Crystalline Forms of Betulin:
Polymorphism or Pseudopolymorphism?

Drebushchak, T. N.; Mikhailovskaya, A. V.; Drebushchak, V. A.; Михайленко, М. А.; Myz, S. A.; Шахтшнейдер, Т. П.; Кузнецова, Светлана А.

doi:10.1134/s0022476620080119

Cited by 6 publications

(12 citation statements)

References 13 publications

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“…In [14], three crystalline forms of betulin were also found. It should be noted that the X-ray powder diffraction patterns of these forms were very similar to those obtained in [12].…”

Section: Introductionsupporting

confidence: 68%

“…Recently [12], it was shown that betulin, crystallized from solution or prepared by decomposition of ethanol solvate at room temperature, is a hemihydrate of botulin. By means of in situ X-ray powder diffraction, it was found that when betulin hemihydrate (betulin III) was heated, a number of structural transformations proceeded in addition to water removal.…”

Section: Introductionmentioning

confidence: 99%

“…In the temperature range from 110 • C to 120 • C, there was a transition to an intermediate crystalline form (betulin II), which transformed into the orthorhombic form of pure betulin (betulin I) [13] before melting. Betulin I could also be prepared by decomposition of betulin ethanol solvate at 200 • C [12,13].…”

Section: Introductionmentioning

confidence: 99%

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Morphological Changes in Betulin Particles as a Result of Polymorphic Transformations, and Formation of Co-Crystals under Heating

Myz

Politov

Kuznetsova

et al. 2023

Powders

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Changes in the morphology of betulin crystals during heating at selected temperatures corresponding to polymorphic transformations were investigated. It was shown that the prismatic crystals of starting betulin form III were converted into needles at 120 °C after water removal, followed by the III→II polymorphic transformation. During further heating up to 180 °C, the whiskers of betulin form I were grown. Experiments on betulin heating in the presence of dicarboxylic acids, adipic or suberic showed that the morphological changes can serve as a test for the formation of cocrystals. According to morphological changes, the formation of cocrystals of betulin with adipic acid under heating was identified. The interaction of adipic acid vapor with the surface of betulin crystals was suggested. In contrast, morphological changes in the mixture of betulin and suberic acid under heating provided only the evidence of polymorphic transformations of the components. The results on cocrystal formation by heating were compared with the preparation of cocrystals by the liquid-assistance grinding method. Despite the fact that polymorphic forms with a high surface area were formed when betulin was heated, dissolution studies showed that the starting betulin polymorph III exhibited the highest dissolution rate in comparison with betulin polymorphs obtained under heating.

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“…In [14], three crystalline forms of betulin were also found. It should be noted that the X-ray powder diffraction patterns of these forms were very similar to those obtained in [12].…”

Section: Introductionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Morphological Changes in Betulin Particles as a Result of Polymorphic Transformations, and Formation of Co-Crystals under Heating

Myz

Politov

Kuznetsova

et al. 2023

Powders

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“…For example, the antimelanoma drug trametinib is a kind of solvate with dimethyl sulfoxide and is in the tablet form for clinical treatment. , Various organic solvents are always used in almost every process of pharmaceutical research, including synthesis, extraction, isolation, purification, and polymorph screening, so solvates will become an inevitable and significant problem during drug development. Apart from the different reported solvates of BE, a hemihydrate of BE (named crystal form E according to the discovery order) with its single crystal structure information and refinement parameters was reported by Drebushchak et al However, its refinement factors, such as R [ F 2 > 2σ( F 2 )], w R ( F 2 ), were extremely poor to be acceptable, which might be due to the quality of the single crystal for experiments.…”

Section: Introductionmentioning

confidence: 99%

“…8,9 Various organic solvents are always used in almost every process of pharmaceutical research, including synthesis, extraction, isolation, purification, and polymorph screening, so solvates will become an inevitable and significant problem during drug development. Apart from the different reported solvates of BE, a hemihydrate of BE (named crystal form E according to the discovery order) with its single crystal structure information and refinement parameters was reported by Drebushchak et al 10 However, its refinement factors, such as R[F 2 > 2σ(F 2 )], wR(F 2 ), were extremely poor to be acceptable, which might be due to the quality of the single crystal for experiments. Cocrystal, as a multicomponent crystal system, can effectively improve the physicochemical properties, such as solubility and physical stability, and enhance the bioavailability of drugs without changing the chemical structure of APIs.…”

Section: ■ Introductionmentioning

confidence: 99%

Characterization, Analysis, and Theoretical Calculation Studies of Solvates and Cocrystals of Betulin: An Exploration of the Boundary between Solvates and Cocrystals

Yuan,

Wang,

Wang

et al. 2023

Crystal Growth & Design

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Cocrystals, as an excellent solid state to improve the physicochemical properties of active pharmaceutical ingredients, have always been discussed together with solvates since the definition of cocrystals was proposed. However, investigation and discussion of the boundary between cocrystals and solvates have not been common. In this work, aiming at betulin (BE), a natural product with multiple pharmacological activities, we designed its polymorphism and cocrystal screening experiments with different liquid organic solvents and solid cocrystal coformers (CCFs) that possess low and high melting points, respectively. Afterward, a hemihydrate, a new solvate with benzyl alcohol, and two new cocrystals of BE with phenol (PHE) and 3-hydroxybenzoic acid (3-HBA), respectively, including their single crystal structures, were designed, prepared, and characterized by single-crystal X-ray diffraction, powder X-ray diffraction, and other solid-state analysis methods. A special thermal property for pharmaceutical cocrystals was found in cocrystal BE−PHE, that is, it possesses an exact CCF loss process, which is different from cocrystal BE−3-HBA but is similar to the solvate of BE. To explain this phenomenon, theoretical calculation studies were performed by molecular electrostatic potential surface analysis, electron density difference analysis, energy decomposition analysis, and energy framework analysis to realize an in-depth study of the sites, quantities, and energy of the intermolecular interactions between BE and different coformer molecules. Results indicated that the fewer interaction sites and the small interaction energy between BE and PHE molecules are possible reasons for the unusual thermal properties of cocrystal BE−PHE. This finding also proved that the structural features of cocrystals can greatly affect their physicochemical properties.

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