Research Article Effects of Diluents on Physical and Chemical Stability of Phenytoin and Phenytoin Sodium Ziyaur Rahman, 1 Sathish Dharani, 1 Sogra F. Barakh Ali, 1 Mohammad T. H. Nutan, 1 and Mansoor A. Khan 1,2 Received 9 December 2019; accepted 12 February 2020 Abstract. The focus of the present work was to investigate compatibility between commonly used diluents and the drug (salt and acid form of the phenytoin). Lactose monohydrate (LMH), lactitol hydrate (LCT), and mannitol (MNT) were selected based on commercial products information of phenytoin sodium (PS) and phenytoin acid (PHT). Binary mixtures of the drug-diluent were stored at 60°C and 40°C/75% RH. Similarly, two commercial products, namely Product-A and Product-B, were also investigated in in-use stability. Color of PS-LMH changed from white to yellowish-brown and pH dropped by 3.4 units after 4 weeks exposure. FTIR, XRPD, and NIR chemical images indicated disproportionation in PS-LMH and PS-LCT mixtures stored at 40°C/75% RH. Furthermore, PS-LMH also indicated chemical interactions as indicated by distortion of LMH peaks. PHT- diluent mixture did not exhibit any physical and chemical modifications. Product-A changed color, increased weight, dropped pH value, and exhibited disproportionation and chemical reactions. The dissolution of Product-A decreased from 83.3 ± 1.4 to 7.1 ± 4.4% on 8 weeks exposure to 30°C/75% RH. On the other hand, Product-B did not change; however, dissolution decreased by 15%. In conclusion, PS showed disproportionation and chemical reactions with LMH. Therefore, LMH should be avoided in PS formulations. KEY WORDS: phenytoin sodium; phenytoin acid; lactose; lactitol; mannitol; Maillard reaction. INTRODUCTION Drugs are not administered as such to derive therapeutic benefit. They are formulated into appropriate dosage forms with the help of excipient(s). Definition of pharmaceutical excipient as per European Pharmacopeia is “any constituent of a medicinal product that is not an active substance” (1). Excipients perform the following function: aid in processing of the dosage form during manufacturing, enhance safety and efficacy of the dosage forms, enhance acceptability of the product, assist in product identification, and also help in maintaining integrity of the dosage forms (2). Excipients are screened through drug-excipients compatibility studies and stability studies. They should be physically and chemically compatible with drug(s) and other components of the formulation. Selection of excipients without thorough scien- tific studies can lead to product failure (3–5) and even severe intoxication (6). Drugs and excipients can interact by hydrolysis, oxidation, isomerization, disproportionation, pho- tolysis and/or polymerization, etc. (7–10). Examples of chemical interactions are Maillard reaction between amine group of chlorpromazine and glycosidic hydroxyl group of reducing group of dextrose to form imine, which eventually break down to Amadori compounds (11) and formation of complex between diclofenac and cationic polymer (12). Interaction reactions are influenced by pH, humidity, tem- perature, concentration, etc. (13). Not only the excipients can react with the drugs but also the impurities present in the excipients can interact with drugs and thus change product quality. Examples are peroxide impurities present in povidone and crospovidone increase formation of N-oxide derivatives in raloxifene hydrochloride (14), Maillard reaction can be induced by reducing sugar impurities present in the microcrystalline cellulose (15), and degradation of protein and monoclonal antibodies by peroxides and formaldehydes impurities present in polyethylene glycol (16). It is very important to consider these aspects of excipients as this information is not available in pharmacopeial monograph of the excipients. Phenytoin sodium (PS) is one of the commonly pre- scribed antiepileptics due to inexpensiveness compared with other antiepileptic drugs. It has the potential to undergo disproportionation reaction, which may be induced by moisture, excipients, or combination thereof (17). In the disproportionation reaction, salt is converted into base form of the drug, which may change physicochemical properties of 1 Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M University, 159 Reynolds Medical Building, College Station, Texas 77843-1114, USA. 2 To whom correspondence should be addressed. (e–mail: mkhan@tamu.edu) AAPS PharmSciTech (2020) 21:104 DOI: 10.1208/s12249-020-1639-x 1530-9932/20/0000-0001/0 # 2020 American Association of Pharmaceutical Scientists