title: Modelling drug degradation in a spray dried polymer dispersion using a modified Arrhenius equation.
abstract: The Pharmaceutical industry is increasingly utilizing amorphous technologies to overcome solubility challenges. A common approach is the use of drug in polymer dispersions to prevent recrystallization of the amorphous drug. Understanding the factors affecting chemical and physical degradation of the drug within these complex systems, e.g., temperature and relative humidity, is an important step in the selection of a lead formulation, and development of appropriate packaging/storage control strategies. The Arrhenius equation has been used as the basis of a number of models to predict the chemical stability of formulated product. In this work, we investigate the increase in chemical degradation seen for one particular spray dried dispersion formulation using hydroxypropyl methylcellulose acetate succinate (HPMC-AS). Samples, prepared using polymers with different substitution levels, were placed on storage for 6 months under a range of different temperature and relative humidity conditions and the degradant level monitored using high-performance liquid chromatography (HPLC). While the data clearly illustrates the impact of temperature and relative humidity on the degradant levels detected, it also highlighted that these terms do not account for all the variability in the data. An extension of the Arrhenius equation to include a term for the polymer chemistry, specifically the degree of succinoyl substitution on the polymer backbone, was shown to improve the fit of the model to the data.
authors.affiliation: Bristol-Myers Squibb, Reeds Lane, Moreton, Wirral CH46 1QW, UK. Electronic address: adele.patterson@bms.com.
authors.forename: Adele
authors.initials: A
authors.lastname: Patterson
authors.affiliation: Bristol-Myers Squibb, Reeds Lane, Moreton, Wirral CH46 1QW, UK.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Ferreira
authors.affiliation: Bristol-Myers Squibb, Reeds Lane, Moreton, Wirral CH46 1QW, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Banks
authors.affiliation: Bristol-Myers Squibb, Reeds Lane, Moreton, Wirral CH46 1QW, UK.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Skeene
authors.affiliation: Bristol-Myers Squibb, Reeds Lane, Moreton, Wirral CH46 1QW, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Clarke
authors.affiliation: Bristol-Myers Squibb, Reeds Lane, Moreton, Wirral CH46 1QW, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Nicholson
authors.affiliation: Bristol-Myers Squibb, Reeds Lane, Moreton, Wirral CH46 1QW, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Rawlinson-Malone
mesh_terms: D000465:Algorithms; D003890:Desiccation; D004339:Drug Compounding; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D006813:Humidity; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D008962:Models, Theoretical; D010069:Oxadiazoles / Q000737:chemistry; D019802:Succinic Acid / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry; D013696:Temperature
chemical_list: C554092:BMS 708163; D005079:Excipients; D010069:Oxadiazoles; D013449:Sulfonamides; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose; D019802:Succinic Acid
keywords: Arrhenius; Chemical stability; Hydroxypropyl methylcellulose acetate succinate; Pharmaceutics; Solid dispersion; Succinoyl substitution