Cocrystal Of Several Small Molecules Of Natural Medicinal:Design And Analysis

Small molecules of natural medicinal have the characteristics of high biocompatibility,diversification of biochemical potency and so on.However,some small molecules of natural medicines have problems such as poor water solubility and low bioavailability,which limits their application.The use of pharmaceutical cocrystal technology is expected to improve the physical and chemical properties of drugs without changing the molecular structure and the activity of drugs,and to improve their dissolution properties and increase their bioavailability.In this paper,two natural products of resveratrol(polyphenols)and naringenin(flavonoids)were selected as research objects.Suitable CCFs were screened to obtain cocrystals of resveratrol and naringenin by solvent evaporation method,suspension method and grinding method.All cocrystals were characterized by a variety of spectral analysis,NMR and thermal analysis,and their dissolution properties were studied.Single crystal of,veratrol was obtained by solvent evaporation method.Crystal data were collected by single crystal X-ray diffraction analyzer and a reasonable crystal structure of resveratrol was solved by OLEX2 program.Hydrogen bonding interactions between three hydroxyl groups on resveratrol molecule and carboxyl and amino groups on sarcosine molecule formed in the cocrystal of resveratrol-sarcosine.Dissolution performance showed that the dissolution rate of resveratrol in the cocrystal is greatly increased and the equilibrium solubility is increased by 1.6 times.The studies on naringenin indicate that the carbonyl and hydroxyl groups on naringenin molecule interact with the pyridine nitrogen and carboxyl groups on 2-picolinic acid molecule in the cocrystal of naringenin-2-picolinic acid.As to naringenin-betaine cocrystal form B,two hydroxyl groups on the molecules of naringenin C4? and C5 have hydrogen bonds interaction with two oxygen atoms on the carboxyl group of betaine molecule,respectively,which is the same as the intermolecular interaction of the naringenin-betaine cocrystal form A.Due to differences in space accumulation methods,the two cocrystals are different,and form B is the stable form.Liquid NMR confirmed that the stoichiometric ratio of the two cocrystals(unknown the structures)naringenin-2-picolinate and naringenin-betaine form B are 1:1.Equilibrium solubility and dissolution rate test results show that the balanced solubility of naringenin increased by approximately 1.3 times,and the dissolution rate increased by 1.6 to 2.8 times of the four cocrystal products obtained.To reduce the hepatotoxicity of isoniazid,isoniazid-naringenin cocrystal was prepared in this paper.The intermolecular interactions were analyzed.Hydrogen bonds interactions are formed between the hydrazide,pyridine nitrogen on isoniazid molecular and three hydroxyls on naringenin molecule in the cocrystal.Liquid NMR confirmed that the molar ratio of isoniazid and naringenin in the cocrystal is 1:1.Dissolution test showed that the equilibrium solubility of naringenin in two simulated physiological fluids increased 1.5-fold and 3.7-fold,respectively.In contrast,isoniazid was decreased to 7.9% and 0.39% of pure isoniazid,respectively.It indicating that the obtained cocrystal can preserve the effect of isoniazid on anti-tuberculosis and weaken the liver damage at the same time.The pharmacological effect is obvious.