Mixed Product Removal System Research Articles

Nucleation and Growth Kinetics for Combined Cooling and Antisolvent Crystallization in a Mixed-Suspension, Mixed-Product Removal System: Estimating Solvent Dependency

Combined cooling and antisolvent crystallization is a critical unit operation in pharmaceutical manufacturing, especially for heat-sensitive or poorly soluble active pharmaceutical ingredients. The model-based design of these systems relies on the accuracy of the underlying growth and nucleation kinetic parameters. Unlike temperature where these kinetic parameters are well-known to follow an Arrhenius relation, their dependency on solvent composition still remains unclear, especially in continuous mixed-suspension, mixed-product removal (MSMPR) systems. In this paper, we use population balance modeling coupled with nonlinear regression to estimate growth and nucleation parameters as a function of both temperature and solvent composition. As solvent composition increases from 44 vol % to 66 vol % solvent, both growth and nucleation rates were observed to decrease monotonically with their values reduced by almost one-third. It was also shown that, if the solvent dependency is ignored, the yield can be overp...

Melamine Crystallization: Physicochemical Properties, Interactions With Other Lithogenic Salts and Response to Therapeutic Agents

There were reports of children in the People's Republic of China being hospitalized with renal stones and/or failure by September 2008, which were caused by melamine and its co-contaminant cyanurate. We investigated the physicochemical behavior of melamine, its interaction with other endogenous urine factors and the response to therapeutic agents in the renal environment in vitro. A mixed suspension, mixed product removal system was set up for crystallization studies of melamine in urine. Crystallization kinetic parameters, including the nucleation and growth rates, and suspension density, were determined according to crystal number and size, as measured by a Coulter particle counter. Melamine crystallized out from urine under normal urinary conditions (pH 5.0 to 6.5) but crystallization was strongly inhibited at pH 4.5 or lower. Melamine significantly enhanced calcium oxalate precipitation while uric acid significantly decreased melamine crystallization. Bacteria mimicking urinary tract infection promoted melamine crystallization. Clinical relevant drugs, such as citrate and bicarbonate, significantly decreased melamine crystallization. This implies that melamine crystallizes under normal urinary conditions and can interact with other lithogenic salts and pose a significant risk for other stones. Urinary tract infection promotes melamine crystallization. Citrate and bicarbonate therapy are effective prophylactic agents against melamine induced crystallization.

A nidus, crystalluria and aggregation: key ingredients for stone enlargement

The in vitro study of calcium oxalate (CaOx) stone formation is usually based on crystallisation models but it is recognised that both healthy individuals and stone formers have crystalluria. We have established a robust in vitro stone growth model based on the principle of mixed suspension, mixed product removal system (MSMPR). Utilising this technique we studied the influence of CaOx crystallisation kinetics and the variation of calcium and oxalate concentrations on CaOx stone growth in vitro. Six stones received standard concentration of Ca (6 mM) and Ox (1.2 mM) in the medium while another six received variable concentrations of both Ca and Ox at various intervals. Stone mass was plotted against the experiment duration (typically 5-7 weeks). The stone growth was dependent on sufficient input calcium and oxalate concentrations and once triggered, stone growth could not be maintained at reduced calcium and oxalate inputs. The stone growth rate was positively correlated to the number of crystals in suspension around the stone and to the crystal nucleation rate and negatively correlated to the crystal growth rates. This leads to the conclusion that aggregation of crystals from the surrounding suspension was the dominant mechanism for stone enlargement.