A New Approach to Accelerated Drug-Excipient Compatibility Testing

The purpose of this study was to develop a method of qualitatively predicting the most likely degradants in a formulation or probing specific drug-excipient interactions in a significantly shorter time frame than the typical 1 month storage testing. In the example studied, accelerated storage testing of a solid dosage form at 50°C, the drug substance SB-243213-A degraded via the formation of two oxidative impurities. These impurities reached a level of 1% PAR after 3 months. Various stressing methods were examined to try to recreate this degradation and in doing so provide a practical and reliable method capable of predicting drug-excipient interactions. The technique developed was able to mimic the 1-month's accelerated degradation in just 1 hr. The method was suitable for automated analysis, capable of multisample stressing, and ideal for use in drug-excipient compatibility screening.

[1]  Crowley.  Excipients as stabilizers. , 1999, Pharmaceutical science & technology today.

[2]  Danièle Giron,et al.  Contribution of thermal methods and related techniques to the rational development of pharmaceuticals—Part 2 , 1998 .

[3]  S. Rabel,et al.  Degradation of a Fluoropyridinyl Drug in capsule Formulation: Degradant Identification, Proposed Degradation Mechanism, and Formulation Optimization , 2000, Pharmaceutical development and technology.

[4]  K. Al-rashood,et al.  Photostability-indicating HPLC method for determination of trifluoperazine in bulk form and pharmaceutical formulations. , 1996, Journal of pharmaceutical and biomedical analysis.

[5]  P. Vavia,et al.  Oxidative degradation study of nitrendipine using stability indicating, HPLC, HPTLC and spectrophotometric method. , 2001, Journal of pharmaceutical and biomedical analysis.

[6]  K R Morris,et al.  Selection of solid dosage form composition through drug-excipient compatibility testing. , 1999, Journal of pharmaceutical sciences.

[7]  K. Hartauer,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.

[8]  Phipps,et al.  Application of isothermal microcalorimetry in solid state drug development. , 2000, Pharmaceutical science & technology today.

[9]  V. Segarra,et al.  Degradation profile and identification of the major degradation products of dobupride under several conditions by GC/MS and HPLC-particle beam/MS. , 1995, Journal of pharmaceutical and biomedical analysis.

[10]  I. Jarvis,et al.  A stability-indicating method for the determination of melphalan and related impurity content by gradient HPLC. , 1999, Journal of pharmaceutical and biomedical analysis.

[11]  George Zografi,et al.  Water Vapor Sorption of Water-Soluble Substances: Studies of Crystalline Solids Below Their Critical Relative Humidities , 1987, Pharmaceutical Research.

[12]  Bruno C. Hancock,et al.  Differential scanning calorimetry: applications in drug development. , 1999, Pharmaceutical science & technology today.

[13]  Donald C. Monkhouse,et al.  Whither Compatibility Testing , 1989 .

[14]  M. Haas,et al.  Isolation and identification of a degradation product in a capsule formulation containing the elastase inhibitor, DMP 777. , 2001, Journal of Pharmaceutical and Biomedical Analysis.

[15]  K. Veal,et al.  A Versatile and Cost-Effective Approach to Automated Laboratory Organic Synthesis , 1999 .

[16]  Bruno C. Hancock,et al.  Water vapour sorption by pharmaceutical sugars , 1998 .

[17]  J. C. Callahan,et al.  Equilibrium Moisture Content of Pharmaceutical Excipients , 1982 .

[18]  P Mura,et al.  Compatibility study between ibuproxam and pharmaceutical excipients using differential scanning calorimetry, hot-stage microscopy and scanning electron microscopy. , 1998, Journal of pharmaceutical and biomedical analysis.

[19]  J. KontnyMark.  DISTRIBUTION OF WATER IN SOLID PHARMACEUTICAL SYSTEMS , 1988 .

[20]  Z. Zhao,et al.  Identification of losartan degradates in stressed tablets by LC-MS and LC-MS/MS. , 1999, Journal of pharmaceutical and biomedical analysis.

[21]  M. Hindle,et al.  A stability-indicating HPLC assay method for budesonide. , 2001, Journal of pharmaceutical and biomedical analysis.

[22]  John K Roberts,et al.  An automated workstation for forced degradation of active pharmaceutical ingredients. , 2002, Journal of pharmaceutical sciences.