Effects of Diluents on Physical and Chemical Stability of Phenytoin and Phenytoin Sodium

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.

[1]  M. Khan,et al.  Quality and In-Use Stability Comparison of Brand and Generics of Extended-Release Phenytoin Sodium Capsules. , 2019, Journal of pharmaceutical sciences.

[2]  B. Macdonald,et al.  Enhancing the Dissolution Stability of Hard Gelatin Capsules Using Activated Carbon as a Packaging Component. , 2018, Journal of pharmaceutical sciences.

[3]  M. Khan,et al.  Effect of processing parameters and controlled environment storage on the disproportionation and dissolution of extended‐release capsule of phenytoin sodium , 2018, International journal of pharmaceutics.

[4]  F. Zheng,et al.  Optimization of reactions between reducing sugars and 1-phenyl-3-methyl-5-pyrazolone (PMP) by response surface methodology. , 2018, Food chemistry.

[5]  N. Davies,et al.  Are Excipients Inert? Phenytoin Pharmaceutical Investigations with New Incompatibility Insights. , 2018, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[6]  M. Khan,et al.  Quantitative estimation of phenytoin sodium disproportionation in the formulations using vibration spectroscopies and multivariate methodologies. , 2018, International journal of pharmaceutics.

[7]  M. Khan,et al.  Evaluation of In-Use Stability of Anticoagulant Drug Products: Warfarin Sodium. , 2015, Journal of Pharmacy and Science.

[8]  Christian Hildebrandt,et al.  The "New Polyethylene Glycol Dilemma": Polyethylene Glycol Impurities and Their Paradox Role in mAb Crystallization. , 2015, Journal of pharmaceutical sciences.

[9]  L. S. Taylor,et al.  Salt Stability - Effect of Particle Size, Relative Humidity, Temperature and Composition on Salt to Free Base Conversion , 2015, Pharmaceutical Research.

[10]  I. Ilič,et al.  Deformation properties of pharmaceutical excipients determined using an in-die and out-die method. , 2013, International journal of pharmaceutics.

[11]  C. Leopold,et al.  Comparison of traditional and novel tableting excipients: Physical and compaction properties , 2012, Pharmaceutical development and technology.

[12]  J. Rantanen,et al.  Disproportionation of the calcium salt of atorvastatin in the presence of acidic excipients. , 2012, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[13]  S. Bharate,et al.  Incompatibilities of Pharmaceutical Excipients with Active Pharmaceutical Ingredients: A Comprehensive Review , 2010 .

[14]  K. Raghavan,et al.  Understanding drug-excipient compatibility: Oxidation of compound A in a solid dosage form , 2009, Pharmaceutical development and technology.

[15]  Lynne S. Taylor,et al.  Role of Salt and Excipient Properties on Disproportionation in the Solid-State , 2009, Pharmaceutical Research.

[16]  M. Roberts,et al.  Assessment of Feasibility of Maillard Reaction between Baclofen and Lactose by Liquid Chromatography and Tandem Mass Spectrometry, Application to Pre Formulation Studies , 2009, AAPS PharmSciTech.

[17]  S. Badawy,et al.  Microenvironmental pH modulation in solid dosage forms. , 2007, Journal of pharmaceutical sciences.

[18]  N. Murti Vemuri,et al.  Use of isothermal microcalorimetry in pharmaceutical preformulation studies , 2004 .

[19]  E. Vranić.  Basic principles of drug--excipients interactions. , 2004, Bosnian journal of basic medical sciences.

[20]  Patrizia Restani,et al.  The safety of pharmaceutical excipients. , 2003, Farmaco.

[21]  P. Tsang,et al.  Influence of Peroxide Impurities in Povidone and Crospovidone on the Stability of Raloxifene Hydrochloride in Tablets: Identification and Control of an Oxidative Degradation Product , 2000, Pharmaceutical development and technology.

[22]  E. Ajandouz,et al.  Nonenzymatic browning reaction of essential amino acids: effect of pH on caramelization and Maillard reaction kinetics. , 1999, Journal of agricultural and food chemistry.

[23]  Y. Ma,et al.  Chronically KIT-stimulated clonally-derived human mast cells show heterogeneity in different tissue microenvironments. , 1997, The Journal of investigative dermatology.

[24]  K. Ikeda,et al.  Photo-enhanced modification of human skin elastin in actinic elastosis by N(epsilon)-(carboxymethyl)lysine, one of the glycoxidation products of the Maillard reaction. , 1997, The Journal of investigative dermatology.

[25]  R. Borchardt,et al.  Effects of reducing sugars on the chemical stability of human relaxin in the lyophilized state. , 1996, Journal of pharmaceutical sciences.

[26]  P M Wax,et al.  Elixirs, Diluents, and the Passage of the 1938 Federal Food, Drug and Cosmetic Act , 1995, Annals of Internal Medicine.

[27]  C. Rhodes,et al.  Solubility and ionization characteristics of phenytoin. , 1977, Journal of pharmaceutical sciences.

[28]  F. Bochner,et al.  Factors involved in an outbreak of phenytoin intoxication. , 1972, Journal of the neurological sciences.

[29]  A. H. Smith,et al.  The influence of water and pH on the reaction between amino compounds and carbohydrates. , 1955, Journal of Biological Chemistry.

[30]  C. Browne.  Moisture Absorptive Power of Different Sugars and Carbohydrates under Varying Conditions of Atmospheric Humidity , 1922 .

[31]  Sarsvatkumar Patel,et al.  Compression physics in the formulation development of tablets. , 2006, Critical reviews in therapeutic drug carrier systems.

[32]  G Pifferi,et al.  Quality and functionality of excipients. , 1999, Farmaco.

[33]  水足 久美子.  Photo-enhanced modification of human skin elastin in actinic elastosis by N[ε]-(carboxymethyl)lysine, one of the glycoxidation products of the maillard reaction , 1998 .

[34]  L. Block,et al.  Use of chitosan in compressed tablets of diclofenac sodium: inhibition of drug release in an acidic environment. , 1997, Pharmaceutical development and technology.

[35]  H. Bundgaard.  Polymerization of penicillins: kinetics and mechanism of di- and polymerization of ampicillin in aqueous solution. , 1976, Acta pharmaceutica Suecica.

[36]  Byron Horton Webb,et al.  Fundamentals of dairy chemistry , 1974 .