Relative stability of Arbaclofen polymorphs: selective pathways to isolate metastable phases via solvates formation
Résumé
When considering polymorphism of a given API, the identification of the phase stability is a critical parameter [1]. In an industrial perspective, specific and robust pathways to isolate either one polymorph or another should be developed. Moreover, the solid-state landscape is often complicated by the presence of hydrates and solvates or non-reproducible chemical purity. Baclofen is a pharmaceutical active ingredient originally produced as a myorelaxant, which recently gain interests to prevent alcoholic addiction [2]. One pathway to limit the dosage without lowering the activity would result in a ‘chiral switch’ towards the main active enantiomer: R-Baclofen or Arbaclofen. The latter crystallizes in two already known polymorphs (A and B). A new polymorphic form (Form C) of enantiopure Baclofen was recently isolated and characterized by our team [3]. Crystal structures of R-Baclofen Form A and Form C were resolved from powder diffraction data, and a structural approach was established for Form B. In this work, we present the relative stability of these three forms based on structural data, thermal analyses and solvent-mediated conversions. The experiments highlight the energetical order A < C < B at 25 °C (A is the most stable form), whereas above 180°C it would likely be:
C < A < B (C being the stable modification). Nevertheless, every polymorph displays a poor solubility in most of the usual solvents. Then, once R-Baclofen crystallizes, it would be difficult to convert, by slurrying, one form into another in a reasonable period of time (without redissolving a significant part of the material by salt formation). We present here a reproducible process to isolate metastable Form B. A new heterosolvate of the molecule was isolated with N,N-DMF and water. This heterosolvate offers a new pathway to isolate pure R-Baclofen Form B by simple desolvation in water, depending on the initial impurity level. Moreover, we discuss the impact of mechanical stress on Arbaclofen which could also lead to undesired polymorphic conversion