Impact of crystallization conditions and filtration cake washing on the clustering of metformin hydrochloride crystals

Abstract

Crystallization is one of the basic methods employed in the pharmaceutical and chemical industry to produce powder products with controlled purity. Crystallization is commonly associated with the filtration and drying of solid material, where these unit operations can significantly affect the properties of the final material. This study focuses on the interplay of crystallization, filtration, cake washing, and drying to prevent the formation of crystal clusters. In this work, metformin hydrochloride crystalizing in rod-like crystals is used as a model drug. First, the crystallization parameters, such as stirring speed, cooling rate, impeller type, and solvent type, were varied. It was found that in all cases, metformin hydrochloride crystalizes in single rod-like crystals with various crystal size distribution, where the cooling rate and solvent type lead to non-uniform crystal growth demonstrated by very polydisperse crystal size distribution. Experimental results and Computational Fluid Dynamics simulation confirmed that stresses during crystallization were not sufficient to cause significant crystal breakup. In the next step, filtration connected with filter cake washing and subsequent drying was used to study the formation of crystal clusters. It was found that crystal cake was significantly stronger for the non-washed samples than for washed cake. Both the measured apparent elasticity modulus and the apparent hardness confirmed a strong impact of the washing solvent, allowing quality control when developing a crystal production process.