Abstract Spherical crystallization can be an important technological step in the production of a solid form active agent. By the production of spherical crystals, direct compression tablet making can be applied to the powder material. This method makes the tableting process quicker, shorter and more economical with reduced amounts of additives and a reduced number of technological steps. This way, the granulation method can be avoided, which is also advantageous for a moisture sensitive drug. In this paper, we presented Focused Beam Reflectance Measurement (FBRM) studies applied in the case of the non-typical spherical crystallization methods of the active pharmaceutical ingredient ambroxol hydrochloride. Spherical agglomeration and controlled cooling crystallization methods were carried out based on our previous studies regarding these methods and the crystal formation processes were investigated with FBRM probe. Critical agglomeration periods and other mechanisms, such as the breakage of the agglomerates and the precipitation of small particles, were investigated. Chord length values were observed continuously and samples were taken out in certain points of the crystallization. Particle size analysis was carried out in each case to obtain information on the particle size enlargement caused by the crystallization methods. With the application of light microscopic analysis, aspect ratio and roundness values were also determined to obtain pieces of information on the sphericity-changes of the particles throughout the crystallization and large improvements were presented either for these parameters (aspect ratio from ~ 1.7 to ~ 1.3; roundness from ~ 2.4 to ~ 1.5) and the mean particle size (from ~13 μm to 120–400 μm). Among others, it was revealed that after the spherical agglomeration method (SA), mostly crystal agglomerates were formed, while slow cooling crystallization with alternating temperature profile (ATP) yielded larger and probably harder individual crystals.

中文翻译：

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盐酸氨溴索非典型球形结晶法晶体生长的在线观察

摘要 球形结晶可以是生产固体形式活性剂的重要技术步骤。通过生产球形晶体，可以将直接压片应用于粉末材料。这种方法使压片过程更快、更短、更经济，同时减少了添加剂的用量和工艺步骤的数量。这样，可以避免造粒方法，这对于湿度敏感的药物也是有利的。在本文中，我们介绍了聚焦光束反射测量 (FBRM) 研究，该研究适用于活性药物成分盐酸氨溴索的非典型球形结晶方法。基于我们之前对这些方法的研究，进行了球形团聚和控制冷却结晶方法，并用 FBRM 探针研究了晶体形成过程。研究了临界团聚期和其他机制，例如团聚体的破裂和小颗粒的沉淀。连续观察弦长值，并在结晶的某些点取出样品。在每种情况下进行粒度分析以获得关于由结晶方法引起的粒度增大的信息。随着光显微分析的应用，还确定了纵横比和圆度值以获得有关整个结晶过程中颗粒球形变化的信息，并且这些参数都有很大的改进（纵横比从 ~ 1.7 到 ~ 1.3；圆度从 ~ 2.4 到 ~ 1.5 ) 和平均粒径（从 ~13 μm 到 120–400 μm）。其中，发现在球形附聚法 (SA) 后，主要形成晶体附聚物，而具有交替温度分布 (ATP) 的缓慢冷却结晶产生更大且可能更硬的单个晶体。