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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