Date of Award


Degree Type


Degree Name

Doctor of Philosophy in Pharmaceutical Sciences


Interdepartmental Program

First Advisor

Christopher T. Rhodes


A program of experiments comparing the formulation of rac-ibuprofen to that of (-)-S-ibuprofen was performed. Early investigations revealed that although complying with the United States Pharmacopeia compendial standards five different sources of rac-ibuprofen had different processing characteristics and as a result variable biopharmaceutical properties. Crystal habits critically influenced processing parameters. It was possible to identify low and high 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 confirmed 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 drop of 8.5 KJ mole-1 in the enthalpy of fusion. This is thought to 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 lattice of (+)-S-Ibuprofen was elucidated and 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 totally independent crystal with a melting point of 54°C and an enthalpy of fusion ΔH of 17.9 KJ mole-1 less. The stereoisomer of ibuprofen was more soluble than rac-ibuprofen in aqueous media. However, a study of the solution thermodynamics revealed that standard free energy of solution (ΔG°rac = 30.3 and ΔG°s = 29.5 in KJ mole) were comparable, whereas heats and entropy of solution were very different at pH 1. 3 (ΔH = rac 32. 2 and ΔHs = 51.5 in KJ mole). The small specific surf ace area of the s isomer (2.8.10-3 m2 g) compared to the racemate (0.34 m2 g) is probably responsible for the slower intrinsic dissolution (IDRrac= 11.6 μg. Sec-1 .cm-2). The study of biopharmaceutical properties of (+)-S-Ibuprofen formulations, 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 (-)-R-ibuprofen systemically rather than pre - systemically. Thus 150 mg of (+)-S-ibuprofen might be therapeutically equivalent to 200 mg of rac-ibuprofen.



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