Betulinic acid (BA) was demonstrated to be a very promising anticancer agent against various tumor cell lines such as breast, colon, lung, and brain. Despite its strong cytotoxic effect, betulinic acid exhibits low water solubility, feature that is reflected in its poor bioavailability. To overcome these drawbacks, numerous strategies were conducted to improve its physicochemical and pharmacokinetic profile, among which cocrystalization emerged as a promising approach. Thus, our work consisted in obtaining slowly grown cocrystals of BA and ascorbic acid (BA+VitC) in isopropyl alcohol obtained in a hydrothermal experiment. The newly formed cocrystals were characterized by physico-chemical methods such asSEM, DSC, XRPD, and FT-IR spectroscopy demonstrating BA+VitC cocrystal formation while their antioxidant activity revealed an additive antioxidant effect. To investigate the biological effect, BA+VitC cocrystals were tested on HaCat (immortalized human keratinocytes), B164A5 and B16F0 (murine melanoma), MCF7 and MDA-MB-231 (human breast cancer), and HeLa (cervical cancer) cell lines. Results of BA upon the tested tumor cell lines, after co-crystallization with vitamin C, indicated a superior cytotoxic effect with the preservation of a good selectivity index assumably due to an improved BA water solubility and consequently an optimized bioavailability.
Combined experimental and theoretical studies on molecular structure of the betulinic acid solvatomorph of ethanol, 2-butanol and isopropyl alcohol solvents, grown by recrystallization method, are reported. Theoretical investigations, in the frame of DFT, are done using the new method of the betulinic acid solvatomorph molecule extraction from the corresponding molecular crystal, based on typical fragmentation scheme and chemical connectivity. For all electrons, a localized basis set of Gaussian type functions TZVP and local gradient corrected functional BP86 were used. Good correlation was found between the calculated and experimental data. Slight differences in the lattice modes spectral range (0-200 cm-1) from experimental Raman spectra suggest slight differences in the crystalline network and highlight the powerful Raman approach in evidencing BA pseudo-polymorphs or solvatomorphs. Data obtained suggest that incorporated solvents to the solvates generaly induced changes in crystal symmetry, intermolecular arrangements, stoichiometry and hydrogen bonding interactions of the analysed solvatomorphs.
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