title: Solid state compatibility studies with tablet excipients using non thermal methods.
abstract: Compatibility between two new active pharmaceutical ingredients (API) and several pharmaceutical excipients used in solid formulations has been investigated by FT-IR and HPLC following storage under two different conditions. Compatibility was investigated by storage at isothermal stress conditions for (i) 3days and subsequently analysed by FT-IR and (ii) 12weeks of storage and analysis by HPLC. For the majority of the examined excipients a large degradation measured by HPLC after 12weeks storage was also detected by FT-IR following storage at isothermal stress conditions for 3days, i.e. there was a general agreement between the results obtained by the two protocols. Further, the FT-IR method showed clear incompatibility with three excipients where no degradation products were detected by HPLC, but where a significant decrease in the API quantified by the HPLC assay, was observed. The accelerated method thus showed a clear advantage: incompatibility found after 12weeks using HPLC was seen after 3days with FT-IR. Furthermore, FT-IR provides an insight into structural changes not seen with HPLC. This is exemplified by the desalting of a hydrogen bromide salt of one of the two compounds, which might lead to changes of the intrinsic dissolution rate and potentially affect the bioavailability of the API.
authors.affiliation: Preformulation, H.Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
authors.forename: Karin
authors.initials: K
authors.lastname: Liltorp
authors.forename: Trine Gorm
authors.initials: TG
authors.lastname: Larsen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Willumsen
authors.forename: René
authors.initials: R
authors.lastname: Holm
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D004356:Drug Storage; D005079:Excipients / Q000032:analysis* / Q000737:chemistry; D015394:Molecular Structure; D010755:Organophosphates / Q000032:analysis* / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D013449:Sulfonamides / Q000032:analysis* / Q000737:chemistry; D013607:Tablets; D013844:Thiazoles / Q000032:analysis* / Q000737:chemistry; D013997:Time Factors
chemical_list: D005079:Excipients; C539255:N-(4-(((4-(2-pyridinyl)-2-thiazolyl)amino)methyl)cyclohexyl)-2-propanesulfonamide; D010755:Organophosphates; D013449:Sulfonamides; D013607:Tablets; D013844:Thiazoles; C559609:phosphoric acid mono-(2-(4-(3,3-dimethylbutyrylamino)-3,5-difluorobenzoylimino)thiazol-3-ylmethyl) ester