January 19, 2009
Infrared Spotlights Crystal Growth
The creation of a reproducible crystallization process is a fundamental challenge to drug manufacturers, but a technique which provides real time detailed analyses of chemical processes could provide an answer.
Developed by engineers at the University of Leeds, the technique uses infrared spectroscopy to monitor supersaturation "“ the levels of chemical saturation in a liquid - required for crystallization to begin to occur.
Most drug compounds are crystalline, manufactured in batch process systems. Small changes in crystallization process conditions, such as temperature and cooling rates, can significantly affect the structure of the resulting crystals, something which affects both their physical properties and their performance.
"For example, when you cool water the molecules in the water have to get into the right position to begin crystallizing into ice crystals and the temperature can have a bearing on the size of ice crystals that are formed," says Dr Tariq Mahmud from the University's School of Process, Environmental and Materials Engineering. "It's similar with chemicals, although there's a wider range of parameters to take into account."
The new technique uses a probe attached to an infrared spectrometer to measure the concentration of a specific chemical in solution. In laboratory experiments, this technique was used on the batch cooling crystallization of chemical L-Glutamic acid (LGA). The information gained from the infrared spectrometer is coupled with detailed statistical "“ or chemometric - data to provide a more detailed analysis of the crystallization process than has been possible with other infrared spectrometry techniques.
Dr Mahmud explains: "Using a chemometric approach enables us to take many more parameters into account, which makes it a more reliable predictor of the optimum concentration levels required to produce a particular crystal structure."
The latest technique was developed by engineers at Leeds in collaboration with researchers at Newcastle and Heriot-Watt universities as part of the Chemicals Behaving Badly program which is funded by the Engineering and Physical Sciences Research Council, along with ten industrial partners.
It is the latest in a raft of new "Quality by Design" (QBD) tools being developed for the pharmaceutical manufacturing sector as part of a drive for increased understanding of drug processing fundamentals. "By developing tools to increase knowledge about, and monitor, batch process systems, we're providing practical solutions to problems faced by industry on a daily basis," says Dr Mahmud. "This sort of technological approach to manufacture will help reduce waste "“ and therefore costs - and could have a significant role to play in increasing the competitiveness of the pharmaceutical sector."
This research is published in a paper entitled "In situ Measurement of Solution Concentration during the Batch Cooling Crystallization of L-Glutamic Acid using ATR-FTIR Spectroscopy Coupled with Chemometrics". The paper has been published online in Crystal Growth & Design.
This work was draws on previous research and experimental systems developed through the Chemicals Behaving Badly II initiative. Led by Professor Kevin J Roberts at the University of Leeds, Chemicals Behaving Badly is an Engineering and Physical Sciences Research Council (EPSRC) and industrial consortium which includes the universities of Leeds, Heriot-Watt and Newcastle, along with ten key industrial partners. It is primarily concerned with optimal design of batch reactors using in-process measurement and advanced modeling techniques. It works in measurement and modeling across the length scales relevant to pharmaceutical and organic fine chemical production.
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