Solubilization and dissolution of insoluble weak acid, ketoprofen: effects of pH combined with surfactant.

This study investigated the combined effect of pH and surfactant on the solubility and dissolution of ketoprofen (KP), a highly permeable and an ionizable and water-poorly soluble drug in gastrointestinal tract. The equilibrium solubility of KP was determined in buffers at the pH range from 4.0 to 6.8 and sodium lauryl sulfate (SLS) concentrations from 0% to 2.0%. Its intrinsic dissolution rate was measured in the same media using a rotating disk apparatus. A simple additive model accounting for the free unionized KP and ionized KP(-) forms, and their corresponding micellar forms was employed to study the in vitro solubility and dissolution behavior. Non-linear regression analysis showed that the proposed model agreed well with the experimental data, with R(sq)=0.96 (P<0.0001) for the solubility study, and R(sq)=0.98 (P<0.0001) for the intrinsic dissolution rate measurement. The pK(a) and c(KP) values are estimated as 4.76+/-0.00 and 0.253+/-0.05 mg/mL, respectively, in good agreement with literature reports. The micellar solubilization coefficient k(*) for the unionized [KP](micelle) is 757+/-165 L/mol, whereas the value k(**) for the ionized [KP(-)](micelle) is 9.88+/-6.70 L/mol. The diffusion coefficients of various species: KP, KP(-), [KP](micelle), and [KP(-)](micelle), are 7.68 x 10(-6), 1.54 x 10(-6), 2.32 x 10(-7), and 2.13 x 10(-20)cm(2)/s, respectively. The maximum enhancement of solubilization is approximately 232-fold, while the maximum dissolution amplification is only 54-fold because of the smaller diffusivity of micellar species. The dramatic enhancement of in vitro solubility/dissolution attributable to an increase of pH and presence of SLS mimics the in vivo solubilization/dissolution behavior of KP along the gastrointestinal tract, when the pH increases from 1-2 in the stomach to 5-6 in the duodenum. The results suggest that the KP dissolves very rapidly in small intestine, implying that its absorption will be predominantly controlled by gastric emptying, and only minimally limited by the subsequent dissolution processes. This behavior is very similar to BCS I drugs, thus KP may be considered for possible waivers of bioequivalence.

Molecular properties of WHO essential drugs and provisional biopharmaceutical classification.

The purpose of this study is to provisionally classify, based on the Biopharmaceutics Classification System (BCS), drugs in immediate-release dosage forms that appear on the World Health Organization (WHO) Essential Drug List. The classification in this report is based on the aqueous solubility of the drugs reported in commonly available reference literature and a correlation of human intestinal membrane permeability for a set of 29 reference drugs with their calculated partition coefficients. The WHO Essential Drug List consists of a total of 325 medicines and 260 drugs, of which 123 are oral drugs in immediate-release (IR) products. Drugs with dose numbers less than or equal to unity [Do = (maximum dose strength/250 mL)/solubility < or = 1] are defined as high-solubility drugs. Drug solubility for the uncharged, lowest-solubility form reported in the Merck Index or USP was used. Of the 123 WHO oral drugs in immediate-release dosage forms, 67% (82) were determined to be high-solubility drugs. The classification of permeability is based on correlations of human intestinal permeability of 29 reference drugs with the estimated log P or CLogP lipophilicity values. Metoprolol was chosen as the reference compound for permeability and log P or CLogP. Log P and CLogP were linearly correlated (r2 = 0.78) for 104 drugs. A total of 53 (43.1%) and 62 (50.4%) drugs on the WHO list exhibited log P and CLogP estimates, respectively, that were greater than or equal to the corresponding metoprolol value and are classified as high-permeability drugs. The percentages of the drugs in immediate-release dosage forms that were classified as BCS Class 1, Class 2, Class 3, and Class 4 drugs using dose number and log Pwere as follows: 23.6% in Class 1, 17.1% in Class 2, 31.7% in Class 3, and 10.6% in Class 4. The remaining 17.1% of the drugs could not be classified because of the inability to calculate log P values because of missing fragments. The corresponding percentages in the various BCS classes with dose number and CLogP criteria were similar: 28.5% in Class 1, 19.5% in Class 2, 35.0% in Class 3, and 9.8% in Class 4. The remaining 7.3% of the drugs could not be classified since CLogP could not be calculated. These results suggest that a satisfactory bioequivalence (BE) test for more than 55% of the high-solubility Class 1 and Class 3 drug products on the WHO Essential Drug List may be based on an in vitro dissolution test. The use of more easily implemented, routinely monitored, and reliable in vitro dissolution tests can ensure the clinical performance of drug products that appear on the WHO Essential Medicines List.