DRUG–EXCIPIENT INTERACTIONS

Excipients are included in dosage forms to aidmanufacture, administration or absorption.

Other reasons for inclusion concern product differ-entiation, appearance enhancement or retention ofquality.1 They rarely, if ever, possess pharmacologicalactivity and are accordingly loosely categorized as‘inert.’ However, excipients can initiate, propagate orparticipate in chemical or physical interactions withan active, possibly leading to compromised quality orperformance of the medication. Chemical interactioncan lead to degradation of the active ingredient,thereby reducing the amount available for thera-peutic effect; reaction products may compromisesafety or tolerance. Physical interactions can affectrate of dissolution, uniformity of dose or ease ofadministration. Understanding the chemical andphysical nature of excipients, the impurities orresidues associated with them and how they mayinteract with other materials, or with each other,forewarns the pharmaceutical technologist of possi-bilities for undesirable developments.

General considerationsExcipients may have functional groups that interactdirectly with active pharmaceutical ingredients.Alternatively, they may contain impurities orresidues, or form degradation products that in turncause decomposition of the drug substance.

Excipients can be a source of microbial contami-nation. They can also cause unwanted effects such as

irritation of the skin or mucosal surfaces, sensitizationreactions or adversely affect appearance ororganoleptic properties. However, such effects arenot usually a consequence of drug–excipient interac-tion per se, so are not considered in this review.

Modes of drug decomposition Medicinal agents invariably have structural featuresthat interact with receptors or facilitate metabolichandling. These inevitably confer some degree oflability, making them vulnerable to degradation (andinteraction with other materials). Common modes ofdegradation are described below.Hydrolysis. Drugs with functional groups such asesters, amides, lactones or lactams may be suscep-tible to hydrolytic degradation. It is probably themost commonly encountered mode of drug andproduct degradation because of the prevalence ofsuch groups in medicinal agents and the ubiquitousnature of water. Water can also act as a vehicle forinteractions or can facilitate microbial growth.Oxidation. Oxidative degradation is probably secondonly to hydrolysis as a mode of decomposition. Incontrast to hydrolysis, oxidative mechanisms arecomplex, involving removal of an electropositiveatom, radical or electron or, conversely, addition ofan electronegative moiety. Oxidation reactions canbe catalysed by oxygen, heavy metal ions and light,leading to free radical formation (induction). Freeradicals react with oxygen to form peroxy radicals,

Although considered pharmacologically inert, excipients can initiate, propagateor participate in chemical or physical interactions with drug compounds, whichmay compromise the effectiveness of a medication. Excipients may also containimpurities or form degradation products that in turn cause decomposition ofdrug substances. This article explores some of these interactions and reactions,and calls for a better understanding of excipient properties.

Patrick Crowley is a Vice President in

Pharmaceutical Development

at GlaxoSmithKline, 1250 South

Collegeville Road, Collegeville,

PA 19426, USA.

Dr Luigi G Martini Manager, Stategic Technologies.

Pharmaceutical Development,

GlaxoSmithKline

Pharmaceuticals, Harlow, Essex,

CM19 5AW, UK.

Drug–Excipient Interactions

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which in turn interact with the oxidizable compound to generateadditional free radicals to fuel further reactions (propagation).Aldehydes, alcohols, phenols, alka-loids and unsaturated fats and oilsare all susceptible to oxidation.Isomerization. Isomerizationinvolves conversion of a chemicalinto its optical or geometric isomer.Isomers may have different pharmacological or toxicologicalproperties. For example, the activityof the laevo (L) form of adrenaline is15–20 times greater than for thedextro (D) form.Photolysis. Reactions such as oxida-tion–reduction, ring alteration andpolymerization can be catalysed oraccelerated by exposure to sunlightor artificial light. Energy absorptionis greater at lower wavelengths and,as many drugs absorb ultravioletlight, degradation by low-wavelengthradiation is common. Exposure tolight almost invariably leads to dis-colouration even when chemicaltransformation is modest, or evenundetectable.Polymerization. Intermolecularreactions can lead to dimeric andhigher molecular weight species.Concentrated solutions of ampicillin,an amino-penicillin, progressivelyform dimer, trimer and ultimatelypolymeric degradation products.2

Table I lists examples of medicinalagents susceptible to such modes ofdegradation. Degradation mayreflect vulnerability to environ-mental stresses such as heat,humidity, light or drug–drug interactions. Degradation may alsobe facilitated or promoted by excipi-ents possessing the requisite func-tional groups for interaction, orcontaining residues that catalyse/par-ticipate in degradation processes. Ifexcipients are also susceptible tochange, this provides additional possibilities for the generation ofspecies that participate in break-down processes.

Direct interactions betweenactives and excipientsExcipients may be inorganic ororganic in composition, synthetic or semi-synthetic, or derived frombiological or natural sources. Manypossess functional groups that caninteract with other materials. It may be possible on occasion toexploit such attributes to stabilizeunstable materials,3 but more usuallyinteractions lead to loss of quality.Charge interactions.Soluble and ion-izable excipients can generatecounter ions that interact with ioniz-able drug substances leading to theformation of insoluble drug–excip-ient products. Suspending agents suchas sodium alginate or sodiumcarboxymethylcellulose dissolve inwater to provide large negativelycharged anions. Co-formulation inaqueous systems with drugs such asneomycin and polymyxin, the activemoieties of which are positivelycharged and of high molecularweight, results in precipitation.Bentonite (negatively charged) andattapulgite (positive) are examples ofmaterials of mineral origin that carryelectrical charges leading to interac-tion with drugs of opposite charge.Such interactions are usually rapidand readily apparent in liquid sys-tems. It is doubtful whether dosageforms containing such incompatibleingredients would progress to clinicalor pharmaceutical evaluation. It canalso be argued that such interactionsonly concern liquid dosage forms.However, the possibility cannot beruled out that they could occur invivo with solid dosage forms, fol-lowing ingestion and hydration in thegastrointestinal tract.Hydrogen-donating interactions.Polyvinylpyrrolidone (PVP or povi-done) can interact with compoundscontaining hydrogen-donating func-tional groups. Incompatibilities ofPVP with lansoprazole, famotidineand atenolol all indicate that its car-bonyl group is pivotal to degradation

reactions.4–7

Direct drug–excipient interactionsseem to be most prevalent when theinteracting species are water solubleand in liquid systems. This is hardlysurprising — interactions in solutionare more facile than in the solid statewhere there is less opportunity forcollision between functional groupsor other reaction-enhancing events.This is why compatibility studiesinvolving solutions give many ‘falsepositives.’ However, adsorbed mois-ture may promote greater molecularflexibility and consequent facilitationof interactions in solid state systems.Solution interaction studies mayhave some predictive capabilitybecause of such possibilities.Reactions with lactose. Lactose canparticipate in complex reactions withcompounds containing primary orsecondary amines. These can lead toassorted low molecular weightproducts and high molecular weight,coloured entities. This ‘Maillard reac-tion’ has been reported for the anti-depressant fluoxetine (a secondaryamine) when formulated with lac-tose. Starch-based formulations didnot yield such degradation products.8

The reactivity of lactose in the solidstate is reportedly related to theproportion of amorphous materialpresent, as this lacks the stabilityprovided by the crystal lattice.Amorphous lactose is also morehygroscopic, thereby increasingpossibilities for moisture-assistedinteractions.9

Reactions with silicon dioxide.Silicon dioxide can act as a Lewisacid (a substance that can accept anelectron pair) under anhydrous con-ditions and promote reactions asdiverse as dehydration, hydrolysis,epimerization, cyclization and trans-esterification. Unwelcome reactionsbetween this excipient and diethyl-stilbestrol have been reported.10

Figure 1 shows the silicon dioxide-catalysed oxidation of diethylstilbestrolto the peroxide and conjugatedquinone degradation products.

Air auto-oxidation of methyllinoleate to peroxides with subse-quent decomposition to aldehydeshas been shown to be accelerated inthe presence of colloidal silicondioxide.11 Interaction betweenchloramphenicol stearate andcolloidal silica during grinding leads

Hydrolysis Oxidation Isomerization Photolysis Polymerization

Table I Modes of degradation of medicinal agents.

Methyl dopa Calcitonin Tetracycline Riboflavin Ceftazidime

Procaine Ascorbic acid Vitamin A Folic acid Ampicillin

Penicillins Isoprenaline Adrenaline Nifedipine

to polymorphic transformation ofthe chloramphenicol, demonstratingthat unwanted effects of excipientsare not restricted to chemical trans-formations.12

Physical interactionsSome excipients are capable ofadsorbing active ingredients to theirsurfaces and this has been used toenhance the surface area of drugsand optimize dissolution rate.However, if forces of attraction arehigh, desorption may be retardedand absorption compromised. In asimilar context, adsorption of a novelK-opoid agonist by microcrystallinecellulose led to incomplete drugrelease from capsules.13 Adsorptionof finely divided excipients on toactive ingredients can also occur and,if such excipients are hydrophobic,dissolution rate and bioavailabilitymay be retarded.

Adsorption may also initiatechemical breakdown. Colloidal silicawas shown to catalyse nitrazepamdegradation in tablet dosage forms,possibly by adsorptive interactionsaltering the electron density in thevicinity of the labile azo group andthus facilitating attack by hydro-lysing entities.14

Although it is prudent to be awareof functional groups associated with

drugs and excipients when consid-ering possibilities for interaction, itmust be stated that reactions ‘onpaper’ may not always occur in prac-tice, particularly in solid state. Manyheterocyclic drugs contain aminogroups. In accordance with the con-siderations above, lactose should beavoided as a formulation aid, but it iswidely and successfully used in tabletand capsule dosage forms. Solutionchemistry does not always translateto reactions in the solid state, partic-ularly in terms of rate of reaction,which may be the all-important con-sideration in a dosage form.Stereochemistry, local environment,degree of crystallinity or indeeddrug–excipient ratio can mean thatsome potential interactions are morea problem in concept than reality.

Excipient residuesExcipients (like drug substances) arenot exquisitely pure. In common withvirtually all materials of mineral, syn-thetic, semi-synthetic or naturalorigin, manufacture involves usingstarting materials, reagents and sol-vents. Residues invariably remainafter isolation. Low levels of residuecan have a greater impact than mightbe expected, however — particularlywhere the ratio of excipient to drugis high, or where the residue has low

molecular weight or acts as a cata-lyst. This is particularly true wherean interaction product may posesafety questions and needs to be‘qualified’ by toxicology studies.Such complications often arise aftermainstream safety studies have com-menced, and can result in delayed orcomplicated programmes.

Table II illustrates how reactivechemical entities are commonplace inwidely used excipients. The list is notcomprehensive, perhaps reflectingthe absence of such information inmost pharmacopoeial monographs, aswell as the reluctance of excipientproviders to be forthcoming aboutmodes of manufacture and types ofresidues in their products.Lactose. Lactose is one of the mostwidely used excipients in tablets.Purification during isolation mayinvolve treatment with sulphurdioxide,15 but no complicationscaused by residues of this powerfuloxidizing agent have been reportednor are limits stipulated for residuesin the pharmacopoeial monographs.Perhaps the volatility of sulphurdioxide results in very effectiveremoval during isolation and drying.

Lactose is a disaccharide of glu-cose and galactose (see Figure 2).These reducing sugars have beenfound in spray-dried lactose,16 as hasthe hexose degradation product,5-hydroxymethylfurfural, probablygenerated by heat encounteredduring spray-drying.17 As an alde-hyde, 5-hydroxymethylfurfural canparticipate in addition reactions withprimary amino groups, resulting inSchiff base formation and colourdevelopment.18

Dextrose is widely used in par-enteral nutrition solutions or as atonicity modifier in parenterals.Sterilization by autoclaving has been

O

O

HO

OH

O

OH

HO

OH

Diethylstilbestrol

Figure 1 Degradation pathways of diethylstilbestrol.

Excipient Residue

Table II Impurities found in common excipients.

Povidone, crospovidone, polysorbates Peroxides

Magnesium stearate, fixed oils, lipids Antioxidants

Lactose Aldehydes, reducing sugars

Benzyl alcohol Benzaldehyde

Polyethylene glycol Aldehydes, peroxides, organic acids

Microcrystalline cellulose Lignin, hemicelluloses, water

Starch Formaldehyde

Talc Heavy metals

Dibasic calcium phosphate dihydrate Alkaline residues

Stearate lubricants Alkaline residues

Hydroxypropylmethyl/ethyl celluloses Glyoxal

OHCOH

O

5-Hydroxymethylfurfural

OHOH

HOHO

HO

O

Glucose

OH

OH OH

OHHO

O

Galactose

Figure 2 Glucose and galactose, and the hexose degradation product 5-hydroxymethylfurfural, are found in spray-dried lactose.

reported as causing some isomeriza-tion to fructose and also formationof 5-hydroxymethylfurfural in electrolyte-containing solutions.19

Parenteral solutions that are steri-lized by heating would clearly be vul-nerable not only to such excipientdegradation but to further reactionswith the drug, leading to the type ofreaction products described earlierwith regard to lactose.

Effect of pH. The presence ofpH-modifying residues can accel-erate hydrolytic degradation or havemore esoteric effects. Most medicinalagents are salts of organic acids orbases. Residues that modify pH maylead to free base or acid formationduring long-term storage. Such prod-ucts may be volatile and lost by sub-limation from the dosage form. This‘disappearance’ without concomitantformation of degradation productscan be mystifying and requires muchtime and effort to elucidate.Thorough characterization of thedrug substance and awareness ofresidues in excipients may helpresolve or obviate such mysteries.Effect of processing. A number offood industry publications provideuseful insights into how processingcan lead to impurity formation infood additives that are also pharma-ceutical excipients. High tempera-tures and low moisture contents caninduce caramelization of sugars andoxidation of fatty acids to aldehydes,lactones, ketones, alcohols andesters.20,21 Such degradation prod-ucts may also be present in the samematerials used in pharmaceuticaldosage forms. Unfortunately,pharmacopoeial monographs rarelylist such organic contaminants.Microcrystalline cellulose. This com-pound is a partially depolymerizedcellulose that is part crystalline andpart non-crystalline; it is also hygro-scopic. Adsorbed water is not held ina ‘bound’ state, but will rapidly equi-librate with the environment (seeFigure 3).22 It is possible that, in adosage form, such water can besequestrated by a more hygroscopicactive ingredient leading to degrada-tion if the drug is moisture sensitive.Drying prior to use will removeunwanted moisture but may make ita less effective compression aid.23 Ina similar context, Perrier andKesselring showed that nitrazepamstability in binary mixes with com-monly used excipients was directlyproportional to their nitrogenadsorption energies (see Figure 4).They suggested that water-bindingenergy, not contact surface energy,may be the stability determinant.24

Water-based reactions. Severalstudies with drug substances haveshown that process operations suchas grinding and drying can release

bound water, which is then ‘free’ toparticipate in hydrolytic reac-tions.25–28 Such process stresses canalso be expected to loosen boundwater in excipients, which may thendegrade moisture sensitive drugswith which they are formulated.Such possibilities make it easy tounderstand why testing simpledrug–excipient mixtures in excipientscreening studies may not predictinteractions in formulated product.Compression, attrition or othercrystal disrupting stresses may be the catalyst for interaction but theseare rarely mentioned as meritinginvestigation.Reactions with residues orimpurities. Peroxide residues inpovidone (binder) and crospovidone(disintegrant) were shown to beresponsible for the enhanced forma-tion of the N-oxide degradationproduct of the oestrogen receptormodulator, raloxifene. Correlationbetween residual peroxide levels andN-oxide formation enabled a limit tobe set for peroxide content of theexcipients.29

Microcrystalline cellulose maycontain low levels of non-saccharideorganic residues. These emanatefrom lignin, a cross-linkedbiopolymer made up primarily of thethree allylic alcohols/phenols in thewood chip starting material (seeFigure 5).30 It is possible that degra-dation products of these phenols, orfree radical combinations may bepresent in microcrystalline cellulose,thereby conferring the potential forchemical interaction with the drug.

Organic solvents may also containperoxides and, furthermore, theseincrease with storage time.31 Solventresidues from crystallization or isolation of active pharmaceuticalingredients are present in most drugsubstances, albeit at low levels. Theymay also be present in excipients,having the same provenance.Peroxides introduced to the dosageform in such a way could fuel thegeneration of novel impurities.

The presence of a residue withinteraction capability does not neces-sarily mean that degradation follows,or does so to any significant extent.The conditions, physical form andenvironment for interaction may notbe appropriate (and drug–excipientratio could be important). However,

Mo

istu

re c

on

ten

t (g

/100

g)

1

0

25

15

20

5

10

20 40 60 80 100

Relative humidity (%)

AbsorptionDesorption

Figure 3 Moisture sorption profile of microcrystallinecellulose at 25 °C. (Reprinted with permission from reference 22.)

Dec

om

po

siti

on

rate

co

nst

ant/

day

� 1

03

1.70

0

20

12

16

4

8

1.80 1.90 2.00 2.10

Nitrogen adsorption energies (kcal/mol)

Figure 4 Relationship between nitrazepam decompositionrate constant and nitrogen adsorption energies of variousexcipients. (Reprinted with permission from reference 12.)

HOY

XOH X and Y = H: p-coumaryl alcohol

X = OMe, Y = H: coniferyl alcoholX and Y = OMe: sinapyl alcohol

Figure 5 Organic impurities in microcrystalline cellulose(Me � methyl group).

if residues are volatile, liquid or oth-erwise ‘mobile,’ possibilities fordestabilization cannot be discountedand warrant investigation.

Biopharmaceutical productsThe relative fragility of the proteina-ceous materials in biopharmaceuticalproducts, and the frequent need formore sophisticated systems for theirdelivery places constraints anddemands on excipients. The physicalstate of most biopharmaceuticalproducts can favour interaction. Theamorphous nature of most lyophilesmeans that destabilizers such asresidual moisture are not held in astructured milieu. This amorphousstate also affords greater molecularflexibility and consequent opportuni-ties for reactions. Constant vigilanceand rigorous screening are requiredif physical and chemical interactionsthat compromise quality, perfor-mance or safety are to be avoided.The reducing sugars in mannitol, anexcipient widely used in parenterals,have been reported as responsiblefor the oxidative degradation of acyclic heptapeptide.32

Non-ionic surfactants have tradi-tionally been used as emulsion for-mers in topical and oral products,and more recently as solubilizers andstabilizers in biotechnology products.They are susceptible to hydrolysis33

and auto-oxidation.34,35 Peroxidelevels in polyethylene glycol solu-tions have been shown to increasewith concentration in solution andstorage time.36 Continuing genera-tion of powerful oxidizing agentscould be very damaging to proteinstructures containing cysteine, histi-dine, methionine or other terminalgroups susceptible to oxidation.

Lipid excipients may be used toform micro-emulsions or other drugtargeting systems. Most food gradelipids contain peroxides that decom-pose under the influence of heat andUV radiation. This can lead to freeradical formation, which can in turnoxidize unsaturated groups leadingto deterioration of the deliverysystem and also, possibly, the activeingredient.37 Storage conditions, useperiods and limits for residues needto be established for such excipients.Such information needs to be gener-ated by rigorous and suitably con-trolled investigative studies.

An antioxidant butylated hydroxytoluene (BHT) has been shown toinhibit peroxide formation inTween 20 during storage.38 It iscommon to include such stabilizersin oxidizable excipients. Inadvertentremoval, or replacement by theexcipient provider, could precipitatea stability crisis in a product wherethe additive was unknowingly stabi-lizing the active ingredient as well.Such possibilities make it imperativethat change control and notificationagreements are in place betweenprovider and pharmaceuticalmanufacturer, particularly for bio-pharmaceutical products, as thesecannot be subject to the same defini-tive analytical characterization assmall molecule medicinal agents.

Excipients may be an indirectcause of degradation in biopharma-ceutical products. Succinate bufferwas shown to crystallize during thefreezing stage of a lyophilizationcycle, with associated pH reductionand unfolding of gamma interferon.39

Human growth hormone, lyophilizedin the presence of sodium chloride,showed severe aggregation and pre-cipitation, as well as accelerated oxi-dation and deamidation.40 Suchexamples of chemical and physicalstability of excipients re-enforce thedesirability of performing process-simulating stress testing.

Conclusions and perspectivesMany stability problems encoun-tered during development and post-commercialization can be ascribed toinadequate matching of the ingredi-ents in dosage forms, lack of aware-ness of the complexities of chemicaland physical interactions, or theunheralded presence of a residue inone of the excipients. Many suchissues concern low levels of novelentities formed by drug–excipientinteractions that pose questions con-cerning safety or tolerance. Suchincidents have probably beenincreased by the growing sophistica-tion of analytical techniques todetect, identify and quantitate lowlevel impurities.

Drug–excipient interactions maytake a long time to be manifested inconventional stability testingprogrammes, and are not alwayspredicted by stress and preformula-tion studies. They can complicate and

compromise a development pro-gramme or the viability of a com-mercial product.41 It is possible toreduce the probability of such unde-sirable and costly scenarios byallying knowledge of the propensityof a drug to undergo degradationreactions with an awareness of excip-ient reactivity and of the residuesthat they may contain. Such aware-ness may help to anticipate undesir-able interactions and avoid theiroccurrence. A judicious choice ofexcipients or control of their qualitywill exclude or limit residues pro-moting degradation. It is surprising,therefore, that there is a paucity ofinformation in compendia or otherpublications on potentially damagingresidues in even the most commonexcipients. It is a sphere of activitythat groups attempting to harmonizeexcipient monographs do not seemto have addressed, and it is to behoped that ‘least common denomi-nator’ considerations in harmoniza-tion initiatives do not exacerbate thesituation. Perhaps it could be a sub-ject for a future initiative.

In summary, knowledge ofdrug–excipient interactions is a nec-essary prerequisite to the develop-ment of dosage forms that are stableand of good quality. It is hoped thatthis review provides some perspec-tive of this important area ofpharmaceutical technology.

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Article Reprinted from the©March 2001 issue of:

Article Reprint Number: 0582