API Attribute Control by Continuous Fast Crystallization/Precipitation

 

            Increased bioavailabilty and/or good API particle size and attribute control is needed to enhance or render robust the pharmacokinetic profile of an increased number of current drugs and/or new molecular entities. Continuous fast crystallization/precipitation is a more effective method compared to batch crystallization/precipitation to control API attributes and produce small particles for a number of reasons. Continuous fast crystallization offers higher mixing intensity and lower mixing times as well as a wider range of these two parameters. This results in increased operational flexibility. In addition, supersaturation is constant during a continuous process thus producing a narrower PSD compared to batch crystallization. Finally, the scale up factor from laboratory to commercial scale is two to three orders of magnitude lower for continuous crystallization. This paper describes a systematic approach for the implementation of continuous fast crystallization processes. Individual case studies showcase the advantages offered by continuous processing.

            We identified three main drivers for the implementation of continuous fast crystallizations. The first is manufacturing API with small particle size to enhance bioavailability. The second is particle size and/or other API attribute control within a tight range. The third is the increased throughput and associated cost reduction offered by continuous processes. We also identified a systematic approach for the implementation of continuous fast crystallization and their scale up from laboratory to pilot plant and commercial scale equipment. This approach includes the determination of the fundamental kinetic constants of the system (mixing and induction time) and the subsequent selection of an appropriate mixer design for scale up.  

The first case study involves the isolation and attribute control of an amorphous API. Its precipitation is characterized by very small induction times (< 60 ms) and is therefore mixing sensitive. The amorphous nature of the API introduced additional complications during the precipitation; local mixing effects and/or elevated temperatures rendered a gummy and therefore not processable API. We developed a continuous tee mixer precipitation process to minimize the effect of mixing on particle size and surface area. The developed precipitation was transferred successfully to commercial scale. The API surface area produced ranged between 25 and 32 m²/g for 10 batches. The equivalent average particle sizes are 220 and 170 nm, values indicating the good PSD control offered by the continuous precipitation process.

            The second case study involves a dissolution limited drug substance, which required micronization to provide adequate exposure. However, we encountered severe clogging of the jet mill chamber during micronization, which severely limited process throughput (3 days to micronize 12 kgs of drug substance). These problems were overcome by altering the input to the micronization process. We found that producing API with a co-axial injection continuous crystallization resulted in high API surface areas. The latter was proven considerably more amenable to jet milling; the process throughput increased more than tenfold, from 200 g/hr to about 1.5-2.0 kg/kr.