RS-ibuprofen and S-ibuprofen (dexibuprofen) - Binary system and unusual solubility behaviour

The solubility C-s of S-(+)-ibuprofen (dexibuprofen, S-ibu) in aqueous HCI/KCl buffer solution, pH 1.5, is about twice that of RS-(+/-)-ibuprofen (rac-ibu) at 20 degrees C and 38 degrees C. Dependent on temperature T (K), the solubility C-s (mmol l(-1)) can be described by In C-s = - 433.45 + 16808.04 . T-1 + 66.02 . In T for S-ibu and by ln C-s = - 464.80 + 17594.54 . T-1 + 70.91 . ln T for rac-ibu. The difference in the heats of solution of S-ibu and rac-ibu aggrees with the difference in the heats of fusion. The solubility of S-ibu is 3.5 times more dependent on addition of polysorbate 80 than that of rac-ibu at 20 degrees C and pH 1.5. The solubility as a function of the pH follows the equation C-s = C-s,C-0.(1 + 10(pH-pK)a,2). At 20 degrees C, C-s,C-0(S-ibu) is 0.336 mmol l(-1) and C-s,C-0(rac-ibu) is 0.145 mmol l(-1); at 38 degrees C the values for C-s,C-0 are 0.622 mmol l(-1) and 0.306 mmol l(-1) (pK(a,2) = 4.430 at 20 and 38 degrees C). The analytical data deviate from theoretical data at pi-I-values higher than 6.5. Formation of liquid crystals (lyotropic mesophases) was discovered as a reason for this deviation. The binary phase diagram confirmed that rac-ibu (melting peak by DSC 74.8 degrees C, heat of fusion 25.7 kJ mol(-1), true density 1.110 g cm(-3)) is a racemic compound. The eutectic points (calculated) are at 49.6 degrees C and at 0.06 and 0.94 mole fractions of S-ibu (melting peak by DSC 51.2 degrees C, heat of fusion 18.7 kJ mol(-1), true density 1.093 g cm(-3)). Furthermore, an unstable phase can be found in the area near the eutectic, yet only in binary mixtures. Its formation is favoured by the low tendency of crystallization between 0.80 and 0.93 mole fractions of S-ibu. It was not possible to gain the corresponding unstable modification either of pure S-ibu or rac-ibu. The main reason is that the unstable phase again induces the crystallization of S-ibu and rac-ibu.