Reactive Crystallization of an API

Goals Development and scale-up of a robust process for the reactive crystallization of an API suitable for downstream formulation 

Issues Crystals formed by reaction are thin needles with an aspect ratio of 10.1 and a diameter of 2 p,m—unsuitable for downstream processing or formulation 

The process for the flnal step in a multistep synthesis produces a sulfate salt by the addition of an etha-nolic-sulfuric acid solution to an ethanolic solution of a free base. The resulting sulfate salt crystals are shown in Fig. 10-3a. 

As discussed above, the causes of these fine crystals include 

Neither of these commonly utilized methods proved to be satisfactory in this case because the reaction is still too fast for local control, and increased mixing—even if effective—would break the fragile needles. 

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Figure 10-3 (a) Needles from the reactive crystallization of an API as described in Example 10-1. The needles... 

In the reactive crystallization of an API, methane sulfonic acid (MSA) is reacted with the free base of the previous intermediate. Due to the highly compressible nature of the resulting crystals on filtration, caused by fines from the crystallization, it is desirable to minimize the level of secondary nucleation by reducing the degree of supersaturation and allowing a slower release of supersaturation during the reactive crystallization. 

Luthra, S. A. Casteel, M. Frericks-Schmidt, H. Krzyzaniak, J., In-situ reactivity of API and excipients in an aqueous oral formulation resulting in formation of a quaternary supramolecular co-crystal complex. In AAPS, Washington, DC, October 25, 2011. 

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