Amorphous Pharmaceutical Compound Molecular Mobility Assessment and Excipient Influence

摘要

Enhanced product dissolution achieved through exploiting the drug amorphous staternproperties (e.g. solubility) is of great interest in pharmaceutical development. Physicalrninstability within the drug product is a serious concern which could result in poor productrnperformance. Several investigators reported that the origin of instabilities might be attributedrnto the molecular motions that can still exist below the glass transition temperature (Tg). Longrntime scales of molecular motions and the heterogeneous nature of glassy systems makes arndirect experimental determination of relaxation times (used as indicators of molecularrnmobility) difficult to characterize. Therefore, most investigations focused on characterizingrnsystems compos ed of a single component.rnIn this context, this work aims at detecting and quantitatively characterizing the timescalesrnof molecular motions in amorphous solids at and below Tg. By using thermallyrnstimulated current (TSC), broad heterogeneous relaxation processes associated with realrnsystems were experimentally resolved into different individual segments. By separating arnrelaxation event into its single narrowly distributed components, molecular mobility below Tgrnwas directly measured experimentally. Distributions of temperature dependent relaxationrntimes associated with different modes of molecular mobility were calculated as opposed to arnsingle average value of relaxation time obtained by other approaches. Furthermore, solidrndispersions formed by incorporating the drug in polymer matrix were analyzed as a functionrnof drug/polymer ratio. This provided a direct experimental determination of the impact ofrnformulation on the molecular mobility of the drug. Kinetic parameters (DH, DS, and DG ofrnactivation) were calculated from the temperature dependence of relaxation times and werernused to mechanistically understand the role of polymer in changing the dynamics ofrnmolecular mobility of the drug as well as in distinguishing between alpha (known as the glassrntransition) and Beta relaxation events. This all can be applied towards a more realisticrncorrelation to the physical stability of an amorphous drug within a formulation and allows forrnan appropriate choice of drug loading and storage temperatures that would lead to retardationrnof molecular motions over meaningful pharmaceutical time -scales.