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A complete temperature-dependent solute-solute-solvent phase diagram is an essential starting point for cooling cocrystallization process development. In this study, the phase diagram of caffeine-glutaric acid-acetonitrile in the temperature range of 10-35 °C was charted using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy to measure concentrations in situ. Solution-mediated phase transformation was exploited to locate the eutectic points. The operating region was then prescribed according to the stoichiometry of the cocrystal, and the boundary of stability zones at the initial and final temperatures of cooling crystallization. It was demonstrated that cocrystal purity could be compromised when crystallization occurs outside the safe operating region. The complete phase diagram has laid the foundation for further cocrystallization process development of the model system.

On-line attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy and focused-beam reflectance measurement (FBRM) were used to monitor and control anti-solvent crystallization of paracetamol from an acetone-water mixture, which was conducted isothermally in a 1-L crystallizer with a flat bottom. After analyzing the particle size distribution (PSD) and transient relative supersaturation data from constant anti-solvent addition rate experiments, a simple calculation method for the set point of anti-solvent addition rate, to maintain constant supersaturation via ATR-FTIR, was developed and implemented for feedback control of unseeded and seeded crystallization. The results of the controlled feeding rate experiments show that the particle size and PSD, as well as the total batch time, can be favorably manipulated simultaneously.

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Focused beam reflectance measurement (FBRM) has gained much popularity as a tool for particle system characterization both in crystallization research and in manufacturing. The precise interpretation of FBRM data, however, still remains an issue of some conjecture and dispute. This study examines the relationship among total counts of chord lengths, statistics of chord length distribution, particle number and average particle size in simulated crystallization, which involves selective introduction of predetermined particle populations into a suspension so as to simulate the occurrence of nucleation and crystal growth as detected by the FBRM. The number of particles and particle size distribution were known precisely. It was found that a linear correlation existed between the counts of chord lengths and the number of particles for monosized populations, but not in the case of a dynamic process where there was a significant change in particle size. Squareweighted mean chord lengths were found to be able to track changes in average particle size qualitatively in some cases. Measured chord length distributions of monosized particle populations differed significantly from theoretically constructed distributions. These results have important implications for the interpretation of practical FBRM data, including the necessity to review the principles used in the restoration of particle size distribution from measured chord length distributions.

The strategy for seeding and supersaturation control can play a critical role in defining the purity and particle size distribution of crystal products. Previous research has demonstrated that operation of crystallizers at constant supersaturation by feedback control is attractive due to its simplicity and resistance to operating disturbances. In this study, the effects of seed loading and seed size distribution were investigated for anti-solvent crystallization of paracetamol from a water-acetone mixture operated at constant supersaturation. A seeding strategy based on a simple mass balance equation provided a good starting point for the refinement of particle size distribution and adjustment of batch time in different circumstances to obtain a target average crystal size with narrow size distribution.

A model polymorphic co-crystallization process for caffeine-glutaric acid from acetonitrile was monitored and controlled using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and particle vision measurement (PVM). A new method to calculate supersaturation for co-crystallization systems was proposed and used in this study. Results showed that feedback control of supersaturation was effective in eliminating the nucleation of the metastable Form I of co-crystal and also produced the largest particles with the lowest proportion of fines.

A simple and practical procedure to facilitate the determination of the design space for seeded cooling crystallization is proposed and demonstrated. Solute supersaturation is used as an effective link between six operational process factors and a chosen critical quality attribute, namely, fines fraction in the crystal product. A semi-mechanistic process model is developed, which accounts for the dynamics of supersaturation via moments of particle size distribution. ATR-FTIR and FBRM data from three batches for the model system myo-inositol dihydrate in water were used to estimate and update the model parameters, and the design space was verified experimentally in a subsequent run.