Effect of solvent composition on the spherical crystallization of salicylic acid

The research described in this dissertation focuses on understanding the effect of solvent composition on the spherical crystallization of salicylic acid. Spherical crystallization is a solvent exchange crystallization method in which crystal agglomeration is purposely induced through the addition of a third solvent termed the “bridging liquid.” Crystal agglomeration is performed in a controlled fashion during spherical crystallization to create spherical crystal agglomerates (SCAs) with improved flow and compaction properties relative to the constitutive crystals. These properties are highly advantageous for pharmaceutical production. The effect of process parameters on spherical crystallization has been unclear, hindering optimization of the process. This work has focused on the effect of the crystallization solvent on the process using a combined experimental and simulation approach.; Two analytical techniques were developed to experimentally examine the process of spherical crystallization. First, semi-automated microscopy and image analysis techniques were developed to measure the size of spherical crystal agglomerates (SCAs). Optimization of these techniques for this system is demonstrated. The microscopy and image analysis techniques were used to obtain the particle size distribution (PSD) of the SCAs at the endpoint of the spherical crystallization process. The concentration of bridging liquid in the solvent system was shown to significantly alter the size and shape characteristics of the SCAs. The effect of the bridging liquid concentration was examined for seven different bridging liquids. The ability of these bridging liquids to form SCAs was correlated to their physical properties, in particular their solubility, surface tension and polarity. The second analytical technique developed to examine the spherical crystallization process was on-line particle size analysis, which was used to measure the chord length distribution (CLD) of the SCAs as a function of time during the process. These measurements were useful for understanding the dynamics of spherical crystallization. The effect of the bridging liquid concentration on the spherical crystallization kinetics was examined for four solvent systems. Kinetic models of the process were developed and the effect of the bridging liquid concentration and on the kinetic parameters was examined for the four systems.; Monte Carlo simulation techniques were used in this work to simulate crystal growth, crystal agglomeration and spherical crystallization. First, the growth of calcium oxalate crystals was simulated. Two models of crystal growth, growth rate dispersion (GRD) and size-dependent growth (SDG), were used to validate the simulation technique. The experimental PSD of calcium oxalate monohydrate (COM) and of a population of all three hydrates of calcium oxalate at were predicted at several time points using the simulation. A similar simulation technique was then used to simulate the size-independent agglomeration of crystals. The formation of porous agglomerates was simulated by using a dual-simulation technique to account for the agglomerate porosity. Finally, the simulation techniques were used to model spherical crystallization. Three models of spherical crystallization were developed to account for the concentration and composition of bridging liquid in the solvent system. Trends in the average diameter, number of agglomerates and PSD as a function of time were similar to those observed experimentally. Bridging liquids with higher surface tensions produced larger crystal agglomerates, due to the formation of stronger liquid bridges during agglomeration.