Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 1981. / MICROFICHE COPY AVIALABLE IN ARCHIVES AND ENGINEERING. / Bibliography: leaves 118-119. / by Jane Ellen Martini. / M.S.

Batch crystallization is used widely in the production of high-value added species. 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. The ability to observe on-line the evolution of the population density and detect a polymorphic transformation would constitute a major asset in understanding crystallizer operation and the phenomena that influence product quality. 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 on-line monitoring of a representation of the crystal population in either batch or continuous crystallization systems. Properly installed, the FBRM allows on-line determination of the chord-length density, which is a complex function of crystal geometry and is statistically related to the population density. A model based on the geometry of the crystal was therefore established to relate both densities and thus enable computation of the population density from a measured chord length density. The evolution of the population density as a function of time leads to the estimation of the supersaturation and therefore allows the determination of the systems kinetics. From there, the population balance can be solved. Paracetamol is a common substance which exhibit polymorphism and is mainly used as an analgesic and antipyretic drug. The developed model was here applied to batch cooling crystallization of paracetamol from ethanol solutions; this system was used to explore the utility of FBRM data in detection of the polymorphic transformations. As different shapes generate different chord length densities, a transition from one polymorphic form with one specific crystal habit to another can be tracked through the FBRM. The purpose of the present study is to use the FBRM to monitor the evolution of the crystallization process, develop a model describing the evolution of the process, and monitor polymorphic transformation. The end results would be the possibility to implement a better control of the crystallization process that would ensure that downstream processing and product quality meet expectations.

The research addressed in this thesis focuses on monitoring and characterization of pharmaceutical compounds by laser backscattering. In particular, this study covers two topics: (1) the determination of naproxen sodium solubility in water, and its phase transition; and (2) comparisons of batch and laminar flow tubular crystallizers for the production of paracetamol (acetaminophen) and D-mannitol. Using a Lasentec™ Focused Beam Reflectance Measurement (FBRM) device, the solubility of naproxen sodium in aqueous solutions was determined over a temperature range from 15.2 to 39.7 ℃ With the determination of the solubilities of two pseudopolymorphs, anhydrous and dihydrated naproxen sodium, the phase transition point between these two forms of the pharmaceutical compound was determined to occur at 30.3 ℃ Enthalpy of solution and metastable zone widths were also determined for the experimental conditions. Crystallizations of paracetamol and D-mannitol were performed in a batch crystallizer and in a laminar flow tubular crystallizer (LFTC) system. In the latter system, supersaturation was generated rapidly in the solution being transported through a temperature-controlled tube and recovered in a batch vessel where product crystals were grown to equilibration. Because of the rapid rate at which supersaturation was generated in the LFTC, the resulting crystals were of smaller mean size than those obtained from batch crystallizations. The total time required for crystallization was significantly less with the LFTC than with the batch unit. Additionally, the rapid cooling in the LFTC led to the formation of two different polymorphs of paracetamol, Forms I and II.