[ 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 if not understood and properly controlled
technical principles associated with pharmaceutical • Drug degradation may be categorized as thermolytic,
product development useful to practitioners in valida- oxidative, and photolytic
tion and compliance. We intend this column to be a • Hydrolysis accounts for the majority of reported drug
useful resource for daily work applications. The primary degradations and it is common for a broad category
objective for this feature: Useful information. of organic molecules derived from weak functional
Reader comments, questions, and suggestions are groups such as carboxylic acids. Moisture, temperature,
needed to help us fulfill our objective for this column. and pH may greatly impact the rate of hydrolysis.
Please send your comments and suggestions to column • Oxidation of drugs is the next greatest cause of degra-
coordinator Yihong Qiu at [email protected] or dation. Three primary mechanisms exist for oxidative
to coordinating editor Susan Haigney at shaigney@ degradations: nucleophilic and electrophilic, electron
advanstar.com. transfer, and autoxidation. Nucleophilic and electro-
philic oxidations are typically mediated by peroxides.
KEY POINTS Transition metal catalyzes oxidation via electron trans-
The following key points are discussed in this article: fer process. Autoxidation involves free-radical initiated
• Stability of pharmaceutical products, including physi- chain reactions. A single free-radical can cause oxida-
cal and chemical stability, is a core quality attribute tion of many drug molecules. Autoxidation is often
potentially impacting efficacy and safety autocatalytic and non-Arrhenius.
•Phase transformation is a common form of physical • Photolytic degradation occurs only when light is
instability. Polymorphic transition; solvation and absorbed. Excited states of drug molecules may have
desolvation; salt and parent conversion or salt and salt enhanced reactivity. Photolytic degradation is complex
exchange; and amorphization and devitrification are but can usually be mitigated by packaging.
the common types of phase transformations. Phase • Reaction order, catalysis, and pH-rate profile are
transformation can occur via solid-state, melt, solution, some of the basic concepts in chemical kinetics,
or solution-mediated mechanisms. which are helpful to the basic understanding of drug
• Pharmaceutical processing such as comminution (mil- degradation
ing), compaction, granulation, drying, and coating • Drug degradation in solid dosage forms is often
may induce partial or complete phase conversion, determined by the surface characteristics of the active
which could lead to inconsistent drug product quality pharmaceutical ingredient (API) and excipient par-

[
ABOUT THE AUTHOR
For more Author Deliang Zhou, Ph.D., is an associate research investigator in Global Formulation Sciences, Global
information, Pharmaceutical R&D at Abbott Laboratories. He may be reached at [email protected]. Yihong
go to Qiu, Ph.D., is the column coordinator of “Product and Process Design.” Dr. Qiu is a research fellow
gxpandjvt.com/bios and associate director in Global Pharmaceutical Regulatory Affairs CMC, Global Pharmaceutical R&D at
Abbott Laboratories. He may be reached at [email protected].

36 j v t . c o m of Validation T echnology [Summer 2009]

g x p a nJdournal iv thome.com
 Yihong Qiu, Coordinator.

ticles, or collectively the microenvironment strength (e.g., tablet hardening/softening), change in

• Defects, disordered or amorphous contents in API, dissolution/release rate, change in content uniformity
and excipients pose significant concerns on drug (suspensions in particular), alteration in bioavailability,
degradations or change in other pharmaceutical elegances. These
• Moisture profoundly affects chemical stability by direct instabilities may impact the handling, purity, bioavail-
involvement in a reaction or by catalyzing a reaction ability, safety, and efficacy of a drug product, or may
via increasing molecular mobility and facilitating the be merely cosmetic changes which can lead to poor
creation of microenvironments. Moisture preferen- patient acceptance.
tially penetrates into amorphous or disordered regions This column discusses the key stability concepts in
and may greatly enhance chemical degradation. drug products, with an emphasis on the basic physi-
• Process-induced phase transformation of API is often a cal and chemical principles applicable to all stages of
leading cause of chemical instability, particularly when product development and manufacture. More in-depth
significant amorphous content is generated treatments on these topics may be found in many text-
• Compatibility is an important factor for excipient books and review articles (1-6).
selection. Timely identification of excipient incom- The role of physical changes in chemical degradation
patibility can result in significant savings in time and is often inadequately acknowledged. Physical stability
resources. Excipients can directly react with drug mol- often contributes greatly to the chemical stability of a
ecules, which may be judiciously avoided based on the drug product and cannot be ignored. This discussion
chemical structures and physicochemical properties begins with an introduction of the basic concepts and
of the drug molecules and excipients. Excipients can general mechanisms on physical and chemical stability
also enhance drug degradation by creating a favorable of drugs, followed by excipient compatibility, and finally
microenvironment such as pH, moisture, metal ions, a brief overview of remedies to instability.
or simply by providing large accessible surfaces.
• Fundamental understanding of general aspects of PHYSICAL STABILITY OF DRUGS
chemical degradation as well as specific physicochemi- In principle, any stability issue not involving chemical
cal properties of a drug molecule is key to its stabili- changes can be considered physical in nature. On the
zation. Stability issues may be mitigated by proper surface, the physical instability may manifest itself in
solid form selection. Formulation and engineering various forms, such as appearance, mechanical strength
approaches may also be used to mitigate a stability of dosage forms, content uniformity, dissolution rate,
issue. and bioavailability. These phenomena may arise from
• Validation and compliance personnel should be various root causes; phase transformation is frequently
aware of the physical and chemical properties of the leading cause of these problems.
the active drugs for which they have responsibility. A drug molecule may exist in different solid forms,
They should become especially knowledgeable about including polymorphs, salts, solvates (hydrates), and
active drugs and products that may be highly prone to amorphous phases. A primary task of preformulation
phase transformation and chemical degradation, and investigation is to select an appropriate solid form which
apply this knowledge in process control and change bears “viable” properties in various aspects. Depend-
management. ing on the specific circumstances, a solid form may
be selected with particular emphasis on its ability to
INTRODUCTION improve one or more characteristics of the drug mol-
Stability is a core quality attribute for any viable drug ecule, such as solubility and dissolution rate, melting,
product. While drug molecules tend to “degrade” over polymorphism, purity, mechanical properties, manu-
time like other chemicals, stability of drug products is facturability, and chemical stability. For example, the
broader than chemical degradation alone. Any aspect bioavailability of a poorly water-soluble compound
related to the change of the physical, chemical, and bio- may be greatly improved by using an amorphous phase.
pharmaceutical properties of a drug product could be Salts have been conventionally used to improve prop-
classified as “instability.” erties such as purity, melting temperature, crystallinity,
Generally speaking, instability of pharmaceuticals hygroscopicy, and/or chemical stability, as well as the
includes but is not limited to: loss of active ingredi- bioavailability of the parent form. A number of prop-
ent potency, increase in levels of impurities, change in erties (e.g., solubility and dissolution, spectroscopic,
appearance (e.g., color, shape), change in mechanical mechanical, chemical) have been shown to be affected
gxpandjv t.com Journal of Validation T echnology [Summer 2009] 37
Product and Process Design.

by polymorphism. When modification of a particular ated hydrate formation, which could occur during various
property is aimed via solid form selection, properties in wet processes or during in vivo dissolution.
other aspects should be balanced to facilitate pharmaceu- Salt and Parent Conversions or Salt and Salt
tical development. It should be understood that a solid Exchange. Salts may be converted to their parent forms
form change during product manufacturing and storage or to salts of different counterion during processing and
could defeat the primary purpose for its selection. storage. The propensity of salt form conversion is deter-
mined by pKa, crystal lattice energy, solubility and solu-
Types of Phase Transformations bility relationship, and other experimental conditions.
The following paragraphs describe the types of phase For example, salts of very weak acids or bases may readily
transformations. convert back to the parent forms upon exposure to mois-
Polymorphic Transition. When a molecule can ture or water. The potential of salt conversion during wet
be packed differently in the crystal lattice, those crys- granulation and other wet processes is more significant
talline forms are called polymorphs. Polymorphic than other dry processes and should be watched closely.
transition refers to the conversion between polymorphs. Similar to other solid form conversions, change of a salt
Polymorphs differ in free energy and could impact to its parent, or to different salt forms, can profoundly
melting, hygroscopicity, solubility and dissolution, alter the quality attributes of a drug product.
bioavailability, chemical stability, mechanical, morpho- Amorphization and Devitrification. When the
logical, and flow properties. Any two polymorphs are long-range order in a crystal lattice is destroyed, an
related thermodynamically as either enantiotropes or amorphous phase is then generated. Partially or fully
monotropes. Enantiotropy exists when one polymorph amorphous phases may be generated (amorphization) by
is more stable below a critical temperature (transition various methods including many unit operations such as
temperature, Tt) and the other more stable above Tt. milling, melting, wet granulation, drying, and compac-
In monotropy, one polymorph is always more stable. tion. Amorphous phases have higher free energy than
Under any circumstances, there is always a most (more) their crystalline counterparts and are often exploited
stable polymorph. to improve the bioavailability of poorly water-soluble
Solvation and Desolvation. This is related to the compounds. However, the reversion to crystalline
conversion between the solvated and unsolvated crystal forms (devitrification) is thermodynamically favorable
forms, or solvated forms of different stoichiometry, based on the thermodynamic principle. When the use
with hydration/dehydration being the most typical. of an amorphous phase is desired, the physical stability
Similarly to polymorphs, differently solvated forms usu- becomes critical because crystallization could lead to a
ally differ in various physicochemical properties. This decrease in bioavailability and thus lose the intended
type of form conversion can affect chemical stability, advantage of the amorphous state. When crystalline
pharmaceutical elegance, and other quality attributes. forms are desired, however, the formation of even a small
Particularly, the differences in apparent solubility and amount of amorphous content during various processes
dissolution rate could impact on the oral absorption is also a concern because this may bring undesired effects
for many poorly or borderline soluble compounds. An to drug products such as enhanced degradation.
important concept for hydration and dehydration is the
critical relative humidity (RH), below which the anhy- Mechanisms of Phase Transformations
drous form is more stable and above which the hydrate The conversion of metastable form to stable form is
is more stable. Similarly, critical RH also exists between thermodynamically favored, which poses a concern
hydrates of different stoichiometry. This concept is vital for any system where a metastable form is employed.
to the stability of hydrates because moisture has to be The transformation of a stable form to a metastable
dealt with everywhere: active pharmaceutical ingre- form, on the other hand, is thermodynamically unfa-
dient (API) manufacture, formulation development, vorable, and is possible only when there is an energy
drug product manufacture, and storage. Changes in input from the environment. The transformation
the environmental humidity could inadvertently cause kinetics in both cases, however, vary greatly, which
hydration or dehydration to occur. In aqueous solu- are compound-specific and depend on the experi-
tions, the hydrated form is usually less soluble than the mental conditions.
anhydrous form because of the nature of equilibrium. The primary mechanisms for phase conversions
The solubility difference between hydrated and anhy- include solid-state, melt, solution, and solution-medi-
drous forms is the driving force behind solution-medi- ated transformations.
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 Yihong Qiu, Coordinator.

Solid-State. Certain phase transitions occur in the mations may be time and equipment dependent. These
solid-state without passing through intervening tran- phase transformations, when not controlled properly,
sient liquid or vapor phases. These solid-state transi- often lead to inconsistent product quality.
tions are generally nucleated by defects or strain. The The application of mechanical and possibly the
physical characteristics of the solids, such as particle accompanying thermal stresses during operations such
size, morphology, crystallinity, mechanical treatments, as milling, dry granulation, and compaction, may lead
and presence of impurities may greatly affect the rate of to phase transformation such as polymorphic transition,
such transformations. dehydration and desolvation, or vitrification via the
Melt. A solid form is destroyed upon melting and may solid-state or melt mechanisms. The rate and extent of
not regenerate when cooled. The melt is often super- these phase transitions will depend on characteristics of
cooled to generate an amorphous phase, which may or the original solid phase and the energy input from these
may not crystallize during further cooling. Even when processes. Caffeine, sulfabenzamide, and maprotiline
it crystallizes, it usually goes through metastable forms, hydrochloride have been reported to undergo polymor-
and may or may not convert to the most stable form phic transformations during compression.
on the experimental time scale. A potential change in A number of wet processes, such as wet granulation,
crystalline form is therefore likely. The final solid phase lyophilization, spray drying, and coating, may induce
may depend on: thermodynamic stability among dif- phase transitions via solution or solution-mediated trans-
ferent forms; the relative nucleation and crystal growth formation. Important factors governing the likeliness
rate of each form; and the kinetics of form conversion. and the extent of conversion include: solubility of the
The solid phases formed in such a process are usually drug substance in the liquid, duration in contacting with
accompanied by relatively high amount of disorders. liquid, other operation parameters such as temperature,
Impurities or excipients are also likely to affect the kinet- drying conditions, and the specific properties of the
ics of crystallization and phase transformation. Presence drug molecule. The presence of other excipients may
of excipients may cause eutectic melting at temperatures also significantly influence the propensity and rate of
much lower than the melting of pure API and give rise a phase transformation. All the aforementioned phase
to potential phase transformations. transitions, such as polymorphic conversion, hydra-
Solution. When solvents are involved in processing, tion and dehydration, salt/parent conversion or salt/salt
solid API may dissolve partially or completely. Subse- exchange, and vitrification and crystallization may occur.
quent solvent removal may cause the dissolved portion For example, a highly water-soluble drug may completely
to change its solid form similar to a melt. It is important dissolve in granulating liquid and subsequently produce
to note that formation of a metastable form (crystal- amorphous phase during drying that may or may not
line or amorphous) is often likely, especially when the convert back to the original solid form. The formation
original solid form is completely dissolved. Particular of a hydrate is also likely to occur in wet granulation.
attention should be paid to drug molecules that have Subsequent drying may dehydrate the formed hydrate. In
high solubility in the processing solvents. any solid-solid conversion; however, it is very likely that
Solution-Mediated. When a metastable solid form a less ordered form will be produced even if conversion
comes to contact a solvent during processing, it may is close to completeness. Therefore, various amounts of
convert to more stable forms due to solubility differ- amorphous content may exist in the end product, which
ence between the metastable form and the stable form. could cause further concerns on its chemical stability. In
As opposed to the solution mechanism, the solution- film coating, due to the relatively short contacting time
mediated mechanism only allows the transition from a between solid surface and liquid, the likelihood of solid
meta-stable form to a more stable form. form change is much lower. However, the potential for
phase transformation can be significant when an active
PHASE TRANSFORMATIONS DURING is present in the coating solution.
PHARMACEUTICAL PROCESSING
Phase transformations can occur in a number of phar- CHEMICAL DEGRADATION OF DRUGS
maceutical unit operations, including milling, wet Chemical degradation represents one of the most
granulation/spray drying/lyophilization, drying, and important stability aspects of pharmaceuticals,
compaction, and therefore may impact drug product because inadequate stability not only limits the
manufacturing and performance (7). Because of their shelflife of a drug product but also potentially impacts
very kinetic nature, the extents of these phase transfor- efficacy and patient safety.
gxpandjv t.com Journal of Validation T echnology [Summer 2009] 39
Product and Process Design.

An important aspect of preformulation characteriza- Transacylation is also likely when appropriate other
tion is to examine the chemical stability of new drug functional groups (i.e., alcohols, amines, esters, etc.)
candidates, assess the impact of stability on pharmaceuti- are present in the environment, either as solvent or
cal development and processing, and design strategies solvent residuals, or more commonly, as excipients
to stabilize an unstable molecule. The understanding of or impurities.
commonly encountered degradation pathways, basic con- Other thermolytic degradation pathways include rear-
cepts in chemical kinetics, and characteristics of chemi- rangement, isomerization and epimerization, cyclization,
cal degradation in drug products are key to the overall decarboxylation, hydration/dehydration, and dimeriza-
success of formulation development and scale up. tion and polymerization.

Common Pathways of Drug Degradation Oxidative Degradation

Drug degradation can be generally divided into ther- Oxidation accounts for 20-30% of reported drug degrada-
molytic, oxidative, and photolytic. By examining tions and is secondary only to hydrolysis. Oxidation can
structural features of a drug molecule, possible deg- proceed with three primary mechanisms: electrophilic/
radation routes and products may be predicted to a nucleophilic, electron transfer, and autoxidation.
certain extent. These may then aid in the design and A drug molecule may be oxidized by electrophilic
execution of stability studies. attack from peroxides, which is the typical scenario of
nucleophilic/electrophilic mechanism. Similarly, the
Thermolytic Degradation electron transfer process shares certain features of the
Thermolytic degradation refers to those that are driven nucleophilic/electrophilic process, except that an electron
by heat or greatly influenced by temperature, to which is transferred from a low electron affinity donor (e.g.,
the following Arrhenius relationship often applies: drug molecule) to an oxidizing agent via the mediation
of transition metal. Fe3+ and Cu2+ are commonly used
k = Aexp(−Ea/RT) to probe such mechanisms.
The autoxidation process involves the initiation of
where k is the rate constant, T is the absolute tempera- free radicals, which propagates through reactions with
ture, Ea is the activation energy, A is the frequency fac- oxygen and drug molecule to form oxidation products.
tor, and R is the universal gas constant. Any degrada- Because of the complexity of the reaction mechanism,
tion mechanism can be considered “thermolytic” if non-Arrhenius behavior is frequently observed. The
high temperature enhances the rate. three stages of autoxidation may be represented as the
Typical activation energies for drug degradation fall in following:
the range of 12-24 kcal/mol (8). The Q10 rule states that
the rate of a chemical reaction increases approximately • Initiation:
two- to threefold for each 10 °C rise in temperature. The
exact value of this increase may be determined based on In • + RH "In − H + R •
the value of the activation energies and is the theoretical
basis behind the International Conference on Harmoni- • Propagation:
sation (ICH) conditions.
Hydrolysis forms a subset of thermolytic degradation R • + O2 "ROO • (fast)
reactions and is the most common drug degradation
pathway. Hydrolysis accounts for more than half of ROO • + RH "ROOH + R • (rate-limiting)
the reported drug degradation. Derivatives of rela-
tively weakly-bonding groups such as esters, amides, • Termination:
anhydride, imides, ethers, imines, oximes, hydrazones,
semicarbazones, lactams, lactones, thiol esters, sulfo- R • + R • "R − R
nates, sulfonamides, and acetals can undergo hydrolysis
both in solution and in the solid state in the presence R • + ROO • "ROOR
of water. In particular, the presence of hydrogen or
hydroxyl ions likely catalyzes the hydrolytic reactions. Free radicals may be generated by homolytic cleavage
Each of these may have different reactivity and may of a chemical bond via thermal, photolytic, or chemical
require different conditions. processes. A drug free radical is formed when one of its
40 Journal of Validation T echnology [Summer 2009] iv thome.com
 Yihong Qiu, Coordinator.

hydrogen atoms is abstracted by the initial free radical. However, mechanisms of photolytic degradations are
The formed drug free radical then quickly reacts with oxy- usually more complex.
gen to form a peroxy free radical. The latter can abstract
a hydrogen atom from another drug molecule so that the Basic Concepts in Chemical Kinetics
drug molecule gets oxidized (forming hydroperoxide) The following sections describe the basic concepts of
and a new drug free radical is re-generated. This chain chemical kinetics.
reaction can continue until the free radical is terminated. Reaction Order. The rate of a reaction is often used
A single free radical can, in principle, cause the oxidation to describe the relationship between reaction rate and
of many drug molecules in its lifetime. Therefore, the the concentration of various species. For example, the
autoxidation is typically auto-catalytic in nature: its initial hydrolysis of aspirin under acidic conditions is first-order
rate may be low; however, the rate increases quickly due with respect to both aspirin and hydrogen ion, but is an
to the gradual buildup of the free radicals. overall second-order reaction:
Multiple oxidation mechanisms can co-exist. For
d[Aspirin]
example, peroxide can undergo homolytic dissociation − = k[Aspirin][H+]
at high temperature to form free radicals; the presence of dt
trace amount of transition metal could react with perox-
ides (e.g., oxidation degradants) and form free radicals. Degradation of most pharmaceuticals are second-
It may be true that multiple oxidative processes occur order in nature, because degradation usually involves two
simultaneously in many cases. molecules to react, one of which being the drug molecule
itself. However, the concentration of the other compo-
Photolytic Degradation nent (i.e., the hydrogen ion, hydroxyl ion, or the buffer
Chemical reactions may occur upon light absorption species) is usually in large excess and can be considered
because light carries certain energy: as constant throughout. Therefore, apparent first-order
reactions are often reported for most pharmaceuticals.
E = hv = hc/λ The apparent rate constant, in this case, includes the
where h is Plank’s constant, c is the speed of light, contribution from the concentration of the other reac-
ν is the frequency, and λ is the wavelength. The Grot- tants. Apparent zero-order degradations may arise in
thuss-Draper law states that photochemical reaction can cases where drug concentrations are maintained as a
occur only after light is absorbed. A simplistic calcula- constant (e.g., suspensions).
tion indicates that the energy associated with UV-visible Catalysis. A catalyst is a substance that influences
light corresponds roughly to the bond energies in typi- the rate of a reaction without itself being consumed. A
cal organic molecules. For example, the weakest single positive catalyst promotes a reaction while a negative
bond is roughly ~35 kcal/mol (e.g., O–O bond) and catalyst demotes a reaction.
the strongest single bond corresponds to ~100 kcal/mol Catalysis occurs by changing the activation energy of
(e.g., C–H bond). a reaction but not changing the thermodynamic nature
Photophysical processes refer to the changes in molec- of the reaction. A catalyst can only influence the rate,
ular orbitals after light absorption (excitation). Proper- but not the equilibrium of the reaction. In some cases,
ties of the excited molecules are expected to differ from a reaction product can catalyze the rate, which is often
those of ground states and are generally more reactive. termed as autocatalysis. The free-radical initiated oxida-
For example, the radical-like structures of some of the tion certainly is such an example.
excited states make (photo) oxidation favorable. For Hydrogen ions and/or hydroxyl ions are often involved
more detailed discussions on the fates of a molecule directly in the degradation of pharmaceuticals. When the
upon light absorption and the potentially increased concentration of hydrogen ion or hydroxyl ion appears
chemical reactivity, readers may refer to the textbook in the rate equation, the reaction is said to be subject
by Turro (9). to specific acid-base catalysis. Drug degradations are
Photolytic degradation is directly initiated by light often determined in buffered solutions and studied by
absorption; therefore, temperature has a negligible effect. monitoring the drug itself. As a result, the degradation
In fact, some photo reactions can occur even at abso- kinetics is often apparent first-order with the apparent
lute zero. Photolytic degradation is not uncommon but rate constant in the following form:
may be minimized during manufacturing, shipping,
and storing of drug products by appropriate packaging. kobs = k0 + kH[H+] + kOH [OH−]
gxpandjv t.com Journal of Validation T echnology [Summer 2009] 41
Product and Process Design.

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

from reference 10). revealed as a sigmoid in the rate-pH profile.
For example, hydrolysis of aspirin (10) (see Figure)
-3 is subject to specific acid catalysis at pH < 2, and spe-
cific 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
-4 the intramolecular catalysis:
log Kobs (s-1)

-5 O
H

O O
H
-6
CH3
O

pH-rate profiles can provide tremendous insights on

-7 the nature of a reaction and can serve as a very useful tool
0 2 4 6 8 10 in developing solution formulations, lyophilized prod-
pH ucts, as well as conventional solid oral dosage forms.

DEGRADATION IN SOLID DOSAGE

For a reaction subject to specific acid catalysis, a plot of FORMS
the logarithm of the apparent first-order rate constant with Drug degradation in solid dosage forms are certainly
respect to pH gives a straight line of slope of –1, while a more complex than those in solution and have some
specific base catalysis generates a straight line of slope of unique features related to the state of the matter.
+1. When both are present, a “V” or “U”-shaped pH-rate Topochemical reactions are a class of reactions that
profile is often observed. are directly related to the molecular packing in the
General acid-base catalysis occurs when the buffering crystal lattice. Certain molecular rearrangements are
components catalyze a reaction. Either the acidic or basic required in order for a reaction to take place truly in
components of the buffer, or both, can catalyze a reac- the solid state (i.e., in the crystal lattice). For example,
tion. General acid-base catalysis often causes deviation the photo-dimerization of cinnamic acid derivatives
of the rate-pH profile from the expected unit slopes. requires certain minimum distance between the double
pH-Rate Profiles. The pH dependence of the rate bonds. As a result, only ß form of p-methylcinnamic
constant of degradation of a compound can be concisely acid is feasible for this dimerization in solid state (11).
represented by a plot of kobs vs. pH. Topochemical reactions can be identified if a reaction
In general, rate of drug degradation can be represented does not occur in solution or is much slower in solu-
by summing up all possible pathways, including intrinsic, tion or if the reaction products are different from those
specific acid-base catalysis, general acid-base catalysis, obtained in solution. For example, the rearrangement
etc., as follows: of methyl p-dimethylaminobenzenesulfonate to the
p-trimethylammoniumbenzenesulfonate zwitterion
kobs = k0 + kH[H+] + kOH [OH−] + k1 [bufferspecies 1] + shows a reaction rate that is 25 times slower in its melt
k2 [bufferspecies 2] + ••• = k0 + Σ ki Ci than in the solid state (12). Because the crystal structure
i
of a solid phase determines its chemical reactivity in
The pH-rate profile provides a summary of the primary the case of topochemical reaction, solid-state forms
features of a specific degradation. Specific acid-base cataly- (e.g., polymorphs, solvates, salts, co-crystals) frequently
sis is designated by the straight line with slope of negative exhibit different reactivity.
or positive unity, while general acid-base catalysis may be Degradations of most drug products, however, are
indicated by the apparent deviation of the slopes. Com- not topochemical in nature. Drug degradations occur
monly, many drug molecules are weak acid or weak base. mostly around the surface of a drug particle. There-
Ionized species may have different reactivity, which is often fore, the surface characteristics of API particles and the
42 Journal of Validation T echnology [Summer 2009] iv thome.com
 Yihong Qiu, Coordinator.

excipients—or collectively, the microenvironment—are chemical reaction. In addition, pharmaceutical solids

of vital importance to the understanding and remedy usually contain various defects and various degrees of
of drug degradation. disordered, amorphous regions. Water molecules are
Solids often contain defects or strains, where mol- preferentially absorbed into the interior of these regions
ecules have higher free energy. These high energy sites (sorption). Because water is an efficient plasticizer, it
usually serve as the initiation (nucleation) sites of a reac- significantly increases molecular mobility in the amor-
tion. Therefore, disorders in crystals may be a key point phous phase and, therefore, enhances degradation. A
in the understanding of solid-state reactions of drugs. simplified calculation indicates that the typical mois-
To extend this concept further, the amorphous phase ture content in pharmaceuticals (e.g., a few percent) far
is highly energetic, is expected, and has been found to exceeds the estimate by mode of adsorption (14, 15).
enhance chemical reactivity. Often crystalline API is Hence, water sorption into the disordered or amorphous
used in drug development. However, a small amount regions is a realistic concern for the stability of pharma-
of disordered or amorphous content is apparent, par- ceutical dosage forms. Greatly enhanced degradation
ticularly after various pharmaceutical operations such of ABT-232 was reported when wet granulated (16).
as milling, wet granulation, drying, and compaction. The presence of moisture also facilitates the creation
Even when the degree of crystallinity is not affected, of microenvironment for drug degradation. The pH of
a solid-state reaction can be enhanced by rendering the microenvironment is often a key parameter that
larger surface area (smaller particle size) because of the greatly influences drug degradation. The pH-rate profile
increased concentrations of possible defects. Regard- can provide significant insight in this case. Microen-
less of how perfect the surface may be, surface itself vironmental pH could be altered by solid forms, such
can be deemed as a type of defect based on the notion as salts, or by buffering agents, such as citric acid and
of crystal orders. It is not uncommon that small API sodium phosphate, or other excipients such as magne-
particles (particularly via milling) exacerbate a stabil- sium stearate. For example, stability of moexipril (17)
ity problem. was improved by wet granulation with basic buffering
Moisture has a profound effect on drug degradation agents. This modification of microenvironmental pH
in solid dosage forms, either as a reactant (e.g., hydro- is one of the modes of drug-excipient interactions.
lysis) or as a promoter or both. The catalytic role of The change of API solid phases in a dosage form can
water in drug degradation is related to its ability as an have profound impacts on its chemical stability. Even
excellent plasticizer. Water greatly increases molecular when topochemical reaction is not observed, the surface
mobility of reactants and enhances drug degradation characteristics of solid forms can differ significantly,
and makes it more solution-like. In the worst scenario, which affects its ability to adsorb, interact, and react.
water can form a saturated solution and maximize the More importantly, solid-form conversion in dosage
rate of degradation. forms is often incomplete, and leaves significant amount
Various mechanisms exist for water molecules to of disordered or amorphous regions behind. The extent
interact with a solid. Water molecules can be incor- of amorphous content can be significant in the case
porated into crystal lattice through hydrogen bonding of wet granulation where a soluble API may dissolve
and/or Van de Waals interactions. Generally, lattice completely and remain as amorphous upon drying,
water is not a cause of chemical instability. Some com- or hydrate formation may occur but dehydrate upon
pounds rely on the interaction of water to form a stable drying while leaving behind a significant portion of
crystal thus improving their chemical stability. Water amorphous phase. Amorphous content may also result
can be also adsorbed to the surface as a monolayer from other processing steps such as milling and compac-
and as multilayers. Water molecules in the monolayer tion. All these process-induced amorphous content, in
may behave significantly differently than those in the combination with typical moisture contents, could be
second or third layers. Water molecules beyond these detrimental to the chemical stability of pharmaceuti-
2-3 layers are expected to behave like bulk water. A cal dosage forms, especially when the dose strength is
more thorough discussion on water-solid interactions in low. The process-induced phase transformations often
pharmaceutical systems can be found elsewhere (13). depend on equipment, time, operational conditions,
Tightly bound water (e.g., hydrate, monolayer) have as well as raw material attributes, which makes scale
decreased activity and are therefore not detrimental to up as well as quality control challenging.
chemical stability. The loosely bound water (other than
the monolayer) or free water is believed to enhance a
gxpandjv t.com Journal of Validation T echnology [Summer 2009] 43
Product and Process Design.

EXCIPIENT COMPATIBILITY Drug-conterion interactions may also occur. Seprox-

Excipient selection is of great importance to accomplish etine maleate was reported to form a Michael addition
the target product profile and critical quality attributes. product. In a broad sense, drug-buffer interactions
Excipient functionality and compatibility with the active can be grouped into this category. Examples of the
drug are two important considerations. latter include the interactions between dexamethasone
Incompatibility may be referred to as the undesirable 21-phosphate and sodium bisulfite, and between epi-
interactions between drug and one or more components nephrine and sodium bisulfite.
in formulation. Incompatibility may adversely alter the Transacylation is another major group of drug-
product quality attributes, including physical, chemical, excipient interaction. Carboxylic moiety can react
biopharmaceutical, or other properties. with alcohols, esters, or other carboxylic derivatives
Excipient compatibility studies are usually conducted to form esters, amides, etc., whether presented in excipi-
in the early phase of drug product development. Their ents or in drug molecules. For example, aspirin can
objective is to further characterize the stability profile undergo transesterification with a number of drugs
of the drug molecule in typical formulation design, including acetaminophen, codeine, sulfadiazine, and
identify potential material incompatibility, charac- polyethylene glycol (PEG). Norfloxacin is reported to
terize the degradants, understand the mechanisms react with magnesium stearate to form stearoyl amide
of degradation, and provide guidance to formulation (18). Similarly, duloxetine reacts with hydroxypropyl
development. A carefully planned and executed com- methylcellulose acetate succinate (HPMCAS) (celluosic
patibility study may result in significant savings in time coating polymer) to form succinamide.
and resources. In addition, as expected by quality- Impurities in excipients can be a major concern to
by-design (QbD) principles, excipient compatibility cause incompatibilities. It is well known that traces of
information is required by the regulatory agencies to peroxides in povidone, crospovidone, hydroxypropyl
justify the selection of formulation components and cellulose (HPC), dicalcium phosphase, PEG, polysor-
to assess the overall risk. bates, and a number of modified excipients containing
It does not mean, however, that one absolutely cannot polyoxyethylene units are responsible for the oxidation
use an incompatible excipient. In some cases, a small of a number of drugs including ceronapril and raloxi-
amount of incompatible excipient may be acceptable fene. Traces of low molecular weight aldehydes such as
based on other benefits it provides. There are also situ- formaldehyde and/or acetaldehyde may exist in a num-
ations where there is simply no other alternate ingredi- ber of excipients such as starch, polysorbate, glycols,
ent and one has to live with an incompatible excipient. povidone, crospovidone, ethylcellulose, which could
However, it is still essential to understand the associated condensate with amine drugs. The 5-hydroxylmethyl-
risks and their mitigations. 2-furfuraldehyde impurity in lactose poses a similar
concern. Transition metals may be present in a num-
Direct Reactions Between Drug and ber of excipients. As mentioned previously, these may
Excipient catalyze the oxidations of many drugs. In principle, it is
Probably the most known excipient incompatibility is very beneficial to have some basic understanding on the
the Maillard reaction between a primary or secondary production, isolation, and purification process of each
amine and a reducing sugar such as lactose and glucose, excipient in order to anticipate the possible impurities
resulting in the production of browning spots. From a and the potential risks to drug product stability.
mechanistic point of view, the reactivity of the amine Complexes between drug and excipients have also
is related to its electronic density. Therefore, salt for- been reported, which could impact the dissolution,
mation of the amines usually improves stability. Like solubility, and bioavailability of a drug product. Tetra-
most solid-state reactions, amorphous characteristics cycline is reported to interact with CaCO3 to form an
of both the amines and the reducing sugar enhance the insoluble complex. Diclofenac and salicylic acid have
reactivity, a concern when using spray-dried lactose. also been reported to complex with Eudragit polymers.
Interactions between acidic drugs and basic excipients The complexation between weakly basic drugs (e.g.,
and vice versa have been reported. Examples include amines) and anionic super-disintegrants such as cros-
the interactions between indomethacin and sodium carmellose sodium and sodium starch glycolate has
bicarbonate, ibuprofen with magnesium oxide, and been reported; metaformin-croscarmellose sodium
citric acid/tartaric acid with sodium bicarbonate, the is an example.
latter of which is utilized in effervescent tablets.
44 Journal of Validation T echnology [Summer 2009] iv thome.com
 Yihong Qiu, Coordinator.

Drug Degradations Enhanced by ent to another as suggested by spectroscopic evidence,

Excipients which could potentially explain how excipients affect
Drug degradation usually occurs on the surface or the stability differently.
interfaces; therefore, the surface characteristics of API
particles and excipients may be of vital importance. General Approaches to Stabilization
Direct reactions between a drug molecule and excipi- Once instability is observed, efforts should be made to
ent do not frequently occur and may be anticipated identify the degradation products which may suggest
based on knowledge of drug degradation pathways possible degradation mechanisms. Anticipation of the
and understanding of the drug molecule. However, the nature of degradation based on molecular structure and
presence of an “inert” excipient could lead to adsorption prior knowledge can greatly assist the efforts and avoid
of drug molecules to the surface of excipient particles. excipient incompatibilities. Preformulation degrada-
Drug molecules adsorbed onto a surface are expected tion studies are essential to obtain useful information.
to have higher mobility and increased reactivity. This Relevant questions include the following:
increase in accessible surface area is expected to con- • What is the type (e.g., hydrolysis, oxidation, or oth-
tribute to increased degradation even for an otherwise ers) of degradation?
inert excipient. The excipient may be considered a het- • Is a general mechanism available?
erogeneous catalyst in this case. Often low strength • What factors are generally influential?
formations are reported to have increased degradation • Is there a general stabilization approach (e.g., pH,
attributed to the increased accessible surface area to anti-oxidant)?
drug ratio. In addition, the presence of excipient might • To what extent is the rate of degradation is affected
also change the moisture, microenvironment pH, and by moisture and/or temperature?
other characteristics which are important considerations • Could any of the processing steps play a role?
regarding drug product stability.
Microenvironmental pH may be an important factor Because fixing a stability issue in late development
on drug degradation in dosage forms. Many excipients phase could be costly both in terms of project delays
are acid or basic, such as citric acid, tartaric acid, stearic and resources, early identification and remediation of
acid, sodium bicarbonate, sodium carbonate, magne- stability issues is beneficial and preferred. Degradation
sium oxide, and magneiusm stearate. In addition, many studies are vital in the preformulation assessments of
otherwise neutral excipients may be weakly acidic or a drug candidate. These studies often employ forced
weakly basic due to the processes used in the produc- degradation studies (i.e., exposure to strong acidic pH,
tion and treatments thereof. All these can cause an strong basic pH, various oxidants, light, etc.) in order
acidic or basic microenvironment around the drug par- to delineate the intrinsic stability profile, potential
ticles, which is facilitated by the presence of moisture. degradants, and degradation pathways. By utilizing
Depending on the particular case, a drug molecule may information obtained from the preformulation studies,
be more or less stable in a particular pH environment. instability concerns can often be addressed and miti-
For example, reduced stability of aspirin was noted in gated before formulation activities start. In the author’s
the presence of acidic excipients such as stearic acid or experience, selection of viable solid forms can be made
basic excipients such as talc, calcium succinate or cal- based on stability in the solid state. Solid forms, par-
cium carbonate. Bezazepines hydrolysis was enhanced ticular salt forms, allow one to modify the surface
in the presence of microcrystalline cellulose, dicalcium characteristics of the API, such as crystallinity, mois-
phosphate, magnesium stearate, and sodium stearyl ture sorption, surface pH, and solubility, all of which
furate. Moexipril and lansoprazole (19) have been may play a significant role in drug degradation. Based
reported to be stabilized by basic excipients. on this principle, a number of solid forms have been
The moisture content and other attributes of excipi- successfully selected to provide viable stability profile
ents may also influence drug degradation. Generally, for otherwise somewhat “labile” compounds.
it is believed high moisture content from excipients A good understanding on the degradation mecha-
may be detrimental to chemical stability. However, nism or even the general features of the class of the
in a number of cases, improved stability has been reactions can be very helpful to the stabilization
attributed to more hygroscopic excipients that may of a formulation. Hydrolytic degradations have
preferentially absorb moisture in the formulation. The been frequently minimized by modification of the
characteristics of moisture may differ from one excipi- microenvironment pH via acidic or basic excipients.
gxpandjv t.com Journal of Validation T echnology [Summer 2009] 45
Product and Process Design.

Antioxidants have been routinely used to alleviate of proposed changes may be necessary in advance of
oxidative degradations. In the latter case, however, large-scale changes. Validation of high-risk process
the optimal antioxidant can only be selected based changes should include appropriate testing to assure
on the understanding of oxidation mechanisms. For the acceptability of the process change. Fundamen-
example, free-radical scavengers such as butylated tal knowledge obtained during development should
hydroxytoluene (BHT) are better for autoxidation, be available to validation and compliance person-
while ascorbic acid may be more suitable for nucleo- nel throughout the product lifecycle and should be
philic/electrophilic type of oxidation. Combination utilized as necessary to evaluate formulation and
of antioxidants may be used and have been reported process changes.
to be more effective, particularly when there is a mix
of oxidative processes. When metal ions play a sig- SUMMARY
nificant role in oxidation, a chelate (such as EDTA or Stability of drug product is complex due to the multi-
citric acid) may be used. particulate and heterogeneous nature of pharmaceuti-
When necessary, engineering approaches can be cal products. Drug degradation in solid dosage forms
used alone or in addition to those mentioned above. is mostly determined by the surface characteristics of
For example, coating, double granulation, and bi-layer both the API and the excipient particles. Solid-state
tablet approaches may be used to separate incompat- forms provide a viable means to the modulation of
ible components in a formulation. When moisture API characteristics and thus can significantly affect
plays a significant role, packaging or packaging with its chemical stability. Phase transformation during
desiccant is routinely used to achieve viable shelf pharmaceutical processing is often a likely cause of
life of a drug product. For drug molecules that react chemical degradation of the drug product even if the
slowly with oxygen, packaging combined with an starting API is stable. In particular, the small amount
oxygen scavenger can be effective. Packaging has of disordered or amorphous content, in combination
been routinely used to alleviate the photolytic (light) with typical moisture absorption in pharmaceuti-
degradation of many drug products. cal products, could greatly impact drug degradation.
Excipients influence drug degradation by direct inter-
PHASE TRANSFORMATIONS, CHEMICAL actions or modification of the microenvironment.
DEGRADATION, AND EXCIPIENT COM- A thorough understanding of the physicochemical
PATIBILITY—IMPLICATIONS FOR VALIDA- principles is critical to the anticipation, identification,
TION AND COMPLIANCE and remediation of stability issues during formula-
Validation and compliance personnel should be tion development, manufacturing, and storage of
knowledgeable of the physical and chemical proper- drug products.
ties of the active drugs for which they have respon-
sibility. They should be especially aware of active
drugs and products that may be highly prone to phase REFERENCES
transformation and chemical degradation (i.e., they 1. Baertschi, S. W., Pharmaceutical Stress Testing. Predicting
must be aware of high risk drugs and products). This Drug Degradation, Taylor & Francis Group: Boca Raton,
information is routinely determined during the phar- Florida, 2005.
maceutical development process and is often filed in 2. Yoshioka, S. and Stella, V. J., Stability of Drugs and Dosage
regulatory submissions. The manufacturing and pro- Forms, Kluwer Academic/Plenum Publishers: New York,
cessing of high-risk drugs should receive heightened NY 10013, 2000.
vigilance by compliance personnel to minimize the 3. Zhou, D.; Porter, W. and Zhang, G. G. Z., “Drug Stability
risk of phase transformations and/or chemical deg- and Stability Studies,” Developing Solid Oral Dosage Forms -
radation. Any changes to the manufacturing process Pharmaceutical Theory & Practice, Qiu, Y., Chen, Y., Zhang,
of susceptible APIs and products should be carefully G., Liu, L., Porter, W., Eds.; Academic Press: San Diego,
evaluated. Referring to previous excipient compat- CA, 2009, pp 87-124.
ibility studies is highly recommended prior to any 4. Narang, A. S.; Rao, V. M. and Raghavan, K. S., “Excipient
changes in formulation. Changes to high risk process- Compatibility,” Developing Solid Oral Dosage Forms—Phar-
es such as wet granulation, milling, and processes with maceutical Theory & Practice; Qiu, Y., Chen, Y., Zhang, G.,
solvents should receive heightened scrutiny as part of Liu, L., Porter, W., Eds.; Academic Press: San Diego, CA,
the change control program. Laboratory evaluations 2009, pp 125-145.

46 Journal of Validation T echnology [Summer 2009] iv thome.com

 Yihong Qiu, Coordinator.

5. Hovorka, S. W. and Schöneich, C., “Oxidative Degrada- 15. Kontny, M. J.; Grandolfi, G. P. and Zografi, G., “Water
tion of Pharmaceuticals: Theory, Mechanisms and Inhibi- Vapor Sorption of Water-soluble Substances: Studies of
tion,” J Pharm Sci 2001, 90, 253-269. Crystalline Solids Below their Critical Relative Humidi-
6. Waterman, K. C.; Adami, R. C.; Alsante, K. M.; Hong, J.; ties,” Pharm Res 1987, 4, 104-12.
Landis, M. S.; Lombardo, F. and Roberts, C. J., “Stabi- 16. Wardrop, J.; Law, D.; Qiu, Y.; Engh, K.; Faitsch, L. and
lization of Pharmaceuticals to Oxidative Degradation,” Ling, C., “Influence of Solid Phase and Formulation Pro-
Pharm Dev Technol, 2002, 7, 1 - 32. cessing on Stability of Abbott-232 Tablet Formulations,”
7. Zhang, G. G. Z.; Law, D.; Schmitt, E. A. and Qiu, Y., “Phase J Pharm Sci 2006, 95, 2380-92.
Transformation Considerations During Process Develop- 17. Gu, L.; Strickley, R. G.; Chi, L. H. and Chowhan, Z. T.,
ment and Manufacture of Solid Oral Dosage Forms,” Adv “Drug-excipient Incompatibility Studies of the Dipeptide
Drug Del Rev 2004, 56, 371-390. Angiotensin-converting Enzyme Inhibitor, Moexipril Hy-
8. Connors, K. A., Chemical Kinetics: The Study of Reaction drochloride: Dry Powder vs Wet Granulation,” Pharm Res
Rates in Solution, Willey-VCH Publishers: New York, 1990, 1990, 7, 379-83.
p 191. 18. Florey, K., Analytical Profiles of Drug Substances, Academic
9. Turro, N. J., Modern Molecular Photochemisty, University Press: New York, 1991, p 588.
Science Books: Sausalito, CA, 1991. 19. Tabata, T.; Makino, T.; Kashihara, T.; Hirai, S.; Kitamori,
10. Garrett, E. R., “Prediction of Stability in Pharmaceuti- N. and Toguchi, H., “Stabilization of a New Antiulcer
cal Preparations. IV. The Interdependence of Solubility Drug (lansoprazole) in the Solid Dosage Forms,” Drug
and Rate in Saturated Solutions of Acylsalicylates,” J Am Dev Ind Pharm 1992, 18, 1437-47. JVT
Pharm Ass 1957, 46, 584-586.
11. Schmidt, G. M. J., “Topochemistry. III. The Crystal Chem- ARTICLE ACRONYM LISTING
istry of Some Trans-cinnamic Acids,” J Chem Soc 1964, API Active Pharmaceutical Ingredient
2014-2021. BHT Butylated Hydroytoluene
12. Sukenik, C. N.; Bonopace, J. A.; Mandel, N. S.; Berg- HPC Hydroxypropyl Cellulose
man, R. C.; Lau, P. Y. and Wood, G., “Enhancement of a HPMCAS Hydroxypropyl Methylcellulose Acetate
Chemical Reaction Rate by Proper Orientation of React- Succinate
ing Molecules in the Solid State,” J Am Chem Soc 1975, ICH International Conference on Harmonisation
97, 5290-5291. PEG Polyethylene Glycol
13. Zografi, G., “States of Water Associated with Solids,” QbD Quality by Design
Drug Dev Ind Pharm 1988, 14, 1905-1926. RH Relative Humidity
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.

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