Ph.D student, The university of western ontario
Integrate crystallization to continuous manufacturing to improve product quality, process robustness
For decades, most drugs have been manufactured using what is known as “batch” technology — a process whereby the ultimate finished product has been made after many stops and starts in a series of steps. Unfortunately each break in the process causes inefficiency and delay, as well as the increased possibility of defects and error. In my study, I combined a continuous MSMPR crystallizer with a home designed coil tubular crystallizer to realize an effective continuous crystallization process. The whole The MSMPR-Tublar series can control nucleation in the MSMPR crystallizer and grow crystals in the Tubular one. High quality crystals has been successfully produced with greatly reducing production time. Coupled with an feedback control model, we realized an robust production process.
Abstract: A continuously operated helically coiled flow tube (HCT) crystallizer is investigated for crystal growth. Inline video-imaging is used for crystal shape analysis and residence time estimation of potash alum. The main finding is that there is a size-dependent particle residence time. Large particles move faster through the HCT than small particles. Consequently, small crystals have more time to grow in the HCT. Physical reasons for this behavior are proposed, for example, small-scale flow characteristics. In a direct numerical simulation of the instationary Navier–Stokes equations, velocity fluctuations and a secondary flow are identified. The presented flow field may have a different impact on the particles and cause the size-dependent particle residence time. A particle size dependent residence time may potentially narrow the crystal size and shape distribution in such a process, frequently a desired feature in solids’ production.
Pub.: 09 Mar '17, Pinned: 16 Aug '17
Abstract: The use of a continuously operated oscillatory flow baffled crystallizer (COBC) has been promoted as a promising alternative crystallizer design for continuous crystallization because of the claim, based on dispersion of liquid, that plug flow can be achieved. Plug flow can lead to uniformity in product quality, if good control over nucleation and the growth of crystals is also achieved. In this study a residence time distribution (RTD) analysis was made for both homogeneous (methylene blue-water) and heterogeneous tracer system (melamine-water). In literature it is proposed, on the basis of homogeneous tracer experiments only, that the velocity ratio ΨΨ (the ratio between the oscillatory velocity and the superficial velocity of the imposed flow) is sufficient to identify optimal operating conditions for plug flow in COBC. Multiple combinations of amplitude and frequency result in the desired ΨΨ value. Our results show that operating at high amplitudes increases dispersion, reducing the plug flow like mixing. Thus ΨΨ alone is not sufficient for optimizing the mixing. Our study for the first time compares dispersion of homogenous and heterogeneous tracer in the commercially available DN15 system, addressing the knowledge gap in handling solids in COBC. Comparable responses were obtained with both the tracer systems for changes in the oscillatory flow variables. Operation at relative low amplitudes was optimal to obtain plug flow like behavior, even with 10% (w/w) slurry with no problems of the particles settling. The optimal operating condition for minimal dispersion was clearly different for the homogenous and the heterogeneous system.
Pub.: 07 Feb '17, Pinned: 16 Aug '17
Abstract: Continuous mixed-solution mixed-product removal (MSMPR) crystallization is considered. This process has been studied well, however, different aspects, in particular, process modeling, monitoring, and control remain challenging. An innovative approach for online measurement of the crystal size distribution is presented. Furthermore, unscented Kalman filtering is applied to overcome biased concentration measurement. Finally, a discrepancy-based control is applied to continuous MSMPR crystallization and its closed-loop performance is evaluated.
Pub.: 08 Jun '17, Pinned: 16 Aug '17
Abstract: Continuous crystallization of lysozyme and a full-length therapeutic monoclonal antibody was performed in a mixed suspension classified product removal tank with a cooled tubular reactor in bypass. High crystallization yields of more than 90% were obtained. Crystals of the monoclonal antibody were continuously produced for the first time with a space−time yield of up to 12 g L−1 h−1.A lab-scale stirred tank with a cooled tubular reactor in bypass was applied for continuous crystallization of lysozyme and a full-length therapeutic monoclonal antibody. The stirred tank was operated as a mixed suspension classified product removal crystallizer. Lysozyme was crystallized by a combination of cooling crystallization and salting-out. The antibody was crystallized by a combination of cooling crystallization and isoelectric crystallization. It was deduced that nucleation rates were enhanced when the protein solutions passed through the cooled tubular bypass. It was further deduced that crystal growth rates were enhanced in the stirred tank which was operated at a higher temperature compared to the tubular reactor. Classified product removal was possible by controlled sedimentation of protein crystals. The continuous crystallization system allowed a targeted control of crystal morphology and size. No sedimentation occurred in the tubular reactor and precipitation was avoided at all times. High crystallization yields of more than 90% were obtained. Crystals of the monoclonal antibody were continuously produced for the first time with a space–time yield of up to 12 g L–1 h–1.
Pub.: 26 Jun '17, Pinned: 16 Aug '17