Production of spherical crystals with an appropriate particle size is an important objective for active agents dedicated to direct tablet making (Nat. Mater.201110867871; Cryst. Growth Des.20151551495156). The material chosen for our experiments, ambroxol hydrochloride, is such a solid compound. The optimal habit for the crystals of direct compressible active agents and additives includes sphericity, proper mean particle size, and appropriate surface. The main objective of the present work is to compare typical and nontypical spherical crystallization methods and to investigate their applicability for ambroxol hydrochloride. The particles were investigated by light microscopy, coupled with an image analyzator program, scanning electron microscopy, powder X-ray diffractometry and differential scanning calorimetry in order to obtain information about particle morphology, mean particle size, aspect ratio, roundness and potential polymorphic transitions. Powder rheology properties were also investigated. The typical crystallization method of quasi-emulsion solvent diffusion was suitable for increasing mean particle size, but large-size spherical crystals did not form. Nontypical spherical crystallization methods (spherical agglomeration and the method of cooling with an alternating temperature profile) caused an increase in mean particle size and an improvement in aspect ratio and roundness. Powder rheology parameters of the spherical agglomeration products improved, too.

This research work presents the use of the Quality by Design (QbD) concept for optimization of the spherical agglomeration crystallization method in the case of the active agent, ambroxol hydrochloride (AMB HCl). AMB HCl spherical crystals were formulated by the spherical agglomeration method, which was applied as an antisolvent technique. Spherical crystals have good flowing properties, which makes the direct compression tableting method applicable. This means that the amount of additives used can be reduced and smaller tablets can be formed. For the risk assessment, LeanQbD Software was used. According to its results, four independent variables (mixing type and time, dT (temperature difference between solvent and antisolvent), and composition (solvent/antisolvent volume ratio)) and three dependent variables (mean particle size, aspect ratio, and roundness) were selected. Based on these, a 2–3 mixed-level factorial design was constructed, crystallization was accomplished, and the results were evaluated using Statistica for Windows 13 program. Product assay was performed and it was revealed that improvements in the mean particle size (from ~13 to ~200 µm), roundness (from ~2.4 to ~1.5), aspect ratio (from ~1.7 to ~1.4), and flow properties were observed while polymorphic transitions were avoided.

Spherical agglomeration (SA) of four products was observed by the focused beam reflectance measurement (FBRM), conclusions, similarities, differences were summarized and the agglomeration mechanism was revealed.  The same was performed in the case of cooling crystallization with an alternating temperature profile (ATP) as well.  Crystallization types were compared in case of using a double-walled glass reactor of 250 ml with a total solvent volume of 80 ml and, as a scale-up, a jacketed reactor of 750 ml with a total solvent volume of 500 ml, while applying different types of agitation.  The effect of the addition of more cycles to the ATP methods was investigated. Light microscopic exposures prove significant differences between the SA and the ATP products.

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