复方甘草酸苷片中甘氨酸与DL-甲硫氨酸原料药的理化性质及晶型稳定性的初步研究

Preliminary study on physicochemical properties and crystal stability of glycine and DL-methionine APIs in compound glycyrrhizin tablets

目的研究复方甘草酸苷片中甘氨酸和DL-甲硫氨酸的固态理化性质和晶型稳定性。方法采用X-射线粉末衍射(X-ray powder diffraction,XRPD)、扫描电镜(Scanning electron microscopy,SEM)、同步热分析(Simultaneous thermal analytical techniques,TGA/DTG-DSC)、傅里叶红外光谱(Fourier transform infrared spectroscopy,FTIR)等分析方法对两种氨基酸原料药固体的理化性质与晶型稳定性进行了表征,探讨其在高温(60℃)、高湿(25℃,相对湿度75%±5%)、粉碎(<10℃)及水中的晶型稳定性。结果室温条件下甘氨酸为块状的α-型晶体,分解温度为257.4℃,ΔHf为773.5 J/g。α-型甘氨酸在高温(60℃)、高湿(25℃,相对湿度75%±5%)、粉碎(湿度<10℃)及60℃水中稳定性较好,未发生转晶;DL-甲硫氨酸为易吸附团聚的片状晶体,易发生固态转晶与溶液介导转晶。在高温(60℃)条件下固体DL-甲硫氨酸会由γ-型转为α-型,热分解温度和ΔH\-f均随α-型增多而增加,低温下γ-型更稳定。由于溶液介导转晶,在60℃水中结晶也只得到γ-型DL-甲硫氨酸。结论α-型甘氨酸与γ-型DL-甲硫氨酸可作为复方甘草酸苷制剂研发的优势晶型。对两个氨基酸固态理化性质及晶型稳定性的考察,可为原料药的物态质量控制和制剂研发的晶型筛选与控制提供实验基础。

Objective To investigate the solid physicochemical properties and crystal stability of glycine(Gly.)and DL-methionine(Met.)in compound glycyrrhizin tablets.Methods X-ray powder diffraction(XRPD),scanning electron microscopy(SEM),simultaneous thermal(TGA/DTG-DSC)analytical techniques and fourier transform infrared spectroscopy(FTIR)was used to investigate the solid physicochemical characterization.The crystal stability of two amino acid under high temperature(60℃),high humidity(25℃,RH 75%±5%),grinding treatment and water dispersion was also studied.Results Gly.was block andα-type crystal.The decomposition temperature was 257.4℃with heats of fusion(ΔHf)of 773.5 J/g.Crystal transition did not occur under high temperature(60℃),high humidity(25℃,RH 75%±5%),grinding(<10℃)treatment and aqueous solution condition,respectively.Met.was flake crystal and easy to occur adsorption and agglomeration.The crystal type of Met.exhibited solid-state and solution-mediated transformations.Under high temperature(60℃),theγ-type was conversed toα-type,and the thermal decomposition temperature andΔH\-f was increased withα-type.Theγ-type was more stable at low temperatures.Theγ-type crystals deposited from aqueous solution due to solution-mediated transformations with maintained at elevated temperature.Conclusionα-type Gly.andγ-type Met.can be used as advantage crystal type for development of compound glycyrrhizin preparation.The investigation of solid physicochemical properties and crystal stability of two amino acids can provide an expe rimental basis for quality control of API and crystal type screening or control for preparation development.