Optimize Reactive Crystallization

Understanding the impact of several key factors is crucial.

By Wayne J. Genck, Genck International

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Fine chemical and pharmaceutical companies often employ reactive crystallization or precipitation to make intermediates and finished products. It is perhaps best to think of precipitation as embodying fast crystallization in which the particles can be either amorphous, crystalline or a combination of the two. The reactions can be very fast compared to the mass transfer rates to the crystals and their growth rates, often leading to high local supersaturations and extensive nucleation. In some cases, due to high supersaturation, the crystals or precipitates are small, in the submicron to several micron range. Such small particles usually are undesirable because they can present problems in downstream operations such as filtration, washing and drying. Agglomeration of some of the individual crystallites frequently occurs — but doesn't remove all small particles.

This is not to imply that precipitations always result in agglomerates. Many cases exist in which the particles are single crystals with different degrees of faceting.

As with any crystallization, the balance between nucleation and growth determines the size distribution. The high level of supersaturation may result in high nucleation rates and a smaller size distribution. Inclusion of solvent and trapping of impurities also can occur. In addition, other physical properties such as bulk density, caking and a small size, broad or bimodal distribution can pose difficulties for storage and formulation.

CONTROL OF CRYSTAL SIZE
For compounds with high kinetic rates, reduced concentration and elevated temperatures often help in making a larger particle. The rate of addition of reactants enables control of supersaturation globally but not locally should the reaction occur at the feed point. Therefore, a careful balance among the reactant addition rate, local and global supersaturation, mass transfer and crystal surface area is crucial. For entities with slow crystallization kinetics, the rate of addition of reactants alone can provide an effective method of supersaturation control. Raising the operating temperature, even by a small amount, decreases the supersaturation due to the increasing solubility versus temperature of most compounds. It's important to generate the solubility curve to determine the operating parameters that facilitate the production of a larger particle, if that's the goal.

Figure 1 shows three potential modes for reactive crystallization. The figure illustrates three reactant addition methodologies: linear (A, B, C), programmed (A, D) and programmed with seeding (A, E). Programmed addition with seeding is preferred if larger crystals are required. The first quantity of reactant added usually creates a high local supersaturation value. Thus, it's desirable to stay within the metastable zone by control of the addition rate and seeding.

KEY PARAMETERS
Many organic bases and acids are prepared by reactive crystallization that can lead to high supersaturation with potential high nucleation. The same occurs for inorganic precipitations. A common method is to add a reactant to a solution with dissolved second reactant to produce the product. Rate processes that can impact results include:

• chemical reaction to make the product;
• formation of clusters in solution that then exceed the solubility and create nuclei;
• production of the insoluble phase either as an amorphous solid and oil or a crystalline solid;
• simultaneous production of supersaturation with reactant addition along with its consumption by nucleation and growth;
• impact of impurities or deliberate dosing of additives on nucleation and growth;
• secondary effects including agglomeration, crystal breakage, ripening and polymorphs;
• impact of mixing including meso- and macromixing during addition to ensure molecular-scale contact and reaction along with meso- and micromixing for molecular-scale homogeneity; and
• effect of operating temperature on solubility and supersaturation and resultant kinetics.

MIXING PARAMETERS
Three modes of mixing — macromixing, mesomixing and micromixing — may affect the resultant product.

Macromixing involves the bulk blending in the vessel. Compounds with long nucleation induction times or slow reaction rates may not form crystals in the micromixing or mesomixing zones but will do so in the bulk blending phase of the overall mixing process.

Mesomixing effects occur in agitated vessels when the reactant feed rate is faster than the local mixing rate, yielding a plume of reactant concentration that's not mixed at the molecular level. This parameter is significant on scaleup and often results in the need for longer addition times in a larger vessel to achieve the same reaction selectivity and particle-size distribution.

Micromixing is key because the time for blending at the molecular level is critical for both the chemical reaction and nucleation induction time and, thus, for determining the nucleation rate and size distribution. The location of the reactant feed pipe, impeller speed, and impeller type and baffling affect the micromixing times. These vary by a large factor at different locations in the vessel and also depending upon agitator speed and design.

A critical factor in both micro- and mesomixing times is the feed pipe location. A change in the size distribution at modified feed pipe locations indicates a mixing dependence. If no substantial variations exist, a different system property such as nucleation induction time may be slow compared to micromixing. If the reaction is slow, it may occur in the bulk mixing volumes of the vessel.

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