oPMIG Preformulation John W. Pi McNeil Can Products © 1982 FMC CorporationaPLMIG, Section 5 Contents Introduction Physical Description Microscope Examination Particle Size Partition Co-efficient and Dissociation Constant (pKa) Polymorphism Solubility Dissolution Stability > Excipients Membrane Permeability Summary BibliographyPMG. Introduction Preformulation, in the broadest sense, éncompass- es all the activities and studies required to prepare an active pharmacological substance into a form suitable for administration to humans. Although preformulation testing has been “formalized” in many firms in the recent past, the activities of the preformulation group, out of necessity, have al- ways been carried out. The extent and sophis- tication of modern preformulation studies are a reflection of advances made in all aspects of phar- maceutical sciences. Significant impact has re- sulted from improved techniques for qualitative and quantitative measurements as well as it creased demand due to regulatory requirements. The object of formulation activities is to prepare a drug delivery system or dosage form to produce an optimum effect, However, the active substance must always be stable for a reasonable period of time in the formulated state and capable of being produced on highiy efficient manufacturing equip- ment. Therefore, pharmaceutical product develop- ment consists of formulating an active pharmaco- logical agent to a convenient dosage system which is manufacturable, stable, and bioaveilable. In the early stages of the pharmaceutical industry, ease of manufacture and palatability, along with the characteristic known as “pharmaceutical ele- gance,” were the prime considerations in dosage form development. The preformulation studies at this time largely consisted of organoleptic tests such as taste and odor. The results of such tests frequently necessitated sugar-coating the dosage forms. The concept of stability became very impor- tant with the advent of mass-produced medicines which would be maintained on shelves and/or ware- houses for long periods. The great effort which centered around evaluation and prediction of sta- bility is evidenced by the many articles published in pharmaceutical literature during the middle of the 20th Century. The criteria for stability during this period generally became chemical stabilit whereas previously, physical stability was the ma- jor consideration, i.e., color changes, sedimenta- tion, and caking. This requirement for chemical stability highlighted the importance of preformula- tion work. In addition, this need for stable products initiated many of the early studies of kinetics and reaction mechanisms of important pharmacological agents. This basic information was necessary in order to stabilize the product and/or prevent in- compatibilities with pharmaceutical excipients. The next important criteria to have a major impact ‘on dosage form development was the concept of bioavailability. The importance of bioavailability was recognized in the 1950's and was continually extended during the decade of the 1960's. This concept, spurred by development of sophisticated analytical instrumentation which permitted blood level studies of low dose potent drugs, demanded a formalization of a preformulation program. This was a necessity to avoid costly development pro- grams on inadequate or inappropriate forms of the active substance and/or drug delivery system. Rarely is a drug of itself used in therapy. Drugs must be administered in pharmaceutical dosage forms, and it is these drug products that are pre- iscribed and dispensed to a patient. Drug products should have adequate stability, uniform composi- ion, preservation protection, and proper packag- ng. Timely and thorough preformulation research allows for easier and more efficient formulation de- yelopment. Preformulation work, in most cases, begins after a ompound is identified as a candidate for human sinical testing. At this point, requests for dosage jorms are submitted to the Pharmacy Research and Development Department. The depth of the nitial studies will depend, to a large extent, on the availability of the initial drug supply and the in- fended route of administration. Some of the most important properties which must be highlighted are particle size, solubility, partition co-efficient, disso- tion characteristics, crystal form and size, and stability. The importance of these parameters can depend to a great extent on the intended use of the drug. For instance, if no liquid dosage forms are contemplated, solution stability is far less im- portant than in most cases where parenteral or oral solution administration is the desired route. As stated earlier, preformulation studies have al- ways been necessary. However, the development of a formal or planned preformulation program is relatively new. Whether this is accomplished by a group in the pharmaceutical companies specifically charged with preformulation or whether the infor- mation is gathered in various areas of the com- pany and collated by the formulation depariment is inconsequential. There are advantages and disad- vantages to both systems. However, the important fact is that the required information is obtained and transmitted to the formulator prior to extensive for- mulation work in order to avoid serious delays and/or major changes in formulation during exten- sive clinical studies. At the time preformulation studies are initiated, the medicinal chemist has already evaluated the com- Pound as to structure and purity and selected Physical-chemical characteristics, such as melting olnt. This information, in conjunction with the In- fended use, is the basis for the preformulation The following is a description of the types of stud- ies which should be considered in a preformulation program. The information obtained and some of the more important experimental techniques em- ployed are also discussed. Ph sical Description It is important to have a formal physical description of the early batches of drug substance for compar- ison with later submissions. This includes color, ‘odor, and taste, All of these organoleptic proper- ties can be important in dosage form development considerations, depending on the intended route of administration and dosage forms. For instance, a foul tasting substance intended for use in a ped atric suspension or solution form may require de- velopment of a less soluble salt or utilization of coating techniques, Microscope Examination Microscope examination, including SEM photo- micrographs of the raw material, is an important facet of preformulation testing. This gives an indi- cation of particie size and range of the raw mate- rial as well as crystal habit. Photomicrographs of the initial and subsequent lots can provide impor- tant information should difficulty arise in process- ing due to some change In the crystal or particle characteristics of the drug on scale-up and/or changes in synthesis. Particle Size A number of physical and chemical properties of drug substances are affected by the particle size distribution. Drug dissolution rate, bioavailability, content uniformity, taste, texture, color, and stabil- ity are all dependent to varying degrees on particle size distribution of pharmacological agents. In ad- dition, properties such as flow characteristics and sedimentation rates, arnong others, are also im- portant factors related to particle size. It is essen- tial to establish at an early time if a relationship exists between the particie size of the active ingre-dient and the important formulation characteristics. Of special interest is the highly important and well documented effects of particle size on absorption of certain drugs. For example, particle size has been shown to significantly influence the oral ab- sorption profiles of griseofulvin, nitrofurantion, spi- ranolactone, and procaine penicillin. Satisfactory content uniformity in solid dosage forms depends to a large degree on particle size and distribution of the active ingredient, particulariy for drugs with high potency with resulting low active to excipient ratios. It is obvious that the particle size and distri- bution of active agents must be optimized, moni- tored, and controlled where applicable. It is crucial that the particle size requirements be established in the early preformulation stage to insure develop- ment of formulations with acceptable bioavailabil- ily, stability, and ease of manufacture. There are many methods available to evaluate particle size and distribution; however, only those used extensively in the pharmaceutical industry will be considered here. These are sieving or screening, microscopy, sedimentation, and stream scanning. For powders in the range of approximately 44 mi- crons and greater, sieving or screening is the most widely used method of size analysis. The difficulty with using this method early in the preformulation program is the requirement of a relatively large sample size. There are other disadvantages to this technique, such as blinding due to clogging of a screen. Use of an Air Jet sieve or Sonic Sifter may overcome these disadvantages. The main advan- tage of the sieve method is simplicity, both in tech- nique and equipment requirements. Optical microscopy is frequently the first determi- nation of particle size and shape on a new prod- uct. This is usually a qualitative assessment since quantitation by the microscope technique is tedi- ous and time consuming. A key element in utilizing the microscope for particle size determination is preparation of the slide. it must be representative Of the bulk of the material and be properly sus- pended and thoroughly dispersed in a suitable liq- uid phase. in order to do a quantitative particle TEMG. size evaluation, the particles counted should be in the range of 1,000. Sedimentation techniques utilize the relationship between rate of fall of particles and their size. A number of classical techniques, based on sedi- mentation methods, utilizing devices such as the Andreasen pipet or recording balances that contin- uously collect a settling suspension, are available. ‘These methods share the disadvantage of the mi- croscope technique in that itis tedious to obtain the data and precautions in experimental tech- niques must be observed. Proper dispersion, con- sistent sampling, temperature control, and other experimental variables must be carefully controlled in order to obtain consistent and reliable results. Stream scanning is another valuable method for determining particle size distribution of powdered drug substances. This technique utilizes a fluid suspension of particles which pass the sensing zone where individual particles are sized, counted, and tabulated. Sensing units may be based on light scattering or transmission as well as conduc- tance. Two popular units in the pharmaceutical in- dustry for this purpose are the Colter Counter and Hiac Counter. Both units electronically size, count, and tabulate the individual particles thal pass through the sensing zone. This technique has ob- vious advantages in that data can be generated in a relatively short time with reasonable accuracy. Thousands of particles can be counted in seconds and used to determine the size distribution curve. All stream scanning units convert the particles to effective diameter, and therefore have the short- coming of not pravicing information relative to particie shape. Nevertheless, stream scanning methods are powerful tools and can be used for evaluation of such parameters as crystal growth in suspension formulations. Partition Co-efficient and Dissolution Constant (pKa) _ In order to produce a biological response, the drug molecule must first cross a biological membrane. The biological membrane acts as a lipid barrier to 3nost drugs and permits the absorption of lipid sol- ible substances by passive diffusion while lipi it joluble substances can diffuse across the barrier mnly with considerable difficulty, if at all. The inter- elationship of the dissociation constant, lipid solu- lity, and pH at the absorption site and absorption +haracteristics of various drugs are the bases of he pH-partition theory. rhe ollwwar partition co-efficient is a measure of he molecule’s lipophilic character. A measurement f this characteristic, particularly if a series of ho- nologous agents are being considered, can be very important in estimating the potential efficiency f the agent as a drug candidate. Methods of de- ermining the partition co-efficient are relatively straightforward. The drug is added to a mixture of 1 pair of immiscible solvents. For example, oc- anol/water is a popular combination, and concen- ration at equilibrium in each of the solvents is neasured and the partition co-efficient calculated. Specifically, the amount of drug in the lipid portion s divided by the amount of drug in the aqueous portion. Partition co-efficients can also be estimated by farious chromatographic procedures, for example, hin layer chromatography \ large number of drugs are either weakly acidic yr weakly basic compounds. Accordingly, depend- ng on the pH value, the compound exists in solu- ion phase as ionized or un-ionized species. The in-ionized species are more lipid soluble and lence more likely to elicit the pharmacological re- sponse. The determination of the degree of ioniza- ion or pKa value of the drug substance is an im- yortant physical-chemical characteristic relative to valuation of possible effects on absorption from jarious sites of administration. Dissociation constant or pKa is usually determined py potentiometric titration. -olymorphism _ Another important factor having a bearing on the sharmaceutical and biopharmaceutical properties of a drug substance is the crystal form of the agent. The ability of a substance to exist in more than one crystal form is a property known as poly- morphism. Polymorphic forms usually exhibit differ- ent physical-chemical properties, including metting point and solubility. At any temperature and pres- sure, only one polymorphic crystal form of a com- pound will be stable, Under the same conditions, another polymorphic form will convert to the stable form. If this conversion to the more stable form is, relatively slow, a specific polymorph may have ad- vantages as far as pharmaceutical properties are concerned. Such a slowly converting form is known as a metastable form and can, in many cases, be considered stable for pharmaceutical purposes. The occurrence of polymorphic forms with drugs Is relatively common, and it has been estimated that polymorphism is exhibited by at least one-third of all organic compounds. For certain classes of drugs, the instances of polymorphism are even greater. For example, approximately one-half of the 22 barbituric acid derivatives and 11 of the 16 steroids that were investigated displayed poly- morphism. At least five distinct crystal forms of cortisone acetate have also been reported. Aside from the polymorphic forms in which com- pounds may exist, they also can occur in non- crystalline or amorphous forms. The energy re- quired for a molecule of drug to escape from a crystal is much greater than required to escape from an amorphous powder. Therefore, the amor- phous form of a compound is always more soluble than a corresponding crystal form and may exhibit correspondingly different biopharmaceutical and pharmaceutical properties. An example of such an effect has been demonstrated for the various forms of the antibiotic novobiocin. ttis obvious that many organic medicinal com- pounds which are capable of existing in more than one crystal form are known. The resulting variation and physical-chemical properties associated with differences in crystal form may be of considerable pharmaceutical importance. In addition to true polymorphic forms, many or-aFlMIG ganic medicinal compounds can form solvent addi- tion compounds, or solvates. When water is the solvent associated with the drug moiety, the sol- vate form is called a hydrate. As with other orystal modifications, the physical-chemical properties of a solvated form may differ significantly from that of a nonsolvated form of the compound. For example, significant differences in the dissolution rate of the anhydrous and hydrated forms of caffeine, the- ophyliine, and glutethamide have been observed. An interesting exampte of the differences in biolog- ical availability between an anhydrous and hy- drated form of a substance was noted for the am- photeric penicillin ampicillin. Itis clear from the foregoing that the evaluation of crystal structure, polymorphism, and solvate form is an important preformulation activity. The changes in crystal characteristics can influence bioavailability, chemical and physical stability, and have important implications in dosage form process functions. For example, it can be a signifi- cant factor relating to the tableting processes due to flow and compaction behaviors, among others Various techniques are available for the investiga- tion of crystal properties. The most widely used methods are hot stage microscopy, thermal analy- sis, infrared spectroscopy, and x-ray diffraction. ‘An extremely important physical-chemical property of drug substances is solubility, especially aque- ous system solubility. The drug must possess some limited aqueous solubility for therapeutic effi- cacy. In order fora drug to enter the systemic culation to exert a therapeutic effect, it must first be in solution. Relatively insoluble compounds: often exhibit incomplete or erratic absorption. If the solubility of the drug substance Is less than re- quired for solubility of the recommended dose in the gastrointestinal tract, consideration must be given to improve its solubility. The methods to ac- complish this will depend on the chemical nature of the drug and the type of drug product under consideration. For example, if the drug substance is acidic or basic, solubility may be influenced by changes in pH. The solubility of weakly acidic and basic drug substances can be predicted as a func- tion of pH by application of the law of mass action, There are many drug substances for which pH ad- justment is not effective as a means of improving solubility. Very weak acidic or basic drugs may re- quire extremes in pH that are outside accepted physiological limits or may cause stability problems with formulation ingredients. Adjustment of pH normally has little effect on the solubility of non- electrolyte substances. In many cases, it may be required to consider the utlization of co-solvents or other techniques such as complexation, microni- zation or solid dispersion to Improve aqueous solu- bility. Although poor solubility of the drug substance is the most frequent concern, there are occasions when a less soluble form is desired. A lower aqueous solubility may be requited to improve the taste of a formula. An exampie of this is the use of an insoluble form of clindamycin, clindamycin pa- moate. Lower solubility may also be indicated in those cases where it is desirable to slow absorp- tion to provide a prolonged action or in those in- stances where the gastro-intestinal contents degrade the active ingredient. In this latter circun- stance, if the drug is relatively insoluble in the inactivating system, a balance can be achieved between the amount degraded and the amount absorbed in the specific physiological millieux. Solubility data is also valuable to the formulator relative to choosing the solvent for purposes of granulation and coating. Solubility is normally determined by the equilibrium solubility method, wherein an excess of the agent is placed in the solvent of interest and shaken at a constant temperature over a prolonged period of time until equilibrium is obtained. issolution PEE Many variations of biological activity of a given drug substance are brought about by the rate atwhich it becomes available to the organism. In many instances, dissolution rato, or the time it takes for the drug to dissolve in the fluids at the absorption site, is the rate-limiting step in the ab- sorption process. This is true for drugs adminis- tered orally in solid forms such as tablets, capsules or suspensions, as well as drugs admin- istered intramuscularly in the form of pellets or suspensions. When dissolution rate is the rate-lim- ting step, anything which affects it will also affect absorption. Consequently, dissolution rate can affect the onset, intensity, and duration of re- sponse, and control the overall bioavailability of the drug from the dosage form. The dissolution of a substance in a nonreacting solvent may be described by the Noyes-Whitney equation shown as equation 1 de 7 KS (Cs ~ 0.1) The term de/at is the rate of solution, S is the sur- face area of a dissolving solid, and K is the disso- lution rate constant, which includes several factors, such as intensity of agitation and the diffusion co- efficient of a dissolved drug. The concentration of the drug in the dissolution medium at some finite lime is represented by C, and Cg is the concentra- tion of the drug in the diffusion layer surrounding the solid material, The diffusion layer is a thin fim salurated with drug. Accordingly, Cs is essentially equivalent to the concentration of a saturate solu- ion of the drug in the solvent, and the rate of dif- fusion of solute molecules through the diffusion layer into the body of the solution. Examination of the Noyes-Whitney equation suggests several ways by which the dissolution rate of a drug may pe increased. Since dissolution rate is directly proportional to surface area, a decrease in particle size will result in greater surlace area and subsequently in more rapid dissolution. Early observation of the effect of particle size on blood levels was made with sev- eral of the sulfa drugs, specifically, sulfadiazine and sulfaethyithiadiazole. Griseofulvin is a drug which provides one of the most striking examples of the role dissolution rate and effect of surface 6 area play in biological availability. It was shown that the amount of griseofulvin absorbed increased linearly with an increase in the specific surface area of this drug. These observations led to mar- keting of micronized preparations of this drug which permit a dosage reduction of 50% compared to the original macro-forms. Particle size reduction can be obtained in several ways. Historically, this was accomplished by grind- ing or micronization. More recently, particle size reductions have been accomplished in a number of Instances by the preparation of microcrystalline molecular dispersions of poorly soluble drugs in a solid matrix of a water soluble carrier. Although reducing particle size will influence disso lution rate in a positive direction, use of this tech- nique to enhance absorption is limited to those cases in which absorption is dissolution-rate lim- ited. Normally, an increase in dissolution rate is of litle value for water soluble drugs or weakly basic drugs administered as their salts since their ab- sorption is usually not dissolution-rate limited. In addition, there are instances in which particle size eduction may result in an overall decrease in bioavailability. For example, a situation may exist In which a drug is unstable in the gastric fluids; rapid dissolution results in a more rapid degrada- ion and an overall redu bioavailability. The dissolution rate of drugs may also be in- creased by increasing the solubility in the diffusion layer. The most effective means of obtaining higher dissolution rates is to use a highly water soluble salt of the parent substance. Although a soluble salt of a weak acid will subsequently pre- cipitate as the free acid in the bulk phase of an acidic solution, (such es gastric fluid) it will do so in the form of very fine particles with a large sur- face area. There are numerous reports in the liter- ature to illustrate the influence of dissolution rate of weak acids and their salts on the rate of drug absorption, bioavailability, and therapeutic re- sponse after oral administration. High solubility is one of several factors affecting the dissolution rate, but this property is not alwaysnecessarily associated with a high dissolution rate. It must be understood that solubility refers to an ‘equilibrium condition, while dissolution is a kinetic process. Saturation is seldom reached in gastroin- testinal fluids, and, since absorption and distribu- tion processes constantly remove dissolved drug, the important factor is how rapidly the solid drug appears in solution in an absorbable and diffus- able form. important factors in dissolution rate which must be considered by the preformulator are particle size, surface properties of the drug, crystal form, and chemical form. Although particle size re- duction oreates a greater surface area and will im- prove dissolution rate, it should be kept in mind that surface properties of the drug can result in high surface eneray of a micronized powder which may retard dissolution. Usually, this is a result of the powder demonstrating poor wettability and the tendency to form agglomerates. As noted earlier, metastable polymorphs have a greater dissolution rate compared to the most stable form. Solvates may also be considered in this category. The chemical form of the substance, that is, free acid or base or salt or ester form, can also result in sig- nificant differences in dissolution rate. Dissolution rates of chemical compounds can be determined by two general methods: the constant surface method which provides the intrinsic disso- lution rate of the agent, and particulate dissolution in which a suspension of the agent is added to a fixed amount of solvent without exact control of surface area. The constant surface method utilizes a com- pressed disc of known area. This method elimi- nates surface area and surface electrical charges as dissolution variables. The dissolution rate ob- tained by this method is termed the intrinsic disso- {ution rate and is characteristic of each solid compound and a given solvent under the fixed ex- perimental conditions. The value is generally ex- pressed as milligrams dissolved per minute centi- meters squared (mg/min/cm?). It has been suggested that this value is useful in predicting probable absorption problems due to dissolution rate. oPINAG. Particulate dissolution is obtained by adding a weighed amount of powdered sample to the disso- lution medium in a constant agitation system. Par- tioulate dissolution is frequently used to study the influence of particle size, surface area, and ex- cipients upon the active agent. On occasion, an in- verse relationship of particle size to dissolution is noted due to the surface properties of the drug. In these cases, surface charge and/or agglomeration results in the reduced particié size form of the drug presenting a lower effective surface area to the solvent due to incomplete wetting or aggiomer- ation. Studies on the effect of excipients on dissolution of active compounds at an early stage can be of great value to the formulator in developing the ini- tial dosage forms and can be used as a bench- mark in the evaluation of the early developed forms. Stability ‘One of the most important functions of a preformu- lation group is the evaluation of the physical and chemical stability of the pure drug substance. It is essential that these initial studies be performed on a drug of known purity. The presence of impurities can lead to erroneous conclusions in such evalua- tions. The types of stability studies initiated in the reformulation phase are: 1) solid state stability of the drug alone, 2) solution phase stability and 3) ‘compatibility studies, that is, stability in the pres- ence of expected excipients. These studies, ideally, should utilize a reliable sta- ilty indicating analytical method. However, at the early preformulation stage, a stability indicating method of analysis is frequently unavailable. Tech niques such as thin layer chromotography, thermal, analysis, and diffuse reflectance can be utilized to provide data to assess preliminary stability. Prime consideration must be given to stability of the bulk chemical as early as possible. Initial in- vestigation begins with examination of the chemi- cal structure which allows the preformulation sci- enlist to anticipate the possible degradation 7reactions. For example, esters, lactams, and amides are susceptible to solvolytic reaction while the presence of unsaturation or electron rich cen- fers predispose the molecule to free radical me- iated or photo-catalyzed oxidation. With pre- iminary deductions made from the chemical knowledge, it is possible to design experiments to identify the problem areas. It is not the prime ob- jective in these early studies to establish the mechanism of degradation; the more important facets of the study are to identify the factors which cause instability in drug substances of interest. Generally, the effects of heat, light, oxygen, and moisture are evaluated. Drug substances may be stable, stable under spe- cial handling conditions or unstable. The initial sta- vlty studies are designed to characterize which of hese classes the drug substance of interest falls. In cases where the compound is found to have stability problems, it then becomes important to define the degradation mechanism and initiate studies to stabilize the substance. Hydrolysis, a solvolysis reaction, is probably the most important degradation reaction of concen with pharmaceutical products. Drugs are normally exposed to water at some point in either process- ing or storage, thereby presenting the conditions jor hydrolysis to occur. Hydrolysis can be intlu- enced by temperature and hydrogen or hydroxyl jon concentration. The effects of temperature allow jor extrapolation of rates obtained at exaggerated conditions to provide reasonable estimates of shelt-lfe stability of potential new drug products. In hose cases where the hydrolysis reaction is sensi- ive to hydrogen or hydroxy! ion concentration or is DH dependent, studies can be designed to estab- ish the pH of maximum stability. A pH stability profile, a plot of the reaction rate against the pH of the system, is one of the most powerful tools in Possession of the formulation pharmacist. This is Particularly true when liquid solution or suspension forms are being considered. 5 Arother process important in the deg- Products. Oxidation reactions de- #S INcluding temperature, ‘oxygen concentration, and impurities which can act as catalysts. Once it has been established that the oxidation route is the principal mechanism for degradation, the effect of additives can be eval- uated as a means of stabilization. Other factors, which also come into play during the study of the oxidation process, are the effects of pH and light. The presence of heavy metal ions frequently cata- lyze such reactions and can be a particularly trou- blesome problem when they are present in so called inert or excipient ingredients. The oxygen concentration in solution is a determi- nant of the oxidative process, and since oxygen is more soluble at lower temperatures, such reac- tions often proceed more rapidly at the lower tem- peratures. It is obvious that oxidation is a very ‘complex process and presents a formidable obsta- cle to the formulation pharmacist. Experiments must be designed to encompass many variables, and conclusions must be drawn, at best, on limited and incompiete data. Although solvolytic (hydrolytic) and oxidation reac- tions are the most frequent types of degradation ‘encountered in drug substances, other mecha- nisms also must be considered during the prefor- mulation stage. For example, optically active sub- stances may lose this property, and if the ‘enantiomorphic compounds possess different de- grees of pharmacologic action, these changes may be unacceptable. Other reactions which must be considered under certain conditions are polymeri- zation and isomerization. Excipients During preformulation stages, the stability of drug substance in the presence of pharmaceutical ex- cipients is extremely valuable to the formulator. ‘Some excipients can be ruled out based on their chemical nature and an obvious incompatibility with the drug of interest. However, this is not true for the large number of possible drug-excipient reactions. The use of qualitative techniques for such studies is frequently satisfactory since the objective is to detect changes of the drug sub- stance in the presence of the excipient. The tech-SIMIC niques often used are diffuse reflectance, spectro- photometry, thermal techniques, and thin layer chromatography. Mixtures containing several levels of drug and ex- cipient concentrations with known quantities of moisture are stored under exaggerated conditions of heat and light for various time periods and then analyzed both physically and by a suitable qualita- tive or quantitative analytical technique. The choice of excipients is another area for pre- formulation research. The types and levels of im- purities in certain pharmaceutically “inert” sub- stances and their physical-chemical characteristics as they relate to their intended end use is valuable information to the formulator. However, this area has been largely neglected to date in the preform- ulation evaluation. The whole area of excipient choice and evaluation may be less difficult upon completion of the Academy of Pharmaceutical Sci- ences Handbook of Pharmaceutical Excipients. This project is under the direction of Dr. Jack Cooper, who conceived the idea of the handbook. The pharmaceutical industry and pharmaceutical scientists concerned with dosage form develop- ment owe a great debt of gratitude to Dr. Cooper and the many collaborators who have contributed to this project. Membrane Permeability Modern preformulation studies include an early as- sessment of passage of drug molecules across biological membranes. As noted earlier, gastroin- testinal membranes and other membranes of the body act as lipid barriers to most drugs and permit the absorption of lipid soluble substances by pas- sive diffusion. Lipid insoluble substances can cross the barrier only with considerable difficulty, if at all. Interrelationship of the dissociation constant, lipid solubility, pH at the absorption site, and the ab- sorption characteristics of various drugs across membranes are explained by the pH partition the- ory. The theory has evolved in a series of investi- gations on laboratory animals and humans, and is the basis of much of the current understanding of absorption of drugs. Data obtained from basic physical-chemical stud- ies described earlier, specitically, pKa, solublity (both lipid and aqueous system), and dissolution rate, is a primary indication of possible absorption difficulty. Other techniques which add to this pre- liminary assessment include in-vitro models in which the rate of transfer of a drug from an aqueous system through a “membrane” into a re- ceptor system have been employed with various degrees of success. ‘One such system which has been used exten- sively with various modifications consists of an aqueousiorganic solvent/aqueous system. This type of in vitro approach has a great advantage in its simplicity, and allows for accurate contro! over pH, membrane thickness, diffusion layer, mixing, and other variables. It can be described mathe- matically in precise terms. However, the interpreta- tion and correlation of such a system is severely limited when applied to a biological system. In par- ticular, the organic solvents constituting the mem- brane barrier has only the lipoid property in ‘common with biological membranes, making ex- trapolation of rate constants for transport in the ac- tual biological system questionable. ‘A technique which has found favor among many pharmaceutical scientists in evaluating absorption characteristics of drug substances is the “everted intestinal sac.” In method, a piece of intestine is removed from an intact animal, everted, filled with a solution of the drug in question, and the passage of the drug through the membrane sac is determined. This technique has several advan- tages over the simpler organic solvent membrane system in that both passive and active transport can be evaluated. Furthermore, the membrane in this case is a tissue membrane. It has a disadvan- tage in that this preparation has been removed from the animal and its normal blood supply. In situ models, where an intestinal loop is perfused with a drug solution, the loss of drug is evaluated from the profusate. This allows calculation of ab- sorption rate as well as relative passage through the biological membrane. All the techniques described, individually or in to-,tal, can give an indication of possible absorption problems or suggest that litle or no difficulty will be observed in the passage of the drug product of interest through the biological membranes. In the latter stages of preformulation testing or early for- mulation studies in vivo models, animals and eventually humans must be studied in order to as- sess the absorption efficiency, pharmacokinetic parameters, and to establish possible in vitrolin vivo correlation for dissolution and bioavailability. This latter information is particularly important in establishing a dissolution test as a quality control. This ensures consistent biological performance from subsequent lots of formulations and assesses the effects or changes in formulation or processing on the drug product. Summary Development of modern pharmaceuticals requires hat active drug substances be formulated for pa- ient administration in dosage forms which are manufacturable on modern-day equipment, stable hrough the processing and storage conditions an- icipated, and bioavailable in order to elicit their ex- 2ected response. Achievement of these objectives s facilitated when preformulation evaluation of fhe drug substance is part of the developmental 2rocess. A thorough understanding of the physical- shemical properties of the new drug substance is >ssential for the efficient development of stable and efficacious dosage forms. The type and depth of studies involved are influenced by both the na- ure of the drug substance and the anticipated oute of administration. "reformulation studies are accomplished either in 1 designated preformulation group or dispersed hroughout various groups within the pharmaceuti- al research and development operations. Either nethod is acceptable; in any event, the informa- ion must be obtained sufficiently early in the pro- ram to be of benefit to the formulation pharma- ist. AE 12835 ° Bibliography 1. T.d Macek: Remington's Pharmaceutical Sciences, Mack Pubiish- ing Company, Easton, Pa, Chap. 7, 1975. 2, E.G, Shami et al: The Theory and Practice of Industral Phar- ‘macy, Lea and Febiger, Philaceiphi, Pa., Chapter 1, 1976. 8. J.T. Carstensen: Pharmaceuticals of Solids and Sold Dosage Forms, John Wiley & Sons, New York, NY, 1977. 4. D.S. Greene: Modern Pharmaceutics, Marcel Dekker, Inc, Now York, NY, Chap. 6, 1978. 5. D. A. Wacke and H. Jacobson: Pnarmaceutcal Dosage Forms: “Tablets, Marcel Dekker, Inc, New York, NY, Chap. 1, 1960, 6. LJ. Ravin: Remingion's Pharmaceutical Sciences, Mack Publish. ing Company, Easton, Pa., Chap. 75, 1980.aPIMIG CoatingaPC, Coating Many products must be coated for reasons of pal- atabilty, stability and/or protection of ingredients. Colors in tablets and coatings also contribute to product identification and differentiation. Coating processes and methods are summarized in this ‘section.Suspensions Bernard J. Idson, Ph.D. Alma J. Scheer Contents Overview .... : Formulating the ‘Suspension ‘Suspension Problems and Remedie: Avicel® RC-581 Microcrystalline Cellulose Characteristics and Properties of Commonly Used Suspending Agents Suspension Excipients Equipment’Suppliers .. Avicel-FMC trademarkSection 8 Suspensions 1. Overview 5. Introduction Physical considerations in formulation Particle size Flocculation and deflocculation— Wetting Additives Stability References ‘ormulating the Suspension Technology—Guidelines Typical suspension formula Suspension formulation—the drug Suspension formulation—the vehicle Processing Evaluation Special suspension—powder for reconstitution © Physical problems © Powder flow Test methods Processing © Sampling © Suspending agents Suspension Problems and Remedies Avicel® RC-591 Microcrystalline Cellulose Typical properties Advantages Processing (dispersion) guidelines Use patterns Avicel RC-591/CMC, MC blends Advantages Use level ratios Processing dispersion blends Avicel RC-591/Veegum blends eeccceren evceeccce eccce ies -FMC trademark for miroeystainecesose 2 Controlled flocculation 7. Characteristics and Properties of Commonly Used Suspending Agents Suspension Excipients © Functions—Problems Equipment/SuppliersaPMAG. Overview Introduction Physical considerations in formulation Particle size Wetting Additives Stability ° ° ° ° ° ° ° ®@ References Introduction The pharmaceutical suspension is a system in which particles of a drug are distributed somewhat uniformly throughout a vehicle in which the drug usually exhibits a minimum degree of solubility. The three general classes of pharmaceutical sus- pension are oral, parenteral and lotions. This chapter will be concerned primarily with oral sus- pensions. The bulk of the information presented are from the reviews by Kennon and Storz (1), Nash (2), Boylan (3), Macek (4) and Haines and Martin (5). The suspension can be defined as a two-phase system consisting of a finely divided solid dis- persed in a solid, liquid or gas. However, the main ‘emphasis is placed on solids dispersed in liquids, where the continuous or external phase is gener- ally a liquid or semisolid, and the dispersed or in- ternal phase is made up of particulate matter which is essentially insoluble in, but dispersed throughout the continuous phase. The dispersed phase may consist of discrete individual particles, or it may be a network of particles resulting from particle-particle interaction. ‘The USP and NF place particular emphasis on the term suspension by providing specific definitions for a wide variety of oral, parenteral and ophthalmic preparations that are formulated in such a way that an insoluble substance is sus- Flocculation and deflocculation—controlled flocculation pended in a liquid at some stage of the manufac- turing or dispensing process. The USP definit begins as follows: “Suspensions are preparations of finely divided, undissolved drugs dispersed in liquid vehicles.” Neither this definition nor the monographs give specific directions for the preparation of the sus- pension. Traditionally, certain kinds of pharmaceu- tical suspensions have been given separate desig- nations such as mucilages, magmas, gels and ‘even aerosols; also included would be dry pow- ders to which a vehicle is added at the time of dispensing. Suspensions present a number of advantages over other. dosage forms. Some drugs are just in- soluble in all acceptable solvents and must, there- fore, be administered as a tablet, capsule or sus- pension. Suspensions can lessen the unpleasant taste of a drug. This is particularly advantageous to children and geriatric patients. Disagreeable tastes can often be modified by the use of deriva- tives of the drug or adsorbing the drug on a clay. ‘Suspensions also offer advantage for those pa- tients who have difficulty swallowing tablets or capsules. Prolonged drug action could be achieved by use of a suspension (@.g., zinc insulin or procaine penicillin G). In addition, the chemical stability of a drug may sometimes be improved by 3aformulating a suspension dosage form instead of a solution. This is particularly important with certain antibiotics. With regard to bioavailability, the aqueous suspen- sion is an efficient dosage form, second only to solutions with respect to availabilty of the drug for absorption. Generally, the absorption rate of a drug from a suspension dosage form is dissolution rate limited. Nevertheless, a large surface area is immediately presented to the fluids at the ab- sorption sites. The drug contained in a tablet or capsule dosage form ultimately may achieve this state of dispersion, but only after a considerable time lag. Physical Considerations _ in Formulation The basic concern and challenge in almost all sus- pension systems is separation on standing. The formulator should not try to eliminate separation, but rather to decrease the rate of settling and to permit easy resuspendability of any settled particu- late matter. A satisfactory suspension must remain sufficiently homogeneous for at least the period of time necessary to remove and administer the re- quired dose alter shaking its containers. Crystal growth must be avoided since it can lead to caking and other difficulties. Crystal growth can occur when the suspended particles are in contact with a solution whose concentration of dissolved material is greater than the solubility of the particular crys- tal form. This condition may be due to changes in temperature, polymorphism, the presence of both crystal line and amorphous material or large differences in crystal size. The tendency for crystal growth may be diminished by using a narrow parti- ole size range, by choosing a different chemical form of the drug, by using a mixture of liquids for the continuing phase, by increasing the viscosity of the suspending medium (to retard diffusion), or by lowering the interfacial tension (to reduce the free surface energy of the particles). The price objective in formulating a suspension is to produce the largest possibie sedimentation vol- ume while retaining adequate flowability. The most obvious method of measuring settling rates of a suspension is to put the product under test into, say, a 100 ml measuring cylinder, allowing it to stand for predetermined times and taking off a sample at a certain level with a pipette. The solids content of the pipetted sample is determined. If these measurements are made at intervals, itis possible to construct a sedimentation curve for the 4 product under the particular test conditions. It is then possible to ascertain the rate of fall of the particles past a certain level. Formulation obviously involves more than simply suspending a solid in a liquid. A knowledge of the theoretical considerations pertaining to suspension technology should ultimately help the formulator to produce products with optimal pharmaceutical properties. Among the more critical factors to con- sider ara particle size, the behavior of particles in liquids, formation of nonabsorbabie complexes, crystal form, viscosity, suspending agents, flavors and colors. Understanding of these parameters will facilitate decisions in the selection of the ingredi- ents that will be most appropriate for the suspen- sion and to use the mixing and milling apparatus available to the best advantage. Particle Size ‘The average particle size diameter and distribution of particle sizes of the dispersed insoluble drug are among the most important considerations in ‘suspension formulation consideration. The sizes of the drug particles are a significant factor in deter- mining formulation elegance, rates of settling, ab- sence of caking, rate of drug release, drug absorp- tion rate as well as influencing the stability of the product. The particle size can also have a pro- found infuence on the viscosity or consistency of a suspension if it s above about 40 per cent solids content. In addition, the individual particles of the drug, their shape, size and related characteristics play an important role in various manufacturing processes (e.g., whether milling is necessary or If special techniques are required in dissolving the drug during processing). Failure to determine the lot-to-lot average particle size and particle size dis- tribution of the suspended active ingredient often leads to erratic product performance. The majority of pharmaceutical suspensions have drug particles with diameters between 1 and 50 microns. The range rarely contains particles less than 1 micron; 0.2 micron is the lower limit of reso- lution of optical microscopes. For purpose of com- parison, a human hair has a diameter of about 75 microns (0.008 inch). In any case, reduction of particle size has a beneficial effect upon the physi- cal stability of a suspension. The most efficient method of producing fine particles is by dry milling, such as micropulverization, prior to suspension. In contrast, dispersion equipment such as colloid mills or homogenizers is used in wet milling fin- ished suspensions to reduce particle agglomer- ates.aPC, Flocculation and Deflocculation The basic concern in developing a suitable sus- pension is to adequately contro} the rate of settling and ease of redispersion as well as the prevention of caking of the particles as a dense mass al the bottom of the container. Particle size reduction produces slower, more uniform rates of settling. Frequently, caking cannot be prevented by adding a suspending agent or reducing the particle size; in fact, these measures sometimes aggravate the problem of caking. The best approach to this prob- lem is to achieve a controlled flocculation of the particles, where they appear as floccules or like tufts of wool with a loose fibrous structure. When such a system settles, two distinct layers form, a clear particle-free supernatant and a sediment. ‘The particles are held together by weak van der Waals forces. Flocculated particles settle rapidly forming a loosely adhering system which has a large sediment height. In contrast to deflocculated particles, flocculated suspensions can always be resuspended with gentle agitation. Prolonged ex- posure to extreme thermal conditions (freeze-thaw cycles or storage at elevated temperatures) will tend to produce agglomerated or coagulated sys- tems. Yet, sufficient suspending agents must be added to prevent the flocculated particles from set- tling rapidly. However, many suspending agents used in pharmacy are anionic hydrophilic colloids. When added to a flocculated system containing a cationic flocculating agent, a rapidly settling, un- sightly mass may form. Use of a nonionic sus- Pending agent will obviate the problem. The ten- dency of particles to flocculate depends on the forces of attraction and repulsion between them. If the repulsion is of sufficient strength, the particles remain dispersed; if not, they coagulate. Good pharmaceutical suspensions are best achieved through the formation of a stable floc which resists the tendency toward either deflocculation or ag- glomeration. If the structure of a flocculated sus- pension is adequately controlled, inelegance and caking do not become problems. With flocculation, the force of attraction between particles predominates, causing the particles to form loose aggregates. Should repulsion forces prevail, however, the particles separate or defloc- culate. In effect, colloidally-stable dispersions are systems in which the particles are completely de- flocoulated. As a rule, since the distribution of par- ticles is generally greater than 1 micron defloccu- lated (or peptized), systems settle very slowly in stages, but ultimately forming a dense sediment which is considerably more compact than the cor- responding sediment of a flocculated system and more difficult to resuspend. In order to stabilize these defiocculated systems, it is necessary to add a suspending and/or a gelling agent. They retard settling and agglomeration of the particles by fune- tioning as an energy barrier, which minimizes in- terparticle attraction and ultimate flocculation. The general choice of suspending agents include pro- tective colloids, viscosity-inducing agents, surfac- tants and dispersing agents. Combinations of var- ious types of suspending agents may be used to achieve the desired rheological properties. These agents do not reduce the surface and interfacial tension to any appreciable degree. They function best in the present of a surfactant which can lower the interfacial tension between the drug particle and vehicle, and also release air which is en- trapped by the drug. Controlled Flocculation The application of zeta potential measurements to the formulation of pharmaceutical suspension was introduced by Haines and Martin in 1961. They pointed out that if a suspension were prepared with a high zeta potential, the mutual repulsion would be strong and, thus, one would expect the rate of sedimentation to be slow. Because the sedimentation rate is slow, the particles in the sed- iment will have plenty of time to pack tightly by falling over each other so as to form a tightly im- pacted bed. If, however, the amount of electrolyte present were reduced, then the system would still be stable for a sufficiently long time for the patient to obtain a uniform dose. The sedimentation would be rapid though and the floccules produced would not have time to impact, and redispersion would be easy. Basically, therefore, this method pro- duces elegant products by controlling zeta poten- tial “not too little, not too much.” The controled flocculation method has been applied to a number of systems with great success. The flocculated state may be reached either di- rectly by welting and dispersing hydrophobic drugs with a suitable flocculating surfactant, or indirectly by first wetting to produce a defiocculated particle and then flocculating with a suitable agent such as a hydrophilic colloid. In any case, suitable wetting of the solid phase by the suspension liquid is nec- essary toward producing a good suspension.Dertain solids are readily wet by liquids whereas thers are not. The degree of wetability is de- yendent on the affinity of the drugs for water, or vhether they are hydrophilic or hydrophobic. Hy- irophilic substances are easily wet by water and an greatly increase the viscosity of water suspen- ions. Hydrophobic substances repel water but an usually be wetted by nonpolar liquids. They isually do not alter the viscosity of aqueous ersions. Hydrophilic solids usually can be incor- orated into suspensions without the use of wetting agent. Yet, the majority of drugs in sus- jensions are hydrophobic. These are extremely ficult to disperse and frequently float on the sur- ace of the fluid due to poor wetting of the patticles F the presence of tiny air pockets. /arious techniques are used to select the better vetting agents. One of the procedures measures he relative ability of solutions of different wetting gents to carry powder through a gauze. The solu- jons are dropped onto the gauze supporting the owder. The better wetters carry more powder hrough the gauze than the poorer wetters. ‘he wet point and flow point methods, applicable 9 pharmaceuticals, were developed by the paint dustry. The wet point measures the amount of ehicle to just wet all of the powder. Reduction of ne wet point by an additive indicates initial surface vetting by that agent in the particular powder- ehicle combination. The flow point measures the mount of vehicle to produce pourability. The ex- ant to which the flow point of a powder-vehicle ystem is reduced by a surface-active agent neasures the degree to which the agent defloccu- ates the system, i.e, inhibits the buildup of a net- york-like structure by the solid phase. A low wet int coupled with a low flow point indicates good flocculation and dispersion. The better the wet- ng agent, the lower is the wet point value. \dditives Vetting influences the rheological or flow proper- es of the suspensions, A clay or surface-active gent may cause changes toward greater viscosity r even greater flow. Surfactants are probably the ost useful additives for modifying the wetting haracteristics of powders. They accomplish this y decreasing the solid-liquid interfacial tension. he addition of a surfactant to a product contain- 1g very fine particles at a high concentration may ause the product to thicken up because of the etter wetting of the particles by the water. It is, in ffect, producing a better dispersion of those parti- cles. The effect can be seen in the microscope. The particles inadequately wetted tend to show up as clusters or aggregates. The right surfactant brings about adsorption to the surfaces of the par- ticles which then separate from each other. The effect in the microscope is observed as discrete particles. Hence, the mechanism of surfactant ac- tion is thought to involve the preferential adsorp- tion of the hydrocarbon chain by the hydrophobic surface, with the polar moiety of the surfactant being then directed toward the aqueous phase. However, certain cautions must be observed. If surfactants with negative charges are adsorbed on the particles, this prevents or minimizes floccula- tion or precipitation in the presence of positive ions because of the mutual repulsion of like chrges. Ex- amples of such agents include sodium lauryl sul- fate and sodium diocty! sulfosuccinate. In practice, a nonionic surfactant is usually used to aid the dis- persion of the insoluble phase, Hydrophilic polymers such as sodium carboxyme- thylealiulose (NaCMC) and certain water-insoluble hydrophilic materials such as bentonite, aluminum- magnesium silicates, colloidal silica, and micro- crystalline cellulose (Avice! RC) either alone or in combination, are often used to aid dispersion of hydrophobic solids. They also exert viscosity-bulld- ing effects, depending on the specific type and concentration used. If used at too high a concen- tration, they can cause an undesirable gelling in- stead of the desired degree of viscosity or thixo- ‘ttopy. Rheologically, the liquid is now in plastic flow or exerting a “yield” value. Plastic flow rarely ‘occurs in solutions of most pharmaceutical gums. The only prominent agent to show a high yield value at low solution concentration and produce a good suspension is the carboxyvinyl polymer Car- bopol (B. F. Goodrich Co.). ‘The primary behavioral difference between hydro- philic and hydrophobic materials is their sensitivity 10 the presence of electrolytes. Hydrophobic mate- fials in suspensions are sensitive to the addition of salts whereas hydrophilic materials are not. A hy- drophilic material, such as a gum, is readily wet by water although large amounts of electrolyte may affect the solution by salting out effects. Polyvalent ions, such as calcium, form insoluble salts with an- ionic polyelectrolytes such as sodium alginate and carrageenan. Due to their charge, they also react with positive groups of proteins whereby large polymers are formed which become less soluble with increasing size until either a gel structure or precipitation occurs. Methyl cellulose and hydroxy- propylmethyl cellulose, both nonionic agents, gelaPlMlG, on heating and are both affected by electrolytes. Anionic water-soluble compounds such as NaCMC, pectin, alginic acid and other hydrocol- loids, although generally considered relatively chemically inert, can undergo reaction with drug compounds. Binding of drug ions by dissolved polyelectrolytes occurs frequently even before the formation of visible haze or precipitation. CMC forms complexes with cationic surfactants and ca- tionic drugs such as quinine, Benadryl, procaine, Pyribenzamine and neomycin. In some instances the complexation has proved an aid to stability, as with the CMC-neomycin adduct The clays (essentially hydrated aluminum and/or magnesium silicates) are also quite useful in sus- pension formulating. They hydrate further in water to a high degree to form colloidal dispersions hav- ing high viscosities. The manner of treatment of the clay in the suspension has a profound effect on the final product. The clay should always be added to the water with high shear to effect uni- form dispersion and maximum gelation. The viscosity of aqueous dispersions of clays var- ies, depending on the type and amount of solids dispersed. Generally, 5 to 10% concentrations of the clay form firm opaque gels. Clays can be for- mulated in systems in which the pH is between 6 and 11, but they are most stable between pH 9 to 11. Alkaline buffers usually are included to main- tain the pH. All dispersions of the clays are drasti- aly affected by electrolytes and by ethanol. The addition of ciay to a dispersion of fine parti- cles is almost wholly a physical phenomenon. The plate-like particles of clay interpose themselves between the patticles of the product imparting a structural viscosity in which the product assumes a geblike character. Stability In general, physical factors governing the stability of suspensions are equal to or more important than chemical factors. Methods for determining the physical stability of suspensive commercial prod- ucts. Measurement of the sedimentation volume and the ‘ease of redispersion are the most common and useful evaluation procedures. Simple graduated cylinders were previously used to determine the setling rates of flocculated and nonflocculated suspensions by making periodic measurement of ‘sedimentation height without disturbing the sys- tem. It is more practical to measure sedimentation height directly in “mm” in undisturbed bottles. De- ‘creases in diameter of small containers like 100-ml cylinders produce a wall effect which can affect the settling rate or ultimate sedimentation height of flocculated systems. Cylinders have a tendency to “hold up” suspensions by increasing surface ten- sion and adhesion forces between cylinder and suspension. Sedimentation volume techniques involve deter- mining the ratio of the height of sediment after a definite time interval, under standard conditions, to the initial height. The larger the fraction, the better is the suspendability. When the ratios are plotted versus time, the more horizontal the slopes the more flocculated the preparation and allow com- parisons of different formulations. However, with highly concentrated suspensions, comparison is difficult because there would be only minimum su- pernatant liquid. Hence, a varied technique in- volves diluting the suspensions with additional ve- hicle and determining the sedimentation volume. The “ultimate” readings become the volume of sediment in the diluted sample, which is again ‘compared to the original volume before dilution, The foregoing determinations are relative “rank correlation” readings. “Absolute” evaluations could be based on considering the degree of settling that ‘would be produced in an ultimate deflocculated state, or the least sedimentation volume to pro- duce the smaliest ratio. Electrolytes that promote settling may be added or the preparation may be centrifuged. The ratio can now serve as a base line of complete defiocculation. Any ratios higher than the minimum represent a desired flocculated state. ‘The freeze-thaw cycle technique is particularly ap- plicable to stressing suspensions for stability test- ing purposes. This treatment promotes particle growth and may predict the results of long storage at room temperature. Particle size distributions can be followed microscopically. This, of necessity, re- quires dilute suspensions that are counted with the aid of an ocular grid. Photomicrographs can serve as permanent records to distinguish between floc- culated and deflocculated particles, and to detect changes in particle-size distribution and crystal form. Unfortunately, the freeze-thaw and micro- scopic methods are quite tedious, especially when large numbers of samples are to be evaluated. Al though freeze-thaw cycles are useful guides, the best stability information is stil obtained from stud- conducted at room temperature.in electrokinetic method measures the migration elocity of the suspension particles with respect to ne net effective charge on the surfaces. This is ne zeta potential, determined with the zeta meter, ihich is essentially a microelectrophoretic mobility pparatus which can be used to characterize floc- ulated and dispersed suspensions, and to follow hanges in physical stability with time, e.g., visu- lly observed caking can be related to changes in eta potential, as well as changes upon addition of dditives, teferences 1) Kennon, L. and Storz, J. K., in Theory and Practice of Industrial Pharmacy, Edited by Lachman, L., Lieberman, H. A. and Kanig, J. Lea & Febiger, Philadelphia, PA, 2nd Ed., 1976, pp. 162-183 2) Nash, R_A., Drug & Cosm, Ind. 97, 843 (1965); 98, 40 (1966). 3) Boylan, J. C., Drug Develop. Communic. 2, 325 (1976). 1) Macek, T. J., in Remington's Pharmaceutical Sciences, Edited by Martin, E. W., Mack Pub- lishing Co., Easton, PA, 13th Ed., 1965, pp. 419-433, ) Haines, B. A. and Martin, A. N., J. Pharm. Sci 50, 228, 753, 756 (1961).SME | Formulating the Suspension ® Technology—Guidelines ® Typical suspension formula @ Preformulation ® Processing @ Evaluation ® Special suspension—Powder for reconstitution Technology-Guidelines _ Suspensions must have the following characteris- tics: 1. The suspended drug must not settle rapidly. There are two basic suspension prototypes: a. The insoluble material is “allowed” to settle but it can be readily resuspended. There is phase separation but no caking, b. The insoluble material is maintained in sus- pension with very little or no phase separa- tion. 2. Drug particles which do settle must be easily redispersed upon shaking. 3. The suspension should not be toa viscous to pour from the container. 4. The suspension must be chemically and physi- cally stable for the shelf-life of the product. The final suspension consistency should be deter- mined in the presence of all formula excipients as excipients can exert an effect on the suspending agent, €.g., flocculation. Selection of the optimum formula content and sus- pending agent(s) for a suspension is, however, de- termined by the properties of the drug. Typical Suspension Formula A typical suspension formula—usually geared to deliver the drug dosage per teaspoontul (5 mi)— normally contains the following basic excipients (see page 6-2 for complete discussion of excip- ients): © Drug © Dispersant ®@ Protective colloid © Suspending agent ‘Sweetener © Bodying agent ® Preservatives ® Buffer system ® Sequestering agent ® Flavor © Colorant © Water, distilled Preformulation Guidelines 1. Drug Analytical Data Sheet A drug data sheet describes physical and chemical properties. It is essential that the formulator take special note of the following specific drug data: © Formula structure © Purity © Decomposition reactions and products * Compound description (crystal form, odor, color, taste) pH, pKa Density Melting point Solubility (water, alcohol, glycerin, propylene glycol, oils) Drug sensitivity (light, moisture, air, pH, metals) ® Stability (drug per se in solution at vatious pH levels) © Static charge The formulator should also be aware of drug phar- macology, toxicity, and analytical methods,