| Ipriflavone is a non-hormonal semi-synthetic isoflavone.Originally,Ipriflavone was found as a plant growth factor in soybeans,and then developed as a new antiosteoporosis drug.Clinically,it is usually used to treat and prevent postmenopausal osteoporosis due to its significant pharmacologic effects with few adverse reactions.Factors such as solubility,particle size distribution and size of the drug crystals will affect the preparation and clinical efficacy of the drug.Solventing out crystallization is one of feasible methods to achieve a controllable crystal size and distribution of drugs.At present,the industrially synthesized ipriflavone has problems of low crystal yield and small particle size.Therefore,it is of great significance to realize the controllable preparation of ipriflavone bulk drug crystals.In light of this,the solid-liquid phase equilibrium and optimization of crystallization process conditions involved in the solventing out crystallization process of ipriflavone was studied in this work.The crystallization thermodynamic data was obtained and the appropriate crystallization process conditions were determined,which provided basic information and guidance for the industrial scale-up and design of ipriflavone crystallization process.The laser dynamic monitoring method was applied to determine the solubility data of ipriflavone in twelve pure solvents and four binary solvents under normal pressure and at a temperature range of 278.15～323.15 K,and the solubility rules in each solution system were summarized.The modified Apelblat equation,λh equation,NRTL equation,Uniquac equation and van’t hoff equation were used to correlate the obtained solubility data,and the correlation equations suitable for each solvent system were determined.The apparent standard dissolution thermodynamic properties of the dissolution process of ipriflavone in pure solvents and binary mixed solvents were calculated by using the van’t hoff equation apparent analysis method,.The results showed that the dissolution process in the studied solution is endothermic and driven by entropy increase,and the contribution of dissolution enthalpy change to the dissolution Gibbs free energy change is greater than the dissolution entropy change.According to the crystallization thermodynamics data,NMP-water was selected as the solvent system for ipriflavone solventing out crystallization.The single factor method was used to explore the process conditions of ipriflavone in the NMP-water system.The effects of factors including crystallization temperature,antisolvent addition amount,antisolvent dropping acceleration,stirring speed,seed crystal addition amount and aging time on the crystal yield,crystal size and distribution were investigated.Based on the research results,the more suitable crystallization process conditions were determined as follows: crystallization temperature 20℃,the added antisolvent 1:0.4,the rate of antisolvent drop 1.2 m L/min,the stirring rate 450 r/min,the amount of seed crystal added 0%,and the aging time 3 h.The prepared crystal product under these conditions has a crystallization yield of 92%.The analysis of the crystal particle size with a laser particle size detector showed that the average crystal size is about 12.90μm,and the coefficient of variation is 0.7095.Compared with the raw materials,the obtained ipriflavone shows an increased main particle size,a narrowed particle size distribution,and a reduced variation coefficient.The infrared spectroscopy analysis and XRD characterization showed that the positions of the characteristic peaks of the samples(before and after crystallization)are consistent;scanning electron microscope observation(SEM)showed that the crystal form of ipriflavone is irregular.Moreover,the grain size of the crystal increased and the crystal shape is more regular after crystallization,which was consistent with the result of the crystallization process. |
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