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DEFINITION: Characterization of physical, chemical and mechanical properties of new drug molecule in order to develop safe, effective,and stable dosage form. GOAL OF PREFORMULATION: To formulate an elegant, safe, efficacious dosage form with good bioavailability. To formulate new dosage form of already existing drug. Determination of all the properties of drug and the best suitable dosage form for the drug molecule.

Pharmaceutical factor mainly include those parameters of drug which affect the final dosage form manufacturing process like….. Flow property Density Compressibility Hygroscopicity Electrostatic charge Osmolarity Rheology Wettability Syringabilty

(A) Introduction

Flow property is an important factor that determines the fate of drug molecule. Sufficient flow is required for uniformity of dosage form. So it is necessary to judge the flow of material in preformulation stage of the dosage form. However extreme increase in flow may improve weight uniformity but may reduce content uniformity through increased segregation.

(B) Method of determination  By Angle of repose  By hopper flow rate  By bulk density  By angle of spatula  By vibrational capillary method


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It is a stable instrument which at best can only indicate comparative flow properties. The formation of sharp cone would mean poor flow property while a good spread would indicate a superior flow property.

• An instrument for measuring flow property. • It can discriminate between the samples that differ by 1% Moisture. • Important for optimizing granulation because moisture variation have significant impact on final product quality.

2007.  The amplitude and frequency of vibration is controlled by computer and mass of powder discharged from vibrating capillary tube is measured by digital balance.  The mass flow rate is measured by digital processing. [Chemical Abstract .Jan. NEW MEASUREMENT SYSTEM TO EVALUATE POWDER FLOWABILITY BASED ON VIBRATIONAL CAPILLARY METHOD:  Evaluates flowability of micrometer sizes particles under actual flow condition. 146:9806] .

 Angle of repose is measured by the equation: tanθ=h /r here.because  of their relationship with interparticle cohesion. It is a maximum angle between the surface of a pile of powder & horizontal plane. h=height of conical heap & r=radius of horizontal plane of powder .Angle of Repose  Indirect method of quantifying powder flowability.

DETERMINATION OF ANGLE OF REPOSE Static angle of repose Fixed height cone. Crater type . Tilting table Rotating cylinder Rotating Drum Dynamic angle of repose Drained angle of repose Ledge type. Fixed base cone.

RELATION BETWEEN ANGLE OF REPOSE & TYPE OF FLOW & TYPE OF POWDER Angle of repose <25 25-30 Type of flow Excellent Good Type of powder Non cohesive Non cohesive 30-40 >40 Passable Very poor Cohesive Very Cohesive .

5 >1.HAUSNER’S RATIO  This is a simplex index that can be determined on small quantities of powder.5 Type of Flow Good flow Moderate Poor flow . Hausner-ratio= Tapped densityβ max) poured density(Pβ min) Hausner ratio <1.25-1.25 1.

(C) FACTOR AFFECTING FLOW PROPERTY     Particle size and Particle size distribution Particle shape and Surface roughness Density and Porosity Hygroscopicity  Electrostatic charge .

(D) IMPROVEMENT OF FLOWABILITY         By addition of glidant By addition of fine or by size reduction By wet granulation By removing static charge By densification with the help of slugging Using auger feed equipment By addition of flow activator. Eg.g. . silicon coated talc or Nabicarbonate  By altering process condition like vibration assisted hopper or forced feeder  By use of spray drying : Advantose 100 maltose powder has improved flow property than MCC by using this process. e. MgO By use silicon treated powder for Hygroscopic & moist powder.

DENSITY (A) INTRODUCTION : The ratio of mass to volume is known as density.2.)/ Volume (ml.may affect compressibility. disintegration. Density = Mass (gms. tablet porosity. dissolution .)  TYPES OF DENSITY : (a) Bulk density (b)Tapped density (c)True density (d)Granule density :.

(B) Method of Determination Parameter Method 1. Tapped Density 3. True Density Measuring cylinder Mechanical Device Mercury Displacement Helium densitometer (Helium Pycnometer) Mercury Instrution Porosimetry . Bulk density 2.

which is operated for a fixed numbers of taps(about-1000)untill the powder bed volume has reached a minimum. Tapped density measurement:  It is determined by placing a graduated cylinder containing an known mass of drug or formulation on a mechanical tapper apparatus.Bulk density measurement :  It is determined by pouring presieved (40-mesh) bulk drug into a graduate cylinder via-a large funnel and measuring the volume and weight. .

typically helium. As an alternative. the floatation method is simple to use and inexpensive. displacement of a gas (pycnometry). Gas pycnometers rely on the measurement of pressure changes. or deleted from. the test cell.Measurement of True Density:        True density can be determined using three methods: displacement of a liquid. but needs relatively expensive instrumentation. added to. The liquid displacement is tedious and tends to underestimate the true density. or floatation in a liquid. Displacement of a gas is more accurate. as a reference volume of gas. .

October 2007) .An improved method for fast online measuring of density of solid substances: A densitometer for measuring of bulk density of solid & liquid consists of one vibrator means. to support pre-weighed samples to be tested in container with predefined shapes on this vibrator & atleast one ultrasonic sensor operatively connected to control unit such that sensor is adapted to transmit and receive reflected ultrasonic pulses to ascertain density of samples utilizing the said values of the fill levels of samples in containers. (chemical abstract .

if both drug or drug & excipients have different density then creates problem of segregation (demixing). (Review article.8g/cm3 & 1. sept-oct. compared GI transit time of multiple unit formulation of densities 2. E.2008) . IJPS.Bulk density/ Tapped density Hausner ratio = Tapped density / Bulk density (D) IMPORTANCE  In case of combination therapy or physical mixture . decide size of capsule formulation.  Devereux et.g.5g/cm3 & found significantly delayed gastric emptying of heavier pdt. Suppositories.  Important in decide size & type of processing CORRELATION WITH FLOWABILITY Carr’s index = Tapped density.

Useful empirical guide is given by the Carr's compressibility index.  . here compressibility is misnomer since compression is not involved.3. %compressibility = Tapped density – bulk density * 100 Tapped density  Neumann and Carr developed a simple test to evaluate flowability of a powder by comparing the poured (fluff) density (Pβmin)and tapped density (Pβmax) of a powder and the rate at which it packed down. COMPRESSIBILITY (A)  INTRODUCTION Compressibility is the ability of powder to decrease in volume under pressure.

NO 1 2 3 4 5 % COMPRESSIBILTY RANGE 5-15 12-16 18-21 23-28 28-35 FLOW DESCRIPTIONS Excellent (free flowing granules) Good ( free flowing powder granules) Fair to passable ( powder granules Poor ( very fluid powder) Poor ( fluid cohesive powder) 6 7 35-38 >40 Very poor ( fluid cohesive powder) Extremely poor ( cohesive powder) .Relationship between powder flowability and % compressibility SR.

 2.(B) The characteristics Of material may be :1. PLASTICITY Plastic material are capable of permanent deformation. FRAGMENTABILITY  If material is fragmentable. also exhibit a degree of brittleness (fragmentability)  But plastic material will get bonding after Viscoelastic deformation. neither lubricant mixing time nor dwell time affecting the tablet strength. .

. it rebound when compression force is released. 4.g.3. PUNCH FILMING [STICKING]:  This may lead to chipping of tablet.  Elastic material may lead to capping & lamination  They require wet massing to induce plasticity or plastic tableting material. ELASTICITY E. acetyl salicylic acid  If material is elastic. paracetamol.

Pre compression.(C) METHOD OF IMPROVEMENT  If plastic material add fragmentable excipient e. By using high excipient ratio..  If Elastic material  If sticky material . By change in salt form.g. By wet massing. Lactose . By plastic tableting material Wet granulation . By addition of Mg-stearate.

NPTAB Technology: Innovative technology combining pellet coating with direct compression.  Active drug is sprayed on carrier containing sugar sphere & these layered spheres are directly compressed.  “ Multifunctional co-processesed excepients with improved compression properties are used for improved tabletting performance. No.2009.3: 63288g) .151.” (CHEMICAL ABSTRACT. July 20.

It is the hygroscopic substance which absorb moisture from air and they can be liquefied by partially or wholly forming solution.4. HYGROSCOPICITY (A) INTRODUCTION  Hygroscopicity: .a substance which loses water to form a lower hydrate or become anhydrous is term as efflorescent.  Efflorescent: . .It is the tendency of material to absorb moisture from atmosphere & be dynamic equilibrium with water in the atmosphere.  Deliquescent: .

.List of examples: Hygroscopic & Deliquescent  Ephedrine  Hyoscymine  Phenobarbital  Pilocarpine  Physostigmine Efflorescent atropine cocaine codeine scopolamine caffeine Glycerinated gelatin & PEG base of suppository are hygroscopic in nature.

(B) METHOD OF DETERMINATION    To carry out study.   . & KF titration Versaperm has deviced a WVTR meter that can measure the permeability of package to moisture in as little as 30 min. sample of compound are accurately weighed into container and placed at various humid condition for period of upto 2 weeks. GC. If Weight gain – Deliquescent or Hygroscopic If Weight loss – Efflorescent Also determined by that humidity can be accurately controlled.

 Affects chemical stability of hydrolysable drug.  Important in aerosol.  .  It affects compression characteristic .  It also affects compaction.(C) IMPORTANCE: It affects the flow property. granulation & hardness of final tablet.

2. foil.  Use of Ion-exchange resins. vol.  Add finely powdered adsorbents like MgO or Mg carbonate. ( Journal of Pharmaceutical Research.No.  Store in desiccant. use anhydrous salt.8. blister. Apr 2009:112-115) .  Perform the entire tableting operation under controlled humidity condition. Complexation of Ranitidine with Indion234.  For efflorescent material . glass bottle. Eg.(E) METHODS OF IMPROVEMENT  For granulation of hygroscopic material use nonaqueous solvent.

Galen IQ. increasing load.Examples:  Starch is hygroscopic . thus providing excellent stabilization for moisture sensitive active drugs.146:9803) . “ The length of stick slip event increases with moisture content.slip mechanism of powder flow: It is pulsatile flow of granular material. Problem associated with Hygroscopic material: Stick. A new multifunctional excipient.but on pregelatinization it exhibits  lower propensity for moisture. It causes problem in die filling for tableting. etc .” (Chemical Abstract vol.

compressing. spray drying & congealing. pan coating & packaging can induce static charge. rubbing. ELECTROSTATIC CHARGE A) INTRODUCTION: Electrostatic charges are the consequence of classic attraction & repulsion effect between the charges. Electrostatic charge is produced:      By separation of positive & negative charge By mechanical impact By friction between two surface By rupturing of particle By separation of solid & liquid surface Pharmaceutical processing procedure such as mixing. sieving. .micronizing. milling.5.

gives detailed charge profile of MDI aerosol particles. ELPI(13-stage Electrical Low Pressure Impactor). . This has practical application on lung deposition of MDI aerosol.(B) METHOD OF DETERMINATION:  INOSTAT.   Electrostatic testers which consists of electrostatic voltage sensing probes. when material is flowing from hopper. measures negative charge on the surface in volts/cm.

g.    . e.g.PCM Fine crystalline form >Crystalline form > Granules with EC > Granules with starch..Acetaminophen with mannitol(+++) > SDL(++) > Mg stearate(+) Effect of Particle size.. e. Effect of tablet excipient. Effect of moisture.C) FACTORS AFFECTING STATIC CHARGE  Effect of particle shape.

(D) IMPORTANCE In preformulation of suspension .  Affects flow property of powder.  It may damage tablet machine.  .  It may affect compression coating.  For thermal stability of emulsions.  Affects mixing process.

. Store under influence of air with sufficient humidity. By granulation. Super critical fluid technology.E) METHOD OF REMOVAL OF STATIC CHARGE       Addition of diluents or lubricant. Use crystallization method using more polar solvent. Eg Aerosol. Surface coating of particle with amphiphilic substance of o/w type. Example: Poloxamer reduce electrostatic charge on the surface of polystyrene.

 Isoosmotic: when two different solutions are separated by semipermiable membrane have same osmotic pressure so called as isoosmotic.6.  Isotonic: when two different solutions are separated by biological membrane have same osmotic pressure so called as isotonic. OSMOLARITY A) INTRODUCTION  It is a colligative property DEFINITIONS: Osmoles : No.  .  Osmolarity : osmoles or milliosmoles per liter of solution. of osmotically active particles in solution.  Osmolality :osmoles or milliosmoles per kg of solvent.

 ( United States Patent 4455864 )  Clifton nanolitre osmometer .P of solution.(B) Method of Determination Osmolality should be measured carefully with a vapour pressure or freezing point osmometer or cryoscopic osmometer.  Membrane osmometer: This invention is directed to a membrane osmometer for direct measurement of osmotic pressures.  Vapour pressure osmometer: Measures concentration of osmotically active particles that reduce V.

(C) IMPORTANCE Normal serum osmolality to be 285 mosmol/kg.  Maintain osmolarity by 1%variation.  It should be proper maintained in   Oral nutrition fluid  Peripheral infusion  Parenteral product  Ophthalmic preparation  Administration of Paratonic solution can lead to crenulation or lysis of RBC. .

(B) TYPE OF FLOW:  Newtonian flow  Non Newtonian flow . RHEOLOGY (A) DEFINITION It describes flow of liquid and/or deformation of solid under stress.7.

water. E. NEWTONIAN FLOW It is a flow in which a direct proportionality exists between shear stress and shear rate. simple organic liquid & dilute suspension . Glycerin.g. .

viscosity decreases and disarranged molecules begin to align their long axes inline of molecules. Eg. Na-CMC. Dispersion of tragacanth. Aq. NON NEWTONIAN FLOW Where there no direct relation between shear stress and shear rate.  There are three type (1) PLASTIC FLOW It is the Newtonian system at shear stress above yield value. PVP. Flocculated suspension.As applies shear stress increasing. E. increasing in resistance to flow as viscosity increases. Eg. deflocculated suspension of Mg magma . (2) PSEUDOPLASTIC FLOW Here yield value not associated . (3) DILATANT FLOW Opposite to pseudoplastic flow Increase in the shear rate.g.


For analysing protein solution rheology.Measures viscosity as a function of rate of shear & temp at a high rate of shear.  Instron Capillary Rheometer :. .(C) DETERMINATION OF VISCOSITY  Capillary viscometer  Falling sphere viscometer  Cup and bob viscometer  Cone and plate viscometer  Brook field viscometer  Ultrasonic Shear Rheometer :.

D)IMPORTANCE [1] FLUID  For mixing  For particle size reduction of disperse system  Passing though orifice. pouring. packaging in bottle. passing though hypodermic needle.  Flow though pipe  Physical stability of disperse system [2] QUASISOLIDS  Spreading and adherence to skin  Removal from jar  Capacity of solids to mix with liquid  Release of drug from base .

 Application :. Parental suspension containing 40-70% w/v of procaine penicillin G  . conc.g. means gel to sol to gel.for stability of suspension  e. [4] PROCESSING  Production capacity of the equipment  Processing efficiency  THIXOTROPHY: In thixotropy apply shear stress convert gel – sol & remove shear stress convert sol – gel.[3] SOLID Flow of powder from hopper and into a die cavity in tableting or in encapsulation  Packagability of powder or granules solids.

WETTABILITY (A) INTRODUCTION  Wettability of a solid is an important property with regards to formulation of solid dosage form.  Adsorption at solid surface is involved in wetting & detergency.  It may influence granulation of solid. .8. penetration of dissolution fluid into tablet and granules & adhesion of coating material to tablet.

Contact angle – 1800 – No wetting . . Contact angle – 00 – complete wetting. By Draves test: (C) IMPORTANCE:   Crystal structure can influence the contact angle.(B) METHOD OF DETERMINATION :   By contact angle: The contact angle is the angle between a liquid droplet and the surface over which it spreads. Problems associated with Wettability of powder are poor dissolution rate & low adhesion of film coating.

Al Mg silicate & colloidal silica (water insoluble). It displaces air & replace it with liquid phase.(C) IMPROVEMENT  Mixing with hydrophilic excipient like Na CMC (water soluble) and bentonite.   . Wetting of powder by non aqueous solvent can be enhanced by certain lanolin derivative. Use of wetting agent (HLB value 6-9) which acts by lowering contact angle.

so. This phenomenon happens when a liquid dosage form passes through a syringe. we can arrange the degree of syringabilty in following way: Plates > Needles > Cubes > Prisms . they can’t pass through the syringe easily. no friction observed & can easily pass through the syringe. The flow of material is dependant on size & shape of crystals of material.9. So. While in case of needles or cubes or prisms . SYRINGABILTY       It is more mechanical property rather than pharmaceutical property. Plates can easily move one over another .

I.2nd edition Leon Lachman. 93:646(2004). Aulton.Kanig . 60:548(1971) S. the science and practice of pharmacy. Journal of Pharmaceutical Science.8. Palermo Journal of Pharmaceutical Science. Lieberman. the theory and practice of industrial pharmacy .REFERENCES                    Alfred Martin. 1999. Journal of Pharmaceutical Research.4) G. Lieberman . Jan 2004 . H. Pharmaceutical dosage form-parental Dosage form volume 1 Michael E. A. 4thedition. 14 Marcel Decker Leon Lachman .T. 21st Edition Encyclopedia of pharmaceutical technology vol. Dec-Jan 2003) Chaquan Sun.Dold.L.Summer et al.Gold et al. vol. B. Pharmaceutics: The science of dosage form design ELBS publication Remington. 2009). Manufaccturing chemist( Jan 2005.No. H. Rhodes Drug and Industrial Pharmacy.Dawoodbhai C.H. physical Pharmacy. New Delhi. Pharmaceutical dosage form –tablet volume 1 Leon Lachman. J. 55:1441(1966) G. B. Danish et al. 15: 1577(1989) Journal of pharmacuetical science( April 1999.vol. 57:667(1968) F.Q. 12) Indian Journal of pharmacuetical science (Sept-Oct 2008) Chemical Abstracts. Journal of Pharmaceutical Science.94 . A.D. Waverly. 54:311. . Journal of Pharmaceutical Science. Journal of pharmacuetical science( Dec 2005 vol. 88 no.T. Lieberman.2(Apr. Journal of Pharmaceutical Science.