Mesure, caractérisation et prédiction de la stabilité des médicaments

Abstract

The development of a hospital pharmaceutic formulation implies an a priori analysis of feasibility and risk. During this analysis, the pharmacist responsible of the formulation development must take a decision about the theoretical risk of instability of the formulation. Then, a prospective analysis of the formulation stability is done. This evaluation is inevitable. It is time consuming, costly, requires equipment and has a risk of failure. This work presents a scientific introduction about kinetic modelling applied to stability studies. During this literature review, the chemical and physical reaction pathways and the impact of temperature and humidity are depicted in mathematical models. Then, two approaches are introduced. The first one proposes a total prediction of the degradation kinetic of an active pharmaceutical ingredient in its formulation. This method is presented and applied to the pharmaceutical development of a formulation. Due to its huge need of computer resources, its applicability will be limited. The second approach is a semi predictive stability assessment. During this method, a few sets of experimental data is compared to a set of kinetic models. The best fitted model is chosen and then extrapolated to predict the stability of a formulation. This method is presented in chapter III and successfully applied to the prediction of the stability of two drugs. Finally, stability data are compared to molecular descriptors and physicochemical property of the studied active pharmaceutical ingredients to understand their impact.The development of a hospital pharmaceutic formulation implies an a priori analysis of feasibility and risk. During this analysis, the pharmacist responsible of the formulation development must take a decision about the theoretical risk of instability of the formulation. Then, a prospective analysis of the formulation stability is done. This evaluation is inevitable. It is time consuming, costly, requires equipment and has a risk of failure. This work presents a scientific introduction about kinetic modelling applied to stability studies. During this literature review, the chemical and physical reaction pathways and the impact of temperature and humidity are depicted in mathematical models. Then, two approaches are introduced. The first one proposes a total prediction of the degradation kinetic of an active pharmaceutical ingredient in its formulation. This method is presented and applied to the pharmaceutical development of a formulation. Due to its huge need of computer resources, its applicability will be limited. The second approach is a semi predictive stability assessment. During this method, a few sets of experimental data is compared to a set of kinetic models. The best fitted model is chosen and then extrapolated to predict the stability of a formulation. This method is presented in chapter III and successfully applied to the prediction of the stability of two drugs. Finally, stability data are compared to molecular descriptors and physicochemical property of the studied active pharmaceutical ingredients to understand their impact