Preparation,Characterization And Preliminary Quality Evaluation Of Bergenin Proline Cocrystals

Research background and purpose:Drug cocrystal technology is a new formulation technology that has developed rapidly in the past few years.By selecting suitable cocrystal ligands,the solubility of insoluble drugs can be improved without changing the structure of the drug molecules,thus increasing the bioavailability of orally administered drugs.At present,Bergenin is mainly used in clinical practice for the treatment of cough expectoration and chronic bronchitis,and the most commonly used formulation is compound Bergenin tablets.Due to the poor water solubility of Bergenin,its oral bioavailability is low,which limits its clinical application to some extent.In this study,to improve the dissolution rate and solubility of the Bergenin,the drug cocrystal technology is used to prepare the drug cocrystal of Bergenin.Preliminary studies on the pharmacological properties are conducted.These studies provided a research base for the development of improved tablets of Bergenin.Methods:1.Research on the basic properties of BergeninThe visual observation of the appearance and shape of Bergenin is used;the equilibrium solubility of Bergenin is determined by the shaking flask method;the content of Bergenin is determined by the high performance liquid chromatography（HPLC）method.2.Preparation of Bergenin（BN）cocrystalThe cocrystal ligands are first screened by COSMO-logical software-assisted simulation to predict the possible cocrystal ligands with BN,and the excess enthalpy is used as the evaluation index to obtain the cocrystal ligands;the ligands obtained from the software screening are further verified and screened by a combination of solution method and grinding method,and the apparent solubility is used as the evaluation index to determine the preparation method and the best ligands.Finally,the cocrystal preparation process conditions are optimized by the single-factor experimental method to obtain the best preparation process.3.Characterization of Bergenin Proline（BN-Pro）cocrystalFive methods,X-ray powder diffraction（PXRD）,differential scanning calorimetry（DSC）and thermogravimetry（TGA）,Fourier transform infrared spectroscopy（FTIR）,and scanning electron microscopy（SEM）,are used for characterization and analysis to determine the formation of cocrystal of Bergenin.4.Preliminary quality evaluation of BN-Pro cocrystalThe dynamic solubility determination method is used to comparatively investigate the dissolution behavior of API,physical mixture and cocrystal within a certain period of time.BN ordinary tablets and BN-Pro cochips are prepared,and HPLC is used to establish the method for determining the tablet content of BN.The second dissolution degree method（paddle method）is used to investigate the dissolution behavior of tablets in dissolution media with different p H values,and the external dissolution rate of BN-Pro cocrystal is comparatively investigated the degree of improvement;the influence factor test is used to investigate the changes of appearance properties,saturation solubility and dissolution degree of cocrystal powder and cocrystal tablet samples when they are placed under different conditions.Result:1.Research on the basic properties of BNBN is a white powder with a saturation solubility in water of 1.28 mg/m L.The HPLC method is performed on a Shim-pack GIST-C18 column（4.6×250 mm,5μm）with acetonitrile-ultrapure water（15%:85%）as the mobile phase,a flow rate of 0.8m L/min,a detection wavelength of 275 nm,and an injection volume of 10μL.The method validation results showed that the method is accurate,sensitive,and specific.2.Preparation of cocrystal BNThe software simulation results show that several amino acids and several common small molecules in cocrystal ligands may form cocrystal with BN.And the best ligand for BN is experimentally determined as proline（proline,Pro）.The cocrystal is prepared by liquid-assisted milling with a milling time of 15 minutes,the molar ratio of BN and Pro is 1:3,the solvent is ethanol,the amount of solvent added is 3 m L,and the drying time is 8 hours.3.Characterization of BN-Pro cocrystalThe PXRD pattern shows that the cocrystal is accompanied by the appearance of new characteristic peaks from 4.68°to 10.96°and the disappearance and weakening of some characteristic peaks of each component from 15.39°to 33.53°;DSC and TGA show that the melting point of BN is 240°C and the decomposition temperature is about301°C;the melting point of Pro is 228°C and the decomposition temperature is about240°C;BN-Pro cocrystal melting point is 180°C and the decomposition temperature is about 210°C;FTIR characterization results show that the absorption peak of Pro at 1640cm^-1to 1408 cm^-1is shifted to 3075 cm^-1to 2815 cm^-1,and the characteristic peak of amino group（N-H）is shifted from 1170 cm^-1to 1726 cm^-1;the hydroxyl group（O-H）peak of BN is shifted from 3387 cm^-1to 3358 cm^-1.The hydroxyl（O-H）peak of BN is shifted from 3387 cm^-1to 3358 cm^-1,and the alkane（C-H）absorption peak is shifted from 966 cm^-1to 856 cm^-1to 1120 cm^-1to 1214 cm^-1;indicating that hydrogen bonds were formed between the O-H and C=O of BN and the N-H and-COOH of Pro after the formation of BN-Pro cocrystal.The SEM results show that the crystal morphology of BN-Pro cocrystal is changed compared with that of BN,Pro,and BN-Pro physical mixture.4.Preliminary quality evaluation of BN-Pro cocrystalThe maximum solubility of BN-Pro cocrystal at 30 minutes is 16.20 mg/m L,which is 12.66 times higher than that of API;the results of tablet dissolution showed that the dissolution of BN-Pro cocrystal is more than 75%in four different dissolution media with a dissolution time of 30 minutes,which is about 42%higher than that of BN tablet dissolution.The results of the stability tests show a good crystallographic stability of the BN-Pro cocrystal powder and the cocrystal wafers.