EDITORIAL

Physicochemical Interactions in Solid Dosage Forms

Ajit S. Narang & Divyakant Desai & Sherif Badawy

Received: 15 August 2012 /Accepted: 15 August 2012 /Published online: 31 August 2012# Springer Science+Business Media, LLC 2012

ABSTRACT Complete characterization and mechanistic un-derstanding of physicochemical interactions in solid dosageforms are not only important for consistent manufacturability,stability, and bioavailability of the drug product, but are alsoexpected under the quality-by-design paradigm of drug devel-opment. Lack of this understanding can impact successful andtimely development, scale-up, and commercial manufacture ofdosage forms. This article highlights the stability and bioavail-ability implications of physicochemical interactions in dosageforms citing a couple of examples where such interactionsnecessitated the recall of commercial drug products.

KEY WORDS physicochemical interactions . productdevelopment . quality by design . solid dosage forms

INTRODUCTION

The need for complete characterization and better under-standing of physiochemical interactions in solid dosage formsis at the forefront of drug product science and technologyresearch. The physicochemical interactions in dosage formscan affect manufacturability, stability, and bioavailability of adrug product, thus often determining the developability andclinical viability of a drug. Proactive detailed characterizationof physicochemical interactions and their mechanistic under-standing are important not only for successful and robustproduct development, but also for patient safety and drugefficacy during the product life. In addition, an understandingof physicochemical interactions in dosage forms is expected

under the quality by design (QbD) paradigm of drug devel-opment, encouraged by the United States Food and DrugAdministration and other regulatory bodies worldwide. Un-der the QbD paradigm, mechanistic understanding of thedegradation mechanism of the dosage form has become anintegral part of the product development process. In mostcases, the expectation regarding a thorough understandingof degradation mechanism in new drug applications hasevolved from “nice to have” to “must have.”

Physicochemical interactions that are not well understoodand controlled can sometimes lead to adverse findings that evennecessitate field alerts, batch recalls, or product withdrawal. Forexample, Viracept® (nelfinavir mesylate) tablets (250 mg) wererecalled in 2007 due to the presence of high levels of ethylmethane sulfonate (EMS) in the drug product (1), and Norvir®(ritonavir) capsules were recalled in 1998 due to the formationof a less soluble crystal form in the capsules (2). Investigationsinto Viracept tablets were initiated by patient complaints of badodor in the marketed product and adverse reactions such asnausea. Analysis of relevant tablet batches by headspace gaschromatography using dimethylsulfoxide as a solvent indicatedthe presence of acetaldehyde and dimethyl sulfide. The pres-ence of these impurities was attributed to the reaction betweendimethylsulfoxide used as solvent in the analysis and ethylmethane sulfonate (EMS) in tablets (Fig. 1a). The formationof EMS was attributed to the use of methane sulfonic acid(MSA) in the final manufacturing step of the drug substance.The storage of MSA under conditions that can lead to contam-ination with ethanol for prolonged periods of time could lead tothe generation of EMS (Fig. 1b). This mechanistic understand-ing enabled the drug product manufacturer to implementseveral control strategies and process modifications that couldensure acceptably low levels of EMS in the drug product (1).

Several aspects of drug product stability and performance arelinked to physicochemical interactions in the dosage form.Theseinclude the robustness of the formulation to the range of vari-ability typically encountered in input materials and processparameters. In addition, the product is expected to remain stablewith consistent bioavailability. Some of the aspects of stabilityand bioavailability are addressed in this theme issue through 11

A. S. Narang (*) :D. Desai : S. BadawyDrug Product Science and TechnologyBristol-Myers Squibb, Co.One Squibb Dr., P.O. Box 191New Brunswick, New Jersey 08903-0191, USAe-mail: ajit.narang@bms.com

D. Desaie-mail: divyakant.desai@bms.com

S. Badawye-mail: sherif.badawy@bms.com

Pharm Res (2012) 29:2635–2638DOI 10.1007/s11095-012-0867-5

original research articles and 2 expert reviews. This theme issuebrings forth emerging trends in pharmaceutical dosage formresearch through the latest work of international (Japan, Ger-many, Finland, France, and United States) leaders in respectiveareas from both academia and pharmaceutical industry.

STABILITY

Excipients influence formulation stability not only by directinteraction with the drug, but also by modifying drug productcharacteristics such as microenvironmental pH, unboundwater, and plasticity/mobility of reactive components (3).Additionally, trace amounts of impurities present in excipientscan react with the drug or other functional excipients (4).

In this theme issue, Narang, Desai, and Badawy review theimpact of excipient interactions on solid dosage form stability.The authors describe common mechanistic themes that oftenunderlie degradation in the solid dosage forms, such as the roleof water and pH on solid-state reactions. This is followed by adiscussion of common pathways of physical and chemicalinstability, and prospective stability modeling and assessmentduring drug development. Several original articles in this themeissue highlight the recent research in these areas. Heljo et al.discuss the role of water in the crystallization tendency ofamorphous materials. Qian et al. discuss the impact of plastici-zation by water on the stability of amorphous systems. Qian,Wurster, and Bogner describe on the role of water in crystallineto amorphous phase transformation of compounds in the pres-ence of porous media. Kindermann et al. describe the role oftemperature and moisture on form and dissolution stability ofdrug-polyelectrolyte complexes in tablets. DeHart and Ander-son report the kinetics and mechanism of chemical instability ofamodel asparagine-containing peptide in amorphous lyophiles.

BIOAVAILABILITY

Physicochemical interactions in dosage forms can signifi-cantly influence drug bioavailability by affecting its dissolu-tion or by interacting with physiologic processes involved indrug absorption. At a simplistic level, these effects can bedirectly related to the functionality of excipients, such as theuse of binder and disintegrant in tablets or direct drug–excipient interactions (5). However, recent research high-lights the role of indirect mechanisms and possible interplayof more than one mechanism. In this theme issue, Panakantiand Narang discuss case studies and the mechanistic basis ofexcipients affecting drug bioavailability through interactionswith physiologic processes and drug product characteristics.

A commonly utilized modality of dissolution rate enhance-ment in solid dosage forms is milling of the active pharmaceu-tical ingredient (API) to reduce its particle size, therebyincreasing the surface area. This process, however, can leadto generation of high-energy surface, leading to processabilityconcerns such as sticking during roller compaction and tabletcompression. Ho et al. discuss the importance of particle shape,attachment energy, and crystal slip systems in understandingfracture behavior of crystalline drugs.

Supersaturation of a drug in an aqueous medium with thechange of pH, such as that of a basic drug transitioning fromthe acidic gastric environment to the basic intestinal milieu,can increase the bioavailability of certain poorly soluble drugs.The supersaturation behavior can be inherent to a drugmolecule (e.g., a drug with surfactant properties) or inducedby the dosage form, such as the use of amorphous soliddispersions or self-emulsifying drug delivery systems (SEDDS).In this theme issue, Hsieh et al. report the precipitation andsupersaturation behavior of 10 weak base compounds by study-ing the pH-concentration-time profiles and the properties of

a

b

Fig. 1 Reaction pathway for (a)the generation of dimethylsulfideduring headspace gaschromatography analysis ofViracept tablets and (b) theformation of ethyl methanesulfonate (EMS) in the tablets.

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the precipitated material. Shah and Serajuddin describe thedevelopment of solid SEDDS and a method of incorporationof the drug in these systems by first dissolving the drug in thelipid in liquid state. Qian et al. report the correlation betweensolution behavior of amorphous solid dispersions made withtwo different polymers to the oral bioavailability of a modelcompound. Kojima et al. explore the stabilization mechanismof a supersaturated solution of mefanamic acid from its soliddispersion in Eudragit® EPO.

Physical stability of amorphous drug–polymer solid disper-sions to crystallization during shelf-life storage is often linkedto drug–polymer miscibility through molecular interactions.In this theme issue, Eerdenbrugh and Taylor report the effectof molecular weight on the miscibility behavior of a lowmolecular weight compound in a polymer, and Greco et al.propose a method to predict the time to crystallization ofamorphous solid dispersions by studying the crystallizationbehavior at different temperature and humidity conditions.

This theme issue on the physicochemical interactions informulations and their impact on the stability and bioavail-ability of drugs from solid dosage forms brings forth severaloriginal articles of current research in this area. In the land-scape of commercial formulations, there are about 15 com-monly used excipients in the oral and parenteral dosage forms.However, stability-related issues keep surfacing during theproduct development, sometimes delaying product launch orduring commercialization triggering batch and/or productrecalls. These observations emphasize the need for bettermechanistic understanding of the physicochemical interac-tions. More scientific advances are needed to comprehendmany of the physicochemical interactions brought forth in thistheme issue. We hope this theme issue draws attention of thepharmaceutical scientists toward knowledge gaps in theseareas and helps foster more research in this field.

REFERENCES

1. Gerber C, Toelle HG. What happened: the chemistry side of theincident with EMS contamination in Viracept tablets. Toxicol Lett.2009;190:248–53.

2. Bauer J, Spanton S, Henry R, Quick J, Dziki W, Porter W, Morris J.Ritonavir: an extraordinary example of conformational polymor-phism. Pharmaceut Res. 2001;18:859–66.

3. Narang AS, Rao VM, Raghavan K. Excipient compatibility. In:Qiu Y, Chen Y, Zhang GGZ, Liu L, Porter W, editors. Developingsolid oral dosage forms: pharmaceutical theory and practice. Bur-lington: Elsevier; 2009. p. 125–46.

4. Wu Y, Levons J, Narang AS, Raghavan K, Rao VM. Reactive impu-rities in excipients: profiling, identification and mitigation of drug-excipient incompatibility. AAPS PharmSciTech. 2011;12:1248–63.

5. Narang AS, Yamniuk A, Zhang L, Comezoglu SN, Bindra DS, VariaS, Doyle ML, and Badawy S. Reversible and pH-dependent WeakDrug-Excipient Binding Does Not Affect Oral Bioavailability of HighDose Drugs. Journal of Pharmacy and Pharmacology. In press 2012.

Dr. Ajit Narang works forthe Drug Product Science &Technology Department ofBristol-Myers Squibb, Co.(BMS) in New Brunswick, NJ,on oral solid dosage forms. Hereceived his Ph.D. from theUniversity of Tennessee inMemphis. He currently servesas the Chair of AAPS FocusGroup on Excipients and Ad-junct Faculty at the Universi-ties of Tennessee and Phoenix.

He holds over 10 years of pharmaceutical industry experiencein the development of oral dosage forms and drug deliveryplatforms working for BMS, Ranabxy, and MGP (currentlyWockhardt) in different capacities. He has published 39 peerreviewed articles, 2 books, 5 patent applications, 43 posterpresentations, and 8 podium presentations at various scientificmeetings and has contributed to the development of severalmarketed drug products.

Dr. Divyakant Desai is aRe-search Fellow in the Bristol-Myers Squibb Company. Heobtained his undergraduate de-gree in pharmacy (B. Pharm.)from University of Bombay, In-dia, and his M.S. in Pharmacyfrom the University of RhodeIsland. After getting his Ph.D.from Rutgers in pharmaceutics,he joined Bristol-Myers Squibb.He has beenworking in the areaof oral dosage form for the last

24 years. He was the lead formulator for nine commercialproducts. He has more than 30 research articles in peer-reviewed journals andmany formulation and technology relatedpatents. He won many prestigious awards at Bristol-MyersSquibb for the formulation design of some key commercialproducts. He was presented the James Palmer Product Devel-opment Award for Onglyza™ tablet formulation in 2009 andthe Ondetti and Cushman Innovation Award for developingAbilify Discmelt™ tablet formulation in 2006. He was declaredthe winner for the 2012 Edison Patent Award in the pharma-ceutical category for the formulation patent of saxagliptin and itsfixed dose formulation with metformin for the treatment of type2 diabetes by the Research and Development Council of NewJersey. His research interests involve designing quality formula-tions and addressing stability and manufacturing process relatedissues.

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Dr. Sherif Badawy is a Re-search Fellow in the Drugproduct Science and Technol-ogy of the Bristol-MyersSquibb Company. He receivedhis B.S. in Pharmacy andM.S. in Pharmaceutics fromCairo University, and hisPh.D. in Pharmaceuticsfrom Duquesne University.He has more than 16 yearsof industrial experience indrug product development.

His current responsibilities at Bristol-Myers Squibb in-clude formulation and process development and scale-upof commercial oral solid and liquid dosage forms. Hisareas of research interest include high shear wet granu-lation, stability of solid dosage forms, and bioavailabilityenhancement of poorly water-soluble compounds. Heauthored 25 manuscripts and numerous abstracts andpresentations in those areas.

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