articulo de comrpimidos

EXPERT REVIEW

Impact of Excipient Interactions on Solid Dosage Form Stability

Ajit S. Narang & Divyakant Desai & Sherif Badawy

Received: 10 January 2012 /Accepted: 14 May 2012 /Published online: 16 June 2012# Springer Science+Business Media, LLC 2012

ABSTRACT Drug-excipient interactions in solid dosage formscan affect drug product stability in physical aspects such as organ-oleptic changes and dissolution slowdown, or chemically bycausing drug degradation. Recent research has allowed the dis-tinction in chemical instability resulting from direct drug-excipientinteractions and from drug interactions with excipient impurities. Areview of chemical instability in solid dosage forms highlightscommon mechanistic themes applicable to multiple degradationpathways. These common themes include the role of water andmicroenvironmental pH. In addition, special aspects of solid-statereactions with excipients and/or excipient impurities add to thecomplexity in understanding and modeling reaction pathways.This paper discusses mechanistic basis of known drug-excipientinteractions with case studies and provides an overview of com-mon underlying themes. Recent developments in the under-standing of degradation pathways further impact methodologiesused in the pharmaceutical industry for prospective stability as-sessment. This paper discusses these emerging aspects in terms oflimitations of drug-excipient compatibility studies, emerging para-digms in accelerated stability testing, and application of mathemat-ical modeling for prediction of drug product stability.

KEY WORDS capsules . compatibility . degradation .dissolution . excipients . granules . impurities . mechanism .reaction . stability . tablets

ABBREVIATIONSAlu aluminumAPI active pharmaceutical ingredientARP Amadori rearrangement productBHA butylated hydroxyanisoleBHT butylated hydroxytolueneGC gas chromatographyHCl hydrochlorideHCTZ hydrochlorothiazideHDPE high density polyethyleneHPLC high performance liquid chromatographyHPMC hydroxypropyl methylcelluloseHPO hydroperoxideICH international conference on harmonizationLC/MS liquid chromatography tandem with mass

spectroscopyMVTR moisture vapor transmission rateNF National FormularyNMR nuclear magnetic resonance (spectroscopy)PEG polyethylene glycolpHmax pH of maximum solubilityPVA polyvinyl alcoholPVP polyvinyl pyrrolidone (povidone)PhEur European PharmacopeiaPVP-VA polyvinylpyrrolidone-vinyl acetate copolymerPXRD powder X-ray diffractionSDMT sorption desorption moisture transferssNMR solid state NMRUSP United States Pharmacopeia

INTRODUCTION

Safety and efficacy are the main considerations in new drugresearch and development. To satisfy these requirements,

A. S. Narang (*) :D. Desai : S. BadawyDrug Product Science and Technology, Bristol-Myers Squibb, Co.One Squibb Dr., P.O. Box 191New Brunswick, New Jersey 08903-0191, USAe-mail: [email protected]

D. Desaie-mail: [email protected]

S. Badawye-mail: [email protected]

Pharm Res (2012) 29:26602683DOI 10.1007/s11095-012-0782-9

dosage forms are designed with an intent to provide adequateand reproducible bioavailability of the drug, while ensuring itsphysico-chemical stability over the designated shelf-life. Whilethe chemical stability of a molecule is an inherent propertygoverned by its chemical structure, a drugs stability in a drugproduct also depends on the dosage form-related character-isticssuch as the presence of other components (excipients),manufacturing process, package, and storage conditions. Drugformulations are designed to maximize the physico-chemicalstability of the drug contained therein, in addition to ensuringdrug bioavailability and dosage form manufacturability. In thiscontext, drug product instability is an area of continued re-search not only because of the diversity in molecular structureand formulation variables; but also to develop fundamentalmechanistic understanding of its causes, which helps designmitigation strategies that form the cornerstone of successfuldrug product development and commercialization.

Physical instability refers to changes in the characteristics ofa drug product that do not involve chemical bond formationor breakage in the drug molecules structure. Physical insta-bility can be exemplified by changes in appearance, drugrelease, polymorphic form, taste, odor, or tensile strength; orphenomena such as crystallization in amorphous systems,physical attrition, segregation, adsorption, and vaporization.

Chemical instability, on the other hand, refers to changesin the chemical structure of the drug molecule in the dosageform. These are related to drug degradation, resulting inreduced potency (drug content) and formation of othermolecules (degradation products or degradants). Formationof degradation products is a toxicity or safety concern, whilereduction in potency is an efficacy concern. Levels of degra-dants are closely regulated in dosage forms with well-defineddetection, identification, and toxicological qualification lim-its based on their maximum permissible daily intake asclearly articulated in ICH guidelines.

Drug-excipient interactions can lead to both physical andchemical instability in solid dosage forms. These interactionscould be due to interactions of drugs with excipients or reac-tive impurities in excipients (1). Early in drug product devel-opment, such instability in the dosage form is sought to beidentified and avoided by prospective screening studies, suchas excipient compatibility testing (2,3). Nevertheless, a thor-ough mechanistic understanding of the underlying causes ofsuch instability is important in mitigating or minimizing theiroccurrence and the associated risks. This review will highlightsome of these pathways of instability and recent developmentsin their mechanistic understanding and mitigation strategies.

GENERAL CONSIDERATIONS

Some of the common underlying mechanisms by whichexcipients affect drug stability in the dosage form are by

altering moisture content in the dosage form, changingmicro-environmental pH in the dosage form, acting as gen-eral acid/base catalysts, directly reacting with drug, or be-coming source of impurities that can either directly reactwith drug substances or participate as catalysts in the drugdegradation (2). Other changes that the excipients maycause to alter the physical and/or chemical form of the drugin the dosage form are mediated through mechanisms suchas complexation, ion-exchange; polymorphic transforma-tion of crystalline or amorphous forms; and the formationof eutectic or solid solutions.

Typical Aspects of Solid State Reactions

A common degradation pattern in the pharmaceutical systemsis rapid initial degradation via first order kinetics, followed byprogressive reduction in the rate of degradation (4). This isobserved when the reaction is dependent upon a depletingconstituent of the system, such as water or small quantities ofreactive impurities in the drug or excipients. Slowing of firstorder degradation kinetics to a pseudo-equilibrium level isalso observed in solid-solid surface reactions where impurityaccumulation on the surface is responsible for the slowdown(2). For example, first order degradation kinetics with pseudo-equilibrium phenomena were reported for the degradation ofthiamine hydrochloride (5) and ascorbic acid (6). The degra-dation pathways can be diverse, such as zero order degrada-tion of aspirin in suspension (7); first order hydrolysis oftriazolam (8); second order interaction of isoniazid with re-ducing sugars (9); consecutive first order degradation reactionsof hydrocortisone hemisuccinate (10); and the reversible andparallel degradation pathways of pilocarpine solution in theneutral pH region (11).

Drug degradation pathways and patterns in solid dosageforms can differ from those in the liquid state due to theheterogeneity of the solid state and changes in physical stateof the drug and other components with time (12). Thesedifferences lead to additional kinetic restrictions and mod-ifications of reactions occurring in the solid state. Examplesof such cases include (a) diffusion controlled reactions, (b)solid-state reactions rate limited by the formation andgrowth of reaction nuclei, (c) reactions that form a liquidproduct, and (d) reactions limited by amount of adsorbedwater.

Diffusion Controlled Reactions

Diffusion controlled reactions are reactions of a solid reac-tant dispersed in another reactant, which is considered as acontinuous medium. This mechanism is applicable to thereactions of solids with gases, liquids, or solids. The reactionproduct, solid or liquid, is deposited on the surface of thesolid reactant as the reaction proceeds.

Stability Impact of Excipient Interactions 2661

In a diffusion controlled reaction, the buildup of alayer of reactants and products on the surface of drugparticles is a function of concentration, time, diffusioncoefficient of reacting species, and the volume of theproduct already formed. Assuming spherical particles ofuniform radii reacting throughout the surface with in-stantaneous surface nucleation and diffusion being therate limiting step, the thickness of interface, x, thatcontains both the reacting components and the productis given by Eq. 1.

x2 2D Vm C0 t 1

where, D is the diffusion coefficient of the slowest trans-porting component, Vm is the volume of product formedfrom 1 mol of the slowest penetrating component, C0 isthe concentration of the penetrating species on theinterfacial boundary, and t is time (13).

The isothermal rate of formation of the product, k, isinversely proportional to time, t, and a function of thefraction decomposed, . Thus,

f a kt 2A plot of f() versus t gives a straight line if the right

reaction kinetics model is used, which depends on theunderlying assumptions about the mechanism controllingthe reaction and the size and shape of reacting particles.In a diffusion controlled reaction, f() is given by theparabolic Eq. 3 for a one dimensional diffusion processwith constant diffusion coefficient, Eq. 4 for two dimen-sional diffusion controlled process in a cylinder, andEq. 5 for a three dimensional diffusion controlled pro-cess in a sphere.

f a a2 3

f a 1 a ln 1 a a 4

f a 1 1 /13h i2

5

Equation 5 was proposed by Jander (14) and has beenused to describe the thermal decomposition of mercuricoxalate, thiamine diphosphate, and propantheline bro-mide (15).

Crystal Imperfections as Reaction Sites

Reactions of crystalline drug in the solid state can belimited to the imperfection sites in the crystal, that canact as sites where the drug preferentially reacts (2). Solidstate reactions of this type limit the growth of impurity,

x, by the presence and growth of crystal imperfectionssites as given by Eq. 6.

dxdt

k N k tn 6

where N is the number of crystal imperfections, n is aconstant, t is time, and k is the rate constant. Thisequation was used to describe the initial hydrolysis rateof meclofenoxate hydrochloride (16), propantheline bro-mide (17), and aspirin (18).

Reactions That Form a Liquid Product

Reaction kinetics of solids leading to the formation of liquidproducts is complicated by reactions occurring in two me-dia: the solid state and the liquid state (2). In this case, theoverall reaction rate is obtained as a summation of thereaction rates in both states as per Eq. 7.

dxdt

ks 1 x Sx k1 Sx 7

where, S is the solubility of the drug in the liquid stateformed, t is time, and ks and k1 are the rate constants inthe solid and the solution states, respectively. In this equa-tion, Sx is the product of fraction degraded and the solubilityof drug in the liquid phase, representing the molar fractionof drug in solution. Thus, (1-x-Sx) represents the molarfraction of the drug in the solid state. This equation canbe integrated to a linear form Eq. 8.

ln 1 S k1 ks ksks

S k1 ks ks t 8

This equation, known as the Bawn equation, was used todescribe the decarboxylation rate of benzoic acid and alkox-yfuroic acid derivatives (19,20).

Reactions Limited by Amount of Adsorbed Water

Reactions occurring in the adsorbed moisture layer arelimited by the amount of adsorbed water. Drug degradationin such cases can be described by the following apparent orreal zero order or first order Eqs. 9 and 10, respectively.

dxdt

k V H2O 9

dxdt

k V C H2O 10

where V is the volume of adsorbed moisture, [H2O] is themolar concentration of water, [C] is the drug concentration,and k is the reaction rate constant. The term V H2O allows the calculation of amount of water. This model was

2662 Narang, Desai and Badawy

used to explain the degradation of aspirin (21), sulpyrine(22), and 4-aminosalicylic acid (23).

Model Independent Approaches

Model-fitting approaches involve the statistical analysis de-termination of best fit model for a given set of data. The useof statistical approaches to best fit the data to one of possiblemechanistic models often leads to similar statistical fit tomore than one kinetic model (24). In addition, solid-statereaction kinetics are not only inherently different from thekinetics of reactions in homogeneous phases, such as thesolution state; but can also involve more than one ratelimiting step. For example, the kinetics of loss of waterinvolved in the dehydration of hydrates of drugs can includeelements of both nucleation and diffusion controlled reac-tions. For crystalline drugs, dehydration usually begins atthe sites of crystal defects, nucleation sites, where latticestrain leads to greater energy and molecular mobility ofdrug molecules in the immediate vicinity of the defect. Thisleads to the formation of a new solid phase, the dehydratedform of the drug, at the nucleation sites. Further progress ofthe reaction could involve the rate limiting steps of either thegrowth of nuclei or the diffusion of water. Further, thedimensionality of the diffusion of water depends on thecrystal structure of the hydrate since water molecules tendto escape from the crystal lattice along certain directions,known as water channels. Thus, dehydration kinetics couldinvolve different and/or sequential rate limiting stepsdepending on the nature of the drug hydrate crystal andexperimental conditions. This was illustrated for the dehy-dration of nedocromil sodium trihydrate (25).

These considerations and limitations in model fitting leadto the use of model-independent or model-free approaches.An example of the model free approach is isoconversionalanalysis, which allows the calculation of the reaction activa-tion energy, Ea, as a function of the extent of reaction andwithout assumption of a single reaction model. Thus, anyvariation in Ea from a constant value as the reaction pro-ceeds could indicate a change in the rate limiting step of thereaction.

Khawam and Flanagan presented an example of thecomplementary application of both model-dependent andmodel-free methods of analyses of solid-state reaction kinet-ics (26). They applied these methods to the desolvation ofsulfameter solvates with tetrahydrofuran, dioxolane, anddioxane, monitored by thermogravimetry. Using themodel-based approach, the authors encountered difficultyin finding the best-fit reaction model for the kinetic data,since the statistical fit parameters for several models weresimilar. The application of the model-independent isocon-versional analyses helped select the best-fit model. Thisexample suggests that the application of model independent

approaches may not be mutually exclusive of the model-dependent approaches, but the two may complement eachother (25).

Role of Water (Moisture)

Most drugs and excipients contain water, which may beeither bound or unbound. The bound water is the waterof hydration or crystallization which is so tightly incorporat-ed in the physical form of the material that it is practicallyimmobile and is not available for reactions. This is exem-plified by the stability of crystalline hydrates of hydrolytical-ly unstable -lactam antibiotics, wherein the water isincorporated in the crystalline matrix and is not availablefor reaction. As expected, the stability of these compounds ishighly dependent on their crystallinity (27). In contrast,unbound water usually exists in equilibrium with the atmo-sphere in an absorbed or adsorbed state by the solid com-ponents and has higher molecular mobility. The variation inthe content of water of an excipient with humidity reflectschanges in the unbound water content.

Water activity is a direct indicator of the amount of free,mobile water in the system. Water activity in a solid isequivalent to the relative humidity in a closed environmentproduced in equilibrium with the solid excipient or drug-excipient mixture. Several authors recommend use of wateractivity determination for drug product stability correlationover total moisture determination by Karl-Fisher titrimetryand/or water uptake by weight gain (28,29). Thus, Burghartet al. correlated the water activity of solid oral dosage formsof levothyroxine and lyothyronine with their chemicalstability (30).

Role of Water in Physical Instability

Slowdown of dissolution and disintegration of solid dosageforms on stability is often induced by moisture uptake in thetablets during manufacturing and/or storage. For example,Fitzpatrick et al. reported slowdown of dissolution and in-crease in the tensile strength of a tablet formulation con-taining povidone (polyvinyl pyrrolidone, PVP) as a binder,but not one containing hydroxypropyl cellulose (HPC) (31).These effects were attributed to moisture sorption by PVPcausing depression of its glass transition temperature (Tg) tobelow the temperature used in accelerated stability studies.This transition from the rigid glassy to the relatively moremobile rubbery state was postulated to lead to increasedtablet densification, reduced dissolution, and increased ten-sile strength. Nevertheless, the long term stability studiesconducted at temperature below Tg did not induce dissolu-tion slowdown. Also, in the authors experience, the use ofPVP as a binder did not show slowdown in dissolutionstability for several drug products. Therefore, the


observation of dissolution slowdown with the use of specificbinders or disintegrants is likely to be drug specific and alsodependent on packaging and storage conditions.

Role of Water in Chemical Instability

The physical state of water in an excipient or the drug-excipient mixture determines its potential role in drug-excipient interactions. The water sorptiondesorption prop-erties of excipients are well documented (32,33). Presence ofwater in the solid-state systems has a significant impact onthe stability not only in causing the hydrolysis of drugs, e.g.,of acetylsalicylic acid (34), but also its participation as areaction medium and in increasing the plasticity and molec-ular mobility of the system. Excipients that strongly adsorbwater may prevent drug degradation by scavenging water ina closed system, e.g., colloidal silica (35) and silica gel (36),thus lowering water activity in the mixture. Excipients withhigher adsorption energy, indicative of their higher bondingstrength with water, can decrease the reactivity of water inthe system compared to those with lower adsorption energy,as was shown in the case of nitrazepam (37). On the otherhand, water in excipients such as microcrystalline cellulose ishighly reactive because it is weakly adsorbed (38). This wasthe reason for the higher rate of hydrolytic degradation ofaspirin in the presence of microcrystalline cellulose versusmicrofine cellulose (39).

Molecular mobility of drug and water molecules in thesolid state directly correlates with their reactivity. The mo-bility of water molecules in a system can be directly mea-sured by nuclear magnetic resonance (NMR) and dielectricrelaxation spectroscopy. Mobility of water in the systemhave been correlated to drug stability in drug-excipientmixtures in several cases, e.g., degradation of trichlormethia-zide in gelatin gels (40) and of cephalothin in its mixtureswith microcrystalline cellulose (41). Unbound, weaklyadsorbed water contributes to molecular mobility withinthe system, which is a prerequisite for chemical reactions.Sorbed water plasticizes amorphous solids by reducing theglass transition temperature, Tg (42,43). The Tg of anamorphous solid represents transition from a highly rigid,less mobile, glassy state to a rubbery, mobile state withhigher free volume. Water sorption leading to reduction inTg is known in excipients such as starch, lactose, and cellu-lose (44), and amorphous drugs such as indomethacin (45).

A study of water sorptiondesorption of a system as afunction of environmental humidity at a fixed temperature(isotherm) can indicate the strength of sorption of water andits mobility within the system. The moisture sorptionde-sorption isotherms frequently present a hysteresis, which areindicative of the way water reacts with the system. Interac-tion of water with a solid phase can lead to formation ofhydrate, adsorption of water on the surface of the solid, or

absorption of water by the amorphous phase leading to theformation of a single phase (46). Cyclic exposure of a solidmaterial to a given level of water in the environment (rela-tive humidity) can change the affinity of the solid material tomoisture. This is evident by the hysteresis loop in watersorptiondesorption isotherms. For example, crystallizationof amorphous material, such as spray dried lactose, duringthe sorption phase can lead to lower water content in thesolid during the desorption phase, causing negative hysteresis(47). Alternatively, molecular reorganization of polymericmaterials can make moisture sorption more favorable, thusleading to positive hysteresis.

Presence of hysteresis in pharmaceutical dosage formscan lead to differences in reactivity when a drug product iscycled between high and low humidities. Waterman et al.cycled a direct compression tablet of an investigational drugthrough high-low-high or low-high-low RH cycles at fixedhumidity and determined the rate of formation of an RH-induced degradant (lactone) at initial and final humidityconditions (46). The authors observed that the degradantformation rate at high humidity condition was same for bothphases of high-low-high cycle. In contrast, the rate of degra-dant formation was higher for the latter of the two phases ofthe low-high-low cycle. This study indicated that reactivitymay not be dependent on the RH only but also on thehumidity exposure history of the system. The authors hy-pothesized that this could be due to formation of solid-solution on the surface, alteration of mechanical propertiesof the surface to cause greater mobility, or alteration of theinterfacial state such that higher amount of moisture waspresent at the interface even after drying (46).

Mitigation Strategies

Moisture-induced changes in physical properties of the dos-age form can be mitigated by package design, such as theuse of desiccants in high density polyethylene (HDPE) bottlepacks or the use of moisture impervious aluminum-aluminum (Alu-Alu) blister pack. In addition, reformulationto reduce moisture sensitivity can help. For example, refor-mulation of ranitidine hydrochloride tablets in the presenceof ion exchange resins, that reduce the equilibrium moisturecontent of tablets at same humidity, stabilized the tabletsagainst changes in disintegration time and friability overstorage (48).

Microenvironmental pH

Excipients can have an acidic or basic surface pH dependingupon their chemical nature and composition. For example,Glombitza et al. measured the surface pH using pH indica-tor dyes and found that the surface of dicalcium phosphatewas more acidic than that of microcrystalline cellulose (49).


For soluble excipients, the pH of the excipient solution is asimple indicator of the pH imparted by the excipients insolid state. For insoluble excipients, the pH of 520% ex-cipient slurry in water could be used as an indirect indicator.The selection of excipients with compatible pH profiles,based on preformulation solubility and stability studies as afunction of pH, is helpful in the design of excipient compat-ibility experiments. For example, acid labile drugs shouldnot be combined with acidic excipients such as hydroxy-propyl methylcellulose (HPMC) phthalate and HPMC ace-tate succinate. Similarly, magnesium stearate imparts abasic pH in its microenvironment and may contribute tothe instability of base-labile drugs. Stanisz found that thechemical stability of quinapril HCl in binary drug-excipientmixtures was significantly better with acidic excipients thanbasic magnesium stearate (50). This study indicated thatboth the microenvironmental pH and humidity were signif-icant factors in drug degradation. Thus, the presence ofmobile water accelerates the surface pH effects of excipientsby creating microenvironmental conditions of dissolved ex-cipient on the interacting surfaces.

Most drugs are salts of organic acids or bases which maydisproportionate to the free acid or base forms at acidic orbasic pH, respectively, depending on the pH of maximumsolubility (pHmax). Thus, pH modifying excipients may re-sult in the formation of the free acid/base form of the drug.If the free acid/base form is more unstable than the saltform, this would lead to enhanced degradation. In addition,dissolution rate of the dosage form may be affected since freeforms are usually less water soluble than their correspondingsalts. The free form may also be volatile and be lost bysublimation from the dosage form, leading to mass balanceissues in terms of loss of drug not being accounted for by thepresence of degradation products (51,52).

PHYSICAL INSTABILITY

Organoleptic Changes

Changes in appearance (such as color or mottling on sur-face), taste, or odor sometimes becomes evident over stor-age, especially for some drugs with amine or sulfur groups.These changes are often associated with chemical changes inthe dosage form, such as degradation of the drug or flavors.For example, reactions of reducing sugars, e.g., lactose, withprimary and secondary amine drugs via Maillard reactionfollowed by Amadori rearrangement can produce a multi-tude of colored products. The general mechanism of thesereactions involves the reaction of the amine compound withthe open form of the carbohydrate to form an imminium ionintermediate, that can either close to a glycosamine com-pound or deprotonate to form the enol version of the

rearrangement product (53). Fluoxetine hydrochloridetablets can undergo Maillard reaction (Fig. 1) with lac-tose to form colored pigments (53). Also, some drugs,such as N-acetyl cysteine, can degrade into odorouschemicals. Stabilization strategies to prevent organolepticchanges often involve preventing drug degradation bychanging the formulation to replace the reactive excipi-ent(s) or by other means. For example, Murugesan et al.reported the use of antioxidants in the formulation of N-acetyl cysteine to prevent its oxidative degradation to anodorous product (54).

Changes in Drug Release

Physical instability in dosage forms is also encountered interms of changes in drug release or dissolution. Significantchanges in drug release during storage may impact its bio-availability. Factors that affect the dissolution stability of aproduct during aging include formulation components (ac-tive drug, excipients, and coating materials), processing fac-tors, storage conditions, and packaging (55). Changes in thedrug release are frequently a result of drug-excipient andexcipient-excipient physico-chemical interactions in the dos-age form. For example, dissolution slowdown of wet granu-lated tablets containing croscarmellose sodium was mostpronounced in formulations containing lactose (56). Thesechanges are often secondary to one or more primary mech-anistic changes which involve phenomena such as changesin tablet porosity or density, change in the form of the drugsubstance (e.g., polymorphism, hydrates, and salts), orreduced disintegration characteristics due to excipientinteractions.

Presence or release of free formaldehyde in solid dosageform due to chemical degradation under stress conditions,such as high temperature and humidity, is well known tocause crosslinking of gelatin and reduce drug release fromhard gelatin capsules. Crosslinking of gelatin shell can causedelayed drug release, which is dependent on dissolutionconditions (57). The in vivo impact of delayed disintegrationis likely to depend on the therapeutic window, inherentvariability, and any site-specific absorption of the drug sub-stance. For example, Digenis et al. reported bioequivalenceof stressed and non-stressed hard gelatin capsules whenamoxicillin was used as the drug marker (58). Using radio-labeled drug and GI transit monitoring using gammascintigraphy studies, the authors observed delay in theonset of amoxicillin absorption, which was dependent onin vivo rupture of the hard gelatin capsule shell. Thisdelayed absorption, however, did not affect the bioequi-valence criteria of Cmax and AUC. Similarly, bioequiva-lence of stressed and nonstressed hard gelatin capsuleswas also observed using acetaminophen (59) and etodolac(60) as a marker.


Form Changes

Change in the form of the drug in a drug product is typicallydetected through its effect on one or more of drug productperformance attributessuch as drug release or dissolutionusing a discriminatory method. For example, significant con-version of the higher solubility form II of the drug glimepiride tothe lower solubility form I (61) and transition from a metastableto a stable form of theophylline on storage (62) in their tabletformulations could be detected using a discriminatory dissolu-tion method. Changes in the polymorphic form of the drug canbe investigated using one or more of X-ray diffraction (XRD);infra-red (IR), near-IR (NIR), solid state nuclear magneticresonance (ssNMR), or Raman spectroscopy; solvent sorptionisotherm; polarized microscopy; and hot stage microscopy.

Drug form changes can be a consequence of the interac-tion of the drug with another component of the formulation,such as an excipient or water. For example, grinding withcolloidal silica led to the reduction in crystallinity and con-version of form B of chloramphenicol acetate to form A (63).The reduction in crystallinity by grinding with an abrasiveexcipient is suggestive of introduction of crystal defectsduring processing, that may then serve as sites of nucle-ation for polymorphic form conversion and/or reactivityof the drug with other components of the formulation(Crystal Imperfections as Reaction Sites).

The effect of water on form conversion of a drug is usuallyobserved during drug product storage, but can also occurduring processing. The effect of moisture content of a formu-lation on its storage stability is a function of free rather thantotal water content of the drug product (Reactions Limited byAmount of AdsorbedWater and Role ofWater (Moisture)).Thus, a film coated tablet formulation of a water sensitive drugshowed greater instability at low total water content (by KarlFisher titrimetry) but high water activity, than another formu-lation that had high total water content but low water activity

(64). Similarly, storage of a drug product above a critical levelof free water can lead to conversion between different hydrateforms of a compound. For example, nitrofurantoin exists intwo anhydrous (designated and ) and two monohydrous(designated I and II) forms. High humidity storage and pro-cessing conditions, e.g., wet granulation, may lead to the con-version of the anhydrous to the monohydrate form, which canbe detected by the appearance of a specific peak in the powderXRD (PXRD) spectrum that indicates the presence of themonohydrate form (65). Excipient interactions can also beuseful to stabilize a drug against form conversion. For example,form transition from a metastable to a stable form of theoph-ylline during wet granulation is inhibited by PVP. Highermolecular weight of povidone was more effective in inhibitingthe transition than lower molecular weight (66).

Disproportionation of salts of weak bases due to moistureuptake and/or interaction with excipient(s) in the dosage formcan lead to the formation or increased proportion of the freebase form, which usually shows lower solubility, dissolutionrate, and bioavailability. For example, Rohrs et al. reporteddissolution slowdown of delavirdine mesylate tablets on stabil-ity, which was closely associated with the moisture content oftablets (67). This was attributed to the dual role of reducedsolubility of the free base form of the drug and protonation ofcarboxyl sites on the croscarmellose sodium by the methane-sulfonic acid (liberated by disproportionation of the drug).The propensity for disproportionation of a salt form of thedrug depends upon solubility of salt, solubility of the free base,and the microenvironmental pH of the formulation relative tothe pH of maximum solubility of the salt (pHmax) (68,69).

CHEMICAL INSTABILITY

Chemical instability in solid dosage forms is frequently aresult of interaction between the drug and one or more

OH O

OH

R2

OOH

OHHO

OHOH

OHHO R1-NH-R2 OH

OH

OH

HO

NR1

Glucose, aldhyde open chain form

OH

Glucose, cyclic form

OH OH

OH

-OH-

R2R2

OHOH

HO

NR1

-H+OH

OH

HO

NR1

R2

OHO

NR1

R2

OH

OH

HOOH

OH

HO

OH

OH

HO

Amadori Rearrangement imminium ionAmadori RearrangementProduct

Fig. 1 Maillard reaction withAmadori rearrangement ofsecondary amine drugs withreducing sugars, resulting in theformation of imminium ion, whichcan deprotonate to form anAmadori rearrangement product.


excipients or impurities in excipients. The most commonreactions observed in pharmaceuticals are hydrolysis, dehy-dration, isomerization, elimination, cyclization, oxidation,photodegradation and specific interactions with formulationcomponents (excipients and their impurities). The mainfactors that affect these reactions are temperature, pH,moisture in solids, relative humidity of the environment,presence of catalysts, light, oxygen, physical form, and par-ticle size of the drug and excipients (2).

A brief review of excipient synthesis, isolation, and/orpurification can give vital clues about their potential impu-rities and other characteristics that may pose problems inthe formulation (Table I). However, due to their proprietarynature, the availability of this information is difficult to comeby and restricted to informal vendor discussions and patentdatabases in most cases. Several examples of the presenceand implication of reactive impurities in pharmaceuticalexcipients are known in literature (2).

Drug-Excipient Interactions

Solid dosage forms are usually less stable than the activepharmaceutical ingredient (API). Excipients in the dosageform typically catalyze the degradation of susceptible APIs.In most chemical reactions that involve excipients or com-ponents in excipients, drug degradation rate is usually pro-portional to its dilution. This is reflective of the diffusioncontrolled reactions (Diffusion Controlled Reactions)wherein the drug particles are dispersed in the other solidcomponents of the formulation. Excipients can enhancedrug degradation rate through a chemical or a physicalinteractions. A chemical interaction refers to cases wherethe excipient reacts directly with the drug molecule, acts acatalyst for a chemical reaction that the drug molecule issusceptible to, or modifies the pH of the microenvironmentsuch that the rate of chemical reaction is enhanced. Aphysical interaction describes scenarios in which the excip-ient does not directly affect the chemical reaction but rathermodulate the physical state of the API such that rate ofchemical reactions is increased.

Chemical Interactions

Chemical interaction of drug and excipient can involvedirect reaction to form a covalent bond, catalysis, or pHmodification effects.

Direct Reaction of the Drug and Excipient. Direct interactionof drug and excipient takes place when a functional groupon the drug molecule is involved in reaction with a func-tional group on the excipient resulting in bond formationbetween the two molecules. The nucleophilic attack by theamine group of the drug molecule on the carbonyl group of

reducing sugar is a typical example of this direct drugexcipient reaction (70,71). The resulting hemiaminal inter-mediate is typically unstable and usually eliminates water toform imine or iminium ion. The reaction is referred to asMaillard reaction and is well known in food science litera-ture. There are many examples in the pharmaceutical liter-ature where amine drugs and lactose are involved in aMaillard reaction (53,7279). The imine resulting from theinitial reaction is in equilibrium with a glycosylamine (hemi-aminal) formed by the addition of a hydroxyl group on thesugar molecule to the imine (Fig. 1). This is usually followedby Amadori rearrangement and then subsequent decompo-sittion of the Amadori rearrangement product which leadsto multiple products such as carbonyl compounds, furans,amide derivatives of the drug, pyrroles and other heterocyles(53). Some of those products have yellowish brown colorand hence the Maillard reaction is known as the browningreaction. Primary aliphatic amines are the most reactive inthe Maillard reaction (7275). However, secondary aliphaticamines have also been reported to undergo the Maillardreaction (53,7678). Maillard reaction involving aminonitrogens in heterocyclic rings have not been reported inthe pharmaceutical literature.

Maillard reaction between proteins and reducing sugarswere also reported. The reaction involves condensation ofthe reducing sugar with the amino groups of the lysine andarginine residues in the protein to form glycosylamino deriv-atives. The glycosylamines may undergo rearrangement andfurther reaction to form multiple products. Aminocabonyladducts formation by Maillard reaction on multiple lysineand arginine residues were reported in a lypohilized glucoseformulation of the recombinant human relaxin (79).

Ester formation of hydroxyl containing drug moleculesrepresents another type of direct drug excipient reaction.The ester can be formed by the reaction of the hydroxylwith a carboxylic acid group on the excipient or by a trans-esterification reaction of the drug hydoxyl group with anester containing excipient. Reaction of carvedilol and 5-aminosalicylic acid with citric acid to form citrate esters inthe solid state has been reported (80,81). The octanoate anddecanoate esters of vitamin D3 were identified in a liquidformulation containing triglycrides (82). These esters areformed by a transesterification with the two major fatty acidesters (octanoate and decanoate) of the triglycerides presentin the formulation. Drugs with alcohol groups can alsoundergo transesterification with the esters preservatives,methyl and propyl parabens.

A similar reaction which results in amide formationinvolves the reaction between an amine drug and carboxylicacids or their esters. Amines are less reactive towards car-boxylic acids than alcohols (83). This was demonstrated bythe interaction of citric acid with carvedilol which has bothhydroxyl and amine groups (80). The higher concentrations


TableITh

eMetho

dof

Manufacture

ofCom

mon

PharmaceuticalExcip

ientsandTh

eirPo

tentiallyRe

activeIm

purities.Re

prod

uced

with

perm

issionfro

mNaranget

al.(2)

Exam

ples

ofexcip

ients

Metho

dof

manufacture

Potentiallyreactiveimpu

rities

Exam

ples

ofknow

nincompatibilities

Lactose

Lactoseisanaturaldisaccharid

econsistingof

galac

tose

andglucoseand

ispresentinthemilk

ofmostm

ammals.C

ommercia

lly,lactose

isprod

uced

from

thewheyof

cowsmilk,w

heybeingtheresid

ual

liquidof

themilk

followingcheese

andcaseinprod

uction.

Cow

smilk

contain

s4.4

5.2%

lactose

anditis38

%of

thetotalsolidcontento

fmilk

(32).

Lactosemay

contain

glucose,

furfu

raldehyde,

form

icacid,acetic

acidandpo

tentiallyother

aldehydes.

Maillardreactions,C

laissen-Schmidtcon

densationreactionofitsimpurity-

hydroxylm

ethyl-2-furfuraldehyde(127

),andcatalysisofhydrolysis

(88,92

).

Microcrystalline

cellulose

Microcrystallinecellulose

ismanufacturedby

thecontrolledhydrolysis,

with

dilute

mineralacid

solutions

of-cellulose,o

btain

edas

apu

lpfro

mfibrous

plantm

aterials.Followinghydrolysis,

thehydrocellulose

ispu

rifiedby

filtrationandtheaqueou

sslu

rryisspray-driedto

form

dry,po

rous

particle

sof

abroad-sizedistrib

ution(32).

Theimpuritiesinmicrocrysta

llinecellulose

are

glucose,formald

ehyde,nitratesandnitrites.

Water

sorptionresultin

ginincreasedhydrolysis(39),M

aillardreaction

with

resid

ualglucose

(169

),adsorptionofbasic

drugs(170

),andno

n-specific

incompatibilitiesdueto

hydrogen

bondingcapability

(171

).

Povido

neand

crospo

vi-

done

Pyrrolidon

eisprod

uced

byreactingbu

tyrolac

tone

with

ammon

ia.Th

isisfollowed

byavinylationreactioninwhich

pyrrolidon

eandacety-

lene

arereactedunderpressure.T

hemon

omer,vinylpyrrolidon

e,is

then

polymerize

dinthepresence

ofacombinationof

catalyststo

prod

ucepo

vido

ne.W

ater-in

solublecross-linkedPV

P(Crospovidon

e)ismanufacturedby

apo

lymeriza

tionprocesswhere

thecross-linkin

gagentisgenerated

insit

u(32).

Povido

neandcrospo

vido

necontain

significantlevelsof

peroxides.Po

vido

nemay

alsocontain

form

icacidand

form

aldehyde(124

).

Oxidationattribu

tableto

peroxides(114

),nucle

ophilic

additionto

aminoacidsandpeptides(172

),andhydrolysisof

sensitive

drugsdu

eto

moisture.

Hydroxyprop

ylcellulose

(HPC

)

HPC

isawater

solublecellulose

etherprod

uced

bythereactionof

cellulose

with

prop

yleneoxide(32).

HPC

may

contain

significantlevelsof

peroxides.

Oxidationof

sensitive

drugsdu

eto

resid

ualp

eroxides.

Croscarmellose

sodium

Toprod

ucecroscarm

ellose

sodium

,alkalicellulose

isprepared

byste

eping

cellulose,o

btain

edfro

mwoo

dpulpor

cotto

nfibers,insodium

hy-

droxidesolution.

Thealkali

cellulose

isthen

reactedwith

sodium

mon

ochloroacetateto

obtaincarboxym

ethylce

llulose

sodium

.Afterthe

substitutionreactioniscompleted

andall

ofthesodium

hydroxidehas

been

used,the

excesssodium

mon

ochloracetateslo

wlyhydrolyzes

togly

colic

acid.T

hegly

colic

acidchangesafewofthesodium

carboxy-

methylgroupsto

thefreeacidandcatalyz

estheform

ationofcrosslinks

toprod

ucecroscarm

ellose

sodium

.The

croscarm

ellose

sodium

isthen

extracted

with

aqueou

salcoh

olandanyremain

ingsodium

chlorideor

sodium

glycolateremoved.A

fterp

urification,croscarm

ellose

sodium

ofgreaterthan99

.5%

purityisob

tained.T

hecroscarm

ellose

sodium

may

bemilledto

breakthepo

lymer

fibersinto

shorterlengths

andhence

improveits

flow

prop

erties(32).

Mon

ochloroacetate,n

itriles,andnitra

tes.

Mon

ochloroacetate

canreactw

ithnucle

ophiles.

Weakly

basic

drugscancompete

with

thesodium

counterio

n,thus

getting

adsorbed

onthesurface

ofthedisin

tegrantp

articles

(173

,174

).Drugsaltform

conversio

nhasalsobeen

repo

rted(67).

Sodium

starch

glycolate

Sodium

starch

glycolateisasubstituted

andcrosslinkedderivativeof

potato

starch.Starchiscarboxym

ethylated

byreactingitwith

sodium

chloroacetateinan

alkaline

medium

followed

byneutralizationwith

citric,o

rsomeotheracid.C

ross

linkin

gmay

beachieved

byeither

physica

lmetho

dsor

chem

ically

byusingreagentssuch

asph

osph

orus

oxytrichlorideor

sodium

trimetapho

sphate.

Mon

ochloroacetate,n

itriles,andnitra

tesare

potentiallyreactiveimpu

rities.

Adsorptionof

weakly

basic

drugsandtheirsalts

dueto

electro

static

interactions

(175

,176

).In

addition,

theresid

ualm

onochloroacetate

may

undergoS N

2nucle

ophilic

reactions.

Starch

Starch

iscompo

sedof

amyloseandam

ylop

ectin,p

olym

ersof

glucose

connectedby

1,4glycosidiclinkages(in

contrastto

cellulose1

,4linkages).A

mylop

ectin

hasoccasio

nalb

ranchchain

sconnectedby

1,6glycosidiclinkages.Starch

isextra

cted

from

plantsou

rces

through

Starch

may

contain

form

aldehyde,

nitritesandnitra

tes.

Term

inalald

ehydes

insta

rchreactw

iththehydrazinemoietyofhydral-

azineHCl(13

5).Starchmay

alsobe

involve

dinmoistu

re-m

ediated

reactions,m

ayadsorb

drugs,andmay

reactw

ithform

aldehyderesultin

ginreducedfunctionality

asadisintegrant(13

0,17

7).


TableI(con

tinued)

Exam

ples

ofexcip

ients

Metho

dof

manufacture


rities

Exam

ples

ofknow

nincompatibilities

asequ

ence

ofprocessin

gstepsinvolvingcoarse

milling,repeated

water

washing,w

etsie

ving,and

centrifugalseparation.

Thewet

starch

obtained

from

theseprocessesisd

riedandmille

dbefore

usein

pharmaceuticalform

ulations.

Pregelatinize

dsta

rchisasta

rchthathasbeen

chem

ically

and/or

mechan-

ically

processedto

ruptureall

orpartofthestarch

granules

andso

render

thesta

rchflowableanddirectlycompressib

le.Partially

pregela-

tinize

dgrades

arealsocommercially

available.

Stearic

acid

Stearic

acidismade

viahydrolysisoffat

bycontinuo

usexpo

sure

toa

counter-currentstre

amofhigh-te

mperature

water

andfat

inahigh-

pressure

cham

ber.Th

eresultant

mixtureispurifiedby

vacuum

-steam

distillationandthedistillatesthen

separatedusingselective

solve

nts.

Stearic

acid

isincompatiblewith

mostm

etalhydroxides

andmay

beincompatiblewith

oxidizing

agents.Insolub

lestearatesareform

edwith

manymetals;o

intm

entb

ases

madewith

stearic

acidmay

show

evidence

ofdrying

outo

rlumpiness

dueto

such

areactionwhen

compo

undedwith

zincor

calcium

salts.A

numberof

differential

scanning

calorim

etry

stud

ieshave

investigated

thecompatibilityof

stearic

acidwith

drugs.Althou

ghsuch

laboratorystud

ieshave

sug-

gested

incompatibilities,

e.g.,n

aproxen,

they

may

notn

ecessarilybe

applica

bleto

form

ulated

prod

ucts.S

tearicacidhasbeen

repo

rtedto

causepitting

inthefilm

-coatingof

tabletscoated

usingan

aqueou

sfilm

-coatingtechniqu

e;thepitting

was

foundto

beafunctionof

the

meltingpo

into

fthe

stearic

acid.Stearicacidcouldaffectthehydrolysis

rate

ofAP

Iifthe

degradationispH

depend

ent.Itcouldalsopo

ten-

tially

reactw

ithan

APIcon

tainingaprimaryam

ineto

form

astearoyl

derivative(178

,179

).

Stearic

acidmay

alsobe

made

viahydrogenationof

cotto

nseedand

othervegetableoils;

bythehydrogenationandsubsequent

sapo

nifi-

cationof

oleicfollowed

byrecrystallizationfro

malc

ohol;and

from

ediblefatsandoilsby

boilin

gwith

NaO

H,separatinganyglycerinand

decompo

singtheresulting

soap

with

sulfuric

orhydrochloricacid.

Thestearic

acidisthen

subsequentlyseparatedfro

manyoleicacidby

coldexpressio

n.Magnesiu

mstearate

Magnesiu

mstearate

isprepared

either

bychem

icalreactionofaqueou

ssolutionof

magnesiu

mchlorid

ewith

sodium

stearate,o

rby

the

interactionof

magnesiu

moxide,

hydroxideor

carbon

atewith

stearic

acidat

elevated

temperatures.

Magnesiu

moxideisaknow

nreactive

impu

rity.

Magnesiu

mstearate

canform

hydrates

with

water

andexistsinfour

hydrationstates

mon

o,di

andtrihydrates

(180

).MgO

impu

rityis

know

nto

reactw

ithibup

rofen(181

).Inaddition,magnesiu

mstearate

provides

abasic

pHenvironm

enta

ndmay

accelerate

hydrolytic

degradation(182

).Th

emagnesiu

mmetalmay

alsocausechelation-

indu

ceddegradation(183

).

Therawmaterialsu

sedinmanufacturingofmagnesium

stearatearerefined

fattyacids,which

isamixtureofpalmitic

andste

aricacidwith

certain

specifications.A

fattyacidsplitting(hydrolysis)

processtakesplacefirst,

where

glycerin

andfattyacidsareseparated.

Thefattyacidsarethen

furth

errefined

toyie

ldtallowacid.M

agnesium

stearatecanbe

prepared

throughtwoprocesses:1)

Fusio

n-simpleacidbase

interactionbetween

tallowacidandmagnesium

hydroxide;or

2)Sapo

nification-tallow

acidis

saponifiedfirstwith

sodium

hydroxide,makingasodium

tallowate(salt),


of the carvedilol citrate esters compared to citric acid amidesindicate that the known higher reactivity of alcohols is alsomanifested in solid dosage forms. Amines also have thepotential to react with esters to form amides. Triacetin, acommonly used plasticizer in film coating formulations, isthe triacetate ester of glycerol. Triacetin in the tablet filmcoat can potentially interact with amine compounds to formthe acetamide derivative of the drug (84).

Ester formation can also take place by the reaction ofdrug molecules with carboxylic acid moiety and the hydrox-yl groups of an excipient. Cetrizine sorbitol and glycerolesters were identified in oral liquid formulation of an anti-allergic drug cetrizine, which were formed by the reaction ofcertrizine with glycerol and sorbitol in the formulation (85).

Drug interaction involving the maleate counter ion in aMichael addition reaction has been reported. Michael ad-dition is a nucleophilic addition reaction of a nucleophile,such as a carbanion or a primary amine, to the ,-unsatu-rated carbonyl compounds (Fig. 2). Michael addition reac-tion of phenylephrine hydrochloride with the maleatecounter ion of dexbrompheniramine maleate was observedin common cold solid dosage forms (86). The nucleophilewas the secondary amine of the phenylephrine which attacksthe olefinic bond in the , position of the carboxylategroup of the maleate. A similar reaction of the primaryamine of seproxetine with its maleate counter ion wasobserved in capsule dosage form of seproxetine maleate(87).

Catalysis of Drug Degradation Reaction by an Excipient. In thisscenario, the excipient acts a catalyst to increase degrada-tion rate of the drug molecule but does not form lastingbond with the drug. Per definition of a catalyst, the exci-pients role is to reduce activation energy of the reaction butis left unchanged at the end of the reaction. Solid statereactions in which excipients catalyze the degradationof a drug are a function of diffusion controlled collisionsof reacting species and the catalyst (Diffusion Con-trolled Reactions), which can be facilitated by plasti-cization by adsorbed water (Reactions Limited byAmount of Adsorbed Water and Role of Water (Mois-ture)), and are generally initiated at the crystal imperfec-tions that offer greater molecular mobility (CrystalImperfections as Reaction Sites). These kinetic factorsadd to the difficulty in elucidating reaction mechanismsin solid state. Degradation mechanisms observed in solu-tion state are in many cases applicable to degradation inthe solid state, although kinetics are usually different.Since the solution system is simpler and lacks the complex-ity of the solid system, it is possible to decouple chemicaland physical mechanisms that confound solid state stabil-ity studies. Solution studies are therefore more usefulwhen the goal is to study underlying mechanisms forTa

bleI(con

tinued)

Exam

ples

ofexcip

ients

Metho

dof

manufacture


rities

Exam

ples

ofknow

nincompatibilities

then

magnesium

sulfateisaddedto

thesodium

tallowsolution,followed

bypH

adjustm

ent,dilutionwith

water,w

ashanddry.

Silicon

dioxide

Colloidalsilica

isprepared

bypartialneutralizationofan

alkali-silicate

solution,which

leadstotheseparationofsilica

nucle

i.Size

ofthecolloidal

silica

particle

sdepends

ontheselectionofpH

andprocessingconditio

ns.

ApH

stabilized

colloidalsuspensio

nisthen

concentratedby

evaporation

oftheliquidphase.

Form

ationofsilica

gelorp

recip

itatedsilica

isassociatedwith

theuseofacidicor

slightly

basic

pH,respective

ly,causing

fusio

nor

grow

thof

silica

particle

s.

May

contain

heavymetalimpu

rities.

May

actasaLewisacid

underanhydrou

scond

ition

sandmay

adsorb

drugs(184

,185

).


chemical reactions. For this reason, chemical stability isusually assessed first in solution studies to gain the under-standing that supports subsequent solids state studies.

Nucleophilic catalysis by polyhydroxy excipients hasbeen reported for ester hydrolysis. For example, hydrolysisrate of p-nitrophenyl esters in neutral to alkaline aqueoussolutions was increased in the presence of dextrose, sucrose,sorbitol, and mannitol in a concentration dependent man-ner (88). Despite the high acidic pKa values for the polyhy-droxy excipients used in the study, kinetic analysis showedthat the catalytic species is the alkoxy anion. Thus, thecatalytic effect of the polyhydric alcohol increased by theincrease in solution pH and the associated increase in thealkoxy anion concentration. Degradation of -lactam anti-biotics was similarly enhanced in aqueous solutions of car-bohydrates and polyhydric alcohols. Degradation ofampicillin in alkaline solutions was accelerated by glucoseand dextrans (89). The first step of the reaction involves anucleophilic attack by the alkoxy anion of the sugar on the-lactam amide bond, eventually resulting in pencilloic acidand a piperazinedione derivative as the final products. Su-crose catalyzed hydrolysis of bezylpenicillin to bezylpenicil-loic acid was also attributed to the nucleophilic mechanism(90). Cephalosporin undergoes a similar carbohydrate andpolyhydric alcohol catalyzed reaction. The degradation rate

of cephaloridine, cepahlothin, and cefazoline increased lin-early with concentration of the polyhydric alcohol in solu-tion (91). This rate accelerating effect by glucose oncephalosporin hydrolysis was directly proportional to thehydroxide ion concentration in the 6.5 to 11 pH range.The pH dependence was attributed to the increased fractionof the alkoxy anion in the solution as the pH increased.

An understanding of potential reaction pathways andkinetics in the liquid state can help delineate the stabilityobserved in solid state. For example, hydrolysis rate of themethyl ester prodrug DMP-754 was substantially enhancedin binary blends with anhydrous lactose compared to theAPI. Since lactose also showed a concentration-dependentincrease in rate of methyl ester hydrolysis in solution, anucleophilic catalysis mechanism was proposed for the effectof lactose (92).

While kinetic analysis in solution studies suggested thatthe nucleophilic catalysis of ester and amide hydrolysis bypolyhydroxy compounds is attributed to the more nucleo-philic alkoxy anion (RO-) rather than the less nucleophilicunionized hydroxyl group (ROH), studies showing furtherinsight into the nucleophilic mechanism have not beenreported. Some reports suggested that the nucleophilicmechanism proceeds via nucleophilic attack by the alkoxyion on the ester or the amide resulting in the formation of

O OH

H H

O

OH

OHRNH2 OH

OHRNH

+O

O O

Maleic acid

O

OH

O

OHRNH

1,4 addition product

Fig. 2 Michael addition reactionof primary amines with maleicacid. Michael addition is anucleophilic addition reaction of anucleophile, such as a carbanionor a primary amine, to the,-unsaturated carbonylcompounds.


sugar ester intermediate that rapidly hydrolyzes to form theacid. Such sugar esters of pencilloic acids were indeedidentified for ampicillin and benzylpenicillin (89,90). How-ever, other studies did not report the existence of suchintermediate esters. In these cases, kinetically indistinguish-able mechanisms involving the polyhydroxy excipient andthe hydroxide ion are also plausible, such as the sugarhydroxyl group facilitating the attack of the hydroxide ionon the ester or the amide (88).

Nucleophilic catalysis is also proposed for the rate accel-erating effect of hydroxypropyl methycellulsoe (HPMC) onthe degradation of an oxadiazole derivative in spray drieddispersions (93). The rate of degradation in the HPMC soliddispersion was higher than in the API or PVP-VA soliddispersion despite the higher moisture uptake by PVP-VAsolid dispersion compared to HPMC. The nucleophilic at-tack by the hydroxyl groups of HPMC on the methinecarbon of the oxadiazole to form a stable tetrahedral inter-mediate was proposed as the mechanism for HPMC catal-ysis. PVP-VA, which lacks the presence of a nucleophile,resulted in a more stable solid dispersion.

In addition to nucleophilic catalysis, reducing sugars havebeen reported to facilitate amide hydrolysis by another mech-anism. Hydrolysis of Trp28Ser29 peptide bond on the B-chainof the protein hormone human relaxin was observed in ly-ophilized solid formulations containing glucose (79). Sinceother lyophilized formulations with mannitol or trehalosedid not exhibit the same reaction, it can be inferred that thecatalysis mechanism is not due to the hydroxyl groups whichare present on all three excipients. Glucose, however, is theonly reducing sugar among the three with a carbonyl group. Amechanism involving initial hemiacetal formation betweenthe serine hydroxyl and glucose carbonyl group was proposed.The hemiactal subsequently forms a cyclic intermediate. Hy-drolysis of the imine bond in this cyclic intermediate yields the

peptide bond hydrolysis products. This mechanism can po-tentially also result in the the hydrolysis of the amides of other2-amino alcohols by reducing sugars (Fig. 3).

pH Effect of Excipients. Degradation rate of many drug mol-ecules in solution is a function of solution pH. For thosecompounds, degradation rate in the solid dosage form is alsoaffected by the microenvironmental pH (94). The microenvir-onmental pH of a formulation is determined by the activeingredient and the excipients in the formulation. Excipientswith inonizable functional groups act as pH modifiers andmay impact formulation pH (68). These excipients includedisintegrants (croscarmellose sodium and sodium starch gly-colate), fillers (calcium carbonate and dicalcium phosphate),and lubricants (magnesium stearate and stearic acid). Thedecrease in microenvironmental pH of solid formulations byenteric coating polymers was also reported (95,96). In certaincases, pHmodifiers are intentionally added in the formulationto modulate the pH and optimize dissolution rate. Organicacids such as citric, tartaric, and succinic acid have been usedin immediate and controlled release dosage forms of weaklybasic drugs to enhance their dissolution rate (97100).

Acceleration of degradation rate by pH modifying exci-pients has been reported (101). In these cases, excipientsresult in enhancement of a degradation pathway inherentto the drug molecule by alteration of the microenvironmen-tal pH to a region on the pH stability profile where degra-dation rate is faster. The counter ion of the salt form alsoimpacts microenvironmental pH. For basic drugs, counterions derived from conjugate acids with higher pKa tend tohave higher microenvironmental pH. Thus, the acetate salt(pKa of acetic acid, ~4.76) of an amidine derivative wasfound to have higher microenvironmental pH than themesylate salt (pKa of methanesulfonic acid, 1.2), whichincreased the rate of drug degradation (102).

HO CH2OH +

OHC

R2

HO O CHR2

O-H2OR1 C

HN CH2

2 +C R2H

R1 CHN

OCH2

CH2

HemiacetalR1 C N CH2

CH2O

O2

s

Reducing sugar2-amino alcohol amide

min

e hy

dro

lysis

I

CR CH

CHR2

O OH2N CH2

CH2HO

CH

HCR2

OHemiacetal hydrolysis Ester hydrolysisOHCR1

H2N CH2

CH2O2-amino alcohol

+

H2N CH2

CH2

+O

CR1

OH

O

C

O

R2H

Reducing sugar

Fig. 3 Mechanism of reducingsugar catalysis of amino alcoholamide hydrolysis. Themechanism involves initialhemiacetal formation betweenthe hydroxyl and reducing sugarcarbonyl group.


Physical Interactions That Lead to Chemical Instability

It is a common experience that drug molecules with inher-ent instability exhibit more degradation in the solid dosageforms compared to the API. The degradation products areusually the same as the API, but the rate of their formation issignificantly higher than in the API. As discussed above, thiscould be attributed in some cases to chemical catalysis of thedegradation by the excipients or due to their effect on themicroenvironmental pH. However, excipients can also ac-celerate drug degradation by a non-chemical mechanism.

Drug degradation in the solid state usually takes place indisordered regions, in crystal defects, or on the surface of thecrystals (Crystal Imperfections as Reaction Sites). Thehigher molecular mobility in those disordered regions resultsin faster degradation rate than the crystal lattice. In addi-tion, the disordered regions have higher water content dueto absorbed water, which further enhances degradation ratein those less ordered regions for reactions in which wateracts as a reactant (e.g. hydrolysis). Mechanical energy expe-rienced by solid formulations during processing can result inthe disruption of API crystallinity and the formation ofamorphous dispersion of a small fraction of the drug sub-stance in amorphous excipients (103106). The exposure ofAPI to shear forces during processing can be enhanced inthe presence of abrasive excipients, such as colloidal silicondioxide (as discussed in Form Changes). Although thefraction of the drug in amorphous state may be small,sometimes even below detectable limits of common analyt-ical instrumentation, this leads to a measurable impact onthe stability of the dosage form since the acceptable specifi-cation limit of a degradant in a drug product is typically verylow.

Drug Interactions with Excipient Impurities

Mechanistic studies on drug degradation in solid dosageforms increasingly highlight the importance of drug inter-actions with impurities in excipients, rather than the exci-pients themselves. Predominant among these reactions aredrug reactions with peroxides, aldehydes and acids, andmetals in the dosage form, which are often present in exci-pients as impurities.

Peroxides

Peroxides are very reactive and they tend to form N-oxidesand other oxidative impurities. Peroxides in solid dosageforms can exist as either alkyl peroxides (ROOR) or hydro-peroxides (ROOH). Both these species are highly labile,reacting directly or breaking down to hydroxyl (HO)and/or alkoxyl (RO) radicals, which are themselves highlyoxidizing species (107).

A general free-radical mechanism of peroxide genera-tion involves homolytic cleavage of the C-H bond nextto a heteroatom, followed by the addition of oxygenwhich leads to peroxy radical formation (ROO) (98).The peroxy radical can then participate in an autocata-lytic cycle by abstraction of hydrogen atom from anotherreactant to form a hydroperoxide, while generating an-other carbon free radical (108). The O-O bond in per-oxides is particularly weak and can cleave to form alkoxy(RO) and hydroxy (OH) free radicals (98). Peroxidesand free radicals can also lead to the formation of otherreactive oxygen species, such as superoxide anion (O2),hydrogen peroxide (H2O2), and organic hydroperoxides(ROOH) (98).

Hydroperoxide (HPO) is a common trace level impurityobserved in excipients such as polyethylene glycol (PEG),povidone, hydroxypropyl cellulose, and polysorbate (109).For example, the formation of N-oxide derivative of ralox-ifene hydrochloride was traced to residual peroxides inpovidone and crospovidone (110). While crospovidone andpovidone could be the source of residual peroxide, exci-pients such as croscarmellose sodium can act a scavengerfor peroxide. Thus, tablet formulation of a compound con-taining piperazine ring showed reduced amount of N-oxidedegradant when croscarmellose sodium was used as a dis-integrant in addition to crospovidone (111). Peroxide medi-ated drug degradation reactions can be investigated duringdrug-excipient compatibility study where, in addition toresidual levels of reactive species, other factors such as drugloading, effects of temperature and humidity, and micro-environmental pH can be studied (112,113).

Control Strategy for Peroxides

Peroxides are highly reactive species and trace levels ofperoxides are found in commonly used excipients such asPEG, povidone, and crospovidone. In studies where perox-ides in excipients were implicated in the oxidative degrada-tion of drugs in their formulations, control of initial peroxideconcentration was recommended for drug product stabili-zation (98,114116). In line with these recommendations,the European Pharmacopoeia does not allow more than400 ppm of peroxides in crospovidone. Although the cro-spovidone monograph in USP/NF still has no official limit,some excipient vendors provide peroxide free crospovi-done, which is produced to meet the PhEur or tighter limit.The compendial limits on peroxide level may or may not besufficient to assure satisfactory product stability. This isbecause peroxide levels often increase in excipients duringstorage (117), which was observed for povidone (118) andPEG (119).

The most prudent approach is to conduct a stability studyusing excipient lots representing a range of concentrations


or spiking one lot of excipient with different amount ofperoxide. For example, raloxifene hydrochloride tabletswere spiked with different quantities of hydrogen peroxideequivalent to 200 to 800 ppm peroxides over the amountalready present in povidone and crospovidone. Based on theformation of the degradant product, a rational limit ofperoxide was proposed for these two excipients (110).

Treatment with silicates reduced peroxide levels in exci-pients (118). Treatment with silicates was shown to not affectthe functionality of the povidone. This approach can furtherbe combined with incorporating antioxidants in a formula-tion. With respect to antioxidants, water soluble antioxidantswere more effective than water insoluble ones (Fig. 4) (118).Other approaches for reducing peroxides from excipientsinclude the use of enzymes (120), metals (120), or other addi-tives (121); chemical modification of the cross-linker (108);supercritical fluid extraction (122); and vacuum drying (123).

The control strategy for peroxides starts with developinga sensitive analytical method not only to monitor their initiallevels in the excipients, but also in the dosage forms. Using asensitive method, excipients or excipient lots with low HPOscan be selected. The analytical method can be furtherleveraged to select a manufacturing process that minimizeHPO levels to improve product stability (109).

Aldehydes and Acids

Formic acid and/or formaldehyde can be present in theexcipients as trace impurities. Drugs with amine group orhydroxyl group can react with formic acid or formate im-purity to form amides or esters, respectively (Fig. 5) (124).Formaldehyde is known to react with amine drugs to formN-formyl adducts (hemi-aminals) that can further react to

form dimer(s). Adefovir is known to react with formaldehydeto produce the reactive imine which can further undergonucleophilic addition with another amine molecule to forma dimer (125). Nassar et al., showed that BMS-204352formed an adduct (hemiaminal) with formaldehyde impurityin the solubilizers, polysorbate 80 and PEG 300 (126). Theimpurity of lactose, 5-hydroxylmethyl-2-furfuraldehyde, hasbeen reported to react with the carbonyl (ketone) of halo-peridol to form a condensation product (127). In addition,aldehyde impurities in excipients are commonly known toaffect the disintegration of capsule formulations by chemicalcrosslinking of gelatin (57). Capsules on storage show slowerdissolution if any aldehyde contaminated excipients are usedin a formulation.

Formaldehyde can also be generated as a degradant of adrug substance. For example, degradation of hydrochloro-thiazide can generate formaldehyde (128). Formaldehydecan cross-link not only gelatin capsule shell, but also exci-pients. Hydrochlorothiazide (HCTZ) bead formulationswith or without sodium starch glycolate (Primojel) as dis-integrant showed different dissolution stability upon expo-sure to humid environment. One with Primojel showedslower dissolution compared to one without it (129). Theamount of formaldehyde detected in Primojel containingHCTZ formulation was less compared to one without itbecause formladehyde probably cross-linked Primojel andreduced its effectiveness as a disintegrant (129).

Moisture was shown to play an important role in disso-lution instability of hydrochlorothiazide (HCTZ) capsules.HCTZ capsule formulation containing Fast-Flo lactose,hydrous lactose, and anhydrous lactose showed 45, 25,and 10% slower dissolution, respectively, after 6 monthstorage at 50C. The slower dissolution was attributed to

140

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Fig. 4 Relative effectiveness ofantioxidants in reducing peroxideconcentration in povidone and itsdependence on humidity at 40C(118). Water soluble antioxidantswere more effective than waterinsoluble ones. Abbreviations:BHA, butylated hydroxy anisole;BHT, butylated hydroxy toluene;AA, ascorbic acid; PG, propylgallate; and SS, sodium sulfite.The results marked with an astrisk(*) were statistically significantly(p < 0.05) different from thesample without an antioxidantusing a two-tailed t-test forcomparing two sample meanswith the assumption of unequalvariances. Reproduced with per-mission from Narang et al. (118)


degradation of HCTZ from moisture released fromexcipients and capsule shell. Anhydrous lactose containsleast amount of moisture and capsules containing anhy-drous lactose showed best dissolution stability. As men-tioned above, formaldehyde was one of the degradantswhich reacted with a disintegrant such as sodium starchglycolate (Explotab), croscarmellose sodium (Ac-Di-Sol), or corn starch. However, when crospovidonewas used as disintegrant, the dissolution stability of thecapsules improved since crospovidone does not reactwith formaldehyde and has good moisture scavengingability (130).

Antioxidants are commonly utilized for stabilization ofsusceptible drug products. Although such functional exci-pients, such as antioxidants, are generally assumed to bechemically pure, sometimes trace impurities in such exci-pients can lead to drug product instability. An example ofsuch a scenario was encountered when commercial tabletsof a drug product that contained BHA (as per the packageinsert) as an antioxidant were encapsulated in hard gelatincapsules for a blinding purpose for clinical studies (131).These capsules were put on long-term stability at roomtemperature to ascertain that the blinding process itself didnot change chemical or dissolution instability for the blindedproduct. During the stability evaluation, dissolution slow-down was observed for some of the batches. Investigationsinto this phenomenon indicated no loss of potency and fastdissolution of encapsulated tablets, i.e., when tablets fromslow dissolving capsule lots were transferred into fresh cap-sule shells, faster dissolution was observed. Also, when new

tablets were encapsulated in aged capsule shells, slowerdissolution was observed. These implicated the capsule shelldisintergation/dissolution as the cause of slowdown in dis-solution. When the tablets from slow dissolving capsuleshells were analyzed using HPLC, a peak for BHT alongwith the BHA peak was observed. This peak was muchsmaller in aged, slow-dissolving capsule lots. BHT can de-grade into 2, 6-di-tert-butyl-4-hydroxy-benzaldehyde. It washypothesized that this aldehyde degradant of BHT cross-linked gelatin capsule shells, causing the slowdown in disso-lution of capsules. Importantly, BHT was not added to thedrug product and was most likely present as a trace impu-rity, in BHA.

PEG is a commonly used plasticizer in coating materials.At elevated temperature and humidity it can generate form-aldehyde. The oxidative degradation of PEG can result inthe generation of formaldehyde and formic acid (132). Bothformaldehyde and formic acid reacted with varenicline, asmoking cessation drug, to produce two separate degradants(132). Formaldehyde adduct was also observed for irbesar-tan tablets coated with HPMC-based formulation at anelevated temperature storage (133). PEG in the coatingformulation was identified as a source of formaldehyde.

There are instances where reducing sugar as an impurityin commonly used excipients can create an instability for theproduct. Such instance was reported for lyophilized productof cyclic heptapeptide (134), where reducing sugar impuri-ties in mannitol acted as an oxidizing agent and causedinstability for the product. In the case of starch, the terminalglucose was reported to have reacted with hydralazine in theformulation (135). For oral ready to use liquid formulation,sucrose is most commonly used sweetener. During the de-velopment of entecavir ready to use liquid formulation, itwas noted that a prototype formulation containing sucroseas a sweetener was degrading more at pH 4 than pH 6 or 7.Similar trend was also observed for two other guanine-basedantivirals, acyclovir and lobucavir. LC/MS analysis of solu-tion showed isomeric adducts of the drugs and reducingsugars. Sucrose, a disaccharide and non-reducing sugarwas the sources of monosaccharides. It was proposed thatmain cause of degradation was nucleophilic addition of theprimary amine group of the drugs to the carbonyl group offructose and glucose. The increased degradation at pH 4was due to more sucrose degradation generating more glu-cose and fructose at pH 4 compared to pH 6 or 7 (136).

Formic acid was observed in coating dispersions contain-ing PEG (137). Formyl content of the drug product increasesupon exposure to high temperature and humidity condi-tions. This is attributed to the degradation of polyethyleneglycol (138142). Formation of formyl species in the combi-nation of PEG and PVA was higher than PEG alone,indicating an effect of PVA increasing the rate of formationof formic acid in PEG (143). The formic acid present in or

Fig. 5 Reactions of drugs with amine or hydroxyl functional groups withformaldehyde and formic acid, or formates, resulting in the formation ofcorresponding adducts. Drugs with amine group or hydroxyl group uponreaction with formic acid or formate impurity to form amides or esters,respectively.


generated from PEG can exist as several species in thedosage form. Among the species that may be present arefree formic acid, formyl ester of polyethylene glycol, formylester of the hydroxyl groups in the polyvinyl alcohol, andpossibly other unknown species. The type and relative pro-portion of formyl species are unknown since the develop-ment of analytical methods for the separate quantitation ofthe different formyl and acetyl species is challenging (124).The formyl species detection methods usually require deriv-atization of the formyl species to an ester followed by highperformance liquid chromatography (HPLC) or gas chro-matography (GC) separation and detection. These methodsare non-specific with respect to type and relative proportionof formyl species present in the starting materials.

Formic acid-induced drug instability in the formulationshas been reported. Waterman et al. observed N-formylationand N-methylation of the secondary amine experimentalcompound varenicline, which were ascribed to the presenceof formaldehyde and formic acid in the formulation (132).The formic acid was generated in the formulation byoxidative degradation of the PEG. The authors proposedthe use of oxygen scavengers and the use of antioxidantsin the coating to prevent PEG degradation and improvedrug stability.

Fukuyama et al. observed the optical isomerization of anexperimental compound (FK480) at an asymmetric carbonlinking the pyrrolobenzodiazepine ring to another heterocy-clic ring through an amide bond (144). The compound wasformulated in a soft gelatin capsule formulation in a mixtureof PEG 400 and glycerol. The authors noted that thedegradation reaction was accelerated by the formic acid inthe formulation and was retarded by the addition of aminoacids to the solution.

Nishikawa and Fujii noted nonspecific degradation of atertiary amine antifungal compound, miconazole, in aliquid formulation of hydrogenated castor oil and lacticacid (145). The degradation was attributed to the gener-ation of hydroperoxides, formaldehyde, and formic acidfrom the hydrogenated castor oil on stability. The degra-dation could be prevented by nitrogen blanketing and theaddition of hydroxyl radical scavengers such as potassiumiodide and thiourea.

Control Strategy for Aldehydes and Acids

Since formaldehyde is very reactive, its presence in the exci-pients should be tested routinely (57). For capsule dosageforms, the dissolution should be conducted without enzymesas well as with enzymes. Normally, pepsin is used at pH 1.2and pancreatin at pH 7.2, representing gastric and intestinalenvironment, respectively. Based on the dissolution data andother biopharmaceutical properties of a molecule an in vivostudy may be needed. For example, using gamma

scintigraphy, it was shown that rupture of severely cross-linked amoxicillin was delayed in the GI tract, but overallexposure was not affected (58). Another approach is to useHPMC-based capsule shells, which show similar performanceto gelatin capsule shells in terms of handling on capsulemachines and also their in vitro performance such as disinte-gration and dissolution (146,147). Some in vivo studies con-cluded that switching from gelatin-based capsule shells toHPMC-based capsule shell should not have any adverse im-pact on the bioavailability of the active ingredient (148,149).

A common approach is to avoid excipients which maydegrade into more reactive species such as reducing sugars.For example, replacement of sucrose, a non-reducing sugarwith a potential to generate reducing sugar, with maltitol, analternate sweetener without any liability to generate reduc-ing sugars improved the stability of guanine-based antivirals(136). The free aldehyde or ketone group in maltitol pre-cursors is reduced to a hydroxyl group after the hydrogena-tion process making maltitol less susceptible to nucleophilicaddition (136). For coating, PEG-free coating material canbe used or even reduced amount of PEG can minimize thestability problem (132). Alternatively, PEG impact can beminimized by inclusion of antioxidants such as BHA.

Packaging modifications that can improve drug productstability include the use of bottles which minimize permeationof oxygen from the atmosphere or canisters which can absorboxygen. Reducing moisture in the packages can also play acritical role. This can be achieved by appropriate selection ofpackaging components including types of bottles, head space,and number of desiccants inside the bottles. Instead of makingthese decisions on trial and error basis, they should be madeusing sound scientific rationale (47). This involves consideringthe initial moisture content of the excipients in the dosageform, moisture exchange based on a vapor moisture transferrate (MVTR), and equilibrium between drug product anddesiccants based on their moisture isotherm to provide relativehumidity within the packaging (47).

Metals

Safety of drug products is a major concern of regulatoryauthorities worldwide. This concern is reflected in numberof guidance documents dealing with impurities, trace met-als, and residual solvents (150152) For safety reasons, re-sidual amounts of metal catalysts or metal reagent is tightlycontrolled in drug substance and excipients based on regu-latory guidances (153,154). Therefore, there are very fewreported cases in the literature where drug product degra-dation was caused by a metallic impurity.

Antioxidants are commonly added in formulations toprevent formation of oxidative degradants. Interestingly,the metallic impurity in antioxidants was linked to acceler-ation of formation of the degradants (155). Similarly, the


source of iron in iron-mediated photodegradation of a mod-el drug was the buffer salt used in the formulation (156).

Control Strategy for Metal Ions

Depending on the degradation pathway of the molecule,stricter limits on metal ion content in excipients may beneeded. The tolerable limits can be identified by spikingthe drug substance or an excipient with metal ions andconducting an accelerated stability study (155). For a drugmolecule susceptible to metal ion catalyzed degradation,instead of using metallic stearate as a lubricant, stearic acidshould be used as a lubricant. Higher concentration ofstearic acid may be needed to obtain optimum lubrication(157).

PROSPECTIVE STABILITY ASSESSMENT

Prediction of drug product stability is an urgent need inpharmaceutical development not only to select the best pathforward in the selection of formulation composition, manu-facturing process, and packaging components for clinicaldevelopment and commercialization, but also for regulatoryfilings to justify proposed shelf life with limited data avail-able at recommended and accelerated storage conditions.

Excipient Compatibility Studies and its Limitations

Significant drug-excipient incompatibilities are routinelysought to be prospectively identified in a series of screeningstudies that are broadly categorized as compatibility studies.These studies are designed to identify significant changes ordrug degradation based on standard protocols and/or exist-ing knowledge on potential degradation pathways or incom-patibilities (2). Accordingly, compatibility studies on newmolecular entities invariably start with evaluation of existinginformation and paper chemistry of the drug candidate toidentify soft spots and potential degradation pathways/instabilities in the molecule. Presence of reactive or unstablefunctional groups, pKa value, outcome of forced degrada-tion studies, and known reactivities of similar compoundsprovide useful information for the selection of excipients. Inaddition, computational programs such as CAMEO,SPARTAN, EPWIN, and Pharm D3 and internaldatabases can help predict potential degradation pathways.

Design of compatibility studies might involve the use ofmixtures of drug with one or more excipients (2). Compat-ibility studies are often carried out at high dilution of drug inthe excipient to increase the proportion of reacting species,if contributed by the excipient, and increase the its diffusivetransport to dispersed drug particles (Diffusion ControlledReactions). Since physical mechanisms of instability in solid

mixtures include the proximity and surface area of contactbetween drug and excipients, compatibility studies aresometimes carried out using compacted mixture of a drugand an excipient. These mixtures may be equilibrated atdifferent stress conditions as physical mixtures per se or aftercompaction. Often water and other potentiators such aslight and hydrogen peroxide are included to evaluate theirrole in accelerating drug-excipient interactions.

Physical observation of study samples forms the initialbasis of excipient compatibility assessment. For example,physical instability evident in change in color, odor, flowproperties (e.g., aggregation of the powder mixture), or phys-ical state (e.g., deliquescence) are

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