Synthesis and Structural Characterization of Cocrystals and Pharmaceutical Cocrystals: Mechanochemistry vs Slow Evaporation from Solution

Abstract

The reliability of solvent drop grinding (SDG), also referred to as liquid assisted grinding, wet cogrinding, or mechanochemistry, to facilitate cocrystal formation is addressed with a series of model cocrystals and pharmaceutical cocrystals. The synthesis and single crystal structures of 17 new cocrystals that are sustained by COOH · · · N arom and OH · · · N arom supramolecular heterosynthons are presented. These cocrystals were prepared by both slow evaporation from solution and SDG. We also investigated whether or not SDG could be used to prepare previously reported carbamazepine (CBZ) pharmaceutical cocrystals. The following eight cocrystal formers were investigated in this context: 4,4′-bipyridine, 4-aminobenzoic acid/H 2 O, 2,6-pyridinedicarboxylic acid, benzoquinone, terephthalaldehyde, saccharin, nicotinamide, and aspirin. Our results reveal that all of the cocrystals that were grown from solution and characterized by single crystal X-ray crystallography can also be prepared by SDG. SDG therefore appears to be a cost-effective, green, and reliable method for discovery of new cocrystals as well as for preparation of existing cocrystals.

4,4′-Bipyridine–trans,trans-hexa-2,4-dienedioic acid (1/1)

“…Considerable effort has been devoted to form co-crystals made up of two or more components because of their potential applications in pharmaceutical chemisty (Weyna et al, 2009), supramolecular chemistry (Bhogala & Nangia, 2003;Gao et al, 2004) and materials chemistry (Hori et al, 2009). In particular, numerous studies have focused on hydrogen bonding between carboxylic acid and pyridine molecules (Bhogala & Nangia, 2003;Hou et al, 2008;Jiang & Hou, 2012).…”

“…For background to the applications of cocrystals, see : Bhogala & Nangia (2003); Gao et al (2004); Hori et al (2009) ;Weyna et al (2009).…”

Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

“…Presence of cocrystals in the drug formulation is thus possible even when not anticipated. Cocrystals are often designed and produced on purpose, to increase the solubility, or the stability, or the tabletability of an active pharmaceutical ingredient (API) [30,92,96,[99][100][101][102][103][104]. However, when a cocrystal is dissolved, the initially high concentration of the API in solution can drop down with time, and sometimes this happens very fast.…”

Clozapine-carboxylic acid plasticized co-amorphous dispersions: Preparation, characterization and solution stability evaluation

“…Solvent evaporation under vacuum was adopted as the method for preparation of co --amorphous systems in a modifi cation of the slow solvent evaporation method usually used for crystallization (where fast evaporation under vacuum with li le heat is used instead of slow evaporation at room temperature) (21). Weighted amounts of clozapine (150 mg) and calculated equivalent amounts of anhydrous CAPs, citric, D-tartaric or oxalic acid (chemical structures given in Fig.…”