Simulation And Experimental Study On The Crystallization Of Aspirin With Addition Of Additives

More than 80% of solid pharmaceuticals are made in crystalline forms,therefore crystallization is a vital unit operation in the pharmaceutical manufacturing industry.Manipulation of crystal morphology,i.e.how to prepare the product with certain crystal habit is a key task of crystallization process design.In this work,crystallization of aspirin was studied and molecular simulation was used as a tool to explore the interaction between solvents and the crystal planes and the interaction between additives and the crystal planes.The characteristics of different crystal planes were analyzed by cutting the crystal planes,which would provide theoretical guidance for the screening of additives as aspirin morphology modifier.In addition,crystallization experiments were conducted to verify the effectiveness of additives in the control of crystal morphology.Based on these,an aspirin cooling-antisolvent crystallization process was developed.The specific research contents are as follows:The solubility of aspirin in ethanol-water with different solvent ratios was determined by a gravimetric method.The result indicated that the solubility of aspirin decreased with the increase of the water content.The effect of polyvinylpyrrolidone(PVP)molecular weights on the solubility of aspirin was also investigated.The result revealed that within the range of concentration used in this study,i.e.?0.1%(w / w),PVP had no noticeable influence on the solubility of aspirin.Four thermodynamic models,including the Apelblat equation,Van't Hoff equation,CNIBS/R-K equation and Jouyban-Acree equation were used to fit the data.CNIBS / R-K equation gave the best fitting result.The influences of solvent ratio,cooling rate,agitation rate,additive and addition amount on the metastable zone width of aspirin crystallization were measured by a turbidity method,which would provide the basic information for the design and optimization of crystallization process.The modified crystal habits of aspirin under different ethanol-water ratios were simulated with molecular simulation and compared with the experimental result.It showed that they were in good agreement.The characteristics of different crystal planes were analyzed by cutting the crystal planes,and the adsorptions of water molecules and ethanol molecules on the aspirin crystal planes were simulated.Molecular dynamics method was employed to simulate the interactions between additives and different crystal planes,which would provide theoretical guidance for the screening of additives.On the basis of simulation,the additives that have obvious effects on the crystal morphology of aspirin,i.e.PVP and hydroxypropylmethylcellulose(HPMC),were selected.Experiments were carried out to study the morphology of aspirin under different solvent ratios and additives.It was found that the aspect ratio of aspirin decreased with the increase of PVP concentration and its molecular weight,and increased with the increase of HPMC concentration.Molecular simulations proved that PVP had the strongest interaction with the(0 1 1)planes.As the degree of polymerization increased,the interaction would also increase.HPMC had the strongest interaction with the(0 0 2)plane.PVP and HPMC inhibited the growth of(0 1 1)and(0 0 2)planes,respectively,which caused changes in the shape of aspirin.Based on the crystallization thermodynamics and crystal morphology,the coolingantisolvent crystallization process of aspirin was designed.The effects of the PVP K88-96 concentration,the amount of seeds,cooling rate,stirring speed and water addition rate on the product morphology,particle size distribution and flowability were investigated.The result demonstrated that as the operation conditions were as following,i.e.initial and end water contents of water were 16.31%wt and 60%wt,with addition 0.05% PVP K88-96(g /g solvent),1% seed,(g / g raw material)and cooling rate of 0.3K/min,stirring speed of 250 rpm,water addition rate of 5ml/min the morphology of product was short prismatic,and it could improve the particle size distribution and flowability significantly.