Mechanochemistry: A Green Approach in the Preparation of Pharmaceutical Cocrystals

Abstract

Mechanochemistry is considered an alternative attractive greener approach to prepare diverse molecular compounds and has become an important synthetic tool in different fields (e.g., physics, chemistry, and material science) since is considered an ecofriendly procedure that can be carried out under solvent free conditions or in the presence of minimal quantities of solvent (catalytic amounts). Being able to substitute, in many cases, classical solution reactions often requiring significant amounts of solvents. These sustainable methods have had an enormous impact on a great variety of chemistry fields, including catalysis, organic synthesis, metal complexes formation, preparation of multicomponent pharmaceutical solid forms, etc. In this sense, we are interested in highlighting the advantages of mechanochemical methods on the obtaining of pharmaceutical cocrystals. Hence, in this review, we describe and discuss the relevance of mechanochemical procedures in the formation of multicomponent solid forms focusing on pharmaceutical cocrystals. Additionally, at the end of this paper, we collect a chronological survey of the most representative scientific papers reporting the mechanochemical synthesis of cocrystals.

Synthesis, Characterization, and Intrinsic Dissolution Studies of Drug–Drug Eutectic Solid Forms of Metformin Hydrochloride and Thiazide Diuretics

“…The depression in the melting point, giving place to the characteristic V-shape in the binary diagram, indicates that a true eutectic composition has been found [20,64,86]. Conversely, a W-shaped graph suggests the formation of a cocrystal.…”

“…The preparation of the solid forms was performed by ball-milling of MET•HCl with CTZ or HTZ (1:1) using neat grinding (NG) or liquid assisted grinding (LAG) [60][61][62][63][64]. In LAG, a solvent-screening, varying their polarity, was carried out using different solvents, such as hexane, acetone, acetonitrile and water, in order to explore their effect in the formation of new solid phases [79].…”

“…Conversely, a W-shaped graph suggests the formation of a cocrystal. [20,64,86]. W-shaped graphics exhibit two eutectic points and in the middle of them resides the zone where the cocrystal exists [20,64,86].…”

“…Taking this into account, we are interested in the preparation of drug-drug solid forms containing MET•HCl (classified as class III, exhibiting high solubility in water but low permeability to cell membranes) [59], in the presence of the thiazide diuretics HTZ or CTZ (Scheme 1), in order to tackle the poor solubility and limited dissolution properties of both drugs, and because many T2D patients medicated with antidiabetic drugs frequently present hypertensive complications. Thus, this paper reports the ball-milling synthesis, using neat grinding (NG) [60][61][62][63][64] or liquid-assisted grinding (LAG) [60][61][62][63][64] (varying the polarity of the solvent), and characterization [57], as well as IDR experiments to determine any modification in the dissolution properties of these solid forms compared with the pure APIs. At first, we thought we had prepared DDCs, however during characterization we discovered the formation of DDESs.…”

Chiral Resolution via Cocrystallization with Inorganic Salts

“…[21] Crystal engineering [22] approaches can be employed to increase the degree of control on the possibility for a compound to crystallize as conglomerate, with salt [23] or solvate [24] formation being, arguably, the most commonly used strategies. Cocrystallization [25] has emerged more recently as a viable tool to transform racemic compounds into conglomerates. [26] In this topical review we describe a novel approach to chiral resolution in the solid state via cocrystallization of a racemic compound with an achiral inorganic salt coformer, with formation of ionic cocrystals (ICCs [28] ).…”