Study on the metastable zone width of ketoprofen

Abstract

With increasing awareness for the need of pure enantiomer drugs, strong emphasis has been focused on the research of chiral drug separation. Compared with other separation methods, crystallization is a simple and economical method, and the metastable zone width (MSZW) is a very important factor for the entire crystallization process. In this paper, the effects of the metastable zones of (R,S)- and (S)-ketoprofen and a 0.94 mole fraction of (S)-ketoprofen in order to enhance the MSZW were studied. Four main factors were studied, namely, temperature, cooling rate, stirring rate, and volume ratio of mixed solvent (water/ethanol). Through the L9 fractional experiment design, it was observed that all samples' MSZWs would increase with an increase in cooling rate and decrease with an increase in the ethanol volume ratio and temperature. The ethanol ratio may have the strongest effect on the process and can greatly enhance the metastable zone, and the other three factors influence the MSZW only slightly. In conclusion, the these four factors for enhancing MSZW have been optimized: water-to-ethanol volume ratio, 1:0.6; temperature, 20 degrees C; stirring rate, 700 rpm; and cooling rate, 12.0 degrees C/h. All of these results will be helpful for the following chiral separation of ketoprofen by crystallization.

Determination of metastable zone width, mean particle size and detectable number density using video imaging in an oscillatory baffled crystallizer

“…As expected, the MSZW decreases with an increase in the mixing intensity. This is similar to the trends observed by O'Grady and co-workers for the anti-solvent crystallization of benzoic acid, 33,34 Lu and Ching for the crystallization of ketoprofen 35 and Ni and Liao for the crystallization of L-glutamic acid. 9 As with the results in Fig.…”

Intrinsic MSZW characteristics of racemic species: Implication for chiral crystallization

“…The MSZW of racemate is wider than that of pure enantiomer because less solute molecules are in the solution to undergo collision to form embryos and develop into nuclei. This case is widely observed in many racemic compound systems such as ketoprofen 20 The solubility of racemate is bigger than that of pure enantiomer, but the ratio is smaller than 2 (1 < α < 2).…”

“…The dependence of MSZW on the enantiomeric excess was reported in the compounds of mandelic acid 15, 16. Our group recently started a series of characterization of MSZW of both conglomerate and racemic compound systems 17–20. Furthermore, the metastable zone of the target enantiomer could be also closely related with the nucleation of the unwanted isomer 8.…”

Application of Preferential Crystallization for Different Types of Racemic Compounds

“…On the other hand, we also employed the above crystallization strategy to ketoprofen in a solvent mixture of ethanol and water in a volume ratio of 0.9:1.0. According to the solubility and MSZW diagrams reported in our previous work, , the eutectic composition of Kp is around 92 mol % of ( S )-Kp. The MSZW of high-mole-percent ( S )-Kp is ca.…”

“…On the other hand, we also employed the above crystallization strategy to ketoprofen in a solvent mixture of ethanol and water in a volume ratio of 0.9:1.0. According to the solubility and MSZW diagrams reported in our previous work, 29,57 4. It can be seen that it was more difficult to obtain pure enantiomer product because of the narrower MSZW and unfavorable phase diagram for Kp.…”