(762b) Use of Process Analytical Technology to Gain Mechanistic Insights into Spherical Agglomeration of Active Pharmaceutical Ingredients

Crystallization is a solid-liquid separation process widely used in the pharmaceutical industry to purify and establish physical properties of the drug substance. The performance of subsequent downstream unit operations often depends on the quality of crystals generated in the crystallization. Drug substance attributes (e.g., crystal size, shape, etc.) directly impact the filtration and drying performance in addition to drug product manufacturing processes.

Although pharmaceutical manufacturing processes such as crystallization are well established, more intensified downstream unit operations are being pursued as alternative manufacturing strategies. Spherical agglomeration is a process intensification unit operation that combines crystallization, milling, and granulation into a single unit operation. Historically, growth dominant crystallization processes have been used to generate large drug substance crystals for improved filterability, impurity control, and process robustness. However, in some cases, the product crystals must then be milled to in order to achieve the desired bioavailability. The powder properties that result from the milling operation are often non-ideal for use in the drug product, since the powders can be poor flowing, cohesive, and electrostatic. A powder granulation step is often required to help mitigate these short comings. Spherical agglomeration might have the ability to address these short comings and combine three unit operations (crystallization, milling, granulation/blending) into a single step process, and deliver a powder with desired drug product manufacturing attributes.

In the present work, Process Analytical Technology¹ (PAT) is used to gain mechanistic insight into the effect of various process parameters on spherical agglomeration. Agglomeration of the drug substance has been carried out using a variant of spherical agglomeration, the Quasi Emulsion Solvent Diffusion (QESD) technique. In this case, a quasi-emulsion is formed and used to agglomerate drug substance crystals inside emulsion droplets. It has been shown in the open literature that changing key process parameters such as the turbulent energy dissipation rate, the concentration of solute in the initial solution, and the solvent to anti-solvent ratio changes the dynamics of quasi-emulsion that is formed and hence the quality of agglomerates that are produced. This contribution proposes a mechanistic understanding of QESD through the utilization of PAT, and provides insight into the fundamental rate processes that are required in order to design QESD processes with tailored powder properties.

References:

[1] Y. Yang et al., “Application of Ultra-Performance Liquid Chromatography as an Online Process Analytical Technology Tool in Pharmaceutical Crystallization.”, Cryst. Growth Des., 2016, 16, 7074−7082