Chemical analysis of crystal growth uses infra-red technique

The creation of reproducible crystallisation processes has long been a fundamental challenge for drug manufacturers. However, help is now at hand with a new technique developed by engineers at the University of Leeds in England that provides real time, detailed analyses of chemical processes.

The technique uses infra-red spectroscopy to monitor supersaturation - the levels of chemical saturation in a liquid - required for crystallisation to begin to occur (see 'Monitoring supersaturation', over).

Most drug compounds are crystalline, manufactured in batch process systems. Small changes in crystallisation process conditions, such as temperature and cooling rates, can significantly affect the structure of the resulting crystals, something that 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 crystallising into ice crystals and the temperature can have a bearing on the size of ice crystals that are formed," says 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 infra-red spectrometer to measure the concentration of a specific chemical in solution. In laboratory experiments, this technique was used on the batch cooling crystallisation of chemical L-Glutamic acid (LGA). The information gained from the infra-red spectrometer is coupled with detailed statistical - or chemometric - data to provide a more detailed analysis of the crystallisation process than has been possible with other infra-red spectrometry techniques.

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 work 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 modelling techniques, and works in measurement and modelling across the length scales relevant to pharmaceutical and organic fine chemical production.

This 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 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."

Monitoring supersaturation

The Leeds research is published in a paper entitled "In situ Measurement of Solution Concentration during the Batch Cooling Crystallisation of L-Glutamic Acid using ATR-FTIR Spectroscopy Coupled with Chemometrics" and has been published online in Crystal Growth & Design.

In it, the authors give details of the in situ measurement of solution supersaturation associated with the batch cooling crystallisation of LGA at both 500ml and 20 l scale sizes. This is assessed via ATR-FTIR spectroscopy.

A partial least-squares chemometric calibration model was developed for the online prediction of LGA concentration from measured FTIR absorbance spectra overcoming some significant challenges related to the low sensitivity of LGA in the mid-IR frequency range, its low solubility in water, and its complex speciation chemistry.

According to the authors, the solubility data of LGA in water over the temperature range from 40-80degC, using ATR-FTIR, reveals excellent agreement with that obtained both from using a gravimetric method and literature data. The metastable zone width determined using the turbidimetric methods as a function of heating/cooling rates and solute concentration is found to increase with increasing cooling rate while it decreases with increasing solution concentration.

Monitoring online crystallisation via both spontaneous and seeded in 500 mL and 20 L crystallisers reveals good concentration predictions for seeded crystallisation, while fouling of the ATR crystal prevents its routine use for unseeded crystallisation studies.

Higher supersaturation levels are found for the larger crystalliser scale-size, consistent with enhancement of secondary nucleation at the smaller scale-size


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