Design,Synthesis And Characterization Of Several Pharmaceutical Cocrystals

In the field of pharmacy,the oral bioavailability and efficacy of most drugs are limited due to their unsatisfactory solubility and dissolution rate.Therefore,with regard to some less soluble active pharmaceutical ingredients,the focus is to change their physical and chemical properties,so as to improve their bioavailability and corresponding efficacy.Cocrystal acts as a feasible strategy to change the physical properties?such as crystallinity,hygroscopicity,solubility,stability and mechanical properties?of active pharmaceutical ingredients,being favored by more and more people.In this paper,less soluble progesterone,testosterone,coumarin,osthol and resveratrol were selected as active pharmaceutical ingredients to prepare pharmaceutical cocrystals with medically acceptable cocrystal cofomers.Six cocrystals and one single crystal of ketones and coumarin compounds were achieved by slow evaporation method.For resveratrol,two cocrystals were obtained by ultrasound assisted cocrystallization method,then these two cocrystals were compared with two other cocrystals prepared by the solution method to study their water solubility and stability in acid.All the crystal structures were characterized and analyzed by single crystal X-ray diffraction,and other corresponding characterization tests include Fourier transform infrared spectroscopy,powder X-ray diffraction and other technical means.The main contents are listed as follows:1.Ketone pharmaceutical cocrystals:progesterone?P?and testosterone?T?were selected as active pharmaceutical ingredient to prepare cocrystals using slow evaporation methods with medically acceptable cocrystal cofomers,including4-fluorobenzoic acid?4-FBA?,2-hydroxy-6-naphthalic acid?2-H-6-NA?and 4,4-dihydroxyl biphenyl?DOD?.Finally,three cocrystals of P·4-FBA·0.5H₂O?1?,P·2-H-6-NA?2?and T·DOD·H₂O?3?were achieved and analyzed by single crystal X-ray diffraction,powder X-ray diffraction,Fourier transform infrared spectroscopy,differential scanning calorimetry and thermogravimetric method,showing the presence of novel cocrystals.Experimental results of solubility and dissolution rate show that the solubilities of three cocrystals of progesterone and testosterone were increased by 1.95 times,1.62 times and 8.37 times respectively,and the powder dissolution rates were increased by 1.56 times,2.07 times and 3.41 times.2.Coumarin pharmaceutical cocrystals:coumarin?C?and osthol were selected as active pharmaceutical ingredient to prepare cocrystals by slow evaporation method with medically acceptable cocrystal cofomers,such as hydroquinone?DUO?,3,5-dihydroxy benzoic acid?3,5-DHBA?,trimesic acid?TA?and malonic acid,finally one osthol single crystal?4?and three cocrystals of C·DUO?5?,C·3,5-DHBA·2H₂O?6?,C·TA·2H₂O?7?were achieved.The cocrystals were characterized and analyzed by single crystal X-ray diffraction,then three cocrystals were further analyzed by powder X-ray diffraction,Fourier transform infrared spectroscopy,differential scanning calorimetry and thermogravimetric.The experimental results of solubility showed that the water solubility of coumarin by the formation of cocrystals was increased by 1.63 times,1.68 times and 2.18 times respectively.3.Comparative study of resveratrol pharmaceutical cocrystals:resveratrol?RES?was selected as active pharmaceutical ingredient to prepare cocrystals by ultrasound assisted cocrystallization method with medically acceptable cofomers,such as 4,4-pyridine?BPY?and phenazine?PHE?,finally two cocrystals of RES·BPY?USSC??8?and RES·PHE?USSC??9?were achieved,then these two cocrystals were compared with two other cocrystals prepared by slow evaporation method to study their water solubility and stability in acid.Four cocrystals were characterized by Fourier transform infrared spectroscopy and powder X-ray diffraction.The experimental results of water solubility showed the water solubility of the cocrystals prepared by these two methods were significantly improved,especially the water solubility of the crystals prepared by ultrasound assisted cocrystallization method were 2.46 times and 1.29 times higher than those crystals prepared by the solution method.The stability in 0.1 M HCl?pH=1?experimental results shows that all cocrystals almost show better acid stability compared with resveratrol,but the crystals prepared by solution method have better stability than crystals prepared by ultrasound assisted cocrystallization method,which may be attributed to the influence of solvent and the size of crystal particles.