Naproxen, enantioseparation

Among brush-type CSPs for HPLC, the Whelk-0(R) CSP, first designed for naproxen enantioseparation, has shown an outstanding applicability for a broad diversity of racemic compounds [72]. Nowadays it has become one of the CSPs of reference included in most screening processes addressed to the search of adequate conditions for enantioselective separation in drug discovery [73, 74]. A CS containing the Whelk-0( skeleton, and a lipophilic chain aimed to enhance solubility... 

Table using 3-3. Enantioseparation of l-methylnaphthoyl-A. A -diethylamide and naproxene CSPs 1-11. methyl ester... 

In a comparable system, (I ,S)-ibuprofen can be separated by a membrane reactor [83], see Fig. 13.10. The technique comprises a stereo-specific hydrolysis by an enzyme. Subsequently, the enantiomeric ester is extracted into the organic phase on the other side of the membrane. In the system developed by Sepracor Inc., (i )-ibuprofen is selectively hydrolyzed by proteases in a hollow-fiber unit and the (S)-ibuprofen ester can be isolated at 100% yield. This configuration also applies for enantioseparation of other acids such as naproxen and 2-chloropropionic acid. 

Brush or Pirkle-type CSPs show promise in the enantioseparation of many classes of compounds, and also have shown to exhibit the high efficiencies expected in CEC separations. The high efficiency of enantioseparations of these CSPs is thought to be due to more favorable mass transfer kinetics between the analytes and these CSPs. Cavender et al. [144] used these CSPs bonded to silica particles to separate 10 chirally active compounds. They used (S)-Naproxen-derived CSP as well as the more widely used (3R, 4S)-Whelk-0. They found that while the (S)-Naproxen-derived CSP gave rise to more reproducible EOF, (3R,4S)-Whelk-0 gave more efficient separations. The reproducibility of the... 

The theory and experiment of direct crystallization of enantiomers is quite well understood at present [10]. There are a number of variables which affect the resolution by direct crystallization in practice. Several technological schemes based on this principle are realized on the commercial scale. These are, for example, the Merck process used for the production of antihypertensive drug methyldopa [11], a process developed by Harman and Reimer for (-)-menthol, which is separated as an ester [12], the process patented by Industria Chimica Profarmaco for the resolution of naproxen enantiomers as the ethylamine salt [13], the production of L-glutamic acid by the Japanese company Ajinomoto on a scale in excess of 10000 tons annually as early as the 1960s [14], etc. In general, it seems that spontaneous crystallization is a very useful technique for the enantioseparation of the naturally occurring a-amino acids. All of them may be resolved either directly or as derivatives [10]. 

A general trend of enantioseparation among the three HPLC separation modes is that the highest enantioselectivity was commonly observed under normal-phase conditions (an example is shown in Fig. 18), while the shortest retention was obtained in polar organic mode. This is not an absolute rule since a great number of exceptions have been noticed. In the case of Nutlin-3, the enantioselectivity and resolution were much higher in reversed-phase mode than in polar organic and normal-phase mode (Fig. 16). Another example is Naproxen, whose enantiomers were baseline resolved on a Chiralpak AD-RH column in RP mode, while no enantioselectivity... 

Chapter 9 is the last chapter in the first section of this book. Its intent is to draw the readers attention to the possible occurrence of specific cases when, in spite of the availability of most efficient tools to perform a successful enanti-oseparation, the goal cannot be obtained. Such bottlenecks occur, for example, in cases when one enantiomer, when dissolved in an ampholytic solvent, can easily and spontaneously change its steric configuration and undergo oscillatory transen-antiomerization in the course of its storage. In the first instance, observation of such behavior was made with selected chiral 2-arylpropionic acids (APAs) that are nowadays very common and in a wide use as nonsteroidal anti-inflammatory drugs (NS aids e.g., ibuprofen and naproxen). In the case of such compounds, both their enantioseparation and reliable densitometric quantification are questionable. 

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