Solubility in binary solvent systems: 8. Estimation of binary alkane plus p-dioxane solvent nonideality from measured anthracene solubilities

Experimental solubilities are reported for anthracene in binary solvent mixtures containing p-dioxane with n-hexane, cyclohexane, n-heptane, methylcyclohexane, n-octane, cyclooctane, and isooctane at 25 degrees C. Results of these measurements, used in conjunction with the nearly ideal binary solvent (NIBS) model, enabled excess Gibbs free energies, delta GBCfh, of the seven binary solvent mixtures to be estimated. Estimated values for p-dioxane plus cyclohexane, p-dioxane plus n-heptane, and p-dioxane plus methylcyclohexane mixtures are in reasonable agreement with published values based on vapor pressure measurements.     

Comparative lethality of methanol, ethanol and mixtures in female rats.

The lethalities of pure methanol and pure ethanol were compared to two mixtures of ethanol/methanol with the following percentages (95/5% and 65/35% v/v). This study was conducted to simulate situations of human exposure to denaturated alcohol (by 5% methanol) or adulterated alcohol (by 35% methanol). Four groups of female adult virgin albino rats were treated with the four mixtures. A fifth group was used as a vehicle control. Graded oral doses were given to eight animals per dose. Lethality over 24 h was used as an end-point. The LD50 was calculated for each of the four treatments on a molar basis. A dose-response function for each mixture was plotted of percentage lethality vs. mmol kg-1 equivalent to the given ml kg-1 dose. Results showed a significantly different LD50 estimates (P less than 0.03) for the four mixtures. The order of lethal toxicity was as follows: 95/5% methanol/ethanol, pure methanol, pure ethanol then 65/35% methanol/ethanol. Slope comparisons indicated two pairs: 65/35% ethanol/methanol and pure ethanol yielding a steep slope, and 95/5% ethanol/methanol and pure methanol yielding a shallow slope. These data indicated that the acute lethality of ethanol/methanol mixtures is a complex unpredictable function. This toxicity presumably depends in a complicated way on the differences in the effective molecular weights of the two alcohols in each of the mixtures.     

Effects of acute and chronic administration of delta 9-tetrahy-drocannabinol or cocaine on ethanol intake in a rat model.

The acute and chronic administration of delta 9-tetrahydrocannabinol (delta 9-THC) or cocaine were studied in rats trained to obtain all of their daily food by lever pressing during four equally-spaced 30-min periods with water and 5% or 7.5% ethanol solutions freely available. With 5% ethanol available, rats consumed almost all of their daily fluid intake as ethanol, while with 7.5% ethanol available, rats consumed water and ethanol solution in approximately equal amounts. Rats consumed more food pellets with 7.5% ethanol available than with 5% ethanol available. Acute administration of delta 9-THC produced a dose-dependent decrease of 5% ethanol intake and food pellets consumed with a small increase in water intake, especially after the higher doses. Acute administration of delta 9-THC also depressed food intake when 7.5% ethanol was available, but decreases in ethanol solution intake were small. Chronic administration of delta 9-THC initially decreased ethanol intake, but tolerance occurred to this effect, so that during chronic delta 9-THC administration ethanol intake not only recovered, but increased above control levels. When the chronic administration of delta 9-THC was discontinued, ethanol intake was increased for 1 (5% ethanol) to 3 (7.5% ethanol) weeks. Animals with initially high, or initially low, but not with initially moderate ethanol intake, accounted for the increased ethanol intake during chronic delta 9-THC administration and withdrawal. Acute cocaine administration, at doses up to 30 mg/kg, had little effect on eating and drinking; however, during chronic cocaine administration, ethanol intake gradually increased, an increase which was sustained during cocaine withdrawal. The increased ethanol drinking was confined to the first 6-h period after cocaine administration. These data suggest that the chronic administration and withdrawal of other drugs can increase ethanol intake in this rat model.     

Determinants of plasma free acetaldehyde levels during the oxidation of ethanol: Effects of chronic ethanol feeding

Plasma free acetaldehyde levels were measured by an improved method in baboons fed ethanol chronically and in pair-fed controls during an intravenous infusion of ethanol. After an appropriate loading dose, ethanol was infused at the rate of its elimination to achieve a steady state at one of three different blood ethanol levels (50 ± 10 mM, 10 ± 2 mM, or 5 ± 1 mM). The rate of production of acetaldehyde was calculated from the rate of ethanol elimination by subtracting losses into urine and expired air. Liver mitochondrial aldehyde dehydrogenase (AlDH) activity was measured in surgical biopsy samples with 50 μM acetaldehyde as substrate. Chronic ethanol administration resulted in both higher plasma free acetaldehyde levels and faster acetaldehyde production at each level of blood ethanol. When the blood level of ethanol was increased from 5 to 50 mM, the level of plasma free acetaldehyde also rose in both groups of animals. The rate of acetaldehyde production, however, increased only in alcohol-fed baboons. Plasma free acetaldehyde had a significant positive correlation with production rate of acetaldehyde (r = 0.69) and a significant negative correlation with liver mitochondrial AIDH specific activity (r = ?0.59). When these two parameters were combined (acetaldehyde production rate/AIDH activity), a correlation coefficient of 0.84 resulted, suggesting that, in addition to increased production, decreased catabolism may contribute to the higher acetaldehyde levels seen after chronic consumption.     

Thermodynamics of cosolvent action: phenacetin, salicylic acid and probenecid

The solubility of phenacetin, salicylic acid, and probenecid in ethanol-water and ethanol-ethyl acetate mixtures at several temperatures (15-40 degrees C) was measured. The solubility profiles are related to medium polarity changes. The apparent thermodynamic magnitudes and enthalpy-entropy relationships are related to the cosolvent action. Salicylic acid and probenecid show a single peak against the solubility parameter delta(1) of both solvent mixtures, at 40% (delta(1) = 21.70 MPa(1/2)) and 30% (delta(1) = 20.91 MPa(1/2)) ethanol in ethyl acetate, respectively. Phenacetin displays two peaks at 60% ethanol in ethyl acetate (23.30 MPa(1/2)) and 90% ethanol in water (delta(1) = 28.64 MPa(1/2)). The apparent enthalpies of solution display a maximum at 30% (phenacetin and salicylic acid) and 40% (probenecid) ethanol in water, respectively. Two different mechanisms, entropy at low ethanol ratios, and enthalpy at high ethanol ratios control the solubility enhancement in the aqueous mixture. In the nonaqueous mixture (ethanol-ethyl acetate) enthalpy is the driving force throughout the whole solvent composition for salicylic acid and phenacetin. For probenecid, the dominant mechanism shifts from entropy to enthalpy as the ethanol in ethyl acetate concentration increases. The enthalpy-entropy compensation plots corroborate the different mechanisms involved in the solubility enhancement by cosolvents.     

Physicochemical investigations on microemulsification of eucalyptol and water in presence of polyoxyethylene (4) lauryl ether (Brij-30) and ethanol

The microemulsification of eucalyptol/polyoxyethylene(4)lauryl ether (Brij-30)/ethanol/water has been investigated. The phase behaviours of the mixed system in pseudoternary and tetrahedral representations have been examined to understand the topological nature of the multicomponent mixtures. Phase volumes of the heterogeneous combinations have been estimated to understand the mixing efficacy of the combinations. Shear viscosities of different monophasic compositions have been measured at different shear rates and temperatures, and the activation parameters for the viscous flow have been evaluated. The dimensions of the nanodispersions of w/o and o/w types, their diffusion coefficients and the polydispersity have been determined by the DLS method. The energetics of solubilisation (dissolution) of water in oil+Brij-30+ethanol as well as oil in water+Brij-30+ethanol forming w/o and o/w microemulsions, respectively, have been calorimetrically determined. Considering the phase separation point to be the point of maximum solubility, the energetic parameters (enthalpy, free energy and entropy) of the microemulsification process have been estimated.     

Comparative studies on the effects of water, ethanol and water/ethanol mixtures on chemical partitioning into porcine stratum corneum and silastic membrane.

The effects of water and ethanol vehicles on stratum corneum and silastic membrane partitioning of 11 industrial and agricultural compounds were studied to aid in characterizing and assessing risk from skin exposure. Zero percent, 50% and 100% aqueous ethanol solutions were used as solvents for (14)C labeled phenol, 4-nitrophenol, pentachlorophenol, dimethyl parathion, parathion, chloropyrifos, fenthion, triazine, atrazine, simazine and propazine. Compound partitioning between the solvents and porcine stratum corneum/silastic membrane were estimated. Stratum corneum was exposed to aqueous ethanol ranging from 0% to 100% v/v ethanol in 20% increments and Fourier transform infrared spectroscopy (FT-IR) was used to obtain an index of lipid disorder. Gravimetry and FT-IR were used to demonstrate lipid extraction in aqueous ethanol solutions. Partitioning patterns in silastic membranes resembled those in stratum corneum and were correlated with octanol/water partitioning. Partitioning was highest in water and was higher from 50% ethanol than from 100% ethanol, except for parathion, 4-nitrophenol, atrazine and propazine. Correlation existed between molecular weight and partitioning in water, but not in ethanol and ethanol/water mixtures. Lipid order, as reflected in FT-IR spectra, was not altered. These studies suggest that stratum corneum partitioning of the compounds tested is primarily determined by relative compound solubility between the stratum corneum lipids and the donor solvent. Linear relationships existed between octanol/water partitioning and stratum corneum partitioning. Partitioning was also correlated with molecular weight in water solvent systems, but not in ethanol and ethanol/water mixtures. Ethanol and ethanol/water mixtures altered the stratum corneum through lipid extraction, rather than through disruption of lipid order.     

The effect of water to ethanol feed ratio on physical properties and aerosolization behavior of spray dried cromolyn sodium particles

Cromolyn sodium (CS) was spray dried under constant operation conditions from different water to ethanol feed ratios (50:50-0:100). The spray dried CS samples were characterized for their physicochemical properties including crystallinity, particle size distribution, morphology, density, and water/ethanol content. To determine quantitatively the crystallinity of the powders, an X-ray diffraction (XRD) method was developed using samples with different crystallinity prepared by physical mixing of 100% amorphous and 100% crystalline CS materials. The aerodynamic behavior of the CS samples was determined using an Andersen Cascade Impactor (ACI) with a Spinhaler at an air flow of 60 L/min. Binary mixtures of each spray dried CS powder and Pharmatose 325, a commercial alpha-lactose monohydrate available for DPI formulations, were prepared and in vitro aerosol deposition of the drug from the mixtures was analyzed using ACI to evaluate the effect of carrier on deposition profiles of the spray dried samples. CS spray dried from absolute ethanol exhibited XRD pattern characteristic for crystalline materials and different from patterns of the other samples. The crystallinity of spray dried CS obtained in the presence of water varied from 0% to 28.37%, depending on the ratio of water to ethanol in the feed suspensions. All samples presented different particle size, water/ethanol content, and bulk density values. CS particles spray dried from absolute ethanol presented uniform elongated shape whereas the other samples consisted mainly of particles with irregular shape. Overall, fine particle fraction increased significantly (p < 0.01) with decreasing d50% and water and ethanol content of spray dried CS samples. Significant difference (p < 0.01) in deposition profiles of the drug were observed between corresponding carrier free and carrier blended formulations. The difference in deposition profiles of CS aerosolized from various spray dried samples were described according to the particle size, shape, and water/ethanol contents of the powders. The results of this study indicate that enhanced aerosol performance of CS can be obtained by spray drying of the drug from suspensions containing > or = 87.5% v/v ethanol.     

Phase behavior of TPGS-PEG400/1450 systems and their application to liquid formulation: a formulation platform approach

Vitamin E D-alpha-tocopheryl polyethylene glycol succinate (TPGS) and polyethylene glycol are common excipients used in both preclinical and commercial formulations. In this paper, the phase diagrams of TPGS and polyethylene glycol 400 (PEG 400) in the presence of either water or ethanol were constructed. The effect of water and ethanol on the cloud point temperature of TPGS-PEG 400 mixtures was investigated. In general, the cloud point temperature was reduced by the presence of either water or ethanol in the formulation. However, water was more effective in lowering the cloud point temperature than ethanol. Similarly, the phase diagram of TPGS-PEG 1450 was constructed. The cloud point temperature was observed to decrease with increasing TPGS concentration. It was found that TPGS and PEG 1450 could form a single phase when TPGS concentration was above 75%, based on differential scanning calorimetry, and FT-Raman analysis indicated that a vibration at 1330 cm(-1) disappeared in the melted single phase. In addition, a systematic melting point depression was observed for the mixtures of TPGS-PEG 1450. In the presence of Ibuprofen, a model compound, the cloud point temperature was also reduced. Finally, the extended Flory-Huggins theory for polymer solution was used to analyze the entropic and enthalpic contributions of water and ethanol to the free energy of mixing.     

Delta 9-tetrahydrocannabinol interactions with phencyclidine and ethanol: effects on accuracy and rate of responding.

The effects of delta 9-tetrahydrocannabinol (delta 9-THC) in combination with phencyclidine (PCP) or ethanol were examined in rats responding under a fixed-consecutive-number schedule of food presentation. Under this schedule, a minimum of 13 consecutive responses on one lever followed by one response on another lever produced food. When administered alone, PCP (0.1-10.0 mg/kg) and delta 9-THC (0.1-5.6 mg/kg), but not ethanol (0.3-1.7 g/kg), decreased accuracy. PCP, delta 9-THC, and ethanol alone all produced dose-dependent decreases in rate of responding. A dose-effect curve for PCP or ethanol was then redetermined in combination with selected doses of delta 9-THC (0.125-1.75 mg/kg) and the data were analyzed according to the effect-addition and dose-addition models of additivity. When administered in combination, delta 9-THC produced dose-dependent leftward shifts in the PCP dose-effect curves for both accuracy and rate of responding. The interactions for PCP + delta 9-THC combinations were effect-additive for accuracy. In contrast, the type of interaction obtained for PCP + delta 9-THC combinations on rate of responding depended upon the particular doses combined, as well as on the model used to analyze the interactions. According to the effect-addition model, these interactions were additive at low doses of delta 9-THC and supraadditive at the highest dose. However, according to the dose-addition model the interactions at the higher doses of delta 9-THC were infraadditive. Delta 9-THC also shifted the ethanol dose-effect curve for rate of responding to the left but did not alter the ethanol dose-effect curve for accuracy. The interactions for ethanol + delta 9-THC combinations were effect-additive for accuracy and both effect- and dose-additive for rate of responding. The present investigation clearly illustrates the importance of examining an extensive range of dose combinations on different behavioral measures, as well as the use of appropriate analyses in studies designed to evaluate the interactions between drugs.     

Drug mixtures and ethanol as compound internal stimuli.

Drug discrimination methods that entail training with mixtures of drugs may shed light on polydrug abuse and on the actions of single drugs that interact with more than one receptor. In AND-discrimination procedures (drug A + drug B vs. vehicle), mixtures are discriminated primarily on the basis of their component drugs: these discriminations may be useful for testing interactions between component drugs in mixtures. The role of training dose, overshadowing and associative blocking in AND-discriminations have been investigated. For example, after prior training with midazolam, it was possible to demonstrate associative blocking of the nicotine element of the mixture stimulus, and vice versa. Using the AND-OR discriminations (drug A + drug B vs. drug A or drug B) increased pharmacological specificity considerably, and these procedures may be valuable for determining whether the effects of a novel mixture are similar to the combined effects of the training drugs. Ethanol is an example of a single drug that may produce a compound cue; rats trained to discriminate ethanol from water generalize (asymmetrically) to GABA(A) enhancers such as chlordiazepoxide (CDP) or pentobarbitone, to NMDA antagonists such as dizocilpine (MK-801), and to some serotonin agonists, such as trifluoromethylphenylpiperazine (5-HT(1B/2C)). In addition, rats trained to discriminate mixtures of either CDP or pentobarbitone plus MK-801 generalize to ethanol. A previous history of training with MK-801 or CDP (prior to ethanol discrimination training) enhanced the MK-801-like and CDP-like effects of ethanol respectively, but associative blocking of proposed elements in the ethanol stimulus was not seen. These studies provide some support for the multielement concept of ethanol discrimination but also suggest that rules governing three-component stimuli (such as those putatively produced by ethanol) may differ from those for the two-component mixtures of drugs studied previously.     

Highly loaded interactive mixtures for dry powder inhalers: prediction of the adhesion capacity using surface energy and solubility parameters

In order to correlate drug adhesion properties of a highly loaded interactive mixture for the use in dry powder inhalers with the surface energy and to establish a link to the solubility parameter, surface free energy was detected for micronized substances (salbutamol sulfate, salbutamol base, theophylline and alpha-lactose monohydrate) using inverse gas chromatography (IGC). Interactive mixtures with coarse crystalline alpha-lactose monohydrate as a carrier were prepared at loading levels from 7.5 to 20% (w/w) and analyzed with respect to their adhesion capacity (CA) using the air jet sieving method. Solubility parameters were taken from literature or calculated. As a result the CA was independent of the drug load and correlated linearly with volume specific surface energy interaction (SEIv) values of the adherents (R2 = 0.98498). A link between SEIv and the size normalized solubility parameter (delta(tot)/d50) was found. Consequently, plotting delta(tot)/d50 versus CA resulted also in a strong linear relationship (R2 = 0.99140). Overall a powerful tool was established to judge and quantify adhesion properties of highly loaded interactive mixtures even for estimates in early preformulation at a time where just the molecular structure of the active ingredient is known.     

Partial molal volumes and solubilities of physostigmine in isopropanol:isopropyl myristate solvents in relation to skin penetrability

Partial molal volumes (Vi infinity) of physostigmine, ranging from 232.9 to 239.8 cm3.mol-1, and its mole fraction solubilities (Xi), ranging from 0.051 to 0.009, were determined at 25 degrees C in solutions of isopropanol (IPA), isopropyl myristate (IPM), and their mixtures. An inverse relation was found between Vi infinity and Xi. At solubility----0, Vi infinity----240.6 (by extrapolation). The experimentally derived liquid molal volume in the standard state, Vi degrees (231.1), of physostigmine was lower than its lowest Vi infinity (value 232.9) in the series tested. Virtual cohesion parameters (lambda i) and excess free energies (delta EGi) of physostigmine in the various solutions were estimated from the partial molal volumes, assuming regular solution behavior. For each solution, the free energy (-RT In Xi) of the drug was estimated from its solubility. An increase in the virtual cohesion parameter and a decrease in the excess free energy and the free energy was found with an increase in volume fraction of IPA in the mixed solvent. The increase in lambda i over the invariant cohesion parameter, delta i (10.2), reflects a compensation effect needed to maintain the geometric mean assumption of Regular Solution Theory. Deviation from the theoretically expected linearity between -RT In Xi and delta EGi of physostigmine is ascribed to the existence of solvated molecules distinct from unsolvated molecules of physostigmine. The highest permeability coefficient of the delivery of physostigmine through excised human skin from IPA:IPM mixtures was seen from the mixture exhibiting the highest solvation effect, giving additional evidence that physostigmine penetrates through the skin, possibly in combination with IPA.     

Influence of ethanol water-content on gatifloxacin recrystallisations

Gatifloxacin is a flouroquinolone anti-bacterial agent. This study proved that even the presence of small amounts of water in the recrystallisation medium influenced the product obtained. Different crystal forms were produced from various binary mixtures of ethanol and water. Where mixtures had a water content greater than (or equal to) 50% v/v, only hydrated crystal forms were produced and no ethanol was incorporated into the lattice.     

Autoshaping induces ethanol drinking in nondeprived rats: evidence of long-term retention but no induction of ethanol preference

The effects of autoshaping procedures (paired vs. random) and sipper fluid (ethanol vs. water) on sipper-directed drinking were evaluated in male Long-Evans rats maintained with free access to food and water. For the paired/ethanol group (n=16), autoshaping procedures consisted of presenting the ethanol sipper (containing 0% to 28% unsweetened ethanol) conditioned stimulus (CS) followed by the response-independent presentation of food unconditioned stimulus (US). The random/ethanol group (n=8) received the sipper CS and food US randomly with respect to one another. The paired/water group (n=8) received only water in the sipper CS. The paired/ethanol group showed higher grams per kilogram ethanol intake than the random/ethanol group did at ethanol concentrations of 8% to 28%. The paired/ethanol group showed higher sipper CS-directed milliliter fluid consumption than the paired/water group did at ethanol concentrations of 1% to 6%, and 15%, 16%, 18%, and 20%. Following a 42-day retention interval, the paired/ethanol group showed superior retention of CS-directed drinking of 18% ethanol, relative to the random/ethanol group, and superior retention of CS-directed milliliter fluid drinking relative to the paired/water group. When tested for home cage ethanol preference using limited access two-bottle (28% ethanol vs. water) procedures, the paired/ethanol and random/ethanol groups did not differ on any drinking measures.     

Effects of sweetened ethanol solutions on ethanol self-administration and blood ethanol levels

The enhancement of voluntary self-administration of ethanol by sucrose or saccharin was tested in conjunction with measurements of blood ethanol levels. Adult male rats were given access to both tap water and one of five solutions: 0.125% saccharin, 10% sucrose, ethanol, saccharin+ethanol, or sucrose+ethanol. The rats receiving the sucrose+ethanol solution drank consistently more ethanol (>5 g/kg/day) than did the rats receiving the saccharin+ethanol solution (<3 g/kg/day) or ethanol only (<2 g/kg/day). Both sweetened solutions produced higher ethanol consumption during these periods than ethanol alone. However, no significant differences in blood ethanol levels were found between the sucrose+ethanol and saccharin+ethanol conditions, when tested at different intervals on Day 44 or Day 45 of ethanol consumption. Following 45 days of consumption, no change in the bicuculline seizure threshold was observed in the ethanol-consuming rats compared to the controls. In a separate study using 90 naive rats, rats were gavaged with ethanol (1, 2, or 3 g/kg) containing either 10% sucrose (n=10 for each dose of ethanol), 0.125% saccharin (n=10 for each dose of ethanol), or ethanol alone (n=10 for each dose of ethanol), and blood was collected from the tip of the tail 30, 60, 180, 300, and 540 min later and analyzed for ethanol concentrations. Sucrose significantly decreased the resultant blood ethanol levels at several time points following gavage. These results indicate that sucrose can significantly alter blood ethanol levels and that chronic self-administration of a sweetened ethanol solution for 6 weeks does not produce ethanol dependence.     

Systematic study of the flow behaviour and mechanical properties of Carbopol Ultrez 10 hydroalcoholic gels.

Flow behaviour and mechanical properties of 0:100, 15:85, and 30:70 v/v gelled ethanol:water mixtures are studied as a function of pH (4.0-7.0) and Carbopol Ultrez 10 concentration (0.1-0.5%). As previously reported individually for 30% v/v alcoholic Ultrez 10 gels, flow curves were adjusted to the Ostwald's model, and similar sigmoidal dose response functions were obtained to describe the pH dependence of consistency index and mechanical properties of the systems. The concentration dependence of flow indexes was also best adjusted to one-phase exponential decay functions. As a result, the influence of ethanol content on polymer network is meaningfully assessed by means of the obtained empirical parameters: bottom value of each variable (Y(max)), pH value required for a 50% polymer network development (pH(50)), and asymptotic flow index value for the fully structured gels (n(min)). Also, it is assessed the influence of cosolvent on the above-mentioned empirical variables, by studying pH-dependence of gelation in methanol:water, 1-propanol:water and 1-butanol:water 15:85% v/v mixtures. As a result, the alcohol induced variations in consistency and mechanical properties of hydroalcoholic gels were well correlated to modifications in the solubility parameter (delta(T)).     

Solubility behavior of polymorphs I and II of mefenamic acid in solvent mixtures

The dissolution profile and solubility of two polymorphic forms of mefenamic acid were studied in solvent mixtures of ethanol-water and ethyl acetate-ethanol. The solubility parameter (delta) was used to study the effect of polarity on the solubility behavior of the two polymorphs. Differential scanning calorimetry and infrared spectroscopy were performed on the original powders and on the solid phases after contact with the solvent systems for the characterization and identification of the polymorphs. The dissolution rates of both polymorphs is greater in the less polar mixtures (ethyl acetate-ethanol) of lower solubility parameter values. Form II showed larger dissolution rates and saturation concentrations than Form I in all the solvent systems studied. The solid phase of Form II converts totally to Form I after equilibration with the solvents. The rate of conversion was faster in the least polar mixtures. The solubility of both polymorphs reaches a single maximum at 80% ethyl acetate in ethanol, delta = 20.09 MPa1/2. The modified extended Hildebrand method was used to predict the solubility profile of each polymorph. A single equation was obtained for both polymorphs which includes the solubility parameter of the mixtures and the logarithm of the solubility mole fraction of each polymorph in water. The Hildebrand solubility parameter of mefenamic acid is independent of the crystalline form and was determined from two methods giving quite similar values, delta 2 = 20-21 MPa1/2.     

Effect of ethanol on the binding of conformationally rigid and labile ligands of opioid receptors to rat brain membranes

The effect of ethanol on the binding of conformationally rigid and labile ligands for mu and delta opioid receptors to rat brain membranes was determined. The mu ligands used for the studies were [3H]naltrexone and [3H]Tyr-D-Ala-Gly-N-MePhe-Gly-ol (DAGO), and delta ligands used were [3H]Tyr-D-Ser-Gly-Phe-Leu-Thr-OH (DSTLE) and [3H]Tyr-D-Ala-Gly-Phe-Leu (DADLE). The binding of all the opioid ligands was inhibited by ethanol in a concentration-dependent manner. For mu ligands the inhibition was greater for [3H]DAGO binding than for the binding of [3H]naltrexone. For delta ligands, the inhibition by ethanol of the binding of [3H]DADLE was greater than that of [3H]DSTLE. Fourier-transform infrared (FT-IR) spectroscopy was used to determine the conformation of opioid peptides. The data indicated that the conformation of peptides was altered in the presence of ethanol. The results suggest that ethanol inhibits the binding of both mu and delta opioid ligands with greater inhibition observed with conformationally labile ligands. Finally, the alteration in the conformation of the peptide ligands by ethanol, in addition to denaturation of the receptor protein, may also account for the observed inhibitory effect of ethanol on brain opioid receptors.     

Prediction of the adsorption of diazepam by activated carbon in aqueous media

Adsorption isotherms for the diazepam-activated carbon system in simulated intestinal fluid (SIF), without pancreatin, and in SIF with different percentages of ethanol were determined as were the solubilities of diazepam in SIF and in SIF with different percentages of ethanol. The surface area of the activated carbon was also evaluated. The results from the experimental work provided information on the relationship between adsorption and solubility. An excellent logarithmic relationship was observed between the adsorption affinity and the solubility of diazepam in the ethanol-SIF mixtures. This relationship was explained by a linear relationship between the differential free energy of displacement and the differential free energy of solution. Excellent correlations were also observed between the amounts of diazepam adsorbed by activated carbon and the solubilities of diazepam in the ethanol-SIF mixtures. This relationship was used to predict the complete isotherm, which was in excellent agreement with the experimental work.