Date of Award


Degree Type


Degree Name

Doctor of Pharmacy (PharmD)

First Advisor

Christopher T. Rhodes


A program of e x perime nt s comparing t he formulation of rac- ibuprofen to t hat of ( - )- S-i buprofen was pe r f or med. Early i nve s tigat i ons revealed that alt h ough complying with t he Unit ed Stat es Pharmacopeia c ompendial standards five different sources of rac-ibuprofen had different processing characteristics and as a result variable biopharmaceutical 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 of tablet manufacture . Phase diagrams c onfirmed that rac- ibuprofen crystallizes preferentially in the monoclinic space P21 c group as a true racemate . It was found that crystal distortion translated into 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 dependent as suggested by the dissolution profiles. Using single crystal x-ray diffraction. the crystal lat tice of (+)- S- Ibuprofen 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 KJ mo le -1 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>Go = rac 30.3 and t>G so = 29.5 in KJ mole ) were comparable. whereas heats 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 (+)-S-Ibuprofen 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 pharmacokinetic of rac- ibuprofen was investigated. Using the Stellatm simulation software it was determined that 1/ 3 of the (+)- S- Ibuprofen 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 .