Department of Pharmaceutical Engg., Inje University, Gimhae, Gyeungnam 621-749, Republic of Korea.
Int J Pharm. 2011 Nov 28;420(2):274-81. doi: 10.1016/j.ijpharm.2011.08.044. Epub 2011 Sep 2.
PAT (process analytical technology) has been emphasized as one of key elements for the full implementation of QbD (quality-by-design) in the pharmaceutical area. NIRS (near-infrared spectroscopy) has been studied intensively as an in-line/on-line monitoring tool in chemical and biomedical industries. A precise and reliable monitoring of the particle characteristics during crystallization along with a suitable control strategy should be highly encouraged for the conformance to new quality system of pharmaceutical products. In this study, the anti-solvent crystallization process of indomethacin (IMC) was monitored using an in-line NIRS. IMC powders were produced via anti-solvent crystallization using two schemes; 'S-to-A' (solvent-to-antisolvent) and 'A-to-S' (antisolvent-to-solvent). In-line NIR spectra were analyzed by a PCA (principal component analysis) method. Although pure α-form IMC powder was resulted under A-to-S scheme, a mixture of the α-form and γ-form was produced for S-to-A case. By integrating the PCA results with off-line characterization (SEM, XRD, DSC) data, the crystallization process under each scheme was elucidated by three distinct consecutive steps. It was demonstrated that in-line NIRS, combined with PCA, can be very useful to monitor in real time and interpret the anti-solvent crystallization process with respect to the polymorphism and particle size.
PAT（过程分析技术）已被强调为在制药领域全面实施 QbD（质量源于设计）的关键要素之一。NIRS（近红外光谱）已在化学和生物医学工业中作为在线/在线监测工具进行了深入研究。在结晶过程中精确和可靠地监测颗粒特性，并结合合适的控制策略，应高度鼓励符合制药产品的新质量体系。在这项研究中，使用在线 NIRS 监测了吲哚美辛（IMC）的反溶剂结晶过程。通过两种方案（“S 到 A”（溶剂到反溶剂）和“A 到 S”（反溶剂到溶剂））使用反溶剂结晶法生产 IMC 粉末。通过 PCA（主成分分析）方法对在线 NIR 光谱进行了分析。虽然在 A 到 S 方案下得到了纯 α 形式的 IMC 粉末，但 S 到 A 情况下产生了 α 形式和 γ 形式的混合物。通过将 PCA 结果与离线特性（SEM、XRD、DSC）数据相结合，根据三种不同的连续步骤阐明了每个方案下的结晶过程。结果表明，在线 NIRS 与 PCA 相结合，可以非常有用，可实时监测并解释有关多晶型和粒径的反溶剂结晶过程。
