Allesø Morten, Velaga Sitaram, Alhalaweh Amjad, Cornett Claus, Rasmussen Morten A, van den Berg Frans, de Diego Heidi Lopez, Rantanen Jukka
Department of Pharmaceutics and Analytical Chemistry, University of Copenhagen, Copenhagen, Denmark.
Anal Chem. 2008 Oct 15;80(20):7755-64. doi: 10.1021/ac8011329. Epub 2008 Sep 18.
Near-infrared (NIR) spectroscopy is a well-established technique for solid-state analysis, providing fast, noninvasive measurements. The use of NIR spectroscopy for polymorph screening and the associated advantages have recently been demonstrated. The objective of this work was to evaluate the analytical potential of NIR spectroscopy for cocrystal screening using Raman spectroscopy as a comparative method. Indomethacin was used as the parent molecule, while saccharin and l-aspartic acid were chosen as guest molecules. Molar ratios of 1:1 for each system were subjected to two types of preparative methods. In the case of saccharin, liquid-assisted cogrinding as well as cocrystallization from solution resulted in a stable 1:1 cocrystalline phase termed IND-SAC cocrystal. For l-aspartic acid, the solution-based method resulted in a polymorphic transition of indomethacin into the metastable alpha form retained in a physical mixture with the guest molecule, while liquid-assisted cogrinding did not induce any changes in the crystal lattice. The good chemical peak selectivity of Raman spectroscopy allowed a straightforward interpretation of sample data by analyzing peak positions and comparing to those of pure references. In addition, Raman spectroscopy provided additional information on the crystal structure of the IND-SAC cocrystal. The broad spectral line shapes of NIR spectra make visual interpretation of the spectra difficult, and consequently, multivariate modeling by principal component analysis (PCA) was applied. Successful use of NIR/PCA was possible only through the inclusion of a set of reference mixtures of parent and guest molecules representing possible solid-state outcomes from the cocrystal screening. The practical hurdle related to the need for reference mixtures seems to restrict the applicability of NIR spectroscopy in cocrystal screening.
近红外（NIR）光谱法是一种成熟的固态分析技术，可提供快速、非侵入性的测量。近红外光谱法用于多晶型物筛选及其相关优势最近已得到证实。本工作的目的是使用拉曼光谱法作为比较方法，评估近红外光谱法用于共晶筛选的分析潜力。吲哚美辛用作母体分子，而糖精和L-天冬氨酸被选作客体分子。每个体系的摩尔比为1:1，并采用两种制备方法。对于糖精，液相辅助共研磨以及从溶液中共结晶产生了一种稳定的1:1共晶相，称为IND-SAC共晶。对于L-天冬氨酸，基于溶液的方法导致吲哚美辛多晶型转变为与客体分子物理混合保留的亚稳α形式，而液相辅助共研磨未引起晶格的任何变化。拉曼光谱法良好的化学峰选择性通过分析峰位置并与纯参比物的峰位置进行比较，从而可以直接解释样品数据。此外，拉曼光谱法还提供了关于IND-SAC共晶晶体结构的额外信息。近红外光谱的宽谱线形状使得光谱的目视解释变得困难，因此，应用了主成分分析（PCA）的多元建模。只有通过纳入一组母体和客体分子的参比混合物，代表共晶筛选可能的固态结果，近红外/PCA才能成功使用。与需要参比混合物相关的实际障碍似乎限制了近红外光谱法在共晶筛选中的适用性。
