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
ABSTRACT: This review describes how best to select the appropriate packaging options for
solid, oral drug products based on both chemical and physical stability, with respect to moisture
protection. This process combines an accounting for the initial moisture content of dosage form
components, moisture transfer into (out of) packaging based on a moisture vapor transfer rate
(MVTR), and equilibration between drug products and desiccants based on their moisture
sorption isotherms to provide an estimate of the instantaneous relative humidity (RH) within
the packaging. This time-based RH is calculationally combined with a moisture-sensitive
Arrhenius equation (determined using the accelerated stability assessment program, ASAP)
to predict the drug products chemical stability over time as a function of storage conditions and
packaging options. While physical stability of dosage forms with respect to moisture has
been less well documented, a process is recommended based on the threshold RH at which
changes (e.g., dosage form dissolution, tablet hardness, drug form) become problematic.
The overall process described allows packaging to be determined for a drug product scientifically, with the effect of any changes to storage conditions or packaging to be explicitly accounted
for. 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:44374452, 2010
Keywords: drug stability; drug packaging; accelerated aging; moisture transfer; desiccants

INTRODUCTION
In this review, the science associated with stabilization of solid, oral drug products by packaging is
discussed. This review aims to lay out a rational
process for package selection based on predicting
drug product shelf-life in different packaging configurations. While many aspects of packaging selection
have been developed and published previously,14
this review attempts to provide a focus on moisture
sensitivity and how packaging can be chosen to
provide adequate product shelf-life while balancing
cost and marketing needs.
Drug product shelf-life is determined based on
the time a product remains within specifications
agreed upon with regulatory agencies. In general,
these specifications can be divided into two aspects of
stability: chemical and physical. Chemical stability,
with regard to expiration dating, involves how long
a drug product, in its packaging, continues to have
adequate potency (typically 100
5% of the label
Correspondence to: Kenneth C. Waterman (Telephone: 860-7153492; Fax: 860-441-3972; E-mail: ken.waterman@pfizer.com)
Journal of Pharmaceutical Sciences, Vol. 99, 44374452 (2010)
2010 Wiley-Liss, Inc. and the American Pharmacists Association

claim, but the specification can sometimes be

broadened with justification) and sufficiently low
levels of any degradation product to assure safety.
Degradants have specification limits agreed upon
with regulatory agencies. These limits depend on
whether the degradant is identified structurally,
whether there is any indication of potential toxicity,
and on the total daily dose of the active pharmaceutical ingredient, API, as described, for example, in the
International Conference for Harmonization (ICH)
guidelines.5,6 Physical instability is associated with
any change to the drug product performance (e.g.,
dissolution, hardness) or appearance. Specifications
for such performance criteria often involve a range
agreed upon with regulatory authorities, rather than
a limit, for acceptable performance. Such changes can
in some cases limit the shelf-life of a product.
One of the major stabilizing influences of packaging
is protection from moisture. In this review, the
influence of moisture on a products chemical and
physical stability is first discussed. This is followed
by a discussion of the role of packaging in limiting
moisture exposure. A drug products moisture sensitivity and the protection afforded packaging are
combined to allow package selection with regard to
moisture.

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4438

WATERMAN AND MACDONALD

MOISTURES EFFECTS ON PRODUCT STABILITY

Water Activity and Psychrometry

Critical Relative Humidity and Deliquescence

Water activity in air, at a given temperature, is

defined as the ratio of the fugacity of the water in
the air to that of pure water.7 This is generally
approximated as equal to the ratio of the actual
partial pressure of water vapor in the air to that of the
air above pure water: the water activity of air above
pure water (closed system) is defined as 1.0 at any
temperature. While the water activity above pure
water remains 1.0 independent of temperature, the
amount 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 in
the air, at a water activity of 1.0, as a function of
temperature can be seen in so-called psychrometry
graphs, such as shown in Figure 1.8 Relative
humidity, RH, is essentially the same as water
activity expressed as a percent; that is, a water
activity of 1.0 corresponds to an RH of 100%. RH will
be used in this review to refer to the air relative
humidity, while water activity will be used to refer to
water molecules in solids and solution. It should be
understood that this is simply convention, and that
the terms are effectively interchangeable.
The water activity value of a solid can be
determined by measuring the RH of air above the
solid when the sample is at equilibrium. This is
essentially the ratio of the concentration of water in
the air over a sample to the concentration of water
vapor over pure water. At equilibrium, the RH in a
closed system must be the same throughout; that is,
the water activity of the solid must equal the RH of air
in equilibrium with it. This is true independent of the
physical state of the water associated with the solid.
In other words, at equilibrium, the water activity of
crystalline hydrates, adsorbed water molecules, and

Saturated H2O Concentration (mg/L)

dissolved water molecules equals the RH of the vapor

phase.

1000

100

10

Some chemicals, when dissolved in water, lower the

activity of the water proportionately to the solute
concentration (as a colligative property). When the
water activity of a concentrated solution of a material
is lower than the storage condition RH, the higher air
RH will cause water to condense. Condensation will
continue until the water activity of the solution
matches the RH of the air. In a similar way, if a solid
has a lower water activity (for its corresponding
saturated solution) than its surroundings, a process
called deliquescence occurs, in which moisture condenses on the solid.9 The liquid condensate will
dissolve the material, and deliquescence will continue
until the water activity of the dissolved material
matches that of the surrounding air. For a solid, the
RH of the air when deliquescence first occurs is
known as the critical relative humidity (CRH).10
When a sample is stored below its CRH, it will adsorb
water as a function of the storage RH and stop
adsorbing at a relatively low level when equilibrium
is reached. This behavior is discussed in the Moisture
Sorption/Desorption Isotherms Section. When a
sample is stored above its CRH, it will deliquesce.
A slurry (saturated solution) of a material, that is, a
solution containing both liquid and undissolved solid,
will reach equilibrium in a closed container at the
CRH.
For most solid dosage forms, deliquescence to any
significant extent will result in a physical or chemical
change (e.g., appearance, dissolution, degradation)
that effectively results in a product failing in one of
its specifications. Consequently, one of the roles of
packaging is to protect a product that can deliquesce
from exposure to RH conditions where such deliquescence can occur. Table 1 shows the CRH of a number
of excipients. As can be seen, some of the excipients
have CRH values that vary with temperature, which
can usually be related to changes in solubility with
temperature.12 It is also important to note that some
combinations of APIs and excipients can show CRH
values that are synergistically depressed; that is,
when these materials are present in the same dosage
form, they can deliquesce at a lower RH than when
the materials are alone.13
Chemical Stability

1
0

10

20

30

40

50

60

70

80

Temperature (C)

Figure 1. Psychrometry graph showing the saturated

moisture content of air as a function of temperature.8
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 11, NOVEMBER 2010

Drug product chemical stability is generally affected

by the RH that the sample experiences. Waterman
and coworkers1416 describe an accelerated stability
assessment program (ASAP) that combines an isoconversion paradigm, a moisture-corrected Arrhenius
equation and statistical design and analysis. The
isoconversion paradigm was developed to compensate
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PACKAGE SELECTION FOR MOISTURE PROTECTION

Table 1. Critical Relative Humidity (CRH) Values for

Representative Excipients11
Excipient
Dextrose
Sorbitol
Sucrose
Xylitol
Tartaric acid
Potassium chloride
Sodium chloride
Sodium citrate
Polyethylene glycol (PEG3350)
Sodium carboxymethylcellulose

CRH at 208C

CRH at 408C

100
80
86
91
84.5
84
75
60.5
94
84

88
69
83
73
78
82
75
78
85
84

for heterogenous kinetics due to the fact that for many

solid dosage forms, the API molecules exist in a
mixture of states (e.g., amorphous, surface, bulk
crystal, etc.). An adjustment of the time in a stability
chamber as a function of temperature and RH is made
such that the proportions of different reactivity drug
states remain about the same at each accelerated
storage condition.
The moisture-modified Arrhenius equation (Eq. 1)
quantifies drug product stability as a function of
temperature and RH.
ln k ln A 

Ea
BRH
RT

(1)

where k is the degradation rate (typically percent

degradant generated per day), A the Arrhenius
collision frequency, Ea the energy of activation for
the chemical reaction, R the gas constant (1.986 cal/
(mol K)), T the temperature in Kelvin, and B the
humidity sensitivity constant. The form of Eq (1)
indicates that chemical instability for API degradation in solid dosage forms increases exponentially
with an increase in RH. In absolute terms, this
dependence will vary with the B-term. To understand
the significance of this B-term and the exponential
dependence on RH, Table 2 shows the effect on the
shelf-life of a hypothetical drug product stored under
different RH conditions. As can be seen, changes in
RH can have very significant effects on chemical
stability, depending on the B-term. One significant
role of packaging is to protect moisture-sensitive drug
Table 2. Calculated Shelf-Life of a Hypothetical Drug
Product Stored at Different RH Conditions without
Packaging (Constant T)
Storage Relative Humidity
B

10%RH

65%RH

75%RH

0.09; high RH dependence

0.04; moderate RH dependence
0.00; low RH dependence

3 years
3 years
3 years

8 days
121 days
3 years

3 days
81 days
3 years

DOI 10.1002/jps

4439

products from their storage environment, as will be

discussed below. For products with low B values, such
protection is usually not needed (assuming physical
stability is maintained, as discussed in the Physical
Stability Section), and package selection can be based
on other considerations (cost, appearance, etc.). When
the B-term is relatively high, packaging plays a more
significant role in determining a drug product shelflife; however, even with high moisture sensitivity, it
is possible to have a sufficiently long shelf-life
such that even with high moisture exposure (highly
permeable packaging), the product can be packaged
without concern. In general, however, products are
more likely to require packaging for protection from
moisture when they have higher B-terms.
Physical Stability
In addition to meeting chemical stability specifications, drug products must maintain acceptable
performance and quality (appearance) standards at
the end of their assigned shelf-lives. These standards
can generally be classified in the following way:
(1) dissolution, (2) tablet hardness, (3) API form, and
(4) physical appearance. Each of these has aspects
that are affected by packaging.
Dissolution
Dissolution testing of drug released from a dosage
form into a medium is carried out for the majority of
oral, solid dosage forms. Even without a specific
correlation between the in vitro and in vivo dissolution, dissolution specifications are often agreed upon
with regulatory agencies.
Oral drug products can broadly be categorized as
being either immediate release (IR) or controlled
release (CR). IR dosage forms provide the active
ingredient to the patient rapidly, and most often
dissolve in the stomach in <1 h. CR dosage forms, on
the other hand, are designed to meter out drug slowly
after the dosage form is swallowed. In either case,
changes upon storage could result in changes to the
drug product performance; however, it should be
mentioned that dissolution tests are often not welldesigned to indicate in vivo performance. In other
words, a change, or lack of change, in dissolution
performance may or may not mean there could be a
change in the pharmacokinetics in vivo. A particular
issue with dissolution testing for stability is that the
test is generally conducted to tell if greater than a
certain amount of drug is dissolved at a particular
time point (e.g., >80% of the drug dissolved in
15 min). The statistical uncertainty in this measurement can result in random failures against specifications at different stability time points. These
stability failures do not in fact indicate that the
dosage form has actually changed performance since
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a larger sampling both at initial and stored conditions

could very well show that the two are indistinguishable. While these types of failures undoubtedly occur
in stability programs, they do not represent an issue
for which packaging selection should play a role since
statistically they are the result of random fluctuations and not due to true changes with time at a
particular storage condition.
Still, changes in dissolution behavior with time can
sometimes be linked to the RH that the dosage form is
exposed to. In order to select appropriate packaging
for a dosage form, it becomes important to determine
the rate of change in the dissolution behavior as a
function of the RH the sample is stored at under open
(equilibrium) conditions. In the simplest case, the
specification limit for dissolution changes is not
reached at expiry even when the sample is exposed
directly to the environment (open). When the shelflife is inadequate at such conditions, the rate needs to
take into account the RH as a function of time in the
packaging (Determination of Relative Humidity
Inside Packaging Section).
Dissolution changes on storage that are affected by
packaging 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 of
packaging for stabilizing drug products, it should
be noted that many of these issues could also be
resolved by selection of different formulations.
Disintegrant Changes. Disintegrants are added to
tablets and capsules to increase the rate at which the
solid material in the dosage form disperses once it hits
the stomach. Since rapid disintegration and the
corresponding rapid drug dissolution can affect
bioavailability, disintegration changes with storage
can impact a products shelf-life. Common disintegrants, including the so-called superdisintegrants
croscarmellose sodium, crospovidone, and sodium
starch glycolate,17 are generally considered to be
chemically stable under any normal storage conditions. Disintegrants can however be affected by
moisture uptake. The moisture sorption properties
of at least some common disintegrants have been
reported;18,19 however, the link to changes in tablet or
capsule dissolution must be inferred from changes
observed in mechanical properties associated with
the moisture uptake. In particular, it has been shown
that moisture uptake associated with disintegrants in
tablets can result in formation of micro-cracks due
to disintegrant swelling,20 which in turn can be
surmised to influence the disintegrants effectiveness.
In Figure 2, the effect of storage RH was examined
for four common disintegrants.21 As can be seen,
there are changes in the dissolution behavior from the
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 11, NOVEMBER 2010

t50 Ratio

WATERMAN AND MACDONALD

5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0

Corn Starch
Croscarmellose sodium
Crospovidone
Sodium starch glycolate

40

50

60

70

80

%RH

Figure 2. Effect of relative humidity (RH) on the dissolution behavior of tablets prepared with 200 mg ketoconazole,
40 mg lactose, 2.64.7 mg gelatin, 13.8 mg talc, 13.8 mg
magnesium stearate, and 20 mg of disintegrant.21 The dissolution time for 50% of the drug to dissolve (t50) was
determined initially (ranging from 9 to 17 min) and again
after storage for 120 days, with the ratio of the two used in
the graph (t50 ratio).21

initial condition in most cases, though it should be

kept in mind that in most cases the dissolution
changes would not result in failures with respect to
specifications. With respect to packaging, the important aspect of these data is that some of the changes
are sensitive to the RH of the environment, and
consequently would be sensitive to packaging. It is
unclear from the studies conducted to date how fast
the changes resulting from exposure to elevated RH
conditions occur. For example, in Figure 3, changes to
the dissolution behavior of tablets at 40 and 60%RH
appear to stabilize in <90 days, while at 80%RH
changes appear to continue through (and beyond)
120 days.21 It should be noted that the moisture
sorption behavior of this disintegrant (croscarmellose

55
50
40%RH
60%RH
80%RH

45
T50 (min)

4440

40
35
30
25
20
15
10
0

25

50

75

100

125

Time (days)

Figure 3. Effect of storage time at 258C on the dissolution

behavior (time for 50% dissolution, t50) of tablets prepared
with 200 mg ketoconazole, 40 mg lactose, 2.64.7 mg
gelatin, 13.8 mg talc, 13.8 mg magnesium stearate and
20 mg of croscarmellose sodium.21
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PACKAGE SELECTION FOR MOISTURE PROTECTION

sodium) changes markedly at 80%RH (water uptake

at 40, 60, and 80%RH is 8%, 13%, and 23%,
respectively).19 While moisture equilibration tends
to be rapid, the effect of this moisture uptake on the
disintegrant appears to be slower, at least in cases
where there is a large amount of water adsorbed.
There have been no systematic studies reported on
the effects of storage at low RH (i.e., below 40%) on
disintegration times with common disintegrants;
however, tablets using maize starch or a-cellulose
at low RH (1%) did not change significantly in 2 weeks
(308C).22
Excipient Changes. Some excipients used in pharmaceutical products are themselves metastable. In
particular, some excipients exist as amorphous
materials or as mixtures of crystalline and amorphous materials. Examples of this include such spraydried sugars as lactose and mannitol, marketed as
Fast FloTM Lactose and MannogemTM, respectively.
The rate of crystallization of spray-dried lactose was
studied as a function of RH.23 As can be seen in
Figure 4, the rate of crystallization does depend on
RH; however, what is less clear is how much any such
change will affect the dissolution stability of a drug
product. Presumably, there will be cases where
excipient crystallization can impact dissolution due
to changes in mechanical properties and water
permeation rates.
Another type of excipient change as a function of
RH that could potentially impact the dissolution
stability of a drug product is plasticization of
polymeric materials.24 Plasticization by moisture
has the potential to lower the glass transition
temperature (Tg) below that of some stability
storage conditions. The result of this can be a rapid
change in mechanical properties of a material, and a

0.16
0.14

1/(tmax in hrs)

0.12
0.1
0.08
0.06
0.04
0.02
0
0

20

40

60

80

%RH

Figure 4. Effect of moisture on the rate of crystallization

(1/tmax) of spray-dried lactose at 258C using microcalorimetry to determine the time for maximum heat flow after
introduction of moist air (derived from Ref. [23]).
DOI 10.1002/jps

4441

corresponding rapid change in dissolution behavior of

the dosage form, when the RH is sufficiently high. An
example of moisture lowering the Tg of a polymeric
excipient was studied with polyvinylpyrrolidone
(povidone).25 This effect could potentially impact
dissolution behavior; however this has not been
documented. Similarly, one could anticipate such
effects will be present with film coatings: lowering the
Tg of polymeric coating materials could potentially
affect dissolution.

Capsule Shell Changes. Hard gelatin capsules can

be physically unstable at both high and low RH
conditions. Under dry conditions, the capsules can
become brittle and crack; under moist conditions, the
capsules can become sticky and in some cases undergo
chemical reactions that affect their dissolution
behavior. The brittleness of hard gelatin capsules
occurs because gelatin is plasticized by moisture: as
the moisture level in the gelatin is reduced, the
corresponding modulus increases making the capsules liable to break under stress conditions. Even
when brittle, specific drug products will have
different mechanical (physical) sensitivity. The
stability will depend on the capsule wall thickness
and the stresses on the capsule. In general, the
brittleness of gelatin capsules has been found to
increase markedly below 30%RH, which corresponds
to about 10% water content.26,27 Since the RH of
storage conditions used for regulatory determination
of shelf lives are higher than this, the packaging
consideration is largely related to the internal
components. In particular, if the RH inside the
packaging is lower than about 30% (see Determination of Relative Humidity Inside Packaging Section),
than there is the potential for cracking issues. This
problem is most likely to occur if capsules are
packaged with desiccants; consequently, desiccants
are generally avoided with hard gelatin capsules.
Gelatin can undergo a cross-linking reaction either
by oxidative condensation processes, or with formaldehyde (typically an impurity or degradant from an
excipient) or other aldehydes.28,29 Crosslinked gelatin
will often be slow to dissolve, and cause the
dissolution rate of the drug to be retarded in standard
dissolution testing. In the presence of the enzyme
pepsin at pH 1.2 (or pancreatin at pH 7.2), the gelatin
release rate is often recovered. Importantly, the
in vivo behavior correlates with the dissolution
behavior in the presence of the enzymes.28 Gelatin
crosslinking is sensitive to the RH of the storage
environment, and could therefore dictate the packaging; however, in most cases, this crosslinking does
not affect bioavailability. It is therefore important
that enzymatic dissolution be conducted before
electing protective packaging to prevent crosslinking.
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4442

WATERMAN AND MACDONALD

Moisture incorporated into gelatin and hydroxypropylmethyl cellulose (HPMC) capsules reduces the
stiffness and hardness of the capsules.30 This softening effect reduces the overall hardness of gelatin
and HPMC capsules by 30% and 40%, respectively, on
going from 35 to 75%RH. Above 80%RH, gelatin
capsules become very soft and sticky. This stickiness
appears to only be an issue above most storage
conditions; however, this can be a potential issue in
Zone 4B countries. In addition, there can be an issue
when capsules are subjected to changing temperatures in packaging: warm, humid air in a package will
increase in RH when the temperature decreases even
causing condensation. While eventually this moisture
will re-equilibrate with all the internal components,
capsules that adhere to each other due to moistureinduced stickiness are likely to remain adhered even
as the RH drops again (often to the same value). In
other words, the rate of RH change in the air around
capsules when temperature changes (minutes) can
exceed the rate of re-equilibration of the moisture
inside the packaging (hours to days).
Tablet Hardness/Friability
Tablets can change hardness with storage as a
function of moisture uptake. This effect is especially
important with uncoated tablets since softer tablets
will generally be more friable. In a reported study of
moisture effects on tablet hardness, it was found that
the hardness of tablets stored at 75%RH was reduced
by a factor of two at room temperature in 4 days, while
at ambient RH, there was no change in 20 days.31 In
another study,32 tablet hardness decreases at 75%RH
(at 6 months) were matched with significant increases
in friability (from an initial of 04% weight loss with
100 revolutions). While this suggests that there are
likely to be conditions where elevated storage RH can
result in performance issues unless protective packaging is employed, the fact that the majority of new
commercial tablets are film-coated makes problems
associated with friability of lower concern.

Since changes in the physical form of an API can

affect the bioavailability of the drug product, one of
roles of packaging is to assure there are no such
transformations during storage. In many cases, the
API in a drug product is in its thermodynamically
most stable form. In those cases, physical stability of
the API form is not an issue, and packaging does not
need 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 contain

waters of hydration where the waters are either
bound in the lattice or more loosely in crystal
channels. In many cases, these waters of hydration
can reversibly come on and off the crystals as a
function of the temperature and RH. It is often
preferable in selecting appropriate packaging to first
determine the phase diagram of the API (i.e., the
region on an RH vs. temperature graph corresponding to hydrate and anhydrous forms). As an example,
near-infrared spectroscopy was used to determine the
phase boundaries between anhydrous and a nonstoichiometric hydrate of caffeine.33 In this case,
shown in Figure 5, the transition from anhydrous to
hydrate is at a relatively high RH. Higher temperatures favor the anhydrous form with caffeine as with
most materials based on the higher entropy for water
vapor, which drives the equilibrium toward anhydrous as temperature increases. In the study on
caffeine, it was noted that the greater the driving
force for form conversion, the faster kinetics for that
process; that is, there is an indication of a linear free
energy relationship between kinetics and thermodynamics. This fact was used to rapidly assess the
phase boundary. The initial rate for form conversion
was plotted against the RH, with the phase boundary

API Form
A solid API can exist in two basic physical forms: a
crystalline form or an amorphous form. Thermodynamically, crystalline drug forms are lower energy
and generally more chemically and physically stable
than amorphous forms, and are therefore most often
the API form commercialized; however, the higher
solubility of amorphous states can make them
attractive in some cases. Crystalline APIs often show
multiple packing forms in their crystal lattices
(polymorphs). In addition, many APIs can include
stoichiometric or nonstoichiometric amounts of solvent in their lattices. When the solvent is water, the
crystals are called hydrates.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 11, NOVEMBER 2010

Figure 5. Phase diagram of caffeine showing the temperature and relative humidity (RH) regions for the hydrate
and anhydrous form of the drug (derived from Ref. [33]).
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PACKAGE SELECTION FOR MOISTURE PROTECTION

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

rate).
Polymorph
Conversion. While
conversions
between hydrates and anhydrous forms are often
reversible, conversions between polymorphic forms
are most often irreversible.34,35 The kinetics of such
conversions are complicated and mostly not directly
influenced by packaging selection. The exception to
this is when the kinetics of the transition depends on
RH.
The first consideration for polymorph conversions
is whether the polymorphic API form being developed
is the thermodynamically stable form throughout the
possible storage temperature range. When a polymorphic form is lowest in energy, one does not have a
concern for transformation to other forms. Determination of polymorphic form thermodynamics often
involves thermal analyses36 or relative solubility
measurements.37
When a metastable polymorphic form of an API is in
a drug product, the possibility exists for this form to
convert to a more stable (and generally less soluble)
form. Adsorbed moisture has been implicated as a
molecular loosener that can enable molecular
rearrangements and thereby allow a crystal to
assume a more stable polymorphic form.38 In general
this phenomenon is mostly associated with at least
some amount of deliquescence (see Critical Relative
Humidity and Deliquescence Section). As an example,
pyridoxal hydrochloride was shown to undergo
polymorphic phase transformation at RH conditions
where it appears to deliquesce.39
Amorphous to Crystalline. When an API is in an
amorphous form (including a mesophase) in the
absence of excipients, crystallization has a thermodynamic driving force. In addition, the mobility of the
molecules is generally significantly higher than for
crystalline materials. Finally, amorphous materials
generally adsorb significantly more moisture than
crystalline ones. The result is that amorphous
materials will generally be more susceptible to RH
and require greater packaging protection to assure
stability. In some cases, amorphous drug dispersions
are used which stabilize the API by interactions
between the API and polymeric excipients. In these
cases, there may be less moisture sensitivity towards
crystallization.
Physical Appearance
Color Stability. Physical appearance changes
of dosage forms can be limiting for shelf-life
and ultimately dictate appropriate packaging. One
important aspect of physical appearance, in terms of
DOI 10.1002/jps

4443

patient perception of quality, is color. Color changes

can occur for most solid dosage forms, but are most
common with tablets. Color changes are associated
with chemical changes and follow the guidelines
described in the Chemical Stability Section under
Moistures Effects on Product Stability Section, with
the differences being related to the assay and
specification limits. For many commercial drug
products, color changes are evaluated visually
against a reference color. This method is difficult to
quantitate, and therefore is almost impossible to use
to accurately predict the effects of temperature and
RH. An alternative assay is to use a tristimulus
colorimeter. Such devices record the reflected light off
a sample with a human visual perspective. There are
various transformations possible for the values,
which can in turn be related quantitatively to the
amount of a colored degradant formed. As an
example, the degradation of vitamin C (ascorbic acid)
was followed using a tristimulus colorimeter and
could be quantitatively linked to the primary
degradant (dehydroascorbic acid).11,40 The degradation behavior was shown to obey Eq. (1). Since color
changes follow the exponential RH dependence of
other chemical changes, packaging considerations are
the same. The challenge therefore is to use a
quantitative method for analysis (e.g., tristimulus
colorimetry) and to assign a specification limit for how
much change is acceptable.
Another source of color changes can be migration of
materials into an outer coating or capsule wall. Since
such movement is affected by solubility and mobility,
it is reasonable to assume that moisture will influence
the rates, and therefore, packaging can be employed
to provide protection.

Other Visual Changes. Among the most common

physical appearance changes observed upon longterm storage, are a number related to materials
(especially tablets) swelling as they adsorb moisture.
This swelling can cause visual defects when the
resulting stresses are relieved by such effects as
tablet coating breaking, tablet cracking or tablet
capping (effectively delaminating internally).41 Also,
under very high RH conditions, tablets and capsules
can adhere to each other (twinning). These phenomena should be related to critical RH values either
in terms of moisture uptake and expansion or in
terms of plasticization (and becoming sticky). In
screening experiments as a function of RH, it should
be possible to define RH values that correspond to
safe storage conditions. The need for protection
from environmental RH will dictate the type of
packaging needed based on the methods discussed in
the Determination of Relative Humidity Inside
Packaging Section.
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4444

WATERMAN AND MACDONALD

DETERMINATION OF RELATIVE HUMIDITY

INSIDE PACKAGING
Moisture Sorption/Desorption Isotherms
A moisture sorption/desorption isotherm is an essential component in modeling moisture equilibration
and drug product stability in pharmaceutical packaging. Water vapor can interact with drug products in
the following ways:10 (1) it can adsorb onto crystalline
surfaces to form a water monolayer, multiple water
layers or even deliquesce (picking up of liquid water,
see Critical Relative Humidity and Deliquescence
Section), (2) water can permeate into the material
bulk (primarily amorphous regions), (3) it can
condense in capillary channels, or (4) react with drug
or excipients to form hydrates. For a particular
sample, the extent of these interactions and the
amount of water taken up by the sample is dependent
on the activity of water in the gas phase surrounding
the sample. For packaging selection, the moisture
sorption isotherm relates the water content of the
dosage form to the solids water activity (which
corresponds to the RH the solid is exposed to) which
determines chemical and physical stability.
While measurement of the moisture sorption
isotherm of a drug product can be straightforward,
in many cases, especially in early drug product
development, simple calculational models are adequate to aid in package selection. The moisture
sorption behavior of pharmaceutical solids can be
described in terms of parametric models.42,43 Monolayer adsorption behavior is generally described by
the BrunauerEmmettTeller (BET) model; however,
the more general GuggenheimAndersonde Boer
(GAB) model is more commonly applicable.44 The
GAB equation can be expressed as follows:
W

Wm CKRH
1  KRH1  KRH CKRH

(2)

where W is the weight of water in the sample at a

given RH, and Wm, C, and K are fitting parameters
which relate to the modes of water adsorption.
Several aspects make the GAB model useful in
generating a drug products moisture sorption iso-

therm: (1) The moisture sorption isotherm of a drug

product depends most heavily on the materials
involved and is relatively insensitive to the process
used to make the drug product;45 (2) the moisture
sorption isotherm of a combination of multiple
components can be modeled using the weighted
sum of the GAB parameters for those components;46
(3) the temperature sensitivity between 20 and 408C
is low (The low temperature sensitivity can be seen
with the common excipients MCC, lactose and starch
in Table 3); and (4) the contribution of crystalline API
in a drug product is generally negligible to the overall
moisture sorption isotherm. These factors mean that
one can reasonably calculate the moisture sorption
isotherm for a drug product based on its formulation
using its component GAB parameters. A number of
these parameters are collected in Table 4.
Calculating the moisture sorption isotherm for a
drug product can therefore be done as a weighted
average of the excipients GAB parameters. The RH of
a formulation at a given water content will vary
significantly, depending on this sorption isotherm. As
examples, the moisture sorption isotherms for formulations 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 materials
show hysteresis; that is, the amount of moisture a
sample holds at a given RH will be greater once it has
a history of being exposed to a higher RH.50,51 This
offset in the sorption and desorption isotherms results
from molecular reorganization of the structure of the
material as it adapts to the adsorbed moisture. While
in many cases, the hysteresis is minor, when it is
significant, it will impact the RH of a system as it
dries because moisture will be held more aggressively. Another consequence of this is that moisture
content specifications may need to be different
depending on the history of a sample: the same
moisture content will correspond to a different water
activity depending on whether a sample is previously
exposed to a high RH or not.
In some cases, the moisture sorption isotherm will
abruptly change as an amorphous excipient crystal-

Table 3. Temperature Effect on the Moisture Sorption Isotherms of Some Common Excipients
% Water (w/w)
Excipient
Corn starch47
Amorphous lactose48
Microcrystalline cellulose

Temp. (8C)

20%RH

40%RH

60%RH

30
45
12
38
25 [FMC Biopolymers, private communication]
40 [MacDonald B. Private communication]

4.0
3.3
3.1
3.2
2.8
2.8

6.0
5.2
6.0
7.0
4.3
4.5

8.6
7.7
9.6
14
6.5
6.1

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DOI 10.1002/jps

4445

PACKAGE SELECTION FOR MOISTURE PROTECTION

Table 4. GAB Parameters for Common Pharmaceutical Excipients

Excipient
Calcium carbonate
Croscarmellose sodium (Ac-di-solTM)
Crospovidone46
Crosslinked polyacrylic acid (CarbopolTM)49
Dibasic calcium phosphate anhydrous
Hydroxypropyl cellulose
Hydroxypropylmethyl cellulose (MethocelTM K4M)49
Lactose monohydrate
Lactose regular
Lactose, spray dried
Magnesium stearate
Magnesium carbonate
Mannitol
Microcrystalline cellulose (AvicelTM)
OpadryTM 85F
OpadryTM 85G18490
OpadryTM clear
OpadryIITM white OY-LS-28914
Polyethylene oxide (PolyoxTM N-80)
Povidone (polyvinylpyrrolidone)
Silicon dioxide
Sodium starch glycolate (ExplotabTM)
Sorbitol
Starch 1500
Talc
Talc (lo micron)
Titanium dioxide

Wm

0.149
10.206
15.688
9.864
0.173
4.507
6.372
0.039
0.647
8.658
1.336
0.665
0.848
3.979
1.013
3.114
2.295
1.013
0.389
0.721
1.039
6.100
357.379
7.400
0.846
0.142
0.202

33.933
3.960
2.630
1.011
37.490
1.526
2.295
7.582
0.023
4.148
1500.488
11.177
0.101
12.524
2.592
1.247
2.918
2.592
1.028
1.962
7.748
5.330
0.087
15.930
8.733
8.964
10.544

0.803
0.822
0.844
0.892
0.671
0.907
0.821
0.967
0.770
0.026
0.004
0.703
0.701
0.770
0.991
0.837
0.956
0.991
1.089
17.471
0.606
0.991
0.372
0.736
0.144
0.854
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.

Percent Water

9
8

DCC/Mannitol

MCC/spray-dried lactose

Initial Moisture Content

Pharmaceutical packaging controls dosage form
exposure to environmental humidity such that
chemical degradation rates and physical stability
for drug products in the packaging will vary as the
1.2
1
Percent Water

lizes. Moisture acts to plasticize the amorphous

material enabling molecular motion that in turn
allows crystallization.48,5153 In this case, as moisture
is adsorbed, the crystallization results in moisture
that was previously adsorbed being released. This can
be seen in Figure 7 with spray-dried (partially
amorphous) lactose. In this case, when the RH hits
about 50%, crystallization occurs which forces water
that was previously adsorbed to be lost. On the
desorption scan, the excipient holds less water since it
is now crystalline.

Sorption

0.8

Desoprtion
0.6
0.4

Starch 1500/lactose
monohydrate

0.2

20

40

60

80

%RH

1
0
0

10

20

30

40
%RH

50

60

70

80

Figure 6. Calculated moisture isotherms for 50%:50%

mixtures of dicalcium phosphate DCP/Mannitol, microcrystalline cellulose (MCC)/spray-dried lactose, and starch
1500/lactose monohydrate.
DOI 10.1002/jps

Figure 7. Moisture sorption and desorption isotherms for

spray-dried lactose (obtained by measurement of moisture
uptake using a gravimetric moisture balance, VTI Instruments, Inc., Hialeah, FL) showing crystallization of the
amorphous material at about 50% relative humidity (RH)
resulting in a lower amount of adsorbed water during
desorption.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 11, NOVEMBER 2010

WATERMAN AND MACDONALD

corresponding RH changes. To calculate the RH

inside a packaged product over time, one of the factors
to be considered is the initial RH of a product
immediately after packaging. There are three sources
of initial moisture in a packaged drug product system:
(1) moisture brought in from the drug product
itself, (2) moisture from any desiccant added to the
packaging, and (3) moisture in the headspace. As will
be seen below, the latter term is generally negligible.
Initial Drug Product Water Activity
The mass of water held by a drug product in its
packaging is a function of its moisture sorption/
desorption isotherm (discussed in the Moisture
Sorption/Desorption Isotherms Section) and its
moisture exposure history. Determining (and controlling) the RH (water content) of dosage forms
prior to packaging has often been under-appreciated
as a significant product stability attribute. In many
cases, water content specifications are arbitrary,
and measurements are carried out in a way that
does not reflect the true dosage form RH in the
packaging. While water content and dosage form
water activity can be related to each other via the
moisture sorption/desorption isotherm, one must be
careful when using water content values across
multiple product lines. While a water content of 3%
in one product could mean an RH of 30%, in another it
could very well be 70%. As an example, in Figure 6 a
water content of 3% corresponds to an RH of about
50% with a 50:50 mixture of MCC/spray-dried lactose
but only an RH of about 20% with a 50:50 mixture of
starch/lactose monohydrate. The result is that a 3%
water content specification in the latter product could
provide a significantly drier (and more stable)
environment than in the other. It has recently been
suggested that water-activity measurement should
replace the widely used Karl Fischer water content
testing.54 Since water-activity is generally more
relevant to drug product stability than water content,
and measuring it is at least as easy as Karl Fischer
measurements, this suggestion seems very reasonable. In using water activity measurements, the
challenge becomes how to measure this parameter
in such a way that it reflects the true water activity of
a drug product as it goes into a package. Tablets
and capsules can adjust to their environments
rapidly (i.e., from 1 h to 2 days, as discussed in the
Moisture Equilibration Within Dosage Forms
Section), such that testing cannot involve having
the dosage forms in environments outside the
package of interest.

packaging.55 The most commonly used desiccants

in the pharmaceutical industry are silica gel, clay
minerals, and molecular sieves. These materials are
typically contained in canisters, cartridges, or
sachets. The moisture sorption isotherms of these
three materials are shown in Figure 8. As can be seen,
in each case, a significant amount of moisture is held
by the desiccant; however, the capacities vary with
RH. Molecular sieves have relatively high capacity at
low RH conditions, and are therefore good for
bringing RH values in packaging down to very low
ranges; however, their capacity for moisture at
higher RH conditions is more limited than the
other desiccants. As a consequence, the quantity of
molecular sieve needed with permeable packaging
can become prohibitive. Moisture sorption by desiccants follows the same pattern as moisture sorption
by dosage forms: as the RH increases, the capacity for
further moisture sorption also changes. The result is
that with moisture permeable packaging (e.g., plastic
bottles) the RH will change as different amounts of
water are taken up.
When desiccants are present with dosage forms in a
package, equilibrium will be established at an RH
where typically some moisture from the dosage forms
transfers to the desiccant. As an example, for 10 g of
50% MCC/50% spray-dried lactose having the moisture sorption isotherm shown in Figure 6 with an
initial RH of 40%, the corresponding water content is
about 2.6% or 262 mg. If 1 g of a silica gel desiccant
having the moisture sorption isotherm shown in
Figure 8 (with no initial water) is added, the excipient
blend will lose about 90 mg of water to the desiccant to
put them both at an RH of about 19%.
Headspace
The mass of water in the headspace is a function of the
headspace volume, temperature and the RH of the
headspace air. The headspace volume can be altered
by changing the packaging size or changing the

35
30
Percent Water

4446

25
20
15

Silica Gel
Molecular Sieves
Clay Mineral

10
5
0
0

10

20

30

40

50

60

70

80

%RH

Desiccants
Desiccants are materials that have high moisture
sorption capacities and thereby can reduce RH inside
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 11, NOVEMBER 2010

Figure 8. Moisture sorption isotherms for three standard

pharmaceutical desiccants at 258C (data provided courtesy
of Sud-Chemie, Inc.).
DOI 10.1002/jps

4447

PACKAGE SELECTION FOR MOISTURE PROTECTION

Moisture Equilibration within Dosage Forms

When a dosage form (tablet, capsule, powder) is
exposed to a different RH than its initial value, it
will re-equilibrate to the new water activity. This
equilibration will depend on a number of factors
including the permeability of the materials, the
temperature, and the difference in RH. Nonetheless,
on the multiyear timescale of most drug product shelflives, the rates are effectively instantaneous. As an
example, two tablets were placed in a bottle which
had been brought to about 0%RH using nitrogen. As
shown in Figure 9, the RH in the bottle increased due
to desorption of moisture from the tablets. In this
case, the equilibration time was less than an hour.
DOI 10.1002/jps

35
30
25

%RH

dosage form count in the case of a bottle. In deference

to the role of RH in drug product stability, the RH of
packaging rooms is often highly controlled since it is
the room environment which determines the initial
headspace RH of a bottle or blister; however, the
impact of controlling headspace RH is minor compared to controlling the initial drug product water
activity, with respect to the initial packaged product
RH and subsequent drug product stability. The effect
of the initial headspace RH on the equilibrated
headspace RH (assuming no moisture transfer, i.e.,
MVTR 0) is generally small because of the moisture
sorption capacity of the dosage form in the packaging
compared 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 isotherm
shown in Fig. 6) with a water activity of 35%
(2.35% water content) were packaged in a 2-cc blister
in either a 20%RH or 75%RH packaging room, the
initial water content of the tablet would be 11.757 mg
and that of the headspace would be 0.005 and
0.007 mg (based on the moisture content of air at
258C, see Fig. 1) at the two headspace RH conditions,
respectively. After equilibration, the tablet would lose
water in the drier condition (0.004 mg) and gain water
in the moist condition (0.008 mg); however, the
equilibrated RH would be essentially 35%RH in both
cases since the quantity of water moving from or to
the tablet is small. With a single such tablet in a 60-cc
bottle, the equilibrated RH in the two packaging
environments would be 34 and 37%RH, respectively;
however, with 40 such tablets in the bottle, the
differences in equilibrated RH values would again
effectively disappear. The mass of water held by
tablets or capsules greatly exceeds that held by
the headspace such that even extreme differences
in headspace RH do not have a large impact on
the overall mass of water available for redistribution.
Similarly, the headspace volume has no significant
impact on the water activity because of the paucity
of water in the headspace relative to the dosage forms.

20
15
10
5
0
0

10

20

30

40

50

60

70

80

90

Time (min)

Figure 9. Kinetics of tablet and headspace humidity

equilibration. Two, 500-mg tablets of 1:1 spray-dried
lactose/microcrystalline cellulose (having a relative humidity, RH, of about 32%) were placed in a nitrogen-purged 120cc glass bottle at the 10-min point. The RH in the tablets
desorbed to reach equilibrium with the air in the bottle in
>1 h.

Film-coated tablets are somewhat slower to equilibrate; however, even coatings advertised as moistureprotective still allow equilibration in <2 days.56,57
While dosage forms exposed to cycling of RH could be
affected by the film coatings, in general, long term
shelf-life will not show any significant impact from
the coatings. For package selection, the RH inside a
package can be assumed to always be in equilibrium
between the air (headspace) and the dosage forms,
with moisture transfer into or out of the package
being rate-limiting.
Moisture Vapor Transmission Rate
Theory
The moisture vapor transmission rate, MVTR,
describes the mass of water permeating into the
headspace volume of a container for a given
temperature and difference between internal and
external RH (DRH) with a given package (bottle,
blister) size in units of mg H2O/day. A related term is
permeability, P, which divides out DRH from the
MVTR as shown in Eq. (3):
P MVTR=DRH

(3)

When an empty container (i.e., one with no

components or moisture) is placed in a stability
chamber, moisture from the chamber environment
will permeate through the walls into the headspace at
a rate proportional to DRH. This can be expressed in
terms of the mass of moisture transferred, Dm, in a
unit time Dt according to Eq. (4).
Dm PDRHDt

(4)

With no water adsorbing components, any moisture

transferred must directly accumulate into (or be lost
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4448

WATERMAN AND MACDONALD

from) the bottle headspace. The changed mass of

water in the headspace will change the RH based on
the ratio of the new water concentration in the
headspace as a proportion to the saturated water
concentration at that temperature, according to
the psychrometry relationship (Fig. 1). This is shown
mathematically in Eq. (5):

75%RH in only about 10 days when stored at

408C/75%RH.
While the MVTR value for any packaging can be
determined explicitly for any temperature, the values
have been shown to obey the Arrhenius equation:58
ln MVTR ln A 

RHt m0 Dm=VCsat RH0 Dm=VCsat (5)

where RHt is the internal RH at time t (after moisture
permeates into the container), m0 the internal mass of
water in the container before water is transferred, V
the volume of the container, Csat is the saturated
water concentration at the study temperature
and RH0 is the RH inside the container before water
transfers. Eq. (5) can be recast as a differential
equation (Eq. 6):
dRH
PDRH
dt

(6)

This equation can be solved to give the following:

ln

DRH0
Pt
DRHt

(7)

RHint;t DRH0 ePt RHint;0

(8)

where DRH0 is the initial difference in internal

(RHint) and external RH (RHext), DRHt is the
difference in the internal and external RH at time
t. The internal RH in a bottle was shown to indeed
obey Eq. (8) experimentally using RH probes sealed in
bottles, as shown in Figure 10 (empty bottle example).
Though the probes themselves do adsorb some
moisture, overall, there is good agreement between
the calculation and the measured values. Interestingly, with standard 60-cc high density polyethylene,
HDPE, pharmaceutical bottles, even with heat
induction seals, the internal RH goes from 20 to
70
60

empty bottle
2 tablets

50
%RH

15 tablets
40
30
15 tablets + desiccant
20
10
0
0

10

20

30

40

50

60

70

Days

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 candidate
CP-481,715, 322.6 mg of microcrystalline cellulose (AvicelTM PH200), 165 mg mannitol, and 2.5 mg of magnesium
stearate.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 11, NOVEMBER 2010

Ea
RT

(9)

where A is the collision frequency, Ea the activation

energy, R the gas constant, and T is the absolute
temperature. Eq. (9) allows the estimation of the
MVTR for any temperature once it is know for at least
two temperatures.
The MVTR for a given package will depend on the
packaging material used and be directly proportional
to the surface area of the package, assuming the same
wall thickness overall. This allows a reasonable
estimation to be made for the MVTR of different size
packages made with the same material and wall
thickness using surface area proportionality. Since
most packaging is characterized in terms of volume,
an approximation can be made according to Eq. (10):
MVTR1 MVTR0 V1 =V0 2=3

(10)

where MVTR1 and MVTR0 are the MVTR values of

the proposed and control packages, respectively; and
V1 and V0 are their corresponding volumes.
Measurement of MVTR
Measurement of MVTR for a package must be
determined with a known difference in RH between
the interior and exterior (stability chamber) of the
container. Most often, the MVTR involves measurement of the weight gain per unit time with a known
temperature and difference in RH. Typically some
type of drying agent is placed inside the package,
with gravitimetric measurements made over time,
generally until a steady state condition is achieved. A
recent example of this used anhydrous calcium
chloride to control the RH inside bottles according
to USP(671).59 Other desiccants have also been
studied, with clay found to perform better than
calcium chloride in many cases.59 These approaches
provide MVTR values of varying precision depending
on the background weight of the container and the
overall weight gain at the time point used. Alternatively, we have found that plotting the weight gain
of a desiccant canister as a function of time (weighed
after removal from a package) can be a practical
alternative since the weight gain is against a lower
reference (just the desiccant) and the experiment can
be carried out to a sufficient time to get statistically
significant weight increases. As a reference, MVTR
values for a number of pharmaceutical packages are
shown in Table 5.
DOI 10.1002/jps

4449

PACKAGE SELECTION FOR MOISTURE PROTECTION

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

Package
HDPE

Polyvinylchoride (PVC) blister (250 mm thick)

Polyvinylidine chloride (PVDC) blister (190 mm thick)
Polychlorotrifluoroethylene (PCTFE), AclarTM UltRx 2000 blister
Polychlorotrifluoroethylene (PCTFE), AclarTM UltRx 3000 blister
Polychlorotrifluoroethylene (PCTFE),
AclarTM RX160 blister (305 mm thick)
Foil-foil cold-formed blister

Package Size

MVTR
(mg/day),
238C/75%RH

40 cm3 bottle1
60 cm3 bottle
180 cm3 bottle
23.9  9.5  8.2 mm capsule
13.3  7.5  4.4 mm capsule2
23.9  9.5  8.2 mm capsule
23.9  9.5  8.2 mm capsule
14.5  0.3 mm round
23.9  9.5  8.2 mm capsule
14.5  0.3 mm round
13.3  7.5  4.4 mm capsule2

0.15
0.262
0.521
1.187
0.259
0.230
0.028
0.013
0.018
0.007
0.008

23.9  9.5  8.2 mm capsule

13.3  7.5  4.4 mm capsule2

0.00067
0.001

MVTR
(mg/day),
408C/75%RH
0.70
1.352
2.688
3.885
1.200
0.142
0.100
0.103
0.062

0.0037

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 of
packaging (Moisture Vapor Transmission Rate Section) with the moisture distribution within the
package (Moisture Sorption/Desorption Isotherms,
Initial Moisture Content, and Moisture Equilibration
Within Dosage Forms Sections), it is possible to
determine the RH inside the package as a function
of time and storage conditions. Computationally, one
can calculate the moisture transfer as shown in
Eq. (8), and then determine the new distribution of
the moisture among the internal components (dosage
forms, desiccants, and head space) based on their
moisture sorption isotherms. A unit of moisture will
result in a change in RH based on the moisture in the
head space, which in turn depends on the sorption
capacity of the components at that RH. This approach
has been used to successfully calculate the RH inside
various packaging as a function of time and storage
conditions. An example of the model predictions and
measured values are shown in Figure 10.

DETERMINING DRUG PRODUCT PACKAGING

FOR STABILITY
Chemical Stability
In the Chemical Stability Section under Moistures
Effects on Product Stability Section, the effect of RH
on the reactivity of solid drug products was discussed
with respect to a moisture sensitivity term B (Eq. 1)
which relates the exponential dependence of such
rates on RH. In the Determination of Relative
Humidity Inside Packaging Section, the elements
that influence RH inside a package were discussed:
DOI 10.1002/jps

the initial RH of the components, the moisture

sorption isotherms of the components and the MVTR
of the package. These elements allow us to calculate
the RH inside a package as a function of time.
Combining the RH as a function of time with the
chemical degradation rate as a function of RH is
possible using an iterative calculation: the degradation rate (rate of formation of degradant) is recalculated corresponding to the instantaneous RH after
each differential moisture transfer into or out of
a package.14 This process is amenable to simple
spreadsheet type calculations. Adding error bars to
these calculations is more complicated since it
involves varying uncertainty as the RH changes:
typically the error bars are minimal at the center of
the data (on the RH axis), and increase away from this
point. One approach to determining the error bars for
the in-package stability is to use error bars for
the rates at each RH based on a Monte-Carlo type
statistical calculation; however, this can be quite
time-consuming.
The effectiveness of these calculations at predicting
drug-product stability in packaging is shown in
Figure 11. As can be seen, the fact that the degradant
formation rate varies exponentially with RH results
in curvature in the degradant as a function of time
graph: degradation rates in moisture-permeable
packaging will generally increase with time until
the RH inside the package becomes relatively
constant. In Figure 11, the effect of higher tablet
count on product stability is accounted for in the
calculation due to the lower RH as a function of time
(greater moisture sorption capacity). Figure 11 also
shows the impact of desiccant on the drug stability
based on the corresponding lowering of the RH as a
function of time.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 11, NOVEMBER 2010

4450

WATERMAN AND MACDONALD

60
Open bottle
2 tablets/60-cc bottle

50

40

%RH

%Degradant

2
15 tablets/desiccant/
60-cc bottle

15 tablets/
60-cc bottle

30
20

40%RH
25C/60%RH
30C/65%RH
30C/65%RH + desiccant

0
0

10

20

30

40

50

60

70

10

Days

Figure 11. Predicted (lines) versus measured (symbols)

drug degradant formation for tablets stored in a 60-cc
HDPE bottle stored at 408C/75%RH. Tablets (500 mg) contained 10 mg of the drug candidate CP-481, 715, 322.6 mg of
microcrystalline cellulose (AvicelTM PH200), 165 mg mannitol, and 2.5 mg of magnesium stearate. The accelerated
stability assessment program (ASAP) was used to determine the moisture-modified Arrhenius parameters.15

0.0

1.0

2.0
3.0
Years

4.0

5.0

Figure 12. Time to reach the relative humidity (RH)

conditions inside packaging where tablets could potentially
show dissolution issues. Tablet calculations assumed behavior for tablets from Figure 2 with the disintegrant being
sodium starch glycolate. Tablets are modeled assuming an
initial water content of 1% with 60 200-mg tablets in a 60-cc
high density polyethylene (HDPE) bottle.

Physical Stability
As discussed in the Physical Stability Section, drug
product stability can be dependent on physical
changes associated with the API or excipients. In
many cases, these physical changes occur at a
threshold RH; that is, the conversions occur rapidly
when a phase boundary is passed, but do not occur at
all at other conditions. In those cases, packaging can
provide protection from the storage condition environment based on the time needed to reach the
threshold RH inside the packaging, which can be
calculated as indicated in the Overall Prediction of
RH Inside Packaging Section. As an example, in
Figure 2, the disintegrant croscarmellose sodium
shows good stability at low RH, with problems for
dissolution occurring somewhere between 40 and
60%RH. If one assumes that it is necessary to stay at
40%RH or lower, calculations of RH as a function of
time for several packaging options can be used to
determine which will provide assured stability with
respect to dissolution, as shown in Figure 12. As can
be seen, bottles would require desiccant to maintain
an RH below 40% at 308C/65%RH for 3 years. From
Figure 12, it also becomes clear how critical it can be
to resolve where the threshold RH is for physical
instability. In this example, if that threshold
were 55%RH, there would be no need for desiccant
for a 3-year shelf-life.

CONCLUSION
The selection of packaging can be one of the most
important decisions in the development of a drug
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 11, NOVEMBER 2010

product. Packaging can have a major impact on a drug

products shelf life as well as the cost of goods;
consequently, it is important that appropriate packaging be selected. Packaging plays a key role in
protecting a drug product from the RH of the
environment. While the state of the art is sufficient
to make good estimates of the impact of RH of
chemical reactivity, there remain gaps in predicting
exactly how RH will impact physical stability. In
cases where chemical stability limits shelf-life, it is
possible to anticipate the packaging impact using a
combination of ASAP to determine the instability as a
function of temperature and RH, and the moisture
transfer and re-equilibration with internal components to determine the RH as a function of time and
storage conditions. With physical stability, it is often
possible to use a worst case scenario: the packaging
can be selected to prevent a threshold RH from being
reached inside a package for the entire shelf-life.
While in many cases this will be overly conservative,
this approach can still allow package selection with
minimal experimentation.

ACKNOWLEDGMENTS
Some data used in this paper was obtained with the
help of Pat Basford, Dan Malinowski and Gerry Enos,
all of Pfizer. The authors also wish to acknowledge the
editing and helpful suggestions of Steve Colgan and
Cindy Oksanen (Pfizer).
DOI 10.1002/jps

PACKAGE SELECTION FOR MOISTURE PROTECTION

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DOI 10.1002/jps