Incidence of T2DM and the role of baseline glycaemic status as a determinant in a metropolitan population in northern Madrid (Spain).

AIM: To estimate the incidence of T2DM and assess the effect of pre-T2DM (isolated impaired fasting glucose [iIFG], isolated impaired glucose tolerance [iIGT] or both) on progress to T2DM in the adult population of Madrid. METHODS: Population-based cohort comprising 1,219 participants (560 normoglycaemic and 659 preT2DM [418 iIFG, 70 iIGT or 171 IFG-IGT]). T2DM was defined based on fasting plasma glucose or HbA1c or use of glucose-lowering medication. We used a Cox model with normoglycaemia as reference category. RESULTS: During 7.26 years of follow-up, the unadjusted incidence of T2DM was 11.21 per 1000 person-years (95 %CI, 9.09-13.68) for the whole population, 5.60 (3.55-8.41) for normoglycaemic participants and 16.28 (12.78-20.43) for pre-T2DM participants. After controlling for potential confounding factors, the baseline glycaemic status was associated with higher primary effect on developing T2DM was iIGT (HR = 3.96 [95 %CI, 1.93-8.10]) and IFG-IGT (3.42 [1.92-6.08]). The HR for iIFG was 1.67 (0.96-2.90). Obesity, as secondary effect, was strongly significantly associated (HR = 2.50 [1.30-4.86]). CONCLUSIONS: Our incidence of T2DM is consistent with that reported elsewhere in Spain. While baseline iIGT and IFG-IGT behaved a primary effect for progression to T2DM, iIFG showed a trend in this direction.

Hildebrand solubility parameter to predict drug release from hydroxypropyl methylcellulose gels.

An equation including the Hildebrand solubility parameter δ of the drugs is used for the first time to model drug release from hydroxypropyl methylcellulose (HPMC) gels: l nM = -21.578 + 2.102 δ-0.037 δ(2)+0.48 ln t + 1.028 ln C(i) (r(2) = 0.94 for a total of 286 cases). The experimentally determined release data of six drugs having different polarity (caffeine, theophylline, paracetamol, salicylic acid, naproxen and diclofenac) at several initial concentrations C(i) were included in the equation. In general, the amount of drug delivered is linear at the first 5-6h of the release profiles and the zero order constants K(o) increase as the solubility parameter of the drugs become larger. The Peppas exponential law M/M(∞) = Kt(n) is applicable to larger fractional release, until 67-87% (48-51 h) for the less polar drugs (diclofenac and naproxen, lower δ values) and more than 80% (26-28 h) for the more polar drugs (higher δ values, theophylline, salicylic acid, caffeine and paracetamol). The Peppas release rate (lnK) shows a parabolic relationship with the drug solubility parameter. The diffusional exponent n varies between 0.40 and 0.58 indicating that drug release is mainly controlled by diffusion. An extended form of the Peppas equation is also tested for each drug including all the initial concentrations: lnM = a + b ln t + c ln C(i) (r(2) = 0.88-0.94). The logarithm of the octanol-water partition coefficients can also be used in combination with the drug concentrations.

Predicción de la solubilidad del Alopurinol en mezclas disolventes / Solubility prediction of Allopurinol in solvent mixtures

La predicción de solubilidad de los principios activos en sistemas codisolventes se estudia para optimizar los procesos tecnológicos de preformulación y resulta clave en procesos de desarrollo e investigación en el diseño farmacéutico racional de medicamentos seguros y eficaces. En este trabajo, algunos métodos de estimación, desarrollados en los últimos años, se han probado con el alopurinol. El alopurinol es un compuesto químico empleado como medicamento frente a la hiperuricemia y sus complicaciones, como la gota. Se obtuvieron excelentes correlaciones entre las solubilidades experimentales y calculadas a 25ºC. Los resultados demuestran la utilidad de estos modelos en preformulación de medicamentos con el fin de reducir el número de experimentaciones, que a menudo consumen tiempo y recursos económicos(AU)

The prediction of solubility of the drugs in co-solvents systems is studied to optimize technological processes of preformulación and it is key in processes of development and research on rational pharmaceutical design of safe and effective medicines. In this work, some methods of estimation, developed in recent years, have been tested with allopurinol. Allopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout. We have obtained excellent correlations between the calculated and experimental solubility at 25 ºC. The results show the usefulness of these models in preformulación from medicines to reduce the number of experiments, which often consume time and resources(AU)

Predicción de la solubilidad del mebendazol en mezclas disolventes / Solubility prediction of mebendazole in solvent mixtures

Los estudios de solubilidad proporcionan una valiosa información que puede emplearse en optimizar el proceso en las fases previas en el desarrollo de medicamentos. En los últimos años, se han desarrollado diferentes métodos de predicción de la solubilidad. En esta investigación se han probado dos modelos de Jouyban con el mebendazol (MB) a 298,15 K en mezclas binarias formadas por etanol y agua y etanol-acetato de etilo. Estos modelos son sencillos de aplicar y resultan muy útiles puesto que sólo se requiere un número pequeño de resultados experimentales. El primer modelo utilizado fue el siguiente: lnXm, = f1 lnX1 + f2 lnX2 + f3 lnX3, B1 (f12f2) + B2 (f1f2) + B3 (f32f2) + B4 (f3f2) (ec.1) en la que, X1, X2, y X3 son las solubilidades del soluto en los disolventes puros 1-3, respectivamente, B1-4 son constantes del modelo. El otro modelo semiempírico de predicción fue: lnXm,T = f1 lnX1,T +(1-f1) lnX2,T +f1 (1-f1) [T T85,254 735,662 (1 ) 1 1 F - - F+ ] (ec. 2)en la que f1 es la fracción de volumen de la mezcla agua-etanol, y T, la temperatura experimental. El tercer término es el factor de exceso de Jouyban-Acree (Factor JA). Los dos modelos semiempíricos de predicción empleados proporcionan una excelente reproducibilidad del perfil de solubilidad. Se concluye que los modelos propuestos, pueden ser útiles en preformulación para predecir el incremento de solubilidad en mezclas disolventes, ahorrando determinaciones experimentales, que consumen tiempo y un importante gasto económico en el diseño de formulaciones líquidas(AU)

Solubility studies provide valuable information that can be used to optimize the process in the previous stages in development of drugs. In recent years, different methods of prediction of solubility have been developed. In this research, two models of Jouyban was tested with mebendazole (MB) to 298,15 K in binary mixtures of water- ethanol and ethanol-ethylacetate. These models are very easy to apply and useful since only a small number of experimental results is required. The first model used was the following: lnXm, = f1 lnX1 + f2 lnX2 + f3 lnX3, B1 (f12f2) + B2 (f1f2) + B3 (f32f2) + B4 (f3f2) (ec.1) where X1, X2 and X3 are the solubility of the solute in the pure solvents, respectively, B1-4 are constant model. The other semiempirical prediction model tested was: lnXm,T = f1 lnX1,T +(1-f1) lnX2,T +f1 (1-f1) [T T85,254 735,662( (1 ) 1 1 F - - F+ ] (ec.2) where f1 is the fraction of the volume of the mixture ethanol-water, and T, the experimental temperature. The third term is the factor of excess Jouyban-Acree (Factor JA). The two semiempirical prediction models employed offer an excellent reproducibility of the profile of solubility. It is concluded that the proposed models may be useful in preformulación to predict increased solubility in mixing solvents, saving experimental determinations, which consume time and economic effort in the design of liquid formulations(AU)

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.

[Comparative study of PTFE grafts in forearm vs cuffed permanent catheters]. / Estudio comparativo del uso de protesis vasculares de PTFE a nivel de antebrazo vs cateter permanente.

INTRODUCTION: As is universally accepted the best form of permanent vascular access for haemodialysis is the native arteriovenous fistula. A second and third options are the politetrafluoroethylene (PTFE) AV grafts and the cuffed, tunneled, internal catheters. The overall performance and complications of catheters is clearly inferior to AV fistula. There are not many studies that compare permanent catheters to grafts in terms of functionality, survival and complications. METHODS: We analyzed 81 vascular accesses carried out from october 99 to december 03 in 59 patients and during a follow-up period of 35 months. Two groups were considered. Group 1, catheters (n 42) and group 2, grafts (n 39). Clinical aspects, comorbidity index (Wright and Kanh), dialysis dose and complications and survival of the access were registered. RESULTS: Both groups were similar in age, sex, time on haemodialysis, number of previous accesses and hospitalization days. Cardiovascular morbidity and comorbidity index were significantly higher in patients with catheter. While blood flow during dialysis was higher in grafts both groups showed no significant differences in parameters of efficacy of dialysis (Kt/V, TAC BUN and PCRn). Serum albumin was lower in patients with catheter. The number of accesses that failed was higher in the graft group being thrombosis the main complication followed by infection. Kaplan-Meier curves showed better accumulated survival of permanent catheters versus grafts (61,4% vs 9,8% at 35 months). The most frequent complication of catheter was infection while in the case of grafts it was thrombosis followed by infection. CONCLUSIONS: Although they were placed in patients with higher comorbidity, cuffed, tunneled catheters showed less number of complications and better survival than PTFE grafts in our patients in haemodialysis. The main cause of failure of both vascular access was thrombosis followed by infection. The dose of dialysis obtained was no different in both groups. Cuffed, tunneled permanent catheters are a very interesting option in a number of patients in haemodialysis and they can be an option to consider in those patients with vascular difficulties and higher comorbidities.

Estudio comparativo del uso de prótesis vasculares de PTFE a nivel de antebravo vs catéter permanente / comparative study of PTFE grafts in forearm vs cuffed permanent catheters

La fístula arteriovenosa (FAV) autóloga es el acceso vascular permanente de elección en los pacientes en hemodiálisis. Cuando esta opción no es posible, se debería optar por una prótesis vascular de politetrafluoroetileno (PTFE) y en tercer lugar por un catéter permanente tunelizado (CPT). Objetivo: Comparar la incidencia de complicaciones, morbilidad, índices de eficacia dialítica, así como la supervivencia de los CPT vs PTFE a nivel de antebrazo. Material y métodos: Estudiamos retrospectivamente 81 accesos vasculares realizados en 59 pacientes, seguidos desde octubre-99 hasta diciembre-03. Dividimos la muestra en dos grupos en función del acceso vascular: G-I (n = 42) CPT; G-II (n = 39) PTFE. Se compararon características clínicas, índice de comorbilidad (Wright y Kanh), eficacia de diálisis, complicaciones y supervivencia. Resultados: No encontramos diferencias significativas en cuanto a los datos antropométricos, tiempo en hemodiálisis, número de accesos previos o el número de ingresos en relación al acceso vascular. Los pacientes portadores de PTFE presentaban un índice de comorbilidad inferior a los portadores de CPT o de ambos accesos. El flujo obtenido con las prótesis de PTFE era superior al obtenido con los CPT (p = 0,003). La albúmina era más elevada en el grupo de las prótesis de PTFE (p = 0,002). El número de complicaciones fue superior en el grupo de los injertos (p < 0,05), siendo la trombosis la más frecuente. Durante el seguimiento hubo que retirar más prótesis que CPT (p < 0,000), siendo el motivo más frecuente de pérdida del acceso vascular la trombosis, seguido de la infección. La supervivencia acumulada del acceso vascular a 35 meses de seguimiento, analizada mediante curvas de Kaplan-Meier, mostró una mayor supervivencia acumulada de CPT (61,4%) frente a prótesis de PTFE (9,8%) (p < 0,01). Conclusiones: Los CPT mostraron menor incidencia de complicaciones y mayor supervivencia que las prótesis de PTFE, a pesar de haber sido colocados en más de la mitad de los casos, en pacientes con una mayor comorbilidad. El principal motivo de fracaso del acceso vascular fue la trombosis seguido de la infección; se retiraron más prótesis que CPT. Finalmente, los parámetros de eficacia de diálisis fueron similares en ambos grupos

Introduction: As is universally accepted the best form of permanent vascular access for haemodialysis is the native arteriovenous fistula. A second and third options are the poliformatetrafluoroethylene (PTFE) AV grafts and the cuffed, tunneled, internal catheters. The overall performance and complications of catheters is clearly inferior to AV fistula. There are not many studies that compare permanent catheters to grafts in terms of functionality, survival and complications. Methods: We analyzed 81 vascular accesses carried out from october 99 to december 03 in 59 patients and during a follow-up period of 35 months. Two groups were considered. Group 1, catheters (n 42) and group 2, grafts (n 39). Clinical aspects, comorbidity index (Wright and Kanh), dialysis dose and complications and survival of the access were registered. Results: Both groups were similar in age, sex, time on haemodialysis, number of previous accesses and hospitalization days. Cardiovascular morbidity and comorbidity index were significantly higher in patients with catheter. While blood flow during dialysis was higher in grafts both groups showed no significant differences in parameters of efficacy of dialysis (Kt/V, TAC BUN and PCRn). Serum albumin was lower in patients with catheter. The number of accesses that failed was higher in the graft group being thrombosis the main complication followed by infection. Kaplan-Meier curves showed better accumulated survival of permanent catheters versus grafts (61,4% vs 9,8% at 35 months). The most frequent complication of catheter was infection while in the case of grafts it was thrombosis followed by infection. Conclusions: Although they were placed in patients with higher comorbidity, cuffed, tunneled catheters showed less number of complications and better survival than PTFE grafts in our patients in haemodialysis. The main cause of failure of both vascular access was thrombosis followed by infection. The dose of dialysis obtained was no different in both groups. Cuffed, tunneled permanent catheters are a very interesting option in a number of patients in haemodialysis and they can be an option to consider in those patients with vascular difficulties and higher comorbidities

Solubility parameter of drugs for predicting the solubility profile type within a wide polarity range in solvent mixtures.

The solubility enhancement produced by two binary mixtures with a common cosolvent (ethanol-water and ethyl acetate-ethanol) was studied against the solubility parameter of the mixtures (delta1) to characterize different types of solubility profiles. Benzocaine, salicylic acid and acetanilide show a single peak in the least polar mixture (ethanol-ethyl acetate) at delta1=22.59, 21.70 and 20.91 MPa1/2, respectively. Phenacetin displays two solubility maxima, at delta1=25.71 (ethanol-water) and at delta1=23.30 (ethyl acetate-ethanol). Acetanilide shows an inflexion point in ethanol-water instead of a peak, and the sign of the slope does not vary when changing the cosolvent. The solubility profiles were compared to those obtained in dioxane-water, having a solubility parameter range similar to that covered with the common cosolvent system. All the drugs reach a maximum at about 90% dioxane (delta1=23 MPa1/2). A modification of the extended Hildebrand method is applicable for curves with a single maximum whereas a model including the Hildebrand solubility parameter delta1 and the acidic partial solubility parameter delta1a is required to calculate more complex solubility profiles (with inflexion point or two maxima). A single equation was able to fit the solubility curves of all drugs in the common cosolvent system. The polarity of the drug is related to the shape of the solubility profile against the solubility parameter delta1 of the solvent mixtures. The drugs with solubility parameters below 24 MPa1/2 display a single peak in ethanol-ethyl acetate. The drugs with delta2 values above 25 MPa1/2 show two maxima, one in each solvent mixture (ethanol-water and ethanol-ethyl acetate). The position of the maximum in ethanol-ethyl acetate shifts to larger polarity values (higher delta1 values) as the solubility parameter of the drug delta2 increases.

Thermodynamic origin of the solubility profile of drugs showing one or two maxima against the polarity of aqueous and nonaqueous mixtures: niflumic acid and caffeine.

The purpose of this work was to investigate the origin of the different solubility profiles of drugs against the polarity of solvent mixtures with a common cosolvent. Niflumic acid and caffeine where chosen as model drugs. The solubilities were measured at five or six temperatures in aqueous (ethanol-water) and nonaqueous (ethyl acetate-ethanol) mixtures. The enthalpies of solution were obtained at the harmonic mean of the experimental temperature. Solid phase changes were analyzed using differential scanning calorimetry and thermomicroscopy. A single solubility maximum was obtained for niflumic acid against the solubility parameter of both mixtures that is not related to solid phase changes. In contrast, caffeine displays two maxima and anhydrous-hydrate transition occurs at the solubility peak in the amphiprotic mixture. The apparent enthalpies of solution of both drugs show endothermic maxima against solvent composition that are related to hydrophobic hydration. A general explanation for the cosolvent action in aqueous mixtures is proposed. The dominant mechanism shifts from entropy to enthalpy at a certain cosolvent ratio dependent on the hydrophobicity and the solubility parameter of the drug. Niflumic acid and caffeine show enthalpy-entropy compensation in ethanol-water, and this relationship is demonstrated for the first time in nonaqueous mixtures. The results support that enthalpy-entropy compensation is a general effect for the solubility of drugs in solvent mixtures. The shape of the solubility curves is correlated with the compensation plots. The solubility peaks separate different enthalpy-entropy relationships that also differentiate the solubility behavior of the hydrate and the anhydrous forms of caffeine.

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.

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.

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.

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.

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.