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.
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