[

Product and Process Design.

Coordinated by Yihong Qiu

Understanding Physicochemical Properties

for Pharmaceutical Product Development
and Manufacturing II:

Physical and Chemical Stability

and Excipient Compatibility
Deliang Zhou
Product and Process Design discusses scientific and
technical principles associated with pharmaceutical
product development useful to practitioners in validation and compliance. We intend this column to be a
useful resource for daily work applications. The primary
objective for this feature: Useful information.
Reader comments, questions, and suggestions are
needed to help us fulfill our objective for this column.
Please send your comments and suggestions to column
coordinator Yihong Qiu at [email protected] or
to coordinating editor Susan Haigney at shaigney@
advanstar.com.

KEY POINTS
The following key points are discussed in this article:
Stability of pharmaceutical products, including physical and chemical stability, is a core quality attribute
potentially impacting efficacy and safety
Phase transformation is a common form of physical
instability. Polymorphic transition; solvation and
desolvation; salt and parent conversion or salt and salt
exchange; and amorphization and devitrification are
the common types of phase transformations. Phase
transformation can occur via solid-state, melt, solution,
or solution-mediated mechanisms.
Pharmaceutical processing such as comminution (miling), compaction, granulation, drying, and coating
may induce partial or complete phase conversion,
which could lead to inconsistent drug product quality

if not understood and properly controlled

Drug degradation may be categorized as thermolytic,
oxidative, and photolytic
Hydrolysis accounts for the majority of reported drug
degradations and it is common for a broad category
of organic molecules derived from weak functional
groups such as carboxylic acids. Moisture, temperature,
and pH may greatly impact the rate of hydrolysis.
Oxidation of drugs is the next greatest cause of degradation. Three primary mechanisms exist for oxidative
degradations: nucleophilic and electrophilic, electron
transfer, and autoxidation. Nucleophilic and electrophilic oxidations are typically mediated by peroxides.
Transition metal catalyzes oxidation via electron transfer process. Autoxidation involves free-radical initiated
chain reactions. A single free-radical can cause oxidation of many drug molecules. Autoxidation is often
autocatalytic and non-Arrhenius.
Photolytic degradation occurs only when light is
absorbed. Excited states of drug molecules may have
enhanced reactivity. Photolytic degradation is complex
but can usually be mitigated by packaging.
Reaction order, catalysis, and pH-rate profile are
some of the basic concepts in chemical kinetics,
which are helpful to the basic understanding of drug
degradation
Drug degradation in solid dosage forms is often
determined by the surface characteristics of the active
pharmaceutical ingredient (API) and excipient par-

ABOUT THE AUTHOR

For more Author

information,
go to
gxpandjvt.com/bios

Deliang Zhou, Ph.D., is an associate research investigator in Global Formulation Sciences, Global
Pharmaceutical R&D at Abbott Laboratories. He may be reached at [email protected]. Yihong
Qiu, Ph.D., is the column coordinator of Product and Process Design. Dr. Qiu is a research fellow
and associate director in Global Pharmaceutical Regulatory Affairs CMC, Global Pharmaceutical R&D at
Abbott Laboratories. He may be reached at [email protected].

g x p a nJdournal
j v t . c o m of Validation T echnology [Summer 2009]
36

iv thome.com

Yihong Qiu, Coordinator.

ticles, or collectively the microenvironment

Defects, disordered or amorphous contents in API,
and excipients pose significant concerns on drug
degradations
Moisture profoundly affects chemical stability by direct
involvement in a reaction or by catalyzing a reaction
via increasing molecular mobility and facilitating the
creation of microenvironments. Moisture preferentially penetrates into amorphous or disordered regions
and may greatly enhance chemical degradation.
Process-induced phase transformation of API is often a
leading cause of chemical instability, particularly when
significant amorphous content is generated
Compatibility is an important factor for excipient
selection. Timely identification of excipient incompatibility can result in significant savings in time and
resources. Excipients can directly react with drug molecules, which may be judiciously avoided based on the
chemical structures and physicochemical properties
of the drug molecules and excipients. Excipients can
also enhance drug degradation by creating a favorable
microenvironment such as pH, moisture, metal ions,
or simply by providing large accessible surfaces.
Fundamental understanding of general aspects of
chemical degradation as well as specific physicochemical properties of a drug molecule is key to its stabilization. Stability issues may be mitigated by proper
solid form selection. Formulation and engineering
approaches may also be used to mitigate a stability
issue.
Validation and compliance personnel should be
aware of the physical and chemical properties of
the active drugs for which they have responsibility.
They should become especially knowledgeable about
active drugs and products that may be highly prone to
phase transformation and chemical degradation, and
apply this knowledge in process control and change
management.

INTRODUCTION
Stability is a core quality attribute for any viable drug
product. While drug molecules tend to degrade over
time like other chemicals, stability of drug products is
broader than chemical degradation alone. Any aspect
related to the change of the physical, chemical, and biopharmaceutical properties of a drug product could be
classified as instability.
Generally speaking, instability of pharmaceuticals
includes but is not limited to: loss of active ingredient potency, increase in levels of impurities, change in
appearance (e.g., color, shape), change in mechanical
gxpandjv t.com

strength (e.g., tablet hardening/softening), change in

dissolution/release rate, change in content uniformity
(suspensions in particular), alteration in bioavailability,
or change in other pharmaceutical elegances. These
instabilities may impact the handling, purity, bioavailability, safety, and efficacy of a drug product, or may
be merely cosmetic changes which can lead to poor
patient acceptance.
This column discusses the key stability concepts in
drug products, with an emphasis on the basic physical and chemical principles applicable to all stages of
product development and manufacture. More in-depth
treatments on these topics may be found in many textbooks and review articles (1-6).
The role of physical changes in chemical degradation
is often inadequately acknowledged. Physical stability
often contributes greatly to the chemical stability of a
drug product and cannot be ignored. This discussion
begins with an introduction of the basic concepts and
general mechanisms on physical and chemical stability
of drugs, followed by excipient compatibility, and finally
a brief overview of remedies to instability.

PHYSICAL STABILITY OF DRUGS

In principle, any stability issue not involving chemical
changes can be considered physical in nature. On the
surface, the physical instability may manifest itself in
various forms, such as appearance, mechanical strength
of dosage forms, content uniformity, dissolution rate,
and bioavailability. These phenomena may arise from
various root causes; phase transformation is frequently
the leading cause of these problems.
A drug molecule may exist in different solid forms,
including polymorphs, salts, solvates (hydrates), and
amorphous phases. A primary task of preformulation
investigation is to select an appropriate solid form which
bears viable properties in various aspects. Depending on the specific circumstances, a solid form may
be selected with particular emphasis on its ability to
improve one or more characteristics of the drug molecule, such as solubility and dissolution rate, melting,
polymorphism, purity, mechanical properties, manufacturability, and chemical stability. For example, the
bioavailability of a poorly water-soluble compound
may be greatly improved by using an amorphous phase.
Salts have been conventionally used to improve properties such as purity, melting temperature, crystallinity,
hygroscopicy, and/or chemical stability, as well as the
bioavailability of the parent form. A number of properties (e.g., solubility and dissolution, spectroscopic,
mechanical, chemical) have been shown to be affected
Journal

of

Validation T echnology [Summer 2009]

37

Product and Process Design.

by polymorphism. When modification of a particular

property is aimed via solid form selection, properties in
other aspects should be balanced to facilitate pharmaceutical development. It should be understood that a solid
form change during product manufacturing and storage
could defeat the primary purpose for its selection.

Types of Phase Transformations

The following paragraphs describe the types of phase
transformations.
Polymorphic Transition. When a molecule can
be packed differently in the crystal lattice, those crystalline forms are called polymorphs. Polymorphic
transition refers to the conversion between polymorphs.
Polymorphs differ in free energy and could impact
melting, hygroscopicity, solubility and dissolution,
bioavailability, chemical stability, mechanical, morphological, and flow properties. Any two polymorphs are
related thermodynamically as either enantiotropes or
monotropes. Enantiotropy exists when one polymorph
is more stable below a critical temperature (transition
temperature, Tt) and the other more stable above Tt.
In monotropy, one polymorph is always more stable.
Under any circumstances, there is always a most (more)
stable polymorph.
Solvation and Desolvation. This is related to the
conversion between the solvated and unsolvated crystal
forms, or solvated forms of different stoichiometry,
with hydration/dehydration being the most typical.
Similarly to polymorphs, differently solvated forms usually differ in various physicochemical properties. This
type of form conversion can affect chemical stability,
pharmaceutical elegance, and other quality attributes.
Particularly, the differences in apparent solubility and
dissolution rate could impact on the oral absorption
for many poorly or borderline soluble compounds. An
important concept for hydration and dehydration is the
critical relative humidity (RH), below which the anhydrous form is more stable and above which the hydrate
is more stable. Similarly, critical RH also exists between
hydrates of different stoichiometry. This concept is vital
to the stability of hydrates because moisture has to be
dealt with everywhere: active pharmaceutical ingredient (API) manufacture, formulation development,
drug product manufacture, and storage. Changes in
the environmental humidity could inadvertently cause
hydration or dehydration to occur. In aqueous solutions, the hydrated form is usually less soluble than the
anhydrous form because of the nature of equilibrium.
The solubility difference between hydrated and anhydrous forms is the driving force behind solution-medi38

Journal

of

Validation T echnology [Summer 2009]

ated hydrate formation, which could occur during various

wet processes or during in vivo dissolution.

Salt and Parent Conversions or Salt and Salt

Exchange. Salts may be converted to their parent forms
or to salts of different counterion during processing and
storage. The propensity of salt form conversion is determined by pKa, crystal lattice energy, solubility and solubility relationship, and other experimental conditions.
For example, salts of very weak acids or bases may readily
convert back to the parent forms upon exposure to moisture or water. The potential of salt conversion during wet
granulation and other wet processes is more significant
than other dry processes and should be watched closely.
Similar to other solid form conversions, change of a salt
to its parent, or to different salt forms, can profoundly
alter the quality attributes of a drug product.
Amorphization and Devitrification. When the
long-range order in a crystal lattice is destroyed, an
amorphous phase is then generated. Partially or fully
amorphous phases may be generated (amorphization) by
various methods including many unit operations such as
milling, melting, wet granulation, drying, and compaction. Amorphous phases have higher free energy than
their crystalline counterparts and are often exploited
to improve the bioavailability of poorly water-soluble
compounds. However, the reversion to crystalline
forms (devitrification) is thermodynamically favorable
based on the thermodynamic principle. When the use
of an amorphous phase is desired, the physical stability
becomes critical because crystallization could lead to a
decrease in bioavailability and thus lose the intended
advantage of the amorphous state. When crystalline
forms are desired, however, the formation of even a small
amount of amorphous content during various processes
is also a concern because this may bring undesired effects
to drug products such as enhanced degradation.

Mechanisms of Phase Transformations

The conversion of metastable form to stable form is
thermodynamically favored, which poses a concern
for any system where a metastable form is employed.
The transformation of a stable form to a metastable
form, on the other hand, is thermodynamically unfavorable, and is possible only when there is an energy
input from the environment. The transformation
kinetics in both cases, however, vary greatly, which
are compound-specific and depend on the experimental conditions.
The primary mechanisms for phase conversions
include solid-state, melt, solution, and solution-mediated transformations.
iv thome.com

Yihong Qiu, Coordinator.

Solid-State. Certain phase transitions occur in the

solid-state without passing through intervening transient liquid or vapor phases. These solid-state transitions are generally nucleated by defects or strain. The
physical characteristics of the solids, such as particle
size, morphology, crystallinity, mechanical treatments,
and presence of impurities may greatly affect the rate of
such transformations.
Melt. A solid form is destroyed upon melting and may
not regenerate when cooled. The melt is often supercooled to generate an amorphous phase, which may or
may not crystallize during further cooling. Even when
it crystallizes, it usually goes through metastable forms,
and may or may not convert to the most stable form
on the experimental time scale. A potential change in
crystalline form is therefore likely. The final solid phase
may depend on: thermodynamic stability among different forms; the relative nucleation and crystal growth
rate of each form; and the kinetics of form conversion.
The solid phases formed in such a process are usually
accompanied by relatively high amount of disorders.
Impurities or excipients are also likely to affect the kinetics of crystallization and phase transformation. Presence
of excipients may cause eutectic melting at temperatures
much lower than the melting of pure API and give rise
to potential phase transformations.
Solution. When solvents are involved in processing,
solid API may dissolve partially or completely. Subsequent solvent removal may cause the dissolved portion
to change its solid form similar to a melt. It is important
to note that formation of a metastable form (crystalline or amorphous) is often likely, especially when the
original solid form is completely dissolved. Particular
attention should be paid to drug molecules that have
high solubility in the processing solvents.
Solution-Mediated. When a metastable solid form
comes to contact a solvent during processing, it may
convert to more stable forms due to solubility difference between the metastable form and the stable form.
As opposed to the solution mechanism, the solutionmediated mechanism only allows the transition from a
meta-stable form to a more stable form.

PHASE TRANSFORMATIONS DURING

PHARMACEUTICAL PROCESSING
Phase transformations can occur in a number of pharmaceutical unit operations, including milling, wet
granulation/spray drying/lyophilization, drying, and
compaction, and therefore may impact drug product
manufacturing and performance (7). Because of their
very kinetic nature, the extents of these phase transforgxpandjv t.com

mations may be time and equipment dependent. These

phase transformations, when not controlled properly,
often lead to inconsistent product quality.
The application of mechanical and possibly the
accompanying thermal stresses during operations such
as milling, dry granulation, and compaction, may lead
to phase transformation such as polymorphic transition,
dehydration and desolvation, or vitrification via the
solid-state or melt mechanisms. The rate and extent of
these phase transitions will depend on characteristics of
the original solid phase and the energy input from these
processes. Caffeine, sulfabenzamide, and maprotiline
hydrochloride have been reported to undergo polymorphic transformations during compression.
A number of wet processes, such as wet granulation,
lyophilization, spray drying, and coating, may induce
phase transitions via solution or solution-mediated transformation. Important factors governing the likeliness
and the extent of conversion include: solubility of the
drug substance in the liquid, duration in contacting with
liquid, other operation parameters such as temperature,
drying conditions, and the specific properties of the
drug molecule. The presence of other excipients may
also significantly influence the propensity and rate of
a phase transformation. All the aforementioned phase
transitions, such as polymorphic conversion, hydration and dehydration, salt/parent conversion or salt/salt
exchange, and vitrification and crystallization may occur.
For example, a highly water-soluble drug may completely
dissolve in granulating liquid and subsequently produce
amorphous phase during drying that may or may not
convert back to the original solid form. The formation
of a hydrate is also likely to occur in wet granulation.
Subsequent drying may dehydrate the formed hydrate. In
any solid-solid conversion; however, it is very likely that
a less ordered form will be produced even if conversion
is close to completeness. Therefore, various amounts of
amorphous content may exist in the end product, which
could cause further concerns on its chemical stability. In
film coating, due to the relatively short contacting time
between solid surface and liquid, the likelihood of solid
form change is much lower. However, the potential for
phase transformation can be significant when an active
is present in the coating solution.

CHEMICAL DEGRADATION OF DRUGS

Chemical degradation represents one of the most
important stability aspects of pharmaceuticals,
because inadequate stability not only limits the
shelflife of a drug product but also potentially impacts
efficacy and patient safety.
Journal

of

Validation T echnology [Summer 2009]

39

Product and Process Design.

An important aspect of preformulation characterization is to examine the chemical stability of new drug
candidates, assess the impact of stability on pharmaceutical development and processing, and design strategies
to stabilize an unstable molecule. The understanding of
commonly encountered degradation pathways, basic concepts in chemical kinetics, and characteristics of chemical degradation in drug products are key to the overall
success of formulation development and scale up.

Transacylation is also likely when appropriate other

functional groups (i.e., alcohols, amines, esters, etc.)
are present in the environment, either as solvent or
solvent residuals, or more commonly, as excipients
or impurities.
Other thermolytic degradation pathways include rearrangement, isomerization and epimerization, cyclization,
decarboxylation, hydration/dehydration, and dimerization and polymerization.

Common Pathways of Drug Degradation

Oxidative Degradation

Drug degradation can be generally divided into thermolytic, oxidative, and photolytic. By examining
structural features of a drug molecule, possible degradation routes and products may be predicted to a
certain extent. These may then aid in the design and
execution of stability studies.

Oxidation accounts for 20-30% of reported drug degradations and is secondary only to hydrolysis. Oxidation can
proceed with three primary mechanisms: electrophilic/
nucleophilic, electron transfer, and autoxidation.
A drug molecule may be oxidized by electrophilic
attack from peroxides, which is the typical scenario of
nucleophilic/electrophilic mechanism. Similarly, the
electron transfer process shares certain features of the
nucleophilic/electrophilic process, except that an electron
is transferred from a low electron affinity donor (e.g.,
drug molecule) to an oxidizing agent via the mediation
of transition metal. Fe3+ and Cu2+ are commonly used
to probe such mechanisms.
The autoxidation process involves the initiation of
free radicals, which propagates through reactions with
oxygen and drug molecule to form oxidation products.
Because of the complexity of the reaction mechanism,
non-Arrhenius behavior is frequently observed. The
three stages of autoxidation may be represented as the
following:

Thermolytic Degradation
Thermolytic degradation refers to those that are driven
by heat or greatly influenced by temperature, to which
the following Arrhenius relationship often applies:
k = Aexp(Ea/RT)
where k is the rate constant, T is the absolute temperature, Ea is the activation energy, A is the frequency factor, and R is the universal gas constant. Any degradation mechanism can be considered thermolytic if
high temperature enhances the rate.
Typical activation energies for drug degradation fall in
the range of 12-24 kcal/mol (8). The Q10 rule states that
the rate of a chemical reaction increases approximately
two- to threefold for each 10 C rise in temperature. The
exact value of this increase may be determined based on
the value of the activation energies and is the theoretical
basis behind the International Conference on Harmonisation (ICH) conditions.
Hydrolysis forms a subset of thermolytic degradation
reactions and is the most common drug degradation
pathway. Hydrolysis accounts for more than half of
the reported drug degradation. Derivatives of relatively weakly-bonding groups such as esters, amides,
anhydride, imides, ethers, imines, oximes, hydrazones,
semicarbazones, lactams, lactones, thiol esters, sulfonates, sulfonamides, and acetals can undergo hydrolysis
both in solution and in the solid state in the presence
of water. In particular, the presence of hydrogen or
hydroxyl ions likely catalyzes the hydrolytic reactions.
Each of these may have different reactivity and may
require different conditions.
40

Journal

of

Validation T echnology [Summer 2009]

Initiation:
In + RH "In H + R
Propagation:
R + O2 "ROO

(fast)

ROO + RH "ROOH + R

(rate-limiting)

Termination:
R + R "R R
R + ROO "ROOR
Free radicals may be generated by homolytic cleavage
of a chemical bond via thermal, photolytic, or chemical
processes. A drug free radical is formed when one of its
iv thome.com

Yihong Qiu, Coordinator.

hydrogen atoms is abstracted by the initial free radical.

The formed drug free radical then quickly reacts with oxygen to form a peroxy free radical. The latter can abstract
a hydrogen atom from another drug molecule so that the
drug molecule gets oxidized (forming hydroperoxide)
and a new drug free radical is re-generated. This chain
reaction can continue until the free radical is terminated.
A single free radical can, in principle, cause the oxidation
of many drug molecules in its lifetime. Therefore, the
autoxidation is typically auto-catalytic in nature: its initial
rate may be low; however, the rate increases quickly due
to the gradual buildup of the free radicals.
Multiple oxidation mechanisms can co-exist. For
example, peroxide can undergo homolytic dissociation
at high temperature to form free radicals; the presence of
trace amount of transition metal could react with peroxides (e.g., oxidation degradants) and form free radicals.
It may be true that multiple oxidative processes occur
simultaneously in many cases.

Photolytic Degradation
Chemical reactions may occur upon light absorption
because light carries certain energy:
E = hv = hc/
where h is Planks constant, c is the speed of light,
is the frequency, and is the wavelength. The Grotthuss-Draper law states that photochemical reaction can
occur only after light is absorbed. A simplistic calculation indicates that the energy associated with UV-visible
light corresponds roughly to the bond energies in typical organic molecules. For example, the weakest single
bond is roughly ~35 kcal/mol (e.g., OO bond) and
the strongest single bond corresponds to ~100 kcal/mol
(e.g., CH bond).
Photophysical processes refer to the changes in molecular orbitals after light absorption (excitation). Properties of the excited molecules are expected to differ from
those of ground states and are generally more reactive.
For example, the radical-like structures of some of the
excited states make (photo) oxidation favorable. For
more detailed discussions on the fates of a molecule
upon light absorption and the potentially increased
chemical reactivity, readers may refer to the textbook
by Turro (9).
Photolytic degradation is directly initiated by light
absorption; therefore, temperature has a negligible effect.
In fact, some photo reactions can occur even at absolute zero. Photolytic degradation is not uncommon but
may be minimized during manufacturing, shipping,
and storing of drug products by appropriate packaging.
gxpandjv t.com

However, mechanisms of photolytic degradations are

usually more complex.

Basic Concepts in Chemical Kinetics

The following sections describe the basic concepts of
chemical kinetics.
Reaction Order. The rate of a reaction is often used
to describe the relationship between reaction rate and
the concentration of various species. For example, the
hydrolysis of aspirin under acidic conditions is first-order
with respect to both aspirin and hydrogen ion, but is an
overall second-order reaction:

d[Aspirin]
= k[Aspirin][H+]
dt

Degradation of most pharmaceuticals are secondorder in nature, because degradation usually involves two
molecules to react, one of which being the drug molecule
itself. However, the concentration of the other component (i.e., the hydrogen ion, hydroxyl ion, or the buffer
species) is usually in large excess and can be considered
as constant throughout. Therefore, apparent first-order
reactions are often reported for most pharmaceuticals.
The apparent rate constant, in this case, includes the
contribution from the concentration of the other reactants. Apparent zero-order degradations may arise in
cases where drug concentrations are maintained as a
constant (e.g., suspensions).
Catalysis. A catalyst is a substance that influences
the rate of a reaction without itself being consumed. A
positive catalyst promotes a reaction while a negative
catalyst demotes a reaction.
Catalysis occurs by changing the activation energy of
a reaction but not changing the thermodynamic nature
of the reaction. A catalyst can only influence the rate,
but not the equilibrium of the reaction. In some cases,
a reaction product can catalyze the rate, which is often
termed as autocatalysis. The free-radical initiated oxidation certainly is such an example.
Hydrogen ions and/or hydroxyl ions are often involved
directly in the degradation of pharmaceuticals. When the
concentration of hydrogen ion or hydroxyl ion appears
in the rate equation, the reaction is said to be subject
to specific acid-base catalysis. Drug degradations are
often determined in buffered solutions and studied by
monitoring the drug itself. As a result, the degradation
kinetics is often apparent first-order with the apparent
rate constant in the following form:
kobs = k0 + kH[H+] + kOH [OH]
Journal

of

Validation T echnology [Summer 2009]

41

Product and Process Design.

Figure: pH-rate profile of hydrolysis of aspirin (adapted

from reference 10).

-3

log Kobs (s-1)

-4

revealed as a sigmoid in the rate-pH profile.

For example, hydrolysis of aspirin (10) (see Figure)
is subject to specific acid catalysis at pH < 2, and specific base catalysis at pH >10. The ionization causes
a difference in reactivity in pH range of 2.5-4. The
broad shoulder in the pH range of 4.5-9 is caused by
the intramolecular catalysis:
O

-5

O
H
O

-6
O

-7

6
pH

10

For a reaction subject to specific acid catalysis, a plot of

the logarithm of the apparent first-order rate constant with
respect to pH gives a straight line of slope of 1, while a
specific base catalysis generates a straight line of slope of
+1. When both are present, a V or U-shaped pH-rate
profile is often observed.
General acid-base catalysis occurs when the buffering
components catalyze a reaction. Either the acidic or basic
components of the buffer, or both, can catalyze a reaction. General acid-base catalysis often causes deviation
of the rate-pH profile from the expected unit slopes.
pH-Rate Profiles. The pH dependence of the rate
constant of degradation of a compound can be concisely
represented by a plot of kobs vs. pH.
In general, rate of drug degradation can be represented
by summing up all possible pathways, including intrinsic,
specific acid-base catalysis, general acid-base catalysis,
etc., as follows:
kobs = k0 + kH[H+] + kOH [OH] + k1 [bufferspecies 1] +
k2 [bufferspecies 2] + = k0 + ki Ci
i

The pH-rate profile provides a summary of the primary
features of a specific degradation. Specific acid-base catalysis is designated by the straight line with slope of negative
or positive unity, while general acid-base catalysis may be
indicated by the apparent deviation of the slopes. Commonly, many drug molecules are weak acid or weak base.
Ionized species may have different reactivity, which is often
42

Journal

of

Validation T echnology [Summer 2009]

CH3

pH-rate profiles can provide tremendous insights on

the nature of a reaction and can serve as a very useful tool
in developing solution formulations, lyophilized products, as well as conventional solid oral dosage forms.

DEGRADATION IN SOLID DOSAGE

FORMS
Drug degradation in solid dosage forms are certainly
more complex than those in solution and have some
unique features related to the state of the matter.
Topochemical reactions are a class of reactions that
are directly related to the molecular packing in the
crystal lattice. Certain molecular rearrangements are
required in order for a reaction to take place truly in
the solid state (i.e., in the crystal lattice). For example,
the photo-dimerization of cinnamic acid derivatives
requires certain minimum distance between the double
bonds. As a result, only form of p-methylcinnamic
acid is feasible for this dimerization in solid state (11).
Topochemical reactions can be identified if a reaction
does not occur in solution or is much slower in solution or if the reaction products are different from those
obtained in solution. For example, the rearrangement
of methyl p-dimethylaminobenzenesulfonate to the
p-trimethylammoniumbenzenesulfonate zwitterion
shows a reaction rate that is 25 times slower in its melt
than in the solid state (12). Because the crystal structure
of a solid phase determines its chemical reactivity in
the case of topochemical reaction, solid-state forms
(e.g., polymorphs, solvates, salts, co-crystals) frequently
exhibit different reactivity.
Degradations of most drug products, however, are
not topochemical in nature. Drug degradations occur
mostly around the surface of a drug particle. Therefore, the surface characteristics of API particles and the
iv thome.com

Yihong Qiu, Coordinator.

excipientsor collectively, the microenvironmentare

of vital importance to the understanding and remedy
of drug degradation.
Solids often contain defects or strains, where molecules have higher free energy. These high energy sites
usually serve as the initiation (nucleation) sites of a reaction. Therefore, disorders in crystals may be a key point
in the understanding of solid-state reactions of drugs.
To extend this concept further, the amorphous phase
is highly energetic, is expected, and has been found to
enhance chemical reactivity. Often crystalline API is
used in drug development. However, a small amount
of disordered or amorphous content is apparent, particularly after various pharmaceutical operations such
as milling, wet granulation, drying, and compaction.
Even when the degree of crystallinity is not affected,
a solid-state reaction can be enhanced by rendering
larger surface area (smaller particle size) because of the
increased concentrations of possible defects. Regardless of how perfect the surface may be, surface itself
can be deemed as a type of defect based on the notion
of crystal orders. It is not uncommon that small API
particles (particularly via milling) exacerbate a stability problem.
Moisture has a profound effect on drug degradation
in solid dosage forms, either as a reactant (e.g., hydrolysis) or as a promoter or both. The catalytic role of
water in drug degradation is related to its ability as an
excellent plasticizer. Water greatly increases molecular
mobility of reactants and enhances drug degradation
and makes it more solution-like. In the worst scenario,
water can form a saturated solution and maximize the
rate of degradation.
Various mechanisms exist for water molecules to
interact with a solid. Water molecules can be incorporated into crystal lattice through hydrogen bonding
and/or Van de Waals interactions. Generally, lattice
water is not a cause of chemical instability. Some compounds rely on the interaction of water to form a stable
crystal thus improving their chemical stability. Water
can be also adsorbed to the surface as a monolayer
and as multilayers. Water molecules in the monolayer
may behave significantly differently than those in the
second or third layers. Water molecules beyond these
2-3 layers are expected to behave like bulk water. A
more thorough discussion on water-solid interactions in
pharmaceutical systems can be found elsewhere (13).
Tightly bound water (e.g., hydrate, monolayer) have
decreased activity and are therefore not detrimental to
chemical stability. The loosely bound water (other than
the monolayer) or free water is believed to enhance a
gxpandjv t.com

chemical reaction. In addition, pharmaceutical solids

usually contain various defects and various degrees of
disordered, amorphous regions. Water molecules are
preferentially absorbed into the interior of these regions
(sorption). Because water is an efficient plasticizer, it
significantly increases molecular mobility in the amorphous phase and, therefore, enhances degradation. A
simplified calculation indicates that the typical moisture content in pharmaceuticals (e.g., a few percent) far
exceeds the estimate by mode of adsorption (14, 15).
Hence, water sorption into the disordered or amorphous
regions is a realistic concern for the stability of pharmaceutical dosage forms. Greatly enhanced degradation
of ABT-232 was reported when wet granulated (16).
The presence of moisture also facilitates the creation
of microenvironment for drug degradation. The pH of
the microenvironment is often a key parameter that
greatly influences drug degradation. The pH-rate profile
can provide significant insight in this case. Microenvironmental pH could be altered by solid forms, such
as salts, or by buffering agents, such as citric acid and
sodium phosphate, or other excipients such as magnesium stearate. For example, stability of moexipril (17)
was improved by wet granulation with basic buffering
agents. This modification of microenvironmental pH
is one of the modes of drug-excipient interactions.
The change of API solid phases in a dosage form can
have profound impacts on its chemical stability. Even
when topochemical reaction is not observed, the surface
characteristics of solid forms can differ significantly,
which affects its ability to adsorb, interact, and react.
More importantly, solid-form conversion in dosage
forms is often incomplete, and leaves significant amount
of disordered or amorphous regions behind. The extent
of amorphous content can be significant in the case
of wet granulation where a soluble API may dissolve
completely and remain as amorphous upon drying,
or hydrate formation may occur but dehydrate upon
drying while leaving behind a significant portion of
amorphous phase. Amorphous content may also result
from other processing steps such as milling and compaction. All these process-induced amorphous content, in
combination with typical moisture contents, could be
detrimental to the chemical stability of pharmaceutical dosage forms, especially when the dose strength is
low. The process-induced phase transformations often
depend on equipment, time, operational conditions,
as well as raw material attributes, which makes scale
up as well as quality control challenging.

Journal

of

Validation T echnology [Summer 2009]

43

Product and Process Design.

EXCIPIENT COMPATIBILITY
Excipient selection is of great importance to accomplish
the target product profile and critical quality attributes.
Excipient functionality and compatibility with the active
drug are two important considerations.
Incompatibility may be referred to as the undesirable
interactions between drug and one or more components
in formulation. Incompatibility may adversely alter the
product quality attributes, including physical, chemical,
biopharmaceutical, or other properties.
Excipient compatibility studies are usually conducted
in the early phase of drug product development. Their
objective is to further characterize the stability profile
of the drug molecule in typical formulation design,
identify potential material incompatibility, characterize the degradants, understand the mechanisms
of degradation, and provide guidance to formulation
development. A carefully planned and executed compatibility study may result in significant savings in time
and resources. In addition, as expected by qualityby-design (QbD) principles, excipient compatibility
information is required by the regulatory agencies to
justify the selection of formulation components and
to assess the overall risk.
It does not mean, however, that one absolutely cannot
use an incompatible excipient. In some cases, a small
amount of incompatible excipient may be acceptable
based on other benefits it provides. There are also situations where there is simply no other alternate ingredient and one has to live with an incompatible excipient.
However, it is still essential to understand the associated
risks and their mitigations.

Direct Reactions Between Drug and

Excipient
Probably the most known excipient incompatibility is
the Maillard reaction between a primary or secondary
amine and a reducing sugar such as lactose and glucose,
resulting in the production of browning spots. From a
mechanistic point of view, the reactivity of the amine
is related to its electronic density. Therefore, salt formation of the amines usually improves stability. Like
most solid-state reactions, amorphous characteristics
of both the amines and the reducing sugar enhance the
reactivity, a concern when using spray-dried lactose.
Interactions between acidic drugs and basic excipients
and vice versa have been reported. Examples include
the interactions between indomethacin and sodium
bicarbonate, ibuprofen with magnesium oxide, and
citric acid/tartaric acid with sodium bicarbonate, the
latter of which is utilized in effervescent tablets.
44

Journal

of

Validation T echnology [Summer 2009]

Drug-conterion interactions may also occur. Seproxetine maleate was reported to form a Michael addition
product. In a broad sense, drug-buffer interactions
can be grouped into this category. Examples of the
latter include the interactions between dexamethasone
21-phosphate and sodium bisulfite, and between epinephrine and sodium bisulfite.
Transacylation is another major group of drugexcipient interaction. Carboxylic moiety can react
with alcohols, esters, or other carboxylic derivatives
to form esters, amides, etc., whether presented in excipients or in drug molecules. For example, aspirin can
undergo transesterification with a number of drugs
including acetaminophen, codeine, sulfadiazine, and
polyethylene glycol (PEG). Norfloxacin is reported to
react with magnesium stearate to form stearoyl amide
(18). Similarly, duloxetine reacts with hydroxypropyl
methylcellulose acetate succinate (HPMCAS) (celluosic
coating polymer) to form succinamide.
Impurities in excipients can be a major concern to
cause incompatibilities. It is well known that traces of
peroxides in povidone, crospovidone, hydroxypropyl
cellulose (HPC), dicalcium phosphase, PEG, polysorbates, and a number of modified excipients containing
polyoxyethylene units are responsible for the oxidation
of a number of drugs including ceronapril and raloxifene. Traces of low molecular weight aldehydes such as
formaldehyde and/or acetaldehyde may exist in a number of excipients such as starch, polysorbate, glycols,
povidone, crospovidone, ethylcellulose, which could
condensate with amine drugs. The 5-hydroxylmethyl2-furfuraldehyde impurity in lactose poses a similar
concern. Transition metals may be present in a number of excipients. As mentioned previously, these may
catalyze the oxidations of many drugs. In principle, it is
very beneficial to have some basic understanding on the
production, isolation, and purification process of each
excipient in order to anticipate the possible impurities
and the potential risks to drug product stability.
Complexes between drug and excipients have also
been reported, which could impact the dissolution,
solubility, and bioavailability of a drug product. Tetracycline is reported to interact with CaCO3 to form an
insoluble complex. Diclofenac and salicylic acid have
also been reported to complex with Eudragit polymers.
The complexation between weakly basic drugs (e.g.,
amines) and anionic super-disintegrants such as croscarmellose sodium and sodium starch glycolate has
been reported; metaformin-croscarmellose sodium
is an example.
iv thome.com

Yihong Qiu, Coordinator.

Drug Degradations Enhanced by

Excipients
Drug degradation usually occurs on the surface or the
interfaces; therefore, the surface characteristics of API
particles and excipients may be of vital importance.
Direct reactions between a drug molecule and excipient do not frequently occur and may be anticipated
based on knowledge of drug degradation pathways
and understanding of the drug molecule. However, the
presence of an inert excipient could lead to adsorption
of drug molecules to the surface of excipient particles.
Drug molecules adsorbed onto a surface are expected
to have higher mobility and increased reactivity. This
increase in accessible surface area is expected to contribute to increased degradation even for an otherwise
inert excipient. The excipient may be considered a heterogeneous catalyst in this case. Often low strength
formations are reported to have increased degradation
attributed to the increased accessible surface area to
drug ratio. In addition, the presence of excipient might
also change the moisture, microenvironment pH, and
other characteristics which are important considerations
regarding drug product stability.
Microenvironmental pH may be an important factor
on drug degradation in dosage forms. Many excipients
are acid or basic, such as citric acid, tartaric acid, stearic
acid, sodium bicarbonate, sodium carbonate, magnesium oxide, and magneiusm stearate. In addition, many
otherwise neutral excipients may be weakly acidic or
weakly basic due to the processes used in the production and treatments thereof. All these can cause an
acidic or basic microenvironment around the drug particles, which is facilitated by the presence of moisture.
Depending on the particular case, a drug molecule may
be more or less stable in a particular pH environment.
For example, reduced stability of aspirin was noted in
the presence of acidic excipients such as stearic acid or
basic excipients such as talc, calcium succinate or calcium carbonate. Bezazepines hydrolysis was enhanced
in the presence of microcrystalline cellulose, dicalcium
phosphate, magnesium stearate, and sodium stearyl
furate. Moexipril and lansoprazole (19) have been
reported to be stabilized by basic excipients.
The moisture content and other attributes of excipients may also influence drug degradation. Generally,
it is believed high moisture content from excipients
may be detrimental to chemical stability. However,
in a number of cases, improved stability has been
attributed to more hygroscopic excipients that may
preferentially absorb moisture in the formulation. The
characteristics of moisture may differ from one excipigxpandjv t.com

ent to another as suggested by spectroscopic evidence,

which could potentially explain how excipients affect
stability differently.

General Approaches to Stabilization

Once instability is observed, efforts should be made to
identify the degradation products which may suggest
possible degradation mechanisms. Anticipation of the
nature of degradation based on molecular structure and
prior knowledge can greatly assist the efforts and avoid
excipient incompatibilities. Preformulation degradation studies are essential to obtain useful information.
Relevant questions include the following:
What is the type (e.g., hydrolysis, oxidation, or others) of degradation?
Is a general mechanism available?
What factors are generally influential?
Is there a general stabilization approach (e.g., pH,
anti-oxidant)?
To what extent is the rate of degradation is affected
by moisture and/or temperature?
Could any of the processing steps play a role?
Because fixing a stability issue in late development
phase could be costly both in terms of project delays
and resources, early identification and remediation of
stability issues is beneficial and preferred. Degradation
studies are vital in the preformulation assessments of
a drug candidate. These studies often employ forced
degradation studies (i.e., exposure to strong acidic pH,
strong basic pH, various oxidants, light, etc.) in order
to delineate the intrinsic stability profile, potential
degradants, and degradation pathways. By utilizing
information obtained from the preformulation studies,
instability concerns can often be addressed and mitigated before formulation activities start. In the authors
experience, selection of viable solid forms can be made
based on stability in the solid state. Solid forms, particular salt forms, allow one to modify the surface
characteristics of the API, such as crystallinity, moisture sorption, surface pH, and solubility, all of which
may play a significant role in drug degradation. Based
on this principle, a number of solid forms have been
successfully selected to provide viable stability profile
for otherwise somewhat labile compounds.
A good understanding on the degradation mechanism or even the general features of the class of the
reactions can be very helpful to the stabilization
of a formulation. Hydrolytic degradations have
been frequently minimized by modification of the
microenvironment pH via acidic or basic excipients.
Journal

of

Validation T echnology [Summer 2009]

45

Product and Process Design.

Antioxidants have been routinely used to alleviate

oxidative degradations. In the latter case, however,
the optimal antioxidant can only be selected based
on the understanding of oxidation mechanisms. For
example, free-radical scavengers such as butylated
hydroxytoluene (BHT) are better for autoxidation,
while ascorbic acid may be more suitable for nucleophilic/electrophilic type of oxidation. Combination
of antioxidants may be used and have been reported
to be more effective, particularly when there is a mix
of oxidative processes. When metal ions play a significant role in oxidation, a chelate (such as EDTA or
citric acid) may be used.
When necessary, engineering approaches can be
used alone or in addition to those mentioned above.
For example, coating, double granulation, and bi-layer
tablet approaches may be used to separate incompatible components in a formulation. When moisture
plays a significant role, packaging or packaging with
desiccant is routinely used to achieve viable shelf
life of a drug product. For drug molecules that react
slowly with oxygen, packaging combined with an
oxygen scavenger can be effective. Packaging has
been routinely used to alleviate the photolytic (light)
degradation of many drug products.

PHASE TRANSFORMATIONS, CHEMICAL

DEGRADATION, AND EXCIPIENT COMPATIBILITYIMPLICATIONS FOR VALIDATION AND COMPLIANCE
Validation and compliance personnel should be
knowledgeable of the physical and chemical properties of the active drugs for which they have responsibility. They should be especially aware of active
drugs and products that may be highly prone to phase
transformation and chemical degradation (i.e., they
must be aware of high risk drugs and products). This
information is routinely determined during the pharmaceutical development process and is often filed in
regulatory submissions. The manufacturing and processing of high-risk drugs should receive heightened
vigilance by compliance personnel to minimize the
risk of phase transformations and/or chemical degradation. Any changes to the manufacturing process
of susceptible APIs and products should be carefully
evaluated. Referring to previous excipient compatibility studies is highly recommended prior to any
changes in formulation. Changes to high risk processes such as wet granulation, milling, and processes with
solvents should receive heightened scrutiny as part of
the change control program. Laboratory evaluations
46

Journal

of

Validation T echnology [Summer 2009]

of proposed changes may be necessary in advance of

large-scale changes. Validation of high-risk process
changes should include appropriate testing to assure
the acceptability of the process change. Fundamental knowledge obtained during development should
be available to validation and compliance personnel throughout the product lifecycle and should be
utilized as necessary to evaluate formulation and
process changes.

SUMMARY
Stability of drug product is complex due to the multiparticulate and heterogeneous nature of pharmaceutical products. Drug degradation in solid dosage forms
is mostly determined by the surface characteristics of
both the API and the excipient particles. Solid-state
forms provide a viable means to the modulation of
API characteristics and thus can significantly affect
its chemical stability. Phase transformation during
pharmaceutical processing is often a likely cause of
chemical degradation of the drug product even if the
starting API is stable. In particular, the small amount
of disordered or amorphous content, in combination
with typical moisture absorption in pharmaceutical products, could greatly impact drug degradation.
Excipients influence drug degradation by direct interactions or modification of the microenvironment.
A thorough understanding of the physicochemical
principles is critical to the anticipation, identification,
and remediation of stability issues during formulation development, manufacturing, and storage of
drug products.

REFERENCES
1. Baertschi, S. W., Pharmaceutical Stress Testing. Predicting
Drug Degradation, Taylor & Francis Group: Boca Raton,
Florida, 2005.
2. Yoshioka, S. and Stella, V. J., Stability of Drugs and Dosage
Forms, Kluwer Academic/Plenum Publishers: New York,
NY 10013, 2000.
3. Zhou, D.; Porter, W. and Zhang, G. G. Z., Drug Stability
and Stability Studies, Developing Solid Oral Dosage Forms Pharmaceutical Theory & Practice, Qiu, Y., Chen, Y., Zhang,
G., Liu, L., Porter, W., Eds.; Academic Press: San Diego,
CA, 2009, pp 87-124.
4. Narang, A. S.; Rao, V. M. and Raghavan, K. S., Excipient
Compatibility, Developing Solid Oral Dosage FormsPharmaceutical Theory & Practice; Qiu, Y., Chen, Y., Zhang, G.,
Liu, L., Porter, W., Eds.; Academic Press: San Diego, CA,
2009, pp 125-145.
iv thome.com

Yihong Qiu, Coordinator.

5. Hovorka, S. W. and Schneich, C., Oxidative Degradation of Pharmaceuticals: Theory, Mechanisms and Inhibition, J Pharm Sci 2001, 90, 253-269.
6. Waterman, K. C.; Adami, R. C.; Alsante, K. M.; Hong, J.;
Landis, M. S.; Lombardo, F. and Roberts, C. J., Stabilization of Pharmaceuticals to Oxidative Degradation,
Pharm Dev Technol, 2002, 7, 1 - 32.
7. Zhang, G. G. Z.; Law, D.; Schmitt, E. A. and Qiu, Y., Phase
Transformation Considerations During Process Development and Manufacture of Solid Oral Dosage Forms, Adv
Drug Del Rev 2004, 56, 371-390.
8. Connors, K. A., Chemical Kinetics: The Study of Reaction
Rates in Solution, Willey-VCH Publishers: New York, 1990,
p 191.
9. Turro, N. J., Modern Molecular Photochemisty, University
Science Books: Sausalito, CA, 1991.
10. Garrett, E. R., Prediction of Stability in Pharmaceutical Preparations. IV. The Interdependence of Solubility
and Rate in Saturated Solutions of Acylsalicylates, J Am
Pharm Ass 1957, 46, 584-586.
11. Schmidt, G. M. J., Topochemistry. III. The Crystal Chemistry of Some Trans-cinnamic Acids, J Chem Soc 1964,
2014-2021.
12. Sukenik, C. N.; Bonopace, J. A.; Mandel, N. S.; Bergman, R. C.; Lau, P. Y. and Wood, G., Enhancement of a
Chemical Reaction Rate by Proper Orientation of Reacting Molecules in the Solid State, J Am Chem Soc 1975,
97, 5290-5291.
13. Zografi, G., States of Water Associated with Solids,
Drug Dev Ind Pharm 1988, 14, 1905-1926.
14. Ahlneck, C. and Zografi, G., The Molecular Basis of
Moisture Effects on the Physical and Chemical Stability
of Drugs in the Solid State, Int J Pharm 1990, 62, 87-95.

gxpandjv t.com

15. Kontny, M. J.; Grandolfi, G. P. and Zografi, G., Water

Vapor Sorption of Water-soluble Substances: Studies of
Crystalline Solids Below their Critical Relative Humidities, Pharm Res 1987, 4, 104-12.
16. Wardrop, J.; Law, D.; Qiu, Y.; Engh, K.; Faitsch, L. and
Ling, C., Influence of Solid Phase and Formulation Processing on Stability of Abbott-232 Tablet Formulations,
J Pharm Sci 2006, 95, 2380-92.
17. Gu, L.; Strickley, R. G.; Chi, L. H. and Chowhan, Z. T.,
Drug-excipient Incompatibility Studies of the Dipeptide
Angiotensin-converting Enzyme Inhibitor, Moexipril Hydrochloride: Dry Powder vs Wet Granulation, Pharm Res
1990, 7, 379-83.
18. Florey, K., Analytical Profiles of Drug Substances, Academic
Press: New York, 1991, p 588.
19. Tabata, T.; Makino, T.; Kashihara, T.; Hirai, S.; Kitamori,
N. and Toguchi, H., Stabilization of a New Antiulcer
Drug (lansoprazole) in the Solid Dosage Forms, Drug
Dev Ind Pharm 1992, 18, 1437-47. JVT

ARTICLE ACRONYM LISTING

API Active Pharmaceutical Ingredient
BHT Butylated Hydroytoluene
HPC Hydroxypropyl Cellulose
HPMCAS Hydroxypropyl Methylcellulose Acetate
Succinate
ICH International Conference on Harmonisation
PEG Polyethylene Glycol
QbD Quality by Design
RH Relative Humidity

Journal

of

Validation T echnology [Summer 2009]

47