Effects of Homochiral Molecules of (S)-(+)-Ibuprofen and (S)-(−)-Sodium Ibuprofen Dihydrate on the Crystallization Kinetics of Racemic (R,S)-(±)-Sodium Ibuprofen Dihydrate

Abstract

The aim of this paper is to identify the effects of homochiral molecules such as (S)-(+)-ibuprofen and (S)-(−)-sodium ibuprofen dihydrate on the crystallization kinetics: the induction period, the crystal growth rate, and the end point of the racemic compound of (R,S)-(±)-sodium ibuprofen dihydrate. Crystallization kinetics of racemic species of sodium ibuprofen dihydrate in the presence of small amounts of homochiral parent molecules of (S)-(+)-ibuprofen and its constituent enantiomers (S)-(−)-sodium ibuprofen dihydrate were studied by electrical conductance, optical microscopy, differential scanning calorimetry, and wide-angle powder X-ray diffraction. Racemic (R,S)-(±)-sodium ibuprofen dihydrate with self-association property was sensitive to processing history and deserved a tight control for reproducibility on scale-up. Crystals grown from a racemic water−acetone solution of sodium ibuprofen dihydrate and vaccuum-dried at 90 °C for 4 h produced racemic species of α-form racemic compounds and γ-form racemic conglomerates having a R:S w/w ratio of about 45:55 (enantiomeric excess of the solids, ee = 10% in S) by the addition of no additives, and 0.02 g of (S)-(+)-ibuprofen or 0.02 g of (S)-(−)-sodium ibuprofen, respectively. Fundamental parameters of the crystallization kinetics of racemic species of sodium ibuprofen dihydrate such as the induction time, τ; the interfacial energy, γ; the Gibbs energetic barrier, ΔG cr; the nucleation rate, J; the critical size of stable nuclei, rc; the crystal mass growth rate, RG; the power number, g; and the end point were evaluated with different initial supersaturation ratios, S0, and compared. In general, τ, ΔG cr, and rc decreased and J increased when S0 increased or homochiral additives were added. γ decreased in the presence of homochiral additives. RG increased as S0 increased in the presence of (S)-(+)-ibuprofen. g ranged from 0.5 to 1.7. The end point decreased in the presence of additives or with the increase in S0. At high S0, the effects of homochiral additives on the induction period, the crystal growth rate and the end point became to diminish. Adoption of such inexpensive, simple, and robust methods as electrical conductance, optical microscopy, and differential scanning calorimetry in common research laboratories offers the opportunity to the pharmaceutical industry to lower manufacturing cycle times and end product variability in a crystallization process that would result in shorter time to market and a reduced likelihood of drug product failures. The addition of configurationally similar homochiral molecules such as the parent acid or the same constituent enantiomer to the racemic solution may have opened a new doorway for the generation of racemic species that cannot be obtained by the addition of other impurities.