| Polymorphs are ubiquitous pharmaceutical preparations,and nearly 57%can form hydrated polymorphs.The water content has a great influence on solubility,bioavailability,production,storage and transportation of drugs.Therefore,the research on thermodynamics,kinetic properties and polymorphic transformation of hydrated polymorphs have become crucially significance on chemical and pharmaceutical industry.In this paper,the crystallization thermodynamics and crystal transformation process of azithromycin and L-phenylalanine were studied as follows.The solubility of azithromycin monohydrate in ethanol,isopropanol,n-propanol,methyl acetate solvent and ethanol-water,n-propanol-water mixed solvent system were determined by static method,and were correlated by various solubility equation models.At the same time,the heat of dissolution in the dissolution process was estimated.In addition,the solubility of azithromycin dihydrate in isopropanol-water and acetone-water mixed solvent system were also determined by static method and correlated by various solubility equation models.The heat of dissolution in the dissolution process was estimated.It is concluded that the solubility of azithromycin monohydrate and dihydrate increases with the temperature and the mass fraction of organic solvent,and the dissolution process is a process of endothermic non-spontaneous.The transition water activity of azithromycin in acetone-water mixed solvent at 293.15,298.15,303.15,and308.15 K were determined to be 0.17,0.21,0.242,and 0.287,and acetone-azithromycin-water ternary phase diagram were established.The laser method was used to determination the metastable zone of azithromycin dihydrate in acetone-water mixed solvent system,and the nucleation series,nucleation rate constant and nucleation rate were calculated,and the effect of initial temperature and cooling rate on the metastable zone of azithromycin dihydrate crystal were also investigated.It is found that the width of the metastable zone narrows with the increase of the initial temperature;as the temperature drop rate increases,the nucleation rate also increases.The solubility of L-phenylalanine in the methanol-water mixed solvent system was determined by static method.A variety of solubility equation models were used to correlate the solubility data.The dissolution heat was estimated.The results showed that the solubility of L-phenylalanine increases with temperature and water activity,and the dissolution process is a process of endothermic non-spontaneous.The transition water activity of L-phenylalanine in methanol-water mixed solvent at 293.15,297.15 and 302.15 were 0.922,0.948,0.982 and methanol-L-phenylalanine-water ternary phase diagram were established.The laser method was used to determination the metastable zone of L-phenylalanine in methanol-water mixed solvent system,and the nucleation series,nucleation rate constant and nucleation rate were calculated,and the effect of initial temperature and cooling rate on the metastable zone of L-phenylalanine crystal were also investigated.It was found that the width of the metastable zone narrows with the increase of the initial temperature;as the temperature drop rate increases,the nucleation rate also increases.The quantitative and qualitative analysis methods for two crystal forms of L-phenylalanine were established by XRD.The polymorphic transformation process of L-phenylalanine in methanol-water mixed solution was investigated.The content of L-phenylalanine two crystal forms was analyzed.When the water activity was 0.84,the crystallization time of 283.15 K was 9 h,the crystallization time of 323.15 K was 3 h,and when the water activity was 0.77,the crystal transformation time of 283.15 K was 12.5 h,and the crystallization time of 323.15K was 5.5 h.The effects of L-glutamic acid,L-tryptophan and L-histidine on the thermodynamics of L-phenylalanine were studied.It was found that all three additives can increase the solubility of L-phenylalanine.The additives effect on the conversion process of L-phenylalanine crystal form was determined,which results were applied by Langmuir model.The addition of L-histidine can inhibit the transformation of crystal form in high temperature zone or low temperature zone,but can not achieve complete inhibition;However,L-tryptophan could not achieve complete inhibition in the high temperature region,and the inhibition of L-phenylalanine crystal form conversion could be completely achieved when the addition amount in the low temperature region was increased to 7.00×10-5 mol/ml.However,L-glutamic acid could not be completely inhibited in the high temperature region,and the inhibition of L-phenylalanine crystal form conversion could be completely achieved when the amount added in the low temperature region was increased to 2.02×10-44 mol/ml. |
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