Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Project Title Details Single-step crystallization in droplets for sustainable drug formulation processes Principal Investigator: Assisstant Professor Saif Khan. Dr. Saif A. Khan received his Ph.D. in chemical engineering from the Massachusetts Institute of Technology in 2006, where he was an R. T. Haslam Presidential Fellow. In 2006 he joined the National University of Singapore (NUS) as Assistant Professor in Chemical and Biomolecular Engineering. He is also a Singapore-MIT Alliance Fellow in the Chemical and Pharmaceutical Engineering Programme. His current research interests include microfluidics, soft condensed matter physics, colloid science, plasmonic nanomaterials and chemical reaction engineering. His research group at NUS focuses on various aspects of microscale fluid physics and phenomena, with the aim of developing new experimental methods for chemistry and biology that complement or extend existing macroscopic methods. Project Synopsis Crystallization plays an important role in the pharmaceutical industry for separation, purification and formulation of active pharmaceutical ingredients (API). Crystal size, shape and polymorphic form are important factors governing a range of crystal properties such as solubility, stability, hardness, color, melting point and reactivity. Crystal polymorphism is of particular interest in pharmaceutical applications as it affects process sustainability as well as physiological uptake. Thus, one of the primary challenges in pharmaceutical crystallization is how to efficiently and robustly produce crystals of uniform size and polymorphic form, a problem which often involves a trial and error approach. Among existing methods to produce polymorph-specific crystals, emulsion-based crystallization represents an attractive process platform to simultaneously control both nucleation of a specific API morphology, while producing crystal agglomerates of desired size and spherical shape that greatly accelerate product formulation and eliminate costly downstream processing (e.g. dry milling and grinding). However, many open questions remain to be answered before emulsion-based crystallization can be applied within an industrial setting. Here, we propose to establish a clear understanding of emulsion-based ‘spherical’ crystallization processes, where spherical agglomerates of API crystals are produced in a single processing step with precise control over the polymorphic form. We will develop experimental and modeling tools that will not only enable us to unravel the physics of emulsion-based crystallization at a hierarchy of length and time scales, but also enable rapid screening and optimization of industrial processes. Large crystals of API are often produced in pharmaceutical industry for facile filtration. These particulates are subsequently grinded down in a milling process to obtain the desired size distribution. Dry milling is a costly process with a reported material loss of 2-5% in large batches, which can be even higher in small batches. In large-scale production (in Pfizer), the financial burden can exceed US$10 million per year, not to mention the capital cost of the equipment of roughly $5 million (Ende and Brenek, American Pharmaceutical Review, 2004). Besides being time and labor intensive, dry milling is associated with additional problems such as dust explosion hazards and worker exposure to API. Furthermore, crystal morphology can change during dry milling, thus affecting bioavailability of the API. The success of this proposal will strengthen fundamental understanding of emulsion-based crystallization, while also enabling the technology for production of spherical API crystal agglomerates with precise control over size and polymorphic crystal form. Using the gained understanding, we will also design a novel continuous crystallization reactor for industrial scale manufacturing of API, thereby eliminating the need for downstream dry-milling and grinding and reducing cost and environmental impacts. Total research team strength and talents training and knowledge transfer potential if any This project is directed by 3 Co-PIs, who bring, respectively, expertise in experimentation in controlled microfluidic environment, molecular modeling of crystal growth and morphology, and systems level modeling of the process. The program will train manpower (1 research engineer and 12 research fellows) in the area of crystallization of polymorphic APIs. Estimated completion date August 2014