Rational Screening of Cocrystals using Thermal Analysis: Benchmarking on Energetic Materials

Abstract

Cocrystal design is an important and well-developed approach in the pharmaceutical industry. Energetic materials can be thought of as unique and challenging objects for cocrystal engineering since abundant explosophoric functionalities prevent exploiting common supramolecular synthons. Screening of cocrystal formation using thermal analysis methods is investigated. A few approaches from the literature are combined in a single procedure that allows for automation, high-throughput screening, and the usage of milligrams of material. To estimate the accuracy of the screening procedure, we compiled available literature data on 213 cocrystals with energetic or very similar to energetic materials. The recommended procedure can detect cocrystal formation in 75% cases (with no false positives), according to a smaller sample data set of 28 cocrystal-forming systems. The procedure was then used to screen for novel cocrystals among several acidic energetic materials, ammonium and hydroxylammonium energetic salts, 3-nitro-1,2,4-triazole as a coformers, and 13 cocrystals were discovered. Then, using the traditional solution procedure, eight novel cocrystals were prepared, and their X-ray structures were reported. One of the cocrystals discovered, a complex of promising energetic material, dihydroxylammonium 5,5′-bistetrazole-1,1′-diolate (also known as TKX-50) with 18-crown-6, is the first cocrystal of TKX-50 with a reported X-ray structure so far. Overall, we present a unified procedure of thermal screening for cocrystals and salts; benchmarking on challenging objects for cocrystal design (energetic materials) shows its high performance.