School of Pharmacy, University of Otago, 18 Frederick Street, Dunedin 9016, New Zealand.
Int J Pharm. 2011 Sep 30;417(1-2):94-100. doi: 10.1016/j.ijpharm.2010.12.019. Epub 2010 Dec 21.
The aim of this study was to investigate if amorphous indomethacin samples, prepared using different preparation methods, exhibit different structural and kinetic characteristics and if these differences can be correlated to their physical stability (time to crystallisation). Samples were prepared by melt quenching, spray drying, ball milling, and cryo-milling. The resulting amorphous materials were characterised using X-ray diffraction, Raman spectroscopy and differential scanning calorimetry. All freshly prepared samples were completely X-ray amorphous (with a halo being the only feature in the diffractograms). The shape of the halos in the diffractograms, however, varied depending on the preparation method, suggesting structural variations in the near order of the molecules between the differently prepared amorphous forms. Principal component analysis of the Raman spectra of the various amorphous forms revealed that the samples clustered in the scores plot according to preparation method, again suggesting structural differences due to preparation method. The range of vibrations associated with the largest spectral differences in the loadings plot showed that these differences were due to a range of molecular conformations and intermolecular interactions. The ranking of the samples with respect to stability was: quench cooled amorphous samples>cryo-milled (α-form)>spray dried>ball milled (α-form)>ball milled (γ-form)=cryo-milled (γ-form). This ranking was not correlated with the diffractogram shapes or sample distribution in the scores plot of the Raman spectra, suggesting that physical stability was not directly affected by structural variation in the samples. However, ranking of stability of the differently prepared amorphous forms of the drug could be predicted by determining the relaxation time values, for all amorphous samples. The relaxation times, calculated by using the Adam Gibbs and Kohlrausch-Williams-Watts equations, were in accordance with the experimentally determined stability order. This study showed that correlation of physical stability with calculated relaxation time is possible for the same amorphous systems prepared by different methods. This could aid in selecting the most appropriate preparation techniques in situations where there are a variety of suitable methods.
本研究旨在探究不同制备方法得到的无定形吲哚美辛样品是否表现出不同的结构和动力学特征，以及这些差异是否与其物理稳定性（结晶时间）相关。采用熔融淬冷法、喷雾干燥法、球磨法和冷冻研磨法制备样品。使用 X 射线衍射、拉曼光谱和差示扫描量热法对所得无定形材料进行表征。所有新制备的样品均完全无定形（仅在衍射图中存在一个宽化的晕）。然而，衍射图中晕的形状因制备方法而异，这表明不同制备方法得到的无定形形式之间分子的近程有序存在结构变化。对不同无定形形式的拉曼光谱主成分分析表明，样品在得分图中根据制备方法聚类，这再次表明由于制备方法的不同导致结构差异。载荷图中与最大光谱差异相关的振动范围表明，这些差异是由于一系列分子构象和分子间相互作用所致。稳定性样品排序为：淬冷无定形样品>冷冻研磨（α 形式）>喷雾干燥>球磨（α 形式）>球磨（γ 形式）=冷冻研磨（γ 形式）。该排序与衍射图谱形状或拉曼光谱得分图中样品分布不相关，表明物理稳定性未受到样品结构变化的直接影响。然而，通过确定所有无定形样品的弛豫时间值，可以预测不同制备方法得到的药物无定形形式的稳定性排序。使用 Adam Gibbs 和 Kohlrausch-Williams-Watts 方程计算得到的弛豫时间与实验确定的稳定性顺序一致。本研究表明，对于相同的无定形体系，通过不同方法制备时，物理稳定性与计算的弛豫时间之间存在相关性。在存在多种合适方法的情况下，这有助于选择最合适的制备技术。
