Determination of the applicability and validity of nonisothermal kinetic methods for use in pharmaceutical stability tests.

摘要

Non-isothermal kinetic methods applied to the evaluation of the stability of pharmaceuticals have been published during the past forty years. Yet, the use of these methods within the pharmaceutical industry is very limited due to the complex nature of the techniques and the lack of understanding of their relationship to isothermal kinetic methods. This dissertation investigates the validity of the non-isothermal methods and their relationship to the isothermal kinetic method.; Non-isothermal simulations and experimental non-isothermal and isothermal analyses of model compounds were used to investigate the linear, hyperbolic and logarithmic non-isothermal methods. The simulations of the non-isothermal methods provided information on aspects of the applicability of the non-isothermal methods and the preliminary framework for laboratory analyses.; Non-isothermal and isothermal kinetic studies were conducted using two model compounds, acetylsalicylic acid and ketotifen fumarate. The model compounds provided contrasting degradation mechanisms and activation energies.; An environmental chamber equipped with a programmable temperature controller was utilized to carry out the non-isothermal temperature profile of the method under investigation. Samples were analyzed using a validated HPLC analysis method. Similarly, samples were analyzed using an isothermal method.; The non-isothermal data was assessed using readily available software programmed to provide the parameters to derive the kinetic information. A Mathematica program was written to perform the polynomial fit and calculate the derivative of the polynomial for the non-linear analysis data. The derivative provided the rate constant at the selected temperatures such that an Arrhenius plot could be utilized derive the kinetic parameters.; The data indicated that the kinetic parameters from the non-isothermal and isothermal analysis were comparable. Estimates of the activation energy were very similar between the non-isothermal and isothermal analyses.; Key parameters were elucidated for conducting a non-isothermal analysis, which if followed, would provide guidance and assurance of the valid application of the non-isothermal technique. Validation parameters were proposed for non-isothermal analysis.; These investigations concluded that the non-isothermal methods could be applied successfully to drug substance and drug product stability analysis in the pharmaceutical industry and provide a valid alternate to isothermal kinetic analysis.