(34g) Mechanistic Insights into a Process Intensification Strategy in Pharmaceutical Manufacturing

Spherical Agglomeration is a novel Process Intensification strategy that has been heralded as a revolution in pharmaceutical manufacturing. It combines the pharmaceutical unit operations of crystallization and granulation into a single unit operation thereby decreasing the cost of manufacturing Active Pharmaceutical Ingredients(APIs). Spherical Agglomeration is also very attractive from a particulate control viewpoint since the two rate processes – crystallization and agglomeration are carried out sequentially, thereby giving greater freedom in the design space to control the process. Typically most drugs sold in the market as tablets also contain other inactive ingredients(excipients). A major bottleneck to industrial implementation of Spherical Agglomeration in Pharmaceutical Manufacturing is the fact that co-agglomerating drugs and excipients within a single stage using a binder is very challenging, albeit impossible in many cases.

Co-agglomeration of APIs and excipients has been achieved using Emulsion Solvent Diffusion(ESD). Despite its initial success, developing a robust ESD process still remains a challenging task. The success of ESD hinges on selecting the right combinations of solvents, antisolvents, API concentration and emulsifier concentration. This is further compounded by the fact that in ESD, the Primary Particle Size Distribution(PSD) and the Agglomerate Size Distribution(ASD) need to be controlled simultaneously during the diffusion process which gives less number of degrees of freedom from a process control standpoint.

Although much work has been done on finding the effect of process conditions(flow rate, concentration of API) on the ASD, there is still a huge knowledge gap in literature regarding the mechanisms of the fundamental rate processes behind ESD. This work delves into gaining a mechanistic understanding of the ESD by giving systemic perturbations to the process and studying the system response characteristics. Process Analytical Technologies(PAT) tools viz. FBRM have also been used in the process to monitor the evolution of the Chord Length Distribution. It has been shown that use of in-situ PAT tools gives novel insights into the mechanisms of ESD process that would have been otherwise unattainable by just studying the end of batch response characteristics to systemic perturbations.