`
`1 The Science and
`Practice of Pharmacy
`
`2 1 S t E D ITI O N
`
`a.
`-
`fil‘DPINCOTT WILLIAMS 6: WILKINS
`
`{an
`
`Novartis Exhibit 2033 .001
`
`Regeneron V. Novartis, IPR2021-00816
`
`Novartis Exhibit 2033.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`21 ST EDITION
`
`Remington
`
`The Science and Practice
`of Pharmacy
`
`~1~ LIPPINCOTT WILLIAMS & WILKINS
`
`A Wolters Kluwer Company
`Philadelphia• Baltimore• New York• London
`Buenos Aires • Hong Kong • Sydney • Tokyo
`
`•
`
`Novartis Exhibit 2033.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Editor: David B. Troy
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`The publisher is not responsible (as a matter of product liability, negligence or otherwise) for any injury resulting from any
`material contained herein. This publication contains information relating to general principles of medical care which should not
`be construed as specific instructions for individual patients. Manufacturer's product information and package inserts should be
`reviewed for current information, including contraindications, dosages and precautions.
`
`Printed in the United States of America
`
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington, in the Office of the Librarian of Congress, at
`Washington DC
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Copyright 1948, 1951, by the Philadelphia College of Pharmacy and Science
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`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Philadelphia College of Pharmacy and Science
`
`Copyright 2000, 2006, by the University of the Sciences in Philadelphia
`
`All Rights Reserved
`Library of Congress Catalog Card Information is available
`ISBN 0-7817-4673-6
`
`The publishers have made every effort to trace the copyright holders for borrowed material. If they have inadvertently overlooked
`any, they will be pleased to make the necessary arrangements at the first opportunity.
`The use of structural formulas from USAN and the USP Dictionary of Drug Names is by permission of The USP Convention. The
`Convention is not responsible for any inaccuracy contained herein.
`
`Notice-This text is not intended to represent, nor shall it be interpreted to be, the equivalent of or a substitute for the official
`United States Pharmacopeia (USP) and I or the National Formulary (NF). In the event of any difference or discrepancy between the
`current official USP or NF standards of strength, quality, purity, packaging and labeling for drugs and representations of them
`herein, the context and effect of the official compendia shall prevail.
`To purchase additional copies of this book call our customer service department at (800) 638-3030 or fax orders to (301)
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`12345678910
`
`Novartis Exhibit 2033.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

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`Stability of Pharmaceutical Products
`Patrick B O'Donnell, PhD
`Allan D Bokser, PhD
`
`CHAPTER 2
`
`Stability of'a pharmac1·ulical product may Ill' dl'lirwcl as till' ca(cid:173)
`pahility of' a particul:rr formulation, in a s1H'cific contairwr/
`closun• systl-m. to n•main within its physical. chemical. micro(cid:173)
`biological. tlwr:qwutic. and toxicological sp!'cilications. Assur(cid:173)
`anc1·s that thl' paekag1•d product will ill' stahil· for its antici(cid:173)
`patl'd slwlf' lili• must conH· from an accumulation of valid data
`on tlw drug in its 1·omnH·rcial packagl'. Tlwsl' stahility data in(cid:173)
`volv<· s1·l1•d1•d paranwt1•rs that., t.ak1·n tog1•tiwr. form tiw stahil(cid:173)
`ity prolih•. l'harmac!'utical products an· l'Xp1•ct1·d to m1•1•t tiwir
`spl'cilieations for id<·ntity, purity. qu:rlit.y, and stn·ngth
`throughout their dl'lirwd storag!' period at spl'cific storagl'
`conditions.
`Tlw stahility or a pharmac1·ut.ical product is invl'st igati-d
`throughout the various stages of' tiw devPlopnwnt procpss. Tlw
`stability of a drug suhst:111c1• is first asscssl'd in the prdi,rmu(cid:173)
`lation stagi·. At this stage, pharmaceutical seicntists d1·tl•r(cid:173)
`mi1w tiw drug su hst:IIH'l' and ils n•lat!'d salts stahility/com(cid:173)
`patihility with various solv<•nts, buffrred solutions, and
`l'Xcipil•nts considerl'd for formulation devl'lopment. Optimiza(cid:173)
`tion of a stable formula! ion or a pharmacl'utical product is
`built upon till' information ohtain!'d from thl' preformulation
`stage and continul's during t.lw formulation devl'lopnll'nt
`stagPs.
`Typically, tiw first formulation developnwnt stage is the
`preparation of a "first in human" formulation which is oftt•n a
`non-!'legant formulation optimiZl'd for short-term dose-rang(cid:173)
`ing clinical xt udics. Tlw second major formul:rtion dcvl'lop(cid:173)
`ment stag!' occurs to xupport Phase II and early l'hasl· 111
`elinical studil'"· Tlw pharmaceutical product dl•vclopcd at this
`stag!' is usually tiw prototype for the comml•rcial product.
`Therl'fi,n•, the pharmm:euticnl product will be formulated
`baxcd in part on the stability information obtain from the pre(cid:173)
`vious formulations and must nwet stability requirements for
`longcr-t<•rm clinical studies. The final formulation develop(cid:173)
`ment stage is for the commercial phannaccutical product. In
`addition to building on the clinical requirements of the drug,
`till' commercial pharmace utical product. must also incorporate
`the commercial or t.lw final market image of the product,
`which includes the containe r closure system. The stability of
`this product must be demonstrated to the appropriate regula(cid:173)
`tory agencies in order to assign an expiration date for the
`product.
`Once a pharmaceutical product has gained regulatory ap(cid:173)
`proval and is marketed, the pha rmacist must understand the
`proper storage and handling of the drug. In some cases, a phar(cid:173)
`macist may need to prepare stable compouncll•d preparations
`from this product. It is the r esponsibility oftlw pharmacist, via
`the information of the manufacturer, to instrud t IH• patient in
`the proper storage and handling of the drug product. The im(cid:173)
`pact of a drug product with a poor stability prolil,· eould delay
`
`approval, affl'ct the safrty and dlicacy of'tlw dnrg. and/or cause
`product recall.
`Much has b<'l'll writ.t.<·n about tlH' dl'Vl'lopnwnt of' a stable
`pharmacl•utical product. Compn•lwns ivl' trl'a!nwnts of' all as(cid:173)
`p<•cts of phan11ac1·utical product s tability has hl'l'n published hy
`Lintrwr, 1 Connors ct al ? and mon• n •c<•ntly Carst<·nsl·n". This
`ehapt<•r will outlirll' tlw appropriat<• stqis f'rom lll'l'formulation
`to drug approval to asslll·<· that tiw pharmaceutical product dl'(cid:173)
`Vl•lopl'cl is stahll'. l{cquin•ml·nt,-; for cornpoundl'd products will
`also hl' discussl'd.
`Thl' USP ddinl's tlH' xtahility of a pharmac1·utical product
`as "pxtl'nt to which a product n•tains , within SJ)l'cifi1•d limits,
`and throug'IHnrt its pl'riod of' storagl' and use ( ic, its shclf~lifo),
`tlw same propl'rtil's and charactPristics that it posx1•ss<·d at the
`tinw of' its manufactun•." Thl'n' arl' fiVl' types of' stability that
`rnust he consid<·rl'cl for l'ach drug.
`
`Physical
`
`Microbiological
`
`Conditions Maintained Throughout
`Type of Sta=b~i~li=t~ - -=th=c~•~S=h~l"~l~f-~L=i~fc~• ~o~f~t=h=c~D~ru~~P~r~o~d~u=c~t~
`<'lwmical
`l~ach actiVl' ingn•dil'nt rl'lains its dwmicnl
`inl!'grity and lab<•lcd pol<•ncy, within llw
`spl'cilil•d limits.
`Tlw original physical prop1•rti1•s, including
`app1·aranc,·. palatability. uniformity, dis(cid:173)
`solution, and suspl'nd:thility
`arl' retairwd.
`St<•rility or· n•s istann· lo microbial growth
`is rl'Lained according to llw spl'cifil'd
`n·quin•111<•11ts. Antimicrobial agents that
`an• prcs1•nt n•tain l'fli•ctiv<•ncss within
`tlw sp<•cifi!'d limits.
`Till' tlwrapl'ulic Plli.•ct n•mains unch,rngPd.
`No significant incrl':tS<' in toxicity occurs.
`
`Tlwrnpl'ulic
`Toxicological
`
`Stability of a drug also can be defirwd as the time from the
`date of manufacture and packaging of th e formulation until its
`chemical or biological activity is not less than a precletermined
`level of labeled potency and its phys ical characteristics have
`not changed appreciably or deleteriously. Although there are
`exceptions, 90'¼ of labeled potency generally is recognized as
`the minimum acceptable potency level. Expiration dating is de(cid:173)
`fined, therefore, as the time in which a drug product in a spe(cid:173)
`cific packaging configuration will remain stable when stored
`under recommended conditions.
`An expiration date, which is expressed traditionally in
`terms of month and year, denotes the last day of the month. The
`expiration date should appear on the immediate container and
`the outer retail package. However, when single-close contairwr:-(cid:173)
`are packaged in individual cartons, the expiration dat<• rna_v Ill'
`
`1025
`
`Novartis Exhibit 2033.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`1026
`
`PART 5: PHARMACEUTICAL MANUFACTURING
`
`placed on the individual carton instead of the immediate prod(cid:173)
`uct container. If a dry product is to be reconstituted at the time
`of dispensing, expiration dates are assigned to both the dry
`mixture and the reconstituted product. Tamper-resistant pack(cid:173)
`aging is to be used where applicable.
`One type of time-related stability failure is a decrease in
`therapeutic activity of the preparation to below labeled content.
`A second type of stability failure is the appearance of a toxic
`substance, formed as a degradation product upon storage of the
`formulation. The numbers of published cases reflecting this sec(cid:173)
`ond type are few . However, it is possible, though remote, for
`both types of stability failures to occur simultaneously within
`the same pharmaceutical product. Thus, the use of stability
`studies with the resulting application of expiration dating to
`pharmaceuticals is an attempt to predict the approximate time
`at which the probability of occurrence of a stability failure may
`reach an intolerable level. This estimate is subject to the usual
`Type 1 or alpha error (setting the expiration too early so that
`the product will be destroyed or recalled from the market ap(cid:173)
`preciably earlier than actually is necessary) and the Type 2 or
`beta error (setting the date too late so that the failure occurs in
`an unacceptably large proportion of cases). Thus, it is obliga(cid:173)
`tory that the manufacturer clearly and succinctly define the
`method for determining the degree of change in a formulation
`and the statistical approach to be used in making the shelf-life
`prediction. An intrinsic part of the statistical methodology must
`be the statements of value for the two types of error. For the
`safety of the patient a Type 1 error can be accepted, but not a
`Type 2 error.
`
`REGULATORY REQUIREMENTS
`Stability study requirements and expiration dating are covered
`in the Current Good Manufacturing Practices (cGMPs),4 the
`USP,5 and the FDA guidelines. 6
`GOOD MANUFACTURING PRACTICES-The GMPs4
`state that there shall be a written testing program designed to
`assess the stability characteristics of drug products. The results
`of such stability testing shall be used to determine appropriate
`storage conditions and expiration dating. The latter is to ensure
`that the pharmaceutical product meets applicable standards of
`identity, strength, quality, and purity at time of use. These reg(cid:173)
`ulations, which apply to both human and veterinary drugs, are
`updated periodically in light of current knowledge and technol(cid:173)
`ogy.
`COMPENDIA-The compendia also contain extensive sta(cid:173)
`bility and expiration dating information. Included are a discus(cid:173)
`sion of stability considerations in dispensing practices and the
`responsibilities of both the pharmaceutical manufacturer and
`the dispensing pharmacist. It now is required that product la(cid:173)
`beling of official articles provide recommended storage condi(cid:173)
`tions and an expiration date assigned to the specific formula(cid:173)
`tion and package. Official storage conditions as defined by the
`USP 265 are as follows: Cold is any temperature not exceeding
`8°C, and refrigerator is a cold place where the temperature is
`maintained thermostatically between 2 and 8°C. A freezer is a
`cold place maintained between - 25 and - l0°C. Cool is defined
`as any temperature between 8 and l5°C, and room temperature
`is that temperature prevailing in a working area. Controlled
`room temperature is that temperature maintained thermostat(cid:173)
`ically between 20 and 25°C. Warm is any temperature between
`30 and 40°C, while excessive heat is any heat above 40°C.
`Should freezing subject a product to a loss of potency or to de(cid:173)
`structive alteration of the dosage form, the container label
`should bear appropriate instructions to protect the product
`from freezing. When no specific storage instructions are given
`in a USP monograph, it is understood that the product's storage
`conditions shall include protection from moisture, freezing, and
`excessive heat.
`As is noted above in USP 26, the definition of controlled
`room temperature was a "temperature maintained thermostat(cid:173)
`ically between 20 and 25°C (68 and 77°F)." This definition was
`
`established to harmonize with international drug standards PC
`forts. The usual or customary temperature range is identifi<'
`as 20 to 25°C, with the possibility of encountering excursions it
`the 15 to 30°C range and with the introduction the mean kincti
`temperature (MKT).
`The mean kinetic temperature is calculated using the fol •
`lowing equation:
`
`T, " [-1n(•-=RT, +,-=ma:::.~-+ ,-=mr. , +,-=RT,)]
`
`in which Tk is the mean kinetic temperature; AH is the heat n
`activation, 83.144kJ·mole 1; R is the universal gas constant
`8.3144 x 10- 3 kJ· mole- 1 · degree- 1; T 1 is the value for the tc111
`perature (in degrees Kelvin [°K]) recorded during the first tim
`period, T2 is the value for the temperature recorded during th
`second time period, eg, second week; T n- l is the value of the soo
`ond to last time period, and Tn is the value for the temperatu1
`recorded during the nth time period. Typically, the time period
`is in days or weeks. The mean kinetic temperature determino
`the thermal exposure of a material. This allows an acceptahl
`estimation to assess if a temperature excursion (or series of PX
`cursions) adversely affected a material.
`FDA Guidelines provide recommendations for:
`1. The design of stability studies to establish appropriate expirat 111
`dating periods and product storage requirements
`2. The submission of stability information for investigational nc,
`drugs, biologicals, new drug applications, and biological product II
`cense applications
`Thus, the guidelines represent a framework for the experimental clu
`sign and data analysis as well as the type of documentation needecl I
`meet regulatory requirements in the drug-development process.
`
`Table 52-1. Stability Protocols
`
`MINIMUM TIME PERIOD
`AT SUBMISSION
`12 mo
`
`CONDITIONS
`Long-term testing
`25°C :!: 2°(/60% :': 5% RH
`Accelerated testing
`4o•c ='= 2·cns% ± 5% RH
`Alternate testinga
`30°c ± 2·cI6s% ='= 5% RH
`•Required if significant change occurs during 6-mo storage under
`conditions of accelerated testing.
`
`6 mo
`
`12 mo
`
`Example Stability Pull Schedule for a Solid Oral Dose
`for Zone I and II
`
`DURATIONS MONTHS
`
`STORAGE
`3
`CONDITIONS
`X
`25°C/60% RH
`0
`30°C/65% RH
`X
`X
`4o•cns% RH
`*From Release testing if testing is within 30 days of stability set down.
`R = Release Tests
`X = Tests at Every Stability Pull
`Appearance (visual)
`Appearance (visual)
`Assay (H PLC)
`Identity
`Impurities (HPLC)
`Assay (HPLC)
`Dissolution (USP < 711 •
`Impurities (HPLC)
`Dissolution (USP < 711 > )
`Moisture Content (Karl
`Fischer)
`Uniformity of Dosage Unit
`0 = Pull and test only after
`4o•cns% is out of
`specification
`Appearance (visual)
`Assay (HPLC)
`Impurities (HPLC)
`Dissolution (USP < 711 > )
`
`0
`
`R*
`
`6
`X
`0
`X, y
`
`9
`X
`0
`
`12
`X, y
`0
`
`18
`X
`
`24
`X
`
`Y = Additional tests periodica
`performed
`Moisture Content (Karl
`Fischer)
`
`Novartis Exhibit 2033.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

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`FDA Guidelines, however, has been reevaluated and revised
`significantly in the last few years, with the aim of harmonizing
`the technical requirements for the registration of pharmaceuti(cid:173)
`cals worldwide. The International Conference on Harmoniza(cid:173)
`tion of Technical Requirements for Registration of Pharmaceu(cid:173)
`ticals for Human Use (ICH) is a unique project that brought
`together regulatory authorities and experts from the pharma(cid:173)
`ceutical industry from three regions of the world; Europe,
`Japan, and the US. The first conference (ICHl) took place in
`November 1991 in Brussels, and the second conference (ICH2)
`in Orlando, FL, in October 1993. These conferences provided an
`open forum for discussion and resulted in the creation of an ex-
`tensive set of guidelines dealing with the many aspects of
`safety, quality, and efficacy of medicinal products. The ICH
`Harmonized Tripartite Guideline provides a general indication
`on the requirements for Stability Testing of New Drug Sub(cid:173)
`stances and Products. The main thrust of the stability guideline
`centers around criteria for setting up stability protocols, shown
`in Table 52-1 and the example Stability Pull Schedule.
`The guidelines were published in a draft form in the Federal
`Register, April 16, 1993. The final guidelines were published in
`1994, with implementation of the guidelines occurring with
`Registration Applications after January 1, 1998. Revision 1 of
`the guidance was published in August 2001. Online computer
`can now access a complete listing of FDA publications and guid(cid:173)
`ances. To view the publications, go to htq)://www.fda .gov/cder/
`guidance/index.htm.
`
`PRODUCT STABILITY
`Many factors affect the stability of a pharmaceutical product
`and include the stability of the active ingredient(s), the poten(cid:173)
`tial interaction between active and inactive ingredients, the
`manufacturing process, the dosage form, the container-liner(cid:173)
`closure system, and the environmental conditions encountered
`during shipment, storage and handling, and length of time be(cid:173)
`tween manufacture and usage.
`Classically, pharmaceutical product stability evaluations
`have been separated into studies of chemical (including bio(cid:173)
`chemical) and physical stability of formulations. Realistically,
`there is no absolute division between these two arbitrary divi(cid:173)
`sions. Physical factors, such as heat, light, and moisture, may
`initiate or accelerate chemical reactions, while every time a
`measurement is made on a chemical compound. Physical di(cid:173)
`mensions are included in the study.
`In this treatment, physical and chemical stability are dis(cid:173)
`cussed along with those dosage form properties that can be
`measured and are useful in predicting shelf life. The effect of
`various physical and chemical phenomena of pharmaceuticals
`also is treated.
`Knowledge of the physical stability of a formulation is very
`important for three primary reasons. First, a pharmaceutical
`product must appear fresh, elegant, and professional, for as long
`as it remains on the shelf. Any changes in physical appearance
`such as color fading or haziness can cause the patient or con(cid:173)
`sumer to lose confidence in the product. Second, since some prod(cid:173)
`ucts are dispensed in multiple-dose containers, uniformity of
`dose content of the active ingredient over time must be ensured.
`A cloudy solution or a broken emulsion can lead to a non-uniform
`dosage pattern. Third, the active ingredient must be available to
`lhe patient throughout the expected shelflife of the preparation.
`A breakdown in the physical system can lead to non-availability
`or "dose dumping" of the medication to the patient. In the case of
`metered-dose inhaler pulmonary aerosols, particle aggregation
`may result in inadequate lung deposition of the medication.
`The chemical causes of drug deterioration have been clas(cid:173)
`Hified as incompatibility, oxidation, reduction, hydrolysis,
`racemization, and other mechanisms. In the latter category,
`decarboxylation, deterioration of hydrogen peroxide and
`hypochlorites, and the formation of precipitates have been
`included.
`
`,
`
`CHAPTER 52: STABILITY OF PHARMACEUTICAL PRODUCTS
`
`1027
`
`PHARMACEUTICAL DOSAGE FORMS
`As the various pharmaceutical dosage forms present unique
`stability problems, they are discussed separately in the follow(cid:173)
`ing section.
`TABLETS-Stable tablets retain their original size, shape,
`weight, and color under normal handling and storage condi(cid:173)
`tions throughout their shelf life. In addition, the in vitro avail(cid:173)
`ability of the active ingredients should not change appreciably
`with time.
`Excessive powder or solid particles at the bottom of the
`container, cracks or chips on the face of a tablet, or appear(cid:173)
`ance of crystals on the surface of tablets or on container walls
`are indications of physical instability of uncoated tablets.
`Hence, the effect of mild, uniform, and reproducible shaking
`and tumbling of tablets should be studied. The recommended
`test for such studies is the determination of tablet friability as
`described in the USP. Tablet Friability < 1216> describes the
`recommended apparatus and the test procedure. After visual
`observation of the tablets for chips, cracks, and splits, the in(cid:173)
`tact tablets are sorted and weighed to determine the amount
`of material worn away by abrasion. In general a maximum
`weight loss of not more than 1 % of the weight of the tablets be(cid:173)
`ing tested is considered acceptable for most products. The re(cid:173)
`sults of these tests are comparative rather than absolute and
`should be correlated with actual stress experience. Packaged
`tablets also should be subjected to cross-country shipping
`tests as well as to various drop tests.
`Tablet hardness (or resistance to crushing or fracturing) can
`be assessed by commercially available hardness testers. As re(cid:173)
`sults will vary with the specific make of the test apparatus used,
`direct comparison of results obtained on different instruments
`may not necessarily be made. Thus, the same instrument should
`be used consistently throughout a particular study.
`Color stability of tablets can be followed by an appropriate
`colorimeter or reflectometer with heat, sunlight, and intense
`artificial light employed to accelerate the color deterioration.
`Caution must be used in interpreting the elevated temperature
`data, as the mechanism for degradation at that temperature
`may differ from that at a lower temperature. It is not always
`proper to assume that the same changes will occur at elevated
`temperatures as will be evidenced later at room temperature.
`Cracks, mottling, or tackiness of the coating indicates evidence
`of instability of coated tablets.
`For tablets containing the more insoluble active ingredients,
`the results of dissolution tests are more meaningful than disin(cid:173)
`tegration results for making bioavailability predictions. Disso(cid:173)
`lution-rate tests should be run in an appropriate medium such
`as artificial gastric and/or intestinal fluid at 37°. When no sig(cid:173)
`nificant change (such as a change in the polymorphic form of
`the crystal) has occurred, an unaltered dissolution-rate profile
`of a tablet formulation usually indicates constant in vivo avail(cid:173)
`ability.
`Uniformity of weight, odor, texture, drug and moisture con(cid:173)
`tents, and humidity effect also are studied during a tablet sta(cid:173)
`bility test.
`GELATIN CAPSULES-Hard gelatin capsules are the
`type used by pharmaceutical manufacturers in the production
`of the majority of their capsule products. The pharmacist in the
`extemporaneous compounding of prescriptions may also use
`hard gelatin capsules. Soft gelatin capsules are prepared from
`shells of gelatin to which glycerin or a polyhydric alcohol such
`as sorbitol has been added to render the gelatin elastic or plas(cid:173)
`tic-like. Gelatin is stable in air when dry but is subject to mi(cid:173)
`crobial decomposition when it becomes moist or when it is
`maintained in aqueous solution. Normally hard gelatin cap(cid:173)
`sules contain between 13% and 16% moisture. If stored in a
`high humidity environment capsule shells may soften, stick to(cid:173)
`gether, or become distorted and lose their shape. On the other
`hand, in an environment of extreme dryness gelatin capsules
`may harden and crack under slight pressure. Gelatin capsules
`should be protected from sources of microbial contamination.
`
`Novartis Exhibit 2033.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`1028
`
`PART 5: PHARMACEUTICAL MANUFACTURING
`
`Encapsulated products, like all other dosage forms, must be
`packaged properly.
`Because moisture may be absorbed or released by gelatin
`capsules depending on the environmental conditions, capsules
`offer little physical protection to hygroscopic or deliquescent
`materials enclosed within a capsule when stored in an area of
`high humidity. It is not uncommon to find capsules packaged in
`containers along with a packet of desiccant material as a pre(cid:173)
`cautionary measure.
`Both hard and soft gelatin capsules exposed to excessive
`heat and moisture may exhibit delayed or incomplete dissolu(cid:173)
`tion due to cross-linking of the gelatin in the capsule shell. The
`cross-linking of gelatin capsules is an irreversible chemical re(cid:173)
`action. Cross-linking may also occur in capsules that are ex(cid:173)
`posed to aldehydes and peroxides. Although cross-linked cap(cid:173)
`sules may fail dissolution due to pellicle formation, digestive
`enzymes will dissolve the capsules. For hard or soft gelatin cap(cid:173)
`sules that do not conform to the dissolution specification, the
`dissolution test may be repeated with the addition of enzymes.
`Where water or a medium with a pH less than 6.8 is specified
`as the medium in the individual monograph, the same medium
`specified may be used with the addition of purified pepsin that
`results in an activity of 750,000 units or less per 1000 mL. For
`media with a pH of 6.8 or greater, pancreatin can be added to
`produce not more than 1750 USP units of protease activity per
`1000 mL.
`SUSPENSIONS-A stable suspension can be redispersed
`homogeneously with moderate shaking and can be poured eas(cid:173)
`ily throughout its shelflife, with neither the particle-size distri(cid:173)
`bution, the crystal form, nor the physiological availability of the
`suspended active ingredient changing appreciably with time.
`Most stable pharmaceutical suspensions are flocculated;
`that is, the suspended particles are bonded together physically
`to form a loose, semi rigid structure. The particles are said to
`uphold each other while exerting no significant force on the
`liquid. Sedimented particles of a flocculated suspension can be
`redispersed easily at any time with only moderate shaking.
`In nonflocculated suspensions, the particles remain as indi(cid:173)
`viduals unaffected by neighboring particles and are affected
`only by the suspension vehicle. These particles, which are
`smaller and lighter, settle slowly, but once they have settled, of(cid:173)
`ten form a hard, difficult-to-disperse sediment. Nonflocculated
`suspensions can be made acceptable by decreasing the particle
`size of the suspended material or by increasing the density and
`viscosity of the vehicle, thus reducing the possibility of settling.
`When studying the stability of a suspension, first determine
`with a differential manometer if the suspension is flocculated.
`If the suspension is flocculated, the liquid will travel the same
`distance in the two side arms. With nonflocculated suspensions,
`the hydrostatic pressures in the two arms are unequal; hence,
`the liquids will be at different levels.
`The history of settling of the particles of a suspension may
`be followed by a Brookfield viscometer fitted with a Helipath at(cid:173)
`tachment. This instrument consists of a rotating T-bar spindle
`that descends slowly into the suspension as it rotates. The dial
`reading on the viscometer is a measure of the resistance that
`the spindle encounters at various levels of the sedimented
`suspension. This test must be run only on fresh, undisturbed
`samples.
`An electronic particle counter and sizer, such as a Coulter
`counter, or a microscope may be used to determine changes in
`particle-size distribution. Crystal form alterations may be de(cid:173)
`tected by microscopic, near-IR or Raman examination and, when
`suspected, must be confirmed by x-ray powder diffraction.
`All suspensions should be subjected to cycling temperature
`conditions to determine the tendency for crystal growth to occur
`within the suspension. Shipping tests, ie, transporting bottles
`across the country by rail or truck are also used to study the
`stability of suspensions.
`SOLUTIONS-A stable solution retains its original clar(cid:173)
`ity, color, and odor throughout its shelf life. Retention of clar(cid:173)
`ity of a solution is a main concern of a physical stability pro-
`
`gram. As visual observation alone under ordinary light is a
`poor test of clarity, a microscope light should be projected
`through a diaphragm into the solution. Undissolved particlcH
`will scatter the light, and the solution will appear hazy. Whil l'
`the Coulter counter also can be used, light-scattering instru (cid:173)
`ments are the most sensitive means of following solution
`clarity.
`Solutions should remain clear over a relatively wide tem (cid:173)
`perature range such as 4 to 4 7°C. At the lower range an ingrl'•
`dient may precipitate due to its lower solubility at that tempe r•
`ature, while at the higher temperature the flaking of partich•M
`from the glass containers or rubber closures may destroy ho
`mogeneity. Thus, solutions should be subjected to cycling tem (cid:173)
`perature conditions.
`The stability program for solutions also should include 11
`study of pH changes, especially when the active ingredients arc•
`soluble salts of insoluble acids or bases. Among other tests arn
`observations for changes in odor, appearance, color, taste, lighl •
`stability, redispersibility, suspendibility, pourability, viscosity,
`isotonicity, gas evolution, microbial stability, specific gravity,
`surface tension, and pyrogen content, in the case of parenteral
`products.
`When solutions are filtered, the filter medium may absorh
`some of the ingredients from the solution. Thus, the same typo
`of filter should be used for preparing the stability samples aM
`will be used to prepare the production-size batches.
`For dry-packaged formulations reconstituted prior to us1• ,
`the visual appearance should be observed on both the original
`dry material and on the reconstituted preparation. The color•
`and odor of the cake, the color and odor of the solution, tlw
`moisture content of the cake, and the rate of reconstitutio n
`should be followed as a part of its stability profile.
`EMULSIONS-A stable emulsion can be redispersed ho,
`mogeneously to its original state with moderate shaking and
`can be poured at any stage of its shelflife. Although most ofthu
`important pharmaceutical emulsions are of the oil in watP1'
`(O/W) type, many stability test methods can be applied to eitlw,
`an O/W or water in oil (W/O) emulsion.
`Two simple tests are used to screen emulsion formulation"
`First, heating to 50 to 70°C and observing its gross physical st 11
`bility either visually or by turbidimetric measurements can do,
`termine the stability of an emulsion. Usually the emulsion th11 L
`is the most stable to heat is the one most stable at room tern,
`perature. However, this may not be true always, because 1111
`emulsion at 60°C may not be the same as it is a