(431c) 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.