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A progra m of e x perime nt s comparing t he formulatio n of rac ibuprofen to t h at of ( )-Si buprofe n was pe r f or med. Early i nve s tigat i on s revealed that al t h ough complying with t he Uni t ed Stat es Pharmac opeia c ompendial standards five different sources of rac-ibuprofen had different processing characteristics and as a result variable biopharmaceuti c al properties. Crystal habits critically influenced process ing parameters. It was possible t o identify l ow and h i gh liquid requirement powders for the wet granulation end point. Further analysis of rac ibuprofen crystals was performed during the different stages o f tablet manufacture . Phase diagrams c onfirmed that rac ibuprofen crystallizes preferentially in the monoclinic space P2 1 c group as a true racemate . It was found that crystal distortion translated int o an hydrophobic network of ibuprofen causing a dr op of 8.5 KJ mole 1 in the enthalpy of fusion. This is thought t o be responsible for the poor performance of ibuprofen tablets. The extent of this network seemed to be dose de pendent as suggested by the dissolution profiles. Using single crystal x-ray diffraction. the crystal lat tice of (+)SIbuprofen was elucidated a nd the molecular pharmaceutics of the S and racemate investigated . The (+) isomer. although crystallizing with the same number of molecules in the unit cell. exhibited a t otally independent crys~al ~ith a mel~ing point of 54°C a~d a~ enthalpy of fu sion ( c.E ) of 17 . 9 -1 KJ mo le less. ".'he stereoisomer of ibuprofec was more soluble than rac ibuprofen in aqueous media . However , a study of the solution thermodynamics revea::.ed that standard free energy of s olution ( L>G o = rac 30.3 and t>G o = 29.5 in KJ mole ) were comparable. whereas heats s and entropy of solution were very different at pH 1. 3 ( L>H = rac 32. 2 and L>HS = 51 . 5 in KJ ! mole ) . The small specific surf ace area of the s isomer ( 2.8.10-3 m 2 g ) compared to the racemate (0. 34 m2 1g ) is pr obably responsible for the slower intrinsic dissolution ( IDRrac = 11.6 μg . sec 1 .cm-2 ) . The study of biopharmaceutical properties of (+)-SIbuprofen f ormulations. however , indicated an excellent flow and better dissolution than the racemate . Extensive eutectic behavior of the S(+) stereoisomer might be of some concern to the formulators. In order to formulate the pure enantiomer. the phar macokinetic of rac ibuprofen was investigated. Using the Stellatm simulation software it was determined that 1 / 3 of the (+)SIbuprofen was derived from the inversion of (-)-Ribuprofen systemically rather than pre systemically. Thus 150 mg of (+)-S-ibuprofen might be therapeutically alent to 200 mg of rac-ibuprofen . equiv-

OPTIMIZATION OF IBUPROFEN FORMULATION: MOLECULAR PHARMACEUTICS OF THE BIOLOGICALLY ACTIVE STEREOISOMER