0840-0843 [1191] Stability Considerations in Dispensing Practice

8/15/2019 0840-0843 [1191] Stability Considerations in Dispensing Practice

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840 〈1184〉 Sensitization Testing / General Information USP 35

all evaluation, should the results of the study provide a sig-Vitamin A Enhancement Testnificant result of the statistical test at p < 0.01 for the con-trol versus test group comparisons, or if at least two testThis test is similar to the Mouse Ear Swelling Test in thatanimals have ear thickness increases in excess of 50% of thetest articles are applied topically to the abdomen, with amaximum control thickness changes and the group compar-challenge application to the ears, followed by measurementsison showed a p < 0.05, sensitization is indicated for the testof ear thickness. A principal difference is the use of mousearticle. feed supplemented with vitamin A acetate. The purpose of

the supplementation is to increase the reactivity of the im-mune system, thereby increasing the potential sensitizationreaction.

ANIMALS

〈1191〉 STABILITYMale, 3- to 4-week old Balb/c mice should be maintained

on a diet supplemented with vitamin A acetate. The diet CONSIDERATIONS INmay be prepared by mixing each kg of feed with 0.477 g of gelatinized vitamin A acetate. The feed mixture should be DISPENSING PRACTICEused within 3 weeks of preparation. Mice intended for usein sensitization studies should have been on the supple-mented diet for at least 4 weeks. The mice at the time of

NOTE—Inasmuch as this chapter is for purposes of generalthe sensitization study should therefore be between 7 andinformation only, no statement in the chapter is intended to10 weeks old. The thickness of both ears of each animalmodify or supplant any of the specific requirements perti-should be measured and recorded at this time.nent to Pharmacopeial articles, which are given elsewhere in

this Pharmacopeia.TEST

MATERIAL

PREPARATION Aspects of drug product stability that are of primary con-cern to the pharmacist in the dispensing of medications are

Although, in theory, one could apply a solid test article to discussed herein.the dorsal surface of the ear of a mouse, in practice an Pharmacists should avoid ingredients and conditions thatextract of such an article should be used. See Biological Re- could result in excessive physical deterioration or chemicalactivity Tests, In Vivo 〈88〉 for information on the extraction. decomposition of drug preparations, especially when com-

pounding (see Pharmaceutical Compounding—Nonsterile Preparations 〈795〉). The stability and clinical effect of manu-

PRELIMINARY TESTING factured dosage forms can be greatly compromised byseemingly negligible alterations or inappropriate prescription

The maximally nonirritating dose and minimally irritating compounding. Pharmacists should establish and maintainconcentrations should be determined using separate groups compounding conditions that include the ensuring of drugof animals. This could be done as described for Preliminary stability to help prevent therapeutic failure and adverseTesting in the Mouse Ear Swelling Test. responses.

Stability—Stability is defined as the extent to which aproduct retains, within specified limits, and throughout its

INDUCTION PHASE

period of storage and use (i.e., its shelf-life), the sameproperties and characteristics that it possessed at the time of The fur of the abdomen and thorax of 10 mice per group its manufacture. Five types of stability generally recognized

should be shaved. Then 100 µL of test article (at the mini- are shown in the accompanying table.mally irritating concentration) should be applied to the testareas on days 0, 2, 4, 7, and 11. Control animals receive

Criteria for Acceptable Levels of Stability100 µL of vehicle alone on the same schedule.Type of Conditions Maintained Throughout theStability Shelf Life of the Drug Product

CHALLENGE PHASEChemical Each active ingredient retains its chemical in-

tegrity and labeled potency, within the spec-This phase should occur 4 days after the final applicationified limits.of the Induction Phase . Twenty-five µL of test article (at the

Physical The original physical properties, including ap-maximally nonirritating concentration) should be applied topearance, palatability, uniformity, dissolu-each ear of each animal in the test and control groups.tion, and suspendability, are retained.

Microbiological Sterility or resistance to microbial growth isOBSERVATIONS retained according to the specified require-

ments. Antimicrobial agents that are presentEar thickness for both ears of each animal should be re- retain effectiveness within the specified lim-

corded after 24 and 48 hours postchallenge. The measure- its.ments should be made with a caliper (a spring-loaded cali- Therapeut ic The therapeutic effect remains unchanged.per is preferable). The percent increase in ear thickness

Toxicological No significant increase in toxicity occurs.should be calculated for each ear by subtracting the pre-treatment measurement from the post-treatment measure-ment, dividing the result by the pretreatment measurement,then multiplying by 100. The response of the test group FACTORS AFFECTING PRODUCT STABILITYversus the control group should be compared statistically.(The Mann-Whitney U test could be used for the Each ingredient, whether therapeutically active or phar-comparison.) maceutically necessary, can affect the stability of drug sub-

The results of individual animals should also be calculated. stances and dosage forms. The primary environmental fac-If an increase in ear thickness for an animal from the test tors that can reduce stability include exposure to adversegroup is at least 50% greater than the largest increase of a temperatures, light, humidity, oxygen, and carbon dioxide.control animal, that is indicative of sensitization. As an over- The major dosage form factors that influence drug stability

ff c a from ay 1 2012

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Accessed from 128 83 63 20 by nEwp0rt1 on Sat Dec 03 01:39:36 EST 2011


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USP 35 General Information / 〈1191〉 Stability Considerations in Dispensing Practice 841

include particle size (especially in emulsions and suspen- sults from the influence of ionic strength on interionic at-sions), pH, solvent system composition (i.e., percentage of traction. In general, the hydrolysis rate constant is inversely“free” water and overall polarity), compatibility of anions proportional to the ionic strength with oppositely chargedand cations, solution ionic strength, primary container, spe- ions (e.g., drug cation and excipient anions) and directlycific chemical additives, and molecular binding and diffusion proportional to the ionic strength with ions of like charge. Aof drugs and excipients. In dosage forms, the following re- reaction that produces an ion of opposite charge to theactions usually cause loss of active drug content, and they original drug ion because of the increasing ionic strength,usually do not provide obvious visual or olfactory evidence can increase the drug hydrolysis rate as the reaction pro-

of their occurrence. ceeds. High ionic strength of inorganic salts can also reducethe solubility of some other drugs.Hydrolysis—Esters and β -lactams are the chemical bonds

that are most likely to hydrolyze in the presence of water. pH Effect—The degradation of many drugs in solutionFor example, the acetyl ester in aspirin is hydrolyzed to ace- accelerates or decelerates exponentially as the pH is de-tic acid and salicylic acid in the presence of moisture, but in creased or increased over a specific range of pH values. Im-a dry environment the hydrolysis of aspirin is negligible. The proper pH ranks with exposure to elevated temperature as aaspirin hydrolysis rate increases in direct proportion to the factor most likely to cause a clinically significant loss of water vapor pressure in an environment. drug, resulting from hydrolysis and oxidation reactions. A

The amide bond also hydrolyzes, though generally at a drug solution or suspension, for example, may be stable for slower rate than comparable esters. For example, procaine days, weeks, or even years in its original formulation, but(an ester) will hydrolyze upon autoclaving, but procaina- when mixed with another liquid that changes the pH, itmide will not. The amide or peptide bond in peptides and degrades in minutes or days. It is possible that a pH changeproteins varies in the lability to hydrolysis. of only 1 unit (e.g., from 4 to 3 or 8 to 9) could decrease

The lactam and azomethine (or imine) bonds in benzodi- drug stability by a factor of 10 or greater.azepines are also labile to hydrolysis. The major chemical A pH buffer system, which is usually a weak acid or baseaccelerators or catalysts of hydrolysis are adverse pH and and its salt, is a common excipient used in liquid prepara-specific chemicals (e.g., dextrose and copper in the case of tions to maintain the pH in a range that minimizes the drugampicillin hydrolysis). degradation rate. The pH of drug solutions may also be ei-

ther buffered or adjusted to achieve drug solubility. For ex-Epimerization—Members of the tetracycline family areample, pH in relation to pKa controls the fractions of themost likely to incur epimerization. This reaction occurs rap-usually more soluble ionized and less soluble nonionizedidly when the dissolved drug is exposed to a pH of an inter-species of weak organic electrolytes.mediate range (higher than 3), and it results in the steric

The influence of pH on the physical stability of two phaserearrangement of the dimethylamino group. The epimer of systems, especially emulsions, is also important. For exam-tetracycline, epitetracycline, has little or no antibacterialple, intravenous fat emulsion is destabilized by acidic pH.activity.

Interionic (IonN+–IonN–) Compatibility—The compatibil-Decarboxylation—Some dissolved carboxylic acids, suchity or solubility of oppositely charged ions depends mainlyas p-aminosalicylic acid, lose carbon dioxide from the car-on the number of charges per ion and the molecular size of boxyl group when heated. The resulting product has re-the ions. In general, polyvalent ions of opposite charge areduced pharmacological potency.more likely to be incompatible. Thus, an incompatibility isβ -Keto decarboxylation can occur in some solid antibioticslikely to occur upon the addition of a large ion with athat have a carbonyl group on the β -carbon of a carboxyliccharge opposite to that of the drug.acid or a carboxylate anion. Such decarboxylations will oc-

cur in the following antibiotics: carbenicillin sodium, Solid State Stability—Solid state reactions are relatively

carbenicillin free acid, ticarcillin sodium, and ticarcillin free slow; thus, stability of drugs in the solid state is rarely aacid. dispensing concern. The degradation rate of dry solids isusually characterized by first-order kinetics or a sigmoidDehydration— Acid-catalyzed dehydration of tetracyclinecurve. Therefore, solid drugs with lower melting point tem- forms epianhydrotetracycline, a product that both lacks an-peratures should not be combined with other chemicals thattibacterial activity and causes toxicity.would form a eutectic mixture.Oxidation—The molecular structures most likely to oxi-

When moisture is present, the solid drug decompositiondize are those with a hydroxyl group directly bonded to anmay change to zero-order chemical kinetics because the ratearomatic ring (e.g., phenol derivatives such as catecho-is controlled by the relatively small fraction of the drug thatlamines and morphine), conjugated dienes (e.g., vitamin Aexists in a saturated solution, which is located (usually im-and unsaturated free fatty acids), heterocyclic aromaticperceptibly) at the surface or in the bulk of the solid drugrings, nitroso and nitrite derivatives, and aldehydes (e.g., fla-product.vorings). Products of oxidation usually lack therapeutic activ-

Temperature—In general, the rate of a chemical reactionity. Visual identification of oxidation, for example, theincreases exponentially for each 10° increase in temperature.change from colorless epinephrine to its amber coloredThis relationship has been observed for nearly all drug hy-products, may not be visible in some dilutions or to somedrolysis and some drug oxidation reactions. The actual fac-eyes.tor of rate increase depends on the activation energy of theOxidation is catalyzed by pH values that are higher thanparticular reaction. The activation energy is a function of theoptimum, polyvalent heavy metal ions (e.g., copper andspecific reactive bond and the drug formulation (e.g., sol-iron), and exposure to oxygen and UV illumination. The lat-vent, pH, additives). As an example, consider a hydrolyzableter two causes of oxidation justify the use of antioxidantdrug that is exposed to a 20° increase in temperature, suchchemicals, nitrogen atmospheres during ampul and vial fill-as that from cold to controlled room temperature (see Gen-ing, opaque external packaging, and transparent amber eral Notices and Requirements ). The shelf life of the drug atglass or plastic containers.controlled room temperature should be expected to de-Photochemical Decomposition—Exposure to, primarily,crease to one-fourth to one-twenty-fifth of its shelf life under UV illumination may cause oxidation (photo-oxidation) andrefrigeration.scission (photolysis) of covalent bonds. Nifedipine, nitroprus-

The pharmacist should also be aware that inappropriatelyside, riboflavin, and phenothiazines are very labile to photo-cold temperatures may cause harm. For example, refrigera-oxidation. In susceptible compounds, photochemical energytion may cause extreme viscosity in some liquid drugs andcreates free radical intermediates, which can perpetuatecause supersaturation in others. Freezing may either breakchain reactions.or cause a large increase in the droplet size of emulsions; it

Ionic Strength—The effect of the total concentration of can denature proteins; and in rare cases, it can cause lessdissolved electrolytes on the rate of hydrolysis reactions re- soluble polymorphic states of some drugs to form.





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842 〈1191〉 Stability Considerations in Dispensing Practice / General Information USP 35

The chemical potency of the active ingredient(s) is re-STABILITY STUDIES IN MANUFACTURINGquired to remain within the limits specified in the mono-graph definition. Potency is determined by means of an as-The scope and design of a stability study vary accordingsay procedure that differentiates between the intactto the product and the manufacturer concerned. Ordinarilymolecule and its degradation products. Chemical stabilitythe formulator of a product first determines the effects of data should be available from the manufacturer. Althoughtemperature, light, air, pH, moisture, trace metals, and com-chemical degradation ordinarily cannot be detected by themonly used excipients or solvents on the active ingredi-pharmacist, excessive chemical degradation sometimes is ac-ent(s). From this information, one or more formulations of companied by observable physical changes. In addition,each dosage form are prepared, packaged in suitable con-some physical changes not necessarily related to chemicaltainers, and stored under a variety of environmental condi-potency, such as change in color and odor, formation of ations, both exaggerated and normal. See Pharmaceutical Sta-precipitate, or clouding of solution, may serve to alert thebility 〈1150〉. At appropriate time intervals, samples of thepharmacist to the possibility of a stability problem. It shouldproduct are assayed for potency by use of a stability-indicat-be assumed that a product that has undergone a physicaling method, observed for physical changes, and, where ap-change not explained in the labeling may also have under-plicable, tested for sterility and or for resistance to microbialgone a chemical change, and such a product is never to begrowth and for toxicity and bioavailability. Such a study, indispensed. Excessive microbial growth, contamination, or combination with clinical and toxicological results, enablesboth, may also appear as a physical change. A gross changethe manufacturer to select the optimum formulation andin a physical characteristic such as color or odor is a sign of container and to assign recommended storage conditionsinstability in any product. Other common physical signs of and an expiration date for each dosage form in its package.deterioration of dosage forms include the following.

Solid Dosage Forms— Many solid dosage forms are de-Responsibility of Pharmacists signed for storage under low-moisture conditions. They re-

quire protection from environmental water and thereforePharmacists help to ensure that the products under their should be stored in tight containers (see Containers in the

supervision meet acceptable criteria of stability by (1) dis- General Notices ) or in the container supplied by the manu-pensing oldest stock first and observing expiration dates, (2) facturer. The appearance of fog or liquid droplets, or clump-storing products under the environmental conditions stated ing of the product, inside the container signifies improper in the individual monographs, labeling, or both, (3) observ- conditions. The presence of a desiccant inside the manufac-ing products for evidence of instability, (4) properly treating turer’s container indicates that special care should be takenand labeling products that are repackaged, diluted, or in dispensing. Some degradation products, for example, sali-mixed with other products, (5) dispensing in the proper cylic acid from aspirin, may sublime and be deposited ascontainer with the proper closure, and (6) informing and crystals on the outside of the dosage form or on the walls of educating patients concerning the proper storage and use the container.of the products, including the disposition of outdated or

HARD AND SOFT GELATIN CAPSULES—Since the capsule formu-excessively aged prescriptions. lation is encased in a gelatin shell, a change in gross physi-

Rotation of Stock and Observance of Expiration cal appearance or consistency, including hardening or soft-Dates—Proper rotation of stock is necessary to ensure the ening of the shell, is the primary evidence of instability.dispensing of suitable products. A product that is dispensed Evidence of release of gas, such as a distended paper seal, isinfrequently should be closely monitored so that old stocks another sign of instability.are given special attention, particularly with regard to expi-

UNCOATED TABLETS—Evidence of physical instability in un-ration dates. The manufacturer can guarantee the quality of

coated tablets may be shown by excessive powder and/or a product up to the time designated as its expiration date pieces (i.e., crumbling as distinct from breakage) of tablet atonly if the product has been stored in the original container the bottom of the container (from abraded, crushed, or bro-under recommended storage conditions. ken tablets); cracks or chips in tablet surfaces; swelling; mot-

Storage under Recommended Environmental tling; discoloration; fusion between tablets; or the appear-Conditions—In most instances, the recommended storage ance of crystals that obviously are not part of the tabletconditions are stated on the label, in which case it is imper- itself on the container walls or on the tablets.ative to adhere to those conditions. They may include a

COATED TABLETS—Evidence of physical instability in coatedspecified temperature range or a designated storage place tablets is shown by cracks, mottling, or tackiness in theor condition (e.g., “refrigerator,” or “controlled room tem- coating and the clumping of tablets.perature”) as defined in the General Notices . Supplemental

DRY POWDERS AND GRANULES—Dry powders and granulesinstructions, such as a direction to protect the product fromthat are not intended for constitution into a liquid form inlight, also should be followed carefully. Where a product isthe original container may cake into hard masses or changerequired to be protected from light and is in a clear or color, which may render them unacceptable.translucent container enclosed in an opaque outer covering,

POWDERS AND GRANULES INTENDED FOR CONSTITUTION ASsuch outer covering is not to be removed and discardedSUSPENSIONS—Dry powders and granules intended for consti-until the contents have been used. In the absence of specifictution into solutions or suspensions require special attention.

instructions, the product should be stored at controlled Usually such forms are antibiotics or vitamins that are partic-room temperature (see Storage Temperature in the General ularly sensitive to moisture. Since they are always dispensedNotices ). The product should be stored away from locationsin the original container, they generally are not subject towhere excessive or variable heat, cold, or light prevails, suchcontamination by moisture. However, an unusual caked ap-as those near heating pipes or fluorescent lighting.pearance necessitates careful evaluation, and the presenceObserving Products for Evidence of Instability—Loss of of a fog or liquid droplets inside the container generallypotency usually results from a chemical change, the mostrenders the preparation unfit for use. Presence of an objec-common reactions being hydrolysis, oxidation-reduction,tionable odor also may be evidence of instability.and photolysis. Chemical changes may also occur through

EFFERVESCENT TABLETS, GRANULES, AND POWDERS—Effervescentinteraction between ingredients within a product, or rarelyproducts are particularly sensitive to moisture. Swelling of between product and container. An apparent loss of po-the mass or development of gas pressure is a specific sign of tency in the active ingredient(s) may result from diffusion of instability, indicating that some of the effervescent actionthe drug into, or its combination with, the surface of thehas occurred prematurely.container-closure system. An apparent gain in potency usu-

ally is caused by solvent evaporation or by leaching of Liquid Dosage Forms— Of primary concern with respect tomaterials from the container–closure system. liquid dosage forms are homogeneity and freedom from ex-





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USP 35 General Information / 〈1195〉 Significant Change Guide 843

cessive microbial contamination and growth. Instability may mediate need, maintain suitable repackaging records show-be indicated by cloudiness or precipitation in a solution, ing name of manufacturer, lot number, date, and designa-breaking of an emulsion, nonresuspendable caking of a sus- tion of persons responsible for repackaging and for checkingpension, or organoleptic changes. Microbial growth may be (see General Notices ), (6) if safety closures are required, useaccompanied by discoloration, turbidity, or gas formation. container closure systems that ensure compliance with com-

pendial and regulatory standards for storage.SOLUTIONS, ELIXIRS, AND SYRUPS—Precipitation and evidenceof microbial or chemical gas formation are the two major Dilution or Mixing— If a product is diluted, or if two prod-signs of instability. ucts are mixed, the pharmacist should observe good profes-

sional and scientific procedures to guard against incompati-EMULSIONS—The breaking of an emulsion (i.e., separationbility and instability. For example, tinctures such as those of of an oil phase that is not easily dispersed) is a characteristicbelladonna and digitalis contain high concentrations of alco-sign of instability; this is not to be confused with creaming,hol to dissolve the active ingredient(s), and they may de-an easily redispersible separation of the oil phase that is avelop a precipitate if they are diluted or mixed with aque-common occurrence with stable emulsions.ous systems. Pertinent technical literature and labeling

SUSPENSIONS—A caked solid phase that cannot be resus-should be consulted routinely; it should be current litera-pended by a reasonable amount of shaking is a primaryture, because at times formulas are changed by the manu-indication of instability in a suspension. The presence of rel- facturer. If a particular combination is commonly used, con-atively large particles may mean that excessive crystalsultation with the manufacturer(s) is advisable. Since thegrowth has occurred.chemical stability of extemporaneously prepared mixtures is

TINCTURES AND FLUIDEXTRACTS—Tinctures, fluidextracts, and unknown, the use of such combinations should be discour-similar preparations usually are dark because they are con- aged; if such a mixture involves an incompatibility, thecentrated, and thus they should be scrutinized carefully for pharmacist might be responsible. Oral antibiotic prepara-evidence of precipitation. tions constituted from powder into liquid form should never

STERILE LIQUIDS—Maintenance of sterility is of course critical be mixed with other products. for sterile liquids. The presence of microbial contamination Combining parenteral products necessitates special care,in sterile liquids usually cannot be detected visually, but any particularly in the case of intravenous solutions, primarilyhaze, color change, cloudiness, surface film, particulate or because of the route of administration. This area of practice flocculent matter, or gas formation is sufficient reason to demands the utmost in care, aseptic technique, judgment,suspect possible contamination. Clarity of sterile solutions in- and diligence. Because of potential unobservable problemstended for ophthalmic or parenteral use is of utmost impor- with respect to sterility and chemical stability, all extempo-tance. Evidence that the integrity of the seal has been vio- raneous parenteral preparations should be used within 24lated on such products should make them suspect. hours unless data are available to support longer storage.

Semisolids (Creams, Ointments, and Suppositories)— For Informing and Educating the Patient— As a final step increams, ointments, and suppositories, the primary indication meeting responsibility for the stability of drugs dispensed,of instability is often either discoloration or a noticeable the pharmacist is obligated to inform the patient about thechange in consistency or odor. proper storage conditions (for example, in a cool, dry

place—not in the bathroom) for both prescription and non-CREAMS—Unlike ointments, creams usually are emulsionsprescription products, and to suggest a reasonable estimatecontaining water and oil. Indications of instability in creamsof the time after which the medication should be discarded.are emulsion breakage, crystal growth, shrinking due to When beyond-use dates are applied, the pharmacist shouldevaporation of water, and gross microbial contamination.emphasize to the patient that the dates are applicable onlyOINTMENTS—Common signs of instability in ointments are

when proper storage conditions are observed. Patientsa change in consistency and excessive “bleeding” (i.e., sepa- should be encouraged to clean out their drug storage cabi-ration of excessive amounts of liquid) and formation of nets periodically.granules or grittiness.

SUPPOSITORIES—Excessive softening is the major indicationof instability in suppositories, although some suppositoriesmay dry out and harden or shrivel. Evidence of oil stains onpackaging material should warn the pharmacist to examineindividual suppositories more closely by removing any foilcovering. As a general rule (although there are exceptions), 〈1195〉 SIGNIFICANT CHANGEsuppositories should be stored in a refrigerator (see Storage Temperature in the General Notices ). GUIDE FOR BULKProper Treatment of Products Subjected to AdditionalManipulations—In repackaging, diluting a product or mix- PHARMACEUTICAL EXCIPIENTSing it with another product, the pharmacist may becomeresponsible for its stability.

Repackaging— In general, repackaging is inadvisable.

However, if repackaging is necessary, the manufacturer should be consulted concerning potential problems. In theBACKGROUND filling of prescriptions, it is essential that suitable containers

be used. Appropriate storage conditions and, when appro-This general information chapter was derived from an in-priate, an expiration date and beyond use date should be

ternational guidance on the evaluation of the significance of indicated on the label of the prescription container. Single-changes involving the manufacture of bulk pharmaceuticalunit packaging calls for care and judgment and for strictexcipients. It is intended to assist excipient manufacturers inobservance of the following guidelines: (1) use appropriatedetermining the need for informing the excipient user andpackaging materials, (2) if stability data on the new packageregulatory authorities about the nature of the change.are not available, repackage at any one time only sufficient

The chapter provides minimum recommendations whenstock for a limited time, (3) include on the unit-dose label aconsidering the effect of a change in the manufacturinglot number and an appropriate beyond-use date, (4) if aprocess on the excipient. When deciding how to use thissterile product is repackaged from a multiple-dose vial intochapter, each manufacturer must consider how it may applyunit-dose (disposable) syringes, discard the latter if not usedto that manufacturer’s product and processes. The diversitywithin 24 hours, unless data are available to support longer of excipients means that some principles of this chapter maystorage, (5) if quantities are repackaged in advance of im-not be applicable to certain products and processes.




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0840-0843 [1191] Stability Considerations in Dispensing Practice