Solubility of (+/-)-ibuprofen and S (+)-ibuprofen in the presence of cosolvents and cyclodextrins.

Aqueous solubility is an important parameter for the development of liquid formulations and in the determination of bioavailability of oral dosage forms. Ibuprofen (IB), a nonsteroidal anti-inflammatory drug, is a chiral molecule and is currently used clinically as a racemate (racIB). However, the S form of ibuprofen or S(+)-ibuprofen (SIB) is the biologically active isomer and is primarily responsible for the antiinflammatory activity. Phase solubility studies were carried out to compare the saturation solubilities of racIB and SIB in the presence of common pharmaceutical solvents such as glycerol, sorbitol solution, propylene glycol (PG), and polyethylene glycol (PEG 300) over the range of 20% to 80% v/v in aqueous based systems. The solubilities of the two compounds were also compared in the presence of cyclodextrins such as beta cyclodextrin (CD), hydroxypropyl beta cyclodextrin (HPCD), and beta cyclodextrin sulfobutyl ether sodium salt (CDSB) over the range of 5% to 25% w/v. Solubility determinations were carried at 25 degrees C and 37 degrees C. Cosolvents exponentially increased the solubility of both SIB and racIB, especially in the presence of PG and PEG 300. Glycerol was not very effective in increasing the aqueous solubilities of both compounds, whereas sorbitol solution had a minimal effect on their solubility. PG and PEG 300 increased the solubility of SIB by 400-fold and 1500-fold, respectively, whereas the rise in solubility for racIB was 193-fold and 700-fold, respectively, at 25 degrees C for the highest concentration of the cosolvents used (80% v/v). Of the two compounds studied, higher equilibrium solubilities were observed for SIB as compared with racIB. The derivatized cyclodextrins increased the aqueous solubility of racIB and SIB in a concentration-dependent manner giving AL type of phase diagrams. The phase solubility diagrams indicated the formation of soluble inclusion complexes between the drugs and HPCD and CDSB, which was of 1:1 stoichiometry. The addition of underivatized CD reduced the solubility of racIB and SIB via the formation of an insoluble complex. The S form formed more stable complexes with HPCD and CDSB as compared with raclB. The solubilization process is discussed in terms of solvent polarity and differential solid-state structure of raclB and SIB. The thermodynamic parameters for the solubilization process are presented.

Controlled-release matrix tablets of ibuprofen using cellulose ethers and carrageenans: effect of formulation factors on dissolution rates.

The study was conducted to investigate the effects of carrageenans, and cellulose ethers on the drug release rates of ibuprofen controlled-release tablet matrices prepared by direct compression. Polymer blends containing carrageenans or cellulose ethers were used for the formulation and the effect of varying the polymer concentration on the release of the drug was studied. Other factors such as changes in surface topography of the matrices due to hydration were observed using a cryogenic scanning electron microscopy technique. Multiple regression analysis was used to predict the time for 50% release (t50) as a function of the concentration of the polymers used. Most of the formulations showed linear release profiles (r(2)>or=0.96-0.99) and sustained the release of ibuprofen over 12-16 h. The highest t50 (9.3 h) was for the formulation that contained a blend of 1:2 ratio of Viscarin and HPMC, while the lowest (3 h) was for the matrices that contained a 2:1 ratio of methylcellulose and Gelcarin. The majority of the matrix tablets that contained 10% polymer disintegrated prematurely. Of all the polymer blends that were investigated, the combination of Viscarin and HPMC gave almost linear release profiles over the entire range of concentration that was studied. The least effective combination was methylcellulose in combination with HPMC. Most of the formulations released ibuprofen by an anomalous (non-Fickian) transport mechanism, except those matrices that contained methylcellulose and Gelcarin (in a 1:1 and 1:2 ratio), which showed zero-order release.

Solubility of guaifenesin in the presence of common pharmaceutical additives.

The aqueous solubility of guaifenesin, a highly water-soluble drug, in the presence of salts, sugars, and cosolvents was determined at 25 degrees C and 40 degrees C. The solubility of drug at both temperatures was reduced with increasing concentrations of salts and sugars. The extent of reduction in drug solubility was dependent on the type of salts and sugars used. The salting-out coefficient of additives was calculated by plotting log-linear solubility profiles of the drug against the concentrations of the additives. The solubility of guaifenesin, a neutral compound, was found to be higher at lower pH values, which could be due to hydrogen-bonding effects. At 25 degrees C, glycerin, PEG 300, and propylene glycol increased the solubility of drug at low solvent concentrations while the solubility was reduced at high concentrations. At 40 degrees C, the solubility of drug was reduced at all concentrations of cosolvents. The thermodynamic events accompanying the solubility process were discussed to explain the solubility phenomena observed in the presence of additives. The reduced aqueous solubility of guaifenesin in the presence of additives greatly improved the entrapment of drug into controlled-release wax microspheres.

Cost/death averted with venous thromboembolism prophylaxis in patients undergoing total knee replacement or knee arthroplasty.

STUDY OBJECTIVE: To compare the cost-effectiveness of warfarin or enoxaparin with no prophylaxis for prevention of venous thromboembolism in patients undergoing total knee replacement (TKR) or knee arthroplasty. DESIGN: Literature search and retrospective database analysis. PATIENTS: Cohort of 42,692 patients over 40 years old who underwent TKR or knee arthroplasty, with a subsequent length of stay of at least 1 day, and who did not die postoperatively. MEASUREMENTS AND MAIN RESULTS: Both warfarin and enoxaparin were superior to no prophylaxis with regard to costs and clinical outcomes. Enoxaparin was associated with medical charges of $26,455/patient and prevented 194 deaths/10,000 patients. Warfarin was associated with medical charges of $27,360/patient and prevented 124 deaths/10,000 patients. CONCLUSIONS: A wide range of model estimates and assumptions identify enoxaparin as the prophylaxis modality of choice for preventing venous thromboembolism and subsequent clinical complications following total knee replacement surgery.