Deliang Zhou
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:
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physical and chemical stability, is a core quality
attribute potentially impacting efficacy and safety
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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.
For more Author
information,
go to
gxpandjvt.com/bios
[
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(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
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thermolytic, oxidative, and photolytic
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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.
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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.
ABOUT THE AUTHOR
Deliang Zhou, Ph.D., is an associated 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].
30 PROCESS VALIDATION – Process Design
Deliang Zhou
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absorbed. Excited states of drug molecules may
have enhanced reactivity. Photolytic degradation
is complex but can usually be mitigated by
packaging.
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some of the basic concepts in chemical kinetics,
which are helpful to the basic understanding of drug
degradation
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often determined by the surface characteristics
of the active pharmaceutical ingredient (API)
and excipient particles, or collectively the
microenvironment
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and excipients pose significant concerns on drug
degradations
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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.
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is often a leading cause of chemical instability,
particularly when significant amorphous content is
generated
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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.
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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.
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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
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
PROCESS VALIDATION – Process Design 31
Deliang Zhou
properties, manufacturability, and chemical stability.
For example, the bioavailability of a poorly watersoluble 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 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:
32
PROCESS VALIDATION – Process Design
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-mediated 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
Deliang Zhou
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 compoundspecific and depend on the experimental
conditions.
The primary mechanisms for phase conversions
include solid-state, melt, solution, and solutionmediated transformations.
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 solution-mediated 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 transformations 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.
PROCESS VALIDATION – Process Design 33
Deliang Zhou
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.
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.
Common Pathways of Drug 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.
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
34
PROCESS VALIDATION – Process Design
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.
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.
Oxidative Degradation
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:
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In \RH In − H R \
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R \O2 ROO \(fast)
ROO \RH ROOH R \(rate-limiting)
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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
Deliang Zhou
Figure: pH-rate profile of hydrolysis of aspirin
(adapted from reference 10).
-3
-4
log Kobs (s-1)
one of its 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.
-5
-6
-7
0
2
4
6
pH
8
10
Basic Concepts in Chemical Kinetics
Photolytic Degradation
Chemical reactions may occur upon light absorption
because light carries certain energy:
E = hv = hc/λ
where h is Plank’s constant, c is the speed of light,
ν is the frequency, and λ 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., O–O bond) and the strongest single bond
corresponds to ~100 kcal/mol (e.g., C–H 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. However, mechanisms of
photolytic degradations are usually more complex.
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 zeroorder 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.
PROCESS VALIDATION – Process Design 35
Deliang Zhou
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−]
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 4ki Ci
i
The pH-rate profile provides a summary of the
primary features of a specific degradation. Specific acidbase 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 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:
36
PROCESS VALIDATION – Process Design
O
O
H
O
O
H
CH3
O
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 ß
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 excipients—or collectively, the
microenvironment—are 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.
Deliang Zhou
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 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.
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
PROCESS VALIDATION – Process Design 37
Deliang Zhou
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 quality-bydesign (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.
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
38 PROCESS VALIDATION – Process Design
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-hydroxylmethyl-2-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.
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
Deliang Zhou
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 excipient 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:
t8IBUJTUIFUZQFFHIZESPMZTJTPYJEBUJPOPS
others) of degradation?
t*TBHFOFSBMNFDIBOJTNBWBJMBCMF
t8IBUGBDUPSTBSFHFOFSBMMZJOGMVFOUJBM
t*TUIFSFBHFOFSBMTUBCJMJ[BUJPOBQQSPBDIFHQ)
anti-oxidant)?
t5PXIBUFYUFOUJTUIFSBUFPGEFHSBEBUJPOJT
affected by moisture and/or temperature?
t$PVMEBOZPGUIFQSPDFTTJOHTUFQTQMBZBSPMF
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 author’s 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. 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.
PROCESS VALIDATION – Process Design 39
Deliang Zhou
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
COMPATIBILITY—IMPLICATIONS 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 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
multi-particulate 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
40
PROCESS VALIDATION – Process Design
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.
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Deliang Zhou
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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
Originally published in the Summer 2009 issue of The Journal of Validation Technology
PROCESS VALIDATION – Process Design 41