| dc.description.abstract | Chirality is an important subject issue in the pharmaceutical industry when designing the small molecules of active pharmaceutical ingredients. Chirality would exist in the molecule when a central carbon atom (chiral center) is attached to four different groups. Among them, enantiomers have identical physico-chemical properties but different in bioactivity and optical property. Ignoring the issue of drug chirality will cause an irreversible tragedy, for example, thalidomide tragedy, caused hundreds of newborn babies with inborn errors. Nowadays, several enantiomeric (chiral) resolution techniques have been developed, for example, diastereomeric salt formation by using an optically resolving agent. (R/S)-(±)-ibuprofen ((R/S)-IBU) is a nonsteroidal anti-inflammatory drug (NASID), in which (S)-(+)-ibuprofen ((S)-IBU) is the main active ingredient for pain relief instead of (R)-(-)-ibuprofen ((R)-IBU). Thus, (S)-IBU would be recovered from (R/S)-IBU in this study. Furthermore, (S)-(-)-α-Methylbenzylamine ((S)-α-MBA) was chosen as the resolving agent to form (S)-(+)-ibuprofen-(S)-(-)-α-MBA ((S)-IBU-(S)-α-MBA)),and (R)-(-)-ibuprofen-(S)-(-)-α-MBA ((R)-IBU-(S)-α-MBA)) diastereomeric salts. The aim of this research is to performed the chiral resolution by diastereomeric crystallization through solvent selection which was divided into four parts: (1) different reaction stoichiometry ratios of the resolving agent ((S)-(-)-α-MBA) and optically inactive base (potassium hydroxide, KOH(aq)) were investigated in the first part to form diastereomeric salts of (S)-IBU-(S)-α-MBA and (R)-IBU-(S)-α-MBA. The diastereomeric salt of (S)-IBU-(S)-α-MBA would selectively precipitated in the first part, called the first enriched diastereomeric salt in (S)-IBU-(S)-α-MBA. The results showed that the diastereomeric salt formation of (R/S)-IBU with a molar ratio of (R/S)-IBU: (S)-α-MBA: KOH of 2:1:1 would give the highest recovery percentage (Re%) of 21%. That is to say, the first enriched diastereomeric salts with above molar ratio would produce the largest amount of (S)-IBU. (2) Cooling recrystallization of diastereomeric salts based on initial solvent screening and solvent selection in seven solvents, including, acetone (ACE), methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA), ethyl acetate (EA), n-butyl alcohol, and benzyl alcohol. Subsequently, ethyl acetate was selected because it gave the largest amount of enriched (S)-IBU-(S)-α-MBA after cooling from 70°C to 25°C and the solvent could be reused. The solids harvested from cooling recrystallization were called the second enriched diastereomeric salts in (S)-IBU-(S)-α-MBA. (3) the second enriched diastereomeric salts were dissolved in methanol and cracked by sulfuric acid. (4) optimization of the operating parameters for antisolvent crystallization to recover the enriched (S)-IBU was conducted. Finally, the recovery process was successfully scaled up to 18 g to exam the reproducibility, and recycle of the ethyl acetate, and the process resulted in 69-60% overall yield and 79-74%ee of the enriched (S)-IBU. All solids were analyzed by HPLC to determine the diastereomeric excess and the enantiomeric excess, and all solids were characterized by Fourier transform infrared spectrometer (FTIR) and powder X-ray diffractometer (PXRD) and differential scanning calorimetry (DSC). Our results were also compared with the ones of others groups doing diastereomeric crystallization. Our method offers the advantages of higher purity and yield, and process scalability. | en_US |