Laboratory note Advantages of cocrystallization in the field of solid-state pharmaceutical chemistry: L-Proline and MnCl 2 Anaëlle Tilborg, Catherine Michaux, Bernadette Norberg, Johan Wouters * Department of Chemistry, University of Namur, rue de Bruxelles, 61, B-5000 Namur, Belgium article info Article history: Received 21 December 2009 Received in revised form 2 April 2010 Accepted 24 April 2010 Available online 4 May 2010 Keywords: L-Proline Cocrystallization Multicomponent molecular complex Crystal structure abstract Cocrystallization (formation of a “cocrystal”) is an emerging method to optimize physico-chemical properties of pharmaceutically active compounds. One elegant technique used to obtain such cocrystals is grinding the components together, either alone or in the presence of a small amount of solvent (so called solvent-drop grinding). Dry grinding has been used here to obtain cocrystals (actually a hydrated salt) of L-Proline and MnCl 2 . In that context, a new crystalline structure of a multicomponent molecular complex composed of L-Proline and MnCl 2 is here reported. The complex was characterized by powder and single-crystal X-ray diffraction and differential scanning calorimetry. This study underlines the interest of grinding as a method to synthesize original solid-state complexes. It also emphasizes the advantage of combining calorimetric and X-ray diffraction to characterize the newly formed solids. Finally, our work provides structural basis for the role that L-Proline can play within multicomponent solid-state molecular complexes, in particular as a potential cocrystal former acting by both ionic and H-bond interactions when combined to molecules of pharmaceutical interest. Ó 2010 Elsevier Masson SAS. All rights reserved. 1. Introduction Different methods can be used to deal with problems when a compound of therapeutic interest (Active Pharmaceutical Ingre- dient or API) presents unsuited physico-chemical properties (e.g. melting point too low for the further development or inappropriate dissolution rate or solubility itself) or exhibits different poly- morphic forms that interconvert at ambient temperature with only one therapeutically active [1e4]. To improve solubility and dissolution rate, formulation scientists turn to various basic methods, like salt formation or solid-state approaches alike amorphization or metastable phase formation [5e7]. Although the formation of salts is an excellent means of altering the physico-chemical properties of an API, this method suffers from some disadvantages. In fact, it requires at least one ionizable center on the API of interest. Furthermore, the number of pharmaceutically acceptable salt formers is relatively small [8]. On the other hand, solid-state manipulations can increase the risk of phase conversion under normal storage conditions [9]. So, when salt formation is not a good solution or when the formation of amorphous or metastable phase is not possible (e.g. for a matter of stability), cocrystallization is a well-adapted method for improving physico-chemical properties of APIs [10]. Cocrystallization can be defined as the formation of a “cocrystal” (or multicomponent molecular crystal: the two terms are used here without discrimination) composed of an API and a cocrystal former that can be organic or metallic. Cocrystallization is one of the emergent promising approaches in the field of pharmaceutical solid-state chemistry [11e 14]. Indeed, a series of recent studies highlight the advantages of using cocrystallization as a mean to optimize physico-chemical properties or avoid the apparition of unwanted polymorphic forms [15e18]. The interest of L-Proline lies in the fact that, besides being one of the natural a-amino acids composing proteins, this molecule is a decent cocrystal former [19,20]. Its precise role to stabilize the cocrystals and a detailed understanding at the molecular level of the interactions involved in that multicom- ponent molecular complex deserves attention. In that context, the present study describing the preparation of an original complex of L-Proline provides structural basis for the role that L- Proline can play within solid-state molecular complexes and opens perspectives for the further use of this compound as a potential cocrystal former when combined to molecules of pharmaceutical interest. * Corresponding author. Tel.: þ32 81 72 45 50. E-mail address: johan.wouters@fundp.ac.be (J. Wouters). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2010.04.028 European Journal of Medicinal Chemistry 45 (2010) 3511e3517