Biomedical subjects

P Bustamante

Publications and source records attributed to P Bustamante.

At least 37 records · Page 2Linked to original sources

PubMed2000

The modified extended Hansen method to determine partial solubility parameters of drugs containing a single hydrogen bonding group and their sodium derivatives: benzoic acid/Na and ibuprofen/Na.

Sodium salts are often used in drug formulation but their partial solubility parameters are not available. Sodium alters the physical properties of the drug and the knowledge of these parameters would help to predict adhesion properties that cannot be estimated using the solubility parameters of the parent acid. This work tests the applicability of the modified extended Hansen method to determine partial solubility parameters of sodium salts of acidic drugs containing a single hydrogen bonding group (ibuprofen, sodium ibuprofen, benzoic acid and sodium benzoate). The method uses a regression analysis of the logarithm of the experimental mole fraction solubility of the drug against the partial solubility parameters of the solvents, using models with three and four parameters. The solubility of the drugs was determined in a set of solvents representative of several chemical classes, ranging from low to high solubility parameter values. The best results were obtained with the four parameter model for the acidic drugs and with the three parameter model for the sodium derivatives. The four parameter model includes both a Lewis-acid and a Lewis-base term. Since the Lewis acid properties of the sodium derivatives are blocked by sodium, the three parameter model is recommended for these kind of compounds. Comparison of the parameters obtained shows that sodium greatly changes the polar parameters whereas the dispersion parameter is not much affected. Consequently the total solubility parameters of the salts are larger than for the parent acids in good agreement with the larger hydrophilicity expected from the introduction of sodium. The results indicate that the modified extended Hansen method can be applied to determine the partial solubility parameters of acidic drugs and their sodium salts.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2000

Proposition of group molar constants for sodium to calculate the partial solubility parameters of sodium salts using the van Krevelen group contribution method.

The aim of this study is to propose, for the first time, a set of group molar constants for sodium to calculate the partial solubility parameters of sodium salts. The values were estimated using the few experimental partial solubility parameters of acid/sodium salt series available either from the literature (benzoic acid/Na, ibuprofen acid/Na, diclofenac Na) or determined in this work (salicylic acid/Na, p-aminobenzoic acid/Na, diclofenac), the group contribution method of van Krevelen to calculate the partial parameters of the acids, and three reasonable hypothesis. The experimental method used is a modification of the extended Hansen approach based on a regression analysis of the solubility mole fraction of the drug lnX(2) against models including three- or four-partial solubility parameters of a series of pure solvents ranging from non-polar (heptane) to highly polar (water). The modified method combined with the four-parameter model provided the best results for both acids and sodium derivatives. The replacement of the acidic proton by sodium increased the dipolar and basic partial solubility parameters, whereas the dispersion parameter remained unaltered, thus increasing the overall total solubility parameter of the salt. The proposed group molar constants of sodium are consistent with the experimental results as sodium has a relatively low London dispersion molar constant (identical to that of -OH), a very high Keesom dipolar molar constant (identical to that of -NO(2), two times larger than that of -OH), and a very high hydrogen bonding molar constant (identical to that of -OH). The proposed values are: F((Na)d)=270 (J cm(3))(1/2) mol(-1); F((Na)p)=1030 (J cm(3))(1/2) mol(-1); U((Na)h)=17000 J mol(-1). Like the constants for the other groups, the group molar constants proposed for sodium are certainly not the exact values. However, they are believed to be a fair approximation of the impact of sodium on the partial solubility parameters and, therefore, can be used as such in the group contribution method of van Krevelen.

Algorithms↗

PubMed2000

Multiple solubility maxima of oxolinic acid in mixed solvents and a new extension of Hildebrand solubility approach.

A new extension of the Hildebrand solubility approach which describes drug solubility in solvent mixtures showing multiple solubility peaks, the chameleonic effect, is proposed. The experimental solubilities of oxolinic acid were measured at 25 degrees C in solvent mixtures of ethanol-water and ethanol-ethyl acetate. A plot of the mole fraction of the drug against the solubility parameter (delta) of the solvent mixtures displays two peaks at delta = 30.78 MPa1/2 (80% v/v of ethanol in water) and at delta = 20.90 MPa1/2 (30% v/v of ethanol in ethyl acetate). The new extension proposed reproduces two solubility peaks. The thermograms of the solid phase before and after equilibration with the solvent mixtures did not show significant changes. The new extension was also tested with experimental data previously reported for drugs showing two solubility peaks of different height. The accuracy of other published models for describing two solubility maxima is also compared.

Algorithms↗

PubMed2000

Partial solubility parameters of lactose, mannitol and saccharose using the modified extended Hansen method and evaporation light scattering detection.

The modified extended Hansen method was tested for the first time to determine partial solubility parameters of non-polymeric pharmaceutical excipients. The method was formerly tested with drug molecules, and is based upon a regression analysis of the logarithm of the mole fraction solubility of the solute against the partial solubility parameters of a series of solvents of different chemical classes. Two monosaccharides and one disaccharide (lactose monohydrate, saccharose and mannitol) were chosen. The solubility of these compounds was determined in a series of solvents ranging from nonpolar to polar and covering a wide range of the solubility parameter scale. Sugars do not absorb at the UV-vis region, and the saturated solutions were assayed with a recent chromatographic technique coupled to an evaporative light scattering detector. This technique was suitable to determine the concentration dissolved in most solvents. The modified extended Hansen method provided better results than the original approach. The best model was the four parameter equation, which includes the dispersion delta d, dipolar delta p, acidic delta a and basic delta b partial solubility parameters. The partial solubility parameters obtained, expressed as MPa1/2, were delta d = 17.6, delta p = 28.7, delta h = 19, delta a = 14.5, delta b = 12.4, delta T = 32.8 for lactose, delta d = 16.2, delta p = 24.5, delta h = 14.6, delta a = 8.7, delta b = 12.2, delta T = 32.8 for mannitol and delta d = 17.1, delta p = 18.5, delta h = 13, delta a = 11.3, delta b = 7.6, delta T = 28.4 for saccharose. The high total solubility parameters delta T obtained agree with the polar nature of the sugars. The dispersion parameters delta d are quite similar for the three sugars indicating that the polar delta p and hydrogen bonding parameters (delta h, delta a, delta b) are responsible for the variation in the total solubility parameters delta T obtained, as also found for drugs. The results suggest that the method could be extended to determine the partial solubility parameters of other non-polymeric pharmaceutical excipients.

Chromatography, Liquid↗

PubMed1999

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.

Acetates↗

PubMed1998

Cephalopods as a vector for the transfer of cadmium to top marine predators in the north-east Atlantic Ocean.

Three hundred and fifty individuals of 12 species of cephalopods which differed in their feeding habitats were sampled from the French Atlantic coast to the sub-Arctic region (Bay of Biscay, English Channel, west Irish coast and Faroe Islands) and analysed for their cadmium contents. Comparison of the Cd levels of the cephalopods showed that those from the sub-Arctic area contained very high Cd concentrations compared to those from lower latitudes such as along the French Atlantic coast. High Cd levels in cephalopods from the sub-Arctic zone correspond closely to the reported high Cd concentrations in the tissues of top vertebrate predators from the same area. Comparison of the weekly Cd intakes for the Faroe Island pilot whales with the 'Provisional Tolerable Weekly Intake' for humans recommended by the World Health Organisation, showed that top vertebrate predators are often subjected to Cd doses far in excess of those recommended for humans. Our limited survey results suggest that cephalopods constitute an important source of Cd for cephalopod predators, and that this bioaccumulation effect is most evident at high latitudes.

Animals↗

PubMed1998

Enthalpy-entropy compensation for the solubility of drugs in solvent mixtures: paracetamol, acetanilide, and nalidixic acid in dioxane-water.

In earlier work, a nonlinear enthalpy-entropy compensation was observed for the solubility of phenacetin in dioxane-water mixtures. This effect had not been earlier reported for the solubility of drugs in solvent mixtures. To gain insight into the compensation effect, the behavior of the apparent thermodynamic magnitudes for the solubility of paracetamol, acetanilide, and nalidixic acid is studied in this work. The solubility of these drugs was measured at several temperatures in dioxane-water mixtures. DSC analysis was performed on the original powders and on the solid phases after equilibration with the solvent mixture. The thermal properties of the solid phases did not show significant changes. The three drugs display a solubility maximum against the cosolvent ratio. The solubility peaks of acetanilide and nalidixic acid shift to a more polar region at the higher temperatures. Nonlinear van't Hoff plots were observed for nalidixic acid whereas acetanilide and paracetamol show linear behavior at the temperature range studied. The apparent enthalpies of solution are endothermic going through a maximum at 50% dioxane. Two different mechanisms, entropy and enthalpy, are suggested to be the driving forces that increase the solubility of the three drugs. Solubility is entropy controlled at the water-rich region (0-50% dioxane) and enthalpy controlled at the dioxane-rich region (50-100% dioxane). The enthalpy-entropy compensation analysis also suggests that two different mechanisms, dependent on cosolvent ratio, are involved in the solubility enhancement of the three drugs. The plots of deltaH versus deltaG are nonlinear, and the slope changes from positive to negative above 50% dioxane. The compensation effect for the thermodynamic magnitudes of transfer from water to the aqueous mixtures can be described by a common empirical nonlinear relationship, with the exception of paracetamol, which follows a separate linear relationship at dioxane ratios above 50%. The results corroborate earlier findings with phenacetin. The similar pattern shown by the drugs studied suggests that the nonlinear enthalpy-entropy compensation effect may be characteristic of the solubility of semipolar drugs in dioxane-water mixtures.

Acetaminophen↗

PubMed1998

Partial-solubility parameters of naproxen and sodium diclofenac.

The expanded Hansen method was tested for determination of the solubility parameters of two non-steroidal anti-inflammatory drugs, naproxen and sodium diclofenac. This work describes for the first time the application of the method to the sodium salt of a drug. The original dependent variable of the expanded Hansen method, involving the activity coefficient of the drug, was compared with the direct use of the logarithm of the mole fraction solubility 1nX2 in the solubility models. The solubility of both drugs was measured in pure solvents of several chemical classes and the activity coefficient was obtained from the molar heat and the temperature of fusion. Differential scanning calorimetry was performed on the original powder and on the solid phase after equilibration with the pure solvents, enabling detection of possible changes of the thermal properties of the solid phase that might change the value of the activity coefficient. The molar heat and temperature of fusion of sodium diclofenac could not be determined because this drug decomposed near the fusion temperature. The best results for both drugs were obtained with the dependent variable 1nX2 in association with the four-parameter model which includes the acidic and basic partial-solubility parameters delta(a) and delta(b) instead of the Hansen hydrogen bonding parameter delta(h). Because the dispersion parameter does not vary greatly from one drug to another, the variation of solubility among solvents is largely a result of the dipolar and hydrogen-bonding parameters, a fact that is being consistently found for other drugs of small molecular weight. These results support earlier findings with citric acid and paracetamol that the expanded Hansen approach is suitable for determining partial-solubility parameters. The modification introduced in the expanded Hansen method, i.e. the use of 1nX2 as the dependent variable, provides better results than the activity coefficient used in the original method. This is advantageous for drugs such as sodium diclofenac for which the ideal solubility cannot be estimated. This paper shows for the first time that the method is suitable for determination of the partial-solubility parameters of a sodium salt of a drug, sodium diclofenac.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1997

The expanded Hansen approach to solubility parameters. Paracetamol and citric acid in individual solvents.

In this study two solubility-parameter models have been compared using as dependent variables the logarithm of the mole fraction solubility, lnX2e, and ln(alpha)/U (originally used in the extended Hansen method), where alpha is the activity coefficient and U is a function of the molar volume of the solute and the volume fraction of the solvent. The results show for the first time the proton-donor and -acceptor hydrogen-bonding capacities of paracetamol, as measured by the acidic and basic partial-solubility parameters. The influence of solvents on the differential scanning calorimetry (DSC) pattern of the solid phases was also studied in relation to the solubility models tested. Citric acid was chosen as a test substance because of its high acidity and its proton donor capacity to form hydrogen bonds with basic solvents. The partial acidic and basic solubility parameters obtained from multiple regression were consistent with this property, validating the model chosen. The results show that the more direct lnX2e variable was more suitable for fitting both models, and the four-parameter model seemed better for describing the interactions between solvent and solute.

Acetaminophen↗

PubMed1996

Nonlinear enthalpy-entropy compensation for the solubility of phenacetin in dioxane-water solvent mixtures.

The solubility of phenacetin was determined at five temperatures in solvent mixtures of aprotic-amphiprotic mixtures of dioxane and water. Enthalpy-entropy compensation analysis is used to study the effect of changing polarity of the medium on the solute. The apparent heats of solution and free energies of solution are nonlinear functions of the cosolvent (dioxane) ratio. The free energy curve goes through a minimum at 80-90% dioxane in water, whereas the apparent heat of solution displays a maximum at low cosolvent ratio (40% dioxane) and a minimum at high cosolvent ratio (90% dioxane). A plot of delta H against delta G shows a nonlinear compensation effect. Two different mechanisms (entropy and enthalpy) are suggested to be the driving forces to increase solubility. These two mechanisms can be related to the nonlinearity of the compensation effect. The slope changes from positive to negative at 40% dioxane. The overall nonlinear function can also be considered as two linear relationships that intersect at 40% dioxane. The results support the usefulness of enthalpy-entropy compensation analysis for a better understanding of the solubility of drugs in aqueous mixtures as related to the role of cosolvents.

Dioxanes↗

PubMed1995

Enthalpy and entropy contributions to the solubility of sulphamethoxypyridazine in solvent mixtures showing two solubility maxima.

The solubility of sulphamethoxypyridazine was measured at several temperatures in mixtures of water:ethanol and ethanol:ethyl acetate. Sulphamethoxypyridazine was chosen as a model drug to compare the solvation effects of proton donor-proton acceptor (water and ethanol) and proton acceptor (ethyl acetate) solvents and mixtures of these solvents because this drug contains functional groups capable of Lewis acid-base interaction. A plot of the mole fraction solubility against the solubility parameter (delta 1 = 30.87 MPa1/2 (20:80 v/v water:ethanol) and another at delta 1 = 20.88 MPa1/2 (30:70 v/v ethanol:ethyl acetate) at all the temperatures under study. The enthalpies and entropies of mixing as well as the enthalpies and entropies of transfer of sulphamethoxypyridazine from ethanol of mixing as well as the enthalpies and entropies of transfer of sulphamethoxypyridazine from ethanol to water:ethanol and ethanol:ethyl acetate mixtures were calculated to compare solvation characteristics of the solvent mixtures toward the drug. As ethanol is added to water, the entropy increases and the structure of the solvent mixture became less ordered, favouring the interaction of the drug with the solvent mixture. On the other hand, in the case of the ethanol:ethyl acetate mixture, solubility is favoured by the more negative enthalpy values. This way, the same result, i.e. a solubility maximum, is obtained by different routes. In the ethanol:water mixtures, the dissolution process if entropy-controlled while enthalpy is the driving force in the case of ethanol:ethyl acetate mixtures. The two solvent systems show enthalpy-entropy compensation. Water deviates from the linear relationship due possibly to its hydrophobic effect.

Acetates↗

PubMed1994

Predicting the solubility of drugs in solvent mixtures: multiple solubility maxima and the chameleonic effect.

An approach to reproduce the solubility profile of a drug in several solvent mixtures showing two solubility maxima is proposed in this work. The solubility of sulphamethoxypyridazine was determined at 25 degrees C in several mixtures of varying polarity (hexane:ethyl acetate, ethyl acetate:ethanol and ethanol:water). Sulphamethoxypyridazine was chosen as a model drug because of its proton-donor and proton-acceptor properties. A plot of the mole fraction of the drug vs the solubility parameter of the solvent mixtures shows two solubility peaks. The two peaks found for sulphamethoxypyridazine demonstrate the chameleonic effect as described by Hoy and suggest that the solute-solvent interaction does not vary uniformly from one mixture to another. The different behaviour of the drug in mixtures of two proton-donor and proton-acceptor solvents (alcohol and water), and in mixtures of one proton acceptor (ethyl acetate) and one proton donor-proton acceptor (ethanol) is rationalized in terms of differences in the proton donor-acceptor ability of the solvent mixtures. An approach based on the acidic and basic partial solubility parameters together with the Hildebrand solubility parameter of the solvent mixtures is developed to reproduce the experimental results quantitatively. The equation predicts the two solubility maxima as found experimentally, and the calculated values closely correspond to the experimental values through the range composition of the solvent mixtures. These results show that the chameleonic effect can be described in a quantitative way in terms of Lewis acid-base interactions; this approach can assist the product formulator to choose the proper solvent mixture for a new drug.

Acetates↗

PubMed1993

Partial solubility parameters and solvatochromic parameters for predicting the solubility of single and multiple drugs in individual solvents.

A modification of the extended Hansen method is used for estimating the solubility of sulfadiazine and other organic drug molecules in a number of individual solvents ranging from nonpolar to highly polar. The equations obtained for each drug involve the partial solubility parameters of the solvents and allow the prediction of solubility of these drugs in a new solvent. Furthermore, a number of drugs (e.g., sulfadiazine, sulfamethoxypyridazine, naphthalene, and some benzoic acid derivatives) are combined in a single expression including the ideal solubility of the drugs and the partial solubility parameters of the solvents. The equation fits the solubilities of these drugs in a wide variety of solvents and may be used to predict the solubility of other sulfonamides and benzoic acid derivatives in semipolar and highly polar solvents. The solvatochromic parameter approach is also used in models for predicting the solubility of single drugs in individual solvents. It was tested with multiple solutes as was the partial solubility parameter approach. However, the latter approach is superior; the parameters of the solubility parameter method are all statistically significant for drugs tested individually or together in a single equation, a condition that is not obtained with the solvatochromic model.

Benzoates↗

PubMed1993

A modification of the extended Hildebrand approach to predict the solubility of structurally related drugs in solvent mixtures.

A modification of the extended Hildebrand equation is proposed to estimate the solubility of an organic drug in solvent mixtures. The equation accurately reproduces the solubility of four sulphonamides in dioxane-water mixtures without requiring the heat of fusion of the solute. A single equation is obtained for predicting the solubility of related drugs using the solubilities of the drugs in the pure solvents, dioxane and water, and solute-solvent interaction terms consisting of the solubility parameter, delta 2, of the solute and the solubility parameter, delta 1, and basic partial solubility parameter, delta 1b, of the solvent mixture. By this procedure a single equation was obtained to estimate the solubilities of three xanthines in dioxane-water and another equation to obtain the solubilities of four sulphonamides. The equation obtained for sulphonamides is able to predict the experimental solubilities of two parent compounds, sulphasomidine and sulphathiazole, and the solubilities of a drug of different structure, p-hydroxybenzoic acid. This suggests that the intermolecular solute-solvent interaction of sulphonamides and p-hydroxybenzoic acid are similar. The results indicate that the solubility behaviour of drugs having different structures may be modelled using a common equation provided that they show similar solute-solvent interactions.

Dioxanes↗

PubMed1991

Statistical analysis of the extended Hansen method using the bootstrap technique.

In this study, simple bootstrap techniques are combined with the extended Hansen solubility approach to calculate biases, standard errors, and confidence limits of the partial solubility parameters and to obtain bias-corrected values for these solubility parameters. The bootstrap method is rather new in its application to problems in the pharmaceutical sciences and, therefore, is described here in some detail. This method provides measures of the statistical variation of ratios of regression coefficients without making unwarranted assumptions about data variability. The bootstrap can be used in many statistical packages such as MINITAB, SPSS, SAS, BMDP, or GLIM, all of which are widely available, and could be useful in other areas of the pharmaceutical sciences where regression analysis is employed.

Computer Simulation↗

PubMed1991

Nutritional considerations in the elderly.

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Aged↗

PubMed1989

Predicting the solubility of sulfamethoxypyridazine in individual solvents. I: Calculating partial solubility parameters.

Sulfamethoxypyridazine, a representative model of a drug molecule, is used to test the extended Hansen method for estimating partial solubility parameters of solid compounds. Solubilities are determined in polar and nonpolar solvents. The method provides reasonable partial parameters for the sulfonamide, and it may be useful in obtaining partial parameters for other drug molecules. A four-parameter extended Hansen approach involving proton donor and acceptor parameters is used in fitting the data to a theoretical model. A term, Wh, is introduced as an empirical measure of solute-solvent interactions due to hydrogen bonding. The use of the empirical term Wh allows the researcher to fit experimental solubilities and thus design regression models and equations which provide a reasonable prediction of solubilities of a polar drug in a number of very different solvents. A Flory-Huggins size correction term improves the prediction of sulfamethoxypyridazine solubilities in these irregular solutions.

Chemical Phenomena↗

PubMed1989

Predicting the solubility of sulfamethoxypyridazine in individual solvents. II: Relationship between solute-solvent interaction terms and partial solubility parameters.

In the first paper in the series, an expanded system of parameters was devised to account for orientation and induction effects, and the term Wh was introduced to replace delta 1h delta 2h of the extended Hansen solubility approach. In the present report, a new term, Kh = Wh/delta 1h delta 2h is observed to take on values larger or smaller than unity depending on whether the hydrogen bonded solute-solvent interaction is larger or smaller than predicted by the term delta 1h delta 2h. The acidic delta a and basic delta b solubility parameters are used to represent two parameters, sigma and tau, suggested by Small in his study of proton donor-acceptor properties. The Small equation, including a heat of mixing term for hydrogen bonded species, is shown to be capable of semiquantitative evaluation. A partial molar heat delta H2h of hydrogen bonding is calculated using delta h and Wh terms; delta H2h is found to be correlated with the logarithm of the residual activity coefficient, In alpha R, a term representing strong solute-solvent interaction. The terms Wh, delta H2h, and In alpha 2R may be used to test the deviation from the geometric mean assumed in regular solution theory, and to replace the hydrogen bonding terms of the extended Hansen three-parameter model. The solubility of sulfamethoxypyridazine in 30 solvents is used to test the semiempirical solubility equations. The results are interpreted in terms of partial solubility parameters and the proton donor-acceptor properties of the solvents.

Chemical Phenomena↗