Polymorphism is an important aspect of crystallization processes used in the pharmaceutical industry, as many solid drugs exist in different crystalline forms. It is widely recognized that product properties, some of which may be related directly to the utility of the drug, and downstream processes, such as tableting, are influenced by crystal morphology, size, and shape. For these reasons and others, being able to detect a polymorphic transformation in situ would have great value.

Focused-beam reflectance measurement (FBRM) is among the process analytical technologies (PAT) that hold promise for enhanced monitoring of pharmaceutical crystallization. It is based on scattering of laser light and provides a methodology for in-line monitoring of a representation of the crystal population in either batch or continuous crystallization systems. If properly installed, it allows in-line determination of the chord-length density, which is a complex function of crystal geometry. In batch crystallizations, which are especially important in pharmaceutical processing, FBRM instrumentation, offers in situ, real-time information regarding the evolution of crystal size distribution.

In the present research, batch cooling crystallization of paracetamol from ethanol solutions is used as a model system for exploring the utility of FBRM data in detection of the formation and transformations of polymorphs. Paracetamol is known to exist under three different polymorphic forms: a stable Form I (monoclinic lattice), a metastable Form II (orthorhombic lattice) and an unstable Form III. Form II is preferred to Form I because of superior tablet-forming properties due to a higher compressibility. Unfortunately, since Form I is more stable, it is the dominant product form.

Our experiments found that both Forms I and II were nucleated upon batch cooling of a paracetamol-ethanol solution. However, Form II disappeared shortly after nucleation as it underwent a solution-mediated transformation and left an end-product that was uniformly Form I. By slightly modifying the experimental conditions, Form II was nucleated in larger amounts and was retained for a longer period of time. The two forms have different crystal habits; Form I crystals are octahedral, Form II crystals are needle-like. Such different shapes generate different chord length densities thus a transition from one form to the other can be detected through an efficient use of the FBRM.

By varying the conditions at which crystallization was induced, it is possible to induce nearly exclusive nucleation of Form II. Tracking the chord-length distribution of the resulting crystal population makes it possible to monitor the transition between Form II and Form I.