CRYSTALLINE FORMS OF BETULIN: POLYMORPHISM OR PSEUDOPOLYMORPHISM?
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CRYSTALLINE FORMS OF BETULIN: POLYMORPHISM OR PSEUDOPOLYMORPHISM? T. N. Drebushchak1,2*, A. V. Mikhailovskaya1,2, V. A. Drebushchak2,3, M. A. Mikhailenko1, S. A. Myz’1, T. P. Shakhtshneider1, and S. A. Kuznetsova4
By recrystallization with different solvents as well as decomposition of betulin ethanol solvate at room temperature a new crystalline form of the biologically active compound betulin, namely hemihydrate of betulin, is obtained. By single crystal X-ray diffraction data the crystal structure of hemihydrate of betulin is determined. By powder X-ray thermodiffraction and differential scanning calorimetry it is found that when hemihydrate of betulin is heated to melting, Н2О molecules are removed and solid-phase transformations occur, which are related to the formation of an intermediate crystalline form and an orthorhombic modification of betulin. DOI: 10.1134/S0022476620080119 Keywords: polymorphism, solid-phase transformations, betulin, pseudopolymorphism.
INTRODUCTION Interest in the problem of polymorphism of molecular crystals has not been weakened over many years [1-5]. The unpredictability of polymorphism and possible polymorphic transformations is one of the main problems in the development and manufacture of drugs [1, 2]. The situation is also complicated by that active drug ingredients can form, apart from polymorphs, various crystalline forms involving molecules of other compounds (hydrates, solvates, adducts, etc.). This phenomenon was generally called pseudopolymorphism [2]. Without the crystal structure solution it is not always possible to predict whether we obtained a pure substance as different polymorphs or some pseudopolymorph during the fabrication or not. In this work, we aimed at sorting out the crystalline forms containing betulin. Do we deal with polymorphism or pseudopolymorphism even when we try to obtain a pure substance without impurities? Betulin (3β,28-dihydroxy-20(29)-lupen C30H50O2) (Scheme 1) exhibits a wide biological activity [6, 7]. It is known to depend on the crystal structure of a substance and differ for different forms [1, 2]. The crystal structure of pure betulin has been unknown at present. Based on powder X-ray diffraction and thermal analysis data, the assumption was made about the occurrence of polymorphism and solvatomorphism for betulin [8-10]. In [10], the unit cell parameters and space group of betulin were determined from the powder X-ray diffraction pattern. This form was called orthorhombic. The crystal structure
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Institute of Solid State Chemistry and Mechanochemistry, Siberian Branch, Russian Academy of Sciences, Novosibirsk, Russia; *[email protected]. 2Novosibirsk State University, Novosibirsk, Russia. 3Sobolev Institute of Geology and Mineralogy, Siberian Branch, Russian Academy of Sciences, Novosibirsk, Russia. 4Institute of Chemistry and Chemical Technology, Krasnoyarsk Scientific Center, Siberian Branch, Russian Academy of Sciences, Krasnoyarsk, Russia. Original article submitted November 8, 2019; revised March 2, 2020; accepted April 9, 2020. 1
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