n a l t e r n a t i v e a p p r o a c h t o s i z e enlargement is by agglomeration by compression , or compaction , where the mixture of particulate matter is fed to a compression device, whichpromotes agglomeration due to pressure. Either continuous sheets of s o l i d m a t e r i a l a r e produced or some solid form such as a briquette or tablet. Compaction processes range fromconfined compression devices, such as tabletting, to continuous devices, such as roll presses( c h a p . 8 ) , b r i q u e t t i n g m a c h i n e s a n d e x t r u s i o n ( c h a p . 1 2 ) . S o m e p r o c e s s e s o p e r a t e i n a semicontinuous fashion such as ram extrusion. Capsule filling operations would be considereda low-pressure compaction process.A t t h e l e v e l o f a m a n u f a c t u r i n g p l a n t , t h e s i z e e n l a r g e m e n t p r o c e s s i n v o l v e s s e v e r a l peripheral, unit operations such as milling, blending, drying or cooling, and classification,r e f e r r e d t o g e n e r i c a l l y a s a n a g g l o m e r a t i o n c i r c u i t ( F i g . 1 ) . I n a d d i t i o n , m o r e t h a n o n e agglomeration step may be present. In the case of pharmaceutical granulation, granulatedm a t e r i a l i s a l m o s t e x c l u s i v e l y a n i n t e r m e d i a t e p r o d u c t f o r m , w h i c h i s t h e n f o l l o w e d b y tabletting. In the context of granulation, therefore, it is important to understand compactionprocesses to establish desirable granule properties for tabletting performance.Numerous benefits result from size enlargement processes as summarized in Table 1. Awide variety of size enlargement methods are available; a classification of available equipmentand initial criteria of process selection is given in Tables 2 and 3. A primary purpose of wetgranulation, in the case of pharmaceutical processing, is to create free flowing, nonsegregatingb l e n d s o f i n g r e d i e n t s o f c o n t r o l l e d s t r e n g t h , w h i c h m a y b e r e p r o d u c i b l y m e t e r e d i n subsequent tabletting or for vial or capsule filling operations. The wet granulation processm u s t g e n e r a l l y a c h i e v e d e s i r e d g r a n u l e properties within some prescribed range. These

attributes clearly depend on the application at hand. However, common to most processes is as p e c i f i c g r a n u l e s i z e d i s t r i b u t i o n a n d g r a n u l e v o i d a g e . S i z e d i s t r i b u t i o n a f f e c t s f l o w a n d segregation properties, as well as compaction behavior. Granule voidage controls strength, andimpacts capsule and tablet dissolution behavior, as well as compaction behavior and tablethardness.Control of granule size and voidage will be discussed in detail throughout this chapter.The approach taken here relies heavily on attempting to understand interactions at a particlelevel, and scaling to bulk effects. Developing an understanding of these microlevel processes of agglomeration allows a rational approach to the design, scale-up, and control of agglomerationprocesses (Figs. 2 and 3). Although the approach is difficult, qualitative trends are uncoveredalong the way, which aid in formulation development and process optimization, and whichemphasize powder characterization as an integral part of product development and processdesign work. Figure 1

A typical agglomeration circuit utilized in the processing of pharmaceuticals involving both granulationand compression techniques. Source : From Refs. 16. Table 1 Objectives of Size EnlargementProduction of useful structural formProvision of a defined quantity for dispensing, with improved flow properties for metering and tablettingImproved product appearanceReduced propensity to cakingIncreased bulk density for storage and tabletting feeds.Creation of nonsegregating blends with ideally uniform distribution of key ingredients.Control of solubility, and dissolution profiles.Control of porosity, hardness and surface to volume ratio and particle size Source : From Refs. 16. Theory of Granulation: An Engineering Perspective 7

Regimes of Nucleation and Wetting The mechanisms of nucleation and wetting may be determined from a wetting regime map(Fig. 16), and is controlled by two key parameters. The first is the time required for a drop tow e t i n t o t h e m o v i n g p o w d e r b e d , i n c o m p a r i s o n t o c i r c u l a t i o n t i m e o f t h e p r o c e s s . A s discussed previously, this wet-in t i m e i s s t r o n g l y i n f l u e n c e d b y f o r m u l a t i o n p r o p e r t i e s [Eq. (5)]. The second parameter is the actual spray rate or spray flux, in comparison with solidsflux moving through the spray zones. Spray flux is strongly influenced by process design ando p e r a t i o n . I f w e t - i n i s r a p i d a n d s p r a y f l u x e s a r e l o w , i n d i v i d u a l d r o p s w i l l f o r m d i s c r e t e nuclei somewhat larger than the drop size in a droplet-controlled regime . At the other extreme, if d r o p p e n e t r a t i o n i s s l o w a n d s p r a y f l u x i s l a r g e , d r o p coalescence and pooling of binder Figure 15 Influence of capillary penetration ondrum granule size. Increasing penetration rate, asreflected by equation (5) increases granule sizea n d d e c r e a s e s a s y m m e t r y o f t h e g r a n u l e s i z e distribution. Source : From Ref. 39. Figure 16 A possible regime map of nucle-ation, relating spray flux, solids mixing (solidsf l u x a n d c i r c u l a t i o n t i m e ) , a n d f o r m u l a t i o n properties. Source : From Refs. 5, 6, and 24. Theory of Granulation: An Engineering Perspective 21

material will occur throughout the powder bed. Shear forces due to solids mixing must thenbreakdown over-wet masses or clumps in a mechanical dispersion regime , independent of dropdistribution. Drop overlap and coalescence occur to varying extents in a

transitional intermediateregime , with an increasingly wider nucleation distribution being formed for increasing sprayflux and decreasing wet-in time.To better understand the impact of process design and scale-up, we will consider dropp e n e t r a t i o n t i m e a n d s p r a y f l u x i n g r e a t e r d e t a i l . S m a l l p e n e t r a t i o n t i m e i s d e s i r a b l e f o r droplet-controlled nucleation. Dimensionless drop penetration time T p is given by Hapgood(24): T p t p t c where t p 1 : 35 V 2 = 3d e 2eff m R eff g cos ! 7 Note the similarity with the Washburn relation equation (5). Dimensionless drop wet-intime decreases with increasing pore radius R eff , decreasing binder viscosity m , increasingadhesion tension g cos y , decreasing drop volume V d , increasing bed porosity e eff , a n d increasing process circulation time t c . Circulation time is a function of mixing and bed weight,a n d c a n c h a n g e w i t h s c a l e up. Effective pore radius R eff

i s r e l a t e d t o t h e s u r f a c e - v o l u m e average particle size d 32 , particle shape f , bed porosity e , tapped porosity e tap , and effectiveporosity e eff by: R eff d 32 3 e eff 1 e eff e eff e tap 1 e e tap 8 To remain within a droplet-controlled regime of nucleation, the penetration time t p should be less than the characteristic circulation time t c of the granulator in question.Now turning attention to spray distribution, the dimensionless spray flux C d is the ratioof the rate at which drops cover a given spray area c d to the rate at which solids move throughthis same zone c s and is a measure of the density of drops falling on the powder surface. The Figure 17

Monte-Carlo simulations ofdrop coverage on a powder bed: ( A ) C d 0.26, ( B ) C d 0.59, and ( C ) C d 2.4. Source : From Refs. 6 and 24. Figure 18 Effect of spray drop distributiona t l o w s p r a y f l u x o n n u c l e i d i s t r i b u t i o n . Lactose feed powder in spinning granulator. Source : From Ref. 31. 22 Ennis

volumetric spray rate V 0 and drop size d d determine the number of drops formed per unit time,and, therefore, both the area occupied by a single drop and the total drop coverage area perunit time, or c d =3 V 0 /2 d d . The dimensionless spray flux is then given by: C d c d c s 32 V 0 d

d c s 9 As with drop penetration time, spray flux plays a role in defining t h e r e g i m e s o f nucleation (Figs. 16 and 17) (5,6,24). For small spray flux ( C d < 0.1), drops will not overlapon contact and will form separate discrete nuclei if the drops also have fast penetration time.For large spray flux ( C d > .5), however, significant drop overlap occurs, forming nuclei muchl a r g e r t h a n d r o p s i z e , and in the limit, independent of drop size. Spray flux is s t r o n g l y influenced by process design.For the case of random drop deposition described by a Poissons distribution (Fig. 18),Hapgood (24) showed the fraction of surface covered by spray as given by: f single 1 exp C d 10 In addition, the fraction of single drops forming individual nuclei (assuming rapid droppenetration) versus the number of agglomerates formed was given by: f single exp 4 C d 11 and f agglom 1 exp 4 C d 12

Examples of the above as applied to nucleation are described by Litster et al. (40). Here,n u c l e i d i s t r i b u t i o n w a s s t u d i e d a s a f u n c t i o n o f d r o p s i z e a n d s p r a y f l u x . F o r a m o d e r a t e , intermediate spray flux of C d 0.22, a clear relationship is seen between nuclei size and spraydistribution, with nuclei formed somewhat larger than the drop size (Fig. 18). In addition, thenuclei distribution widens with the increasing formation of agglomerates for increasing sprayflux (Fig. 19), as given by equation (12), for the case of rapid drop penetration.The spray flux captures the impact of equipment operating variables on nucleation andwetting, and as such is very useful for scale-up if nucleation rates and nuclei sizes are to bemaintained constant (Fig. 16). A droplet-controlled nucleation regime occurs when there is bothlow spray fluxrelatively few drops overlap; and fast droplet penetrationdrops wet into theb e d c o m p l e t e l y b e f o r e b e d m i x i n g a l l o w s f u r t h e r drop contact. Nuclei will be formed of Figure 19 Agglomerate formation with lactose, water, and HPLC spray solutions. Source : From Refs. 6 and 25. Theory of Granulation: An Engineering Perspective 23

somewhat larger than the drop size. A mechanical dispersion regime occurs at the other extremeof high spray fluxgiving large drop overlap and coalescence, and large drop penetrationt i m e s , p r o m o t e d b y p o o r w e t - i n r a t e s a n d s l o w c i r c u l a t i o n t i m e s a n d p o o r m i x i n g . I n t h i s regime, nucleation and binder dispersion occurs by mechanical agitation. Viscous, poorlyw e t t i n g b i n d e r s a r e slow to flow through pores in the powder bed in the case of p o o r penetration time. Drop coalescence on the powder surface occurs (also known as pooling)c r e a t i n g v e r y b r o a d n u c l e i s i z e d i s t r i b u t i o n s . B i n d e r s o l u t i o n d e l i v e r y m e t h o d ( d r o p s i z e , nozzle height) typically has minimal effect on the nuclei size distribution, though interfacialp r o p e r t i e s m a y a f f e c t n u c l e i a n d f i n a l g r a n u l e strength. An

intermediate regime e x i s t s f o r moderate drop penetration times and moderate spray flux, with the resulting nuclei regimenarrowing with decreases in both.T h e r e a r e s e v e r a l i m p l i c a t i o n s w i t h regard to the nucleation regime map in troubleshooting of wetting and n u c l e a t i o n p r o b l e m s . I f d r o p p e n e t r a t i o n t i m e s a r e l a r g e , m a k i n g adjustments to spray may not be sufficient to narrower granule size distributions if remainingin the mechanical regime. Significant changes to wetting and nucleation occur only if changestake the system across a regime boundary. This can occur in an undesirable way if processesare not scaled with due attention to remaining in the drop controlled regime, or alternatively,w i t h i n the mechanical dispersion regime. For example, scale-up may cause a g r a n u l a t i o n process to move from one regime on wetting to another, resulting in unexpected behavior andan entirely different dependence of atomization method and mixing. Example of Wetting Regime Calculation As an example of wetting calculations, consider an idealized powder bed shown in Fig. 20 of width B 0.10 m, moving past a flat spray of spray rate d V/ d t 1 0 0 m L / m i n a s a s o l i d s velocity of w 1.0 m/sec. For a given spray rate, the number of drops is determined by dropvolume or diameter d d 100 m m, which in turn defines the drop area a per unit time, whichwill be covered by the spray, giving a spray flux c d of: c d d a d t d V = d tV d p d 2d 4 32 d V

= d t d d 32 100 10 6 = 60m = s 100 10 6 m 0 : 025m 2 = s 13 As droplets contact the powder bed at a certain rate, the powder moves past the spray zone atits own velocity, or at solids flux c s given for this simple example by: c s d A d t B w 0 : 1m 1 : 0m = s 0

: 1m 2 = sec 14 This gives a dimensionless spray flux of: C d c d c s 0 : 025m 2 = sec0 : 1m 2 = sec 0 : 25 15 Figure 20 Idealized flat spray zone in a spinning riffle granulator. Source : From Refs. 6 and 24. 24 Ennis

This is at the limit of allowable spray flux to remain within a dropletc o n t r o l l e d r e g i m e . I f double the spray rate is required, wetting and nucleation would occur within the mechanicaldispersion regime, diminishing the need for spray nozzles. To lower the spray rate by a factoro f t w o , a s a s a f e t y f o r d r o p l e t - c o n t r o l l e d n u c l e a t i o n , e i t h e r t w o n o z z l e s s p r e a d w e l l a p a r t , double the solids velocity, or half the spray rate would be needed (e.g., doubling the spraycycle time). Alternately, smaller drops might prove helpful.The last requirement for droplet-controlled growth would be a short drop penetrationt i m e . F o r a l a c t o s e p o w d e r o f d 32 20 m m, and loose and tapped voidage of e 0.60 and e tap 0.40, the effective voidage and pore radius are given by: e eff e

tap 1 e e tap 0 : 4 1 0 : 6 0 : 4 0 : 32 16 R eff d 32 3 e eff 1 e eff 0 : 9 2030 : 321 0 : 32 2 : 8 m m

 17 The penetration time should be no more than 10% of the circulation time. For water with aviscosity of m 1, cp =0.001 Pa/sec, and adhesion tension of g cos y =.033 N/m, we obtain apenetration time of t p 1 : 35 V 2 = 3d e 2eff m R eff g cos ! 1 : 35 100 10 6 p = 6 2 = 3 0 : 32 2 0 : 0012 : 8 10

6 0 : 033 ! 0 : 0009sec 18 Note that the penetration time is a strong function of drop size ( / d 2 d ) a n d v i s c o s i t y . F o r a 100-fold increase in viscosity representative of a typical binding solution and twice the dropsize, the penetration time would increase to 0.4 seconds. This time could, in fact, be short whenc o m p a r e d w i t h t h e c i r c u l a t i o n t i m e s o f h i g h s h e a r s y s t e m s , s u g g e s t i n g a m o v e t o w a r d mechanical dispersion. GRANULE GROWTH AND CONSOLIDATIONMechanics of Growth and Consolidation The evolution of the granule size distribution is controlled by several mechanisms. Nucleationof fine powders and coating of existing granules by the fluid phase have been discussed in thep r e v i o u s section. Breakage mechanisms will be treated in the following. Here, we f o c u s particularly on growth and consolidation mechanisms. Granule growth includes the coalescence of existing granules as well as the layering of fine powder onto previously formed nuclei orgranules. The breakdown of wet clumps into a stable nuclei distribution can also be includedamong coalescence mechanisms. As granules grow by coalescence, they are simultaneouslycompacted by consolidation mechanisms, which reduce internal granule voidage or porosity,which impacts granule strength and breakage.T h e r e a r e s t r o n g i n t e r a c t i o n s b e t w e e n g r o w t h a n d consolidation, as illustrated inFigure 21. For fine powder feed, granule size o f t e n p r o g r e s s e s t h r o u g h r a p i d , e x p o n e n t i a l growth in the initial nucleation stage, followed by linear growth in the transition stage, finishingwith very slow growth in a final balling stage. Simultaneously with growth, granule porosity isseen to decrease with time as the granules are compacted. Granule growth and consolidationa r e i n t i m a t e l y connected; increases in granule size are shown here to be associated with a decrease in granule porosity. This is a dominant theme in wet granulation.A s originally outlined in Ennis (4), these growth patterns are common throughoutfluidized bed, drum, pan, and high-shear mixer processes for a v a r i e t y o f f o r m u l a t i o n s . Specific mechanisms of growth may dominate for a process sometimes to the exclusion of others, with the prevailing mechanisms dictated by the interaction of formulation properties,which control granule deformability, and operating variables, which control the local level of shear, or bed agitation intensity.For two colliding granules to coalesce rather than breakup, the collisional kinetic energymust first be dissipated to prevent rebound as illustrated in Figure 22. In addition, the strengtho f t h e b o n d must resist any subsequent breakup forces in the process. The ability of t h e granules to deform during processing may be referred to as the formulations deformability , and Theory of Granulation: An Engineering Perspective 25

deformability has a large effect on growth rate, as well as granule consolidation. Increases indeformability increase the bonding or contact area, thereby dissipating and resisting breakupforces. From a balance of binding and separating forces and torque acting within the area of g r a n u l e c o n t a c t , O u c h i y a m a a n d T a n a k a ( 4 1 ) d e r i v e d a c r i t i c a l l i m i t o f s i z e a b o v e w h i c h coalescence becomes impossible, or a maximum growth limit given by: D c AQ 3 = 2 K 3 = 2 s T 1 = 4 plastic deformation K / 1 = H AQK 3 = 2 s T 1 = 3 elastic deformation K / 1 = E 2 = 3 ( 19 Here,

K is deformability , a proportionality constant relating the maximum compressive force Q to the deformed contact area, A is a constant with units of [L 3 /F] and s T is the tensile strength of the granule bond. Depending on the type of collision, deformability K is a function of eitherhardness H , or reduced elastic modulus E * . G r a n u l e s a r e c o m p a c t e d a s t h e y c o l l i d e . T h i s expels pore fluid to the granule surface, thereby increasing local liquid saturation in the contactarea of colliding granules. This surface fluid ( i ) increases the tensile strength of the liquid bond s T , and ( ii ) increases surface plasticity and deformability K .T h e d e g r e e o f g r a n u l e d e f o r m a t i o n t a k i n g p l a c e d u r i n g g r a n u l e c o l l i s i o n s d e f i n e s possible growth mechanisms (Fig. 22). If little deformation takes place, the system is referred toas a low-deformability / low-shear p r o c e s s . T h i s g e n e r a l l y i n c l u d e s f l u i d b e d , d r u m , a n d p a n granulators. Growth is largely controlled by the extent of any surface fluid layer and surfaced e f o r m a b i l i t y , w h i c h a c t t o d i s s i p a t e c o l l i s i o n a l k i n e t i c e n e r g y a n d a l l o w p e r m a n e n t coalescence. Growth generally occurs at a faster timescale than overall granule deformationa n d c o n s o l i d a t i o n . T h i s i s d e p i c t e d i n F i g u r e 2 2 , w h e r e s m a l l e r g r a n u l e s c a n s t i l l b e distinguished as part of a l a r g e r g r a n u l e s t r u c t u r e , o r a p o p c o r n - t y p e a p p e a r a n c e a s o f t e n occurs in fluid-bed granulation. Note that such a structure may not be observed if layering ornucleation alone dominates. Granules may also be compacted, becoming smoother over timebecauseof the longer-timescaleprocess of consolidation. Granulecoalescence and consolidationhave less interaction than they do with high deformability systems, making lowdeformability/low-shear systems easier to scale-up and control, for systems without high recycle.For high-shear rates, large granule deformation occurs during collisions, and granuleg r o w t h a n d c o n s o l i d a t i o n o c c u r o n t h e s a m e t i m e s c a l e . S u c h a system is referred to as a Figure 21 Granule porosity and mean (pellet) size. Typical regimes of granule growth and consolidation, shownfor drum granulation of fine limestone. Source : From Refs. 1619. 26 Ennis

deformable/high-shear process, and includes continuous pin and plow shear type mixers, as wellas batch high-shear pharmaceutical mixers. In these cases, kinetic energy is dissipated throughd e f o r m a t i o n o f the wet mass composing the granule. Rather than the sticking togethermechanism of low-deformability processes such as a fluid-bed, granules are smashed or kneaded together, and smaller granules are not distinguishable within the granule structure (Fig. 22).H i g h - s h e a r a n d h i g h - d e f o r m a b l e p r o c e s s e s g e n e r a l l y p r o d u c e d e n s e r g r a n u l e s t h a n t h e i r low-deformability counterpart. In addition, the combined and competing effects of granulecoalescence and consolidation make high-shear processes difficult to scale-up.Although these extremes of growth are still the subject of much research investigation, ag e n e r a l m o d e l h a s e m e r g e d t o h e l p p r o c e s s e n g i n e e r s u n r a v e l t h e i m p a c t o f o p e r a t i n g variables and process selection. Two key dimensionless groups control growth. As originallydefined by Ennis (4) and Tardos and Khan (42), these are the viscous and deformation Stokesnumbers given, respectively, by: St v 4 r u o d 9 m 20 St def

 r u 2o s y impact or r d u = d x 2 d 2 s y shear 21 The viscous Stokes number St v is the ratio of kinetic energy to viscous work due to bindingfluid occurring during granule/particle collisions. Low St v or low granule energy representsincreased likelihood of granule coalescence and growth, and this occurs for small granule orparticle size ( d is the harmonic average of granule diameter), low relative collision velocity u o or granule density r , and high binder phase viscosity m . The deformation Stokes numberrepresents the amount of granule deformation taking place during collisions, and is similarly aratio of kinetic energy to wet mass yield stress, a measure of granule deformability.Bed agitation intensity is controlled by mechanical variables of the process such as fluid-bed excess gas velocity or mixer impeller and chopper speed. Agitation intensity controls therelative collisional and shear velocities of granules within the process and therefore growth,breakage, consolidation, and final product density. Figure 23 summarizes typical characteristicv e l o c i t i e s , a g i t a t i o n i n t e n s i t i e s a n d c o m p a c t i o n p r e s s u r e s , a n d p r o d u c t r e l a t i v e d e n s i t i e s achieved for a variety of size enlargement processes.Note that the process or formulation itself cannot define whether it falls into a low or highagitation intensity process. As discussed more fully below, it is a function of both the level of Figure 22 Mechanisms of granule coalescence for low and high deformability systems. Rebound occurs foraverage granule sizes greater than the critical granule size D c

. K deformability. Granule structures resulting from( A ) low and ( B ) high deformability systems, typical for fluid-bed and high-shear mixer granulators, respectively. Source : From Refs. 1, 2, and 4. Theory of Granulation: An Engineering Perspective 27

shear as well as the formulation deformability. A very stiff formulation with low deformabilitymay behave as a low-deformability system in a high-shear mixer, or a very pliable formulationmay act as a high-deformable system in a fluid-bed granulator.G r a n u l e c o n s o l i d a t i o n o r d e n s i f i c a t i o n i s a l s o c o n t r o l l e d b y S t o k e s n u m b e r s , a n d typically increases for all processes with increasing residence time, shear levels, bed height,b e d m o i s t u r e o r g r a n u l e s a t u r a t i o n , p a r t i c l e f e e d s i z e o r p o r e r a d i u s , surface tension, anddecreasing binding fluid viscosity. Simultaneous drying o r r e a c t i o n u s u a l l y a c t s t o a r r e s t granule densification. Interparticle Forces Interstitial fluid and resulting pendular bridges play a large role in both, granule growth andg r a n u l e d e f o r m a b i l i t y . A s s h o w n p r e v i o u s l y , t h e y c o n t r o l t h e s t a t i c y i e l d stress of wetagglomerates [Fig. 8, Eq. (2)]. Pendular bridges between p a r t i c l e s o f w h i c h a g r a n u l e i s composed give rise to capillary and viscous interparticle forces, which allows friction to actbetween point contacts (Fig. 24). Interparticle forces due to pendular bridges and their impacton deformability warrant further attention. Note that capillary forces for small contact angleattract particles (but repel for y >

90 8 ), whereas viscous and frictional forces always act to resistthe direction of motion.Consider two spherical particles of radius a separated by a gap distance 2 h o approachingone another at a velocity U (Fig. 24). The particles could represent two primary particles withinthe granule, in which case we are concerned about the contribution of interparticle forces ongranule strength and deformability. Or they could represent two colliding granules, in whichc a s e w e a r e concerned with the ability of the pendular bridge to dissipate granule k i n e t i c energy and resist breakup forces in the granulation process. The two particles are bound by apendular bridge of viscosity m , density r , and surface tension g . The pendular bridge consistso f t h e b i n d i n g f l u i d i n t h e p r o c e s s , w h i c h i n c l u d e s t h e a d d e d s o l v e n t a n d a n y s o l u b i l i z e d components. In some cases, it may also be desirable to also include very fine solid components Figure 23 Classification of agglomeration processes by agitation intensity and compaction pressure. Source :From Refs. 1, 3, and 5. 28 Ennis

The ability to control the particle size and density of particles for inhalation wasinvestigated using lactose solutions atomized with a t w o - f l u i d n o z z l e a n d d r i e d i n a laboratory-scale dryer. It was found that d r o p l e t s i z e d u r i n g a t o m i z a t i o n w a s a f f e c t e d b y nozzle orifice diameter and atomization airflow but not by feed concentration. However, driedparticle size was influenced by feed concentration and it was suggested that the shell thicknessof the hollow particles increased with increasing feed concentration (44).An alternative method of atomization for the formation of respirable particles is the airblast atomizer. This type of two-fluid nozzle introduces a liquid feed pumped at a slow rateinto a high-velocity gas stream via single or multiple jets. This atomizer type was utilized atl a b o r a t o r y s c a l e t o e v a l u a t e t h e e f f e c t o f g r o u n d e d v e r s u s e l e c t r o s t a t i c a l l y c h a r g e d t o w e r configurations on the median particle size of the spray-dried product (45). This study founds i g n i f i c a n t differences between the two configurations, with the latter producing s m a l l particles but compromising collection efficiency. Microparticles and Nanoparticles Despite the availability of numerous crystal engineering techniques, generating drugrichm i c r o p a r t i c l e s w i t h a p r e d e t e r m i n e d s i z e , m o r p h o l o g y , a n d c r y s t a l l i n i t y s t i l l r e p r e s e n t a challenge. Amongst many techniques, spray drying, because of its ability to control the size,shape, and other properties of the resulting particles, has become a versatile technology for thepreparation of microparticles and, more importantly, nanoparticles for the pharmaceutical/b i o t e c h a p p l i c a t i o n s . F o r e x a m p l e , i n a r e c e n t s t u d y , i t w a s s h o w n t h a t t h e a d s o r p t i o n o f excipients onto micrometersize drug substrates using spray drying process was found to bean attractive approach to engineer drug-rich microparticles with characteristics suitable fordrug delivery (46). In another recent study, ***fast-dissolving mucoadhesive microparticulatedelivery system was developed using spray drying method for piroxicam, which is a drugwith low water solubility and high membrane permeability (47). It is known that such deliverys y s t e m s

intended for sublingual administration could be a suitable a l t e r n a t i v e t o f a s t - dissolving tablets because the sublingual absorption can be improved as a consequence of prolonging residence time on the mucosa and reducing the amount of swallowed drug (48).A t t e m p t s h a v e b e e n m a d e t o m a n u f a c t u r e p a r t i c l e s o n t h e n a n o m e t e r s c a l e f o r applications such as controlled-release and intravenous delivery systems. A c o m p a r i s o n evaluating the processability and solid dosage performance of spray-dried nanoparticles andmicroparticles was conducted (49). In this study, nanoparticle suspensions were prepared bywet comminution in the presence of stabilizers and converted into dried particles using a spraydrying process and subsequently compressed. Compacts prepared from micro- and nano-particles were found to differ in their internal structure and micromechanical deformations.I n a n o t h e r s t u d y , s o l i d a n d l i p i d n a n o p a r t i c l e s w e r e p r o d u c e d u s i n g h i g h - p r e s s u r e homogenization and loaded with drug using hot or cold methods for lipophilic or hydrophilicdrugs, respectively (50). Surfactant addition was investigated, and stability and entrapmentefficiency were evaluated. Long-term sterile storage of these dispersions was difficult, andspray drying was investigated as a potential, feasible technique.The feasibility of developing nanoparticles for aerosol delivery has also been investigated(51). The spray-dried nanoparticles, produced using one carrier type, were found to be hollowwhile others had a continuous matrix. Particle size was measured before spray drying andafter the spray-dried powder was redissolved. Both carrier types resulted in an increase inparticle size after spray drying, although both were found to remain in the nanometer rangeafter drying and were suitable for efficient lung delivery. Liposomes Another particle type capable of being produced by spray drying is liposomes. Traditionalpreparation of liposomes begins with the preparation of a solution containing the lipids to beu s e d i n a v o l a t i l e o r g a n i c s o l v e n t m i x t u r e . F o l l o w i n g f i l t r a t i o n o f t h e s o l u t i o n , t h e s o l v e n t mixture is removed under conditions that ensure phase separation does not occur. The drylipid mixture is then hydrated by an aqueous mixture containing the drug to be entrapped.Lastly, this mixture is dried. Spray drying is one method available for accomplishing one or 118 Celik and Wendell both of these drying steps. For example, lipid vesicles were produced using a spray dryingp r o c e s s i n s t e a d o f t h e f i r s t s t e p o f t h e t r a d i t i o n a l p r o c e s s ( 5 2 ) . V e s i c l e s c o n t a i n i n g phosphatidylcholine (soybean lecithin) were produced by extruding the phospholipid througha 0 . 2 m m polycarbonate membrane followed by spray drying with 10% lactose. The particlesize, vesicle size distribution, and stability of the multilamellar vesicles were measured. Them e a n p a r t i c l e d i a m e t e r a f t e r s p r a y d r y i n g w i t h a r o t a r y atomizer was 7 m m a n d t h e d r y particles could be reconstituted in water to liposomes without any major change to the vesiclesize distribution. In addition, the chemical stability of the liposomes was not significantlyaffected by the spray drying process. In subsequent work, the same authors utilized spraydrying for the hydration step of the traditional process (53). Peptides and Proteins Recent advances in biotechnology have made it possible to use macromolecules such aspeptides and proteins as therapeutic agents. Spray d r y i n g h a s b e e n u s e d f o r d e c a d e s f o r processing antibiotics, vaccines, and, for the last few decades, macromolecular drugs.The effect of spray drying process parameter settings on the activity of peptides andproteins is often difficult to study. Consequently, enzymes are frequently used as model proteindrugs because of the ease with which their activity can be determined. Investigations of thea p p l i c a t i o n o f s p r a y d r y i n g f o r t h e p r o d u c t i o n o f s o m e e n z y m e s a n d p r o t e i n s a n d t h e e f f e c t s t h a t processing parameters have on enzyme activity have been discussed in a review article (23).Many proteins and peptides are susceptible to degradation upon spray drying because of relatively high temperatures. In a recent study, the effects of inlet and outlet temperatures onsome spray-dried peptides and proteins were reported (54). In another study,

enzyme activitywas found to be susceptible to spray drying temperature, and only half of its activity remainedafter spray drying without additives at outlet temperatures below 50 8 C (55). In this study, itw a s f o u n d t h a t t h e a c t i v i t y o f a f o r m u l a t i o n c o m p r i s e d o f e n z y m e a n d m a n n i t o l w a s maintained at outlet temperatures below 50 8 C and compromised above 50 8 C. Replacingmannitol with trehalose stabilized the spray-dried enzyme and its activity was maintained at100% at an outlet temperature of 100 8 C.The antigenic extract hot saline from Brucella ovis was microencapsulated by the sprayd r y i n g t e c h n i q u e w i t h d i f f e r e n t p o l y e s t e r s and blends with polye -caprolactone [PEC]) too b t a i n m i c r o p a r t i c l e s s m a l l e r t h a n 5 m m. The microparticulated antigenic formulationc o n t a i n i n g t h e h i g h e r r a t i o o f P E C w a s s h o w n t o b e s u s c e p t i b l e t o b e u s e d i n a n i m a l vaccination studies (56).Another method of producing protein powders is spray freeze drying process. Sprayfreeze drying process involves spraying the solution into freezing air, causing the resultantdroplets to freeze. The frozen droplets are subsequently sublimed under vacuum conditionsproducing a dry product. Spray drying and spray freeze drying were compared to producep r o t e i n i n h a l a t i o n p o w d e r s a n d s p r a y d r y i n g w a s f o u n d t o b e s u p e r i o r i n s c a l a b i l i t y , operational cost, and product yield than spray freeze drying (57). Comparisons of freezedrying with spray d r y i n g t o p r o d u c e d r y p o w d e r d i s p e r s i o n s f o r n o n v i r a l g e n e d e l i v e r y showed that spray drying produces stable, efficient, and potentially respirable particles (58).A number of methods, including spray drying, lyophilization, pulverization, precipita-tion, and some other techniques, currently available for protein powder preparation wereevaluated in a review article based on the following criteria: control on particle size and sizedistribution, efficiency (yield), powder flowability, scalability, and longterm protein bio-c h e m i c a l s t a b i l i t y ( 5 9 ) . O n t h e b a s i s o f t h e s e c r i t e r i a , s p r a y d r y i n g w a s f o u n d t o b e advantageous for its convenience and simplicity, as well as for controlling the particle size andshape and attaining fine ( < 5 m m) spherical particles of proteins. Dry Elixirs and Emulsions A dry elixir is a novel dosage form developed by spray drying actives and excipients dissolvedor suspended in ethanol and water mixtures. One example is a dry elixir in which the feedsolution contained active, dextrin, and sodium lauryl sulfate in a mixture of ethanol/water( 6 0 ) . T h e s p r a y - d r i e d p r o d u c t w a s s p h e r i c a l i n s h a p e w i t h a smooth surface and a mean Spray Drying and Pharmaceutical Applications 119 diameter of 13 m m. A comparison with the active in powder form revealed a major decrease indissolution time from over 60 to 2 minutes.A dosage form similar to dry elixir is dry emulsion. In this case, the emulsified drug oro i l y d r u g s o l u t i o n w i t h a d d i t i v e s i s s p r a y - d r i e d t o p r o d u c e d r y e m u l s i o n p a r t i c l e s . A d r y emulsion of a water-insoluble nutrient was studied, and release from the spray-dried particlewas found to be dependent on the type and amount of oily carrier and surfactant used (61).Differences in release among the different formulations were attributed to the differences inthe physical state of the drug and surfactant in the dried particle. Effervescent Products

Spray-dried particles have also been incorporated into effervescent products. In one study,spray drying was used to protect a degradation-sensitive active by coating fine particles of thedrug with a sugar alcohol solution (62). In vivo results of tablets made using the spray-driedparticles combined with coated citric acid and sodium bicarbonate revealed that the active wasrapidly absorbed from the tablet. Other Process Variations Two variations of the spray drying process have been developed in r e s p o n s e t o p r o d u c t requirements. The first variation is spray congealing. In this process, solids such as wax orm o n o g l y c e r i d e s a r e m e l t e d . O t h e r i n g r e d i e n t s s u c h a s d r u g s , f l a v o r s , o r f r a g r a n c e s a r e dissolved or suspended in the molten material. This molten feed is sprayed using the sameb a s i c s p r a y d r y i n g e q u i p m e n t e x c e p t t h a t n o h e a t s o u r c e i s r e q u i r e d . D e p e n d i n g o n t h e freezing point of the feed, ambient or chilled air may be used during the drying process. Thisprocess has been described in more detail and a comparison between particles produced byboth the spray drying and spray congealing techniques has also been drawn (63). One studycompared microcapsules produced using both methods and found that the solvent used, thelipid type, and the chain length were variables that influenced the surface properties of bothparticle types (64,65).A second variation of the spray drying process is spray freeze drying. In this process, thef e e d i s s p r a y e d i n t o f r e e z i n g a i r c a u s i n g t h e droplets to freeze. The frozen droplets aresubsequently sublimed under v a c u u m c o n d i t i o n s p r o d u c i n g a d r y p r o d u c t . O n e s t u d y investigated this method further by eliminating the use of vacuum conditions for sublimation(66). In this study, the feasibility of spraying pharmaceutical solutions at atmospheric pressurewas investigated using very low air temperatures and desiccated air for the removal of thewater from the frozen particles. The process resulted in fine, free-flowing powder with highsurface area, good wetting, and good solubility characteristics.A n o t h e r t y p e o f a t o m i z a t i o n e m p l o y e d f o r p h a r m a c e u t i c a l s i s s u p e r c r i t i c a l f l u i d nebulization. The process uses carbon dioxide as an aerosolization aid, which permits dryinga t l o w e r t e m p e r a t u r e s t h a n u s u a l l y n e e d e d i n c o n v e n t i o n a l s p r a y d r y i n g ( 6 7 ) . W i t h i n t h e atomization system, supercritical carbon dioxide is intimately mixed with aqueous solutionscontaining API, often proteins or peptides. The outcome is the formation of microbubbles,which are rapidly dried in less than five seconds, resulting in dried particles predominatelyl e s s t h a n 3 m m in diameter (68,69). This method is generally applied for the production o f materials for pulmonary use or to achieve increased bioavailability (70). APPLICATION OF PAT TO SPRAY DRYING PROCESS Process Analytical Technology (PAT) is defined as a system for designing, a n a l y z i n g , a n d controlling manufacturing through timely measurements (i.e., during processing) of criticalquality and performance attributes of raw and in-process materials and processes with the goalof ensuring final product quality (71). It is important to note that the term analytical in PATi s v i e w e d b r o a d l y t o i n c l u d e c h e m i c a l , p h y s i c a l , microbiological, mathematical, and riskanalysis conducted in an integrated m a n n e r . A s P A T w i l l b e t h e s u b j e c t m a t t e r o f e n t i r e chapter 29, the focus of discussion here is not what PAT is but how it applies to spray dryingprocess. 120 Celik and Wendell The specific application of this relative new initiative to spray drying is currently focusedon the continuous real-time quality assurance aspect.In a recent study, employing PAT for particle sizing during spray drying with the use of an in-line and at-line laser diffraction system was employed for monitoring the particle sizingduring spray drying, and the particle size data were compared with those determined with off-line laser diffraction and light microscopy (72).The in-line laser diffraction system comprised the optical head, interface box, computer,a n d data analysis software. The optical head was directly connected in-line to t h e p r o c e s s stream. The main components used for the at-line laser diffraction system were the same asthose used in the in-line system, except that for the at-line system, the laser module was notphysically connected to the product flow stream. Instead, it was positioned adjacent to thespray dryer and worked as a separate system. Sampling and sizing were performed after theproduct had left the process stream (Fig. 16).T h e system was found to be a rapid and convenient method, w h i c h p r o v i d e d instantaneous information about the particle size

d i s t r i b u t i o n o f t h e m i c r o s p h e r e s ( o f maltodextrin and modified starch) as they were made. The at-line setup was reported to besuperior to the in-line setup in this particular application. The workers pointed out the need fortaking into account the cohesiveness of material measured and cautioned about the importanceof the judicious data management and interpretation of results from PAT-enabled instrumentsto make valid conclusions.O n e m u s t bear in mind that the goal of PAT is to understand and c o n t r o l t h e manufacturing process and quality cannot be tested into products but it should be built-in orshould be by design. Therefore, the real-time monitoring (on-line or at-line measurements) orincrease of process sample size or automated end product testing alone does not qualify asP A T . T h e c r i t i c a l i s s u e i s t h e u n d e r s t a n d i n g o f t h e s p r a y d r y i n g p r o c e s s b y a p p l y i n g t h e science and not regarding that as an art. Otherwise, what will be monitored in real time willnot necessarily ensure a quality product.A process is generally considered well understood when all critical sources of variabilitya r e identified and explained, variability is managed by the process, and product qualityattributes can be accurately and reliably predicted over the ranges of a c c e p t a n c e c r i t e r i a established for materials used, process parameters, and manufacturing environmental andother conditions. The ability to predict reflects a high degree of process understanding. Figure 16 Layout of the spray dryer with the in-line and at-line laser diffraction setup. Source : Adapted fromRef. 72. Spray Drying and Pharmaceutical Applications 121

In spray drying, some of the critical formulation and process factors are:1. material and feed properties (such as melting point of the material, feed type, solidcontent in the feed, additives, etc.),2. process variables (such as feed rate, atomizer type and speed, air pressure, inlet andoutlet gas temperatures, etc.), and3. product specifications (such as moisture content, particle size, particle density, flowcharacteristics, etc.).T h e knowledge acquired for these factors during the structured product and p r o c e s s development studies can assure the quality of the spray-dried product as one would expectan inverse relationship between the level of process understanding and the risk of producinga poor-quality product. In this respect, there were studies conducted before the publicationof the FDAs PAT guidelines. An example for such a

study involved the use of experimentalf a c t o r i a l d e s i g n s t o i n v e s t i g a t e t h e e f f e c t s o f a n u m b e r o f f o r m u l a t i o n a n d p r o c e s s parameters on production yields and moisture contents of spray-dried products. T h e s e factors concerned both the solution feed (drug concentration, c o l l o i d a l s i l i c a c o n c e n t r a t i o n , and polymer/drug ratio) and the spray dryer (inlet temperature and feed rate). In this study,the optimal operating conditions were estimated by response surface methodology. Centralrotational composite designs showed that quadratic models were found to be adequate. Theresults showed that the control of processing variables, especially inlet temperature and feedr a t e , a l l o w e d production of microparticles of low moisture content with high y i e l d s . Experimental factorial design was claimed to be necessary before new production runs todetermine the values of the parameters to be used f o r t h e o p t i m i z a t i o n o f t h e s p r a y d r y i n g process (73).Another example will be the subject matter of chapter 27 on expert systems in which aknowledge-based expert system will be described in some detail. CONCLUSION Spray drying has found many applications in numerous industries d e s p i t e i t s i n i t i a l installation, training, and operation-related costs. The scale-up of the spray drying process isless troublesome as the operation requirements of small and large dryers are the same whenc o m p a r e d w i t h o t h e r c o n v e n t i o n a l g r a n u l a t i o n p r o c e s s e s s u c h a s h i g h - s h e a r g r a n u l a t i o n method.Spray drying, being a continuous process, is well suited for the production of bulk drugsubstances and excipients. Using this process, the physical properties of the resulting product( s u c h a s p a r t i c l e size and shape, moisture content, and flow properties) can be c o n t r o l l e d through the selection of equipment choices and manipulation of process variables; thus, thefinal spray-dried particulate matter may not need further processing (wet or dry granulations)before compaction. In addition, the spray drying process matches the directives outlined in thePAT initiative currently being guided and championed by the FDA.Spray drying processes offer several advantages when solid-state properties of drugs u b s t a n c e s need to be modified. Using this process, solubility and dissolution r a t e s o f properties of poorly soluble materials can be increased by several folds and the stability of theamorphous form of the materials can be improved significantly.Because of its initial inherent costs, spray drying is not always considered as a processingo p t i o n f o r m a n y conventional formulations, especially for small batch size o p e r a t i o n s . However, when a specialized particle type is required by the active ingredient or dosage form,spray drying can become a feasible alternative to more conventional manufacturing processes.Such particle types include microcapsules, controlled-release particles, nanoparticles, andliposomes. ACKNOWLEDGMENT We gratefully acknowledge the extensive contribution of Keith Masters whose handbook wasreferenced extensively as a leading text in the field. 122 Celik and Wendell REFERENCES 1. Traub DA. Spray dryers. Part 1. Process heating, August 2001. Available at: http://www.processheating.com/CDA/ArticleInformation/Drying_Files_Item/0,3274,61137,00.html.2. Percy SR. Improvement in drying and concentrating liquid substances by atomizing, U.S. Patent125,406. 9 April 1872.3. Masters K. Introduction. Spray Drying Handbook. 5th ed. Essex: Longman Scientific Technical,1991:120.4. Parikh DM. Advances in spray drying technology: new applications for a proven process. Am PharmRev 2008; 11(1):3441.5. Traub DA. Spray dryers. Part 2. Process heating, September 2001. Available at: http://www.processheating.com/CDA/ArticleInformation/Drying_Files_Item/0,3274,63175,00.html.6. Masters K. Spray drying fundamentals: process stages and layouts. In: Spray Drying Handbook.5th ed. Essex: Longman Scientific Technical, 1991:24.7. Masters K. Spray drying fundamentals: process stages and layouts. In: Spray Drying Handbook.5th ed. Essex: Longman Scientific Technical, 1991:26.8. Masters K. The process stages of spray drying. In: Spray Drying Handbook. 5th ed. Essex: LongmanScientific Technical, 1991:268.9. Masters K. Spray drying fundamentals: process stages and layouts. In: Spray Drying Handbook.5th ed. Essex: Longman Scientific Technical, 1991:31.10. Masters K. The process stages of spray drying. In: Spray Drying Handbook. 5th ed. Essex: LongmanScientific Technical,

1991:271.11. Masters K. Spray drying fundamentals: process stages and layouts. In: Spray Drying Handbook.5th ed. Essex: Longman Scientific Technical, 1991:43.12. Masters K. Spray drying fundamentals: process stages and layouts. In: Spray Drying Handbook.5th ed. Essex: Longman Scientific Technical, 1991:47.13. Masters K. The process stages of spray drying. In: Spray Drying Handbook. 5th ed. Essex: LongmanScientific Technical, 1991:199.14. Masters K. The process stages of spray drying. In: Spray Drying Handbook. 5th ed. Essex: LongmanScientific Technical, 1991:255.15. Masters K. Drying of droplets/sprays. In: Spray Drying Handbook. 5th ed. Essex: Longman ScientificTechnical, 1991:309.1 6 . T r a u b D A . T h e d r y i n g c u r v e . P a r t 2 . P r o c e s s h e a t i n g , O c t o b e r 2 0 0 2 . A v a i l a b l e a t : h t t p : / / w w w . processheating.com/CDA/ArticleInformation/Drying_Files_Item/0,3274,84744,00.html.17. Masters K. Drying of droplets/sprays. Spray Drying Handbook. 5th ed. Essex: Longman ScientificTechnical, 1991:326.18. Charlesworth DA, Marshall WR. Evaporation for drops containing dissolved solids. AIChE J 1960; 6(1):923.19. Masters K. Drying of droplets/sprays. Spray Drying Handbook. 5th ed. Essex: Longman ScientificTechnical, 1991:345.20. Adhikari B, Howes T, Lecomte D, et al. A glass transition temperature approach for the prediction of the surface stickiness of a drying droplet during spray drying. Powder Technol 2005; 149:168179.21. Shaw F. Spray drying as a granulation technique. In: Parikh DM, ed. Handbook of PharmaceuticalGranulation Technology. New York: Marcel Dekker, 1997:9396.2 2 . F i l k o v a I , Weberschinke J. Apparent viscosity of non-Newtonian droplet on the outlet o f w h e e l atomizers. In: Mujumdar AS, ed. Drying 82. New York: McGrawHill, 1982:165170.23. Broadhead J, Rouan SK, Rhodes CT. The spray drying of pharmaceuticals. Drug Dev Ind Pharm 1992;18(1112):11691206.24. Wendel SC, Celik M. An overview of spray-drying applications. Pharm Technol 1997; 21(10):124156.25. Kadam KL. Granulation Technology for Bioproducts. Boca Raton: FL CRC Press, 1990.26. Fincher JH. Particle size of drugs and its relationship to absorption and activity. J Pharm Sci 1968;57(11):18251835.27. Kostewicz ES, Wunderlich M, Brauns U, et al. Predicting the precipitation of poorly soluble weakbases upon entry in the small intestine. J Pharm Pharmacol 2004; 56:4351.28. Kawashima Y, Satio M, Takenaka H. Improvement of solubility and dissolution rate of poorly watersoluble salicylic acid by a spray-drying technique. J Pharm Pharmacol 1975; 27:15.29. Pikal MJ, Lukes AL, Land JE, et al. Quantitative crystallinity determination for beta-lactam antibioticsby solution calorimetry: correlations with stability. J Pharm Sci 1978; 67:767773.30. Morris KR, Griesserb UJ, Eckhardt CJ, et al. Theoretical approaches to physical transformations of active pharmaceutical ingredients during manufacturing processes. Adv Drug Deliv Res 2001; 48:91114.31. Junginger H, Wedler M. Acta Pharm Technol 1984; 30(1):68. Spray Drying and Pharmaceutical Applications 123 32. Corrigan OI, Holohan EM, Reilly MR. Physicochemical properties of i n d o m e t h a c i n a n d r e l a t e d compounds co-spray dried with polyvinyl-pyrrolidone. Drug Dev Ind Pharm 1985; 11(23):677695.33. Corrigan DO, Healy AM, Corrigan OI. The effect of spray drying solutions of polyethylene glycol(PEG) and lactose/PEG on their physicochemical properties. Int J Pharm 2002; 235(12):193205.34. Berggren J, Alderborn G. Effect of polymer content and molecular weight on the morphology andheat- and moisture-induced transformations of spray-dried composite particles of amorphous lactoseand poly(vinylpyrrolidone). Pharm Res 2003; 20:10391046.35. Re MI. Microencapsulation by spray drying. Drying Technol 1998; 16(6):11951236.3 6 . W a n L S , H e n g P W , C h i a C G . S p r a y d r y i n g a s a p r o c e s s f o r m i c r o e n c a p s u l a t i o n a n d t h e e f f e c t o f different coating polymers. Drug Dev Ind Pharm 1992; 18(9):9971011.37. Sutinen R, Laasanen V, Paronen P, et al. pHcontrolled silicone microspheres for controlled drugdelivery. J Control Release 1995; 33:163 171.38. Palmieri GF, Wehrle P, Stamm A. Evaluation of spray-drying as a method to prepare microparticlesfor controlled drug release. Drug Dev Ind Pharm 1994; 20(18):28592879.39. Takeuchi H, Handa T, Kawashima Y. Controlled release theophylline with acrylic polymers preparedby spray drying technique. Drug Dev Ind Pharm 1989; 15(12):19992016.40. Pavanetto F, Genta I, Giunchedi P, et al. Evaluation of spray drying as a method for polylactide andpolylactideco-glycolide microsphere preparation. J Microencapm 1993; 10(4):487497.41. Gonda I. Targeting by deposition. In: Hickey AJ, ed. Pharmaceutical Inhalation Aerosol Technology.New York: Marcel Dekker, Inc., 1992:6182.4 2 . C o r r i g a n D O , C o r r i g a n O I , H e a l y A M . P r e d i c t i n g t h e p h y s i c a l s t a t e o f s p r a y d r i e d c o m p o s i t e s : salbutamol sulphate/lactose and salbutamol sulphate/polyethylene glycol co-spray dried systems.Int J Pharm 2004; 273(12):171182.43. Vidgren P, Vidgren M, Aronen P, et al. Nasal distribution of radioactive drug administered using twodosage forms. Eur J Drug Metab Pharmacokinet 1991; 3:426432.44. Elversson J, Millqvist-Fureby A,

Alderborn G, et al. Droplet and particle size relationship and shellthickness of inhalable lactose particles during spray drying. J Pharm Sci 2003; 92, 900910.4 5 . D u n b a r C A , Concessio NM, Hickey AJ. Evaluation of atomizer performance in production o f respirable spray-dried particles. Pharm Dev Technol 1998; 3(4):433441.46. Buttinia F, Soltani A, Colombo P, et al. Multilayer PVA adsorption onto hydrophobic drug substratesto engineer drug-rich microparticles. Eur J Pharm Sci 2008; 33(1):2028.47. Cilurzo F, Selmin F, Minghetti P, et al. Fastdisolving mucoadhesive microparticulate delivery systemcontaining piroxicam. Eur J Pharm Sci 2005; 24:355361.4 8 . A h u j a A , K h a r R P , A l i J . M u c h o a d h e s i v e d r u g d e l i v e r y s y s t e m s . D r u g D e v I n d P h a r m 1 9 9 7 ; 2 3 : 489515.49. Lee J. Drug nano- and microparticles processed into solid dosage forms: physical properties. J PharmSci 2003; 92(10):20572068.50. Muller-Mehnert RH, Lucks JS, Schwarz C, et al. Solid lipid nanoparticles (SLN)-alternative colloidalcarrier system for controlled drug delivery. Eur J Pharm Biopharm 1995; 41(1):6269.5 1 . S h a m J O , Z h a n g Y , F i n l a y W H , e t a l . F o r m u l a t i o n a n d c h a r a c t e r i z a t i o n o f s p r a y - d r i e d p o w d e r s containing nanoparticles for aerosol delivery to the lung. Int J Pharm 2004; 269:457467.52. Goldbach P, Brochart H, Stamm A. Spray-drying of liposomes for a pulmonary administration. Part 1.Chemical stability of phospholipids. Drug Dev Ind Pharm 1993; 19(19):26112622.53. Goldbach P, Brochart H, Stamm A. Spray-drying of liposomes for a pulmonary administration. Part 2.Retention of encapsulated materials. Drug Dev Ind Pharm 1993; 19(19):26232636.54. Costantino HR, Andya JD, Nguyen PA, et al. Effect of mannitol crystallization on the stability andaerosol performance of a spray-dried pharmaceutical protein, recombinant humanized anti-IgEmonoclonal antibody. J Pharm Sci 1998; 87:1406 1411.55. Broadhead J, Ruan SK, Rhodes CT. The effect of process and formulation variables on the propertiesof spray dried b -galactosidase. J Pharm Pharmacol 1994; 46:458467.56. Murillo M, Gamazo C, Goni MM, et al. Development of microparticles prepared by spray-drying as avaccine delivery system against brucellosis. Int J Pharm 2002; 242(12):341344.5 7 . M a a Y F , N g u y e n P A , S w e e n y T , e t a l . P r o t e i n i n h a l a t i o n p o w d e r s : s p r a y d r y i n g v s . s p r a y f r e e z e drying. Pharm Res 1999; 16(2)249254.58. Sevelle PC, Kellay LW, Birchall JC. Preparation of dry powder dispersions for non-viral gene deliveryby freeze-drying and spray-drying. J Gene Med 2002; 4:428437.59. Maa YF, Prestrelski SJ. Biopharmaceutical powders: particle formation and formulation consid-erations. Curr Pharm Biotechnol 2000; 1:283302.60. Kim CK, Soon YS. Development of digoxin dry elixir as a novel dosage form using a spray-dryingtechnique. J Microencap 1995; 12(5):547566. 124 Celik and Wendell 61. Takeuchi H, Sasaki H, Niwa T, et al. Design of redispersible dry emulsion as an advanced dosagef o r m o f o i l y d r u g ( v i t a m i n E n i c o t i n a t e ) b y s p r a y - d r y i n g t e c h n i q u e . D r u g D e v I n d P h a r m 1 9 9 2 ; 18(9):919937.62. Timmington H. Improved aspirin. Chem Drug 1973; 482483.63. Killen MJ. Process of spray drying and spray congealing. Pharm Eng 1993; 13:5862.64. Eldem T, Speiser P, Altorfer H. Polymorphic behavior of sprayed lipid micropellets and its evaluationby differential scanning calorimetry and scanning electron microscopy. Pharm Res 1991; 8:178184.65. Eldem T, Speiser P, Hincal A. Optimization of spray-dried and -congealed lipid micropellets andc h a r a c t e r i z a t i o n o f t h e s u r f a c e m o r p h o l o g y b y s c a n n i n g e l e c t r o n m i c r o s c o p y . P h a r m R e s 1 9 9 1 ; 8(1):4754.66. Mumenthaler M, Leuenberger H. Atmospheric spray-freeze drying: suitable alternative in freeze drytechnology. Int J Pharm 1991; 72:97110.6 7 . S i e v e r s R E , H u a n g E T S , V i l l a J A , e t a l . L o w - t e m p e r a t u r e m a n u f a c t u r i n g o f f i n e p h a r m a c e u t i c a l powders with supercritical fluid aerosolization in a bubble dryer. Appl Chem 2001; 73(8):12991303.68. Sievers RE, Karst U. Methods for fine particle formation. U.S. Patent 5,639,441, June 1997.69. Sievers RE, Karst U. Methods and apparatus for fine particle formation. U.S. Patent 6,095,134, August2000.70. Sievers RE, Karst U, Milewski PD, et al. Formation of aqueous small droplet aerosols assisted bysupercritical carbon dioxide. Aerosol Sci Technol 1999; 30:315.71. U.S. Department of Health and Human Services, Food and Drug Administration, Center for DrugEvaluation and Research (CDER), Center for Veterinary Medicine (CVM), Office of Regulatory Affairs(ORA). Guidance for industry: PATa framework for innovative pharmaceutical development,manufacturing, and quality assurance. September 2004.72. Chan L, Tan L, Heng P. Process analytical technology: application to particle sizing in spray drying.AAPS Pharm Sci Technol 2008; 9(1):259266.73. Billon A, Bataille B, Cassanas G, et al. Development of spray-dried acetaminophen microparticlesusing experimental designs. J Pharm Int 2000; 203(12):159168.

Spray Drying and Pharmaceutical Applications 125 6 Supercritical Fluid Technology Martin A. Wahl Pharmaceutical Technology and Biopharmacy, Institute of Pharmaceutical Sciences, Eberhard-KarlsUniversity Tu bingen, Tu bingen, Germany INTRODUCTION Supercritical fluid (SCF) technology experienced a significant boost over the past years. Apartfrom the classical use in extraction, preparative techniques like particle design or functionalizationofmaterialgrewup.Today,thesetechniquescanbeappliedunderGMP c o n d i t i o n s , m a k i n g them available for use in drug formulation or food industry. One must, however, admit thatsome of these techniques actually are rather in an experimental state, but because of increasingspeed of scientific development, they may become available in a short time. It seems, therefore,important to present these techniques within the actual standards of granulation. HISTORICAL VIEW ON THE USE OF SUPERCRITICAL FLUIDS INPHARMACEUTICAL TECHNOLOGY Formation of fine particles by a rapid release of the pressure was initially observed by Hannayand Hogarth in 1879 (1). This report is seen as the beginning of particle design by the use of SCF. It took, however, almost 100 years to understand the process and invent the technique tohandle high-pressure fluids. From the 1960s, development of the use of SCF for extractionp u r p o s e w a s g e t t i n g m o r e p o p u l a r , w i t h d e c a f f e i n a t i o n o f c o f f e e a n d t e a b e i n g t h e m o s t important industrial application in the 1980s with respect to the amount of material processed.In parallel, from the 1980s, the development of the different particle generating processes liketherapid expansion ofsupercritical solutions (RESS) process came up, earlyreports (2)followedby patents (3). Because of the fact that drugs frequently were rather insoluble than soluble inSCF, the antisolvent techniques were developed, starting with early reports in 1954 (4) andfollowed by numerous patents (5), a summary of the early patents was published by Jung andPerrut in 2001 (6). Industrial use of the techniques is so far mainly limited to extraction (coffee,tea, hops), but the presence of companies in the market supporting the development of particlea n d f o r m u l a t i o n t e c h n i q u e s b y t h e c o n s t r u c t i o n o f p i l o t p l a n t s ( e . g . , S I T E C A G , Z u rich,Switzerland), by the offer of development or handling techniques (e.g., Natex, Ternitz, Austria;Phasex Corporation, Lawrence, MA; Separex, Champigneulles, France), or by the constructionof large facilities (e.g., Uhde GmbH, Dortmund, Germany) clearly shows that SCF play a role inactual developments. Because of the fact, that modern drug development lasts for up to 20 yearsuntil the market is reached, one can assume that in the near future the first products based onSCF production technique will be approved. SUPERCRITICAL FLUIDS Gases or liquids, which were used under pressure and temperature above the critical point,reach an aggregate state, which is called the SCF state (Fig. 1). Under these conditions, whichare typical for individual substances (Table 1), the fluid possesses properties that are uniqueand different from the liquid or gaseous state. Fluid Properties In many cases, the use of SCF is thought as a replacement for organic solvents. Comparingt h e p r o p e r t i e s o f S C F w i t h t h e p r o p e r t i e s o f a n o r g a n i c s o l v e n t , h o w e v e r , s h o w s , b e s i d e similarities, significant differences too. Similarities are lipophilicity or density; differences areseen in viscosity or volatility. CO 2 , for example, above the critical point shows viscosities in ther a n g e o f a b o u t 5 0 t o 1 5 0 m Pa sec (CO 2 at 273 K and 0.1 MPa: approx. 14 m Pa sec), increasingwith increasing pressure but decreasing with increasing temperature. The absolute values hereare slightly above the viscosity of gases; pressure- and temperature-dependent changes are as

for liquids (7). The density of the SCF is dependent on temperature a n d p r e s s u r e , t h e correlation subject to intense research (11). In addition, no surface tension is seen in SCF (8).B e c a u s e o f t h e h i g h p r e s s u r e r e q u i r e d f o r t h e e x i s t e n c e o f t h e s u p e r c r i t i c a l s t a t e , supercritical solutions can easily be used for spray-expansion technologies. Chemistry and, atleast for the most frequently used CO 2 , moderate temperatures required make the use of SCF as solvents less dangerous for drug stability. Fluids Used In pharmaceutical technology, the primary choice of SCF is scCO 2 , trifluoromethane, andn o r f l u r a n e . s c C O 2 is the preferred fluid because of its inert behavior, easy-toh a n d l e supercritical parameters, and nontoxicity. Here, even residues in the preparation will not bemeasurable. The supercritical conditions for the latter two are comparable to scCO 2 except thehigher temperatures required for the work with norflurane. Carbon Dioxide The most preferred SCF is definitely scCO 2 . Its rather low critical temperature and pressuremake it an easy-to-handle tool for extraction and particle generation. Apart from the rapidd i s a p p e a r a n c e o f t h e solute at the end of the processes caused by d e p r e s s u r i z a t i o n , remaining residues in the product would not be seen as critical. The low reactivity, even underhigh pressure, makes it suitable to be used for sensible drug molecules. The lipophilicity of scCO 2 can be influenced by the addition of modifiers or cosolvents like methanol, ethanol, oracetone (12). These additives, if they do not reach their supercritical state under the conditionsapplied, must be removed separately at the end of the process from the product. Water, Nitrous Oxide, Norflurane, Trifluoromethane All other SCF actually play a minor role in pharmaceutical technology. Despite its importantr o l e i n w a s t e d e c o m p o s i t i o n ( 1 3 ) , s u p e r c r i t i c a l w a t e r i s rarely used in pharmaceutical Table 1 Critical Pressure and Temperature of Supercritical Fluids (Examples)Type of fluid P c (MPa) T c (K)Trifluoromethane4 . 7 2 9 9 CO 2 7 . 4 3 0 4 . 1 Ethane4 . 8 3 0 5 . 3 N 2 O7 . 2 3 0 9 . 6 Propane4 . 2 3 6 9 . 8 Norflurane (R134a)4 . 0 3 7 4 . 2 n

-Hexane3 . 0 5 0 7 . 5 Water2 2 . 1 6 4 7 . 1 Abbreviations : P c , critical pressure; T c , critical temperature. Source : From Refs. 710. Figure 1 S c h e m a t i c o f P - T p h a s e d i a g r a m i n d i c a t i n g t h e s u p e r - critical state. The volume is assumed as constant. Supercritical Fluid Technology 127

technology because of its high critical temperature and high reactivity; both can be expected toaffect drug stability under these conditions, as it is expected to do in waste decomposition.N 2 O, which has similar critical properties as CO 2

, was sometimes used as SCF (14); a reporta b o u t a n e x p l o s i o n w i t h t h i s S C F ( 1 5 ) , h o w e v e r , s e e m e d t o h a v e t e r m i n a t e d t h e u s e . Norflurane (HFA 134a) might be interesting because of its acceptance in the formulation of pharmaceutical products in the past; its relatively high critical temperature makes handling of drugs under these conditions critical (16), even though it is used in food chemistry (17). A SCF with less lipophilicity and higher polarity compared with scCO 2 is trifluoromethane (R23); thismight be useful for treatment of compounds that do not dissolve sufficiently in scCO 2 becauseof their polarity, like griseofulvin (18). Drug Solubility in Supercritical Fluid SCF possess properties similar to those of organic solvents. The solubility of drugs in the SCF isstrongly dependent on the type of SCF and the properties of the drug. For scCO 2 , similaritywith hydroalkane solvents can be seen. Apart from experimental data, which can be obtainedby cloud-point determination in phase behavior experiments (19), knowledge of the chemicalp r o p e r t i e s o f t h e d r u g i n t h e S C F c a n h e l p t o p r e d i c t s o l u b i l i t y . W i t h regard to scCO 2 , t h e presence of functional groups, which can interact with CO 2 as Lewis acid or base, would beb e n e f i c i a l . I n a d d i t i o n , c e r t a i n k i n d o f p o l a r i t y w o u l d i m p r o v e t h e i n t e r a c t i o n w i t h t h e quadrupole moment of CO 2 . Free volume and flexibility of the molecule would also facilitatedissolution in the SCF; this may be seen by low glass transition temperature of polymers. Inaddition, a molecular weight above 500 seems to be critical (20).For solubility of drugs in scCO 2 , data for a broad variety of drugs are summarized byGupta and Shim (21). PARTICLE DESIGN TECHNIQUES Solubility of drugs in water is a key element of the action. Drugs with high in vitro activity ont h e p h y s i o l o g i c a l t a r g e t s t r u c t u r e a r e f r e q u e n t l y h i g h l y l i p o p h i l i c , l e a d i n g t o p o o r w a t e r solubility. A common method to improve water solubility is the reduction of particle size,t h e r e b y i n c r e a s i n g t h e d i s s o l u t i o n s p e e d a c c o r d i n g t o t h e N o y e s - W h i t n e y e q u a t i o n . T h e production of smallmainly in the submicron or even nanoscale rangeparticles can be doneby either milling or precipitation technologies. If the compound of interest is soluble in SCF, atleast to an acceptable extent, precipitation of very small particles can be obtained by a releaseof the pressure and, therefore, high precipitation speed (e.g., in the RESS process). This willdirectly lead to solid particles in the expected size range. Another possibility is the removal of asolvent by the use of SCF, which will again lead to supersaturation of the solution followed byprecipitation of small particles. This technique is applied in the antisolvent processes (e.g., theG A S p r o c e s s ) . B o t h t e c h n i q u e s l e a d t o f r e e - f l o a t i n g p a r t i c l e s a t t h e e n d o f t h e p r o d u c t i o n process. Since handling of nanoscaled particles is difficult and the subsequent processing toformulations sometimes just impossible, techniques that deposit the particles directly in theformulation are useful, like the drying of aerogels or the impregnation techniques [e.g., thecontrolled particle deposition (CPD) process]. Direct Particle Production I: Solvent Techniques The basic mechanisms of the solvent techniques is solubility of the drug in the SCF. This leadst o a supercritical solution, which can, subsequently, be expanded. The e x p a n s i o n l e a d s t o supersaturation and particle precipitation. Rapid Expansion of Supercritical Fluids The RESS is the simplest process in SCF technology used for particle p r o d u c t i o n . F o r t h i s process, the drug has to be dissolved in the SCF. The hereby formed supercritical solution ist h e n e x p a n d e d t h r o u g h a n o z z l e i n t o a n e x p a n s i o n c h a m b e r ( F i g . 2 ) . T h i s l e a d s t o p a r t i c l e precipitation (6). With the RESS process, care is taken that the drugs dissolving in the SCF donot melt. This may sometimes be difficult because of melting point depression under highpressure. Characteristics of the product obtained are dependent on the working conditions. 128 Wahl

consider whether a bond formed on impact is strong enough to survive subsequent impacts orthey fail to consider the possibility of bond rupture after formation at all. He developed a newm o d e l t h a t takes into account both the effects of bond strengthening with time, and t h e distribution of impact forces. He suggest that his models be combined with existing modelsthat predict whether or not two granules stick initially on impact, to then be able to predict theprobability of permanent coalescence.Most of the fluid-bed granulated products require an amount of wetting much less thanthe high shear granulation or spray dryer processed product.In the fluid-bed granulation process, the particles are suspended in the hot air streama n d t h e a t o m i z e d l i q u i d i s s p r a y e d o n i t . T h e d e g r e e o f b o n d i n g b e t w e e n t h e s e p r i m a r y particles to form an agglomerated granule depends upon the binder used, physicochemicalcharacteristics of the primary particles being agglomerated, and upon process parameters.Schaefer et al. (38) and Smith and Nienow (39) have reported a description of the growthmechanisms in the fluid bed, where the bed particles are wetted by liquid droplets in the sprayzone. Atomized liquid from the nozzle tends to spread over the particle surface, as long asthere is an adequate wettability of the particle by the fluid (40). Wet particles on impact form aliquid bridge and solidify as the agglomerate circulates throughout the remainder of the bed.Solid bridges then hold particles together. The strength of the binder determines whether theseparticles stay as agglomerates. These binding forces should be larger than the breakup forcesand in turn depend on the size of the solid bridge. The breakup forces arise from movement of the randomized particles colliding with each other and are related to the excess gas velocityand particle size.If the binding forces are in excess of the breakup forces, either in the wet state or in thedry state, uncontrolled growth will proceed to an overwetted bed or production of excessivefines, respectively. If a more reasonable balance of forces is present, controlled agglomerationw i l l o c c u r , g r o w t h o f which can be controlled. Maroglou and Nienow presented a granulegrowth mechanism in the fluid bed by the use of model materials and scanning electronmicroscope (41). Goldschmidt et al. (42) described the granule growth proportional to thecollision frequency between the particles present i n t h e g r a n u l a t o r , a n d t h e f r a c t i o n o f collisions that are successful, that is, the fraction of collisions that lead to coalesce rather thanr e b o u n d . F o r c o l l i s i o n t o b e successful, two conditions must be met: ( i ) t h e p a r t i c l e s m u s t contact each other by a binder wet region, and ( ii ) the viscous binder layer in this region mustbe able to dissipate the kinetic energy of the particles. Thielmann et al. (43) investigated thea s s u m p t i o n t h a t b e t t e r wetting means better granulation. Their experimental s t u d y concluded that effect of surface properties resulted in having the h y d r o p h i l i c p a r t i c l e s resulting in smaller granules than hydrophobic ones and better wettability does not necessarilymean better granulation.Figure 16 shows the various paths a liquid droplet can take and its consequences on theparticle growth.The mechanism of formation of a granule and subsequent growth primarily progressesthrough following three stages:1 . N u c l e a t i o n 2 . T r a n s i t i o n 3 . B a l l g r o w t h Figure 17 shows the growth of the granule relative to the liquid added. In the beginningof the spraying stage, primary particles form nuclei and are held together by liquid bridges in apendular state. The size of these nuclei depends upon the droplet size of the binder solution.A s t h e l i q u i d a d d i t i o n continues, more and more nuclei agglomerate and continue t h e transition from the pendular state to the capillary state.The uniqueness of the fluidbed agglomeration process is how the liquid addition andd r y i n g ( e v a p o r a t i o n ) s t e p s are concurrently carried out. When the granulation liquid issprayed into a fluidized bed, the primary particles are wetted and form together with t h e binder, relatively loose and very porous agglomerates. Agglomeration between two particleswill take place if the particles collide with each other and at least one of them is wet enough to 218 Parikh and Jones form a liquid bridge. A sufficiently high moisture content of one colliding particle depends ont h e w e t t i n g a n d d r y i n g p r o c e s s e s . D e n s i f i c a t i o n o f t h e s e a g g l o m e r a t e s i s b r o u g h t a b o u t s o l e l y b y the capillary forces present in the liquid bridges. It is therefore important that the quantity of liquid sprayed into the bed should be relatively larger compared with that used in high shear

Figure 16 Mechanism of granulation in fluid bed. Figure 17 States of liquid saturation. Batch Fluid Bed Granulation 219

granulation. Although wetting and nucleation step may be seen as a m i n o r p a r t o f t h e granulation process it is nevertheless a vital part of the process, and spray rate conditions andparticle flux in the spray zone have primary importance for the entire process and the resultinggranule properties. Agglomerate can exist in a number of different spatial structures dependingo n t h e b i n d e r l i q u i d s a t u r a t i o n . I t i s t h e a m o u n t o f l i q u i d b i n d e r a s w e l l a s t h e h u m i d i t y conditions in the bed that determines the degree of saturation, which again determines thespatial structure of the final granule (44). Drying a wet product in a fluid bed is a separate topicbutduring the granulation process it becomes integral part of the process; hence,understandingfluid-bed drying is important before we review the agglomeration process. FLUID-BED DRYING Drying is usually understood to be removal of moisture or solvent. Drying i n v o l v e s h e a t transfer and mass transfer. Heat is transferred to the product to evaporate liquid, and mass istransferred as a vapor in the surrounding gas; hence, these two phenomena are interdepen-dent. The drying rate is determined by the factors affecting the heat and mass transfer. Thetransfer of heat in the fluid bed takes place by convection. Convection is the transfer of heatfrom one point to another within a fluid (gas, solid, and liquid) by the mixing of one portion of the fluid with another. The removal of moisture from a product granulated in the fluid-bedgranulator or in other equipment essentially removes the added water or solvent. This freemoisture content is the amount of moisture that can be removed from the material by drying ata specified temperature and humidity. The amount of moisture that remains associated withthe material under the drying conditions specified is called the equilibrium moisture content orEMC.The evaporation rate of liquid film surrounding the granule being dried is related to therate of heat transfer by the equation: dwdt h AH d T where dw/dt is the mass transfer rate (drying rate), h is the heat transfer coefficient, A i s t h e surface area, H is the latent heat of evaporation, and d T is the temperature difference betweenthe air and the material surface.B e c a u s e f l u i d - b e d p r o c e s s i n g i n v o l v e s d r y i n g o f a p r o d u c t i n s u s p e n d e d h o t a i r , t h e heat transfer is extremely rapid. In a properly fluidized processor, product temperature andt h e exhaust air temperatures should reach equilibrium. Improper air distribution, hencepoor heat transfer in fluidized bed, causes numerous problems such as caking, channeling,o r s t i c k i n g . T h e c a p a c i t y o f the air (gas) stream to absorb and carry away m o i s t u r e determines the drying rate and establishes the duration of the drying cycle. Controlling thisc a p a c i t y i s t h e k e y t o c o n t r o l l i n g t h e d r y i n g p r o c e s s . T h e t w o e l e m e n t s e s s e n t i a l t o t h i s control are inlet air temperature and air flow. The higher the temperature of the drying air,the greater is its vapor holding capacity. Since the temperature of the wet granules in a hotg a s d e p e n d s o n t h e r a t e o f e v a p o r a t i o n , t h e k e y t o a n a l y z i n g t h e d r y i n g p r o c e s s i s psychrometry (4547).P s y c h r o m e t r y i s d e f i n e d a s t h e s t u d y o f t h e r e l a t i o n s h i p s b e t w e e n t h e m a t e r i a l a n d energy balances of water vaporair mixture. Psychrometric charts (Fig. 18) simplify the crucialcalculations of how much heat must be added and how much moisture can be added to the airo r r e m o v e d f r o m

the air. The process of drying involves both heat and mass transfers. F o r drying to occur, there must be a concentration gradient, which must exist between the moistg r a n u l e a n d t h e s u r r o u n d i n g e n v i r o n m e n t . A s i n h e a t t r a n s f e r , t h e m a x i m u m r a t e o f m a s s transfer that occurs during drying is proportional to the surface area, turbulence of the dryingair, the driving force between the solid and the air, and the drying rate. Because the heat of vaporization must be supplied to evaporate the moisture, the driving force for mass transfer isthe same driving force required for heat transfer, which is the temperature difference betweenthe air and the solid.Schaefer and Worts (48) have shown that the higher the temperature differences betweenincoming air and the product, the faster is the drying rate. Therefore, product temperatureshould be monitored closely to control the fluidized bed drying process. 220 Parikh and Jones During fluid-bed drying, the product passes through three distinct temperature phases(Fig. 19).A t t h e b e g i n n i n g o f t h e d r y i n g p r o c e s s , t h e m a t e r i a l heats up from the ambienttemperature to approximately the wetb u l b t e m p e r a t u r e o f t h e a i r i n t h e d r y e r . T h i s temperature is maintained until the granule moisture content is reduced to the critical level. Atthis point, the material holds no free surface water, and the temperature starts to rise further.The drying capacity of the air depends upon the relative humidity (RH) of the incominga i r . A t 1 0 0 % R H , t h e air is holding the maximum amount of water possible at a g i v e n temperature, but if the temperature of the air is raised, the RH drops and the air can hold moremoisture. If air is saturated with water vapor at a given temperature, a drop in temperaturew i l l f o r c e t h e a i r m a s s t o r e l i n q u i s h s o m e o f i t s m o i s t u r e t h r o u g h c o n d e n s a t i o n . T h e temperature at which moisture condenses is t h e d e w p o i n t t e m p e r a t u r e . T h u s , t h e d r y i n g capacity of the air varies significantly during processing. By dehumidifying the air to a presetd e w p o i n t , incoming air can be maintained at a constant drying capacity (dew point) a n d hence provide reproducible process times. Figure 18 Psychrometric chart. Figure 19 P r o d u c t t e m p e r a t u r e c h a n g e s during drying. Source : From Ref. 21. Batch Fluid Bed Granulation 221

Julia ZH Gao et al. (49) studied importance of inlet air velocity to dry product granulatedin a high shear granulator and dried in a fluid-bed dryer. The manufacturing process involvedgranulating the dry components containing 63% water-insoluble, low-density drug in a highshear granulator, milling the wet mass, and drying in a fluid-bed dryer. The granules wered r i e d a t a n i n l e t a i r t e m p e r a t u r e 6 0 8 C. Two different air velocities were examined for theireffect on drying uniformity of the product. The authors observed that the excessive velocityindicated by the rapid rise in the exhaust air temperature resulted in nonuniform drying of thep r o d u c t b e s i d e s r e s u l t i n g i n a n i n e f f i c i e n t p r o c e s s . G r a n u l e s e x h i b i t a n i n t r i n s i c b r e a k a g e propensity during drying, which is dependent on water content and extent of stress exposed tothe granules (50). Water content and granule size are critical process and quality parametersd u r i n g drying process. Nieuwmeyer et al. (51) expanded on the concept that the

l a r g e r granules contain more water than smaller granules and developed a model to determine thewater content of granule based on near infrared (NIR) to monitor the drying process in fluidbed. This model provided median water content of granules and hence the drying end point.According to the authors, based on the amount of moisture in the granules, determined by theNIR technique, granule size determination can be made This approach provides faster way todetermine the water content than the off-line measurement more commonly employed.The combination of granulating solvent and drying conditions could result in conversionof some of the products to alternate crystalline forms during the drying process. Using NIRs p e c t r o s c o p y , k n o w i n g b a s i c p r o p e r t i e s o f t h e d r u g s u b s t a n c e b e i n g g r a n u l a t e d iscriticalduringfluid-beddrying.Davisetal. ( 5 2 ) s t u d i e d d r y i n g o f g l y c i n e a n d m i c r o c r y s t a l l i n e c e l l u l o s e ( M C C ) (1:1) aqueous granulation in a fluid-bed unit as well as in a tray dryer. Using NIR researcherconcluded that the slower drying techniques, such as tray drying, resulted in significantly lessformationof a glycineapolymorph.Thedryingratedeterminedtheoverallpolymorphcontent.T h e fasterthegranulationwasdried,themorerapidtheincreaseinsupersatura t i o n w i t h r e s p e c t to the metastable form and the greater the thermodynamic driving force for the nucleation andcrystallization of the metastable form. The granulation rapidly dried by fluidized bed drying,resulted in more crystallization of a -glycine than the granulations that were tray dried. Drying ahigh shear wet granulated if not wet milled could be very cohesive. In case of cohesive materialsin the fluid bed, the interparticle forces are considerable and they control the behavior of a bed.T h u s , d u r i n g t h e f l u i d i z a t i o n , t h e b e d c r a c k s i n t o l a r g e p o r t i o n s a n d t h e g a s t e n d s t o f l o w i n t o t h e gap between the fissures. Then, channeling occurs in the bed, and eventually, the gas-solidc o n t a c t i s v e r y l o w a n d h e a t a n d m a s s t r a n s f e r o p e r a t i o n i s w e a k e n e d . I n s u c h c a s e s , a mechanical agitator as a part of the product container, for breaking up the cohesive granulationcake, is employed. Alternative is to pass the wet granulated product through a mill with four toeight mesh screen to break up the lumps. PROCESS AND VARIABLES IN GRANULATIONGranulation Process As with any granulating system, with fluid-bed granulation processing, the goal is to formagglomerated particles through the use of binder bridges between the particles. To achieve agood granulation, particles must be uniformly mixed, and liquid bridges between the particlesmust be strong and easy to dry. Therefore, this system is sensitive to the particle movement of the product in the unit, the addition of the liquid binder, and the drying capacity of the air. Thegranulation process in the fluid bed requires a binary nozzle, a solution delivery system, andc o m p r e s s e d a i r t o a t o m i z e t h e l i q u i d b i n d e r . F i g u r e 2 0 s h o w s t h e e q u i p m e n t s e t u p f o r granulation using the fluid-bed processor.Thurn (53) in a 1970 thesis investigated details of the mixing, agglomerating, and dryingoperations, which take place in the fluid-bed process. Results indicated that the mixing stagewas particularly influenced by airflow rate and air volume. It was suggested that the physicalproperties of the raw materials such as hydrophobicity might exert a strong influence upon themixing stage. At the granulation stage, particular attention was paid to the nozzle and it wasc o n c l u d e d that a binary design (two-fluid) nozzle gave a wide droplet size distributionyielding a homogeneous granule. The need for strong binders was recommended to aidgranule formation and it was suggested that the wettability of the raw materials requiredparticular attention. Several research papers have been published on the influence of raw 222 Parikh and Jones material (38,49,5368), binder type (5,8,48,53,62,64,6979), binder concentration, and binderquantity (8,55,60,64,66,7173,8096). Binder in the form of foam instead of liquid has beenu t i l i z e d b y s o m e p h a r m a c e u t i c a l c o m p a n i e s . U s i n g f o a m s o f a q u e o u s s o l u t i o n s o f l o w molecular weight methocel h y p r o m e l l o s e p o l y m e r s ( E 3 P L V a n d E 6 P L V ) o r c o n v e n t i o n a l solution for fluidbed granulation did not have effect on physical properties of granules ort a b l e t s compressed from these granules. However, they found that because of f o a m , t h e granule formation is achieved more efficiently. It was further claimed that variables

associatedw i t h n o z z l e s w e r e e l i m i n a t e d b y u s i n g f o a m a n d t h a t t h e w a t e r r e q u i r e m e n t w a s r e d u c e d along with shorter production time (97).Each phase of the granulation process must be controlled carefully to achieve processreproducibility. When binder liquid is sprayed into a fluidized bed, the primary particles arewetted and form together with the binder, relatively loose and very porous agglomerates.D e n s i f i c a t i o n o f t h e s e a g g l o m e r a t e s i s b r o u g h t a b o u t a l m o s t s o l e l y b y t h e c a p i l l a r y f o r c e s present in the liquid bridges. A portion of the liquid is immediately lost by evaporation, it istherefore important that the liquid binder sprayed into the bed should be relatively large inquantity compared with that used in high or low shear granulation process. The particle size of the resulting granule can be controlled to some extent by adjusting the quantity of binder liquidand the rate at which it is fed, that is, the droplet size. The mechanical strength of the particlesd e p e n d s p r i n c i p a l l y o n t h e c o m p o s i t i o n o f t h e p r i m a r y p r o d u c t b e i n g g r a n u l a t e d a n d t h e t y p e o f the binder used. Aulton et al. (86) found that lower fluidizing air temperature, a dilute solutionof binder fluid, and a greater spray rate produced better granulation for tableting. Variables Factors affecting the fluid-bed granulation process can be divided into three broad categories:1. Formulation-related variables2. Equipment-related variables3. Process-related variables Figure 20 A typical fluid bed processor setup for fluid-bed granulation. Batch Fluid Bed Granulation 223

Formulation-Related Variables Properties of primary material.

Ideally, the particle properties desired in the starting materialinclude a low particle density, a small particle size, a narrow particle size range, the particleshape approaching spherical, a lack of particle cohesiveness, and a lack of stickiness duringt h e processing. Properties such as cohesiveness, static charge, particle size d i s t r i b u t i o n , crystalline or amorphous nature, and wettability are some of the properties that have impacton the properties of granules formed. The cohesiveness and static charges on particles presentfluidization difficulty. The same difficulties were observed when the formulation containedhydrophobic material or a mixture of hydrophilic and hydrophobic materials. The influence of hydrophobicity of primary particles has been shown by Aulton and Banks (17), where theydemonstrated that the mean particle size of the product was directly related to wettability of the primary particles expressed as cos y (where y is the contact angle of the particles). It wasalso reported that as the hydrophobicity of the mix is increased, a decrease in granule growthis observed. Aulton, Banks, and Smith in a later publication showed that addition of a surface-active agent such as sodium laurel sulfate improves the fluidized bed granulation (60). In am i x t u r e c o n t a i n i n g h y d r o p h o b i c a n d h y d r o p h i l i c p r i m a r y p a r t i c l e s , g r a n u l e g r o w t h o f hydrophilic materials takes place selectively creating content uniformity problems. Formulat-ing a controlled release granulation can be accomplished by using fluid-bed granulation. Acontrolled release matrix formulation of naproxen was successfully developed using fluid-bedgranulation (98).T h e c h a n g e in granulation when a new active pharmaceutical ingredient (API) i s introduced, even the same material with a different lot number, can be caused by severalfactors. Surface free-energy is considered as one of the m a t e r i a l p r o p e r t i e s f o r s u c c e s s f u l outcome of the granulation process (43). Low-dose drug content. Wan et al. (27) studied various methods of incorporating a low-dosedrug such as cholrpheniramine maleate in lactose formulation with polyvinylpyrrolidone(PVP) as the granulating solution. They concluded that the randomized movement of particlesin the fluid bed might cause segregation of the drug and that uniform drug distribution wasbest achieved by dissolving the drug in granulating solution. The mixing efficiency of drugparticles with the bulk material was found to increase in the proportion of the granulatingliquid used to dissolve the drug. The optimum nozzle atomizing pressure was deemed to beimportant to avoid spray drying the drug particles or overwetting, which creates uneven drugdistribution. Higashide et al. (99) studied the fluidized-bed granulation using 5-fluorouracil inconcentration of 0.3% in 1:1 mixture of starch and lactose. The hydroxypropyl cellulose (HPC)w a s used as the binder. The ratios of starch and lactose contained in t h e g r a n u l e s w e r e measured gravimetrically. The researchers found that bigger amount of the drug and starchw a s f o u n d i n l a r g e r g r a n u l e s t h a n i n s m a l l e r g r a n u l e s . T h e r e s u l t s w e r e a t t r i b u t e d t o t h e hydrophobicity of the 5-fluorouracil, starch, and the hydrophilicity of lactose. Binder. A more general discussion on the types of binders used in the p h a r m a c e u t i c a l granulations and their influence on the final granule properties can be studied in chapter 4 of t h i s b o o k . D i f f e r e n t b i n d e r s h a v e d i f f e r e n t b i n d i n g p r o p e r t i e s , a n d t h e c o n c e n t r a t i o n o f individual binder may have to be changed to obtain similar binding of primary particles. Thus,the type of binder, binder content in the formulation, and concentration of the binder havemajor influence on granule properties. These properties include friability, flow, bulk density,porosity, and size distribution.Davies and Gloor (100,101) reported that the types of binder such as povidone, acacia,gelatin, and HPC all have different binding properties that affect the final granule propertiesmentioned above. Hontz (94) investigated MCC concentration, inlet air temperature, binder(PVP) concentration, and binder solution concentration effects on tablet properties. Binder andMCC concentrations were found to have significant effect on tablet properties. Alkan et al. (79)studied binder (PVP) addition in solution and as a dry powder in the powder mix. They founda larger mean granule size when the dry binder was granulated with ethanol. However, whenthe binder was in solution the granules produced were less friable and more freeflowing.Similar finding was confirmed by other researchers (95,96). Binder temperature affects the 224 Parikh and Jones

viscosity of the solution and in turn affects the droplet size. I n c r e a s e d t e m p e r a t u r e o f the binder solution reduces the viscosity of the solution reducing the droplet size and henceproducing smaller mean granule size. Binder solution viscosity and concentration affect thedroplet size of the binder. Polymers, starches, and high molecular weight PVP cause increasedv i s c o s i t y , w h i c h i n t u r n c r e a t e l a r g e r d r o p l e t s i z e a n d s u b s e q u e n t l y l a r g e r m e a n g r a n u l e particle size (71).D i l u t e d b i n d e r s a r e p r e f e r r e d b e c a u s e t h e y f a c i l i t a t e f i n e r a t o m i z a t i o n o f t h e b i n d e r solution, provide the control of the particle size, reduce friability, and increase the bulk densityeven though the tackiness or binding strength may suffer (8,72,82,86,101).Under conditions that optimal process parameters are selected, spreading of the binderover a substrate, binder-substrate adhesion, and binder cohesion are the main parameters thatinfluence optimum granulation (102). Planinsek et al. (103) investigated and concluded that thes u r f a c e f r e e energy of the formulation ingredients is important, and they found a g o o d correlation between the spreading coefficient of binder over the substrate and the friability of the granules. Binder solvent. In most instances water is used as a solvent. The selection of solvent such asaqueous or organic depends upon the solubility of the binder and the compatibility of productbeing granulated. Generally organic solvents, because of their rapid vaporization from theprocess, produce smaller granules than the aqueous solution. Different solvents have differentheats of vaporization as shown in Table 1. Incorporating binder or mixture of binders of lowm e l t i n g p o i n t a n d i n c o r p o r a t i n g i t w i t h t h e d r u g s u b s t a n c e i n t h e d r y f o r m c a n e l i m i n a t e requirement of solvent for the binder. The temperature of the incoming air is sufficient to meltt h e b i n d e r a n d f o r m t h e g r a n u l e s . S e o e t a l . ( 1 0 4 ) s t u d i e d f l u i d - b e d g r a n u l a t i o n u s i n g meltable polymers such as p o l y e t h y l e n e g l y c o l ( P E G ) 3 0 0 0 , o r e s t e r s o f P E G a n d g l y c e r o l (Gelucire 50/13). They showed that melt agglomeration by atomization of a melted binder in afluid bed occurs by initial nucleation followed by coalescence between nuclei. The nuclei areformed by immersion of the solid particles in the binder droplets provided that the droplet sizeis larger than the size of the solid particles. The agglomerate growth rate is supposed to bepractically independent of the droplet size if the binder viscosity is so low that the droplets areable to spread over the agglomerate surface. If the droplets are unable to spread because of high viscosity, the growth rate is supposed to be inversely proportional to the droplet size.These effects of droplet size are different from those seen in aqueous fluid-bed granulation,probably because the aqueous process is affected by evaporation of binder liquid. Equipment-Related Variables Design. To fluidize and thus granulate and dry the product, certain quantity of process air isrequired. The volume of the air required will vary based upon the amount of material thatn e e d s t o b e p r o c e s s e d . T h e r a t i o o f d r y i n g c a p a c i t y o f t h e p r o c e s s a i r a n d q u a n t i t y o f t h e product needs to be maintained constant throughout the scaling up process. Most of the fluid-bed units available are modular ones, where multiple processes such as drying, granulating,b o t t o m ( W u r s t e r ) c o a t i n g , r o t a r y f l u i d - b e d g r a n u l a t i n g , o r c o a t i n g c a n b e c a r r i e d o u t b y changing the container specially designed for individual process. The recent offerings by somemanufacturers offer single unit with nozzle configuration such that all of these processes canbe carried out without changing of the containers (105). Table 1 Heats of Vaporization for Commonly Used SolventsS o l v e n t S o l v e n t b o i l i n g p o i n t 8 C D e n s i t y ( g / m L ) H e a t o f v a p o r i z a t i o n ( k c a l / g ) M e t h y l e n e c h l o r i d e 4 0 . 0 1 . 3 2 7 7 7 A c e t o n e 5 6 . 2 0 . 7 9 0 1 2 3 . 5 M e t h a n o l 6 5 . 0 0 . 7 9 1

2 6 2 o l 0 . 7 2 0 4 o p a n 0 . 7 8 1 7 5 . 1 0 0 1 . 0 5 4 0 Batch Fluid Bed Granulation 225

7 8 . o 6 0 . 0 .

8 9 3 l W 0 0 0

. I 8 a

t s

5 o 2 t

h p . e

a r 4 r

Air-distributor plate. The process of agglomeration and attrition because of r a n d o m fluidization requires control of the particle during the granulation process. Optimization of the process requires control over fluidized particles. This is a complex phenomenon because of the prevailing fluidizing conditions and particle size distribution, which undergoes changesduring the process. As the conditioned air is introduced through the lower plenum of the batchfluid bed, the fluidizing velocity of a given volume of air determines how fluidization will beachieved.Perforated air-distributor plates, described previously, provide an appropriate meansof supplying air to the product. These plates are identified by their percentage of open area.A i r - d i s t r i b u t o r p l a t e s t h a t h a v e 4% to 30% open area are normally available. T h e s e interchangeable plates or plates with adjustable openings p r o v i d e a r a n g e o f l o a d i n g capacities so that batches of various sizes c a n b e p r o d u c e d e f f i c i e n t l y a n d w i t h u n i f o r m quality. To prevent channeling, an operator can select a plate with optimum lift properties. Forexample, a product with low bulk density requires low fluidizing velocity. A distributor plateh a v i n g a s m a l l o p e n area to give large enough pressure drop may provide u n i f o r m fluidization of such a product without reaching entraining velocity and impinging the processfilters. Alternatively, a product with higher bulk density can be fluidized and processed usinga plate with a larger open area. Pressure drop ( D P ). The blower creates flow of air through the fluid-bed processor or a f a n located downstream from the process chamber. This fan imparts motion and pressure to airu s i n g a p a d d l e - w h e e l a c t i o n . T h e m o v i n g a i r a c q u i r e s a f o r c e or pressure component in itsdirection of motion because of its weight and inertia. This force is called velocity pressurea n d i s m e a s u r e d i n i n c h e s o r m i l l i m e t e r s o f w a t e r c o l u m n . I n o p e r a t i n g d u c t s y s t e m s , a second pressure that is independent of air velocity or movement is always present. Knowna s s t a t i c p r e s s u r e , i t a c t s e q u a l l y i n a l l d i r e c t i o n s . I n e x h a u s t s y s t e m s s u c h a s f l u i d - b e d processors, a negative static pressure exists on the inlet side of the fan. Total pressure is thusa c o m b i n a t i o n o f s t a t i c a n d v e l o c i t y p r e s s u r e s . B l o w e r s i z e i s d e t e r m i n e d b y c a l c u l a t i n g t h e pressure drop ( D P ) created by all the components of the fluid-bed processing system. Propers e l e c t i o n of blower is essential in fluid-bed design. A blower with appropriate D P

willf l u i d i z e t h e p r o c e s s m a t e r i a l a d e q u a t e l y . H o w e v e r , a b l o w e r w i t h o u t enough D P will notallow proper fluidization of the product resulting in longer p r o c e s s t i m e a n d i m p r o p e r granulation. A similar effect can be seen when a product with unusually high bulk density isp r o c e s s e d i n p l a c e o f n o r m a l p h a r m a c e u t i c a l m a t e r i a l s , o r a n a i r - d i s t r i b u t o r p l a t e o f f e r i n g high resistance because of its construction. This creates a pressure drop that the blower wasn o t designed to handle. A proper sized blower or fan should develop sufficient D P so thatt h e e x h a u s t d a m p e r c a n b e u s e d i n t h e 3 0 % t o 6 0 % o p e n p o s i t i o n . A n y a d d i t i o n a l components such as scrubbers, exhaust HEPA, police filters, catalytic thermal oxidizer, oro v e r a l l l e n g t h of the inlet or outlet duct and additional components in the AHU w o u l d require a larger blower/static pressure, which can be recommended b y t h e s u p p l i e r o f t h e fluid-bed processor. Shaker/blow back cycle mechanism. To retain entrained particles of a process material,process filters are used. T o m a i n t a i n t h e s e f i l t e r s f r o m b u i l d i n g u p l a y e r s o f f i n e p r o c e s s material, and causing higher pressure drop and thus improper fluidization, these filters arecleaned during the granulation process. When bag filters are used mechanical means are usedto clean them. This mechanical cleaning of the bag filters requires a cessation of air flow andthus the fluidization during the filter cleaning process. In units with a single-bag house, thisresults in a momentary dead bed, where no fluidization takes place. This interruption in theprocess extends the process time. To avoid process interruptions, a multishaking filter baga r r a n g e m e n t i s d e s i r e d , w h e r e g r a n u l a t i o n p r o c e s s i s c o n t i n u o u s . U s i n g b a g f i l t e r s w i t h a blowback or using cartridge filters, where air under pressure is pulsed through the filters, alsoa c h i e v e s t h e c o n t i n u o u s p r o c e s s . G e n e r a l l y , f i l t e r s s h o u l d b e c l e a n e d f r e q u e n t l y d u r i n g the granulation step, so as to incorporate the fines in the granulation. This is possible if thecleaning frequency is high and the period between the filter cleanings is short. Rowley (106)reported the effect of bag-shake/interval cycle. He discussed the possibility of improving 226 Parikh and Jones particles size distribution by optimizing the shake time and the c o r r e s p o n d i n g i n t e r v a l between bag shakes.F o l l o w i n g g e n e r a l g u i d e l i n e s f o r f i l t e r c l e a n i n g f r e q u e n c y a n d d u r a t i o n a r e recommended. Single-bag shaker unit Frequency is 2 to 10 minutes between filter cleanings, and 5 to 10 seconds for shaking. Thismay vary as the fine powders form granules and the frequency between the shakes or durationof shaking interval can be extended. In any case, the occurrence of collapsed bed should bekept at a minimum in a single shaker unit. Multiple-bag shaker unit Since this is a continuous process, frequency of shaking for each section is approximately 15 to3 0 seconds between filter cleanings, and about 5 seconds for shaking the filters. If a low-pressure blow back system is used for the bags, the f r e q u e n c y o f c l e a n i n g i s a b o u t 1 0 t o 30 seconds. Cartridge filters These offer continuous processing and require cleaning frequency of 10 to 30 seconds.The cleaning frequency and cleaning duration are now offered as an automated systemw h e r e i n s t e a d o f h a v i n g t o b a s e t h e c l e a n i n g f r e q u e n c y o n t i m e , t h e t r i g g e r p o i n t f o r f i l t e r cleaning is the buildup of a pressure drop across the filters. This automates the process andeliminates operator input. Other miscellaneous equipment factors. G r a n u l a t o r b o w l g e o m e t r y i s c o n s i d e r e d t o b e a factor that may have impact on the agglomeration process. The fluidization velocity must dropfrom bottom to the top rim of the bowl by more than half to prevent smaller, lighter particlesbeing impinged into the filter creating segregation from heavier product components in thebowl. Generally, conical

shape of the container and expansion chamber are preferred whereratio of crosssectional diameter of the distributor plate to the top of the vessel is 1:2. Most of the suppliers of this equipment offer units with a multiprocessor concept where a single unitcan be used for drying, agglomerating, air suspension coating, or rotary fluid-bed processingby changing the processing container while the rest of the unit is common. This approach doeseliminate the concerns about the geometry of the processor because of the way these units areconstructed. Process-Related Variables The agglomeration process is a dynamic process where a droplet is created b y a t w o - f l u i d nozzle and deposited on the randomly fluidized particle. The binder solvent evaporates leavingbehind the binder. Before all of the solvent is evaporated other randomized particles formb o n d s o n t h e w e t s i t e . T h i s p r o c e s s i s r e p e a t e d n u m e r o u s t i m e s t o p r o d u c e d e s i r e d agglomerated product. There are number of process variables that control the agglomeration.Process variables most important to consider are listed as follows:1 . P r o c e s s i n l e t a i r t e m p e r a t u r e 2 . Atomization air pressure3. Fluidization air velocity and volume4 . L i q u i d s p r a y r a t e 5. Nozzle position and number of spray heads6. Product and e x h a u s t a i r t e m p e r a t u r e 7. Filter porosity and cleaning frequency8 . B o w l c a p a c i t y These process parameters are interdependent and can produce desirable product if thisinterdependency is understood. Inlet process air temperature is determined by the choice of b i n d e r v e h i c l e , w h e t h e r a q u e o u s o r o r g a n i c , a n d t h e h e a t s e n s i t i v i t y o f t h e p r o d u c t b e i n g agglomerated. Generally, aqueous vehicles will enable the use of temperatures between 60 8 C Batch Fluid Bed Granulation 227 FLUID-BED TECHNOLOGY DEVELOPMENTS Parikh (146) has presented review of all of the fluid-bed equipment developments. Amongv a r i o u s a d v a n c e s , d e v e l o p m e n t o f p r o d u c t i o n u n i t s t h a t c a n w i t h s t a n d more than 12-barpressure shock resistance is a very significant d e v e l o p m e n t . T h e s e u n i t s d o n o t r e q u i r e pressure relief duct and associated cleaning problems. Units are now equipped with the airhandler that can provide designated humidity and dew point air, throughout the year and ata n y g e o g r a p h i c a l location. The fluid-bed cleaning in place (CIP) became a reality with t h e introduction of the overlap gill air distributors and the stainless steel cartridge filters describedearlier in this chapter. Bottom Spray Particle Coating/Agglomeration The coating of the particles is carried out most frequently using Wurster column (Fig. 42A, B).The Wurster process is the most popular method for coating particles. The Wursterbasedc o a t i n g p r o c e s s d o e s n o t c o n t a i n a n y f l u i d - b e d r e g i o n s i n t h e traditional sense, as it is a Figure 42 ( A ) Typical Wurster coater. ( B ) Precision Coater 1 . Source : Part A courtesy of The Glatt Group, andpart B courtesy of GEA Pharma Systems. Batch Fluid Bed Granulation 251

circulating fluid-bed process. Four different regions within the equipment can be identified:the upbed region, the expansion chamber, the downbed region, and the horizontal transportregion. The coating process consists of three phases: the start up phase, the coating phase,a n d t h e d r y i n g a n d c o o l i n g p h a s e . D u r i n g t h e c o a t i n g phase, several processes take placesimultaneously. They are as follows: a t o m i z a t i o n o f t h e c o a t i n g s o l u t i o n o r s u s p e n s i o n , transport of the atomized droplets of the coating solution to the substrate, and the drying of thefilm. Even though particle coating with a bottom spray is preferred, numbers of products haveb e e n c o a t e d u s i n g t o p s p r a y i n f l u i d b e d . R e c e n t l y , E h l e r s a n d c o w o r k e r s ( 1 4 7 ) c o a t e d ibuprofen powder particles with HPMC using a top spray without agglomerating powders.Bottom spray coating is also used for agglomeration as well as particle coating as it

wasdeveloped originally. As seen earlier in this chapter, by placing the nozzles tangentially, mostof the manufacturers have improved the operational difficulties encountered when nozzleplugging required that the process be stopped to pull the nozzle during the coating process.B y p l a c e m e n t o f n o z z l e s t a n g e n t i a l l y , s o m e m a n u f a c t u r e r s c l a i m t h a t s e p a r a t e m o d u l e s t o carry out agglomeration, coating, and drying will not be needed. Of the modification of theb a s i c W u r s t e r T e c h n i q u e , a column within column (HS collar) was introduced by Glatt tominimize agglomeration during coating and enabling the higher spraying rate. F u r t h e r modification of the Wurster was introduced by GEA Pharma systems as a coating as well asbottom spray granulating technique with an introduction of Precision Coater 1 a s s h o w n i n Figure 42B.Researchers have discussed the incorporation of microwave in the laboratory fluid-bedprocessor (148,149). Fluid-bed process using organic solvent requires inert gas such as nitrogento replace the air used for fluidization as discussed earlier in the chapter. It is accompaniedwith the solvent recovery system. Rotary Fluid Bed The other advance of significance is the development of a rotary fluid bed, f o r p r o d u c i n g denser granulation. Modules were introduced by various manufacturers and the technology isd i s c u s s e d b e l o w . T h e 1 9 7 2 p a t e n t ( 1 5 0 ) f o r t h e r o t o r t e c h n o l o g y w a s a w a r d e d f o r t h e equipment and coating of the granular m a t e r i a l . T h e s u b s e q u e n t p a t e n t s ( 1 5 1 , 1 5 2 ) w e r e awarded for the coating of the spherical granules. An advantage of rotary fluid-bed processingto produce granules was reported by Jager and Bauer over conventional top spray granulationtechnique (153). In this unit, the conventional air distributor is replaced by the rotating disk.T h e m a t e r i a l t o b e granulated is loaded on the rotating disk. The binder solution is a d d e d through the atomization nozzle located tangentially to the wall of the bowl. The centrifugalforce creates a dense, helical doughnut-shaped pattern. This type of motion is caused by thethree directional forces.T h e v e r t i c a l m o v e m e n t i s c a u s e d b y t h e g a p o r s l i t a i r a r o u n d t h e r o t a t i n g d i s k , t h e gravitational force folds back the material to the center, and the centrifugal force caused by therotating disk pushes the material away from the center. The granulation produced in the rotaryf l u i d - b e d p r o c e s s o r s h o w s l e s s p o r o s i t y c o m p a r e d w i t h t h e c o n v e n t i o n a l l y a g g l o m e r a t e d product in the fluid-bed processor. The rotary fluid bed (Fig. 43) does provide granules, whichhave less porosity and higher bulk density compared with the granulation produced by thetypical top spray granulated fluid-bed process.Turkoglu et al. produced theophylline granulation using a rotary fluid bed (154). Theformulation contained lactose, starch, and MCC along with theophylline. They reported thatthe granules produced were spherical and dense. Three different drug level formulations wereevaluated. The authors concluded that rotary fluid bed as a wet granulator has the potential too b t a i n a b e t t e r d r u g c o n t e n t u n i f o r m i t y f o r t a b l e t s e v e n a t l o w a c t i v e l e v e l s s u c h a s 1 % i n comparison with conventional fluidized beds. The use of rotary fluid bed to produce sphericalgranules for modified release application is reported by number of authors. Rotary fluid-bedtechnology was reviewed by Li et al. (155) and its usefulness was described to produce thepellets. The comparison of the rotary fluid-bed processing with the multiple step extrusion andspheronization was reported by Robinson et al (156). The authors manufactured acceptableimmediate release acetaminophen pellets using both of these techniques. The quality of thepellet produced improved as the minimum quantity of product was increased in the rotary 252 Parikh and Jones fluid-bed processor. The advantage of using a single unit such as rotary f l u i d b e d o v e r multiple unit process involving several pieces of equipment was described.The rotary fluid bed is used for producing a pellet by layering the active drug suspensiono r s o l u t i o n o n t o n o n p a r e i l c o r e s a n d s u b s e q u e n t l y c o a t i n g t h e m w i t h p o l y m e r s t o i m p a r t modified release properties (157). Hileman et al. (158) reported manufacture of immediates p h e r e s o f a p o o r l y w a t e r - s o l u b l e d r u g i n a r o t a r y f l u i d b e d b y l a y e r i n g t h e a c t i v e d r u g suspension onto nonpareil cores. These immediate release spheres were then overcoated withan ethyl cellulose/HPMC hydroalcoholic solution in the same unit eliminating the need foradditional process and handling steps. Iyer et al. evaluated layering of aqueous solution of phenylpropanolamine hydrochloride with different binders (159). The layered beads werecoated in the rotoprocessor and

the Wurster Coater to compare the utility of rotoprocessor asa n e q u i p m e n t n o t only to produce pellets but to coat them as well. Various e q u i p m e n t manufacturers have promoted powder layering on the pellets, in a rotary fluid bed. In 1992,Jones et al. received patent for such a process (160). The process claims to have advantages of layering a drug substance with relatively small amount of liquid, thus making this layeringprocess more efficient. The commercial application of this process has not been reported in thel i t e r a t u r e . K o r a k i a n i t i e t a l . ( 1 6 1 ) s t u d i e d t h e p r e p a r a t i o n o f p e l l e t s u s i n g r o t a r y f l u i d - b e d granulator. Authors concluded that the rotor speed and amount of water significantly affectedt h e g e o m e t r i c m e a n d i a m e t e r o f t h e p e l l e t s a n d t h e y p r o p o s e d a n e q u a t i o n t o s h o w t h a t correlation. Pisek et al. (162) studied the influence of rotational speed and surface of rotatingdisk on pellets produced by using rotary fluid bed. They used mixture of pentoxifylline andM C C t o produce pellets using suspension of Eudragit 1 N E 3 0 D a s a b i n d e r . T h e r e s u l t s showed that both surface and rotational speed of the disk have influence on shape, surface,and size of the pellets while there was less effect on the density, humidity content, and yield.T h e y f o u n d t h e t e x t u r e d s u r f a c e o f t h e d i s k p r o d u c e d p e l l e t s w i t h r o u g h e r s u r f a c e w h e n rotational speed was increased compared with the smooth surface, where increased rotationalspeed produced more spherical pellets with larger diameter.Kristensen and Hansen (163) compared granulation prepared in the fluid bed with a topspray and rotary processor, and concluded that the rotary processor offers better maneuver-ability in terms of the obtainable granule size and was less influenced by the flow properties of the starting materials. Similar tablet characteristics were found in the investigated types of equipment. The applicable range of liquid addition rates was found to be similar in the rotaryprocessor and in the top spray fluid-bed module. Generally, wet granulation in the rotaryp r o c e s s o r w a s found to be a good alternative to conventional fluid-bed granulation, Figure 43 ( A ) Rotary fluid-bed processing modules. ( B ) SPIRA flow design. Source : Part A courtesy of TheGlatt Group, and part B courtesy of Vector Corporation Web site. Batch Fluid Bed Granulation 253

particularly when cohesive powders with poor flow properties or formulations with low drugcontent are to be granulated by a fluidizing air technique. Kristensen (164) in another study of granulation of binary mixtures of MCC and either lactose, calcium phosphate, acetaminophen,or theophylline, in a 1:3 ratio, using a 50% (w/w) aqueous solution of PEG and water as thebinder liquid, demonstrated that up to 42.5% w/w PEG can be incorporated and may be analternative process to the melt granulation with hydrophilic meltable binders. Integrated Systems The fluid-bed technology is used for drying, agglomerating, coating, and pelletization.However, the industry is using fluid-bed processor for drying in c a s e s w h e r e h i g h e r b u l k density, low drug content formulations of a hydrophobic drug substance that may have to beincorporated in a larger batch of excipients sizes, and granulation are carried out in high shearm i x e r a n d t h e f l u i d b e d i s u s e d a d r y e r .

T o f a c i l i t a t e t h e s e t w o s e p a r a t e o p e r a t i o n s , a n integrated system is set up in number of companies where the transfer of wet mass from highshear is passed through a mill prior to loading in the fluid bed.Figures 44 and 45 shows typical integrated system where containment is considered forcontrolling dust and cross contamination. When these two-unit operations are integrated as asingle unit, number of points must be considered. Following is the list of some of the questionsreader may want to consider:1. Engineering layout and the footprint, ceiling height requirements.2. How will the high shear mixer be loaded by gravity, vacuum, or manually?3. How will the binder solution be prepared and delivered to the mixer?4. How will the granulation end point be determined and reproduced? Figure 44 Integrated system showinghigh shear mixer next to fluid-bed unit. Source : Courtesy of LB Bohle. Figure 45 Integrated system with in-line conical mill at the discharge of high shear mixer. Source : Courtesy ofQuadro Engineering. 254 Parikh and Jones

5. How will the discharge from the high shear mixer be accomplished?6. Are the process parameters for granulation and fluid-bed drying established and arereproducible, indicating a robust process?7 . H o w w i l l t h e p r o d u c t d i s c h a r g e d f r o m t h e f l u i d - b e d d r y e r b e h a n d l e d ? D o e s i t require sizing and blending with the lubricants?8. Is this system dedicated for a single product or multiple products?9. How will this system be cleaned?10. Will the control of a process be done individually for each unit or by an integratedcontrol system?For the potent compound processing requiring high shear granulation and fluid-bedd r y i n g , s o m e c o m p a n i e s h a v e i n t r o d u c e d a l a b s i z e u n i t w i t h i s o l a t o r s a n d g l o v e b o x . F o r commercial scale, a totally contained unit is designed that minimize or eliminate the operatorexposure to the potent compound. Such a system is costly and does require enormous amountof time for process and cleaning validation. CONCLUSION The fluid-bed dryer was used as an efficient way to dry a product because of suspension of wetp a r t i c l e s i n t h e h o t a i r s t r e a m . H o w e v e r , o v e r t h e l a s t 4 0 y e a r s o f d e v e l o p m e n t i n t h e pharmaceutical industry and the proliferation of the batch fluid-bed processing technology inother industries such as food, polymer, detergent, etc., have provided the opportunity to uset h e b a t c h f l u i d - b e d p r o c e s s o r f o r g r a n u l a t i o n , d r y i n g , p a r t i c l e c o a t i n g , a n d p e l l e t i z a t i o n . The advances in the fluid bed can be attributed to the several factors. The needs of formulators,the requirements of the regulators, and technological innovations from the manufacturersof this technology are responsible for these advances. The result of these changes providedunits that are paint-free, modular, and safer, in compliance with the cGMPs, and are capable of performing various processes that were not thought of before.T h e f l u i d - b e d p r o c e s s l i k e o t h e r g r a n u l a t i o n t e c h n i q u e r e q u i r e s u n d e r s t a n d i n g t h e importance of characterization of the raw materials,

especially of a drug substance, the processe q u i p m e n t , l i m i t a t i o n s o f t h e s e l e c t e d p r o c e s s , e s t a b l i s h m e n t o f a n i n - p r o c e s s c o n t r o l specifications, characterization of the finished product, and cleaning and process validation.Over the last 10 years, process analytical technology has provided different approachesto understand this complicated unit operation. The interrelationship of process parameters isvery critical as you establish the process parameters. We now have the modern computerizedcontrol panels and various on-line/in-line measurement options available for process control.I f o n e r e v i e w s t h e h i s t o r y o f i n n o v a t i o n f o r t h i s u n i t o p e r a t i o n , t h e r a t e o f e q u i p m e n t modification or improvement is relatively slow compared with the various process-controloptions being developed. The proper understanding of the process during the developmentstage will provide a robust process for the commercial application. REFERENCES 1. Kunii D, Levenspiel O. Fluidization Engineering. New York: John Wiley & sons Inc., 1968.2. Wurster DE. Preparation of compressed tablet granulations by the air-suspension technique. II. J AmPharm Assoc 1960; 49:82.3. Wurster DE. Air-suspension technique of coating drug particles; a preliminary report. J Am PharmAssoc (Sci Edi) 1959; 48(8):451454.4. Scott MW, Liberman HA, Rankell AS, et al. Continuous production of tablet granulation in Fluid BedI. Theory and design consideration. J Pharm Sci 1964; 53(3):314319.5 . R a n k e l l A S , S c o t t M W , L i b e r m a n H A , e t a l . C o n t i n u o u s p r o d u c t i o n o f t a b l e t g r a n u l a t i o n s i n a fluidized bed. II. Operation and performance of equipment. Pharma Sci 1964; 53(3):320.6 . C o n t i n i S , A t a s o y K. Fluid bed granulation, a modern economic method for tabletting a n d encapsulation. Pharm Ind 1966; 28:144146.7. Wolf G. Fluidized layer spray granulation. Drugs Made Germany 1968; 11:172180.8. Liske T, Mobus W. The manufacture and comparative aspects of fluidized layer spray granulation.Drugs Made Germany 1968; XI:182189.9. Sherrington PJ, Oliver R. Granulation monograph. In: Goldberg AS Sr., ed. Powder Science andTechnology. London: Heyden, 1981. Batch Fluid Bed Granulation 255 10. Pietch WB. Fluidization phenomena and fluidized bed technology. In: Fayed ME, Otten L, eds.Handbook of Powder Science and Technology. New York: Van Nostrand Reinhold, 1984.11. Hersey JA. Fluidized bed technologyan overview. Int J Pharm Tech Prod Manuf 1981; 2(3).12. Thiel WJ. The theory of fluidization and application to the industrial processing of pharmaceuticalproducts. Int J Pharm Tech Prod Manuf 1981; 2(5).13. Thiel WJ. Solids mixing in gas fluidized beds. Int J Pharm Tech Prod Manuf 1981; 2(9).14. Littman H. An overview of flow in fluidized beds. Pharm Technol 1985; 9(3):48.15. Whitehead AB. Behavior of fluidized bed systems. Pharm Technol 1981; 2(13).16. Story MJ. Granulation and film coating in the fluidized bed. Pharm Technol 1981; 2(19).17. Aulton MJ, Banks M. Fluidized bed granulation, factors influencing the quality of the product.Pharm Technol 1981; 2(24).18. Kulling W, Simon EL. Fluid bed Technology applied to pharmaceuticals. Pharm Technol 1980; 4(1).19. Gomezplata A, Kugelman AM. Processing systems. In: Marchello JM, Gomezplata A, eds. Gas-SolidHandling in the Process Industries. Chemical Processing and Engineering. Vol. 8. New York: MarcelDekker Inc., 1976.2 0 . R a sanen E. Rantanen J, Mannermaa JP, et al. The characterization of fluidized behavior using a novelmultichamber microscale fluid bed. J Pharm Sci 2004; 93:780791.21. Parikh DM. Airflow in batch fluidbed processing. Pharm Technol 1991; 15(3):100110.22. Row PN, et al. Trans Inst Chem Eng 1965; 32T:271.23. Davis L, et al. Trans Inst Chem Eng 1966; 44T:293.24. Gorrodnichev VI, et al. (English Translation). Pharm Chem J (USSR) 1974; 8:298.25. Kirk-Othmer. Fluidization in Encyclopedia of Chemical Technology. Vol. 10, 3rd ed. New York:WileyInterscience, 1981:548581.26. Ennis BJ, Tardos GI, Pfeffer R. A micro-levelbased characterization of granulation phenomena.Powder Technol 1991; 65:257272.2 7 . W a n Lucy SC, Heng Paul WS, Muhuri G. Incorporation and distribution of a low d o s e d r u g i n granules. Int J Pharm 1992; 88:159163.28. Long GE. Spraying theory and practice. Chem Eng 1978; PP73PP77.29. Masters K. Spray Drying: An Introduction to Principles, Operational Practice and Application. 2nded.New York: John Wiley & Sons Inc., 1976.30. Japanese Patent Application 61-259696, 1986.31. Swiss Patent 0176/93, 1993, US Patent 5,444,892, 1995, European Patent number 0572356A1.32. Guidance for Industry, Part 11, Electronic Records; Electronic SignaturesScope and application.2003.33. Newitt DM, Conway-Jones JM. A contribution to the theory and practice of granulation. Int J PharmTech Prod Manuf 1958; 36:422.34. Record PC. A review of pharmaceutical granulation technology. Int J Pharm Tech Prod Manuf 1980;1:32.35. Rumpf H. The strength of

granules and agglomerates. In: Krepper W, ed. Agglomeration. NewYork: Interscience, 1962:379418.36. Tardos GI, Khan MI, Mort PR. Critical parameters and limiting conditions in binder granulation of fine powders. Powder Technol 1997; 94:245258.3 7 . I v e s o n S M . G r a n u l e coalescence modeling: including the effects of bond strengthening a n d distributed impact separation forces. Chem Eng Sci 2001; 56:22152220.38. Schaefer T, Worts O. Control of fluidized bed granulation I effects of spray angle, nozzle height andstarting materials on granule size and size distribution. Arch Pharm Chem Sci Ed 1977; 5:5160.39. Smith PJ, Nienow AW. Particle growth mechanism in fluidized bed granulation. Chem Eng Sci 1983;38(8):12231231, 13231240.40. Aulton ME, Banks M. Fluidized bed granulationfactors including the quality of the product. Int JPharm Tech Prod Manuf 1981; 2(4):24 29.41. Maroglou A, Nienow AW. Fourth Symposium on Agglomeration. Toronto, Canada: Iron & SteelSociety Inc., 1985:465470.4 2 . G o l d s c h m i d t M J V . H y d r o d y n a m i c m o d e l i n g o f f l u i d i z e d b e d s p r a y g r a n u l a t i o n . P h D T h e s i s , Twente University, Enschede, The Netherlands, 2001.4 3 . T h i e l m a n n F , e t a l . T h e e f f e c t o f p r i m a r y p a r t i c l e s u r f a c e f r e e - e n e r g y o n a g g l o m e r a t i o n r a t e i n fluidized bed wet granulation. Powder Technol 2007; doi:10.1016/j.powtec.2006.12.015.44. Jain K. Discrete characterization of cohesion in gas-solid flows. Master Thesis, School of Engineering,University of Pittsburg, 2002.45. McCabe W L, Smith JC. Unit Operations of Chemical Engineering. New York, NY: McGraw-Hill, 1956.46. Green Don W, ed. Perrys Chemical Engineers Handbook, Section 20. New York, NY: McGraw-Hill,Inc., 1984. 256 Parikh and Jones 47. Rankell RS, Liberman HA, Schiffman RF. Drying in the Theory and Practice of Industrial Pharmacy.3rd ed. Philadelphia: Lea & Feabiger, 1986.48. Schaefer T, Worts O. Control of fluidized granulation III, effects of the inlet air temperature, andliquid flow rate on granule size and size distribution. Control of moisture content of granules in thedrying phase. Arch Pharm Chem Sci Ed 1978; 6(1):113.49. Julia ZH Gao, Gary DB, Motheram R, et al. Importance of inlet velocity in fluid bed drying of agranulation prepared in a high shear mixer. AAPS PharmSciTech, 2000; 1(4).50. Nieuwmeyer FJS, Vromans H. Granule breakage during drying processes. Int J Pharm 2007; 329:8187.51. Nieuwmeyer FJS, Damen M, Gerich A, et al. Granule characterization during fluid bed drying bydevelopment of a near infrared method to determine water content and median granule size. PharmRes 2007; 24(10):18541861.52. Davis TD, Peck GE, Stowell JG, et al. Modeling and monitoring of polymorphic transformationsduring the drying phase of wet granulation. Pharm Res 2004; 21(5).53. Thurn U. Dissertation no. 4511, Eidgenossischen Technischen, Hochschule, Zurich, 1970.54. Liske T, Mobus W. Drugs Made Germany 1968; 11(4):182189.55. Schaefer T, Worts O. Control of fluidized bed granulation V, factors affecting granule growth. ArchPharm Chem Sci Ed 1978; 6:6982.56. Ormos Z, Pataki K. Hung J Indust Chem 1979; 7:89103.57. Ormos Z, Pataki K. Hung J Indust Chem 1979; 7:105117.58. Banks M. Ph.D. Thesis. C.N.A.A. Leicester Polytechnic, 1981.59. Galmen MJ, Greer W. Fluid Technol Pharm Manuf International Conference, Paper 2, 1982.60. Aulton ME. Fluid Technol Pharm Manuf International Conference, Paper 3, Powder AdvisoryCenter, London, 1982.61. Veillard M, et al. Int J Pharm Tech Prod Mfg 1982; 3(4):100107.62. Georgakopoulos PP, et al. The effects of using different grades of PVP and gelatin as binders in thefluidized bed granulation and tabletting of lactose. Pharmazie 1983; 38(4):240243.63. Jinot JC, et al. STP Pharma 1986; 2(13):126 131.64. Shinoda A, et al. Yakuzaigaku 1976; 36(2):8388.65. Aulton ME, et al. The wettability of powders during fluidized bed granulation. J Pharm Pharmacol1977; 59P(suppl)66. Schepky G. Acta Pharm Technol 1978; 24(3):185212.67. Aulton ME, Banks E. Proc Intl Conf Powder Technol Pharm Basel, Switzerland: Powder AdvisoryCenter, 1979.68. Kocova El, Arini S, et al. Drugs Made Germany 1983; 26(4):205211.69. Davies W L, Gloor WT. Batch production of pharmaceutical granulations in a fluidized bed. IIEffects of various binders and their concentrations on granulations and compressed tablets. J PharmSci 1972; 61(4):618622.70. Rouiller M, et al. Acta Pharm Technol 1975; 21(2):129138.71. Schaefer T, Worts O. Control of fluidized bed granulation II, estimation of droplet size of atomizedbinder solution. Arch Pharm Chem Sci Ed 1977; 5:178193.72. Ormos Z, Pataki K, Stefko B. Studies in granulation in a fluidized bed IX. Effects of concentration of various binders upon granule formation. Hung J Indust Chem 1979; 7:131140.7 3 . O r m o s Z , P a t a k i K , S t e f k o B . S t u d i e s i n g r a n u l a t i o n i n a f l u i d i z e d b e d X . E f f e c t s o f t h e r e l a t i v e amounts of various binders upon granule formation. Hung J Indust Chem 1979; 7:141151.74. Ormos Z. Studies in granulation in a fluidized bed XI Approximate description of the particle sizedistribution. Hung J Indust Chem 1979; 7:153163.75. Ormos Z. Studies in granulation in a fluidized bed XII, Bed expansion of fluidized heterodispersegranule masses. Hung J

Indust Chem 1979; 7: 221235.76. Kocova El-Arini S. Pharm Ind 1981; 43(7):674679.77. Jager KF, Bauer KH. Acta Pharm Technol 1984; 30(1):8592.78. Nouh ATI. Pharm Ind 1986; 48(6):670673.79. Alkan H, et al. Doga Tu J Med Pharm 1987; 11(1):17.80. Bank A, et al. Proc Conf Appl Phys Chem 1971; 2:687692.81. Davies W L, Gloor WT. Batch production of pharmaceutical granulations in a fluidized bed. IIIBinder dilution effects on granulation. J Pharm Sci 1973; 62(1):170172.82. Ormos Z, Pataki K, Csukas B. Hung J Indust Chem 1973; 1:307328.83. Ormos Z, Pataki K, Csukas B. Hung J Indust Chem 1973; 1:463474.84. Johnson MCR, et al, J Pharm Pharmacol 1975; 80P(suppl).8 5 . Schaefer T, Worts O. Control of fluidized bed granulation IV. Effects of b i n d e r s o l u t i o n a n d atomization on granule size and size distribution. Arch Pharm Chem Sci Ed 1978; 6:1425.86. Aulton ME, et al. Mfg Chem Aerosol News 1978; 12:5056. Batch Fluid Bed Granulation 257 87. Gorodnichev VI, et al. Pharm Chem J (USSR) 1980; 14(10):7277.88. Ceschel GC, et al. II Farmaco Ed Prat 1981; 36(6):281293.89. Rangnarsson G, et al. Int J Pharm 1982; 12:163171.90. Meshali M, El-Banna H M, El-Sabbagh H. Pharmazie 1983; 38(5):323 325.91. Hajdu R, Ormos Z. Hung J Ind Chem 1983; 12:425430.92. Devay A, et al. Acta Pharm Technol 1984; 30(3):239242.93. Alkan MH, Yuksel A. Granulation in fluidized bed IIEffect of binder amount on the final granules.Drug Dev & Ind Pharm 1986; 12(10):15291543.94. Hontz J. Assessment of Selected Formulation and Processing Variables in Fluid Bed Granulation.Ph.D. Thesis, University of Maryland at Baltimore, 1987. Dissertation Abs Int 1987; (6):1655-B.95. Wan LSC, Lim KS. STP Pharm 1988; 4(7):560571.96. Wan LSC, Lim KS. Mode of action of polyvinylpyrrolidine as a binder on fluidized bed granulationof lactose and starch granules. STP Pharm 1989; 5(4):244250.97. Sheskey P, Keary C, Inbasekaran P, et al. Foam technology: the development of a novel technique forthe delivery of aqueous binder systems in high shear and fluid-bed wet-granulation applications.Poster @ AAPS Annual Meeting, October 2630, 2003.98. Dahl TC, Bormeth AP. Naproxen controlled release matrix tablets: fluid bed granulation feasibility.Drug Dev Ind Pharm 1990; 16(4):581590.99. Higashide F, Miki Y, Nozawa Y, et al. Dependence of drug content uniformity on particle sizes influidized bed granulation. Pharm Ind 1985; 47(11):12021205.100. Davies WL, Gloor WT Jr. Batch production of pharmaceutical granulation in fluidized bed II: effectsof various binders and their concentrations on granulations and compressed tablets. J Pharm Sci1972; 61:618.101. Davies WL, Gloor WT Jr. Batch production of pharmaceutical granulation in fluidized bed III: binderdilution effects on granulation. J Pharm Sci 1973; 62:170.1 0 2 . K r y c e r I , P o p e D G , Hersey JA. An evaluation of tablet binding agents: Part 1: solution b i n d e r . Powder Tech 1983; 34:3951.1 0 3 . P l a n i n s e k O , P i s e k , R , T r o j a k A , e t a l . T h e u t i l i z a t i o n o f s u r f a c e f r e e - e n e r g y p a r a m e t e r s f o r t h e selection of a suitable binder in fluidized bed granulation. Intl J Pharm 2000; 207:7788.104. Seo A, Holm, P, Schaefer T. Effects of droplet size and type of binder on the agglomerate growthmechanisms by melt agglomeration in a fluidized bed. Eur J Pharm Sci 2002; 16:95105.105. GEA Pharma Flexstream Brochure and Web site. Available at: http://www.GEApharma.com, andA Company Brochure and Web site. Available at: http://www.niro-pharma-systems.com.106. Rowley FA. Effects of the bag shaking cycle on the particle size distribution of granulation. PharmTechnol 1989; 13(9):7882.107. Davies WL, Gloor WT Jr. Batch production of Pharmaceutical granulation in fluidized bed. I: Effectsof process variables on physical properties of final granulation. J Pharm Sci 1971; 60(12):18691874.108. Maroglou A, Nienow AW. Fluidized bed granulation technology and its application to tungstencarbide. Powder Metallurgy 1986; 29(4):1525.109. Workman J Jr. A review of process near infrared spectroscopy: 1980-1994. J Near Infrared Spectrosc1993; 1:221245.110. Osborne BG, Fearn T, Hindle PH. In Practical NIR Spectroscopy with Applications in Food andBeverage Industry Analysis. 2nd ed. Harlow, UK: Longman, 1993:227.111. USP XXVII 2004.112. European Pharmacopoeia. Near Infra Red Spectrometry, 2004:59.113. Callis J, Illman D, Kowalski B. Process analytical chemistry. Anal Chem 1987; 59:624A637A.114. Beebe K, Blaser W, Bredeweg R, et al. Process analytical chemistry. Anal Chem 1993; 65:199R216R.115. Blaser W, Bredeweg R, LaPack M, et al. Process analytical chemistry. Anal Chem 1995; 67:47R70R.116. Hassel D, Bowman E. Process analytical chemistry for spectroscopists. Appl. Spectrosc 1998; 52:18A29A.117. Workman J Jr., Veltkamp D, Doherty S, et al. Process analytical chemistry. Anal Chem 1999. 71:121R 180R.1 1 8 . B r i t t a i n H . M e t h o d s f o r t h e c h a r a c t e r i z a t i o n o f p o l y m o r p h s a n d s o l v a t e s i n p o l y m o r p h i s m i n pharmaceutical solids. In: Brittain H, ed. Polymorphism in Pharmaceutical Solids. Vol. 95, 1st ed.New York: Marcel Dekker Inc., 1999:227278.119.

Frake P, Greenhlgh D, Grierson SM, et al. Process control and end-point determination of fluid bedgranulation by application of near-infrared spectroscopy. Int J Pharm 1997; 151:7580.1 2 0 . Rantanen J, Antikanen O, Mannermaa JP, et al, Use of near-infrared r e f l e c t a n c e m e t h o d f o r measurement of moisture content during granulation. Pharm Dev Technol 2000; 5(2):209217.121. Rantanen J, Lehtola S, Ramet P, et al. On-line monitoring of moisture content in an instrumentedfluidized bed granulator with multi-channel NIR moisture sensor. Powder Technol 1998; 99:163170. 258 Parikh and Jones in the granulation. The ram extruder has been used to characterize the flow o f w e t m a s s e s through a die as shown by Baert et al. (39). Granulation flow has been divided into stages. Theya r e : ( i ) compression, where the materials are consolidated under slight pressure, ( ii ) steady-state flow, where the pressure required to maintain the flow is constant, and ( iii ) forced flow,where an increase in force is required to maintain flow. The three stages are shown in the forceversus displacement profile in Figure 4. The change from steady state to forced flow is causedby the movement of fluid under pressure. Extrusion in a ram extruder is continuous, and thisphenomenon is less likely to be seen in extruders that are discontinuous such as gravity-fedmodels. A diagram of a ram extruder is shown in Figure 5.Regardless of the mixer used, one must remember that the downstream process steps of extrusion and spheronization are very dependent on the level of water contained in the Figure 4 A force-displacement profile for a microcrystalline celluloselactose-water mixture showing the threestages of extrusion on a ram extruder: compression, steady-state flow, and forced flow (ram speed: 4 mm/sec; diediameter: 1.5 mm; L / R ratio: 12). Source : From Ref. 42. Figure 5 Schematic diagrams of extruder types used in extrusion-spheronization. 286 Erkoboni

granulation and the quality of its dispersion. High-energy mixers such as high-shear mixersand high-shear twin-screw mixer/extruders can cause a significant rise in temperature. It maybe necessary to use a jacket to guard against heat build-up. High temperatures can result in agreater than tolerable level of evaporation or an increase in the solubility of some of the solidsa s d e m o n s t r a t e d b y B a e r t e t a l . ( 4 0 ) . A r e d u c t i o n i n f l u i d w i l l r e d u c e t h e p l a s t i c i t y o f t h e granulation. This will likely cause a finer, more porous, less dense, less uniform, and sphericalgranulation to be produced. The objective of downstream processing will determine whethersome of these effects are desirable or not. If some of the effects are desirable, it is better to addlesser water and control the environmental conditions and mixing better. If the effects areundesirable, better control of the process is necessary.An increase in the solubility of the drug due to an increase in temperature

will increasethe weight ratio of granulating fluid to solids since the solute is then part of that fluid. Ku et al.demonstrated that temperature of the granulating fluid had a significant effect on the sizedistribution of pellets or spherical granules produced (41). The water solubility of the drug int h e g r a n u l a t i o n p l a y s a k e y r o l e i n d e t e r m i n i n g g r a n u l a t i o n e n d p o i n t f o r e x t r u s i o n - spheronization process. A highly water soluble drug will dissolve in the granulation fluidwhereas a highly insoluble drug will have wetting problems during the granulation step andremain part of the solid during granulating and wet massing. Extrusion The third step is the extrusion step that forms the wet mass into rod-shaped particles. The wetm a s s is forced through dies and shaped into small cylindrical particles having a uniformdiameter. The extrudate particles break at similar lengths under t h e i r o w n w e i g h t . T h e extrudate must have enough plasticity to deform but not so much to adhere to other particleswhen collected or rolled in the spheronizer.Extruders come in many varieties, but can generally be divided into three classes on thebasis of their feed mechanism. They include those that rely on a screw, gravity, or a piston tofeed the wet mass into the extrusion zone as described by Rowe (42). Examples of extrudersfrom each class are shown in Figure 5. Screw-fed extruders include the ( i ) axial or end plate,( ii ) dome, and ( iii ) radial types, while gravity-fed extruders include ( iv ) cylinder, ( v ) gear, and( vi ) radial types. The screw- and gravity-fed types are used for developing and manufacturingwith the radial varieties being the most popular for pharmaceutical applications. The pistonfeed or ram extruder is primarily used in research as an analytical tool.Screw extruders have either one (single) or two (twin) augers that transport the wet massfrom the feed area to the extrusion zone. During the transport process, the screws compress thew e t m a s s r e m o v i n g m o s t o f t h e entrapped air. Studies have been conducted on the rame x t r u d e r t o understand this compression or consolidation stage. They have shown theapparent density of the wet mass plug prior to extrusion i s a p p r o x i m a t e l y e q u a l t o t h e theoretical apparent particle density, indicating that nearly all of the voids were eliminated asdetermined by Harrison et al. (43). Twin-screw extruders generally have a higher throughputthan single-screw models, while single-screw extruders compress and increase the density of the extrudate more. Other features that can affect the density of the extrudate are the spacingsof the turnings on the screw and the space between the end of the screw and the beginning of the die as described by Hicks and Freese (44). Turnings that are wide and regularly spacedm i n i m i z e t h e a m o u n t o f compression during material transport. Screws with closer o r progressively closer spacing between the turnings will result in more c o m p r e s s i o n a n d produce a denser extrudate. Space between the screw and the die result in a void into whichmaterial is deposited and compressed. The greater the space, the more the compression takesplace prior to extrusion. As material builds up, pressure increases and causes the material to beforced, under hydraulic pressure, to flow through the die. When space between the screw andthe die is at a minimum, extrusion takes place as material is compressed in the nip, betweenthe extruder blade and the die.The primary difference between the various types of screw extruders is in the extrusionzone. An axial or dome extruder transports and extrudes the wet mass in the same plane. Axialextruders force the wet mass through a flat, perforated endplate, typically prepared by drillingh o l e s i n a p l a t e . T h e thickness of the plate can be more than four times the hole diameter, Extrusion-Spheronization as a Granulation Technique 287 resulting in high die length to radius ( L /

R ) ratios. A twin-screw axial endplate extruder isshown in Figure 6.Dome extruders use a dome or half sphereshaped screen as the die. It is prepared bystamping holes in metal stock having a similar thickness as the hole diameter. This results in adie L / R ratio to about 2:1; however, variations in screen thickness are possible resulting in aslightly higher or lower ratio. A dome extruder is shown in Figure 7.Unlike axial and dome extruders, radial extruders extrude the wet mass perpendicular tothe plane of transport. Material is transported to the extrusion zone where it is wiped againstthe screen die by an extrusion blade. The mass is forced through the die by pressure generatedat the nip. A screw-fed radial extruder is shown in Figure 8.A s w i t h d o m e - t y p e e x t r u d e r s t h e d i e i s a stamped screen. Because of the shorter dielengths and the increased n u m b e r o f h o l e s o r d i e s , d o m e a n d r a d i a l e x t r u d e r s h a v e t h e advantage of higher throughput as compared with the axial type.As with almost every step in extrusionspheronization, heat build-up during extrusion isa s i g n i f i c a n t c o n c e r n . T h i s i s e s p e c i a l l y t r u e o f t h e s c r e w - f e d e x t r u d e r s . A x i a l e x t r u d e r s generate heat because of their long die lengths. Radial extruders can have a significant heatdifferential over the width of the screen. Materials fed into the extrusion zone will have thelowest temperature. However, as material moves to the front of the zone, the temperatureincreases due to the longer residence time of material. Of the screw-fed extruders, the domet y p e h a s the highest rates and is least likely to generate significant heat over an e x t e n d e d period, since it allows for uniform extrusion and shear over the extrusion screen. Since radial Figure 6 Twin-screw axial extruder. Source : Courtesy of LCI Corporation. Figure 7 Dome extruder. Source : Courtesy of LCI Corporation. 288 Erkoboni

and dome extruders use stamped dies or screens, they are the most fragile and susceptible todamage due to high forces. Care must be taken to minimize the force required by formulationand fluid optimization, which will be discussed later in the chapter.Gravity-fed extruders include cylinder, gear, and radial types. The cylinder and gearboth belong to a broader class referred to as roll extruders. Both use two rollers to exert forceo n t h e wet mass and form an extrudate. The cylinder extruder has rollers in the f o r m o f cylinders, one solid and one hollow with drilled holes to form the dies. The wet mass is fed bygravity into the nip area between the two cylinders and forced through the dies into the hollowof the cylinder. Gear-type extruders have rollers in the form of hollow gears. The dies are holesd r i l l e d a t the base of each tooth. Wet mass is forced through the holes and collected in thehollow of the gears as the teeth and the base areas mesh. The gears o f a g e a r e x t r u d e r a r e shown in Figure 9 to illustrate the teeth.The last type of gravityfed extruder to be discussed is the radial type. Of the gravity-fedextruders, it is the most widely used. One or more arms rotate to stir the wet mass as it is fedby gravity. Rotating blades wipe the wet mass against the screen, creating localized forcessufficient to extrude at the nip. There is no compression prior to extrusion, which is the majord i f f e r e n c e b e t w e e n t h e g r a v i t y - a n d s c r e w - f e d r a d i a l e x t r u d e r s . A g r a v i t y - f e d e x t r u d e r i s shown in Figure 10. Additionally, a schematic showing the extrusion zone and principle of operation are shown in Figure 11A and B, respectively. Figure 8 Side views of the extrusion zone of radial extruder. Source

: Courtesy of LCI Corporation. Figure 9 Gears of a gear-type extruder Source : C o u r t e s y o f A C C o m p a c t i n g Corporation. Extrusion-Spheronization as a Granulation Technique 289

The primary extrusion process variables are the feed rate, die opening, and die length.The water content of the granulation is also very critical, since the properties of the extrudateand resulting spheres are very dependent on the plasticity and cohesiveness of the wet mass.The process variables and water content have been the focus of many studies. Harrison et al.(37,43,45,46) studied the flow of the wet mass as it is forced through a die. They determinedsteady-state flow (described above, Fig. 4) was essential to produce smooth extrudate thatresults in uniformly sized spherical particles having good sphericity and surface character-istics. Materials and processes that did not result in steady state, a condition referred to asforced flow, produced extrudate having surface impairments. In moderate cases, the surface isrough, while in more severe cases, a phenomenon commonly referred to as shark-skinningoccurs. Examples of smooth extrudate and shark-skinned extrudate are shown in Figure 12.There continues to be differences of opinions regarding the value of smooth extrudate in theproduction of spherical particles, commonly referred to as spheres, beads, and pellets, intendedfor use in multiparticulate drug delivery systems. Spherical granules intended for applicationssuch as tablet or capsule granules, as well as granules for filling into sachet-type units, do notrequire uniformity in size and therefore less care need to be taken in the extrusion step. Figure 10 Gravity-fed rotary extruder ( A

) front view and ( B ) close-up showing extrusion zone. Source : Courtesyof Niro Pharma Systems. Figure 11 Gravity-fed rotary extruder ( A ) schematic of the extrusion zone and ( B ) p r i n c i p l e o f o p e r a t i o n o f gravity-fed extruder. Source : Courtesy of Niro Pharma Systems. 290 Erkoboni

Force-displacement profiles of MCC and water at various ratios, MCC, lactose, and waterat a 5:5:6 ratio, and lactose and water at 8:2 ratio, developed by Harrison et al. (37), are shownin Figure 13. Steady state was possible with the MCC and MCC-lactose samples but not withlactose alone. As can be seen with the MCC samples, the duration of the compression stagewas water level dependent with no effect seen on the steady-state stage. Additional studiesindicated the effect of ram speed (extrusion speed) and die L / R ratio. An increase in ram speedincreased duration of the steady-state stage with no effect on the compression stage. The L / R ratio had no effect on either compression or steady state. Wet mass composition, therefore,influenced the ability to achieve steady state while the water level and ram speed influencedduration. Higher water levels decreased the force to produce steadystate flow but increasedthe duration. Faster ram speeds (extrusion rates) increased the duration of steady state andincreased the force. As discussed below, other

investigators have reported the correlationbetween extrusion force and sphere quality.Harrison et al. (37) also indicated that a uniform lubricating layer at the die wall interfacemust occur to eliminate the slip-stick phenomenon responsible for forced flow. Developmentof a lubricating layer was dependent on the length of the die (a minimum length required),wall shear stress, and upstream pressure loss. They represent the frictional forces at the die-w a l l i n t e r f a c e a n d t h e e s t i m a t e d p r e s s u r e l o s s a t z e r o d i e length in the barrel of the ramextruder. The method for deriving these v a l u e s i s d e s c r i b e d i n r e f e r e n c e a r t i c l e . T h e s e parameters allow for a quantitative comparison between formulations and process; however,no specific values can be targeted since they vary with materials. Figure 12 SEMs showing an example of ( A ) smooth extrudate and ( B ) extrudate having surface impairment,or shark-skinning. Figure 13 Force-displacement profiles at variousm o i s t u r e c o n t e n t s o f m i x t u r e s o f m i c r o c r y s t a l l i n e cellulose and water: (ad) microcrystalline cellulose-lactose-water (5:5:6); (e) lactose-water (8:2); (f) at aram speed of 4 mm/sec, die diameter of 1.0, and al e n g t h / r a d i u s r a t i o o f 1 2 . P e r c e n t a g e o f m o i s t u r e content of microcrystalline cellulosewater mixture:a, 59.4; b, 51.1; c, 45.0. Source : From Ref. 37. Extrusion-Spheronization as a Granulation Technique 291

Pinto et al. (47) also showed that, at slow ram speeds, water moves toward the die wallinterface and acts as a lubricant resulting in reduced extrusion forces. At higher speeds, wateris unable to move rapidly through the mass resulting in higher forces. They indicated the watercontent and its distribution are critical in determining the particle size and sphericity of thep r o d u c t . L o w e r w a t e r c o n t e n t a n d h i g h e r s p e e d w i l l r e d u c e t h e s i z e a n d s p h e r i c i t y o f t h e particles. The extrusion speed and water content should be adjusted to achieve the desiredeffect. Other researchers have investigated the effect of die length using gravity-fed radialextruder. Hellen et al. indicated that the extrudate became smoother and more bound as the

L / R ratio of the die was increased (48). Vervaet et al. reported that a higher L / R ratio enablesthe use of lower water levels to achieve a more bound extrudate (49). This also increased therange (drug loading and water level) over which quality spheres could be produced. Theyattributed the increased latitude and capability to increased densification and resulting well-bound extrudate. The average pore diameter and bulk density reported for extrudate preparedfrom various MCC:DCP:water ratios at two L / R ratios are shown in Table 1.B a e r t e t a l . ( 5 0 ) a l s o i n d i c a t e d a s i m i l a r i n c r e a s e i n l a t i t u d e w h e n a c y l i n d e r e x t r u d e r having a L / R ratio of 4 was compared with a twin-screw extruder having a L / R ratio of closet o 1 . 8 . O t h e r s t u d i e s h a v e s h o w n t h e r e i s a n o p t i m a l p r e s s u r e r a n g e o v e r w h i c h e x t r u d a t e that is capable of yielding acceptable spheres can be produced. Shah et al. (51) demonstratedt h e c o r r e l a t i o n b e t w e e n s c r e e n p r e s s u r e yield and density. A high yield of spheres withina t a r g e t e d n a r r o w s i z e distribution was produced as long as the screen pressure w a s maintained within a given range. The relationship between yield and screen pressure isshown in Figure 14.While many of the researchers have indicated a need for a more cohesive extrudate,f e w h a v e e x p r e s s e d a need to remove all surface impairments. Some researchers h a v e indicated that spheres having acceptable characteristic can be p r o d u c e d f r o m e x t r u d a t e having shark-skinning. OConnor and Schwartz have found the presence of shark-skinning Table1 Average Pore Diameter and Bulk Density of Extrudate Composed of DCPAvicelPH-101Water Mixture, Extrudated Using Screens with a Different L / R RatioComposition DCP-Avicel-water (w/w) L / R ratio ofscreenAverage porediameter ( m m)Bulk density(g/mL)1 5 0 : 3 8 0 : 4 7 0 4 0 . 9 8 2 1 . 1 3 2 1 5 0 : 4 0 0 : 4 5 0 4 0 . 9 9 2 1 . 2 1 1 1 5 0 : 3 8 0 : 4 7 0 2 1 . 2 4 9 0 . 9 4 9 1 5 0 : 4 0 0 : 4 5 0 2 1 . 2 9 2 0 . 9 4 7 Source : From Ref. 49. Figure 14

The effect of extruder screen pressure on the yield of particles within an acceptable distribution. Source : From Ref. 51. 292 Erkoboni

this technology, a 23% reduction in floor space was reported compared with a conventionalbatchwise granulation process, which requires larger units for high-shear granulation andfluid-bed drying.Another type of mechanical mixer is the Lodige continuous granulation, which consistsof a horizontal granulation chamber with a rotating shaft, equipped with different elements toprovide different functionalities (preblending, granulation, and shaping of granules). The highr o t a t i o n s p e e d o f t h e b l e n d i n g / a g g l o m e r a t i o n e l e m e n t s ( s h o v e l s ) c r e a t e s a f l u i d b e d l i k e behavior of the material. The granulation process in this system is highly efficient, however,because of the throughput rate of these systems (smallest capacity 50100 kg/hr, up to 50 ton/hr), the number of pharmaceutical applications is limited. REFERENCES 1. Pellek A, Arnum PV. Continuous processing: moving with or against the manufacturing flow. PharmTechnol 2008; 32(9):5558.2. Rios M. Continuous processingfinally. Pharm Technol 2007; 31(4):3134.3. Bush L. FDA lowers barriers to process improvement. Pharm Technol 2005; 29(10):3943.4. Vervaet C, Remon JP. Continuous granulation in the pharmaceutical industry. Chem Eng Sci 2005;60:39493957.5 . J a c o b M . G r a n u l a t i o n equipment. In: Salman AD, Hounslow MJ, Seville JPK, eds. G r a n u l a t i o n . Amsterdam: Elsevier, 2007:417476.6 . G o t t h a r d t S , K n o c h A , L e e G . C o n t i n u o u s w e t g r a n u l a t i o n u s i n g f l u i d i z e d - b e d t e c h n i q u e s . I . Examination of powder mixing kinetics and preliminary granulation experiments. Eur J PharmBiopharm 1999; 48:189197.7. Lindberg NO. Some experiences of continuous wet granulation. Acta Pharma Suec 1988; 25:239246.8 . A p p e l g r e n C , E s k i l s o n C , M e d i c a l L . A n o v e l m e t h o d f o r t h e g r a n u l a t i o n a n d c o a t i n g o f pharmacologically active substances. Drug Dev Ind Pharm 1990; 16:23452351.9. Lodaya M, Mollan M, GhebreSellassie I. Twin-screw wet granulation. In: Ghebre-Sellassie I, MartinC, eds. Pharmaceutical Extrusion Technology. New York: Marcel Dekker, 2003:323343.10. Gamlen MJ, Eardley C. Continuous extrusion using a baker Perkins MP50 (multipurpose) extruder.Drug Dev Ind Pharm 1986; 12:17011713.11. Lindberg NO, Tufvesson C, Holm P, et al. Extrusion of an effervescent granulation with twin screwextruder, baker Perkins MPF50D. Influence of intragranular porosity and liquid saturation. Drug DevInd Pharm 1988; 14:17911798.12. Keleb EI, Vermeire A, Vervaet C, et al. Continuous twin screw extrusion for the wet granulation of lactose. Int J Pharm 2002; 239:6980.1 3 . K e l e b E I , V e r m e i r e A , V e r v a e t C , e t a l . T w i n s c r e w g r a n u l a t i o n a s a s i m p l e a n d e f f i c i e n t t o o l f o r continuous wet granulation. Int J Pharm 2004; 273:183194.14. Keleb EI, Vermeire A, Vervaet C, et al. Extrusion granulation and high shear granulation of differentg r a d e s o f l a c t o s e a n d h i g h l y d o s e d d r u g s : a c o m p a r a t i v e s t u d y . D r u g D e v I n d P h a r m 2 0 0 4 ; 3 0 : 679 691.1 5 . D j u r i c D , V a n M e l k e b e k e B , K l e i n e b u d d e P , e t a l . C o m p a r i s o n o f t w o t w i n - s c r e w e x t r u d e r s f o r continuous granulation. Eur J Pharm Biopharm 2009; 71:155

160.16. Djuric D, Kleinebudde P. Impact of screw elements on continuous granulation with a twin-screwextruder. J Pharm Sci 2008; 97:49344942.1 7 . D j u r i c D . C o n t i n u o u s G r a n u l a t i o n w i t h a T w i n - S c r e w E x t r u d e r . D u sseldorf: Heinrich-HeineUniversitat Dusseldorf, 2008.18. Van Melkebeke B, Vermeulen B, Vervaet C, et al. Melt granulation using a twin-screw extruder: a casestudy. Int J Pharm 2006; 326:8993.19. Schroeder R, Steffens KJ. Continuous granulation technologies. In: Parikh DM, ed. Handbook of Pharmaceutical Granulation Technology. 2nd ed. New York: Taylor & Francis, 2005:431457.20. Van Melkebeke B, Vervaet C, Remon JP. Validation of a continuous granulation process using a twin-screw extruder. Int J Pharm 2008; 356:224230.21. Van Melkebeke B. Development and evaluation of a continuous granulation technique using a twin-screw extruder. Ghent University, Ghent, 2009.2 2 . B e t z G , Junker-Burgin P, Leuenberger H. Batch and continuous processing in the p r o d u c t i o n o f pharmaceutical granules. Pharm Dev Technol 2003; 8:289297.23. Werani J, Grunberg M, Ober C, et al. Semicontinuous granulationthe process of choice for theproduction of pharmaceutical granules? Powder Technol 2004; 140:163168.24. Leuenberger H. New trends in the production of pharmaceutical granules: batch versus continuousprocessing. Eur J Pharm Biopharm 2001; 52:289296. 322 Vervaet and Remon 14 Effervescent Granulation Guia Bertuzzi IMA SPA ACTIVE Division, Bologna, Italy INTRODUCTION Effervescence has proved its utility as an oral delivery system in the p h a r m a c e u t i c a l a n d dietary industries for decades. In Europe, effervescent dosage forms are widespread, and theiru s e i s g r o w i n g i n t h e U n i t e d S t a t e s a n d o t h e r c o u n t r i e s . E f f e r v e s c e n t g r a n u l a t i o n i s a n important step of fizzy dosage forms production that most of the time cannot be avoided toachieve the desired characteristics of the effervescent tablets. It is very critical also because itcan affect stability of the final dosage forms. The first effervescent preparations were describedover two centuries ago, in the official compendia; they were in powders to use as cathartics a l t s . L a t e r , i n 1 8 1 5 , a p a t e n t d e s c r i b e s a c o m b i n a t i o n o f n e u t r a l s a l t o r p o w d e r w h i c h possesses all the properties of the medicinal spring of Seidlitz in Germany, under the name of Seidlitz Powders, which contains sodium potassium tartrate, sodium bicarbonate, and tartaricacid, in the proportions 3:1:1, respectively (1). Effervescent granules and tablets have becomemore and more popular as dosage forms because they are promptly soluble and easy to take.T o state the growing interest in such forms, in the 1980s, the results o f a l i t e r a t u r e search about effervescent forms were published so as to h e l p s c i e n t i s t s w o r k i n g o n n e w development (2).A c c o r d i n g t o t h e 6 t h E d i t i o n European Pharmacopoeia, the effervescent forms ared e f i n e d a s t h o s e granules or tablets to be dissolved in water before administration t o patients. Effervescent tablets or granules are uncoated and generally contain acidic substancesand carbonate or bicarbonate that react rapidly to release carbon dioxide once dissolved inwater. Disintegration of the tablets usually occurs within two minutes or even less, because of the evolution of carbon dioxide.Effervescent forms have many advantages over conventional pharmaceutical forms.They substitute liquid forms when the active ingredient has a little stability in liquid formb e c a u s e t h e y c a n b e a d m i n i s t e r e d o n l y b y p r i o r d i s s o l v i n g t h e t a b l e t i n w a t e r . A c t i v e ingredients that are not stable in liquid form are most of the times stabler in effervescent form.This dosage form is easier to administer, particularly helpful to patients, like children, who arenot able to swallow capsules or tablets. A pleasant taste, because of carbonation, helps to maskthe bad taste of certain drugs. This could help to avoid the gastric side effect of certain drugs.I n c e r t a i n c a s e s , they can shorten drug absorption rate in the body as compared w i t h traditional tablets, with a quicker therapeutic effect (3). They are easy t o u s e a n d a p p e a l consumers for color and fizzy appearance more than traditional dosage forms.Effervescent dosage form also helps with patient compliance. For example, chloroquineremains the most widely used medicine for treatment of malaria in endemic countries despiteresistance of up to 50% in some areas, because of its affordable price. A study showed thatp a t i e n t c o m p l i a n c e i n c r e a s e d w h e n t h e c h l o r o q u i n e p h o s p h a t e w a s a d m i n i s t e r e d a s a n effervescent tablet because of the faster response onset than uncoated tablets (4).Disadvantages of such solid dosage forms are more related

to production technologyeven if processing methods and equipment are the same as the conventional ones. In general,product requirements are similar to conventional granules, namely particle size distributionand shape, uniformity of active distribution, to produce satisfactory free-flowing granules, andcapable of tableting using high-speed rotary tablet press. However, it is also necessary to focusattention on some aspects of the process procedure, including compression and packagingbecause effervescent dosage forms are challenging and consequently difficult to make.P h a r m a c e u t i c a l i n d u s t r y faces many problems, especially in the preparation of effervescent tablets as it is certainly the application for which the choice of t h e p r o c e s s i n g equipment is at least as important as the formulation design.

THE EFFERVESCENT REACTION Effervescence is the evolution of gas bubbles from a liquid, as a result of a chemical reaction.T h e m o s t c o m m o n r e a c t i o n f o r p h a r m a c e u t i c a l p u r p o s e i s t h e a c i d b a s e r e a c t i o n b e t w e e n sodium bicarbonate and citric acid. 3NaHCO 3 aq 252g 3 mol H 3 C 6 H 5 O 7 aq 192g 1 mol ) 3H 2 O aq 54g 3 mol 3CO 2 132g 3 mol

3Na 3 C 6 H 5 O 7 aq 258g 1 mol This reaction starts in presence of water, even with a very small amount, as a catalyzingagent, and because water is one of the reaction products, it will accelerate and will be verydifficult to stop. For this reason, the whole manufacturing and storage of effervescent productshas to be planned by minimizing the contact with water.L o o k i n g a t the stechiometric ratios in the reaction, it is quite easy to understand t h e reason why effervescent tablets are so large.Recently, some effervescent systems have been prepared to act as penetration enhancersfor drug absorption, not only in oral forms but also in some topical products, such as skin orvaginal applications. In these cases, the reaction takes place directly after administration, in themouth because of saliva (5), on the wounds because of blood serum (6), or when formulated ina suppository, the effervescence can be provoked by the moisture of the vaginal mucosa totreat vaginal infections or simply adjust the pH.T h e r e a r e o t h e r f o r m s , t h e e f f e r v e s c e n c e o f w h i c h i s b a s e d o n a d i f f e r e n t r e a c t i o n u p o n c a r b o n dioxide formation. Effervescence is due to reactants that evolve oxygen or other gasses, which aresafe for human consumption even if they are not suitable for oral administration but can beemployed in preparations for external use such as antibacterial for dental plate cleaning. FORMULATION The criteria to choose the raw materials for effervescent products are similar to those for theconventional tablets, since in either case, good compressibility and compactability are thetargets to achieve. The intrinsic characteristics of effervescent forms bring some considerationst h a t w i l l l i m i t t h e c h o i c e o f t h e r a w m a t e r i a l , i n c l u d i n g t h e selection of active ingredient.M o i s t u r e c o n t e n t o f t h e r a w m a t e r i a l i s a v e r y s i g n i f i c a n t a s p e c t , b e c a u s e i t a f f e c t s compressibility and stability of the tablets. To avoid premature effervescent reaction duringthe process or once the tablets are formed, raw materials with very low moisture content have tobe used. Since an effervescent tablet is required to dissolve within two minutes or less in a glasso f w a t e r (about100mL),rawmaterialssolubilityandtheir rateofsolubilityareother s i g n i f i c a n t aspects. The active ingredient must be either soluble, water dispersible or at least solubilized bysalt formation during the dissolution in the glass of water. The rest of the excipients, such asadditives like sweeteners, coloring agent, and flavors, also have to be water soluble.For all these considerations, the list of the excipients for this dosage form has not changedf o r many years. However, the physical properties of these raw materials have r e c e n t l y improved. Many different grades for each material are now commercially available, includings o m e p r e f o r m u l a t e d g r a d e s , w h i c h a r e h i g h l y r e c o m m e n d e d f o r d i r e c t c o m p r e s s i o n . Formulators must choose the excipient grade on the basis of the characteristics of the activeingredient, tablets size, and process technology they have. Therefore, the ultimate use of theeffervescent granules or tablets mainly affects the choice of the raw materials.To design an effervescent formula, it is necessary to consider the stechiometric ratios inthe reaction, and the carbon dioxide solubility in water, which is 90 mg/100 mL of water (inSTP conditions). The suggested ratio between acid and alkaline components is about 0.6, butsometimes it might be required to increase the acid source to get a pleasant taste. In fact, thealkaline-acid ratio controls both the effervescence capacity and the taste of the solution toadminister. When the active ingredients solubility is not pH dependent, the alkaline-acid ratioc a n b e o p t i o n a l l y s e l e c t e d . T h i s r a t i o c a n a l s o b e d e t e r m i n e d a c c o r d i n g t o t h e p H t h a t i s required for dissolving the active. In fact, when the active solubility increases at the acid side,the pH of the solution is lowered by adding an excess of the acidic agent. Conversely, an excessof alkaline sources must be added when the active ingredient is more

soluble at higher pH (7).However, another approach that can be used to increase the active ingredient solubility is to 324 Bertuzzi increase the volume of carbon dioxide to be generated by increasing the alkaline component inthe formulation.As far as other excipients, such as diluents or binders, are concerned, there is a very littlespace for the formulator to play with, because of the large dimension of the tablet due to theeffervescent system. Compressibility cannot be enhanced by additional binders for efferves-cent dosage form, because of the larger size of the tablet in the first place.In the latest development in effervescent forms, there are some formulations that havebeen designed to control the rate of effervescence, so as to obtain a rapid, intermediate or slowrate. The rate control is strictly related to the acid-alkaline components ratio, but the chemicalproperties of the effervescent excipients or their combinations can have an influence on it,especially when a slow rate of effervescence is required. RAW MATERIALS Because of the nature of the effervescence reaction, additional excipients are sparingly used asthe alkaline and acid ingredients are also the fillers to get a tablet bulk. They are, indeed, insuch a large amount that tablets are much larger than the conventional ones. In case it wouldb e n e c e s s a r y t o a d d a f i l l e r , s o d i u m b i c a r b o n a t e i s s e l e c t e d b e c a u s e o f i t s l o w e r c o s t a n d because it does not influence final pH of the solution and increases effervescence effect.S o d i u m c h l o r i d e a n d s o d i u m s u l f a t e a r e o t h e r p o s s i b l e f i l l e r s ; t h e y a r e h i g h - d e n s i t y crystalline powders that are very compatible with the other ingredients.A d d i t i v e s a r e a d d e d i n s m a l l a m o u n t s t o m a k e t h e t a b l e t s m o r e a t t r a c t i v e f o r u s e r s . Flavors, colors, and sweeteners are used as usual in all the formulations. Acid Materials Necessary acidity for effervescence can be provided by three main sources: food acids, acidanhydrides, and acid salts. Food acids, citric acid, tartaric acid, and ascorbic acid are the mostcommonly used because these have a nice taste, are odorless, not expensive, and easy to handle. Citric Acid Citric acid is the more often used acidic ingredient because of its good solubility and pleasanttaste. It is mainly commercially available in powder and is either colorless or in white crystals.The particle size grades are: coarse, medium, fine, and powder (only anhydrous). It is verys o l u b l e i n w a t e r a n d s o l u b l e i n e t h a n o l ( 8 ) . I t c a n b e used as monohydrate or anhydrate,d e p e n d i n g o n t h e s e l e c t e d equipment technology and process conditions. It is v e r y hygroscopic; however, anhydrous form is less hygroscopic than t h e m o n o h y d r a t e ( 9 ) . However, caking of the anhydrous ingredient may occur upon prolonged storage at humiditygreater than 70%. The monohydrate melts at 100 8 C , a n d r e l e a s e s t h e w a t e r o f h y d r a t i o n a t 75 8 C. For this reason, it can be used as binder source in hot melt granulation. Tartaric Acid It is very soluble in water and very hygroscopic, more than citric acid. In the effervescencer e a c t i o n w i t h s o d i u m b i c a r b o n a t e , i t b e h a v e s l i k e c i t r i c a c i d i n p r o d u c i n g a n e v i d e n t effervescence. It must be used in a higher amount to get the proper stechiometric proportions,b e i n g a d i p r o t i c a c i d , w h i l e c i t r i c i s a t r i p r o t i c a c i d . I n t e r m s o f c o m p r e s s i b i l i t y , i t i s a l s o comparable to citric acid (8). Ascorbic Acid It is white in crystalline form and light yellow in fine powder. It is not hygroscopic, and thismay be helpful in production because it is easier to handle. It is freely soluble in water (1 g inabout 3 mL) and absolute ethanol (7). If exposed to light, it gradually gets dark. Its behavior inthe effervescent reaction with sodium bicarbonate is comparable to the other acids (citric andtartaric) in terms of release rate of carbon dioxide. Acid Anhydrides Anhydrides of food acids are a potential acid source as they a r e p r e c u r s o r s o f t h e corresponding acid by hydrolization in water. The effervescent effect is strong and sustained Effervescent Granulation

325 by the continuous production of acid in the solution. Water has to be avoided for the wholeprocess when anhydrides are part of a formulation, otherwise they would be hydrolyzed intothe corresponding acid before its use (10). Acid Salts Sodium dihydrogen phosphate and disodium dihydrogen pyrophosphate are acid salts thathave been used in effervescent formulation. They are water soluble, produce acid solution, andr e a c t q u i c k l y w i t h a l k a l i n e s o u r c e s . T h e y a r e c o m m e r c i a l l y a v a i l a b l e i n e i t h e r g r a n u l a r o r powder form. Other Less Frequent Sources of Acid Fumaric and nicotinic acids, which are not hygroscopic, but have low water solubility. Malic acid has recently been introduced in effervescent formulations because of itss m o o t h a n d l i g h t t a s t e . I t i s h i g h l y h y g r o s c o p i c a n d s o l u b l e b u t h a s l e s s a c i d strength than the tartaric or citric acids. Acetylsalicylic acid, though active ingredient, which is very commonly administeredi n e f f e r v e s c e n t p r e p a r a t i o n s , c a n n o t b e u s e d a s a c i d s o u r c e f o r i t s l o w w a t e r solubility. Adipic acid deserves to be mentioned even if it is useless as acid source because of itsl o w w a t e r s o l u b i l i t y . I t h a s g i v e n g o o d r e s u l t s a s l u b r i c a n t f o r e f f e r v e s c e n t calcium carbonate tablets (11). Sources of Carbon Dioxide Solid carbonates salts are the most popular source for effervescents; bicarbonate forms aremore reactive than carbonates. Sodium Bicarbonate It is the major source of carbon dioxide in effervescent forms, able to provide a yield of 52% of carbon dioxide. It is commercially available in five grades according to particle size, from free-flowing uniform granule to fine powder, which are odorless and slightly alkaline in taste. Whenheated, the bicarbonate is converted into anhydrous sodium carbonate. This reaction is time andtemperature dependent. Ninety percent of the conversion is achieved within 75 minutes at 93 8 C,but starts at 50 8 C, which must be considered as a critical temperature in processing (7).B e i n g a n o n e l a s t i c m a t e r i a l i t h a s a v e r y l o w c o m p r e s s i b i l i t y b u t t h i s i s s u e h a s b e e n improved since it has been produced by spray-drying technique. Direct compressible grades arenow available but contain some additives such as polyvinylpirrolidone (PVP) or silicone oil. Sodium Carbonate It is commercially available in three different forms, all very soluble in water: anhydrous,monohydrate, and decahydrate (7). It is more resistant to the effervescent reaction, and in someformulationscan beused asstabilizing agent inan amountnotexceeding 10% ofthe batchsize.Iti s u s e d a s s t a b i l i z i n g a g e n t i n c e r t a i n e f f e r v e s c e n t f o r m u l a s b e c a u s e i t a b s o r b s m o i s t u r e preferentially, preventing the effervescent reaction to start. Of course the anhydrous form isp r e f e r r e d f o r t h i s p u r p o s e . R e c e n t l y , a p a r t i c u l a r g r a d e o f s o d i u m b i c a r b o n a t e h a s b e e n p r o d u c e d in round-shaped particles, coated with a carbonate layer to increase bicarbonate stability (12). Potassium Bicarbonate and Potassium Carbonate They substitute the sodium salts when sodium ion is not required (13). They are lesser solublethan the corresponding sodium salts and are more expensive. Calcium Carbonate Precipitated calcium carbonate occurs as fine, white odorless, and tasteless powder or crystals.I t s water solubility is very poor, and is not soluble in ethanol or i s o p r o p a n o l . I t i s a high-density powder, not suitable for compression. It is normally used as drug in effervescenttablets for patients who suffer from calcium shortage.I t c a n a l s o be used as alkaline source because it provides stability to the e f f e r v e s c e n t system (14). 326 Bertuzzi Sodium Glycine Carbonate Sodium glycine carbonate provides a light effervescence reaction, but rapid disintegration of the tablets, so it has been applied in the preparation of fast dissolving sublingual tablets. It ismuch more compressible than the other alkaline compounds, and it has been found suitablefor direct compression (15).

Binders The use of a binder in effervescent formulations is limited by the fact that any binder, even if water soluble, will retard the tablet disintegration. Therefore, the amount of binder in a givenformula will be a compromise between desired granule strength and desired disintegrationtime.As will be described in section Wet Granulation, water itself is an effective binder foreffervescent granules when granulated with all the components together. A small amount of water, finely distributed on the powder bed, acts as a binder by partially dissolving the rawmaterials and preparing them for agglomeration. Other solvents, for example, ethanol andisopropanol, can be use as granulating liquid to dissolve dry binders.Binders for dry granulation, such as lactose, mannitol, dextrose, are almost inappropri-ate, because they would be effective only in larger amount than that allowed by an effervescentformulations. The binder choice in wet granulation is also limited by the method of productionand consequently by the amount of granulating liquid.In case of granulation of both the alkaline and acidic components together with water, itwould not make sense to put a binder in the formulation because the small amount of waterwill never be able to dissolve the binder.The most popular binder for effervescent tablets is PVP. Types K25 and K30 are preferredf o r t h e i r w a t e r s o l u b i l i t y a n d d i s s o l u t i o n r a t e , w h i c h a r e a n i m p o r t a n t i s s u e f o r t h e f i n a l purpose of effervescent tablets. PVP is effective at low percentage in the formula, starting from2% and above. It is feasible either for dry or wet granulation. It is soluble in water, alcohols,and hydroalcoholic liquids (7). Lubricants Because tableting is a critical step of effervescent production, selecting the lubricant is one of the most important issues. Lubrication of effervescent mixture is quite problematic because of the chemical-physical nature of the lubricants. Most of the lubricants, because of their lowwater solubility, inhibit the tablet disintegration, which, as already said, must be very rapid incase of effervescent tablets. The effervescent tabletsmainly for marketing reasonsare oftenrequired to provide a clear transparent solution, that is, without any insoluble film formationon the water surface or any residue left. In selecting a lubricant, proper attention must be givento its solubility in water, along with its compatibility with the active ingredient.M a n y d i f f e r e n t l u b r i c a n t s h a v e b e e n t e s t e d f o r a l o n g t i m e t o e s t a b l i s h t h e m o s t appropriate for effervescent tablets (16), including the opportunity to carry out e x t e r n a l lubrication of the granules directly in the dies of the tablet press.L u b r i c a n t substances, which are reported in literature as suitable for e f f e r v e s c e n t manufacturing because they are water soluble, are sodium benzoate, sodium acetate, L -leucine,a n d c a r b o w a x 4 0 0 0 . A v e r y r e c e n t a p p l i c a t i o n i s a c o m b i n a t i o n o f c a l c i u m a n d p o t a s s i u m sorbates and micronized polyethylene glycol (PEG) with calcium ascorbate or trisodium citrate(17). Combination of spray dried L-leucine and PEG 6000 has been reported as successful onein literature (18). Other lesser soluble lubricants have been used in formulating effervescentt a b l e t s , h o w e v e r , a b a l a n c e s h o u l d b e f o u n d b e t w e e n c o m p r e s s i o n e f f i c i e n c y a n d w a t e r solubility. Magnesium stearate is, however, employed but the most suitable, commerciallyavailable type is its combination with sodium lauryl sulfate, a surface-active agent that helpsits dispersion (19). Additives: Sweeteners, Coloring Agents, and Flavors Coloring agents can include all the dyes soluble and suitable for food such as the FD & C onesand all the natural coloring substances in amounts variable in the range 0.1% to 3.5% of thetotal weight of the formulation. Effervescent Granulation 327 Flavors can be selected from synthetic flavors or natural extracts. Lemon, orange, ando t h e r f r u i t e s s e n c e s a r e p a r t i c u l a r l y s u i t a b l e t o o b t a i n t h e o r g a n o l e p t i c r e q u i r e m e n t i n a n amount variable in a range of 0.5% to 3.0% of the total weight of the formulation. MANUFACTURING OF EFFERVESCENT FORMS Manufacturing conditions are crucially important even with regard to stability of the productso n c e they have been packed. Almost all the raw materials u s e d f o r e f f e r v e s c e n t s manufacturing are hygroscopic, so moisture absorption from the air must be prevented toavoid the effervescent reaction to start prior to use the tablets.The whole production process, as shown in Figure 1 (dosing of the

ingredients, mixing orgranulating, lubricating, tableting, and packaging), can be carried out in a completely closedand integrated handling system, consisting of intermediate bulk containers (IBCs), tumblersfor IBCs, docking and dosing stations.In this case, only the packaging area will be ventilated with low moisture content of air.Otherwise, traditional open handling systems can be employed but the whole facility has to bec o n d i t i o n e d w i t h a i r at minimum level of moisture content (20). In fact, the suggestedconditions throughout the plant are: relative humidity ( R H ) b e l o w 2 0 % a n d u n i f o r m temperature at 21 8 C , t h o u g h i t i s k n o w n t h a t 2 5 % o f R H a t c o n t r o l l e d r o o m t e m p e r a t u r e (25 8 C) is, however, enough to avoid instability caused by atmospheric moisture (21).Manufacturing effervescent drugs on a large scale is usually done in a semicontinuousprocedure,bypayingattentiontosynchronizealltheprocesssteps,toachieveth elargestproductionthroughput. A continuous process flow, with continuous feeding of raw materials and collection of granules, can be performed by extrusion of the wet mass and drying in a continuous fluid-beddryer. Granulation of effervescent mixtures must be, most of the times, executed in batches and isdefinitelythemostcritical stepofthisparticularkindof pharmaceuticalmanufacturing,asithardlyinfluencesthecharacteristicsofthefinalforms,granules,ortablets,andconsequently thefollowingsteps of production. Lubrication of the granulation, compression of tablets, and packaging of effervescent tablets should be carefully planned to produce suitable effervescent product.The critical issues discussed earlier, for the compression of effervescent granules, arerelated to the low compressibility of the majority of the raw materials, large dimensions of thetablets, poor content of binder in the formulation, and difficulties to lubricate the mixture. Forall these reasons, the tableting phase has to be carried out carefully, and even the choice of thetablet press is of great importance. To overcome lubrication difficulties, some suppliers of tablet press have developed equipments that are capable of carrying out an external lubricationof the granules. Antiadherent materials are sprayed directly into the dies of the tablet press,d u r i n g t h e pause phase of compression, so as to prevent sticking of granules on dies a n d punches. External lubrication is not as good a method as using lubricant substances to dispersein the granules. It is not considered the best solution for lubrication because it is consideredless compliant to the standard GMP rules. In addition, the assembling and disassembling of t h e t a b l e t p r e s s i s m o r e c o m p l e x . A n a l t e r n a t i v e t o a c h i e v e b e t t e r t a b l e t s , f a c i l i t a t i n g t h e compression, is to tablet the granules while they are still slightly wet, or not dried yet as we arestill considering very low moisture content, that is less than 1%. Tablets are then dried andbrought to stability by a step in static ventilated oven.Packaging for both, granules and tablets, must be operated, as already mentioned, in alow humidity environment. The critical aspects about packaging of effervescent drugs areobviously related to stability of the tablets and granules, and the main objective is to protectt h e m , a s m u c h a s p o s s i b l e , n o t o n l y d u r i n g p a c k a g i n g o p e r a t i o n s , b u t a l s o o n c e t h e y a r e packed, so as to preserve them a reasonable shelf-life. The oldest packaging for effervescentpreparations consisted of wrapping the acid and alkaline components separately, to avoid thep r e m a t u r e e f f e r v e s c e n t reaction until use. All the effervescent drugs can be packed i n individual dose units, in airtight containers made of protective aluminum f o i l o r p l a s t i c laminates. Tablets can be packed also by stacking them one by one in plastic or metal tubes,which have almost the same diameter of the tablets so as to minimize the air, which remains incontact with the tablets. The tubes must be resealed every time, after taking out each tablet.Certain tablets are also wrapped in an aluminum foil before packaging in the tube, andthis seems to be the best solution for long-term stability. Patented types of tubes containingsilica gel at the internal side of the cap are the most recent invention (22). 328 Bertuzzi For tablets that are packed in strips, it is essential that the packaging machine must havea fine control on the temperature of the welding unit, so as to obtain an accurate sealing of thestrips and avoid overheating phenomenon that could provoke release of residual water fromthe tablets (21). Figure 1 Integrated production plant. Granulation Methods

Two main granulation methods have been known for a long time. The 1911 edition of BritishPharmacopoeia reported a detailed description of the manufacturing procedure (23).Effervescent granules are made by mixing citric and tartaric acids with the medicament,and the sodium bicarbonate with the sugar when present; and then thoroughly mixing Effervescent Granulation 329

the one with the other, and granulating the resulting mixture by stirring in a pan heatedt o b e t w e e n 9 3 8 and 104 8 , passing through sieves of a suitable size, and drying attemperature not exceeding 54 8 . T h i s m e t h o d f o r p r e p a r i n g t h e g r a n u l e s y i e l d s satisfactory results, but the following alternative method has also been suggested: mixt h e s o d i u m bicarbonate, the sugar, and the medicament, pass the mixture through a number 20 to number 30 stainless steel sieve, subject the mixed acids to the same process,a n d thoroughly mix the two sifted powders. Place the mixed powders in layers o n suitable dish, pan or glass tray, heated to 75 8 to 85 8 , if required but not exceeding thehigher temperature. When the mass, after being suitably kneaded and compressed, hasassumed a uniform plastic condition, suitable for granulation, rub it to a number 5 tonumber 10 stainless steel sieve, according to the size of granules desired, and dry thegranules at a temperature not exceeding 50 8 .Only a few aspects have substantially changed in the modern methods.Two main methods can be executed with various type of granulation equipment:a. Single-step method: All the components of an effervescent formula are granulatedtogether, handled with care, running the process in a contained manner to maintaint h e s t a b i l i t y o f t h e m i x t u r e until the step is completed. This single-step method,normally carried out u s i n g d r y g r a n u l a t i o n , h o t m e l t g r a n u l a t i o n , a n d c e r t a i n processes, which are carried out via wet granulation.b. Multi-step method: The alkaline and the acid components are granulated separately,then mixed together, just before the tableting or packaging step. Usually, these arealso typical applications of wet granulation technologies. Dry Granulation Dry granulation by roller compactor is definitely the most a p p r o p r i a t e m e t h o d f o r i t s simplicity, low costs, and higher product throughput. Number of operations and requireds p a c e a r e l e s s a n d c o n s e q u e n t l y a i r v e n t i l a t i o n i s r e d u c e d . O n t h e o t h e r h a n d , n o t a l l t h e excipient grades are suitable for such a technology. More sophisticated and thus expensivegrades prepared by raw material bulk suppliers are required.An alternate process to dry granulation is direct compression of the blend of all the rawm a t e r i a l s , i n a n a t t e m p t t o a v o i d o p e r a t i n g a n d s t a b i l i t y p r o b l e m s . I t w o u l d b e t h e i d e a l process for effervescent tablet manufacturing, but its application is limited to a few cases, forexample, when the active ingredient cannot be granulated (for instance, when it is alreadyincluded in a complex like with a cyclodextrine), or contains some water of crystallization. Wet Granulation Despite some disadvantages, wet granulation is still the m o s t p r e f e r r e d m e t h o d f o r effervescent granulation.A s r e q u i r e d f o r c o n v e n t i o n a l t a b l e t s , t h i s m e t h o d a s s u r e s h o m o g e n e o u s g r a n u l e s , suitable for compression, able to provide uniform tablets either in terms of weight or activeingredient content.S i n c e , f o r t h i s t e c h n i q u e i t i s n e c e s s a r y t o u s e a g r a n u l a t i n g l i q u i d t h a t m i g h t i n t e r a c t w i t h t h e powders initiating the effervescent reaction, it is essential to handle the process with great care.A wet granulation process in two separate steps is what is mostly recommended andsuitable for conventional equipment like high-shear granulator-dryer and fluidbed processor.Acidic and alkaline ingredients are granulated separately. The two granules are then mixedtogether, just before adding the lubricant for tableting. Water, alcohols, or hydroalcoholicsolutions can be used indifferently as binding liquid also, because this process is a standardwet granulation process. It is also quite usual to granulate only one of the effervescent sourcesa n d a d d t h e o t h e r o n e i n p o w d e r d u r i n g t h e f i n a l b l e n d i n g . A l l t h e s e p o s s i b i l i t i e s a r e illustrated in the schematic of Figure 2.In certain cases, only the acid components of the formulation are granulated and thenmixed with the sodium bicarbonate, preferably if it is fine granular grade. Other additives,such as flavors and lubricants, can be then added and mixed later on. This

approach increasesproductivity and reduces costs since one granulation step has been eliminated. 330 Bertuzzi The peculiar process that distinguishes effervescent granulation consists a singlestepg r a n u l a t i o n o f a l l t h e c o m p o n e n t s o f t h e f o r m u l a t i o n , t h a t c a n b e p e r f o r m e d e i t h e r w i t h nonreactive or reactive liquids with reference to the effervescence reaction. Single-Step Granulation Single-step granulation process provides dry effervescent granules directly by granulating thea c i d and the alkaline materials together. It is possible to use only water as the g r a n u l a t i n g liquid, thus controlling the effervescent reaction to granulate, or using a nonreactive liquid,like absolute ethanol or isopropanol, but in this case, it is necessary to use a binder to get theagglomeration of the raw materials particles. Process with water. A very small amount of water, less than 1% of the batch size, can be usedto initiate the effervescent reaction. Some carbon dioxide is released, and some water too,which acts as the binding liquid as well. It takes a few minutes (from 5 to10 minutes) to obtainwet granules. The effervescent reaction rate rapidly increases and becomes difficult to stop; itmust, however, be terminated very quickly. An immediate start of the drying of the granulesw i l l c o n t r o l and stop the effervescent reaction. Single-step technology, such as fluidb e d granulator and high-shear granulator-dryer, are suitable for this purpose.In highshear granulator-dryer technology, it is possible to suddenly switch to dryingphase by creating vacuum inside the bowl, just after the granulation phase when wet granulesa r e w e l l massed. Vacuum is created in a few seconds, which immediately provokes t h e decrease of the water boiling point down to about 20 8 C. At the same time, the bowl is heatedup to provide more energy for water evaporation. In a few seconds, the water released on thegranules surface will be removed and the effervescent reaction will stop.The application of microwaves, combined with vacuum inside the bowl of the high-sheargranulator (24), can also be used to stop the effervescent reaction and dry the effervescentgranules (25).Thus, drying effervescent granules will, however, be shorter than drying conventionalgranules granulated with water, because of the very small amount of water involved in the Figure 2 Alternative granulation processes. Effervescent Granulation 331

process. However, drying still remains a critical step since it is very hard to remove even thesmallest quantity of water from hydrophilic or hygroscopic materials. Typical drying time isabout 50 minutes for 20 kg batch of effervescent granulation under vacuum. See Figure 3 forcomparison of drying of conventional and effervescent granules by vacuum technology.Drying rate for effervescent granules is lower because moisture content to remove is in arange below 2% of the batch size. Consequently, the drying time, passing from pilot scale toindustrial scale, does not increase as much as for conventional granules (Fig. 4).T h e g r e a t a d v a n t a g e o f t h i s m e t h o d f o r e f f e r v e s c e n t p r e p a r a t i o n c o n s i s t s o f t h e opportunity to install equipment with no explosion-proof requirements.A n e x a m p l e o f e f f e r v e s c e n t a s p i r i n p r o d u c e d i n 6 0 0 - L h i g h - s h e a r g r a n u l a t o r - d r y e r equipped with vacuum and tilting bowl (Fig. 5) (12).Formulation consists of: Figure 3 Drying rate of effervescent granules, compared with conventional granules. Figure 4 Drying time scale up for high-shear granulator-dryer. Anhydrous citric acid 116.6 kgS o d i u m b i c a r b o n a t e 1 5 4 . 2 k g S o d i u m c a r b o n a t e 3 9 . 2 k g A c e t y l s a l i c y l i c a c i d 5 0 k g 332 Bertuzzi

The effervescent system is granulated for first, with very small amounts of w a t e r (24 mL/kg), sprayed in very fine droplets. The acetylsalicylic acid is added later, in the finalblending, after granulation is completed.The results of three batches are reported in Table 1.T h e l o w e r y i e l d o f t h e t h i r d b a t c h i s d u e t o p r o d u c t s t i c k i n g o n t o t h e b o w l w a l l s t h a t could not be discharged. The reason why it happened is related to the set parameters duringdrying phase: in the batch number 3, drying was performed keeping the bowl static, instead of t i l t i n g i t a s i n t h e o t h e r b a t c h e s . T h e b a t c h s i z e i n a c t u a l p r o d u c t i o n w a s t h e n i n c r e a s e d t o 644 kg in 1400-L equipment.All the components of an effervescent mixture can be granulated together in a single-stepp r o c e s s i n a conventional fluid-bed granulator-dryer. Granulation occurs when water i s sprayed on the fluidized bed, initiating the effervescent reaction. The reaction is stopped whenwater is not sprayed anymore and drying phase is carried out with warm dry air. It

is quiteunderstandable that this method is difficult to control and reproduce (26). A subsequent patenta p p l i c a t i o n ( 2 7 ) d e s c r i b e s a n i m p r o v e m e n t o f t h e m e t h o d r e p r o d u c i b i l i t y , w h i c h c a n b e achieved by controlling the air humidity (it has to be less than 1 g/m 3 ), using a hydroalcoholicsolution instead of water. Further better results in controlling the effervescent reaction areachieved if spraying and drying phase are combined together.I t i s , h o w e v e r , v e r y d i f f i c u l t t o r e p r o d u c e s u c h a p r o c e s s ; t h e r e f o r e , a n a l t e r n a t i v e procedure to manufacture effervescent granules has been invented using a rotor fluid-bedspray granulator (28).Warm air, which is the only device for drying in fluid-bed technology, is not able to stopthe reaction all at once as it happens by applying vacuum inside the processing bowl. Therefore,t h e o n l y w a y t o p r o c e e d w a s t o m i n i m i z e , in some way, the contact between the two F i g u r e 5 R o t o c u b e h i g h - s h e a r granulator-dryer equipped with vacuumand tilting bowl. Effervescent Granulation 333

components of the effervescent system. An intelligent, brilliant hypothesis by Gauthier andA i a c h e ( 2 8 ) i s t o a l t e r n a t e t h e g r a n u l a t i o n o f t h e a c i d m a t e r i a l s w i t h t h a t o

n e o f a l k a l i n e m a t e r i a l s while still using a single equipment such as rotary fluid-bed system. In literature, a vitamin Cformulation is reported to explain this technique but other active ingredients can be used (29).The process consists of two or three continuous steps to produce effervescent spheres bylayering the acid components over alkaline spheres or vice versa. Binding liquid is, however, ahydroalcoholic solution where polyvinylpyrrolidone, the binder must be previously dissolved. l The first step is the granulation of alkaline components in the rotary fluid bed. In thes e c o n d s t e p , t h e g r a n u l a t i n g s o l u t i o n i s s p r a y e d i n c o m b i n a t i o n w i t h t h e acidicp o w d e r s , w h i c h d e p o s i t o n t h e a l k a l i n e s p h e r e s c r e a t i n g a n e x t e r n a l a c i d l a y e r separated by a neutral layer of the binder. As a g g l o m e r a t i o n i s c o m p l e t e d , d r y i n g phase with hot air starts without any interruptions (28). Process with alcohol or hydroalcoholic solution. A s i t h a s b e e n r e p o r t e d i n t h e p r e v i o u s example, it is sometimes preferable to granulate with a hydroalcoholic solution to initiate alighter effervescence so as to keep the reaction under a better control during the process. Use of a l c o h o l s i s i n d i s p e n s a b l e i n c a s e a b i n d e r , l i k e p o l y v i n y l p y r r o l i d o n e i s i n c l u d e d i n t h e formulation. In fact, the required water amount to dissolve polyvinylpyrrolidone, so as too b t a i n t h e b i n d i n g action, would be too much, and it would not be possible to keep t h e effervescent reaction under control.A s a l w a y s s u g g e s t e d f o r a c o n v e n t i o n a l g r a n u l a t i o n p r o c e s s t h a t r e q u i r e s u s i n g inflammable liquid, it is c o n v e n i e n t t o i n s t a l l f u l l y e x p l o s i o n - p r o o f e q u i p m e n t w i t h a n accessory solvents recovery utility that will limit the emission of vapors in atmosphere. Solventsrecovery will be more advantageous while drying under vacuum than with a fluid bed.Certain high-shear granulator-dryers are equipped to achieve 99% of solvent recovery byinstalling a tank to collect the condensate, and by bringing down the possible residual exhaustwith a shower of water. Table 1 Granules Produced with Single-Step Technology in a High-Shear Granulator-DryerYieldResults of samplesBatch codeBatchs i z e ( k g ) k g % Samplingtime (min)Moisturecontent( 0.1%)Acid neutralizingpower ( ! 185 mL0.1 N acid/tablet)pH(6.06.4)Batch 1 granulatedwith 720 mLof water(2 mL/kg)3 6 0 3 5 2 . 2 9 7 . 8 0 3 0 0 . 0 4 8 % 60 < 0.01%90 < 0 . 0 1 % 2 4 4 . 6 6 . 1 Batch 2 granulatedwith 1440 mLof water(4 mL/kg)3 6 0 3 3 6 . 4 9 3 . 4 4 3 0 < 0.01%60 < 0.015%Afterdischarge < 0 . 0 1 % 2 4 4 . 6 6 . 4 Batch 3 granulatedwith 1440 mLof water (4 mL/ kg). Note: notilting of the bowlwhile drying3 6 0 3 2 3 . 5 8 9 . 8 6 6 0 0 . 0 7 5 % 2 2 9 . 8 Afterdischarge < 0 . 0 1 % 2 4 5 . 5 6 . 2 5 334 Bertuzzi

Hot Melt Granulation Hot melt is an alternative technology to wet granulation (which is discussed in detail inanother chapter of this book). Agglomeration of the particles of a p o w d e r m i x e r c a n b e achieved by melting hydrated citric acid, so as to release the hydration water, which acts as thegranulating liquid. Once granules are formed, it is necessary to cool them to achieve the properhardness and mechanical stability. There are two different techniques: Surface hot melt granulation (SHMG) consists mixing all the raw materials together ina blender, and then drying the mix in a tray oven at 90 8 C. Water is then releasedfrom citric acid and other ingredients to form granules (30). Unfortunately batchreproducibility of this method is very low. Hot melt granulation is normally carried out in high-shear granulator-dryer with thecapability to heat up the bowl. In certain cases, the released hydration water of citricacid, starts the effervescent reaction to produce additional water, which acts as thebinding liquid. However, this process, for obvious reasons, is difficult to control.T h e s a m e p r o c e s s h a s b e e n a p p l i e d t o f l u i d - b e d s p r a y g r a n u l a t o r w h e r e l o w m e l t i n g point polymers, like PEG or polyoxyethylene glycols can also be used as binders (31). Hot Melt Extrusion Hot melt extrusion is a recent patented method to produce effervescent, specially dedicated toproduce granules having a controllable rate of effervescence (32). The formulations for thistechnology must contain a hot melt extrudable binder. Preferred binders are the PEG withm o l e c u l a r w e i g h t i n t h e r a n g e 1 0 0 0 t o 8 0 0 0 d , b u t s o m e o t h e r p o l y m e r s h a v e a l s o b e e n investigated. Binder percentage varies according to the formulation in a range of 20% to 40% of the total weight. There are two main extrusion techniques to carry out in extruders that mustbe equipped with a solid conveying zone, multiple separate temperature controllable heatingzones, and an extrusion die:a. A blend of all the ingredients, including the active ingredient of the formulation, ishot melt extruded at high temperature, to melt or soften the binder. The extrudate isthen ground or chopped to obtain effervescent granules.b. The acidic agent and the hot melt binder are formulated in the right proportions toobtain a eutectic mixture that has decreased the melting point temperature. Thisbinary mixture is separately melted; the alkaline agent is added as powder in then e x t s t e p . T h e m e l t e d m i x t u r e i s t h e n e x t r u d e d , c h o p p e d , o r g r o u n d a s i n t h e previous method.T o c o n t r o l e f f e r v e s c e n c e r a t e o f t h e f i n a l d o s a g e f o r m , i t i s p o s s i b l e t o a d j u s t s o m e parameters like the temperature and rate of extrusion. The temperature range to select can bec r i t i c a l b e c a u s e degradation of the active may occur as well as decomposition of t h e effervescent components. This range is usually from about 50 8 C to about 120 8 C.The rate of extrusion is related to the time of materials exposure to high temperature,which is usually less than five minutes.The hot melt extrusion technology, in some cases, can be run as a continuous process,having a higher throughput than batch hot melt granulation process per batch.A l l t h e p r e v i o u s s e c t i o n s p r o v i d e d

a n o v e r v i e w o f a l l t h e p o s s i b l e t e c h n o l o g i e s t o manufacture effervescent granules but how to choose the most appropriate technique for ac e r t a i n f o r m u l a t i o n . A n i n t e r e s t i n g s t u d y t o f i g u r e o u t t h e b e s t p r o d u c t i o n m e t h o d f o r effervescent tablets was presented by Laugier and Rona (Table 2) (33).T h r e e t e c h n o l o g i e s w e r e e v a l u a t e d : d r y g r a n u l a t i o n , h o t m e l t g r a n u l a t i o n , a n d w e t granulation. The choice of the process technology was strictly related to the physical propertiesof the raw materials that are particle size, density, flowability, and moisture content. Moisturecontent is definitely the most significant parameter since the powders mixture has less than0.2% to 0.3% of moisture content. It would be stable but difficult to tablet and at that point awet granulation process is required. Effervescent Granulation 335 Table2 ManufacturingProcessforEffervescentTabletsDrygranulationGranulationbyheatingWetgranulationProc essSluggingorlaminatingDirectcompressionSurfacehotmeltgranulationHotmeltgranulationGranulation drying(twosteps)Granulation drying(onestep)Numberofsteps636564Estimatedtime(hr)231022141512AdvantagesFastprocessNopro ducttransfersNogranulatingliquidNoproducttransfersBatchreproducibilityBatchreproducibilityNoproduct transfersNogranulationTotallyclosedNogranulatingliquidNogranulationShorttimeDisadvantagesRawma terialsatlowresidualmoistureRawmaterialsfordirectcompressionatlowresidualmoisture(moreexpensive) LossofeffervescenceDifficulttocarryoutDifficulttocleanDifficulttocleanDustyprocessLongtimeDifficulttocl eanHighmanpowerrequiredDustyprocessHighmanpowerrequiredNoteObsoleteRarelyapplied 336 Bertuzzi

The use of high-shear granulator-dryer has been found as the more economic and flexibleproduction method also by others (34). This technology allows using a wider range of excipientsgrades, avoiding problems related to particle size or moisture content of the raw materials. Evenif the granules produced by this technology appear finer, their flow properties are good despitethe large fraction of fines. Tableting properties are always in line within the specifications. REFERENCES 1. Homan P. Pharm J; 267(7179):911936.Available at: http://www.pharmj.com.2. Notiziario Chimico Farmaceutico (NCF) December 1984, 1922; May 1985, 2123.3 . M o l l e r P L , N o r h o l t S E , Ganry HE, et al., Time to onset of analgesia and analgesic efficacy of effervescent acetaminophen 1000 mg compared to tablet acetaminophen 1000 mg in postoperativedental pain: a single-dose, double-blind, randomized, placebo-controlled study. J Clin Pharmacol2000; 40(4):370378.4. Yanze MF, Duru C, Jacob M, et al. Rapid therapeutic response onset of a new pharmaceutical form of chloroquine phosphate 300mg: effervescent tablets. Trop Med Int Health 2001; 6(3):196.5. U.S. Patent 6,200,604, 1999.6. Rapp M. PCT Int Appl 2000.7. U.S. Patent 6,077,536, 1998.8. Handbook of Pharmaceutical Excipients, The American Pharmaceutical Association and The RoyalPharmaceutical Society of Great Britain. Washington and London, 1986:68, 7880, 263265, 234239.9. Schmidt PC, Brogmann B. Dtsch Apoth-Ztg 1987; 127:991997.10. Repta AJ, Higuchi T. Synthesis, isolation, and some chemistry of citric acid anhydride. J Pharm Sci1969; 58:11101113.11. IMA Zanchetta R&D Laboratory Archive, IMA SPA ACTIVE Division, Bolgna, Italy.12. SPI Pharma Group Fall, 2001.13. Duvall R N., Gold G. Miles Inc., 1990, 6.14. U.S. Patent 6,242,002, 1999.15. U.S. Patent 6,284,272, 1999.16. Strickland WA Jr., Higuchi T, Busse L. J Am Pharm Assoc 1956; 45:5155.17. Daher LJ. Bayer Corporation, USA.U.S. Patent, 1999:6.18. Rotthaeuser B, Kraus G, Schmidt PC. Pharmazeutisches Inst., Eberhard-Karls-Univ., Tuebingen,Germany. Pharm Ind 1998; 60(6).19. Rudnic EM, Schwatrtz JD. Oral Solid Dosage Forms. 861.20. Armandou J-P, Mattha AG. Establishment of a geographical and chronological map for relativehumidity (R.H.) in an effervescent tablets manufacturing and storage building. Pharm Acta Helv1982; 57:287289.21. Mohrle R. Effervescent tablets. In: Lieberman HA, Lachman L, eds. Pharmaceutical Solid DosageForms. Vol 1. New York: Marcel Dekker, Inc., 1980:225 258.22. http://www.desiccantcity.com/CASE_HISTORIES/History11.htm.23. The British Pharmaceutical Codex. Published by direction of the Council of the PharmaceuticalSociety of Great Britain, 1911. Available at: http://www.scocca.org/herbmed/eclectic/bpc1911/granulae.html.24. Collette News, Vol 2, Issue 1, May 2001, GEA Powder Technology Division.25. Aiache JM, Cardot JM. Utilisation des micro-ondes dans la fabrication des formes pharmacutiques.Conference at National Institute for Applied Sciences, Roeuen, France, 1999.26. J Pharm Sci 1964; 53:1524 1525.27. U.S. Patent EP 673,644, 2001.28. Gauthier P, Aiache J-M. Biopharmaceutics department, faculty of pharmacy, clermont-ferrand. Fr.Pharm Technol Eur 2001; 13(10):32, 34, 3637.29. U.S. patent 6,210,711, 1999.3 0 . Y a n z e F M , D u r u C , J a c o b M . Laboratoire de pharmacie galenique, pharmacotechnie et d e biopharmacie, universite Montpellier I, UFR de sciences pharmaceutiques, Montpellier, Fr. Diepharmazie, December, 2000.3 1 . Y a n z e F M , D u r u C , J a c o b M . Laboratoire de pharmacie galenique, pharmacotechnie et d e biopharmacie, universite Montpellier I, UFR de sciences pharmaceutiques, Montpellier, Fr. DrugDev Ind Pharm 2000; 26(11):11671176.32. U.S. Patent 6,488,961, 1999.33. Laugier M, Rona R. Pharmaceutical manufacturing and Packing Sourcer (PMPS) 2002:26 28.34. Pearlswig DM. Simulation modeling applied to the single pot processing of effervescent tablets.Masters Thesis, North Caroline State University, Raleigh, North Carolina. Effervescent Granulation 337 15 Granulation Approaches in Biotech Industry Tuo Jin, Weien Yuan, and Hui Li School of Pharmacy, Shanghai Jiaotong University, Shanghai, P.R. China INTRODUCTION Becauseoftherapidadvanceinmolecularbiology,immunology,andmicrobiologyo v e r t h e p a s t decades, biological therapeutics has become a major category of drugs in clinical applications tod a t e . W h i l e b i o l o g i c a l d r u g s p o s s e s s g r e a t a d v a n t a g e s i n t e r m s o f t h e r a p e u t i c p o t encyandtargetspecificity, their structural instability has been a long-

s t a n d i n g i s s u e i n f o r m u l a t i n g t h e s e macromolecules into convenient dosage forms. To avoid denaturing in formulation processesand shelf life, preconverting biotech drugs into solid particles is widely accepted as a useful unitoperation. However, the particle-forming processes themselves must not be hazardous to thesusceptible structures of biologicals.The objective to formulate biological agents into solid particles without compromisingdenaturing has attracted considerable research efforts and alternative approaches in recentyears, such as supercritical fluid technology, microcrystallization technology, and protein-protected microencapsulation. To summarize these microparticulate strategies for formulatingbiological products (defined as proteins, peptides, antibodies, and nucleic acids) in thisindustrial reader-targeted handbook, we would rather extend the meaning of granulationfrom the conventional understanding to an alternative extent in this chapter.Since formulating biological agents to particulate systems will mostly encounter thedifficulties associated with these macromolecules delicate nature and structural susceptibility,a mechanistic discussion regarding the instability issue of biological products will be a greathelp to discuss granulation approaches in this chapter. Therefore, we will start our story withthe physiochemical basis of biomolecules instability. THE CHALLENGES IN GRANULATING BIOLOGICAL PRODUCTSInstability due to Temperature and Moisture Temperature is a typical formulation parameter used for preparing pharmaceutical dosageforms, and concurrently a susceptible factor to cause biological macromolecules to denature.The biological functions of macromolecules, such as proteins and subunit vaccines, invariablyrely on their native conformations, which are maintained by temperaturesensitive hydrogenbonds or other noncovalent interactions between functional groups of the macromolecule.I n t h e p r o c e s s o f s p r a y - d r y i n g , f o r e x a m p l e , a p p l i c a t i o n o f a s u f f i c i e n t l y h o t g a s s t r e a m i s indispensable to evaporate water of the drug droplets in a short time (few seconds in length).When a protein is exposed to drastically increased temperature over a critical level known asthe melting temperature ( T m ) or the denaturation temperature ( T d ) , i t u n d e r g o e s a s h a r p transition and denatures. For most of proteins, such temperatureinduced structural transitionis irreversible.A strategy to avoid temperature-induced denaturing is shortening the time for proteinsto be exposed to high temperature during the drying. Temperature exposure is defined bysome researchers arbitrarily as the product of temperature and time (1). It has been reported,for example, that exposing tissue plasminogen activator (t-PA) solution at 50 8 C f o r 4 0 s e c o r at 80 8 C for 20 sec caused negligible degradation. However, increasing the protein exposure at80 8 C for 40 sec resulted in 16% (w/w) degradation (1).A s a n a s s o c i a t e d f a c t o r , w a t e r content has a great impact on thermal denaturation of proteins being formulated to or stored as powder form. When water content of a proteinloaded powder is increased, the value of T d and enthalpy of denaturation ( D H hyd ) decreasedrastically because of increased protein mobility. For example, human growth hormone (hGH)and bovine growth hormone (bGH) formulated to powder form are stable at 100 8 C when themoisture is below 1% (w/w), but turn to be highly susceptible under higher moisture (2,3).

It is of interesting to note that dispersing proteins in a hydrophilic glassy matrix maysignificantly enhance proteins resistance to temperature and moisture. Breen et al. reportedthat as long as the glassy state is maintained, proteins dispersed in solid polysaccharide matrixmay even gain stability upon absorption of moisture (4). Instability due to Freeze-Drying Process Freeze-drying, another well-used method to form powdered pharmaceuticals, consists twou n i t p r o c e s s e s : f r e e z i n g a n d d r y i n g ; b o t h c a n b e h a z a r d o u s t o b i o l o g i c a l m a c r o m o l e c u l e s . Freezing of an aqueous solution associates with ice formation, which generates shear stress tobiomolecules dissolved in the solution from two aspects. First, the sharp ice crystals formedduring freezing may pierce or squeeze biological agents; and then, the scattered ice particlesformed from a continuous aqueous solution create a large specific surface area (SSA) to adsorbbiomolecules dehydrated and phase-separated during freezing (58). The two destabilizingm e c h a n i s m s s e e m t o b e c o m p l i m e n t a r y t o e a c h o t h e r i n t e r m s o f d e n a t u r i n g p r o t e i n s . F o r example, slow freezing increased protein damage prone to phase separation of the originals o l u t i o n ( 9 ) , w h e r e a s h i g h f r e e z i n g r a t e i s a c h i e v e d a t v e r y l o w t e m p e r a t u r e s , g e n e r a t i n g smaller ice particles and thus enlarging SSA (6). Adsorption of proteins to ice surfaces easilyl e a d s to partial unfolding (10). In addition, fast cooling process itself was r e p o r t e d t o b e damaging to some proteins, such as phosphofructokinase (11), bovine immunoglobulin G (12),catalase (13), and b -galactosidase (13,14).Dehydration is another protein-denaturing factor involved in a freeze-drying process.U p o n d e h y d r a t i o n , t h e w a t e r m o l e c u l e s a s s o c i a t e d w i t h p r o t e i n s m a y t a k e o f f s o t h a t t h e water-soluble protein (most of therapeutic proteins are water soluble) may be exposed to ahydrophobic environment (15).On the basis of the mechanistic discussion above, a freeze-drying protector for proteinsshould be able to create hydrophilic environment surrounding the biomolecules thermodynamically upon freezing and dehydration. It is even better that the hydrophilic environmentforms a glassy matrix by dehydration to immobilize the macromolecules and prevent themfrom conformation changes or approaching each other. While application of surfactants and/or raising the concentration of the proteins to be lyophilized (as self-surfactant) was reported tobe an effective approach to create hydrophilic microenvironment during freeze-drying, theylack the immobilization effect and may even induce protein aggregation (15). Hydrophilic-Hydrophobic Interfacial Tension Most of particle-forming processes rely on hydrophilic-hydrophobic interfacial tension.However,macromoleculespossessinghigherstructures,suchasproteins ,arehighlysusceptibletowater-oilorwater-airinterfacialtension.Watersolubleproteinsare,ingeneral,foldedinsucha w a y t h a t t h e i r h y d r o p h o b i c a m i n o a c i d s a r e b u r i e d i n s i d e t o f o r m a h y d r o p h o b i c c o r e a n d t h e i r hydrophilic peptide chain forms the hydrophilic surface. Since protein-folding is maintained bynoncovalent interactions between its amino acids, a molecular force in the same magnitude of hydrophobic interactions, proteins (in a mobile form) may easily refold when being exposed towater-oil or water-air interfaces to reduce the system free energy (16). Being driven by thethermodynamic potential for reducing surface tension, the hydrophobic peptide chains of aprotein may move up from the core and insert into the hydrophobic phase of the system. Inaddition, the sticking out hydrophobic chains from adjacent protein molecules may associatewith each other due to hydrophobic force and result in irreversible protein aggregation, a majorproblem for packing proteins of sufficient dosage in microparticles (1719). Figure 1 describesthe mechanisms of protein aggregation and adsorption schematically. Immunogenicity due to Denatured Proteins Aggregation and denaturation do not only compromise proteins bioactivity, but also associatew i t h severe consequences. Denatured or aggregated proteins are often a n t i g e n i c a n d sometimes result in severe immunogenicity and serious clinical issues.

Neutralizing antibodiesresulted from denatured proteins cannot only attenuate the efficacy of the protein drug butalso induce significant side effects if the antibodies crossreacting with patients endogenousproteins. For example, protein-induced neutralizing antibodies to erythropoietin (EPO) result Granulation Approaches in Biotech Industry 339 in red cell aplasia (20) and induced antifactor VIII (FVIII) antibodies worsen the pathologyassociated with hemophilia (21). While immunogenicity induced by denatured or aggregatedproteins has been a long-standing concern, there has not yet been a regulatory guideline fora c c e p t a b l e l e v e l s o f s u c h i m m u n e r e s p o n s e s . I n t h e d e v e l o p m e n t o f n e w p r o t e i n d e l i v e r y systems, avoiding any increased protein aggregation, as compared with already approvedproducts, is crucial. Encapsulation Efficiency Encapsulation efficiency is an important parameter for assessing microencapsulation processesof biological therapeutics such as proteins. For microencapsulation using the so-called doubleemulsion method, proteins in solution state may easily leak to the outer aqueous continuousphase, resulting in unacceptable low encapsulation efficiency (22,23). Replacing the innerprotein solution with solidified protein particles may substantially improve encapsulatione f f i c i e n c y , b u t p r o t e i n p a r t i c l e s s t i l l h a v e t h e c h a n c e t o c o n t a c t w i t h t h e o u t e r a q u e o u s continuous phase, leading to considerable loss of proteins. How to secure higher encapsulationefficiency is another challenge needing to be addressed. Chemical Basis of Protein Denaturing There are many mechanisms responsible for the instability of biological therapeutics uponformulating particulate systems from chemical, biological, and physical aspects. Among thesem e c h a n i s m s , i r r e v e r s i b l e c o n f o r m a t i o n c h a n g e , i n c l u d i n g a g g r e g a t i o n , is the mechanismlacking in peptides and responsible for the deferred s u c c e s s t o c o m m e r c i a l i z e a d v a n c e d particulate dosage forms of proteins than that of peptides and small molecules. Therefore, wewill focus our instability discussion on the noncovalent chemistry.The energy barrier for protein conformation alteration in solution is in the range of 5 to20 kcal/mol (24,25), which is much lower than covalent changes ( > 100 kcal/mol) but similar tothose of water-oil interfacial tension and hydrophobic interactions (24). To prevent proteinsfrom denaturing (i.e., irreversible conformation changes), a particulate formulation processshould ensure proteins to be maintained with reduced chemical potential (free energy) or to beblocked by an increased the energy barrier for conformation transfer (Fig. 2A, B). For example,loading water-soluble proteins in a solid hydrophilic matrix with abundant hydroxyls maysignificantly reduce the proteins free energy and at the same time increase the kinetic energybarrier for their mobility (Fig. 2C). Carpenter et al. reported that while loading proteins in apolyethylene glycol (PEG) solution of low concentration may cause an increase in the proteins D G because of the unfavorable PEG environment, the PEG solution prevented proteins fromaggregation by resulting in a shrinkage of protein molecules that raised the energy barrier fort h e p r o t e i n m o l e c u l e s t o e x t e n d t h e i r h y d r o p h o b i c d o m a i n s t o e a c h other (26). The sameauthors also found that increasing PEG concentration, o n t h e c o n t r a r y , r e s u l t e d i n p r o t e i n precipitation out of the solution and facilitated protein aggregation. This phenomenon may beexplained in that low-concentration PEG only slightly raised the proteins free energy ( D G ) butsignificantly prohibited the protein-protein contact, while for high PEG concentration, the D G increase was substantial for protein molecules to separate out and aggregate (Fig. 2D, E). Phases e p a r a t i o n o f a p r o t e i n o u t o f a c o s o l u t i o n w i t h P E G a s a f u n c t i o n o f t e m p e r a t u r e a n d P E G concentration was reported by Morita et al (27). Figure 1 Protein aggregation and adsorption. 340

Jin et al.

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