Selection of solubility parameters for characterization of pharmaceutical excipients.

The solubility parameter (delta(2)), corrected solubility parameter (delta(T)) and its components (delta(d), delta(p), delta(h)) were determined for series of pharmaceutical excipients by using inverse gas chromatography (IGC). Principal component analysis (PCA) was applied for the selection of the solubility parameters which assure the complete characterization of examined materials. Application of PCA suggests that complete description of examined materials is achieved with four solubility parameters, i.e. delta(2) and Hansen solubility parameters (delta(d), delta(p), delta(h)). Selection of the excipients through PCA of their solubility parameters data can be used for prediction of their behavior in a multi-component system, e.g. for selection of the best materials to form stable pharmaceutical liquid mixtures or stable coating formulation.

Gas sorption and barrier properties of polymeric membranes from molecular dynamics and Monte Carlo simulations.

It is important for many industrial processes to design new materials with improved selective permeability properties. Besides diffusion, the molecule's solubility contributes largely to the overall permeation process. This study presents a method to calculate solubility coefficients of gases such as O2, H2O (vapor), N2, and CO2 in polymeric matrices from simulation methods (Molecular Dynamics and Monte Carlo) using first principle predictions. The generation and equilibration (annealing) of five polymer models (polypropylene, polyvinyl alcohol, polyvinyl dichloride, polyvinyl chloride-trifluoroethylene, and polyethylene terephtalate) are extensively described. For each polymer, the average density and Hansen solubilities over a set of ten samples compare well with experimental data. For polyethylene terephtalate, the average properties between a small (n = 10) and a large (n = 100) set are compared. Boltzmann averages and probability density distributions of binding and strain energies indicate that the smaller set is biased in sampling configurations with higher energies. However, the sample with the lowest cohesive energy density from the smaller set is representative of the average of the larger set. Density-wise, low molecular weight polymers tend to have on average lower densities. Infinite molecular weight samples do however provide a very good representation of the experimental density. Solubility constants calculated with two ensembles (grand canonical and Henry's constant) are equivalent within 20%. For each polymer sample, the solubility constant is then calculated using the faster (10x) Henry's constant ensemble (HCE) from 150 ps of NPT dynamics of the polymer matrix. The influence of various factors (bad contact fraction, number of iterations) on the accuracy of Henry's constant is discussed. To validate the calculations against experimental results, the solubilities of nitrogen and carbon dioxide in polypropylene are examined over a range of temperatures between 250 and 650 K. The magnitudes of the calculated solubilities agree well with experimental results, and the trends with temperature are predicted correctly. The HCE method is used to predict the solubility constants at 298 K of water vapor and oxygen. The water vapor solubilities follow more closely the experimental trend of permeabilities, both ranging over 4 orders of magnitude. For oxygen, the calculated values do not follow entirely the experimental trend of permeabilities, most probably because at this temperature some of the polymers are in the glassy regime and thus are diffusion dominated. Our study also concludes large confidence limits are associated with the calculated Henry's constants. By investigating several factors (terminal ends of the polymer chains, void distribution, etc.), we conclude that the large confidence limits are intimately related to the polymer's conformational changes caused by thermal fluctuations and have to be regarded--at least at microscale--as a characteristic of each polymer and the nature of its interaction with the solute. Reducing the mobility of the polymer matrix as well as controlling the distribution of the free (occupiable) volume would act as mechanisms toward lowering both the gas solubility and the diffusion coefficients.

Solvation of dried dentin matrix by water and other polar solvents.

PURPOSE: To develop a simple method for measuring the degree of solvation of dried, demineralized dentin matrix by water and other polar solvents. The null hypothesis was that there are no differences in expansion forces produced by different polar solvents. MATERIALS AND METHODS: Midcoronal dentin discs were prepared from extracted, unerupted human third molars. The discs were cut into square specimens with surface areas of 2 x 2, 3 x 3 and 4 x 4 mm and thicknesses of 0.5, 1.0 and 1.5 mm. After demineralization in 0.5 M EDTA (pH 7), the dimensions of the specimens were measured both wet and dry. Dry specimens were held between two parallel steel plates connected to a 50 N load cell which measured the solvation force when water or other polar solvents were added. After measuring the expansion force induced by water, the specimens were fixed in glutaraldehyde and the trials repeated. On additional specimens, repeated measures of expansion forces were obtained using water, methanol, ethanol, n-propanol, n-butanol, ethylene glycol, formamide, hydroxyethylmethacrylate, N,N-dimethyl formamide and acetone in unfixed specimens. RESULTS: Water produced hydration forces as high as 204 g before, and 428 g after glutaraldehyde treatment. The hydration force correlated better with specimen thickness than with surface area. Water solvated the matrix faster than methanol > ethanol > formamide > ethylene glycol. Hydroxyethylmethacrylate, N,N-dimethyl formamide and acetone were unable to solvate the dried matrix. Regression analysis of solvation force vs. Hansen's solubility parameters for dispersive, polar and hydrogen bonding forces demonstrated that solvation force correlations were highest with hydrogen bonding solubility parameters. Measurements of solvation forces provides a simple method for determining solvent-collagen matrix interactions.

Physico-chemical determinants of dermal drug delivery: effects of the number and substitution pattern of polar groups.

The aim of this study was to investigate the effect of number and substitution pattern of -OH groups of a set of phenols on the in vitro permeation of heat-separated human epidermis. The diffusion was calculated from Log(D/x)=logk(p)-0.59logK(oct)+0.024 (D, diffusion coefficient; x, pathlength; k(p), permeability coefficient (cm/h); and K(oct), octanol-water partition coefficient). The main factors reducing D were the dipolar and hydrogen bonding capabilities of the permeants quantified as their Hansen partial solubility parameters delta(p) and delta(h). These parameters are significantly reduced by the degree of symmetry of the molecule, so that phloroglucinol (1,3,5-benzenetriol), with three -OH groups, diffuses more rapidly that phenol. When symmetry is absent, as in 1,2,4-benzenetriol, the number of -OH groups results in very slow diffusion. D/x (cm/h) was related to the combined solubility parameter delta(a) defined as radical(delta(p)(2)+delta(h)(2)) by: (D/x)=0.0024-0.000065delta(a) (n=7, R(2)=0.70, P=0.012).

A robust structure-activity relationship (SAR) model for esters that cause skin irritation in humans.

A structure-activity relationship (SAR) model has been developed to discriminate skin irritant from nonirritant esters. The model is based on the physicochemical properties of 42 esters that were tested in humans for skin irritation. Nineteen physicochemical parameters that represent transport, electronic, and steric properties were calculated for each chemical. Best subsets regression analysis indicated candidate models for further analysis. Regression analyses identified significant models (p < 0.05) that had variables that were also significant (p < 0.05). These candidate models were evaluated using linear discriminant analysis to determine if the irritant esters could be discriminated from nonirritant esters. The stability of the model was evident from the consistency of parameters among ten submodels generated using multiple random sampling of the database. The sensitivity of the ten models, evaluated by "leave-one-out" cross-validation, ranged from 0. 846 to 0.923, with a mean of 0.885 +/- 0.025 (95% CI). The specificity ranged from 0.615 to 0.923, with a mean of 0.738 +/- 0.06 (CI). Compared with nonirritant esters, irritant esters had lower density, lower water solubility, lower sum of partial positive charges, higher Hansen hydrogen bonding parameter, and higher Hansen dispersion parameter. The results indicate that physicochemical features of esters contribute to their ability to cause skin irritation in humans, and that chemical partitioning into the epidermis and intermolecular reactions are likely important components of the response. This model is applicable for prediction of human irritation of esters yet untested.

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.

Interactions between cationic liposomes and an antigenic protein: the physical chemistry of the immunoadjuvant action.

The 18 kDa antigenic protein from Mycobacterium leprae (P) or its N-acyl derivative (AP) was incorporated in dioctadecyldimethylammonium bromide (DODAB) liposomes in water or in phosphate-buffered saline (PBS). In water, 100% P incorporation in liposomes contrasts with 65% in PBS. There is 75-80% AP incorporation to liposomes in water against 55-65% in PBS, showing that attachment of hydrophobic residues to the protein, instead of increasing, further decreases incorporation to the liposomes. From protein adsorption on latex, P affinity is larger than AP affinity for the latex surface whereas limiting adsorption for AP is much larger than that obtained for P, possibly due to AP aggregation in solution. P-induced rupture of liposomes containing [14C]sucrose was evaluated from dialysis of protein/liposomes mixtures. In water, P incorporation to the liposomes causes leakage of radioactive contents contrasting with the absence of leakage for P incorporation in PBS. Immunization tests for delayed type hypersensitivity indicate a enhancement of cell-mediated immunological response towards P/DODAB complexes that is not obtained for the isolated protein. Absence of leakage for P in PBS is associated with a P "lying-over" on the liposome and optimization of protein presentation to the immunological system.

Physico-chemical properties of a rifampicin-releasing polydimethylsiloxane shunt.

Infection of implanted polymeric devices is a major problem in modern medicine. Silicone shunts were modified in order to prevent microbial colonization by incorporating rifampicin. The release mechanism and the altered properties of the silicone were studied. Release rates of rifampicin out of the polymeric shunt materia were measured in vitro for up to 60 d. For high velocity of rifampicin in the polymeric matrix and long-lasting controlled release rates, high compatibility of polymer and drug was required. Compatibility and therefore miscibility of drug and polymer were estimated by reduced solubility and cohesion energy densities (Hansen parameter, solubility parameter delta). Mechanical properties of the polymer were influenced by incorporation of small drug amounts, characterized by stress-strain curves. Differential scanning calorimetry (DSC) measurements suggested thermodynamically controlled interaction of the macromolecules with the incorporated substance. The physico-chemical state of the drug in the internal phase and the surface of the polymer was studied by scanning electron micrography (SEM), showing homogeneous molecular dispersion of the drug in the polymeric material as well as crystalline structures on the surface.

[The biological activity of the transfer factor induced by bacterial antigens]. / Biolohichna aktyvnist' faktora perenosu, indukovanoho bakterial'nymy antyhenamy.

Today's statement of transfer factor, an immunostimulator derived from leukocytes which enhances antiinfectious immunity, is observed in the review. Basic biological, physical and chemical characteristics of the transfer factor, its possible action mechanisms, and laboratory and clinical methods of use to cure infectious fungal (Candida, Coccidium), invasive (schistosomiasis, leishmaniasis, cryptosporidiosis), viral (varicella zoster, ophthalmic herpes, Herpes simplex types 1 and 2, H. zoster, H. simplex ceratitis, genital herpes, human herpes virus type 6, postherpetic neuritis, hepatitis B, AIDS), and bacterial infections (Mycobacterium leprae, M. tuberculosis, M. fortuitum, Salmonella cholerae suis, S. dublin, S. Virchov, Brucella abortus, Actinobacillus pleuropneumoniae, bacterial sepsis, Staphylococcus) are described.

Three-dimensional solubility parameters and their use in characterising the permeation of drugs through the skin.

The physico-chemical properties of drug substances are major determinants of their transdermal absorption. In the present study the concept of the three-dimensional solubility parameters of Hansen was applied in conjunction with the Bagley projection to describe the permeation of drugs and model substances through the skin. Drug permeation data from the literature were compared with the calculated solubility parameters of the drugs. It was demonstrated that the permeation of drugs can be estimated by their position in the Bagley diagram. There is a linear correlation between the logarithm of the skin permeation of drugs and the exchange cohesive energy for the steroids testosterone, progesterone, hydrocortisone acetate, corticosterone, cortisone, and dexamethasone. A linear correlation can be confirmed for the permeation of glyceryl trinitrate, digitoxin, oestradiol, scopolamine, atropine, diethylcarbamazine, fentanyl, and chlorpheniramine. In the case of morphine, codeine, sufentanil, meperidine and hydromorphone there is a linear relationship, too.

Immunomodulation by thalidomide: systematic review of the literature and of unpublished observations.

Three decades of immunological investigations using thalidomide are reviewed. Both in vitro and in vivo investigations are in accordance with the clinical finding that thalidomide does not impede T-cell competence in the control of infection by mycobacteriae. The term immunosuppressant does not apply. The immunomodulatory effects of thalidomide are evident in a myriad of phenomenological changes, and a molecularly defined common denominator of these activities is not known at present. Critical assessment with the objective to account for the clinical activity of thalidomide in specific human diseases leads to a focus on effects of thalidomide on phagocytic leukocytes and endothelia. The former are responsive to thalidomide by modulation of cytokine synthesis in vitro and in vivo; this activity can be shown using monocyte-specific stimuli in peripheral blood mononuclear cells but also in other phagocytic cells like microglia. For technical reasons, endothelial cells have until now been tested primarily in vitro. However, there is solid evidence now from intravital microscopy that the induction of adhesivity in postcapillary venules by LPS is modulated by thalidomide. Altered surface antigen expression has been described on leukocytes obtained from humans and experimental animals treated with thalidomide, but convincing evidence is lacking for in vitro modulation of surface antigen expression on leukocytes (as opposed to the modulation of adhesion antigens on endothelial cells stimulated by LPS or exogenous TNF alpha in the presence of thalidomide). Therefore, in vivo redistribution is likely to account for some, if not all, changes in circulating leukocyte phenotypes. The immunopathological conditions most clearly responsive to thalidomide are vasculitic alterations of post-capillary venules either in the context of mycobacterial infection (in the case of erythema nodosum leprosum) or mucocutaneous aphths. In both instances (as in the majority of focal inflammatory lesions), leukocyte infiltration and cytokine responses, in particular TNF alpha, are present. Thalidomide acts clinically not only by palliation of existing lesions but also by prevention of recurrence. The mechanism operates in skin, mucosa and parts of the nervous system and is most readily explained by synergism of TNF alpha modulation and a separate point of action on leukocyte migration patterns.

On the mapping of electrostatic properties from the multipole description of the charge density.

A method is presented to calculate the electrostatic potential, the electric field and the electric-field gradient in a crystal from the atomic multipole expansion of the experimental charge density, as described by the Hansen-Coppens formalism [Hansen & Coppens (1978), Acta Cryst. A34, 909-921]. The electrostatic properties are expressed in terms of the positions and the charge-density parameters of the individual atoms. Contributions due to the procrystal charge density and the deformation charge density are compared. The method is illustrated by the calculation of the electrostatic potential maps of fully deuterated benzene and of iron(II) tetraphenylporphyrin.

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.

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.

Determination of partial solubility parameters of lactose by gas-solid chromatography.

On the basis of the Snyder/Karger-Hansen interaction model, where delta EA = Vi(delta di delta dj + delta pi delta pi + delta hi delta nj), the partial solubility parameters of a solid used as the stationary phase may be determined through gas-solid chromatography by null-injection of solutes with known solubility parameters. Using n-decane, acetonitrile, and 1-propanol as molecular probes, the values found for unhydrated lactose were 9.6, 12.8, 11.3, and 19.5 (cal1/2/cm3/2) for delta d, delta p, delta h, and delta t, respectively; relative standard errors were better than 3%. The choice and the minimum number of the best molecular probes were determined by optimization of the experimental matrix according to the D-criterion, which permits considerable reduction of experimental time yet enhances total precision.

Expanded solubility parameter approach. I: Naphthalene and benzoic acid in individual solvents.

An expanded solubility parameter system was tested in conjunction with the extended Hansen solubility approach and the UNIFAC method to calculate the solubilities of naphthalene and benzoic acid in polar and nonpolar solvents. The expanded parameter system is characterized by delta d for the dispersion force, delta p for dipolar forces, a basic or electron-donor parameter, delta b, and an acidic or electron-acceptor parameter delta a. The correlation between the calculated and observed solubilities of benzoic acid was increased by use of the four-parameter system. An indicator variable was required to bring the solubilities into line in strongly dipolar solvents such as N,N-dimethylformamide. For naphthalene, use of the four-parameter approach proved not to be an improvement over the three-parameter extended Hansen solubility approach. The UNIFAC method was not successful in calculating solubilities of benzoic acid in the 40 polar and nonpolar solvents. A triangular plot of the three Hansen parameters for benzoic acid, p-hydroxybenzoic acid, and methyl p-hydroxybenzoate illustrated the contributions of dispersion, dipolar, and Lewis acid-base (hydrogen bonding) interaction forces among the three benzoic acid compounds and the various classes of solvents. A multiple regression procedure for calculating the four partial solubility parameters of drug solutes was developed.

Expanded solubility parameter approach. II: p-Hydroxybenzoic acid and methyl p-hydroxybenzoate in individual solvents.

The recently introduced four-parameter extended Hansen approach was used to study the solubility of p-hydroxybenzoic acid and methyl p-hydroxybenzoate in 32 and 35 individual solvents, respectively. The results are compared with those for benzoic acid in 40 solvents. Seventeen of the thirty-two or 53% of the calculated solubilities of p-hydroxybenzoic acid were within the established solubility criterion (i.e., less than 30% error from the experimental value). Twenty-two of thirty-six or 61% of the calculated solubility values for methyl p-hydroxybenzoate met the solubility criterion. Experimental excess free energies of solution for p-hydroxybenzoic acid and methyl p-hydroxybenzoate were plotted against theoretical values using the expanded four-parameter solubility regression equations. From such results, adjustments may be made in the partial solubility parameters to bring the calculated solubilities in line with experimental results. Multiple regression analyses were used to estimate the total solubility parameter and the four partial solubility parameters of the two benzoic acid derivatives. Satisfactory results were obtained for methyl p-hydroxybenzoate, but poor agreement was found for p-hydroxybenzoic acid for the total parameter when compared with the Fedors group contribution method. Both the multiple regression and group contribution methods may yield inaccurate solubility parameters for relatively polar solid solutes. Factor analysis was used to test the adequacy of three- and four-parameter approaches in the evaluation of drug solubility. A principal factor method without iteration and orthogonal factor rotation were used to compare the two expanded solubility parameter approaches.(ABSTRACT TRUNCATED AT 250 WORDS)

Extended Hansen approach: calculating partial solubility parameters of solid solutes.

A multiple linear regression method, known as the extended Hansen solubility approach, was used to estimate the partial solubility parameters, delta d, delta p, and delta h for crystalline solutes. The method is useful, since organic compounds may decompose near their melting points, and it is not possible, to determine solubility parameters for these solid compounds by the methods used for liquid solvents. The method gives good partial and total solubility parameters for naphthalene; with related compounds, less satisfactory results were obtained. At least three conditions, pertaining to the regression equation and the solvent systems, must be met in order to obtain reasonable solute solubility parameters. In addition to providing partial solubility parameters, the regression equations afford a calculation of solute solubility in both polar and nonpolar solvents.

Extended Hansen solubility approach: naphthalene in individual solvents.

A multiple regression method using Hansen partial solubility parameters, delta D, delta p, and delta H, was used to reproduce the solubilities of naphthalene in pure polar and nonpolar solvents and to predict its solubility in untested solvents. The method, called the extended Hansen approach, was compared with the extended Hildebrand solubility approach and the universal-functional-group-activity-coefficient (UNIFAC) method. The Hildebrand regular solution theory was also used to calculate naphthalene solubility. Naphthalene, an aromatic molecule having no side chains or functional groups, is "well-behaved', i.e., its solubility in active solvents known to interact with drug molecules is fairly regular. Because of its simplicity, naphthalene is a suitable solute with which to initiate the difficult study of solubility phenomena. The three methods tested (Hildebrand regular solution theory was introduced only for comparison of solubilities in regular solution) yielded similar results, reproducing naphthalene solubilities within approximately 30% of literature values. In some cases, however, the error was considerably greater. The UNIFAC calculation is superior in that it requires only the solute's heat of fusion, the melting point, and a knowledge of chemical structures of solute and solvent. The extended Hansen and extended Hildebrand methods need experimental solubility data on which to carry out regression analysis. The extended Hansen approach was the method of second choice because of its adaptability to solutes and solvents from various classes. Sample calculations are included to illustrate methods of predicting solubilities in untested solvents at various temperatures. The UNIFAC method was successful in this regard.