Understanding Physicochemical Properties for Pharmaceutical

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“Product and Process Design” discusses scientific and technical principles associated with pharmaceutical product development useful to practitioners in valida-tion 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 [email protected].

KEY POINTSThe following key points are discussed in this article:

• Stability of pharmaceutical products, including physi-cal and chemical stability, is a core quality attribute potentially impacting efficacy and safety

• Phase transformation is a common form of physical instability. Polymorphic transition; solvation and desolvation; salt and parent conversion or salt and salt exchange; and amorphization and devitrification are the common types of phase transformations. Phase transformation can occur via solid-state, melt, solution, or solution-mediated mechanisms.

• Pharmaceutical processing such as comminution (mil-ing), compaction, granulation, drying, and coating may induce partial or complete phase conversion, which could lead to inconsistent drug product quality

if not understood and properly controlled• Drug degradation may be categorized as thermolytic,

oxidative, and photolytic• Hydrolysis accounts for the majority of reported drug

degradations and it is common for a broad category of organic molecules derived from weak functional groups such as carboxylic acids. Moisture, temperature, and pH may greatly impact the rate of hydrolysis.

• Oxidation of drugs is the next greatest cause of degra-dation. Three primary mechanisms exist for oxidative degradations: nucleophilic and electrophilic, electron transfer, and autoxidation. Nucleophilic and electro-philic oxidations are typically mediated by peroxides. Transition metal catalyzes oxidation via electron trans-fer process. Autoxidation involves free-radical initiated chain reactions. A single free-radical can cause oxida-tion of many drug molecules. Autoxidation is often autocatalytic and non-Arrhenius.

• Photolytic degradation occurs only when light is absorbed. Excited states of drug molecules may have enhanced reactivity. Photolytic degradation is complex but can usually be mitigated by packaging.

• Reaction order, catalysis, and pH-rate profile are some of the basic concepts in chemical kinetics, which are helpful to the basic understanding of drug degradation

• Drug degradation in solid dosage forms is often determined by the surface characteristics of the active pharmaceutical ingredient (API) and excipient par-

Understanding Physicochemical Properties for Pharmaceutical Product Development and Manufacturing II:

Physical and Chemical Stability and Excipient CompatibilityDeliang Zhou

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

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Product and Process Design.Coordinated by Yihong Qiu

36 Journal of Validation technology [Summer 2009] i v t home.com

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Yihong Qiu, Coordinator.

ticles, or collectively the microenvironment• Defects, disordered or amorphous contents in API,

and excipients pose significant concerns on drug degradations

• Moisture profoundly affects chemical stability by direct involvement in a reaction or by catalyzing a reaction via increasing molecular mobility and facilitating the creation of microenvironments. Moisture preferen-tially penetrates into amorphous or disordered regions and may greatly enhance chemical degradation.

• Process-induced phase transformation of API is often a leading cause of chemical instability, particularly when significant amorphous content is generated

• Compatibility is an important factor for excipient selection. Timely identification of excipient incom-patibility can result in significant savings in time and resources. Excipients can directly react with drug mol-ecules, which may be judiciously avoided based on the chemical structures and physicochemical properties of the drug molecules and excipients. Excipients can also enhance drug degradation by creating a favorable microenvironment such as pH, moisture, metal ions, or simply by providing large accessible surfaces.

• Fundamental understanding of general aspects of chemical degradation as well as specific physicochemi-cal properties of a drug molecule is key to its stabili-zation. Stability issues may be mitigated by proper solid form selection. Formulation and engineering approaches may also be used to mitigate a stability issue.

• Validation and compliance personnel should be aware of the physical and chemical properties of the active drugs for which they have responsibility. They should become especially knowledgeable about active drugs and products that may be highly prone to phase transformation and chemical degradation, and apply this knowledge in process control and change management.

INTRODUCTIONStability 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 bio-pharmaceutical properties of a drug product could be classified as “instability.”

Generally speaking, instability of pharmaceuticals includes but is not limited to: loss of active ingredi-ent 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, bioavail-ability, 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 physi-cal and chemical principles applicable to all stages of product development and manufacture. More in-depth treatments on these topics may be found in many text-books 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 DRUGSIn 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. Depend-ing 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 mol-ecule, such as solubility and dissolution rate, melting, polymorphism, purity, mechanical properties, manu-facturability, and chemical stability. For example, the bioavailability of a poorly water-soluble compound may be greatly improved by using an amorphous phase. Salts have been conventionally used to improve prop-erties such as purity, melting temperature, crystallinity, hygroscopicy, and/or chemical stability, as well as the bioavailability of the parent form. A number of prop-erties (e.g., solubility and dissolution, spectroscopic, mechanical, chemical) have been shown to be affected

Journal of Validation technology [Summer 2009] 37

Product and Process Design.

by polymorphism. When modification of a particular property is aimed via solid form selection, properties in other aspects should be balanced to facilitate pharmaceu-tical 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 TransformationsThe following paragraphs describe the types of phase transformations.

Polymorphic Transition. When a molecule can be packed differently in the crystal lattice, those crys-talline 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, morpho-logical, 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 usu-ally 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 anhy-drous form is more stable and above which the hydrate is more stable. Similarly, critical RH also exists between hydrates of different stoichiometry. This concept is vital to the stability of hydrates because moisture has to be dealt with everywhere: active pharmaceutical ingre-dient (API) manufacture, formulation development, drug product manufacture, and storage. Changes in the environmental humidity could inadvertently cause hydration or dehydration to occur. In aqueous solu-tions, the hydrated form is usually less soluble than the anhydrous form because of the nature of equilibrium. The solubility difference between hydrated and anhy-drous forms is the driving force behind solution-medi-

ated hydrate formation, which could occur during various wet processes or during in vivo dissolution.

Salt and Parent Conversions or Salt and Salt Exchange. Salts may be converted to their parent forms or to salts of different counterion during processing and storage. The propensity of salt form conversion is deter-mined by pKa, crystal lattice energy, solubility and solu-bility 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 mois-ture 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 compac-tion. 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 TransformationsThe conversion of metastable form to stable form is thermodynamically favored, which poses a concern for any system where a metastable form is employed. The transformation of a stable form to a metastable form, on the other hand, is thermodynamically unfa-vorable, and is possible only when there is an energy input from the environment. The transformation kinetics in both cases, however, vary greatly, which are compound-specific and depend on the experi-mental conditions.

The primary mechanisms for phase conversions include solid-state, melt, solution, and solution-medi-ated transformations.


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Solid-State. Certain phase transitions occur in the solid-state without passing through intervening tran-sient liquid or vapor phases. These solid-state transi-tions 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 super-cooled 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 dif-ferent 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 kinet-ics 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. Subse-quent 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 (crystal-line 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 differ-ence 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 PROCESSINGPhase transformations can occur in a number of phar-maceutical 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 transfor-

mations may be time and equipment dependent. These phase transformations, when not controlled properly, often lead to inconsistent product quality.

The application of mechanical and possibly the accompanying thermal stresses during operations such as milling, dry granulation, and compaction, may lead to phase transformation such as polymorphic transition, dehydration and desolvation, or vitrification via the solid-state or melt mechanisms. The rate and extent of these phase transitions will depend on characteristics of the original solid phase and the energy input from these processes. Caffeine, sulfabenzamide, and maprotiline hydrochloride have been reported to undergo polymor-phic 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 trans-formation. 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, hydra-tion and dehydration, salt/parent conversion or salt/salt exchange, and vitrification and crystallization may occur. For example, a highly water-soluble drug may completely dissolve in granulating liquid and subsequently produce amorphous phase during drying that may or may not convert back to the original solid form. The formation of a hydrate is also likely to occur in wet granulation. Subsequent drying may dehydrate the formed hydrate. In any solid-solid conversion; however, it is very likely that a less ordered form will be produced even if conversion is close to completeness. Therefore, various amounts of amorphous content may exist in the end product, which could cause further concerns on its chemical stability. In film coating, due to the relatively short contacting time between solid surface and liquid, the likelihood of solid form change is much lower. However, the potential for phase transformation can be significant when an active is present in the coating solution.

CHEMICAL DEGRADATION OF DRUGSChemical 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 characteriza-tion is to examine the chemical stability of new drug candidates, assess the impact of stability on pharmaceuti-cal development and processing, and design strategies to stabilize an unstable molecule. The understanding of commonly encountered degradation pathways, basic con-cepts in chemical kinetics, and characteristics of chemi-cal degradation in drug products are key to the overall success of formulation development and scale up.

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

Thermolytic DegradationThermolytic 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 tempera-ture, Ea is the activation energy, A is the frequency fac-tor, and R is the universal gas constant. Any degrada-tion 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 Harmoni-sation (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 rela-tively weakly-bonding groups such as esters, amides, anhydride, imides, ethers, imines, oximes, hydrazones, semicarbazones, lactams, lactones, thiol esters, sulfo-nates, sulfonamides, and acetals can undergo hydrolysis both in solution and in the solid state in the presence of water. In particular, the presence of hydrogen or hydroxyl ions likely catalyzes the hydrolytic reactions. Each of these may have different reactivity and may require different conditions.

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 rear-rangement, isomerization and epimerization, cyclization, decarboxylation, hydration/dehydration, and dimeriza-tion and polymerization.

Oxidative DegradationOxidation accounts for 20-30% of reported drug degrada-tions 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:

• Initiation:

In • + RH "In − H + R •

• Propagation:

R • + O2 "ROO • (fast)

ROO • + RH "ROOH + R • (rate-limiting)

• Termination:

R • + R • "R − R

R • + ROO • "ROOR

Free radicals may be generated by homolytic cleavage of a chemical bond via thermal, photolytic, or chemical processes. A drug free radical is formed when one of its


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hydrogen atoms is abstracted by the initial free radical. The formed drug free radical then quickly reacts with oxy-gen 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 perox-ides (e.g., oxidation degradants) and form free radicals. It may be true that multiple oxidative processes occur simultaneously in many cases.

Photolytic DegradationChemical reactions may occur upon light absorption because light carries certain energy:

E = hv = hc/λwhere h is Plank’s constant, c is the speed of light,

ν is the frequency, and λ is the wavelength. The Grot-thuss-Draper law states that photochemical reaction can occur only after light is absorbed. A simplistic calcula-tion indicates that the energy associated with UV-visible light corresponds roughly to the bond energies in typi-cal 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 molec-ular orbitals after light absorption (excitation). Proper-ties 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 abso-lute 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.

Basic Concepts in Chemical KineticsThe 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]

dt= k[Aspirin][H+]−

Degradation of most pharmaceuticals are second-order in nature, because degradation usually involves two molecules to react, one of which being the drug molecule itself. However, the concentration of the other compo-nent (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 reac-tants. Apparent zero-order degradations may arise in cases where drug concentrations are maintained as a constant (e.g., suspensions).

Catalysis. A catalyst is a substance that influences the rate of a reaction without itself being consumed. A positive catalyst promotes a reaction while a negative catalyst demotes a reaction.

Catalysis occurs by changing the activation energy of a reaction but not changing the thermodynamic nature of the reaction. A catalyst can only influence the rate, but not the equilibrium of the reaction. In some cases, a reaction product can catalyze the rate, which is often termed as autocatalysis. The free-radical initiated oxida-tion certainly is such an example.

Hydrogen ions and/or hydroxyl ions are often involved directly in the degradation of pharmaceuticals. When the concentration of hydrogen ion or hydroxyl ion appears in the rate equation, the reaction is said to be subject to specific acid-base catalysis. Drug degradations are often determined in buffered solutions and studied by monitoring the drug itself. As a result, the degradation kinetics is often apparent first-order with the apparent rate constant in the following form:

kobs = k0 + kH[H+] + kOH [OH−]



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 reac-tion. 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 + Σ ki Ci

i

The pH-rate profile provides a summary of the primary features of a specific degradation. Specific acid-base cataly-sis 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. Com-monly, 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 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 the intramolecular catalysis:

O

O

O

O

OH

H

CH3

pH-rate profiles can provide tremendous insights on the nature of a reaction and can serve as a very useful tool in developing solution formulations, lyophilized prod-ucts, as well as conventional solid oral dosage forms.

DEGRADATION IN SOLID DOSAGE FORMSDrug 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 solu-tion 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. There-fore, the surface characteristics of API particles and the

-3

-4

-5

-6

-70 2 4 6 8 10

pH

log

Ko

bs

(s-1)

Figure: pH-rate profile of hydrolysis of aspirin (adapted from reference 10).


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excipients—or collectively, the microenvironment—are of vital importance to the understanding and remedy of drug degradation.

Solids often contain defects or strains, where mol-ecules have higher free energy. These high energy sites usually serve as the initiation (nucleation) sites of a reac-tion. Therefore, disorders in crystals may be a key point in the understanding of solid-state reactions of drugs. To extend this concept further, the amorphous phase is highly energetic, is expected, and has been found to enhance chemical reactivity. Often crystalline API is used in drug development. However, a small amount of disordered or amorphous content is apparent, par-ticularly 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. Regard-less 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 stabil-ity problem.

Moisture has a profound effect on drug degradation in solid dosage forms, either as a reactant (e.g., hydro-lysis) 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 incor-porated into crystal lattice through hydrogen bonding and/or Van de Waals interactions. Generally, lattice water is not a cause of chemical instability. Some com-pounds 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 amor-phous phase and, therefore, enhances degradation. A simplified calculation indicates that the typical mois-ture 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 pharma-ceutical 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. Microen-vironmental 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 magne-sium 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 compac-tion. All these process-induced amorphous content, in combination with typical moisture contents, could be detrimental to the chemical stability of pharmaceuti-cal 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 COMPATIBILITYExcipient selection is of great importance to accomplish the target product profile and critical quality attributes. Excipient functionality and compatibility with the active drug are two important considerations.

Incompatibility may be referred to as the undesirable interactions between drug and one or more components in formulation. Incompatibility may adversely alter the product quality attributes, including physical, chemical, biopharmaceutical, or other properties.

Excipient compatibility studies are usually conducted in the early phase of drug product development. Their objective is to further characterize the stability profile of the drug molecule in typical formulation design, identify potential material incompatibility, charac-terize the degradants, understand the mechanisms of degradation, and provide guidance to formulation development. A carefully planned and executed com-patibility study may result in significant savings in time and resources. In addition, as expected by quality-by-design (QbD) principles, excipient compatibility information is required by the regulatory agencies to justify the selection of formulation components and to assess the overall risk.

It does not mean, however, that one absolutely cannot use an incompatible excipient. In some cases, a small amount of incompatible excipient may be acceptable based on other benefits it provides. There are also situ-ations where there is simply no other alternate ingredi-ent 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 ExcipientProbably 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 for-mation 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. Seprox-etine 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 epi-nephrine and sodium bisulfite.

Transacylation is another major group of drug-excipient interaction. Carboxylic moiety can react with alcohols, esters, or other carboxylic derivatives to form esters, amides, etc., whether presented in excipi-ents or in drug molecules. For example, aspirin can undergo transesterification with a number of drugs including acetaminophen, codeine, sulfadiazine, and polyethylene glycol (PEG). Norfloxacin is reported to react with magnesium stearate to form stearoyl amide (18). Similarly, duloxetine reacts with hydroxypropyl methylcellulose acetate succinate (HPMCAS) (celluosic coating polymer) to form succinamide.

Impurities in excipients can be a major concern to cause incompatibilities. It is well known that traces of peroxides in povidone, crospovidone, hydroxypropyl cellulose (HPC), dicalcium phosphase, PEG, polysor-bates, and a number of modified excipients containing polyoxyethylene units are responsible for the oxidation of a number of drugs including ceronapril and raloxi-fene. Traces of low molecular weight aldehydes such as formaldehyde and/or acetaldehyde may exist in a num-ber 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 num-ber 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. Tetra-cycline 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 cros-carmellose sodium and sodium starch glycolate has been reported; metaformin-croscarmellose sodium is an example.


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Drug Degradations Enhanced by ExcipientsDrug 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 excipi-ent do not frequently occur and may be anticipated based on knowledge of drug degradation pathways and understanding of the drug molecule. However, the presence of an “inert” excipient could lead to adsorption of drug molecules to the surface of excipient particles. Drug molecules adsorbed onto a surface are expected to have higher mobility and increased reactivity. This increase in accessible surface area is expected to con-tribute to increased degradation even for an otherwise inert excipient. The excipient may be considered a het-erogeneous 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, magne-sium oxide, and magneiusm stearate. In addition, many otherwise neutral excipients may be weakly acidic or weakly basic due to the processes used in the produc-tion and treatments thereof. All these can cause an acidic or basic microenvironment around the drug par-ticles, 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 cal-cium 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 excipi-ents 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 excipi-

ent to another as suggested by spectroscopic evidence, which could potentially explain how excipients affect stability differently.

General Approaches to StabilizationOnce 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 degrada-tion studies are essential to obtain useful information. Relevant questions include the following:

• What is the type (e.g., hydrolysis, oxidation, or oth-ers) of degradation?

• Is a general mechanism available?• What factors are generally influential?• Is there a general stabilization approach (e.g., pH,

anti-oxidant)?• To what extent is the rate of degradation is affected

by moisture and/or temperature?• Could any of the processing steps play a role?

Because fixing a stability issue in late development phase could be costly both in terms of project delays and resources, early identification and remediation of stability issues is beneficial and preferred. Degradation studies are vital in the preformulation assessments of a drug candidate. These studies often employ forced degradation studies (i.e., exposure to strong acidic pH, strong basic pH, various oxidants, light, etc.) in order to delineate the intrinsic stability profile, potential degradants, and degradation pathways. By utilizing information obtained from the preformulation studies, instability concerns can often be addressed and miti-gated 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, par-ticular salt forms, allow one to modify the surface characteristics of the API, such as crystallinity, mois-ture 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 mecha-nism 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 nucleo-philic/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 sig-nificant role in oxidation, a chelate (such as EDTA or citric acid) may be used.

When necessary, engineering approaches can be used alone or in addition to those mentioned above. For example, coating, double granulation, and bi-layer tablet approaches may be used to separate incompat-ible 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 COM-PATIBILITY—IMPLICATIONS FOR VALIDA-TION AND COMPLIANCEValidation and compliance personnel should be knowledgeable of the physical and chemical proper-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 transformation and chemical degradation (i.e., they must be aware of high risk drugs and products). This information is routinely determined during the phar-maceutical development process and is often filed in regulatory submissions. The manufacturing and pro-cessing of high-risk drugs should receive heightened vigilance by compliance personnel to minimize the risk of phase transformations and/or chemical deg-radation. Any changes to the manufacturing process of susceptible APIs and products should be carefully evaluated. Referring to previous excipient compat-ibility studies is highly recommended prior to any changes in formulation. Changes to high risk process-es 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. Fundamen-tal knowledge obtained during development should be available to validation and compliance person-nel throughout the product lifecycle and should be utilized as necessary to evaluate formulation and process changes.

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

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ARTICLE ACRONYM LISTING API Active Pharmaceutical IngredientBHT Butylated HydroytolueneHPC Hydroxypropyl CelluloseHPMCAS Hydroxypropyl Methylcellulose Acetate

SuccinateICH International Conference on HarmonisationPEG Polyethylene GlycolQbD Quality by DesignRH Relative Humidity


Understanding Physicochemical Properties for Pharmaceutical

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