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Cristallisation d’un sel pharmaceutique : Développement de méthodologies d’étude

Abstract : The salt formation of an active pharmaceutical ingredient (API) changes some physical and chemical properties of an API, namely its stability and its bioavailability. Pharmaceutical salts represent two thirds of the APIs in the pharmaceutical market world. Salt formation (acid-base reaction) can be coupled with its precipitation and pH monitoring helps understanding the chemical equilibriums. The bibliography part of this document focuses on Cs = f (pH) theoretical curves writing and the reasons leading to a choice of a particular salt of an API. The chosen API for this work is an hydrochlorate that crystallizes as needles. The work at the CINaM lab consisted first in developing a polymorphs screening method with the fewest materials (5 grams) in a short time-lapse (4 weeks). 12 phases have been discovered, 2 as anhydrous phases, 5 hydrates and 5 solvates. A monocrystal of the API base has been prepared to analyze its crystalline structure and to compare it to a salt structure solved by molecular modelling. Solubility measurements in ethanol/water mixtures helped us to prepare our work at the LAGEP lab for crystallization studies in an homothetic stirred reactor. In situ monitoring with FBRM and video probes helped us understand the effect of a particular crystallization process on crystal properties. The best process, crystallization with seeding, has been studied in details. We confirmed that the salt/solvent combination chosen did not allow to improve the acicular habit.
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Contributor : Veesler Stephane <>
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Thibaud Detoisien. Cristallisation d’un sel pharmaceutique : Développement de méthodologies d’étude. Génie des procédés. Aix-Marseille III, 2010. Français. ⟨tel-02003175⟩

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