Continuous Heterogeneous Crystallization on Excipient Surfaces

A novel continuous heterogeneous crystallization process is developed in which the active pharmaceutical ingredient (API) is crystallized directly on the surface of an excipient within the crystallizer. The product is subsequently dried and formed into tablets without the need for complex downstream processing steps, such as milling, sieving, granulation, and blending. The aim is to eliminate many steps of the particle processing in drug product manufacturing. The APIs and excipients systems were selected by investigating heteroepitaxial mechanisms. The effects of various process parameters, such as temperature, residence time, and mode of operation, on drug loading were studied. Three different process designsmixed suspension mixed product removal with a traditional impeller, Viscojet mixing, and a fluidized bed crystallizerwere utilized for direct crystallization of the API on the surface of the crystalline excipient. The excipient selection and process design parameters have a significant impact on drug loading, avoidance of bulk nucleation and crystallization, control of API crystal shape and size, and process control. The maximum drug loading of the excipient with API in this study was 47%. Also, it was demonstrated that increasing the supersaturation ratio and residence time increased the drug loading. The products were collected from the crystallizer and directly compressed into tablet form. The tablet hardness and dissolution profile were also studied. The fully continuous process eliminates the downstream steps, resulting in the production of crystalline compounds and the final form (tablets) in a significantly faster, more efficient, and more economical manner with a smaller footprint.