(572g) Process Intensification through Continuous Spherical Crystallization Using a Two-Stage Mixed Suspension Mixed Product Removal System

Process intensification through
continuous spherical crystallization using a two-stage Mixed Suspension Mixed
Product Removal system

Ramon Peña and Zoltan K. Nagy School
of Chemical Engineering, Purdue University, West Lafayette, IN 47907, US

Of utmost importance in
the crystallization of active pharmaceutical ingredients (APIs) in the
pharmaceutical industry is to produce crystals of good physical, processing,
and biopharmaceutical properties. The definition of good physical properties
depends on what the end goal and the drug formulation that the crystals will be
a part of, but often processing and biopharmaceutical properties are competing
interests. In most cases, the crystallization process is tailored to
improve downstream process efficiency rather than improve drug molecule
efficacy in the human body. Herein a novel concept
and method to help satisfy both processing and biopharmaceutical interests is
proposed, which is based on performing crystallization and spherical
agglomeration in a two-stage continuous mixed suspension mixed product removal
(MSMPR) system. With the suitable operating mode, the system enables to
decouple the nucleation and growth from the agglomeration mechanisms, while
performing efficient continuous manufacturing of particles with desired
properties. Decoupling will offer more degrees of freedom for the control of
each mechanisms. This in turn provides the means by which properties in the
nucleation/growth stage can be tailored to those of most biopharmaceutical
benefit and efficacy (e.g. bioavailability, dissolution, morphology) while
allowing the agglomeration stage to be tailored to produce spherical
agglomerates of the most processing efficiency (e.g. filtering, drying,
friability).

Continuous
spherical crystallization (CSC) of a model drug compound was first carried out
by Kawashima et al.¹ after Kawashima and Capes³ realized
that resulting products from spherical agglomeration had very good flow
properties. In this work, a model continuous mixed suspension, mixed product
removal (MSMPR) crystallizer consisting of one stage was fed an aqueous
suspension. The critical parameters were identified as agitation rate,
suspension feed rate, and bridging liquid feed rate². Since Kawashima
et al.¹ very little work has been done on CSC and few references
make use of process analytical technology (PAT) tools. An abundance of work exists
on spherical crystallization in batch operation. The first batch spherical
crystallization (BSC) was carried out by Kawashima et al.² who
crystallized salicylic acid in ethanol by pouring the solution into a
water-chloroform mixture and found the critical parameters to be similar to
that in a continuous system: agitation rate, temperature, bridging liquid
content, and residence time. In this study a ternary solvent system was used.
This consisted of good solvent to dissolve the drug, poor solvent to
precipitate it, and bridging liquid to promote agglomeration of the
precipitated crystals.

In
this work, a novel two-stage continuous spherical crystallization system in
which the nucleation and growth processes are separated (in the first stage)
from the agglomeration mechanism (in second stage), enabling precise and
independent control of the internal crystal size distribution (CSD) and the
agglomerate size distribution (ASD). This can enable the simultaneous control
of product properties (e.g. dissolution profile) and processing requirements
(flowability, compressibility, etc.)

1.      Kawashima,
Y.; Kurachi, Y.; Takenaka, H. Preparation of spherical wax matrices of
sulfamethoxazole by wet spherical agglomeration technique using a CMSMPR
agglomerator. Powder Technol. 1982, 32, 155?161.

2.      Kawashima,
Y.; Okumura, M.; Takenaka, H. Spherical crystallization: direct spherical
agglomeration of salicylic acid crystals during crystallization. Science.
1982, 20?21

3.      Kawashima,
Y.; Capes, C. An experimental study of the kinetics of spherical agglomeration
in a stirred vessel. Powder Technol. 1974, 10, 85?92.