Initial Salt Screening Procedures for Manufacturing Ibuprofen

Abstract

The aim of this paper is to design initial salt screening procedures for manufacturing ibuprofen. Salt forms of a pharmaceutical acid racemic (R,S)-(±)-ibuprofen and their “developable” synthetic routes were ferreted out simultaneously through the screening of seven bases of sodium hydroxide, potassium hydroxide, l-arginine, l-histidine, l-lysine, diethanolamine, and tris(hydroxymethyl)aminomethane (THAM), and the match with the use of nine organic solvents of methanol, dimethyl sulfoxide, ethanol, N, N-dimethylformamide, acetonitrile, isopropyl alcohol, 1,4-dioxane, acetone, and tetrahydrofuran mainly in the presence of water in 20 mL scintillation vials. Racemic (R,S)-(±)-sodium ibuprofen dihydrate, a well-known ibuprofen salt and the newly discovered racemic (R,S)-(±)-THAM ibuprofen, appeared as white-squared powders with a molecular weight of 327.42 g/mol, a melting point of 160.17°C, and the apparent solubility product, K′_sp, of 6.0 × 10⁻⁴ M² at 25°C were successfully synthesized by the initial salt screening methods. The new amine salt of ibuprofen was monoclinic and had a space group of P2₁/c and lattice parameters of a = 17.578(8)°, b = 10.428(4)°, c = 9.991(4) Å, α = 90.00°, β = 97.17(1)°, γ = 90.00°, and V = 1,817.05(244) ų. The aspect ratio of the amine salt crystals of ibuprofen of ≈ 1.0 implied that the crystals had a better flowability than the sodium salt counterparts. This amine salt of ibuprofen was more stable in moist or dried atmospheres and was more hydrophobic than the sodium salt of ibuprofen. Moreover, the slow dissolution of this amine salt of ibuprofen might have made it less bitter and more suitable as a sustained release drug than the sodium salt of ibuprofen. The future work is to search for the different polymorphs of this amine salt of ibuprofen and to extend the initial salt screening working logics to the formation of co-crystals.

Keywords:

• ibuprofen
• tris(hydroxymethyl)aminomethane
• Trizma base
• sodium ibuprofen dihydrate
• initial salt screening

ACKNOWLEDGMENTS

This work was supported by a research grant from the National Science Council of Taiwan, ROC (NSC 95-2113-M-008-012-MY2). Suggestions from Ms. Jui-Mei Huang in DSC and TGA, Ms. Shew-Jen Weng in XRD at National Central University Precision Instrument Center and High Valued Center and Ms. Pei-Lin Chen in SXD at Instrument Center at National Tsing Hua University, Hsin-chu, Taiwan, ROC are gratefully acknowledged.