Package Selection of Solid Orals

REVIEW

Package Selection for Moisture Protection for Solid,Oral Drug Products

KENNETH C. WATERMAN, BRUCE C. MACDONALD

Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340

Received 18 December 2009; revised 17 February 2010; accepted 19 February 2010

Published online 10 May 2010 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.22161

Corresponde3492; Fax: 860-

Journal of Pharm

� 2010 Wiley-Liss

ABSTRACT: This review describes how best to select the appropriate packaging options forsolid, oral drug products based on both chemical and physical stability, with respect to moistureprotection. This process combines an accounting for the initial moisture content of dosage formcomponents, moisture transfer into (out of) packaging based on a moisture vapor transfer rate(MVTR), and equilibration between drug products and desiccants based on their moisturesorption isotherms to provide an estimate of the instantaneous relative humidity (RH) withinthe packaging. This time-based RH is calculationally combined with a moisture-sensitiveArrhenius equation (determined using the accelerated stability assessment program, ASAP)to predict the drug product’s chemical stability over time as a function of storage conditions andpackaging options. While physical stability of dosage forms with respect to moisture hasbeen less well documented, a process is recommended based on the threshold RH at whichchanges (e.g., dosage form dissolution, tablet hardness, drug form) become problematic.The overall process described allows packaging to be determined for a drug product scientifi-cally, with the effect of any changes to storage conditions or packaging to be explicitly accountedfor. � 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4437–4452, 2010

Keywords: drug stability; drug packaging;
accelerated aging; moisture transfer; desiccants
INTRODUCTION

In this review, the science associated with stabiliza-tion of solid, oral drug products by packaging isdiscussed. This review aims to lay out a rationalprocess for package selection based on predictingdrug product shelf-life in different packaging config-urations. While many aspects of packaging selectionhave been developed and published previously,1–4

this review attempts to provide a focus on moisturesensitivity and how packaging can be chosen toprovide adequate product shelf-life while balancingcost and marketing needs.

Drug product shelf-life is determined based onthe time a product remains within specificationsagreed upon with regulatory agencies. In general,these specifications can be divided into two aspects ofstability: chemical and physical. Chemical stability,with regard to expiration dating, involves how longa drug product, in its packaging, continues to haveadequate potency (typically 100� 5% of the label

nce to: Kenneth C. Waterman (Telephone: 860-715-441-3972; E-mail: [email protected])

aceutical Sciences, Vol. 99, 4437–4452 (2010)

, Inc. and the American Pharmacists Association

JOURNAL OF P

claim, but the specification can sometimes bebroadened with justification) and sufficiently lowlevels of any degradation product to assure safety.Degradants have specification limits agreed uponwith regulatory agencies. These limits depend onwhether the degradant is identified structurally,whether there is any indication of potential toxicity,and on the total daily dose of the active pharmaceu-tical ingredient, API, as described, for example, in theInternational Conference for Harmonization (ICH)guidelines.5,6 Physical instability is associated withany change to the drug product performance (e.g.,dissolution, hardness) or appearance. Specificationsfor such performance criteria often involve a rangeagreed upon with regulatory authorities, rather thana limit, for acceptable performance. Such changes canin some cases limit the shelf-life of a product.

One of the major stabilizing influences of packagingis protection from moisture. In this review, theinfluence of moisture on a product’s chemical andphysical stability is first discussed. This is followedby a discussion of the role of packaging in limitingmoisture exposure. A drug product’s moisture sensi-tivity and the protection afforded packaging arecombined to allow package selection with regard tomoisture.

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4438 WATERMAN AND MACDONALD

MOISTURE’S EFFECTS ON PRODUCT STABILITY

Water Activity and Psychrometry

Water activity in air, at a given temperature, isdefined as the ratio of the fugacity of the water inthe air to that of pure water.7 This is generallyapproximated as equal to the ratio of the actualpartial pressure of water vapor in the air to that of theair above pure water: the water activity of air abovepure water (closed system) is defined as 1.0 at anytemperature. While the water activity above purewater remains 1.0 independent of temperature, theamount of water in the air (mg/L) varies widely:warmer air can hold much more water than cold air.The relationship between the amount of water held inthe air, at a water activity of 1.0, as a function oftemperature can be seen in so-called psychrometrygraphs, such as shown in Figure 1.8 Relativehumidity, RH, is essentially the same as wateractivity expressed as a percent; that is, a wateractivity of 1.0 corresponds to an RH of 100%. RH willbe used in this review to refer to the air relativehumidity, while water activity will be used to refer towater molecules in solids and solution. It should beunderstood that this is simply convention, and thatthe terms are effectively interchangeable.

The water activity value of a solid can bedetermined by measuring the RH of air above thesolid when the sample is at equilibrium. This isessentially the ratio of the concentration of water inthe air over a sample to the concentration of watervapor over pure water. At equilibrium, the RH in aclosed system must be the same throughout; that is,the water activity of the solid must equal the RH of airin equilibrium with it. This is true independent of thephysical state of the water associated with the solid.In other words, at equilibrium, the water activity ofcrystalline hydrates, adsorbed water molecules, and

1

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100

1000

0 10 20 30 40 50 60 70 80

Temperature (C)

Sat

ura

ted

H2O

Co

nce

ntr

atio

n (

mg

/L)

Figure 1. Psychrometry graph showing the saturatedmoisture content of air as a function of temperature.8

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dissolved water molecules equals the RH of the vaporphase.

Critical Relative Humidity and Deliquescence

Some chemicals, when dissolved in water, lower theactivity of the water proportionately to the soluteconcentration (as a colligative property). When thewater activity of a concentrated solution of a materialis lower than the storage condition RH, the higher airRH will cause water to condense. Condensation willcontinue until the water activity of the solutionmatches the RH of the air. In a similar way, if a solidhas a lower water activity (for its correspondingsaturated solution) than its surroundings, a processcalled deliquescence occurs, in which moisture con-denses on the solid.9 The liquid condensate willdissolve the material, and deliquescence will continueuntil the water activity of the dissolved materialmatches that of the surrounding air. For a solid, theRH of the air when deliquescence first occurs isknown as the critical relative humidity (CRH).10

When a sample is stored below its CRH, it will adsorbwater as a function of the storage RH and stopadsorbing at a relatively low level when equilibriumis reached. This behavior is discussed in the MoistureSorption/Desorption Isotherms Section. When asample is stored above its CRH, it will deliquesce.A slurry (saturated solution) of a material, that is, asolution containing both liquid and undissolved solid,will reach equilibrium in a closed container at theCRH.

For most solid dosage forms, deliquescence to anysignificant extent will result in a physical or chemicalchange (e.g., appearance, dissolution, degradation)that effectively results in a product failing in one ofits specifications. Consequently, one of the roles ofpackaging is to protect a product that can deliquescefrom exposure to RH conditions where such deliques-cence can occur. Table 1 shows the CRH of a numberof excipients. As can be seen, some of the excipientshave CRH values that vary with temperature, whichcan usually be related to changes in solubility withtemperature.12 It is also important to note that somecombinations of APIs and excipients can show CRHvalues that are synergistically depressed; that is,when these materials are present in the same dosageform, they can deliquesce at a lower RH than whenthe materials are alone.13

Chemical Stability

Drug product chemical stability is generally affectedby the RH that the sample experiences. Watermanand coworkers14–16 describe an accelerated stabilityassessment program (ASAP) that combines an iso-conversion paradigm, a moisture-corrected Arrheniusequation and statistical design and analysis. Theisoconversion paradigm was developed to compensate

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Table 1. Critical Relative Humidity (CRH) Values forRepresentative Excipients11

Excipient CRH at 208C CRH at 408C

Dextrose 100 88Sorbitol 80 69Sucrose 86 83Xylitol 91 73Tartaric acid 84.5 78Potassium chloride 84 82Sodium chloride 75 75Sodium citrate 60.5 78Polyethylene glycol (PEG3350) 94 85Sodium carboxymethylcellulose 84 84

PACKAGE SELECTION FOR MOISTURE PROTECTION 4439

for heterogenous kinetics due to the fact that for manysolid dosage forms, the API molecules exist in amixture of states (e.g., amorphous, surface, bulkcrystal, etc.). An adjustment of the time in a stabilitychamber as a function of temperature and RH is madesuch that the proportions of different reactivity drugstates remain about the same at each acceleratedstorage condition.

The moisture-modified Arrhenius equation (Eq. 1)quantifies drug product stability as a function oftemperature and RH.

ln k ¼ ln A� Ea

RTþ BðRHÞ (1)

where k is the degradation rate (typically percentdegradant generated per day), A the Arrheniuscollision frequency, Ea the energy of activation forthe chemical reaction, R the gas constant (1.986 cal/(mol K)), T the temperature in Kelvin, and B thehumidity sensitivity constant. The form of Eq (1)indicates that chemical instability for API degrada-tion in solid dosage forms increases exponentiallywith an increase in RH. In absolute terms, thisdependence will vary with the B-term. To understandthe significance of this B-term and the exponentialdependence on RH, Table 2 shows the effect on theshelf-life of a hypothetical drug product stored underdifferent RH conditions. As can be seen, changes inRH can have very significant effects on chemicalstability, depending on the B-term. One significantrole of packaging is to protect moisture-sensitive drug

Table 2. Calculated Shelf-Life of a Hypothetical DrugProduct Stored at Different RH Conditions withoutPackaging (Constant T)

B

Storage Relative Humidity

10%RH 65%RH 75%RH

0.09; high RH dependence 3 years 8 days 3 days0.04; moderate RH dependence 3 years 121 days 81 days0.00; low RH dependence 3 years 3 years 3 years

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products from their storage environment, as will bediscussed below. For products with low B values, suchprotection is usually not needed (assuming physicalstability is maintained, as discussed in the PhysicalStability Section), and package selection can be basedon other considerations (cost, appearance, etc.). Whenthe B-term is relatively high, packaging plays a moresignificant role in determining a drug product shelf-life; however, even with high moisture sensitivity, itis possible to have a sufficiently long shelf-lifesuch that even with high moisture exposure (highlypermeable packaging), the product can be packagedwithout concern. In general, however, products aremore likely to require packaging for protection frommoisture when they have higher B-terms.

Physical Stability

In addition to meeting chemical stability specifica-tions, drug products must maintain acceptableperformance and quality (appearance) standards atthe end of their assigned shelf-lives. These standardscan generally be classified in the following way:(1) dissolution, (2) tablet hardness, (3) API form, and(4) physical appearance. Each of these has aspectsthat are affected by packaging.

Dissolution

Dissolution testing of drug released from a dosageform into a medium is carried out for the majority oforal, solid dosage forms. Even without a specificcorrelation between the in vitro and in vivo dissolu-tion, dissolution specifications are often agreed uponwith regulatory agencies.

Oral drug products can broadly be categorized asbeing either immediate release (IR) or controlledrelease (CR). IR dosage forms provide the activeingredient to the patient rapidly, and most oftendissolve in the stomach in <1 h. CR dosage forms, onthe other hand, are designed to meter out drug slowlyafter the dosage form is swallowed. In either case,changes upon storage could result in changes to thedrug product performance; however, it should bementioned that dissolution tests are often not well-designed to indicate in vivo performance. In otherwords, a change, or lack of change, in dissolutionperformance may or may not mean there could be achange in the pharmacokinetics in vivo. A particularissue with dissolution testing for stability is that thetest is generally conducted to tell if greater than acertain amount of drug is dissolved at a particulartime point (e.g., >80% of the drug dissolved in15 min). The statistical uncertainty in this measure-ment can result in random ‘‘failures’’ against speci-fications at different stability time points. Thesestability failures do not in fact indicate that thedosage form has actually changed performance since

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00.5

11.5

22.5

33.5

44.5

5

40 50 60 70 80

%RH

t50

Rat

io

Corn StarchCroscarmellose sodiumCrospovidoneSodium starch glycolate

Figure 2. Effect of relative humidity (RH) on the dissolu-tion behavior of tablets prepared with 200 mg ketoconazole,40 mg lactose, 2.6–4.7 mg gelatin, 13.8 mg talc, 13.8 mgmagnesium stearate, and 20 mg of disintegrant.21 The dis-solution time for 50% of the drug to dissolve (t50) wasdetermined initially (ranging from 9 to 17 min) and againafter storage for 120 days, with the ratio of the two used inthe graph (t50 ratio).21

10

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20

25

30

35

40

45

50

55

0 25 50 75 100 125

Time (days)

T50

(m

in)

40%RH60%RH80%RH

Figure 3. Effect of storage time at 258C on the dissolutionbehavior (time for 50% dissolution, t50) of tablets preparedwith 200 mg ketoconazole, 40 mg lactose, 2.6–4.7 mggelatin, 13.8 mg talc, 13.8 mg magnesium stearate and20 mg of croscarmellose sodium.21


a larger sampling both at initial and stored conditionscould very well show that the two are indistinguish-able. While these types of failures undoubtedly occurin stability programs, they do not represent an issuefor which packaging selection should play a role sincestatistically they are the result of random fluctua-tions and not due to true changes with time at aparticular storage condition.

Still, changes in dissolution behavior with time cansometimes be linked to the RH that the dosage form isexposed to. In order to select appropriate packagingfor a dosage form, it becomes important to determinethe rate of change in the dissolution behavior as afunction of the RH the sample is stored at under open(equilibrium) conditions. In the simplest case, thespecification limit for dissolution changes is notreached at expiry even when the sample is exposeddirectly to the environment (open). When the shelf-life is inadequate at such conditions, the rate needs totake into account the RH as a function of time in thepackaging (Determination of Relative HumidityInside Packaging Section).

Dissolution changes on storage that are affected bypackaging are associated with the following changes:(1) disintegrant changes, (2) excipient form changes,(3) capsule shell changes, and (4) API form changes(discussed in the Tablet Hardness/Friability Section).While the subject of this review is selection ofpackaging for stabilizing drug products, it shouldbe noted that many of these issues could also beresolved by selection of different formulations.

Disintegrant Changes. Disintegrants are added totablets and capsules to increase the rate at which thesolid material in the dosage form disperses once it hitsthe stomach. Since rapid disintegration and thecorresponding rapid drug dissolution can affectbioavailability, disintegration changes with storagecan impact a product’s shelf-life. Common disinte-grants, including the so-called ‘‘superdisintegrants’’croscarmellose sodium, crospovidone, and sodiumstarch glycolate,17 are generally considered to bechemically stable under any normal storage condi-tions. Disintegrants can however be affected bymoisture uptake. The moisture sorption propertiesof at least some common disintegrants have beenreported;18,19 however, the link to changes in tablet orcapsule dissolution must be inferred from changesobserved in mechanical properties associated withthe moisture uptake. In particular, it has been shownthat moisture uptake associated with disintegrants intablets can result in formation of micro-cracks dueto disintegrant swelling,20 which in turn can besurmised to influence the disintegrant’s effectiveness.

In Figure 2, the effect of storage RH was examinedfor four common disintegrants.21 As can be seen,there are changes in the dissolution behavior from the


initial condition in most cases, though it should bekept in mind that in most cases the dissolutionchanges would not result in failures with respect tospecifications. With respect to packaging, the impor-tant aspect of these data is that some of the changesare sensitive to the RH of the environment, andconsequently would be sensitive to packaging. It isunclear from the studies conducted to date how fastthe changes resulting from exposure to elevated RHconditions occur. For example, in Figure 3, changes tothe dissolution behavior of tablets at 40 and 60%RHappear to stabilize in <90 days, while at 80%RHchanges appear to continue through (and beyond)120 days.21 It should be noted that the moisturesorption behavior of this disintegrant (croscarmellose

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sodium) changes markedly at 80%RH (water uptakeat 40, 60, and 80%RH is 8%, 13%, and 23%,respectively).19 While moisture equilibration tendsto be rapid, the effect of this moisture uptake on thedisintegrant appears to be slower, at least in caseswhere there is a large amount of water adsorbed.There have been no systematic studies reported onthe effects of storage at low RH (i.e., below 40%) ondisintegration times with common disintegrants;however, tablets using maize starch or a-celluloseat low RH (1%) did not change significantly in 2 weeks(308C).22

Excipient Changes. Some excipients used in phar-maceutical products are themselves metastable. Inparticular, some excipients exist as amorphousmaterials or as mixtures of crystalline and amor-phous materials. Examples of this include such spray-dried sugars as lactose and mannitol, marketed asFast FloTM Lactose and MannogemTM, respectively.The rate of crystallization of spray-dried lactose wasstudied as a function of RH.23 As can be seen inFigure 4, the rate of crystallization does depend onRH; however, what is less clear is how much any suchchange will affect the dissolution stability of a drugproduct. Presumably, there will be cases whereexcipient crystallization can impact dissolution dueto changes in mechanical properties and waterpermeation rates.

Another type of excipient change as a function ofRH that could potentially impact the dissolutionstability of a drug product is plasticization ofpolymeric materials.24 Plasticization by moisturehas the potential to lower the glass transitiontemperature (Tg) below that of some stabilitystorage conditions. The result of this can be a rapidchange in mechanical properties of a material, and a

0

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0.04

0.06

0.08

0.1

0.12

0.14

0.16

0 20 40 60 80

%RH

1/(t

max

in h

rs)

Figure 4. Effect of moisture on the rate of crystallization(1/tmax) of spray-dried lactose at 258C using microcalorime-try to determine the time for maximum heat flow afterintroduction of moist air (derived from Ref. [23]).

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corresponding rapid change in dissolution behavior ofthe dosage form, when the RH is sufficiently high. Anexample of moisture lowering the Tg of a polymericexcipient was studied with polyvinylpyrrolidone(povidone).25 This effect could potentially impactdissolution behavior; however this has not beendocumented. Similarly, one could anticipate sucheffects will be present with film coatings: lowering theTg of polymeric coating materials could potentiallyaffect dissolution.

Capsule Shell Changes. Hard gelatin capsules canbe physically unstable at both high and low RHconditions. Under dry conditions, the capsules canbecome brittle and crack; under moist conditions, thecapsules can become sticky and in some cases undergochemical reactions that affect their dissolutionbehavior. The brittleness of hard gelatin capsulesoccurs because gelatin is plasticized by moisture: asthe moisture level in the gelatin is reduced, thecorresponding modulus increases making the cap-sules liable to break under stress conditions. Evenwhen brittle, specific drug products will havedifferent mechanical (physical) sensitivity. Thestability will depend on the capsule wall thicknessand the stresses on the capsule. In general, thebrittleness of gelatin capsules has been found toincrease markedly below 30%RH, which correspondsto about 10% water content.26,27 Since the RH ofstorage conditions used for regulatory determinationof shelf lives are higher than this, the packagingconsideration is largely related to the internalcomponents. In particular, if the RH inside thepackaging is lower than about 30% (see Determina-tion of Relative Humidity Inside Packaging Section),than there is the potential for cracking issues. Thisproblem is most likely to occur if capsules arepackaged with desiccants; consequently, desiccantsare generally avoided with hard gelatin capsules.

Gelatin can undergo a cross-linking reaction eitherby oxidative condensation processes, or with formal-dehyde (typically an impurity or degradant from anexcipient) or other aldehydes.28,29 Crosslinked gelatinwill often be slow to dissolve, and cause thedissolution rate of the drug to be retarded in standarddissolution testing. In the presence of the enzymepepsin at pH 1.2 (or pancreatin at pH 7.2), the gelatinrelease rate is often recovered. Importantly, thein vivo behavior correlates with the dissolutionbehavior in the presence of the enzymes.28 Gelatincrosslinking is sensitive to the RH of the storageenvironment, and could therefore dictate the packa-ging; however, in most cases, this crosslinking doesnot affect bioavailability. It is therefore importantthat enzymatic dissolution be conducted beforeelecting protective packaging to prevent crosslinking.


Figure 5. Phase diagram of caffeine showing the tem-perature and relative humidity (RH) regions for the hydrateand anhydrous form of the drug (derived from Ref. [33]).


Moisture incorporated into gelatin and hydroxy-propylmethyl cellulose (HPMC) capsules reduces thestiffness and hardness of the capsules.30 This soft-ening effect reduces the overall hardness of gelatinand HPMC capsules by 30% and 40%, respectively, ongoing from 35 to 75%RH. Above 80%RH, gelatincapsules become very soft and sticky. This stickinessappears to only be an issue above most storageconditions; however, this can be a potential issue inZone 4B countries. In addition, there can be an issuewhen capsules are subjected to changing tempera-tures in packaging: warm, humid air in a package willincrease in RH when the temperature decreases evencausing condensation. While eventually this moisturewill re-equilibrate with all the internal components,capsules that adhere to each other due to moisture-induced stickiness are likely to remain adhered evenas the RH drops again (often to the same value). Inother words, the rate of RH change in the air aroundcapsules when temperature changes (minutes) canexceed the rate of re-equilibration of the moistureinside the packaging (hours to days).

Tablet Hardness/Friability

Tablets can change hardness with storage as afunction of moisture uptake. This effect is especiallyimportant with uncoated tablets since softer tabletswill generally be more friable. In a reported study ofmoisture effects on tablet hardness, it was found thatthe hardness of tablets stored at 75%RH was reducedby a factor of two at room temperature in 4 days, whileat ambient RH, there was no change in 20 days.31 Inanother study,32 tablet hardness decreases at 75%RH(at 6 months) were matched with significant increasesin friability (from an initial of 0–4% weight loss with100 revolutions). While this suggests that there arelikely to be conditions where elevated storage RH canresult in performance issues unless protective packa-ging is employed, the fact that the majority of newcommercial tablets are film-coated makes problemsassociated with friability of lower concern.

API Form

A solid API can exist in two basic physical forms: acrystalline form or an amorphous form. Thermody-namically, crystalline drug forms are lower energyand generally more chemically and physically stablethan amorphous forms, and are therefore most oftenthe API form commercialized; however, the highersolubility of amorphous states can make themattractive in some cases. Crystalline API’s often showmultiple packing forms in their crystal lattices(polymorphs). In addition, many API’s can includestoichiometric or nonstoichiometric amounts of sol-vent in their lattices. When the solvent is water, thecrystals are called hydrates.


Since changes in the physical form of an API canaffect the bioavailability of the drug product, one ofroles of packaging is to assure there are no suchtransformations during storage. In many cases, theAPI in a drug product is in its thermodynamicallymost stable form. In those cases, physical stability ofthe API form is not an issue, and packaging does notneed to protect the drug product. In other cases,moisture plays a critical role in the rate of conversion,and packaging becomes important.

Hydrate/Anhydrate. API crystals can containwaters of hydration where the waters are eitherbound in the lattice or more loosely in crystalchannels. In many cases, these waters of hydrationcan reversibly come on and off the crystals as afunction of the temperature and RH. It is oftenpreferable in selecting appropriate packaging to firstdetermine the phase diagram of the API (i.e., theregion on an RH vs. temperature graph correspond-ing to hydrate and anhydrous forms). As an example,near-infrared spectroscopy was used to determine thephase boundaries between anhydrous and a non-stoichiometric hydrate of caffeine.33 In this case,shown in Figure 5, the transition from anhydrous tohydrate is at a relatively high RH. Higher tempera-tures favor the anhydrous form with caffeine as withmost materials based on the higher entropy for watervapor, which drives the equilibrium toward anhy-drous as temperature increases. In the study oncaffeine, it was noted that the greater the drivingforce for form conversion, the faster kinetics for thatprocess; that is, there is an indication of a linear freeenergy relationship between kinetics and thermo-dynamics. This fact was used to rapidly assess thephase boundary. The initial rate for form conversionwas plotted against the RH, with the phase boundary

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estimated to be at the intercept (i.e., zero conversionrate).

Polymorph Conversion. While conversionsbetween hydrates and anhydrous forms are oftenreversible, conversions between polymorphic formsare most often irreversible.34,35 The kinetics of suchconversions are complicated and mostly not directlyinfluenced by packaging selection. The exception tothis is when the kinetics of the transition depends onRH.

The first consideration for polymorph conversionsis whether the polymorphic API form being developedis the thermodynamically stable form throughout thepossible storage temperature range. When a poly-morphic form is lowest in energy, one does not have aconcern for transformation to other forms. Determi-nation of polymorphic form thermodynamics ofteninvolves thermal analyses36 or relative solubilitymeasurements.37

When a metastable polymorphic form of an API is ina drug product, the possibility exists for this form toconvert to a more stable (and generally less soluble)form. Adsorbed moisture has been implicated as a‘‘molecular loosener’’ that can enable molecularrearrangements and thereby allow a crystal toassume a more stable polymorphic form.38 In generalthis phenomenon is mostly associated with at leastsome amount of deliquescence (see Critical RelativeHumidity and Deliquescence Section). As an example,pyridoxal hydrochloride was shown to undergopolymorphic phase transformation at RH conditionswhere it appears to deliquesce.39

Amorphous to Crystalline. When an API is in anamorphous form (including a mesophase) in theabsence of excipients, crystallization has a thermo-dynamic driving force. In addition, the mobility of themolecules is generally significantly higher than forcrystalline materials. Finally, amorphous materialsgenerally adsorb significantly more moisture thancrystalline ones. The result is that amorphousmaterials will generally be more susceptible to RHand require greater packaging protection to assurestability. In some cases, amorphous drug dispersionsare used which stabilize the API by interactionsbetween the API and polymeric excipients. In thesecases, there may be less moisture sensitivity towardscrystallization.

Physical Appearance

Color Stability. Physical appearance changesof dosage forms can be limiting for shelf-lifeand ultimately dictate appropriate packaging. Oneimportant aspect of physical appearance, in terms of

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patient perception of quality, is color. Color changescan occur for most solid dosage forms, but are mostcommon with tablets. Color changes are associatedwith chemical changes and follow the guidelinesdescribed in the Chemical Stability Section underMoisture’s Effects on Product Stability Section, withthe differences being related to the assay andspecification limits. For many commercial drugproducts, color changes are evaluated visuallyagainst a reference color. This method is difficult toquantitate, and therefore is almost impossible to useto accurately predict the effects of temperature andRH. An alternative assay is to use a tristimuluscolorimeter. Such devices record the reflected light offa sample with a human visual perspective. There arevarious transformations possible for the values,which can in turn be related quantitatively to theamount of a colored degradant formed. As anexample, the degradation of vitamin C (ascorbic acid)was followed using a tristimulus colorimeter andcould be quantitatively linked to the primarydegradant (dehydroascorbic acid).11,40 The degrada-tion behavior was shown to obey Eq. (1). Since colorchanges follow the exponential RH dependence ofother chemical changes, packaging considerations arethe same. The challenge therefore is to use aquantitative method for analysis (e.g., tristimuluscolorimetry) and to assign a specification limit for howmuch change is acceptable.

Another source of color changes can be migration ofmaterials into an outer coating or capsule wall. Sincesuch movement is affected by solubility and mobility,it is reasonable to assume that moisture will influencethe rates, and therefore, packaging can be employedto provide protection.

Other Visual Changes. Among the most commonphysical appearance changes observed upon long-term storage, are a number related to materials(especially tablets) swelling as they adsorb moisture.This swelling can cause visual defects when theresulting stresses are relieved by such effects astablet coating breaking, tablet cracking or tabletcapping (effectively delaminating internally).41 Also,under very high RH conditions, tablets and capsulescan adhere to each other (‘‘twinning’’). These phe-nomena should be related to critical RH values eitherin terms of moisture uptake and expansion or interms of plasticization (and becoming sticky). Inscreening experiments as a function of RH, it shouldbe possible to define RH values that correspond to‘‘safe’’ storage conditions. The need for protectionfrom environmental RH will dictate the type ofpackaging needed based on the methods discussed inthe Determination of Relative Humidity InsidePackaging Section.



DETERMINATION OF RELATIVE HUMIDITYINSIDE PACKAGING

Moisture Sorption/Desorption Isotherms

A moisture sorption/desorption isotherm is an essen-tial component in modeling moisture equilibrationand drug product stability in pharmaceutical packa-ging. Water vapor can interact with drug products inthe following ways:10 (1) it can adsorb onto crystallinesurfaces to form a water monolayer, multiple waterlayers or even deliquesce (picking up of liquid water,see Critical Relative Humidity and DeliquescenceSection), (2) water can permeate into the materialbulk (primarily amorphous regions), (3) it cancondense in capillary channels, or (4) react with drugor excipients to form hydrates. For a particularsample, the extent of these interactions and theamount of water taken up by the sample is dependenton the activity of water in the gas phase surroundingthe sample. For packaging selection, the moisturesorption isotherm relates the water content of thedosage form to the solid’s water activity (whichcorresponds to the RH the solid is exposed to) whichdetermines chemical and physical stability.

While measurement of the moisture sorptionisotherm of a drug product can be straightforward,in many cases, especially in early drug productdevelopment, simple calculational models are ade-quate to aid in package selection. The moisturesorption behavior of pharmaceutical solids can bedescribed in terms of parametric models.42,43 Mono-layer adsorption behavior is generally described bythe Brunauer–Emmett–Teller (BET) model; however,the more general Guggenheim–Anderson–de Boer(GAB) model is more commonly applicable.44 TheGAB equation can be expressed as follows:

W ¼ WmCKðRHÞ½1� KðRHÞ�½1�KðRHÞ þ CKðRHÞ� (2)

where W is the weight of water in the sample at agiven RH, and Wm, C, and K are fitting parameterswhich relate to the modes of water adsorption.Several aspects make the GAB model useful ingenerating a drug product’s moisture sorption iso-

Table 3. Temperature Effect on the Moisture Sorption Isothe

Excipient Temp. (8C)

Corn starch47 3045

Amorphous lactose48 1238

Microcrystalline cellulose 25 [FMC Biopolymers, private comm40 [MacDonald B. Private commu


therm: (1) The moisture sorption isotherm of a drugproduct depends most heavily on the materialsinvolved and is relatively insensitive to the processused to make the drug product;45 (2) the moisturesorption isotherm of a combination of multiplecomponents can be modeled using the weightedsum of the GAB parameters for those components;46

(3) the temperature sensitivity between 20 and 408Cis low (The low temperature sensitivity can be seenwith the common excipients MCC, lactose and starchin Table 3); and (4) the contribution of crystalline APIin a drug product is generally negligible to the overallmoisture sorption isotherm. These factors mean thatone can reasonably calculate the moisture sorptionisotherm for a drug product based on its formulationusing its component GAB parameters. A number ofthese parameters are collected in Table 4.

Calculating the moisture sorption isotherm for adrug product can therefore be done as a weightedaverage of the excipients’ GAB parameters. The RH ofa formulation at a given water content will varysignificantly, depending on this sorption isotherm. Asexamples, the moisture sorption isotherms for for-mulations containing 50% dicalcium phosphate(DCP)/50% mannitol, 50% microcrystalline cellulose(MCC)/50% spray-dried lactose, and 50% starch 1500/50% lactose monohydrate are shown in Figure 6.

The moisture sorption isotherms of many materialsshow hysteresis; that is, the amount of moisture asample holds at a given RH will be greater once it hasa history of being exposed to a higher RH.50,51 Thisoffset in the sorption and desorption isotherms resultsfrom molecular reorganization of the structure of thematerial as it adapts to the adsorbed moisture. Whilein many cases, the hysteresis is minor, when it issignificant, it will impact the RH of a system as itdries because moisture will be held more aggres-sively. Another consequence of this is that moisturecontent specifications may need to be differentdepending on the history of a sample: the samemoisture content will correspond to a different wateractivity depending on whether a sample is previouslyexposed to a high RH or not.

In some cases, the moisture sorption isotherm willabruptly change as an amorphous excipient crystal-

rms of Some Common Excipients

% Water (w/w)

20%RH 40%RH 60%RH

4.0 6.0 8.63.3 5.2 7.73.1 6.0 9.63.2 7.0 14

unication] 2.8 4.3 6.5nication] 2.8 4.5 6.1

DOI 10.1002/jps

Table 4. GAB Parameters for Common Pharmaceutical Excipients

Excipient Wm C K

Calcium carbonate 0.149 33.933 0.803Croscarmellose sodium (Ac-di-solTM) 10.206 3.960 0.822Crospovidone46 15.688 2.630 0.844Crosslinked polyacrylic acid (CarbopolTM)49 9.864 1.011 0.892Dibasic calcium phosphate anhydrous 0.173 37.490 0.671Hydroxypropyl cellulose 4.507 1.526 0.907Hydroxypropylmethyl cellulose (MethocelTM K4M)49 6.372 2.295 0.821Lactose monohydrate 0.039 7.582 0.967Lactose regular 0.647 0.023 0.770Lactose, spray dried 8.658 4.148 0.026Magnesium stearate 1.336 1500.488 0.004Magnesium carbonate 0.665 11.177 0.703Mannitol 0.848 0.101 0.701Microcrystalline cellulose (AvicelTM) 3.979 12.524 0.770OpadryTM 85F 1.013 2.592 0.991OpadryTM 85G18490 3.114 1.247 0.837OpadryTM clear 2.295 2.918 0.956OpadryIITM white OY-LS-28914 1.013 2.592 0.991Polyethylene oxide (PolyoxTM N-80) 0.389 1.028 1.089Povidone (polyvinylpyrrolidone) 0.721 1.962 17.471Silicon dioxide 1.039 7.748 0.606Sodium starch glycolate (ExplotabTM) 6.100 5.330 0.991Sorbitol 357.379 0.087 0.372Starch 1500 7.400 15.930 0.736Talc 0.846 8.733 0.144Talc (lo micron) 0.142 8.964 0.854Titanium dioxide 0.202 10.544 0.771

Except where noted, data reported herein were generated by using commercial moisture sorption, gravitimetric, instrumentation.Parameters are based on a best fit to the data without regard to a physical model.

1

1.2

r Sorption


lizes. Moisture acts to plasticize the amorphousmaterial enabling molecular motion that in turnallows crystallization.48,51–53 In this case, as moistureis adsorbed, the crystallization results in moisturethat was previously adsorbed being released. This canbe seen in Figure 7 with spray-dried (partiallyamorphous) lactose. In this case, when the RH hitsabout 50%, crystallization occurs which forces waterthat was previously adsorbed to be lost. On thedesorption scan, the excipient holds less water since itis now crystalline.

0

1

2

3

4

5

6

7

8

9

0 10 20 30 40 50 60 70 80

%RH

Per

cen

t W

ater

DCC/Mannitol

MCC/spray-dried lactose

Starch 1500/lactosemonohydrate

Figure 6. Calculated moisture isotherms for 50%:50%mixtures of dicalcium phosphate DCP/Mannitol, micro-crystalline cellulose (MCC)/spray-dried lactose, and starch1500/lactose monohydrate.

DOI 10.1002/jps JOU

Initial Moisture Content

Pharmaceutical packaging controls dosage formexposure to environmental humidity such thatchemical degradation rates and physical stabilityfor drug products in the packaging will vary as the

0

0.2

0.4

0.6

0.8

0 20 40 60 80

%RH

Per

cen

t W

ate

Desoprtion

Figure 7. Moisture sorption and desorption isotherms forspray-dried lactose (obtained by measurement of moistureuptake using a gravimetric moisture balance, VTI Instru-ments, Inc., Hialeah, FL) showing crystallization of theamorphous material at about 50% relative humidity (RH)resulting in a lower amount of adsorbed water duringdesorption.


0

5

10

15

20

25

30

35

0 10 20 30 40 50 60 70 80

%RH

Per

cen

t W

ater

Silica Gel

Molecular Sieves

Clay Mineral

Figure 8. Moisture sorption isotherms for three standardpharmaceutical desiccants at 258C (data provided courtesyof Sud-Chemie, Inc.).


corresponding RH changes. To calculate the RHinside a packaged product over time, one of the factorsto be considered is the initial RH of a productimmediately after packaging. There are three sourcesof initial moisture in a packaged drug product system:(1) moisture brought in from the drug productitself, (2) moisture from any desiccant added to thepackaging, and (3) moisture in the headspace. As willbe seen below, the latter term is generally negligible.

Initial Drug Product Water Activity

The mass of water held by a drug product in itspackaging is a function of its moisture sorption/desorption isotherm (discussed in the MoistureSorption/Desorption Isotherms Section) and itsmoisture exposure history. Determining (and con-trolling) the RH (water content) of dosage formsprior to packaging has often been under-appreciatedas a significant product stability attribute. In manycases, water content specifications are arbitrary,and measurements are carried out in a way thatdoes not reflect the true dosage form RH in thepackaging. While water content and dosage formwater activity can be related to each other via themoisture sorption/desorption isotherm, one must becareful when using water content values acrossmultiple product lines. While a water content of 3%in one product could mean an RH of 30%, in another itcould very well be 70%. As an example, in Figure 6 awater content of 3% corresponds to an RH of about50% with a 50:50 mixture of MCC/spray-dried lactosebut only an RH of about 20% with a 50:50 mixture ofstarch/lactose monohydrate. The result is that a 3%water content specification in the latter product couldprovide a significantly drier (and more stable)environment than in the other. It has recently beensuggested that water-activity measurement shouldreplace the widely used Karl Fischer water contenttesting.54 Since water-activity is generally morerelevant to drug product stability than water content,and measuring it is at least as easy as Karl Fischermeasurements, this suggestion seems very reason-able. In using water activity measurements, thechallenge becomes how to measure this parameterin such a way that it reflects the true water activity ofa drug product as it goes into a package. Tabletsand capsules can adjust to their environmentsrapidly (i.e., from 1 h to 2 days, as discussed in theMoisture Equilibration Within Dosage FormsSection), such that testing cannot involve havingthe dosage forms in environments outside thepackage of interest.

Desiccants

Desiccants are materials that have high moisturesorption capacities and thereby can reduce RH inside


packaging.55 The most commonly used desiccantsin the pharmaceutical industry are silica gel, clayminerals, and molecular sieves. These materials aretypically contained in canisters, cartridges, orsachets. The moisture sorption isotherms of thesethree materials are shown in Figure 8. As can be seen,in each case, a significant amount of moisture is heldby the desiccant; however, the capacities vary withRH. Molecular sieves have relatively high capacity atlow RH conditions, and are therefore good forbringing RH values in packaging down to very lowranges; however, their capacity for moisture athigher RH conditions is more limited than theother desiccants. As a consequence, the quantity ofmolecular sieve needed with permeable packagingcan become prohibitive. Moisture sorption by desic-cants follows the same pattern as moisture sorptionby dosage forms: as the RH increases, the capacity forfurther moisture sorption also changes. The result isthat with moisture permeable packaging (e.g., plasticbottles) the RH will change as different amounts ofwater are taken up.

When desiccants are present with dosage forms in apackage, equilibrium will be established at an RHwhere typically some moisture from the dosage formstransfers to the desiccant. As an example, for 10 g of50% MCC/50% spray-dried lactose having the moist-ure sorption isotherm shown in Figure 6 with aninitial RH of 40%, the corresponding water content isabout 2.6% or 262 mg. If 1 g of a silica gel desiccanthaving the moisture sorption isotherm shown inFigure 8 (with no initial water) is added, the excipientblend will lose about 90 mg of water to the desiccant toput them both at an RH of about 19%.

Headspace

The mass of water in the headspace is a function of theheadspace volume, temperature and the RH of theheadspace air. The headspace volume can be alteredby changing the packaging size or changing the

DOI 10.1002/jps

0

5

10

15

20

25

30

35

0 10 20 30 40 50 60 70 80 90

Time (min)

%R

H

Figure 9. Kinetics of tablet and headspace humidityequilibration. Two, 500-mg tablets of 1:1 spray-driedlactose/microcrystalline cellulose (having a relative humid-ity, RH, of about 32%) were placed in a nitrogen-purged 120-cc glass bottle at the 10-min point. The RH in the tabletsdesorbed to reach equilibrium with the air in the bottle in>1 h.


dosage form count in the case of a bottle. In deferenceto the role of RH in drug product stability, the RH ofpackaging rooms is often highly controlled since it isthe room environment which determines the initialheadspace RH of a bottle or blister; however, theimpact of controlling headspace RH is minor com-pared to controlling the initial drug product wateractivity, with respect to the initial packaged productRH and subsequent drug product stability. The effectof the initial headspace RH on the equilibratedheadspace RH (assuming no moisture transfer, i.e.,MVTR¼ 0) is generally small because of the moisturesorption capacity of the dosage form in the packagingcompared to the amount of moisture held in the air(based on the psychrometry curves shown in Fig. 1).As an example, if one 500 mg tablet of 50% MCC/50%spray-dried lactose (moisture sorption isothermshown in Fig. 6) with a water activity of 35%(2.35% water content) were packaged in a 2-cc blisterin either a 20%RH or 75%RH packaging room, theinitial water content of the tablet would be 11.757 mgand that of the headspace would be 0.005 and0.007 mg (based on the moisture content of air at258C, see Fig. 1) at the two headspace RH conditions,respectively. After equilibration, the tablet would losewater in the drier condition (0.004 mg) and gain waterin the moist condition (0.008 mg); however, theequilibrated RH would be essentially 35%RH in bothcases since the quantity of water moving from or tothe tablet is small. With a single such tablet in a 60-ccbottle, the equilibrated RH in the two packagingenvironments would be 34 and 37%RH, respectively;however, with 40 such tablets in the bottle, thedifferences in equilibrated RH values would againeffectively disappear. The mass of water held bytablets or capsules greatly exceeds that held bythe headspace such that even extreme differencesin headspace RH do not have a large impact onthe overall mass of water available for redistribution.Similarly, the headspace volume has no significantimpact on the water activity because of the paucityof water in the headspace relative to the dosage forms.

Moisture Equilibration within Dosage Forms

When a dosage form (tablet, capsule, powder) isexposed to a different RH than its initial value, itwill re-equilibrate to the new water activity. Thisequilibration will depend on a number of factorsincluding the permeability of the materials, thetemperature, and the difference in RH. Nonetheless,on the multiyear timescale of most drug product shelf-lives, the rates are effectively instantaneous. As anexample, two tablets were placed in a bottle whichhad been brought to about 0%RH using nitrogen. Asshown in Figure 9, the RH in the bottle increased dueto desorption of moisture from the tablets. In thiscase, the equilibration time was less than an hour.

DOI 10.1002/jps JOU

Film-coated tablets are somewhat slower to equili-brate; however, even coatings advertised as moisture-protective still allow equilibration in <2 days.56,57

While dosage forms exposed to cycling of RH could beaffected by the film coatings, in general, long termshelf-life will not show any significant impact fromthe coatings. For package selection, the RH inside apackage can be assumed to always be in equilibriumbetween the air (headspace) and the dosage forms,with moisture transfer into or out of the packagebeing rate-limiting.

Moisture Vapor Transmission Rate

Theory

The moisture vapor transmission rate, MVTR,describes the mass of water permeating into theheadspace volume of a container for a giventemperature and difference between internal andexternal RH (DRH) with a given package (bottle,blister) size in units of mg H2O/day. A related term ispermeability, P, which divides out DRH from theMVTR as shown in Eq. (3):

P ¼MVTR=DRH (3)

When an empty container (i.e., one with nocomponents or moisture) is placed in a stabilitychamber, moisture from the chamber environmentwill permeate through the walls into the headspace ata rate proportional to DRH. This can be expressed interms of the mass of moisture transferred, Dm, in aunit time Dt according to Eq. (4).

Dm ¼ PDRHDt (4)

With no water adsorbing components, any moisturetransferred must directly accumulate into (or be lost



from) the bottle headspace. The changed mass ofwater in the headspace will change the RH based onthe ratio of the new water concentration in theheadspace as a proportion to the saturated waterconcentration at that temperature, according tothe psychrometry relationship (Fig. 1). This is shownmathematically in Eq. (5):

RHt ¼ ðm0 þ DmÞ=ðVCsatÞ ¼ RH0 þ Dm=ðVCsatÞ (5)

where RHt is the internal RH at time t (after moisturepermeates into the container), m0 the internal mass ofwater in the container before water is transferred, Vthe volume of the container, Csat is the saturatedwater concentration at the study temperatureand RH0 is the RH inside the container before watertransfers. Eq. (5) can be recast as a differentialequation (Eq. 6):

dRH

dt¼ PDRH (6)

This equation can be solved to give the following:

lnDRH0

DRHt¼ Pt (7)

RHint;t ¼ DRH0e�Pt þ RHint;0 (8)

where DRH0 is the initial difference in internal(RHint) and external RH (RHext), DRHt is thedifference in the internal and external RH at timet. The internal RH in a bottle was shown to indeedobey Eq. (8) experimentally using RH probes sealed inbottles, as shown in Figure 10 (empty bottle example).Though the probes themselves do adsorb somemoisture, overall, there is good agreement betweenthe calculation and the measured values. Interest-ingly, with standard 60-cc high density polyethylene,HDPE, pharmaceutical bottles, even with heatinduction seals, the internal RH goes from 20 to

0

10

20

30

40

50

60

70

0 10 20 30 40 50 60 70

Days

%R

H

2 tablets

15 tablets

15 tablets + desiccant

empty bottle

Figure 10. Predicted (lines) versus measured (symbols)RH inside a 60-cc HDPE bottle stored at 408C/75%RH.Tablets (500 mg) contained 10 mg of the drug candidateCP-481,715, 322.6 mg of microcrystalline cellulose (Avi-celTM PH200), 165 mg mannitol, and 2.5 mg of magnesiumstearate.


75%RH in only about 10 days when stored at408C/75%RH.

While the MVTR value for any packaging can bedetermined explicitly for any temperature, the valueshave been shown to obey the Arrhenius equation:58

ln MVTR ¼ ln A� Ea

RT(9)

where A is the collision frequency, Ea the activationenergy, R the gas constant, and T is the absolutetemperature. Eq. (9) allows the estimation of theMVTR for any temperature once it is know for at leasttwo temperatures.

The MVTR for a given package will depend on thepackaging material used and be directly proportionalto the surface area of the package, assuming the samewall thickness overall. This allows a reasonableestimation to be made for the MVTR of different sizepackages made with the same material and wallthickness using surface area proportionality. Sincemost packaging is characterized in terms of volume,an approximation can be made according to Eq. (10):

MVTR1 ffiMVTR0½V1=V0�2=3 (10)

where MVTR1 and MVTR0 are the MVTR values ofthe proposed and control packages, respectively; andV1 and V0 are their corresponding volumes.

Measurement of MVTR

Measurement of MVTR for a package must bedetermined with a known difference in RH betweenthe interior and exterior (stability chamber) of thecontainer. Most often, the MVTR involves measure-ment of the weight gain per unit time with a knowntemperature and difference in RH. Typically sometype of drying agent is placed inside the package,with gravitimetric measurements made over time,generally until a steady state condition is achieved. Arecent example of this used anhydrous calciumchloride to control the RH inside bottles accordingto USP(671).59 Other desiccants have also beenstudied, with clay found to perform better thancalcium chloride in many cases.59 These approachesprovide MVTR values of varying precision dependingon the background weight of the container and theoverall weight gain at the time point used. Alter-natively, we have found that plotting the weight gainof a desiccant canister as a function of time (weighedafter removal from a package) can be a practicalalternative since the weight gain is against a lowerreference (just the desiccant) and the experiment canbe carried out to a sufficient time to get statisticallysignificant weight increases. As a reference, MVTRvalues for a number of pharmaceutical packages areshown in Table 5.

DOI 10.1002/jps

Table 5. Representative Moisture Vapor Transmission Rates (MVTR) for a Number of Pharmaceutical Packages

Package Package Size

MVTR(mg/day),

238C/75%RH

MVTR(mg/day),

408C/75%RH

HDPE 40 cm3 bottle1 0.15 0.7060 cm3 bottle 0.262 1.352180 cm3 bottle 0.521 2.688

Polyvinylchoride (PVC) blister (250 mm thick) 23.9�9.5� 8.2 mm capsule 1.187 3.88513.3� 7.5� 4.4 mm capsule2 0.259

Polyvinylidine chloride (PVDC) blister (190 mm thick) 23.9�9.5� 8.2 mm capsule 0.230 1.200Polychlorotrifluoroethylene (PCTFE), AclarTM UltRx 2000 blister 23.9�9.5� 8.2 mm capsule 0.028 0.142

14.5�0.3 mm round 0.013 0.100Polychlorotrifluoroethylene (PCTFE), AclarTM UltRx 3000 blister 23.9�9.5� 8.2 mm capsule 0.018 0.103

14.5�0.3 mm round 0.007 0.062Polychlorotrifluoroethylene (PCTFE),

AclarTM RX160 blister (305 mm thick)13.3� 7.5� 4.4 mm capsule2 0.008

Foil-foil cold-formed blister 23.9�9.5� 8.2 mm capsule 0.00067 0.003713.3� 7.5� 4.4 mm capsule2 0.001

The MVTR values were determined using gravitimetric changes for each container according to USP24/NF18 at 238C, and modified accordingly for 408C.


Overall Prediction of RH Inside Packaging

By combination of the moisture transfer into or out ofpackaging (Moisture Vapor Transmission Rate Sec-tion) with the moisture distribution within thepackage (Moisture Sorption/Desorption Isotherms,Initial Moisture Content, and Moisture EquilibrationWithin Dosage Forms Sections), it is possible todetermine the RH inside the package as a functionof time and storage conditions. Computationally, onecan calculate the moisture transfer as shown inEq. (8), and then determine the new distribution ofthe moisture among the internal components (dosageforms, desiccants, and head space) based on theirmoisture sorption isotherms. A unit of moisture willresult in a change in RH based on the moisture in thehead space, which in turn depends on the sorptioncapacity of the components at that RH. This approachhas been used to successfully calculate the RH insidevarious packaging as a function of time and storageconditions. An example of the model predictions andmeasured values are shown in Figure 10.

DETERMINING DRUG PRODUCT PACKAGINGFOR STABILITY

Chemical Stability

In the Chemical Stability Section under Moisture’sEffects on Product Stability Section, the effect of RHon the reactivity of solid drug products was discussedwith respect to a moisture sensitivity term B (Eq. 1)which relates the exponential dependence of suchrates on RH. In the Determination of RelativeHumidity Inside Packaging Section, the elementsthat influence RH inside a package were discussed:

DOI 10.1002/jps JOU

the initial RH of the components, the moisturesorption isotherms of the components and the MVTRof the package. These elements allow us to calculatethe RH inside a package as a function of time.Combining the RH as a function of time with thechemical degradation rate as a function of RH ispossible using an iterative calculation: the degrada-tion rate (rate of formation of degradant) is recalcu-lated corresponding to the instantaneous RH aftereach differential moisture transfer into or out ofa package.1–4 This process is amenable to simplespreadsheet type calculations. Adding error bars tothese calculations is more complicated since itinvolves varying uncertainty as the RH changes:typically the error bars are minimal at the center ofthe data (on the RH axis), and increase away from thispoint. One approach to determining the error bars forthe in-package stability is to use error bars forthe rates at each RH based on a Monte-Carlo typestatistical calculation; however, this can be quitetime-consuming.

The effectiveness of these calculations at predictingdrug-product stability in packaging is shown inFigure 11. As can be seen, the fact that the degradantformation rate varies exponentially with RH resultsin curvature in the degradant as a function of timegraph: degradation rates in moisture-permeablepackaging will generally increase with time untilthe RH inside the package becomes relativelyconstant. In Figure 11, the effect of higher tabletcount on product stability is accounted for in thecalculation due to the lower RH as a function of time(greater moisture sorption capacity). Figure 11 alsoshows the impact of desiccant on the drug stabilitybased on the corresponding lowering of the RH as afunction of time.


0

10

20

30

40

50

60

0.0 1.0 2.0 3.0 4.0 5.0

Years

%R

H

40%RH25C/60%RH30C/65%RH30C/65%RH + desiccant

Figure 12. Time to reach the relative humidity (RH)conditions inside packaging where tablets could potentiallyshow dissolution issues. Tablet calculations assumed beha-vior for tablets from Figure 2 with the disintegrant beingsodium starch glycolate. Tablets are modeled assuming aninitial water content of 1% with 60 200-mg tablets in a 60-cchigh density polyethylene (HDPE) bottle.

0

1

2

3

4

5

0 10 20 30 40 50 60 70

Days

%D

egra

dant

2 tablets/60-cc bottle

15 tablets/ 60-cc bottle

15 tablets/desiccant/ 60-cc bottle

Open bottle

Figure 11. Predicted (lines) versus measured (symbols)drug degradant formation for tablets stored in a 60-ccHDPE bottle stored at 408C/75%RH. Tablets (500 mg) con-tained 10 mg of the drug candidate CP-481, 715, 322.6 mg ofmicrocrystalline cellulose (AvicelTM PH200), 165 mg man-nitol, and 2.5 mg of magnesium stearate. The acceleratedstability assessment program (ASAP) was used to deter-mine the moisture-modified Arrhenius parameters.15


Physical Stability

As discussed in the Physical Stability Section, drugproduct stability can be dependent on physicalchanges associated with the API or excipients. Inmany cases, these physical changes occur at athreshold RH; that is, the conversions occur rapidlywhen a phase boundary is passed, but do not occur atall at other conditions. In those cases, packaging canprovide protection from the storage condition envir-onment based on the time needed to reach thethreshold RH inside the packaging, which can becalculated as indicated in the Overall Prediction ofRH Inside Packaging Section. As an example, inFigure 2, the disintegrant croscarmellose sodiumshows good stability at low RH, with problems fordissolution occurring somewhere between 40 and60%RH. If one assumes that it is necessary to stay at40%RH or lower, calculations of RH as a function oftime for several packaging options can be used todetermine which will provide assured stability withrespect to dissolution, as shown in Figure 12. As canbe seen, bottles would require desiccant to maintainan RH below 40% at 308C/65%RH for 3 years. FromFigure 12, it also becomes clear how critical it can beto resolve where the threshold RH is for physicalinstability. In this example, if that thresholdwere 55%RH, there would be no need for desiccantfor a 3-year shelf-life.

CONCLUSION

The selection of packaging can be one of the mostimportant decisions in the development of a drug


product. Packaging can have a major impact on a drugproduct’s shelf life as well as the cost of goods;consequently, it is important that appropriate packa-ging be selected. Packaging plays a key role inprotecting a drug product from the RH of theenvironment. While the state of the art is sufficientto make good estimates of the impact of RH ofchemical reactivity, there remain gaps in predictingexactly how RH will impact physical stability. Incases where chemical stability limits shelf-life, it ispossible to anticipate the packaging impact using acombination of ASAP to determine the instability as afunction of temperature and RH, and the moisturetransfer and re-equilibration with internal compo-nents to determine the RH as a function of time andstorage conditions. With physical stability, it is oftenpossible to use a worst case scenario: the packagingcan be selected to prevent a threshold RH from beingreached inside a package for the entire shelf-life.While in many cases this will be overly conservative,this approach can still allow package selection withminimal experimentation.

ACKNOWLEDGMENTS

Some data used in this paper was obtained with thehelp of Pat Basford, Dan Malinowski and Gerry Enos,all of Pfizer. The authors also wish to acknowledge theediting and helpful suggestions of Steve Colgan andCindy Oksanen (Pfizer).

DOI 10.1002/jps


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