School of Cancer and Pharmaceutical Sciences, Institute of Pharmaceutical Science, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.
SciCore Industries, 20 Thomas Hamer Place, Auckland, 0632, New Zealand.
AAPS PharmSciTech. 2021 Mar 14;22(3):105. doi: 10.1208/s12249-021-01971-6.
Medicine regulators require the melting points for crystalline drugs, as they are a test for chemical and physical quality. Many drugs, especially salt-forms, suffer concomitant degradation during melting; thus, it would be useful to know if the endotherm associated with melt degradation may be used for characterising the crystallinity of a powder blend. Therefore, the aim of this study was to investigate whether melt-degradation transitions can detect amorphous content in a blend of crystalline and amorphous salbutamol sulphate. Salbutamol sulphate was rendered amorphous by freeze and spray-drying and blended with crystalline drug, forming standards with a range of amorphous content. Crystalline salbutamol sulphate was observed to have a melt-degradation onset of 198.2±0.2°C, while anhydrous amorphous salbutamol sulphate prepared by either method showed similar glass transition temperatures of 119.4±0.7°C combined. Without the energy barrier provided by the ordered crystal lattice, the degradation endotherm for amorphous salbutamol sulphate occurred 50°C below the melting point, with an onset of 143.6±0.2°C. The enthalpies for this degradation transition showed no significant difference between freeze- and spray-dried samples (p>0.05). Distinct from convention, partial integration of the crystalline melt-degradation endotherm was applied to the region 193-221°C which had no contribution from the degradation of amorphous salbutamol sulphate. The linear correlation of these partial areas with amorphous content, R=0.994, yielded limits of detection and quantification of 0.13% and 0.44% respectively, independent of drying technique. Melt-degradation transitions may be re-purposed for the measurement of amorphous content in powder blends, and they have potential for evaluating disorder more generally.
药物监管机构要求结晶药物的熔点，因为它们是化学和物理质量的测试。许多药物，特别是盐形式，在熔化过程中会同时降解；因此，如果可以知道与熔融降解相关的吸热是否可用于表征粉末混合物的结晶度，这将是非常有用的。因此，本研究的目的是研究熔融降解转变是否可以检测结晶和无定形硫酸沙丁胺醇混合物中的无定形含量。硫酸沙丁胺醇通过冷冻和喷雾干燥使其无定形，并与结晶药物混合，形成具有一系列无定形含量的标准品。观察到结晶硫酸沙丁胺醇的熔融降解起始温度为 198.2±0.2°C，而通过任何方法制备的无水无定形硫酸沙丁胺醇均显示出相似的玻璃化转变温度 119.4±0.7°C 相结合。由于没有有序晶格提供的能量障碍，无定形硫酸沙丁胺醇的降解吸热在熔点以下 50°C 发生，起始温度为 143.6±0.2°C。这个降解转变的焓没有在冷冻干燥和喷雾干燥样品之间显示出显著差异（p>0.05）。与传统方法不同，结晶熔融降解吸热的部分积分应用于没有无定形硫酸沙丁胺醇降解贡献的区域 193-221°C。这些部分区域与无定形含量的线性相关性，R=0.994，产生了 0.13%和 0.44%的检测限和定量限，独立于干燥技术。熔融降解转变可重新用于粉末混合物中无定形含量的测量，并且它们具有更广泛评估无序的潜力。
