Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water-soluble drug from solid dispersions.

Solid dispersions of a poorly water-soluble drug [REV 5901; alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; 1] in an amphiphilic vehicle [Gelucire 44/14; 2] and in polyethylene glycol (PEG) 1000, PEG 1450, and PEG 8000 were prepared. The vehicle 2 was a mixture of hydrogenated fatty acid esters with a mp of 44 degrees C, and had a HLB value of 14. Compound 1 was dissolved or dispersed in molten vehicles at elevated temperatures. The pulverization and compression of solid dispersions were avoided by encapsulating the hot solutions directly into hard gelatin capsules. At room temperature, the dispersions solidified forming plugs inside the capsules. On storage, greater than 180 mg of 1 remained dissolved per gram of vehicle, while the excess drug formed fine crystals (less than 20 micron). When mixed with water, the dissolved drug separated as a metastable liquid. Due to the surfactant property of 2, the oily form of 1 that separated from this vehicle formed an emulsified system with a globular size of less than 1 micron, while greater than 80% of 1 that separated from the other three formulations coalesced to form large oily masses. As a result of the large difference in surface area, the dissolution rate of 1 in simulated gastric fluid from capsules containing 2 was much higher than that of a PEG-based formulation. The bioavailability (AUC) of 1 in dogs from capsules containing 2 was also higher than that from PEG 1000-based capsules.

Physicochemical basis of increased bioavailability of a poorly water-soluble drug following oral administration as organic solutions.

The physicochemical basis of improvement of the bioavailability of a poorly water-soluble drug [REV 5901; alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; 1] after oral administration as organic solutions was investigated. The drug, which exists in solid and metastable liquid forms, had a pKa value of 3.7 and a solubility of approximately 0.002 mg/mL in water (pH approximately 6) at 37 degrees C. It had appreciable aqueous solubility only at pH values less than 2. The dissolution rate of 1 at pH values greater than 3 was practically zero. On dilution of the water-miscible organic solutions (polyethylene glycol 400 and polysorbate 80) of 1 with aqueous media, the drug instantaneously formed saturated solutions and the excess drug separated as emulsified oily globules. The dispersibility of the globules improved in the presence of surfactants. The average globule size of the oily form of 1 was 1.6 micron or less, as compared with a particle size of 5-10 microns for the solids. Thus, a high surface area of 1 was obtained after oral intake of water-miscible organic solutions. Although 1 was practically insoluble under intestinal pH conditions, its solubility was greatly increased in the presence of bile salts, lecithin, and lipid-digestion mixtures. The high surface area of 1 separating from organic solutions would facilitate its dissolution rate in the presence of biological surfactants and lipids and, therefore, would increase its bioavailability.

Preformulation study of a poorly water-soluble drug, alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol: selection of the base for dosage form design.

The physicochemical properties of the base and hydrochloride salt of the poorly water-soluble drug alpha-pentyl-3-(2-quinolinylmethoxy) benzenemethanol (REV 5901) were investigated in order to select an appropriate form of the drug for dosage form development. The pH-solubility profiles of both the base and the salt at 37 degrees C were identical and were in agreement with a pKa value of 3.67 determined by the UV spectral method. The solubility of the drug (approximately 0.002 mg/mL at pH 6) increased gradually with a decrease in pH and reached a value of 0.95 mg/mL at pH 1; at pH values less than 1, the solubility decreased due to the common-ion effect. The pHmax, i.e., the pH of maximum solubility of the drug was, therefore, 1.0. The role of the pHmax in the selection of a salt or base form of a compound was investigated. Due to the conversion of the salt to the base at the surface of the dissolving solid at pH values greater than pHmax, the dissolution rates of both the base and the salt were identical. In the solid state, the salt existed in anhydrous and monohydrate forms; the anhydrous salt converted to the hydrate at greater than 40% relative humidity, and the hydrate lost water at 40-60 degrees C. The thermal properties of the salt were indicative of its potential instability, which was confirmed by accelerated stability studies. The base existed in a stable crystalline solid form, and also in an oily liquid form which converted to crystals on standing.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of thermal history on the glassy state of indapamide.

The effects of thermal history, e.g. cooling rate, annealing, etc., on the thermal behaviour of indapamide glass were determined by differential scanning calorimetry (DSC). The glass was prepared by heating indapamide crystals (m.p. 162 degrees C) to 180 degrees C, and then cooling the melt to room temperature. The glass transition temperature (Tg) of the material was 98 degrees C. An endotherm, due to thermal relaxation of the glass, was observed in the DSC thermogram when indapamide glass was prepared by slow cooling or was annealed isothermally at a temperature below Tg. Such enthalpy relaxation may be observed during ageing of pharmaceutical glasses and might influence their physico-chemical properties.

Selecting child care workers for adolescents: the California Psychological Inventory.

The findings of this study suggest that the CPI can be used to identify characteristics of desirable CCWs for emotionally disturbed adolescents. They include the ability to make intelligent decisions and exert reasonable leadership (Do); to be effective in dealing with others (Cs); to be outgoing and enterprising (Sy); to be socially poised (Sp); to be assertive and self-assured (Sa); to be broad-minded and accepting of different people and values (To); and to be direct, active, and realistic (low Fe). These seven scales of the CPI showed significant difference between the most desirable (Group D) and the unacceptable (Group U) CCWs. Discriminant analysis revealed that selection of the most desirable CCWs can be achieved by using only five of the scales: high Do, Sp, Sa, To, and low Fe; this process identified the most acceptable and unacceptable employees over 85% of the time. If the CPI is used as an adjunct to interviews and adequate reference checks, this multi-evaluative process can greatly improve the likelihood of selecting the best potential CCW candidates. Since CCWs play a direct role with the young people in their charge, and the most effective treatment for disturbed youths can be carried out by the most effective CCWs, the selection process of CCWs becomes a critical factor in the development of any program for emotionally disturbed adolescents.

pH-Solubility Profiles of Organic Bases and Their Hydrochloride Salts.

Knowledge of comparative solubility profiles of a base and its hydrochloride salt is important in selecting one form over the other for dosage form design. The studies with two model bases, namely, tiaramide and papaverine, showed that, except during phase transition from a base to a salt or vice versa, the pH-solubility profiles are identical whether a base or a salt are used. The solubilities were determined by equilibration after addition of hydrochloric acid or sodium hydroxide solutions to suspensions of bases and salts. With the addition of hydrochloric acid solution, the pH values of the suspensions of tiaramide and papaverine dropped to 5.0 ± 0.1 and 4.0 ± 0.1, respectively, and then remained constant until supersaturated solutions were formed. After nucleation of supersaturated solutions with the addition of hydrochloride salt or the reduction of temperature, the precipitation of hydrochloride salt occurred. The solubilities of salts decreased at low pH due to common ion effect. The K(o) sp values, however, did not remain constant and the solubility profiles showed positive deviations from the theoretical ones. These may be due to a possible self-association and the resultant difference between the solubilities and activities of the compounds in solutions. The reported differences between the solubilities of bases and their respective hydrochloride salts at a particular pH and the lack of common ion effects on the solubilities and dissolution rates of bases are explained.

Chlorthalidone analysis using carbonic anhydrase inhibition.

Chlorthalidone was analyzed in the concentration range of 0.1-3.0 microgram/ml with a precision of +/- 0.05 microgram/ml. Chlorthalidone inhibition of the enzymatic hydrolysis rate of p-nitrophenyl acetate by bovine erythrocyte carbonic anhydrase was used as a basis for the determination. The amount of p-nitrophenol formed was measured by monitoring the absorbance at 400 nm, and its formation rate was proportional to the chlorthalidone concentration. The mixing of the enzyme, substrate, and sample, the incubation of the reaction mixture, and the recording of the absorbance were automated. A survey of urine samples from 26 normal human subjects did not reveal any endogenous substances that interfered with the assay. Analyses of urine samples from six subjects after oral administration of 100 mg of chlorthalidone indicated rapid absorption and a biphasic elimination. The alpha-phase half-life was 1.5 hr, and the beta-phase half-life was 35 hr.

GLC determination of urinary chlorthalidone levels.

A sensitive and specific GLC method for the determination of urinary chlorthalidone levels was developed using on-column methylation. Chlorthalidone is converted to a tetramethylated derivative with trimethylanilinium hydroxide in methanol. This method which permits the determination of as little as 0.1 microgram of chlorthalidone/ml of dog urine, should be adequate for use with human subjects receiving a clinical dose.

Cholesterol solubility in lecithin-bile salt systems.

The method of sample preparation can markedly influence the rate of dissolution and attainment of supersaturated states of cholesterol. The equilibrium solubility of cholesterol, studied as a function of its physical state in a model bile system, is almost half that of previously accepted values. Slow attainment of the equilibrium state may have acted to bias previous studies. Extrapolation of our data to the clinical situation reveals that many persons considered normal by present standards actually possess bile that is supersaturated with respect to cholesterol and are thus potential gallstone formers.