Example crystallization ibuprofen lysinate

A high degree of control can also be achieved in continuously stirred tank crystallizers. Temperature differences between feed and crystallizer can be regulated as necessary. The seed is the product and will normally be present at the slurry concentration as determined by the feed rate, concentration, and solubility differences achieved. However, in cases in which this amount of seed is not sufficient, cross-flow filtration on the discharge of the crys-tallizer(s) can be used to increase the slurry density. See Example 7-4 for a discussion of the resolution of ibuprofen lysinate. 

Metastability and induction time can play an interesting role in the kinetic resolution of optical isomers, such as of resolution of ibuprofen lysinate (see Example 7.4). On the one hand in order to maintain the optical purity of the desired isomer, it is necessary to keep the (undesired) isomer in its supersaturated state for the entire crystallization period. If the undesired isomer crystallizes out from the solution, the optical purity of the desired isomer will decrease. On the other hand, it is important to release the supersaturation of the desired isomer, which starts at the same initial level of supersaturation as the undesirable isomer. These are two conflicting requirements. To overcome this dilemma, it is critical to maintain a large amount of seed bed of the desired isomer to accelerate the release of super-saturation of the desired isomer, whereas the undesired isomer remains supersaturated. As mentioned, a detailed description of the resolution process of optical isomers is given in Example 7-4. 

Solvated crystals are also common in the chemical and pharmaceutical industries. Figure 2-18 shows the room temperamre solubility curve of ibuprofen-lysinate as a function of water content in ethanol. As shown in the figure, the crossover point between anhydrous solid and monohydrate is < 5% water. At room temperamre, ibuprofen-lysinate remains anhydrous when the water content is below 5% and transforms into monohydrate when the water content is above 5%. In this example, solvate and anhydrous materials also have different crystal habits, as shown in Fig. 2-19. 

Another interesting example of combining diastereomeric salt formation and racemization was reported by Bhattacharya." In this work, selective crystallization of ibuprofen/lysinate from 1 mol of (/ ,5)-(racemic) ibuprofen and <0.5 mol of (5)-lysine in aqueous ethanol affords either (S)-(- -)-ibuprofen/(5)-lysinate or (/ )-ibuprofen/(5)-lysinate (in preponderance) depending on the crystallization conditions. Then, the unwanted enantiomeric ibuprofen could be recovered from the mother liquor and racemized by a simple, relatively waste-free thermal process. The combination of the thermal racemization process and the selective crystallization technology provides an efficient and environmentally friendly means to prepare (S)-(- -)-ibuprofen lysinate in an overall essentially quantitative yield (Figure 56.8). 

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