Optimization of crystallization processes using vibrational spectroscopies

Control of crystallization directly affects the physical and chemical properties of the resulting crystals. Current studies demonstrate that optimal crystallization conditions can be determined using in situ vibrational spectroscopies.; The first study discusses optimization of pH swing crystallization of nicotinic acid (HNic). HNic is produced by adding hydrochloric acid (HCl) to a sodium nicotinate (NaNic) aqueous solution. In situ Attenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) spectroscopy allowed us to measure solubility and supersaturation including the metastable limit of HNic. The Partial Least Squares regression (PLS) method was employed for IR data analysis. The solubilities of HNic vary significantly with pH and the concentration of NaNic. Metastable zone width is dependent on the process parameters including the concentration of HCl, the addition rate of HCl and the agitation speed. A set of optimized parameters was obtained to produce crystals of HNic with larger mean size through spontaneous (primary) crystallization. The metastable zone defines the operation range for the controlled crystallization of HNic. We seeded HNic within the operation range to greatly increase mean crystal size of HNic. The degree of secondary nucleation is demonstrated to be dependent on the level of relative supersaturation at which seeding is performed. Throughout the post seeding acid addition, crystallization was controlled by keeping relative supersaturation at a constant level, which was realized by feedback control of relative supersaturation. It was found that keeping the solution at low relative supersaturation throughout seeding and post seeding acid addition processes promotes crystal growth and suppresses secondary nucleation to the largest degree. Therefore, we are able to obtain HNic crystals with larger mean size with the optimized process parameters for both seeded and unseeded crystallization processes.; The second study covers an investigation of solvent-mediated polymorphic transformation of progesterone using in situ Raman spectroscopy. Many analytical techniques, such as Differential Scanning Calorimetry (DSC), X-Ray Diffraction (XRD), Infrared Spectroscopy (IR) and Raman spectroscopy can differentiate between crystalline polymorphs of the same chemical entity. While all of these techniques are routinely applied to off-line analysis of materials, only Raman instrumentation technology currently exists for in situ monitoring of solid phase behavior. We employed Raman spectroscopy to demonstrate the solvent-mediated polymorphic phase transformation of progesterone. In situ Raman analysis showed that the appearance of Form I progesterone is always preceded by the formation of Form II. Phase transformation rates increase monotonically as temperature increases, which indicates that the polymorphic system is monotropic. Form I is thermodynamically more stable than Form II, while Form II is kinetically favored over Form I. The results support Ostwald's law of stages and also lead to an in-depth understanding of the polymorphic transformation process. The in situ capabilities of Raman spectroscopy allowed us to define the processing parameters required to control the morphology of progesterone.