Crystallization of Pure Bulk with Polymorphism

EXAMPLE 7-5 Crystallization of Pure Bulk with Polymorphism 

Variables. Polymorph solubilities, control of supersaturation, ciystal growth rate 

As discussed in Chapter 1, polymorphism is a common problem encountered in the synthesis of pharmaceuticals. In the process development for a drug candidate of reverse transcriptase inhibitor, six crystal forms were identified. The first pilot plant batch produced all Form III, not the desired Form I. The purpose of this example is to illustrate the development of a robust crystallization process to consistently grow the desired crystal form. 

The process illustrated here is a simple modification of a previous example. Shown in Fig. 7-25, this modified process prepares the crude ding as a slurry in a feed vessel. The slurry feed was continuously charged to a dissolver that was maintained at a temperature of about 50 C. The feed rate was controlled such that the slurry was put into solution in the dissolver, and the dissolved solution charged continuously to the crystallizer through an in-line filter to remove extraneous insoluble particles and traces of the undissolved product. The crystallizer contained the seed slurry with the correct form at a lower temperature, about 25 C. The crystallizer slurry was continuously filtered through a ceramic cross-flow Alter system with a pore size of 0.2 p-m, and the clear permeate was sent back to the dissolver for further solubilization of product. This was inn until the feed tank was empty and all supersaturation was relieved. The critical parameters for successful development of this process were solubilities of the polymorphs, seeding, and control of supersaturation. 

As mentioned earlier, a total of six crystal forms were identified with this dmg candidate. The solubilities of Forms I and III are shown in Fig. 2.10. It is likely that Form I is the most stable form at room temperature, whereas Form III appears to be the most stable form at a temperamre above 75 C. Based upon the data, it is clear that the solution concentration during the crystallization should not exceed the solubilities of undesired forms in order to prevent the formation of undesired crystal forms. Additionally, there is an upper limit on the operating temperamre and the solution concentration due to the presence of enantiotrophic Form III. 

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