Formulation design and development of parenteral suspensions

Downloaded from journal.pda.org on July 18, 2016 Formulation Design and Development of Parenteral Suspensions M J Akers, A L Fites and R L Robison PDA J Pharm Sci and Tech 1987, 41 88-96 Downloaded from journal.pda.org on July 18, 2016 REVIEW ARTICLE Formulation Design and Development of Parenteral Suspensions M J AKERSA, A L FITES, and R L ROBISON Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana Introduction Parenteral suspensions are dispersed, heterogeneous systems containing insoluble drug particles which, when resuspended in either aqueous or vegetable oil vehicles, are injected either by intramuscular or subcutaneous routes Newer suspension delivery systems, containing drug in microparticulate forms, can be injected intravenously or intra-arterially There are at least three reasons why parenteral suspensions are developed: The drug is too insoluble to be formulated as a solution The drug is more stable as a suspended solid than in solution There is a need to retard or control the release of drug from a suspension The purpose of this article is to suggest ideas and review principles for the scientist responsible for the design and development of parenteral suspension dosage forms Desirable Parenteral Suspensions Suspensions possibly are the most difficult of all pharmaceutical dosage forms to develop in terms of stability, elegance, manufacture, and use The desirable parenteral suspension is sterile,1 stable, resuspendable, syringeable injectable, and isotonic/nonirritating Characteristics of a Well-Formulated Suspension Resuspension of drug particles occurs easily with mild shaking The dispersed particles not settle rapidly after • shaking Resuspension produces a homogeneous mix of drug particles such that the same concentration of drug can be removed repeatedly During the shelf-life of the suspension product no hard cake, too difficult to redisperse, will form The suspension product maintains its stability and elegance during its shelf-life Parenteral suspensions must possess at least two additional characteristics: Received December 23 1986 Accepted for publication April 9, 1987 Author to whom inquiries should be directed Sterile, in context of this paper, also includes freedom from pyrogenic contamination 86 The suspension product is manufactured and tested to be free from microbial contamination and maintains its sterility during its storage and use The suspension is easily drawn into a syringe through a 20-25 gauge needle (syringeability) and is readily ejected from the syringe into the patient (injectability) Parenteral suspensions also limit the formulator in what ingredients are parenterally acceptable as suspending agents, viscosity-inducers, wetting agents, stabilizers, and preservatives This is because of very stringent requirements regarding safety and performance of parenteral ingredients not required of other dosage form ingredients (Table I) Also, special facilities are required to maintain aseptic conditions for manufacturing processes such as crystallization, particle size reduction, wetting, sterilization, and aseptic dispersion filling and packaging Potential Problems in Developing Stable, Usable Suspensions Converse to the ideal characteristics of a parenteral suspension, a myriad of potential problems must be recognized which, in reality, frequently are prevalent and provide incredible challenges to the development scientist The most important of these are: crystal growth, caking, and product-package interactions Other factors discussed in the following sections include syringeability and scale-up problems Crystal Growth The following factors affect the potential for crystal growth in pharmaceutical suspensions: particle size distribution dissolution and «crystallization changes in pH and temperature polymorphism and solvate formation The Ostwald-Freundlich equation, (Eq 1), where C is the solubility of particles of radius R\ and R2, M is molecular weight, is the surface energy of the solid in contact with solution, P is the density of the solid, R is the gas constant and T is absolute temperature, shows that smaller particles (/?i) have a higher solubility (C|) than the solubility (C2) of larger particles (R2) The common Journal of Parenteral Science & Technology Downloaded from journal.pda.org on July 18, 2016 TABLE I Parenteral Suspension Formulation Additives • • • • • • • • Nontoxic Nonantigenic Nonirritating Nonhemolytic Nonpyrogenic Effective at low concentrations Stable to heat sterilization FDA approvabile suspension will have a normal distribution of particle sizes Variable particle size distribution results from various factors including: (a) preparation of the suspension by precipitation methods where the degree of supersaturation and rate of nucleation are greatest at the beginning of the process resulting in large particles initially and smaller particles subsequently, (b) changes in pH caused by drug decomposition, and (c) temperature changes With time the smaller particles will disappear and larger particles will grow To retard or prevent crystal growth, viscosityinducing agents are included in the formulation Increasing viscosity minimizes the probability of crystal growth according to Eq (1) k„ = Ae-""+à (Eq 2) where kcr is the rate of crystal growth, r¡ is the viscosity of the solution and A, a, and /3 are constants Also, it is well known that certain hydrophilic gums (gelatin, polyvinylpyrrolidone, polysorbates) will adsorb at particle surfaces and retard crystal growth Crystal growth as a result of dissolution and recrystallization phenomena is also caused by polymorphism, solvate formation, and temperature flucuations All organic compounds have different crystal structures, in turn dependent on solvent(s) used to crystallize the drug, different cooling or drying rates, and storage temperature The use of polymorphic forms other than the most thermodynamically stable form could lead to dissolution of the more soluble crystal form followed by recrystallization and conversion to a more stable form resulting in crystal growth and problems in resuspending the drug in the vehicle Solvate formation can occur, for example, when an anhydrous drug is suspended in an aqueous vehicle and a hydrate is formed The hydrate form, being a more energetic crystal, will more likely develop large crystals Temperature fluctuations cause drug crystals to be subject to undersaturated conditions for awhile then to saturated conditions and so forth Not only will small crystals disappear and large crystals grow, but also chemical instability of the drug likely may occur Thus, to minimize crystal growth the formulator must understand the theory behind the formation of large particles, know the particle size distribution of the drug to be suspended, select appropriate suspending and viscosity inducing agents, use the right drug polymorph and solvate form, and conduct meaningful temperature cycling studies to evaluate the rate and extent of temperature effects on physical as well as chemical stability of the suspension Vol 41, No 3/May-June 1987 Caking The inability to resuspend drug particles upon shaking usually results from particles settling as a hardened sediment at the bottom of the container This hardened sediment, called a "cake," will occur when attractive forces among drug particles are greater than forces between solid particles and the suspension vehicle Crystal growth and extremes in flocculated and deflocculated suspensions can lead to caking (Fig 1) (2) Ways to minimize crystal growth have already been discussed Flocculated systems will cake if excessive flocculating agent is used Deflocculated systems by their definition will settle slowly as individual particles which will become closely packed sediments Thus, complete dispersion of small, narrow-ranged particles with appropriate amounts of wetting agent and/ or other agents which increase zeta potential will minimize the tendency of these particles to agglomerate and form a hard cake Product-Package Interactions Two potential problems may occur with a rubber stoppered vial containing a suspension Agglomeration of fine particles on the surface of the glass promoted by changes in temperature and handling of the stored vials (shipping test) Efficient siliconization of the vial will promote efficient drainage of the suspension and reduce the probability of particle agglomeration Interactions between product and rubber closure Extractables from the closure might be masked in a cloudy suspension product Antimicrobial preservatives and antioxidants are known to volatilize or adsorb through the rubber closure causing not only potential loss of sterility and stability but also problems in flocculation and resuspendability Formulation Approaches When given the assignment to design and develop a parenteral suspension, the pharmaceutical formulator should attempt to provide a formulation to production that meets the requirements of an ideal suspension as closely as possible What are some of the things the formulator 89 Downloaded from journal.pda.org on July 18, 2016 TABLE II Brief Descripiion of Marketed Parenteral Suspension Products Drug Manufacturer Brand Name Strength(s) Aurothioglucose Solganol® Schering Betamethasone Sodium Phosphate and Betamethasone acetate Celestone® Soluspan® Schering Desoxycorticosterone Pivalate Percorten® Pivalate CIBA 25 mg/mL Dexamethasone acetate Decadron-LA® Merck mg/mL Hydrocortisone acetate Hydrocortone® Acetate sterile ophthalmic suspension Merck 25 mg/mL Methylprednisoione acetate Depo-Medrol® Upjohn 20, 40, 80 mg/mL Medroxyprogesterone acetate Depo-Provera® Upjohn 100 and 400 mg/mL can to assure that as many of these ideal characteristics as possible are in fact achieved Factors Important in Design of Parenteral Suspensions Preformulation data such as drug solubility, particle size, and chemical stability provide valuable information regarding potential problems, need for adjustments, and required formulation additives Of course, the formulator will know the dose range and should know what additives are parenterally acceptable As the formulation is being developed, viscosity measurements usually are necessary to impart useful knowledge regarding settling rates, syringeability, and physical stability Formulation Ingredients Used in Parenteral Suspensions The typical suspension contains the active ingredient, an antimicrobial preservative, a surfactant, a dispersing or suspending agent, possibly a buffer for pH stability, and salt for isotonicity purposes As with most parenteral products, the formula for a parenteral suspension is relatively simple and contains relatively few ingredients This is because of the strict requirements governing the type and amount of additives acceptable for parenteral administration Acceptability of an additive usually means that 90 50 mg mg/mL mg/mL Formulation Aluminum Monostearate Propylparaben Sesame Oil Phosphate Buffer Edetate Disodium Benzalkonium Chloride Methylcellulose Sodium CMC Polysorbate 80 Sodium Chloride Thimerosal Sodium CMC Polysorbate 80 Creatinine Sodium bisulfite Disodium edetate Sodium chloride Benzyl alcohol Phosphate Buffer PEG 4000 Polysorbate 80 Sodium citrate Sodium chloride Benzyl alcohol Benzalkonium chloride PEG 3350 Sodium Chloride M-G-P Chloride PEG 3350 Polysorbate 80 Sodium Chloride Parabens at low concentrations it is nontoxic, nonantigenic, nonirritating, nonhemolytic, and nonpyrogenic Such strict requirements limit the actual number of parenterally acceptable formulation additives A partial review of parenteral suspensions described in the 1985 Physicians' Desk Reference (3) will indicate that most suspensions are composed of water insoluble drugs in relatively simple formulations used for noncontrolled release of the drug (Table II) Flocculated vs Deflocculated Suspensions The formulator should also understand the basic differences between flocculated and deflocculated suspensions (4) Deflocculated Particles exist in suspension as separate entities Rate of sedimentation is slow, since each particle settles separately and particie size is minimal, A sediment is formed slowly, Flocculated Particles form loose aggregates Rate of sedimentation is high, since particles settle as afloe,which is a collection of particles A sediment is formed rapidly Journal of Parenteral Science & Technology Downloaded from journal.pda.org on July 18, 2016 TABLE II Continued Drug Brand Name Manufacturer Strength(s) Penicillin G Benzothine and Penicillin G Procaine Bicillin® C-R Wyeth 600,000 U/mL Penicillin G Procaine Bicillin® C-R Crysticillin® Penicillin G Procaine Pflizerpen®-AS Wycillin® Wyeth Squibb Lilly Pfipharmecs Wyeth 300,000 U/mL 10 Prednisolone Acetate Metimyd® Ophthalmic Schering 11 Pednisolone Tebutate Hydeltra-T.B.A.® Merck 20 mg/mL 12 Triamcinolone acetonide Kenalog® Squibb 10,40 mg/ mL 13 Triamcinolone diacetate Aristocort® Lederle 40 mg/mL 14 Triamcinolone hexacetonide Aristospan® Lederle 5,20 mg/ mL The sediment eventually becomes very closely packed, due to weight of upper layers of sedimenting material Repulsive forces between particles are overcome and a hard cake is formed which is difficult, if not impossible, to redisperse The suspension has a pleasing appearance, since the suspended material remains suspended for a relatively long time The supernatant also remains cloudy, even when settling is apparent The sediment is loosely packed and possesses a scaffold-like structure Particles not bond tightly to each other and a hard, dense cake does not form The sediment is easy to redisperse, so as to reform the original suspension The suspension is somewhat unsightly, due to rapid sedimentation and the presence of an obvious, clear superantant region, This can be minimized if the volume of sediment is made large Ideally, volurne of sediment should encompass the volume of the suspension Flocculated suspensions are the more common type of parenteral suspension because most injectable suspensions contain low concentrations of solids Additionally, Vol 41, No 3/May-June 1987 mg/mL Formulation CMC Povidone Lecithin Citrate buffer Parabens Sodium CMC Lecithin Sorbitol Povidone Citrate buffer Parabens Phosphate buffer Tyloxapol Sodium thiosulfate Disodium edetate Phenethyl alcohol Benzalkonium chloride Sorbitol Polysorbate 80 Sodium citrate Benzyl alcohol Sodium CMC Polysorbate 80 Sodium chloride Benzyl alcohol PEG 4000 Polysorbate 80 Sodium chloride Benzyl alcohol Polysorbate 80 Sorbitol Benzyl alcohol they are easier to formulate, less viscous and have less potential to cause physical stability problems The deflocculated approach is used for oleaginous suspensions (where low dielectric constant causes a very thick double layer) and for suspension containing relatively high concentrations of solids, e.g., procaine pencillin G Two Hypothetical Examples of Parenteral Suspension Formulation Compound A is an insoluble steroid, stable, and effective at a dose of mg When injected as unmilled crystals in a water slurry, it shows sustained action over a period of several weeks Compound A seems to have most of the desired characteristics for use in a suspension In formulating Compound A, the major consideration beyond the basic requirements for injections would probably involve methods of producing a physically stable suspension which would remain homogeneous or which could be readily and completely resuspended to a homogenous suspension Although resuspension is important for all types of suspensions, the highly potent drugs have a special requirement for good resuspendability Control of particle size would also be important because of the effect on release rate Very fine particles might be more quickly released and present a 91 Downloaded from journal.pda.org on July 18, 2016 toxicity problem Large particles might be released too slowly for it to be effective Because of the low concentration Compound A suspension particles, per se would likely not have much effect on the total suspension characteristics Flocculation would seem to be a logical approach to the desired product characteristics A viscosity imparting agent should be avoided because of the possible cementing action on sedimented particles Compound B is slightly soluble, saturated solutions show some instability, it gives effective blood levels following administration of a slurry in water, but it requires injection every six hours because of rapid absorption and excretion Compound B represents a different type of suspension problem to the formulator Preparation at a high concentration should improve chemical stability, prolong activity through a slower release rate, and decrease the frequency of injection Suspension properties will be greatly dependent upon the particle characteristics The high concentration of particles would contribute a significant viscosity so a viscosity imparting agent could either not be used or would be used only in very low concentration Flocculation would not be applicable because the void spaces are already filled with solids One approach would be to attempt to produce a suspension with thixotropic properties which would thin upon agitation Filling would be easier if the suspension thinned when mixed, the physical stability and shipping qualities would be improved by the structure and the syringeability and injectability would be improved by its thinning properties Influence of Suspension Formulation on Drug Absorption There are several physical and chemical characteristics of suspension dosage forms which affect drug absorption and other performance factors following parenteral administration (5) Solubility, particle size, and drug concentration each affect rate and duration of drug release from suspensions While the pharmaceutical formulator usually is constrainted with respect to the solubility of drug in the suspension and dose of suspended drug injected, he can manipulate drug particle size to achieve different rates and durations of drug release from the suspension formulation The profound effect of particle size on drug availability from suspensions makes it imperative that the formulation developed provide acceptable stability against crystal growth Changes in crystal size, resulting from adverse effects of temperature extremes during storage or changes in relative rates of solution and crystallization of drug particles during storage, will lead to changes in the rate and duration of drug release and subsequent biological response following parenteral administration of the drug suspension Changes in crystal habit resulting in more stable polymorphic or solvate forms of the drug also will affect absorption parameters Increasing suspension viscosity will retard the onset and duration of drug activity An especially attractive application of this viscosity effect is to develop thixotropic sus92 pensions Thixotropic suspensions are highly viscous unshaken or with minor agitation However, when vigorously shaken the viscosity is greatly reduced Thus, shaking will allow the suspension to readily flow for resuspendability, syringeability, and injectability purposes, yet, once injected, a compact highly viscous depot will form and slowly release the drug from the injection site Thixotropic suspensions of Procaine Pencillin G are available on the marketplace Preparation of Parenteral Suspensions The formulation approach and ingredients (for any pharmaceutical dosage form) must be adaptable to a practical, achievable manufacturing method Thus, the parenteral suspension formulator, in developing the product, must be knowledgeable of the basic methods of parenteral suspension manufacturers Two basic methods are used to prepare parenteral suspensions: (7) sterile powder and vehicle are combined aseptically, or (2) sterile solutions are combined and the crystals are formed in silu Examples of these types of preparations are: (/) Procaine Penicillin G Suspensions, and (2) Testosterone or Insulin Suspensions The incorporation of a sterile powder into an aqueous vehicle containing components such as polyoxyethylene sorbitan monooleate, sodium citrate, lecithin, povidone, methylparaben and propylparaben is the more common method of preparing sterile suspensions The vehicle may be sterilized through a sterilizing filter if the components are soluble and the viscosity is acceptable The vehicle may also be sterilized by autoclaving The sterile powder may be produced by crystallization, lyophilization, or spray drying Sterile Crystallization: The drug is dissolved in an appropriate solvent and sterile filtered A sterile solution of "antisolvent" is added or the pH is significantly changed to cause the drug to crystallize out of solution The crystals are collected and washed with the appropriate solvent The retained drug crystals are dried and milled Lyophilization: A sterile solution of the drug is bulk lyophilized Excipients may be included with the drug as a bulking or stabilizing agent The product is milled after freeze drying Spray Drying: A solution or slurry of the drug is metered into the drying chamber, where it comes into contact with a stream of hot sterile gas The solvent evaporates rapidly, forming spheres Typical Manufacturing Method When utilizing the above methods for preparing sterile drug, the particular process should be strictly controlled so that the particle characteristics are uniform from batch to batch For example, factors such as stirring rates, temperature, pH, and concentration must be controlled during a sterile crystallization to obtain a crystalline material with comparable density characteristics from each crystallization Once the sterile powder is dried sufficiently, it will Journal ot Parenteral Science & Technology Downloaded from journal.pda.org on July 18, 2016 usually require some method of particle size reduction Because of the small quantity of powder usually available for development work, fluid energy mills such as the JetO-Mizer or Gem Mill are more practical They are available for sterile milling and particle size reduction may be reproduced from batch to batch Fitzpatrick mills may be utilized for larger quantities Particle size and surface area are determined for each batch A vehicle is composed of preservatives, suspending agents, stabilizers, wetting agents, and flocculating agents These ingredients are incorporated into the aqueous or oil medium and rendered sterile Vehicles which contain soluble ingredients may be sterilized by filtration Viscous vehicles or vehicles which are colloidal are steam sterilized This process obviously must be validated The milled, sterile powder is aseptically incorporated into the sterile vehicle Further particle size reduction may be obtained by a Waring Blender or other means of wet-milling Manufacture of Specific Suspension Products Testosterone suspension is prepared by the precipitation method The vehicle is prepared and sterilized The testosterone is dissolved in an organic solvent and sterile filtered The testosterone and solvent are aseptically added to the vehicle, causing the testosterone to crystallize The resulting suspension is further diluted with vehicle, agitated, and the crystals allowed to settle The solvent is removed and the suspension is brought to value Insulin suspensions are another example of suspensions prepared by the combination of sterile solutions Isophane insulin is a neutral suspension of crystalline protamineinsulin which contains no excess of either protamine or insulin Isophane insulin is prepared by dissolving zinc insulin and protamine sulfate at pH to in Water for Injection containing glycerin, phenol, and cresol A second solution which contains phosphate buffer, glycerin, phenol and cresol, is combined with the insulin solution Both solutions are filtered through sterile membrane filters before combining (Fig 2) The solutions can be filled separately into vials or combined in a tank and filled as a suspension When the solutions are combined, a suspension is formed from which tetragonal or rod-shaped crystals develop in 8-24 hr at ambient temperature The time required for complete conversion to crystals depends on temperature, pH, and the concentration of ingredients Duracillin® AS (Penicillin G Procaine Suspension, USP) manufactured by Eli Lilly and Co., has the following formula Each mL contains 300,000 units crystalline Vol 41 No 3/May-June 1987 penicillin G procaine; sodium citrate, 4%; lecithin, 1%; povidone, 0.1%; with methylparaben, 0.15%, propylparaben, 0.02%, and benzyl alcohol 1% as preservatives; Water for Injection, q.s The suspension vehicle is prepared by dissolving the sodium citrate, povidone and parabens in heated Water for Injection Lecithin is then added slowly and dispersed with agitation Benzyl alcohol is then added This vehicle is transferred into a suspension tank which contains a variable speed agitator and is steam-jacketed The vehicle is sterilized at 121 -124 °C for the appropriate time and then cooled to room temperature Sterile penicillin G procaine powder is then incorporated with continuous agitation The penicillin powder is obtained from a sterile controlled crystallization procedure and is aseptically micronized to obtain the proper surface area After all the powder has been incorporated, the suspension is agitated at a high speed to produce a homogenous suspension The suspension is transferred through stainless-steel mesh screens into a filling tank equipped with agitators The suspension under continuous agitation is filled into the appropriate containers Additional Manufacturing Considerations \ Entrapped air and foam: Entrapped air and foam are two problems frequently observed at the time of manufacture of a suspension Although a surfactant is usually included in the formula it may be several days or more before some suspension particles are properly wetted One of the most effective methods of dealing with the problem of foam and powder wetting is to incorporate the powder into the minimum volume of vehicle that will wet the powder and still be compatible with the mixing equipment Following the wetting of the powder the remainder of the vehicle can be added, usually with a minimum of foam Entrapped air may be undesirable in parenteral suspension because of stability consideration or Theological effects or it may present problems infillingor dose control Suspensions with a persistent air problem may require deaeration by vacuum or other means Suspension deaeration is facilitated in thin films The procedure may be in combination with a transfer from one vessel to another, the suspension entering the tank and striking the baffle plate to spread into an easily deaerated film Parenteral suspensions, as a result of the method of manufacture and handling of the powder or as a result of the suspension manufacture, may contain particles which will not pass through the needle bore Bulk suspensions should be passed through a suitable size mesh screen to remove any potential oversize particles as well as any extraneous matter which might have accidentally gotten into the suspension Type III or better glass vials are used for packaging suspensions Vials may be silicone treated to enhance drainage and reduce aggregation Various types of glass and plastic syringe units are also utilized Particulate Matter Control: Particulate matter in injectables has received increased attention during the past decade Most of this attention has been focused on Downloaded from journal.pda.org on July 18, 2016 large and small volume solutions products, but all types of injectables are important, including the IM suspension products There is an added reason, aside from the good practice aspects, to control particulate matter in suspensions This is because of the injectability problems that can occur from uncontrolled particles Powders for suspensions are usually crystallized or precipitated, collected on filters, washed, dried, milled, and/or micronized Processing includes several types of equipment and several transfer steps increasing the possibility of particulate matter such asfilterfibers,gasket materials, tubing, particles, etc It should be obvious that every effort should be made from the first step of the crystallization to the incorporation of the powder into a vehicle to the filling into a vial to exclude particulate matter Solutions can be rendered sterile by final filtration or terminal sterilization, but there is nothing that can be done to the final suspension to render it totally free of undesirable particulate matter ; Scale-up Problems: Preparing sterile suspensions on a small laboratory scale is difficult enough Having to prepare sterile suspensions on a production scale is possibly the most difficult of all production processes to master Recrystallization and size reduction techniques are common in large-scale manufacturing, but if these must be done under aseptic conditions, a significant challenge must be confronted Sterilization of drug and vehicle may not be unusually difficult, but aseptically combining, dispersing, and mixing drug and vehicle again cause great potential difficulties on a large scale Finally, aseptic filling offinishedsuspension into sterile containers and aseptically stoppering the container present real challenges for production engineers and technologists One of the major keys to successful scale-up preparation of sterile suspensions is to design and develop as simple a formulation as possible using conventional or reasonable methods of manufacture Evaluation of Parenteral Suspensions There are numerous tests and methods available and required for evaluation of suspension stability and performance Some references are recommended for further reading on this broad subject (6-8) In the case of parenteral suspensions, a particularly difficult property to possess and evaluate is the ability of the suspension to be withdrawn from a vial and ejected from a syringe This property and its evaluation will be discussed in some detail Additionally, this property as well as other physical properties is greatly affected by how the product is handled during distribution from manufacturer to user This article will conclude with a discussion of evaluation of the shipping characteristics of the suspension product Flow Properties Parenteral suspensions have distinct requirements for flow properties This requirement is especially significant when it is considered that parenteral suspensions are frequently administered through one inch or longer needles having internal diameters in the range of only 300-600 94 microns The flow properties of parenteral suspensions are usually characterized on the basis of syringeability and injectability Syringeability refers to the handling characteristics of a suspension while withdrawing it into and manipulating it in a syringe equipped with a properly sized needle Syringeability includes characteristics such as ease of withdrawal, clogging and foaming tendencies, and accuracy of dose measurement Injectability refers to performance of the suspension during injection It includes factors such as pressure or force required for injection, evenness of flow, aspiration qualities, and freedom from clogging The syringeability and injectability characteristics of a suspension are closely related to the viscosity and to the particle characteristics Although viscous suspensions may settle more slowly, they may require excessive pressure for injection Where viscosity is inherent because of high solids content and where it is required for good physical stability or for shipping qualities, an attempt is usually made to formulate a thixotropic suspension which will thin when agitated or expelled through the needle (9) Particle size and the particle size distribution both have an important bearing on the thixotropic structure and thus the success of this type approach to stabilization may be critically dependent on control of the particle characteristics during crystallization and throughout size reduction steps Clogging Clogging or blockage of the syringe needle while administering a suspension is very disconcerting to the clinician and may be traumatic for the patient Obviously every effort should be made to prevent its happening Clogging may result from several sources and by different mechanisms The most obvious cause of clogging would be that resulting from a single large particle or aggregate occluding the lumen of the needle Clogging may also result from a particle "bridging" effect This is most likely to occur when the suspension contains particles exceeding a certain size in relation to the needle diameter The size particle at which this begins to occur will be dependent on many factors but as a general rule, it is advisable to avoid any particle greater than 'A-'/j the needle I.D Particle shape plays an important role in a similar type blockage referred to as log-jamming Long needle-like crystals are believed more likely to produce this effect In contrast to occlusion or bridging which occurs in the needle shaft, clogging may also occur at or near the needle end Clogging of this type results when the flow of suspension out of the needle end is inhibited or restricted in some manner There is usually some separation of vehicle from the suspension particles which are left deposited in the needle as a dry plug This is generally the most serious type of clogging not only because of the incidence, but also because of the problems sometimes encountered in determining the source of difficulty A combination of factors may be involved including the vehicle, particle wetting, the particle size, shape and distribution, the suspension Journal of Parenteral Science & Technology Downloaded from journal.pda.org on July 18, 2016 ' viscosity and its Theological or flow characteristics Concentrated suspensions have a greater tendency to clog than the more dilute ones The injection rate and the technique may influence clogging Since there is really very little the manufacturer can to assure a particular injection technique will be followed, it is essential the suspension be as clog resistant as possible under actual conditions of use There are a variety of techniques and tests used in evaluating the injectability of suspensions As might be expected many of them are highly subjective in nature Syringeability The evaluation of syringeability is fairly straightforward It is determined using syringes equipped with one or more sizes of needles In selecting the needles, consideration should be given to both gauge and length of needle The test is performed by withdrawal of doses of suspension into the syringe, progressing from the larger to smaller bore needles The severity of the test and thus the level of confidence in the result will vary depending on the needles selected It should be noted that smaller needles may be used in pediatric practice Withdrawals should be at both rapid and slow rates It is sometimes helpful to make several short intermittent withdrawals each followed by a slight pause to allow the barrel to fill This start-stop technique provides a lag in the flow which accentuates the potential for particle build-up and clogging of the needle tip Depending on the characteristics of the suspension, it may be advisable to conduct withdrawal tests both before and after vigorous agitation Suspensions with a tendency to foam may present problems in dose measurement Also, some concentrated suspensions may become less syringeable following vigorous agitation because of dilatancy or a thickening in response to shear of agitation Some suspensions with dilatant properties may thicken as a result of being expelled through the syringe needle Due to the changes that may occur in a suspension upon aging such as aggregation, crystal growth, polymorphism, etc it is always advisable to include syringeability as one of the physical stability tests Injectability The most direct method of testing the injectability of a suspension is to inject it into a live animal Rabbits are frequently used for this purpose, but the results may not be as revealing as with larger animals with more rigid muscles The frequently large number of tests that may be needed in evaluating formulations coupled with the expense of animals and the relative inaccessability of animals to the development pharmacist usually make it desirable to have some laboratory method which can be used for the bulk of the evaluations A certain amount of information can be learned about the injectability of a suspension by the simple technique of ejection into the open This is done very slowly with only intermittent pressure applied to the plunger Suspensions with oversize particles and poor particle size distribution can frequently be made to clog using this technique As Vol 41, No 3/May-June 1987 with syringeability the severity of the test can be altered by changing the needle size There are two laboratory tests which we have found useful in assessing the injectability characteristics and clog resistance of some types of suspensions In one test, the suspension is ejected through fine mesh screen held firmly across the bevel opening This is best done by supporting the screen in a holder or frame The screen should be stretched tight and the needle held firmly in place so that suspension does not escape from around the bevel edge Care must also be taken to avoid puncturing the screen around the needle tip and across the bevel In another modification, a squared-off needle is inserted through a rubber stopper so that the end of the needle is just flush with the top surface The screen is then held firmly over the open end of the needle while ejecting the suspension through the screen Clogging which occurs with the screen test may be due to an induced "bridging" or the blinding of the screen opening with large particles The test is useful, however, in evaluating clogging resulting from less discernible factors such as the particle size distribution, the vehicle, and wetting, etc in which there may be separation of vehicle from suspension particles when the particle size is not directly responsible Another method useful in evaluating injectability utilizes a polyurethane sponge plug as the injection medium The test is simple and direct and offers a high degree of predictability as to the clog resistance of a suspension In performing the test, the sponge is wetted with water and squeezed free of any excess The injection is made directly into the sponge which may be held under various degrees of compression Glass cylinders or beakers of various diameters can be used to provide the desired compression The force or pressure required to inject a suspension is an important consideration Suspension characteristics having an effect include viscosity, concentration, Theological character, lubricity, and possibly particle characteristics The syringe bore and the needle length and gauge also affect the force required The simplest method for evaluating the pressure requirement is to manually expel the suspension or inject it into a suitable medium The method is probably acceptable on a pass-fail basis but it is of little use where quantitative data is needed to compare different formulations or batches A crude quantitative test can be run by placing thefilledsyringe in a holder or device equipped with a pan to which weights can be added The weight required to cause expulsion in a given time interval can be determined by trial and error A force monitoring device can be used to determine ejection and injection pressure The Instron device is one example of this type of instrument When equipped with an X-Y recorder a permanent record can be made of the test results Shipping Characteristics A suspension may show excellent physical stability while stored on the shelf in the plant and yet undergo setting and caking during shipment To guard against this, 95 Downloaded from journal.pda.org on July 18, 2016 it is important to determine that the product will withstand the various stresses of shipping such as vibration, impaction, shaking, etc For many suspensions actual shipment is the only satisfactory test method and then only if the product is shipped by a variety of methods and to different destinations The seriousness of settling, whether it occurs on the shelf or during shipment, depends on how easily the product can be resuspended to its original condition If the particles settle to a hard cake which cannot be simply resuspended, it may be not only a pharmaceutical matter but also one of clinical concern In devising laboratory procedures to simulate shipping conditions it is important to have some understanding, at least qualitatively, of the various types of motion generated during shipment and of the possible particle responses to these forces of motion In a suspension at rest on the shelf the major external force acting on the suspended particles is that of gravity The rate at which particles settle will be influenced by particle characteristics such as size, shape, and density and by vehicle characteristics such as viscosity and specific gravity Although Stoke's formula for sedimentation cannot be applied because of the interaction of particles which occurs in all but the very dilute suspensions it is still valid to consider that on the basis of gravity alone, the large particles will settle more rapidly than the smaller ones When dispersed particles settle in this manner it would be expected that the lower portions of the sediment would be richer in large particles than the upper portions and that there would be some progression in size from top to bottom When a suspension system is subjected to the various forms of motion occurring during shipment the particle response may be quite different resulting in different patterns of deposit in the sedimented cake The actual collective response is dependent on so many variables that it is usually not possible to predict the shipping behavior of a suspension on the basis of laboratory tests alone Common among the laboratory test methods are centrifuges, vibrators, shakers, and impact devices In most cases centrifuging is not a reliable method for estimating the shelf stability or the shipping quality of a suspension Vibrators and shakers are frequently combined to provide dual effect When properly adjusted, this combination can give a stiff test of the physical stability However, the adjustments are critical and it is possible to 96 keep the preparation in suspension rather than cause settling or caking If a suspension product is in the development stages, samples prepared for shipping test evaluation should be packaged in the same manner and bulk mass as would be planned for the marketed product Where temperature control is important, a recorder should be sent to monitor the temperature Shipping containers holding test samples should always be shipped both directions in the same position Otherwise a product might cake while being shipped in one direction and then become resuspended if turned over for the return trip A small position indicator should be included with the shipment Summary To design and develop parenteral suspension formulations is not an easy task Many factors interplay in the ultimate achievement of a stable, resuspendable, and usable sterile suspension product This article has attempted to identify the most important factors involved in suspension development and provide practical information to assist the formulator in developing as ideal a parenteral suspension as possible References Carstensen T J., Theory of Pharmaceutical Sys:ems, Vol 11, Academic Press, NY, 1973 p 59 Nash, R A., "The pharmaceutical suspension Part 1," Drug Cosmet Ind 97, 843, (1965) Physicians' Desk Reference, 39th ed Medical Economics Co., Inc., Oradell NJ, 1985 Higuchi W I., Swarbrick, J., Ho N F H„ Simonelli A P., and Martin, A., "Particle phenomena and coarse dispersions," Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 1985 Chap 21 p 314 Feldman, S., "Physicochemical factors influencing drug absorption from the intramuscular injection site," Bull Parenter Drug Assoc 28,53,(1974) Hiestand E N., "Theory of coarse suspension formulation," J Pharm Sci 53, 1,(1964) Portnoff J B., Cohen, E M., and Henley M W., "Development of parenteral and sterile ophthalmic suspensions—The R&D approach." Bull Parenter Drug Assoc, 31,136, (1977) Patel, N K., Kennon, L., and Levinson, R S., "Pharmaceutical suspensions," The Theory and Practice of Industrial Pharmacy 3rd ed Lachman L., Lieberman H A., and Kanig, J L., eds Lea & Febiger, Philadelphia, PA, 1986, pp 479-501 Boylan, J and Robison, R., "Rheological stability of a procaine pencillin G suspension." J Pharm Sci., 57, 1796, (1968) Journal of Parenteral Science & Technology Downloaded from journal.pda.org on July 18, 2016 An Authorized User of the electronic PDA Journal of Pharmaceutical Science and Technology (the PDA Journal) is a PDA Member in good standing Authorized Users are permitted to the following: ·Search and view the content of the PDA Journal ·Download a single article for the individual use of an Authorized User ·Assemble and distribute links that point to the PDA Journal ·Print individual articles from the PDA Journal for the individual use of an Authorized User ·Make a reasonable number of photocopies of a printed article for the individual use of an Authorized User or for the use by or distribution to other Authorized Users Authorized Users are not permitted to the following: ·Except as mentioned above, allow anyone other than an Authorized User to use or access the PDA Journal · Display or otherwise make any information from the PDA Journal available to anyone other than an Authorized User ·Post articles from the PDA Journal on Web sites, either available on the Internet or an Intranet, or in any form of online publications ·Transmit electronically, via e-mail or any other file transfer protocols, any portion of the PDA Journal ·Create a searchable archive of any portion of the PDA Journal ·Use robots or intelligent agents to access, search and/or systematically download any portion of the PDA Journal ·Sell, re-sell, rent, lease, license, sublicense, assign or otherwise transfer the use of the PDA Journal or its content ·Use or copy the PDA Journal for document delivery, fee-for-service use, or bulk reproduction or distribution of materials in any form, or any substantially similar commercial purpose ·Alter, modify, repackage or adapt any portion of the PDA Journal ·Make any edits or derivative works with respect to any portion of the PDA Journal including any text or graphics ·Delete or remove in any form or format, including on a printed article or photocopy, any copyright information or notice contained in the PDA Journal ... 28,53,(1974) Hiestand E N., "Theory of coarse suspension formulation, " J Pharm Sci 53, 1,(1964) Portnoff J B., Cohen, E M., and Henley M W., "Development of parenteral and sterile ophthalmic suspensions? ??The... the tank and striking the baffle plate to spread into an easily deaerated film Parenteral suspensions, as a result of the method of manufacture and handling of the powder or as a result of the... scale-up preparation of sterile suspensions is to design and develop as simple a formulation as possible using conventional or reasonable methods of manufacture Evaluation of Parenteral Suspensions There