【作者】 张颖；

【导师】 苏伟怡；

【作者基本信息】 河北工业大学 ， 化学工程， 2020， 硕士

【摘要】 多晶型现象在固态有机药物中普遍存在。同一分子的不同晶型往往在空间晶格排列中存在差异,从而导致药物不同晶型在理化性质、生物利用度以及相关制剂质量等方面均有不同。因此,近年来医药工作者对多晶型现象的研究日益重视。其中,不同晶型的成核和晶型转变条件尤为重要。通过控制多晶型的转晶过程,可以提高得到目标晶型的效率,因此转晶过程逐渐成为科学研究的热点问题。本文以壬二酸多晶型为研究对象,对多晶型的制备和转变进行了深入研究。首先,通过在不同溶剂中冷却结晶,制备出了壬二酸的两种晶型,初步明确了溶剂和降温速率对两种晶型的影响。同时,采用XRD、FT-IR以及DSC等仪器,对两种晶体的结构和形貌进行了表征与分析。并利用BFDH模型及AE模型对壬二酸不同晶型的晶习进行了预测,为后续晶面建模和分子模拟奠定了基础。通过静态法测定了壬二酸两种晶型在水、无水乙醇和丙酸三种溶剂中的溶解度,并用修正的Apelblat模型对溶解度数据进行了关联。溶解度结果表明,壬二酸的溶解度随温度升高而增大;且壬二酸两种晶型在无水乙醇中溶解度最大,在水中溶解度最小;除此之外,不论在哪种溶剂中,壬二酸alpha晶型的溶解度均大于beta晶型,这从热力学角度证实了beta晶型在实验温度范围内更加稳定。此外,利用Materials Studio软件模拟了壬二酸多晶型在上述溶剂中的溶解过程,发现两者在不同溶剂中的扩散速率不同可能会直接导致其溶解度存在差异。在热力学数据的基础上,重点研究了壬二酸alpha晶型向beta晶型转变的过程。分别利用XRD和紫外分光光度计对过程中壬二酸两种晶型的固相组成和液相浓度进行定量监测。通过浓度分析,初步判断beta晶型的生长是整个转晶过程的速率控制步骤。同时,考察了温度和溶剂对转晶速率的影响,实验发现溶剂的影响最大,两晶型在无水乙醇中的转化速率大于在丙酸中的,而水中的转晶速率最小。在转晶实验的基础上,利用Materials Studio软件分析对比了壬二酸不同晶型的分子结构,并进一步模拟了壬二酸在无水乙醇和丙酸溶剂中的转晶过程。初步揭示了溶剂影响壬二酸多晶型转晶速率的原因:首先,由于丙酸分子更易吸附在晶面上,可能竞争性地阻碍溶质分子在晶面上的生长,从而导致转晶时间较长;同时,从溶质分子扩散的角度,乙醇中的壬二酸分子更易扩散,从而更易成为有效的生长单元而促进稳定晶型的生长,进而促进转晶过程;最后,模拟发现相较于丙酸,乙醇溶液中的壬二酸分子构象更接近稳定晶型(beta)内的分子构象,这说明在本文实验的条件下,乙醇对于beta晶型可能是更优势的溶剂。更多还原

【Abstract】 Polymorphism is very common in solid organic drugs.Generally,different crystal forms of the same molecule often have different spatial lattice arrangement,which could lead to different physical and chemical properties,bioavailability,and even the efficacy of drugs.Therefore,researchers have paid more and more attention to the research of polymorphism in recent years.Among them,the nucleation of different crystal forms and the conditions for polymorphic transformation are particularly important.Typically,by controlling those processes,the efficiency of obtaining the target polymorph should be improved significantly.In this thisis,the preparation and transformation of azelaic acid polymorphs were studied in-depth,and the details were as followed.Two polymorphs of azelaic acid were sucessfully prepared by cooling crystallization in different solvents,and the effects of the solvents and the cooling rates on the two crystal forms were initially obtained.At the same time,the structures and morphologies of the two forms were characterized and identified by XRD,FT-IR and other instruments.In addition,the crystal habit of different polymorphs were predicted by using the BFDH model and AE model,which laid the foundation for subsequent crystal surface modeling and molecular simulation.The solubility of both polymorphs of azelaic acid in pure water,ethanol and propionic acid were measured by a gravimetric method,and the data were correlated by the Apelblat model.The results showed that the solubility of the two forms both increased with temperature,while both were the most soluble in ethanol and the least soluble in water.What’s more,the solubility of the alpha form of azelaic acid was greater than that of beta form in all solvents,which confirmed that the beta form was thermodynamically more stable than the alpha form under our experimental condition.In addition,the dissolution process of azelaic acid polymorphs in the above solvents were simulated using Materials Studio software.It was found that the discrepancy of diffusion rates of the two polymorphs in different solvents might be the reason for their solubility differences.The polymorphic transformation from the alpha to the beta form of azelaic acid was mainly studied.XRD and UV spectrophotometer were respectively used to quantitatively monitor the solid phase composition and liquid phase concentration during the transformation.As a result,it was concluded that the growth of the beta form should be the rate-controlling step in the entire polymorphic transformation process according to the concentration analysis.Specifically,the effect of temperature and solvents on the transformation rate were systematically studied.The experiments found that the effect of the solvent was the largest,and the transformation in ethanol was faster than that in propionic acid,while the conversion rate in water was the smallest.Based on the experiments and the molecular structures of different azelaic acid crystal forms,the polymorphic transformation in ethanol and propionic acid were further stimulated using Materials Studio software in order to reveal that how the solvent could affect the transformation process.First of all,it was found that the propionic acid molecules are more easily to be adsorbed on the crystal surface,which may competitively hinder the growth of solute molecules on the surface,resulting in a longer transition time.Then on the perspective of solute molecule diffusion,the calculation results indicated that the azelaic acid molecules in ethanol are more likely to diffuse in the solution,which make them effective growth units to promote the growth of stable beta forms so as to promote the transformation process.Finally,after the molecular dynamic calculation,it was found that the molecular conformation of azelaic acid in the ethanol solution was more similar to that in the beta lattice,which indicates that ethanol may be more advantageous solvent for the beta form than propionic acid under the experimental conditions.更多还原