Screening for Pharmaceutical Cocrystal Hydrates via Neat and Liquid-Assisted Grinding

Abstract

The formation of cocrystal hydrates represents a potential route to achieve molecular materials with improved properties, particularly stability under conditions of high relative humidity. We describe the use of neat and liquid-assisted grinding for screening for hydrated forms of pharmaceutical cocrystals. In the case of liquid-assisted grinding, water is present in the reaction mixture as a liquid, whereas in the case of neat grinding, it is introduced by employing crystalline hydrates as reactants. The ability to form a cocrystal hydrate by either of the two methods appears to be variable, depending on the choice of cocrystal components. Theophylline readily forms a cocrystal hydrate with citric acid. This contrasts with the behavior of caffeine, which provides only an anhydrous cocrystal ("caffeine citrate") even when both reactants are crystalline hydrates. The preference of theophylline to form a cocrystal hydrate is qualitatively explained by similarity between crystal structures of the products and reactant hydrates. Overall, liquid-assisted grinding is less sensitive to the form of the reactant (i.e., hydrate or anhydrate) than neat grinding. For that reason liquid-assisted grinding appears to be a more efficient method of screening for cocrystal hydrates, and it is also applicable to screening for hydrates of APIs.

New Insights into an Old Molecule: Interaction Energies of Theophylline Crystal Forms

“…In addition to these crystal forms, THEO readily forms a range of other co-crystals and 5 is commonly studied as a co-crystal former. [37][38][39][40][41][42] Recently, a new anhydrous form IV has been reported. 43,44 However, reproduction of this form following the published procedure of slurry conversion in methanol failed in our hands.…”

Pharmaceutical Cocrystals: An Overview

“…Different types of solution methods such as solvent evaporation [76] , solution crystallization technique [41] , antisolvent addition [82] , slurry conversion method [83] and reaction crystallization method [84] are discussed with suitable examples. Grinding methods are of two types: neat grinding and solvent drop grinding [85,86] . Some newly emerging methods used for the formation of cocrystals are ultrasound assisted solution method [87,88] , supercritical fluid atomization technique [46,89] , spray drying technique [90,91] , hot melt extrusion technique [92,93] .…”

“…Grinding methods have been widely used for the for the cocrystal formation over the past few years and found to be superior than other methods (solution or melt) [85,86] . Grinding techniques are of two types: neat or dry grinding and wet grinding.…”

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“…However, drug content analysis was done on cocrystals prepared by all methods in triplicate. [45] The fenofibrate content in the prepared cocrystals showed in range of 60-94% as mentioned in Table 10.…”