Translation. Region: Russian Federation –
Source: Novosibirsk State University –
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The template effect of a small amount of additives of compounds with a similar structure (various saturated carboxylic acids and alkanes) on the process of self-assembly and crystallization of the channel trigonal structure of carbamazepine using a mechanochemical approach, crystallization in solution and melt was demonstrated by a first-year master's student in the Chemistry program and the training profile "Methodological support for physicochemical studies of condensed phases" Faculty of Natural Sciences of Novosibirsk State University (NSU Natural Sciences Department) Daria Zheltikova, under the supervision of Evgeny Losev, a research fellow at the Boreskov Institute of Catalysis SB RAS, senior lecturer in the Department of Solid State Chemistry at the NSU Natural Sciences Department, and candidate of chemical sciences. The key focus of her research was studying the phenomenon of polymorphism and the conditions for the formation of new solid forms of medicinal compounds, particularly carbamazepine, as well as methods for their controlled production. The effect of the compounds examined in the study on carbamazepine had never been previously studied.
Polymorphism is the ability of the same substance to exist in different crystal structures (polymorphic modifications). These structures differ in the arrangement of atoms (or molecules) and may have different physicochemical properties (e.g., solubility, melting points).
"The pharmaceutical industry is focused on studying the conditions for the formation of new crystalline forms of medicinal compounds, investigating their structures and physicochemical properties, and their interconversions. These processes address such important issues as the reproducibility of obtaining the desired substances, establishing the stability of drugs prone to polymorphism, and improving fundamentally important pharmaceutical characteristics: dissolution rate, bioavailability, storage stability, hygroscopicity, and other properties. To screen new crystalline forms, we primarily used a mechanochemical approach. This is a common method for screening the conditions for obtaining new solid forms of molecular compounds. Thanks to the wide range of parameters available for mechanochemical experiments, researchers can comprehensively study a selected system and draw conclusions about the putative mechanism of the processes occurring during the experiment. In recent years, mechanochemical reactions and transformations initiated by mechanical stress have been actively studied using various in situ methods using synchrotron radiation," explained Daria Zheltikova.
The young researcher's object of study was carbamazepine, a drug with antiepileptic and anticonvulsant properties, widely used in the treatment of nervous system disorders. According to the biopharmaceutical classification system, carbamazepine belongs to class II drugs, meaning it has low solubility in aqueous solutions and high intestinal permeability. Currently, five polymorphic modifications of this drug are known, which is quite unique and places carbamazepine in the class of highly polymorphic molecular compounds. Each polymorphic modification has a different crystal structure and molecular packing. In 1987, polymorphic modification II of carbamazepine, which has a trigonal space symmetry group, was first isolated and characterized. A distinctive feature of the crystalline structure of this form is the presence of extended tubular voids (channels) formed by the CH groups of the benzene fragments of the carbamazepine molecules. This substance is a good model object for studying the influence of experimental parameters on the selective production of specific polymorphic modifications and crystalline forms. The knowledge and patterns gained can be further transferred to other systems prone to polymorphism.
— The trigonal structure of carbamazepine, since its elucidation in 1987 and for several decades, was considered a polymorph. However, using a combination of physicochemical methods, it was recently established that the trigonal structure, which should have consisted solely of carbamazepine molecules, is a host-guest inclusion compound, where the carbamazepine molecules form a channel-type framework with solvent molecules embedded within the voids. The inclusion molecules will vary depending on the experimental conditions. It is the inclusion molecules that stabilize the trigonal crystal structure and enable its formation. Currently known inclusion compounds of carbamazepine are characterized by the presence of a small number of guest molecules in a highly disordered state, making their study quite labor-intensive. Various inclusion bodies of the trigonal form of carbamazepine can be classified as clathrates—compounds in which molecules of one substance (the "guest") are trapped within the crystal lattice of another substance (the "host"). The host molecules form a framework, while the guest molecules are located within it and held in place by weak intermolecular interactions, explained Daria Zheltikova.
Research into carbamazepine polymorphism and its formation of various crystalline forms began quite some time ago and was conducted as part of several projects implemented over the years with support from the Russian Foundation for Basic Research, the Russian Science Foundation, and the Priority-2030 program. The results were published in peer-reviewed international journals. This study continues work conducted earlier in the previous stages of the NSU Physics Faculty's youth competition "X-ray, Synchrotron, and Neutron Methods of Interdisciplinary Research," with support from the Priority-2030 program.
The aim of this study is to optimize the conditions for obtaining single crystals of carbamazepine clathrates with various guest molecules using various crystallization techniques and their analysis using a set of physicochemical methods.
Such exploratory work, despite its significant fundamental component, often leads to the establishment of the existence of new, previously unknown polymorphic modifications of medicinal compounds, which has direct practical significance, and also establishes correlations between the parameters and results of crystallization experiments, which can be useful in the study of systems similar in structure and properties.
One of the new scientific results obtained in this study is the demonstration of the template effect of small amounts of structurally similar compounds on the self-assembly and crystallization of the channel trigonal structure of carbamazepine using various methods—a mechanochemical approach, solution crystallization, and melt crystallization. Saturated carboxylic acids and alkanes—compounds containing a long, unbranched carbon chain—were used as structurally similar compounds. The template effect observed in the preparation of carbamazepine clathrates is based on the ability of the template (in this case, various carboxylic acids and alkanes) to organize the reactant (carbamazepine) molecules around itself, enabling the formation of a seed cluster, which serves as a precursor for the targeted formation of the final crystalline structure. All newly obtained compounds are clathrates of the trigonal form of carbamazepine, that is, the structure of carbamazepine contains inclusion molecules of the corresponding acids and alkanes.
— Currently, we are focused on optimizing methods for obtaining single crystals of various carbamazepine clathrates for further study and investigation of their stability at elevated temperatures. We obtained nine clathrates with saturated carboxylic acids and alkanes under various conditions. Our study examined six carboxylic acids and three alkanes. We have focused on only a few compounds from each group, as obtaining single-crystal samples for each individual compound is quite labor-intensive due to differences in formation conditions and certain experimental details. The compounds obtained have an acicular morphology—in simpler terms, they are thin, needle-like crystals. In some cases, the needle size is so small that it precludes single-crystal X-ray diffraction analysis using laboratory diffractometers. For this reason, not all of them have had their crystal structures determined yet. We characterized compounds whose crystal structures had not been obtained using Raman and NMR spectroscopy, said Daria Zheltikova.
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