Advances in on-line monitoring and control of the morphological and polymorphic forms of organic crystals grown from solution

Abstract

Organic crystals grown from solution are known to exhibit multiple morphology as well as habits which are of great importance to the end-use property of the product such as the bioavailability and the downstream processing such as in filtration and drying. The crystal morphology can also dictate other quality measures such as the size. Compared with the great amount of research work that has been done on the on-line measurement of other quality measures such as the size and concentration using various spectroscopy techniques, the literature on the on-line measurement and manipulation of crystal morphology is scarce. Attempts were made in the past to use laser diffraction and ultrasound spectrometry for shape monitoring. These methods have not proved to be very successful due to the difficulty in extracting detailed shape information from the signals corrupted by noise and multiple scattering. In this paper, we describe a new approach for on-line crystal morphology measurement and control which is based on the integration of online imaging, multi-scale image analysis and crystal morphology modelling, and present the results obtained on applying the approach to the batch crystallisation of (L)-glutamic acid. Online imaging proved capable of capturing high f idelity crystal shapes and polymorphic transitions in real time. A multi-scale image analysis method was proposed to extract the crystals from the image background and to calculate shape descriptors which were then used for shape recognition and to derive monitoring charts showing the ratios of dif ferent polymorphs in real time as well as the relative average growth rates of facets of crystals. Calculating crystal growth rates and estimating kinetics parameters for needle-shaped crystals was also investigated. Finally, a methodology called ‘camera model’ for integrating on-line imaging and crystal morphology modelling was presented.