| Selecting an applicable solid form of active pharmaceutical ingredient(API)is very important during the development of the pharmaceutical products.As we all know,different forms of drugs show different physicochemical properties.The cocrystal and coamorphous have witnessed increasing academic and industrial interest due to its potential to deliver better physicochemical properties in the pharmaceutical product in recent years.The introduction of the second component could change the crystal structure of active pharmaceutical ingredient.So,the pharmaceutical cocrystal/salt and coamorphous as new drug forms of API are feasible approaches to tailor physicochemical and mechanical properties of drugs.For example,solubility,dissolution rate,permeability and tabletability.In this work,we studied the antiviral drug fapiravir(FPV)and antihypertensive drug nifedipine(NIF):(i)three eocrystals(FPV-theophylline,FPV-5-fluorouracil and FPV-sacaccharin)and one salt(FPV-piperazine)of FPV were synthesized.The crystal structures of the four new crystals were obtained by single crystal X-ray diffraction,powder X-ray diffraction(PXRD),and Fourier transform infrared spectrometer(FTIR).Thermal analysis was used to characterize their thermal properties.The apparent solubility,permeability and tabletability of the multicomponent crystals were studied.(ii)Two coamorphous forms of NIF were synthesized(the ratios of molar of the two components were 1:1 and 2:1),and were characterized by powder X-ray diffraction,thermal analysis and FTIR.Then,the stability,hygroscopicity,apparent solubility and dissolution rate of them were checked.The main contents are as follows:(1)Four multicomponent formulations of antiviral drug FPV were successfully prepared by slow evaporation or liquid-assisted grinding method,including three cocrystals(FPV-theophylline,FPV-5-fluorouracil and FPV-saccharin)and one salt(FPV-piperazine).The crystal structures of new crystals were obtained by single crystal X-ray diffraction.Then,these multicomponent crystals were characterized by PXRD,DSC and TGA.There are plenty of cavities and obvious slip planes in the crystal structure of FPV-piperazine salt.The crystal structure of FPV-theophylline is similar to that of FPV.The molecules are arranged in the interwoven in the crystal structure.FPV-5-fluorouracil and FPV-saccharin have layered structures.(2)The solubility,permeability and tabletability of the multicomponent crystals were studied.Because of the salinization and special cavity structure,the solubility of FPV-piperazine could significantly improve comparing of the solubility of FPV.The permeability of the cocrystals and salt could all improve comparing of FPV FPV-piperazine,FPV-5-fluorouracil and FPV-saccharin showed good tabletability due to the existence of slip planes in the crystal structure.Our work indicates that cocrystallization or salinization can significantly improve the permeability and tabletability of FPV,which provides a new idea for the subsequent research and development of this important antiviral drug.(3)Coamorphous with two molar ratios(1:1 and 2:1)of NIF-rosuvastatin calcium were synthesized by melt quenching method.PXRD and DSC were used to determine their crystal structures and the thermal properties.The stability,hygroscopicity and solubility behavior of these coamorphous forms were studied.In the stability experiment(40℃,75%R.H.),the coamorphous of RSC-NIF(1:1)could be stabilized for 24 days,and the coamorphous of RSC-NIF(2:1)could be stabilized for 43 days,indicating that the amorphous state of NIF could be effectively maintained for a long time via the formation of coamorphous.In the hygroscopicity experiment,the hygroscopicities of the two coamorphous systems are significantly lower than that of the amorphous NIF.In the phosphate buffer(pH 6.8),the solubility of coamorphous is about twice that of the NIF,and the dissolution rate of coamorphous NIF-rosuvastatin calcium is about seven times that of the NIF. |
