Formulation design and development of parenteral suspensions

ROBISON Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana Introduction Parenteral suspensions are dispersed, heterogeneous systems containing insoluble drug p

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PDA J Pharm Sci and Tech

M J Akers, A L Fites and R L Robison

Formulation Design and Development of Parenteral Suspensions

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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

intrave-nously or intra-arterially

There are at least three reasons why parenteral

suspen-sions are developed:

1 The drug is too insoluble to be formulated as a

solution

2 The drug is more stable as a suspended solid than in

solution

3 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

phar-maceutical 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

1 Resuspension of drug particles occurs easily with

mild shaking

2 The dispersed particles do not settle rapidly after

• shaking

3 Resuspension produces a homogeneous mix of drug

particles such that the same concentration of drug

can be removed repeatedly

4 During the shelf-life of the suspension product no

hard cake, too difficult to redisperse, will form

5 The suspension product maintains its stability and

elegance during its shelf-life

Parenteral suspensions must possess at least two

addi-tional characteristics:

6 The suspension product is manufactured and tested

to be free from microbial contamination and main-tains its sterility during its storage and use

7 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 suspend-ing agents, viscosity-inducers, wettsuspend-ing agents, stabilizers, and preservatives This is because of very stringent re-quirements regarding safety and performance of paren-teral ingredients not required of other dosage form ingre-dients (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 recog-nized which, in reality, frequently are prevalent and pro-vide incredible challenges to the development scientist The most important of these are: crystal growth, caking, and product-package interactions Other factors dis-cussed in the following sections include syringeability and scale-up problems

Crystal Growth

The following factors affect the potential for crystal growth in pharmaceutical suspensions:

1 particle size distribution

2 dissolution and «crystallization

3 changes in pH and temperature

4 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, 7 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

Received December 23 1986 Accepted for publication April 9, 1987

4 Author to whom inquiries should be directed

1 Sterile, in context of this paper, also includes freedom from

pyrogen-ic contamination

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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

vari-ous factors including: (a) preparation of the suspension by

precipitation methods where the degree of

supersatura-tion and rate of nucleasupersatura-tion 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,

viscosity-inducing agents are included in the formulation

Increas-ing viscosity minimizes the probability of crystal growth

according to Eq 2 (1)

k„ = Ae-"" +à (Eq 2)

where k cr 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,

polyvinyl-pyrrolidone, polysorbates) will adsorb at particle surfaces

and retard crystal growth

Crystal growth as a result of dissolution and

recrystalli-zation phenomena is also caused by polymorphism,

sol-vate formation, and temperature flucuations All organic

compounds have different crystal structures, in turn

de-pendent on solvent(s) used to crystallize the drug,

differ-ent cooling or drying rates, and storage temperature The

use of polymorphic forms other than the most

thermody-namically 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

ener-getic crystal, will more likely develop large crystals

Temperature fluctuations cause drug crystals to be

sub-ject to undersaturated conditions for awhile then to

satu-rated conditions and so forth Not only will small crystals

disappear and large crystals grow, but also chemical

insta-bility of the drug likely may occur

Thus, to minimize crystal growth the formulator must

understand the theory behind the formation of large

parti-cles, 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

stud-ies to evaluate the rate and extent of temperature effects

on physical as well as chemical stability of the

suspen-sion

Caking

The inability to resuspend drug particles upon shaking usually results from particles settling as a hardened ment at the bottom of the container This hardened sedi-ment, 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 Defloccu-lated systems by their definition will settle slowly as indi-vidual particles which will become closely packed sedi-ments Thus, complete dispersion of small, narrow-ranged particles with appropriate amounts of wetting agent and/

or other agents which increase zeta potential will mini-mize the tendency of these particles to agglomerate and form a hard cake

Product-Package Interactions

Two potential problems may occur with a rubber stop-pered vial containing a suspension

1 Agglomeration of fine particles on the surface of the glass promoted by changes in temperature and hand-ling of the stored vials (shipping test) Efficient sili-conization of the vial will promote efficient drainage

of the suspension and reduce the probability of parti-cle agglomeration

2 Interactions between product and rubber closure Extractables from the closure might be masked in a cloudy suspension product Antimicrobial preserva-tives and antioxidants are known to volatilize or adsorb through the rubber closure causing not only potential loss of sterility and stability but also prob-lems 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

close-ly as possible What are some of the things the formulator

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TABLE II Brief Descripiion

Drug

1 Aurothioglucose

2 Betamethasone Sodium

of Marketed Parenteral Suspension

Phosphate and Betamethasone acetate

3 Desoxycorticosterone

Pivalate

4 Dexamethasone acetate

5 Hydrocortisone acetate

6 Methylprednisoione acetate

7 Medroxyprogesterone acetate

Brand Name Solganol®

Celestone®

Soluspan®

Percorten®

Pivalate

Decadron-LA®

Hydrocortone®

Acetate sterile ophthalmic suspension

Depo-Medrol®

Depo-Provera®

Products Manufacturer Schering

Schering

CIBA

Merck

Merck

Upjohn

Upjohn

Strength(s)

50 mg

3 mg/mL

3 mg/mL

25 mg/mL

8 mg/mL

25 mg/mL

20, 40, 80 mg/mL

100 and 400 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

can do 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,

syrin-geability, 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

rela-tively simple and contains relarela-tively few ingredients This

is because of the strict requirements governing the type

and amount of additives acceptable for parenteral

admin-istration Acceptability of an additive usually means that

at low concentrations it is nontoxic, nonantigenic, nonirri-tating, nonhemolytic, and nonpyrogenic Such strict re-quirements limit the actual number of parenterally ac-ceptable formulation additives A partial review of paren-teral suspensions described in the 1985 Physicians' Desk Reference (3) will indicate that most suspensions are com-posed of water insoluble drugs in relatively simple formu-lations used for noncontrolled release of the drug (Table II)

Flocculated vs Deflocculated Suspensions

The formulator should also understand the basic differ-ences between flocculated and deflocculated suspensions (4)

Deflocculated Flocculated

1 Particles exist in sus- Particles form loose aggre-pension as separate en- gates

tities

2 Rate of sedimentation is Rate of sedimentation is slow, since each particle high, since particles settle settles separately and as a floe, which is a collec-particie size is minimal, tion of particles

3 A sediment is formed A sediment is formed rap-slowly, idly

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TABLE II Continued

Drug

8 Penicillin G Benzothine and

Penicillin G Procaine

9 Penicillin G Procaine

10 Prednisolone Acetate

11 Pednisolone Tebutate

12 Triamcinolone acetonide

13 Triamcinolone diacetate

14 Triamcinolone hexacetonide

Brand Name

Bicillin® C-R

Bicillin® C-R Crysticillin®

Penicillin G Procaine Pflizerpen®-AS Wycillin®

Metimyd® Ophthalmic

Hydeltra-T.B.A.®

Kenalog®

Aristocort®

Aristospan®

Manufacturer

Wyeth

Wyeth Squibb Lilly Pfipharmecs Wyeth Schering

Merck

Squibb

Lederle

Lederle

Strength(s) 600,000 U/mL

300,000

U / m L

5 mg/mL

20 mg/mL

10,40 mg/

mL

40 mg/mL

5,20 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

4 The sediment eventual- The sediment is loosely

ly becomes very closely packed and possesses a

packed, due to weight scaffold-like structure

of upper layers of sedi- Particles do not bond

tight-menting material Re- ly to each other and a

pulsive forces between hard, dense cake does not

particles are overcome form The sediment is easy

and a hard cake is to redisperse, so as to

re-formed which is diffi- form the original

suspen-cult, if not impossible, sion

to redisperse

5 The suspension has a The suspension is

some-pleasing appearance, what unsightly, due to

rap-since the suspended ma- id sedimentation and the

terial remains suspend- presence of an obvious,

ed for a relatively long clear superantant region,

time The supernatant This can be minimized if

also remains cloudy, the volume of sediment is

even when settling is made large Ideally,

vol-apparent urne of sediment should

encompass the volume of the suspension

Flocculated suspensions are the more common type of

parenteral suspension because most injectable

suspen-sions contain low concentrations of solids Additionally,

they are easier to formulate, less viscous and have less potential to cause physical stability problems The defloc-culated approach is used for oleaginous suspensions (where low dielectric constant causes a very thick double layer) and for suspension containing relatively high con-centrations of solids, e.g., procaine pencillin G

Two Hypothetical Examples of Parenteral Suspension Formulation

1 Compound A is an insoluble steroid, stable, and effective at a dose of 2 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 charac-teristics for use in a suspension In formulating Compound

A, the major consideration beyond the basic requirements for injections would probably involve methods of produc-ing a physically stable suspension which would remain homogeneous or which could be readily and completely resuspended to a homogenous suspension Although re-suspension is important for all types of re-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

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toxicity problem Large particles might be released too

slowly for it to be effective Because of the low

concentra-tion Compound A suspension particles, per se would

likely not have much effect on the total suspension

charac-teristics Flocculation would seem to be a logical approach

to the desired product characteristics A viscosity

impart-ing agent should be avoided because of the possible

ce-menting action on sedimented particles

2 Compound B is slightly soluble, saturated solutions

show some instability, it gives effective blood levels

fol-lowing 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

concen-tration should improve chemical stability, prolong activity

through a slower release rate, and decrease the frequency

of injection Suspension properties will be greatly

depen-dent upon the particle characteristics The high

concen-tration 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

Floccula-tion would not be applicable because the void spaces are

already filled with solids One approach would be to

at-tempt 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

ad-ministration (5) Solubility, particle size, and drug

con-centration 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

inject-ed, he can manipulate drug particle size to achieve

differ-ent rates and durations of drug release from the

suspen-sion formulation

The profound effect of particle size on drug availability

from suspensions makes it imperative that the

formula-tion 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

applica-tion of this viscosity effect is to develop thixotropic

sus-pensions Thixotropic suspensions are highly viscous un-shaken or with minor agitation However, when

vigorous-ly shaken the viscosity is greatvigorous-ly reduced Thus, shaking will allow the suspension to readily flow for resuspendabi-lity, syringeabiresuspendabi-lity, 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 prod-uct, must be knowledgeable of the basic methods of paren-teral suspension manufacturers Two basic methods are used to prepare parenteral suspensions: (7) sterile powder and vehicle are combined aseptically, or (2) sterile

solu-tions 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

1 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 appropri-ate solvent The retained drug crystals are dried and milled

2 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

3 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 evapo-rates 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, tem-perature, pH, and concentration must be controlled dur-ing a sterile crystallization to obtain a crystalline material with comparable density characteristics from each crys-tallization

Once the sterile powder is dried sufficiently, it will

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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

Jet-O-Mizer or Gem Mill are more practical They are

avail-able 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

aque-ous 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

precipita-tion method The vehicle is prepared and sterilized The

testosterone is dissolved in an organic solvent and sterile

filtered The testosterone and solvent are aseptically

add-ed 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

protamine-insulin which contains no excess of either protamine or

insulin Isophane insulin is prepared by dissolving zinc

insulin and protamine sulfate at pH 3 to 4 in Water for

Injection containing glycerin, phenol, and cresol A

sec-ond 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

sus-pension 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

follow-ing formula Each mL contains 300,000 units crystalline

penicillin G procaine; sodium citrate, 4%; lecithin, 1%; povidone, 0.1%; with methylparaben, 0.15%, propylpara-ben, 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

add-ed

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 penicil-lin G procaine powder is then incorporated with continu-ous agitation The penicillin powder is obtained from a sterile controlled crystallization procedure and is asepti-cally micronized to obtain the proper surface area After all the powder has been incorporated, the suspen-sion is agitated at a high speed to produce a homogenous suspension The suspension is transferred through stain-less-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 manufac-ture 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 equip-ment 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 suspen-sion because of stability consideration or Theological ef-fects or it may present problems in filling or dose control Suspensions with a persistent air problem may require deaeration by vacuum or other means Suspension deaera-tion 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 acci-dentally 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 aggre-gation Various types of glass and plastic syringe units are also utilized

2 Particulate Matter Control: Particulate matter in

injectables has received increased attention during the past decade Most of this attention has been focused on Vol 41 No 3/May-June 1987

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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

suspen-sions This is because of the injectability problems that

can occur from uncontrolled particles Powders for

sus-pensions are usually crystallized or precipitated, collected

on filters, washed, dried, milled, and/or micronized

Processing includes several types of equipment and

sever-al transfer steps increasing the possibility of particulate

matter such as filter fibers, gasket materials, tubing,

par-ticles, etc It should be obvious that every effort should be

made from the first step of the crystallization to the

incor-poration of the powder into a vehicle to the filling into a

vial to exclude particulate matter Solutions can be

ren-dered sterile by final filtration or terminal sterilization,

but there is nothing that can be done to the final

suspen-sion to render it totally free of undesirable particulate

matter ;

3 Scale-up Problems: Preparing sterile suspensions on

a small laboratory scale is difficult enough Having to

prepare sterile suspensions on a production scale is

possi-bly the most difficult of all production processes to

mas-ter 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,

dis-persing, and mixing drug and vehicle again cause great

potential difficulties on a large scale Finally, aseptic

fill-ing of finished suspension into sterile containers and

asep-tically stoppering the container present real challenges for

production engineers and technologists One of the major

keys to successful scale-up preparation of sterile

suspen-sions 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

perfor-mance Some references are recommended for further

reading on this broad subject (6-8) In the case of

paren-teral suspensions, a particularly difficult property to

pos-sess 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

de-tail Additionally, this property as well as other physical

properties is greatly affected by how the product is

han-dled 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

fre-quently administered through one inch or longer needles

having internal diameters in the range of only 300-600

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 Syrin-geability includes characteristics such as ease of with-drawal, 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 pres-sure 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 characteris-tics during crystallization and throughout size reduction steps

Clogging

Clogging or blockage of the syringe needle while ad-ministering a suspension is very disconcerting to the clini-cian 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 differ-ent 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 parti-cles 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 suspen-sion 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 deter-mining the source of difficulty A combination of factors may be involved including the vehicle, particle wetting, the particle size, shape and distribution, the suspension

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' viscosity and its Theological or flow characteristics

Con-centrated suspensions have a greater tendency to clog

than do the more dilute ones

The injection rate and the technique may influence

clogging Since there is really very little the manufacturer

can do 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

straightfor-ward It is determined using syringes equipped with one or

more sizes of needles In selecting the needles,

consider-ation should be given to both gauge and length of needle

The test is performed by withdrawal of doses of

suspen-sion into the syringe, progressing from the larger to

small-er bore needles The sevsmall-erity 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

fol-lowed by a slight pause to allow the barrel to fill This

start-stop technique provides a lag in the flow which

ac-centuates 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

syringea-ble following vigorous agitation because of dilatancy or a

thickening in response to shear of agitation Some

suspen-sions 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

ex-pense of animals and the relative inaccessability of

ani-mals to the development pharmacist usually make it

desir-able 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

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

insert-ed through a rubber stopper so that the end of the neinsert-edle 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 uti-lizes 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 di-ameters can be used to provide the desired compression The force or pressure required to inject a suspension is an important consideration Suspension characteristics hav-ing 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 re-quirement is to manually expel the suspension or inject it into a suitable medium The method is probably accept-able on a pass-fail basis but it is of little use where quanti-tative data is needed to compare different formulations or batches A crude quantitative test can be run by placing the filled syringe 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,

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it is important to determine that the product will

with-stand 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

origi-nal condition If the particles settle to a hard cake which

cannot be simply resuspended, it may be not only a

phar-maceutical 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

generat-ed 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

oc-curs in all but the very dilute suspensions it is still valid to

consider that on the basis of gravity alone, the large

parti-cles will settle more rapidly than the smaller ones When

dispersed particles settle in this manner it would be

ex-pected 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

bot-tom 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

pat-terns of deposit in the sedimented cake The actual

collec-tive 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,

vibra-tors, 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

com-bined 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

keep the preparation in suspension rather than cause set-tling 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 formula-tions is not an easy task Many factors interplay in the ultimate achievement of a stable, resuspendable, and us-able sterile suspension product This article has attempted

to identify the most important factors involved in suspen-sion development and provide practical information to assist the formulator in developing as ideal a parenteral suspension as possible

References

1 Carstensen T J., Theory of Pharmaceutical Sys:ems, Vol 11,

Aca-demic Press, NY, 1973 p 59

2 Nash, R A., "The pharmaceutical suspension Part 1," Drug Cosmet

Ind 97, 843, (1965)

3 Physicians' Desk Reference, 39th ed Medical Economics Co., Inc.,

Oradell NJ, 1985

4 Higuchi W I., Swarbrick, J., Ho N F H„ Simonelli A P., and

Martin, A., "Particle phenomena and coarse dispersions,"

Reming-ton's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA,

1985 Chap 21 p 314

5 Feldman, S., "Physicochemical factors influencing drug absorption

from the intramuscular injection site," Bull Parenter Drug Assoc

28,53,(1974)

6 Hiestand E N., "Theory of coarse suspension formulation," J

Pharm Sci 53, 1,(1964)

7 Portnoff J B., Cohen, E M., and Henley M W., "Development of parenteral and sterile ophthalmic suspensions—The R&D

ap-proach." Bull Parenter Drug Assoc, 31,136, (1977)

8 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

9 Boylan, J and Robison, R., "Rheological stability of a procaine

pencillin G suspension." J Pharm Sci., 57, 1796, (1968)

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