Crystallization of Salicylic Acid via Chemical Modification

Overview

Source: Kerry M. Dooley and Michael G. Benton, Department of Chemical Engineering, Louisiana State University, Baton Rouge, LA

Processing of biochemicals involves unit operations such as crystallization, ultracentrifugation, membrane filtration, and preparative chromatography, all of which have in common the need to separate large from small molecules, or solid from liquid. Of these, crystallization is the most important from a tonnage standpoint. For that reason, it is commonly employed in the pharmaceutical, chemical and food processing industries. Important biochemical examples include chiral separations,¹ purification of antibiotics,² separation of amino acids from precursors,³ and many other pharmaceutical,^4-5 food additive,^6-7 and agrochemical purifications.⁸The control of crystal morphology and size distribution is critical to process economics, as these factors affect the costs of downstream processing operations such as drying, filtration, and solids conveying. For more information about crystallization, consult a specialized textbook or a Unit Operations textbook.⁹

The crystallizer unit (Figure 1) enables study of: (a) the effects of key parameters, such as supersaturation and cooling/heating rates, on solids content, morphology and crystal size distribution; (b) and the on-line control of crystallization processes. Supersaturation can be controlled by altering conditions such as agitation rate and temperature. The different classifications of crystallization include cooling, evaporative, pH swing and chemical modification. In this experiment,an offline microscope will measure from crystals ranging in size from 10-1000 μm, a typical size range for biologicals.

Figure 1: P&ID schematic (left)and picture (right)of Crystallizer. Please click here to view a larger version of this figure.

This experiment will demonstrate a "chemical modification",or "pH-swing" crystallization, to generate salicylic acid (SAL) (precursor of aspirin) crystals from the rapid reaction of aqueous solutions of basic sodium salicylate (NaSAL), which are basic, and sulfuric acid (H₂SO₄) at anywhere from 40 - 80°C.¹¹

Na⁺SAL^{+ 0.5 H}₂SO₄ SAL (ppt) + Na⁺ + 0.5 SO₄^2-

The byproduct sodium sulfate remains soluble. The apparatus consists of two feed tanks, three variable speed (peristaltic) pumps, the crystallizer (stirred tank to approximate uniform temperature and concentration, ~5 L), a circulating bath for temperature control, power controller, product tank, and a makeup tank for feed regeneration with NaOH solution (if desired). Samples will be analyzed by a UV-Vis spectrometer for the residual soluble salicylate ion, and the salicylic acid crystal product will be dried and weighed.A pH probe can be used to determine steady-state when reaction conditions are altered.

Procedure

Organic (sodium salicylate, NaSAL) and acid (sulfuric acid, 0.25 M = 0.50 N) solutions will be fed to the crystallizer. Make sure to wear latex gloves when handling NaSAL, salicylic acid or their solutions, and the 0.25 M sulfuric acid.

The entire system is controlled from a PC using a commercial distributed controller with an interface similar to the one in Figure 1. All on-off or 3-way solenoid valves and controller set points can be operated and changed using t

Results

Figure 2 presents representative data that suggests modest deviations from the crystal size distribution of the MSMPR ideal even at relatively high speeds and low feed concentrations.

Figure 2. Crystal size distribution for 0.16 M NaSAL feed, 540 rpm, 60 ° C

The crystals that form from this experiment are typicall

Application and Summary

This experiment demonstrated how to take raw concentration, flow and temperature measurements and use MSMPR theory to estimate the key parameters needed to design a large, complex crystallizer system. The critical role that residence time plays in obtaining high crystal yields and in controlling the average size of the crystals, was explored. Often there is an optimal residence time because very large crystals are seldom desirable. The same is true for mixing - mixing must be sufficient to keep the solid crystals from se

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