On-line observation of the crystal growth in the case of the non-typical spherical crystallization methods of ambroxol hydrochloride

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. [Display omitted] •Spherical agglomeration (SA) of four products was observed by the focused beam reflectance measurement (FBRM).•The same was performed in the case of cooling crystallization with an alternating temperature profile (ATP) as well.•Crystallization types were compared, and a scale-up was performed applying different types of agitation.•The effect of the addition of more cycles to the ATP methods was investigated. Light microscopic exposures proved differences between the SA and the ATP p