DSC as a screening tool for rapid co-crystal detection in binary mixtures of benzodiazepines with co-formers

Abstract

In recent years, co-crystals have been the subject of increasing interest within the pharmaceutical industry because these new solid forms of active pharmaceutical ingredients have the ability to enhance the bioavailability of poorly water-soluble drugs with a low dissolution rate. For this reason, it is crucial to prepare co-crystals of benzodiazepines, i.e. psychoactive drugs with a wide range of medical applications but classified as very slightly or practically insoluble in water. Thus, the objective of this research was to show to what extent the DSC method can be used as a screening tool for detection of co-crystal formation in binary physical mixtures of drugs and co-formers. To obtain potential co-crystals, eight benzodiazepines (diazepam, temazepam, oxazepam, lormetazepam, lorazepam, clonazepam, estazolam and chlordiazepoxide) were gently mixed in an agate mortar at 1:1 molar ratios with nine co-formers—succinic, glutaric, fumaric, citric and p-aminobenzoic acids, nicotinamide, saccharin, urea and caffeine, and heated under DSC conditions. A detailed comparison of the DSC scans of mixtures against scans of both ingredients in isolation indicates the occurrence of subtle physical changes in the samples. Thus, additional endothermic or exothermic peaks due to melting or crystallisation suggested the formation of potential co-crystals. To conclude, this study confirms that the DSC method can be used as a rapid screening tool for co-crystal detection. In this case, based on the DSC scans, 15 physical mixtures of benzodiazepines (clonazepam, diazepam, lorazepam, oxazepam and temazepam) with co-formers (citric, fumaric, glutaric, p-aminobenzoic and succinic acids, nicotinamide, saccharin and urea) have been selected as potential co-crystals for further detailed study.