(509a) API Particle Size Engineering by Continuous Crystallization

A current trend in the pharmaceutical sector is the need to drive down manufacturing costs resulting in the development of new, cost-efficient processing strategies. One potential area for cost-savings is to move from batch to continuous processing; some benefits may include lower capital expenditure and operating costs, improved flexibility, shorter down-times, and the capability for better product property control. One key step in the drug manufacturing process is the formation of the final active pharmaceutical ingredient (API) which usually is done by crystallization. Key properties of the final drug product such as form, size, and shape are generally difficult to control, yet they can have a great effect on formulation, dosage, and drug solubility. For many crystallization processes the desired properties, like the particle size distribution (PSD), cannot be achieved directly from the crystallizer thus requiring post-processing steps such as milling to achieve the product specification. This paper presents research-scale case studies demonstrating the flexibility of continuous crystallization for engineering a PSD. A robust process can be designed using multiple continuous crystallizers (either cooling and/or antisolvent) in series. A continuous crystallization provides a number of important manipulated variables that can be used to control the steady-state supersaturation across a series of tanks. Every crystallization process is characterized by a unique set of crystallization kinetics for nucleation and growth, both of which depend on supersaturation, and the correct design of these effects can yield a range of product properties. The manipulated variables that are investigated include tank temperatures (and/or antisolvent flowrates), residence times, and inlet feed concentration. It is demonstrated how simple changes in any or all of these parameters can drastically effect the final crystal properties and how the competing effects of nucleation and growth can be used across multiple tanks to manipulate the final PSD. One clear advantage to this approach over batch crystallization is taking advantage of a continuously self-nucleating process over a ?seeded' batch crystallization which reduces overall process productivity. However, the real benefit is the ability to produce a final product directly from the crystallization that is ready for formulation eliminating the need for any size-manipulation steps such as high-shear dry milling.