Cocrystal Formation of Betulinic Acid and Ascorbic Acid: Synthesis, Physico-Chemical Assessment, Antioxidant, and Antiproliferative Activity

Abstract

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.

Levofloxacin Cocrystal/Salt with Phthalimide and Caffeic Acid as Promising Solid-State Approach to Improve Antimicrobial Efficiency

“…Furthermore, the CFA carbonyl band in the LEV-CFA salt spectrum appeared at a different position with low intensity while a broad band formed in the tentative range 2700–2400 cm −1 due to protonated piperazine nitrogen (NH + ). Different FT-IR patterns (bands attenuation, shifting and disappearance) of LEV-PTH and LEV-CFA than respective parental material particularly NH, OH and C=O bands lead to the conclusion that cocrystal/salt is formed due to intermolecular interactions [ 67 ]. The pka 1 (carboxylic group) and pKa 2 (piperazine) have been reported 5.59 and 7.94, respectively [ 55 ].…”

Enhancing Dissolution Rate and Antibacterial Efficiency of Azithromycin through Drug-Drug Cocrystals with Paracetamol

“…However, attenuation, broadening and slight change in position of peaks can give a hint for Van der Waals interactions [ 49 , 50 ]. An abnormally broad peak formed in the region of 3600–3015 cm −1 indicates some new set of H-bond interactions [ 51 , 52 ], while no such peak formation is observed in the physical mixture spectrum. The OH of PCM is involved in intermolecular hydrogen bonding with N in pure solid state while in cocrystal the OH stretching peak (3319 cm −1 ) and NH bending peak (1557 cm −1 ) of PCM have shifted to 3327 and 1565 cm −1 , respectively.…”

Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications

“… Therapeutic category API Coformer Ref. Anticancer Tegafur Syringic acid 179 5-Fluorouracil l -Phenylalanine 180 Cinnamic acid 181 Piperazine 182 Gentisic acid 176 3,4-Dihydroxybenzoic acid 176 4-Aminopyridine 176 Hydroquinone 183 Quinoxaline 3-Thiosemicarbano-butan-2-one-oxime 189 Benzotriazole p -Hydroxybenzoic acid 190 Temozolomide Oxalic acid 191 Quercetin Pyrazole 192 Imidazolidinone 192 Baclofen 192 Metformin Dichloroacetate 193 Dabrafenib Ethylenediamine hydrate 194 Berberine Chloride Myricetin 195 Betulinic acid Ascorbic acid 196 Antibacterial Nitrofurantoin Trimethoprim 197 Ciprofloxacin Carvacrol 198 Thymol 198 Sulfathiazole Amantadine hydroch...…”