Scale reactive crystallization

Figure 17-8 Photomicrographs of crystals from manufacturing scale reactive crystallizations using two addition rates, showing (a) minimization of fines by essentially all-growth at low rates, and (b) fines formation and bimodal distribution at high rates caused by nucleation.

Jones also tested the reactivity of neutral group 13 trihydride reagents toward the 1,3,5-triphosphinine. The reaction of 3equiv [AlH3(NMe3)] with the heterocycle in diethyl ether afforded a mixture of the crystalline compounds 32, 33, and 34. They could not be separated on a preparative scale but crystals of pure 33b and 34 could be selected and characterized by X-ray analyses (Scheme 12). 

Several investigators have developed models for the effectiveness of collisions that lead to agglomeration including Nyvlt et al. (1985) and Sohnel and Garside (1992). This complex interaction of hydrodynamics and crystallization physical chemistry is difficult to predict or describe but can be critical to the successful operation and scale-up of a crystallization process. In particular, for reactive crystallization in which high supersaturation levels are inherently present, agglomeration is very likely to occur as the precipitate forms. Careful control may be necessary to avoid extensive agglomeration, as outlined in Section 5.4.3. below and in Examples 10-1 and 10-2 for reactive crystallization. 

Reactive crystallization operations are subject to oiling out and/or agglomeration because of the inherently high local supersaturations encountered. As indicated in Section 10.3, the formation of a crystal may be preceded by oiling out as the first physical form that may or may not be observed (see also Chapter 5, Section 5.4). This oil may separate as a second phase because of the normally extremely low solubilities of the reaction products that result from the chemical reaction. This low solubility can cause a second liquid phase to form on a time scale that is shorter than the nucleation induction time. These issues are considered in Ostwald s Rule of Stages. 

Development and scale-up of reactive crystallization/precipitation processes can present some of the most difficult challenges in the field. The reader is referred to the quotation in Section 10.1.2 above as a reminder of this difficulty. 

However, the authors have participated in development and scale-up of some successfiil reactive crystallization processes, and the examples to follow (Examples 10-1 and 10-2) are included to illustrate the concepts and application of the principles discussed above in these processes. These developments were based on the three essential concepts of seeding, control of supersaturation and promotion of growth, as described above. The key variables are, therefore,... 

Goals Development and scale-up of a robust process for the reactive crystallization of an API suitable for downstream formulation... 

The mixing conditions in the plant reactor are different from those in a smaU-scale laboratory (see detailed discussion of this topic below). Different mixing conditions mean different mass and heat transfer capabilities of the equipment. Such differences must be understood and used to benefit the process. Some processes, such as reactive crystallizations and fast reactions, are much more sensitive to mixing than other processes. 

Larson, K. A., M. Midler, and E. Paul (1995). Reactive crystallization control of particle size and scale-up, presented at the Association for Crystallization Technology Meeting, Charlottesville, VA. 

Goal scale-up of a reactive crystallization with crystal growth and impurity... 

Properties Wh. scales, needles, crystals, benzoin odor sol. in alcohol, ether, chloroform, benzene, carbon disulfide si. sol. in water m.w. 122.13 dens. 1.2659 m.p. 121.25 C b.p. 249.2 C subl. at 100 C flash pt. 121.1 C Toxicology LD50 (oral, rat) 2530 mg/kg, (IP, mouse) 1460 mg/kg mod. toxic by ingestion, IP routes poison by subcut. route severe eye/skin irritant may cause human intolerance reaction, asthma, hyperactivity in children TSCA listed Precaution Combustible when exposed to heat or flame reactive with oxidizing materials... 

Atmospheric sensitivity renders the preparation of ultrapure samples difficult. Nevertheless, vacuum distillation ", ultra-high-vacuum reactive distillation " and crystal growth purification methods " are described zone-refining methods have been applied on a limited scale only - , presumably because of the high volatility of the metals and the unfavorable distribution coefficients. 

A highly detailed picture of a reaction mechanism evolves in-situ studies. It is now known that the adsorption of molecules from the gas phase can seriously influence the reactivity of adsorbed species at oxide surfaces[24]. In-situ observation of adsorbed molecules on metal-oxide surfaces is a crucial issue in molecular-scale understanding of catalysis. The transport of adsorbed species often controls the rate of surface reactions. In practice the inherent compositional and structural inhomogeneity of oxide surfaces makes the problem of identifying the essential issues for their catalytic performance extremely difficult. In order to reduce the level of complexity, a common approach is to study model catalysts such as single crystal oxide surfaces and epitaxial oxide flat surfaces. 

The concept is demonstrated for a simultaneous immunoassay of (32-microglobulin, IgG, bovine serum albumin, and C-reactive protein in connection with ZnS, CdS, PbS, and CuS colloidal crystals, respectively (Fig. 14.6). These nanocrystal labels exhibit similar sensitivity. Such electrochemical coding could be readily multiplexed and scaled up in multiwell microtiter plates to allow simultaneous parallel detection of numerous proteins or samples and is expected to open new opportunities for protein diagnostics and biosecurity. 

In dispersed-metal catalysts, the metal is dispersed into small particles, on the order of 5 to 500 A in diameter, which are generally located in the micropores (20-1000 A) of a high surface area support. This provides a large metal surface area per gram for high, easily measurable reaction rates, but hides much of the structural surface chemistry of the catalytic reaction. The surface structure of the small particles is unknown only their mean diameter can be measured and the pore structure could hide reactive intermediates from characterization. Some of the same difficulties also hold for thin films. However, we can accurately characterize and vary the surface structure of our single-crystal catalysts, and in our reactor the surface composition can also be readily measured both are prerequisites for the mechanistic study of the catalysis on the atomic scale. 

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