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, R G; the power number, g; and the end point were evaluated with different initial supersaturation ratios, S 0, and compared. In general, τ, ΔG cr, and r c decreased and J increased when S 0 increased or homochiral additives were added. γ decreased in the presence of homochiral additives. R G increased as S 0 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 S 0. At high S 0, 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.

Propagation of Biochirality: Crossovers and Nonclassical Crystallization Kinetics of Aspartic Acid in Water

“…() (Table ). The free energy change for the phase transformation, ΔG υ , the energy required to form a critical size of cluster in nucleation, ΔG cr , the rate of primary nucleation, J , the critical size, r c , and the critical nucleus, i * , could then be derived from γ and J 0 (Table ) …”

“…The preexistence of a liquid structure before nucleation would create a problem for the CNT stemming from the belief in homogeneous nucleation, as we will see shortly. The classical nucleation relationship stated that: where J is the rate of primary nucleation, J 0 is the preexponential factor (i.e., the number of molecules of the crystallizing phase in a unit volume × the frequency of molecular transport at the nucleus‐liquid interface), γ is the solution‐solid interfacial energy, υ is the molecular volume (i.e., molecular weight/(density × Avogadro's number)), k is the Boltzmann's constant, T is the temperature, and S 0 is the initial supersaturation ratio (i.e., C 0 /C * = the initial bulk concentration of solutes/equilibrium solubility of solutes) may therefore be written: where τ is the induction period, and t n is the nucleation time, which suggests that for a given temperature, a plot of ln τ versus (ln S 0 ) ‐ 2 should yield a straight line, the slope and the y‐intercept of which should allow a value of the interfacial tension, γ , and a value of the preexponential factor to be calculated.…”

Dissolution Enhancement by Bio-Inspired Mesocrystals: The Study of Racemic (R,S)-(±)-Sodium Ibuprofen Dihydrate

“…1c). This hypothesis was supported substantially the a-axis of the unit cell of racemic (R,S)-(±)-sodium ibuprofen dihydrate) designated by the elongated pores which were the unzipped locations of the removal of water from the sandwiched layer of (R)-(+)-sodium ibuprofenwater-(S)-(−)-sodium ibuprofen (32). The racemic (R,S)-(±)-sodium ibuprofen dihydrate crystalline platelets grown in the presence of SDS also appeared to be larger and thicker (Fig.…”

“…5a) most likely under the guidance of hydrogen bondings between the carboxylate head groups in the axial [001] direction of the molecule and the π-π interactions between the aromatic rings in the lateral [100] direction of the molecule (32). As the crystal face grew larger, a two-dimensional nucleus was created on the (010) face surface by an epitaxial matching (32). Once the surface nucleus was born, it spread across the surface to produce another layer of island (Fig.…”

“…The racemic compound (R,S)-(±)-sodium 2-(4-isobutylphenyl) propionate dihydrate or (R,S)-(±)-sodium ibuprofen dihydrate (Fig. 2a) was chosen as the model API in this work to test out the concept, because (1) its parent acid (R/S)-(±)-ibuprofen has worldwide commercial values in analgesic, anti-inflammatory, and antipyretic therapies (31), (2) we are familiar with this compound (32), (3) it is a chiral molecule (33), (4) it can be crystallized into α, β, and γ polymorphs depending on the processing conditions (34), (5) its electrical conductance in aqueous solution allows the simple use of an electrical conductivity meter to monitor the nucleation phase in the crystallization event and the dissolution behavior of the derived mesocrystals, and finally, (6) its inherent high aqueous solubility can be used to challenge the dissolution characteristics of the derived mesocrystals.…”