Thesis defence
Title : Microfluidic approach to crystallize the different phases of an active pharmaceutical ingredient
The jury will be composed by :
Valérie DUPRAY, Rapporteuse
SMS – Université de Rouen Normandie (Rouen)
François PUEL, Rapporteur
CentraleSupélec – Université Paris Saclay (Gif-sur-Yvette)
Alexandra PEÑA REVELLEZ, Examinatrice
Institut Néel – CNRS (Grenoble)
Pierrette GUICHARDON, Présidente du jury
Centrale Marseille (Marseille)
Stéphane VEESLER, Directeur de thèse
Aix-Marseille Univ, CNRS, CINAM (Marseille)
Nadine CANDONI, Codirectrice de thèse
Aix-Marseille Univ, CNRS, CINAM (Marseille)
Benoît ROBERT, Invité
Sanofi-Aventis R&D (Vitry-sur-Seine)
Romain GROSSIER, Invité
Aix-Marseille Univ, CNRS, CINAM (Marseille)
Abstract :
Most of the active pharmaceutical ingredients (API) can exist, in the solid state, under several crystalline phases (polymorphs, solvates, cocristals…). These phases have different physicochemical properties, which can affect the drug efficacy and its manufacturing process. In the pharmaceutical industry, a solid-state screening is thus carried out in the early stages of a drug development, to identify the existing phases and choose the one to develop. At this step, only a small amount of raw material is available, reducing the number of experiments. Droplet microfluidics is used to reduce the crystallization volumes to nanoliter scale, and thus the amount of product. This makes it possible to increase the number of experiments, bringing a statistical approach to address the stochasticity of nucleation. This thesis presents the development of a modular microfluidic platform, easy to use and compatible with most solvents, for solid-state screening of active pharmaceutical ingredients and fundamental nucleation studies. It enables to generate saturated solutions and droplets starting from powder and their characterization, to measure solubility, to crystallize API by cooling or non-solvent addition processes and to monitor nucleation in time and as a function of the temperature to establish global statistics on nucleation (all phases included). Lastly, the different phases are identified in situ by Raman spectroscopy to perform phase to phase statistics.