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.
Keywords: ambroxol hydrochloride; factorial design; powder rheology analysis; quality by design; spherical crystallization; spherical morphology; statistical analysis.