Solubility Of Sulfadiazine Research Articles

Thermodynamic Analysis of the Solubility of Sulfadiazine in (Acetonitrile 1-Propanol) Cosolvent Mixtures from 278.15 K to 318.15 K

Drug solubility is one of the most significant physicochemical properties as it is related to drug design, formulation, quantification, recrystallization, and other processes, so understanding it is crucial for the pharmaceutical industry. In this context, this research presents the thermodynamic analysis of the solubility of sulfadiazine (SD) in cosolvent mixtures {acetonitrile + 1-propanol} at 9 temperatures (278.15 K–318.15 K), which is a widely used drug in veterinary therapy, and two solvents of high relevance in the pharmaceutical industry, respectively. The solubility of SD, in cosolvent mixtures {acetonitrile + 1-propanol} is an endothermic process where the maximum solubility was reached in pure acetonitrile at 318.15 K and the minimum in 1-propanol at 278.15 K. Although the solubility parameters of acetonitrile and propanol were similar, the addition of acetonitrile to the cosolvent mixture leads to a positive cosolvent effect on the solubility of DS. As for the thermodynamic functions of the solution, the process is strongly influenced by enthalpy, and according to the enthalpy–entropy compensation analysis, the process is enthalpy-driven in intermediate to rich mixtures in 1-propanol and entropy-driven in mixtures rich in acetonitrile.

Inclusion complex formation between sulfadiazine and various modified β-cyclodextrins and characterization of the complexes

β-Cyclodextrin (β-CD) and its derivatives are cyclic oligosaccharides which present the ability to form inclusion complexes with hydrophobic molecules and can bring new functionalities to a wide range of materials. As of today, the most used prophylactic drugs for wound dressing applications are sulfadiazine (SD) and its derivatives silver sulfadiazine (SSD). These drugs are used to prevent infections of the wounds; however, their low intrinsic water-solubility is a hindrance to their use. In this study, the inclusion complex formation between SD/SSD and the various β-CDs were assessed with various protocols. Isothermal Titration Calorimetry (ITC) experiments led to the conclusion that the formation constants measured for SD and SSD are sufficiently similar meaning that SD can be considered as a satisfactory model molecule. Phase Solubility Diagram (PSD) were built for SD and the various β-CDs, highlighting a 1:1 stoichiometry of inclusion and a linear increase in solubility of SD with increasing concentration of β-CDs- The formation constant ranged from 197 M−1 to 245 M−1 for the different β-CDs. X-Ray diffraction (XRD) and Differential Scanning Calorimetry (DSC) experiments revealed the different physico-chemical properties affected by the formation of an inclusion complex. Finally, Nuclear Magnetic Resonance (NMR) experiments confirmed the depth of penetration of SD inside the β-CDs cavity as well as the orientation of SD, highlighting the fact that CM-β-CDs induce a deeper penetration than other β-CDs.

Solubility, dissolution thermodynamics and preferential solvation of sulfadiazine in (N-methyl-2-pyrrolidone + water) mixtures

Solubility of sulfadiazine in {N-methyl-2-pyrrolidone (NMP) + water} mixtures from 278.15 K to 313.15 K has been determined and correlated by means of the Jouyban-Acree model. Discontinuous solubility trends are observed in NMP-rich mixtures at low temperatures. By using the van't Hoff and Gibbs equations the respective apparent thermodynamic quantities for the dissolution and mixing processes, namely Gibbs energy, enthalpy, and entropy, were calculated. Non-linear enthalpy–entropy relationships were observed in the plot of enthalpy vs. Gibbs energy exhibiting negative but variant slopes in the composition region 0.00 < w1 < 0.60 and variant negative and positive slopes in the other mixtures for the first case. Otherwise, a variant negative slope from neat water to w1 = 0.80 but a positive slope from this mixture to neat NMP were observed for the second case. Based on the inverse Kirkwood-Buff integrals it follows that sulfadiazine is preferentially solvated by water molecules in water-rich mixtures but preferentially solvated by NMP molecules in mixtures 0.17 < x1 < 1.00 at 313.15 K.

Prediction of sulfadiazine solubility in some cosolvent mixtures using non-ideal solution models

The experimental data of sulfadiazine in (methanol + water), (ethanol + water) and (1-propanol + water) cosolvent mixtures at some temperatures were correlated using non-ideal solution models, namely, the modified Apelblat and Buchowski-Ksiazaczak equations and the van’t Hoff equation. The calculated results agreed well with the experimental data. According to the Buchowski equation, the solubility of sulfadiazine in the three co-solvent mixtures shows important deviations from ideality, which is consistent with the literature.

Artificial Lipid Membrane Permeability Method for Predicting Intestinal Drug Transport: Probing the Determining Step in the Oral Absorption of Sulfadiazine; Influence of the Formation of Binary and Ternary Complexes with Cyclodextrins.

We propose an in vitro permeability assay by using a modified lipid membrane to predict the in vivo intestinal passive permeability of drugs. Two conditions were tested, one with a gradient pH (pH 5.5 donor/pH 7.4 receptor) and the other with an iso-pH 7.4. The predictability of the method was established by correlating the obtained apparent intestinal permeability coefficients (Papp) and the oral dose fraction absorbed in humans (fa) of 16 drugs with different absorption properties. The Papp values correlated well with the absorption rates under the two conditions, and the method showed high predictability and good reproducibility. On the other hand, with this method, we successfully predicted the transport characteristics of oral sulfadiazine (SDZ). Also, the tradeoff between the increase in the solubility of SDZ by its complex formation with cyclodextrins and/or aminoacids and its oral permeability was assessed. Results suggest that SDZ is transported through the gastrointestinal epithelium by passive diffusion in a pH-dependent manner. These results support the classification of SDZ as a high/low borderline permeability compound and are in agreement with the Biopharmaceutics Classification Systems (BCS). This conclusion is consistent with the in vivo pharmacokinetic properties of SDZ.

Research of sulfadiazine using subcritical water and water + alcohol mixtures as the solvent: Solubility and thermodynamic property

Sulfonamides are drugs extensively used for the treatment of infections caused by gram-positive and gram-negative microorganisms, some fungi, and certain protozoa. They are also used in agriculture to prevent and treat diseases in livestock. Sulfadiazine is a member of the sulfonamide family. In this study, the solubility of sulfadiazine in pure subcritical water and water + alcohol mixtures has been measured using a homemade system at (298 to 403) K under a constant pressure of 5.1 MPa. Our results revealed that the solubility of sulfadiazine was enhanced with increasing temperature and higher percentage of ethanol or propanol in water. Modified Apelblat equation and CNIBS/R-K model were used to correlate and predict the solubility of sulfadiazine in pure subcritical water as well as in subcritical water + alcohol mixtures. The predicted solubility values are in good correlation with the experimental data. In addition, “Apparent thermodynamic analysis” was applied to calculate the dissolution enthalpy property of the solution process.

Solubility temperature dependence and preferential solvation of sulfadiazine in 1,4-dioxane + water co-solvent mixtures

The solubility of sulfadiazine (SD) in some 1,4-dioxane+water co-solvent mixtures was measured at five temperatures from 293.15 to 313.15K in all the polarity range. By using the van’t Hoff and Gibbs equations the thermodynamic functions Gibbs energy, enthalpy, and entropy of solution were obtained from these data. The maximal solubility of this drug expressed in mole fraction was found in the mixture with 0.85 in mass fraction of 1,4-dioxane (w1=0.85, δ1+2=24.7MPa1/2) and the minimum solubility in pure water (δ=47.8MPa1/2) at almost all the temperatures studied. By using the ideal solubility values reported in literature, the thermodynamic quantities of mixing were also calculated. Non-linear enthalpy–entropy relationship was observed for SD in the plot of enthalpy vs. Gibbs energy of solution with variable positive slopes in the regions with 0.00≤w1≤0.90 and 0.95≤w1≤1.00. Hence, the driving mechanism for SD solution process is the enthalpy in nearly all the compositions. In addition, the preferential solvation of this drug by both solvents was analyzed by means of the inverse Kirkwood–Buff integrals observing that it is preferentially solvated by water in water-rich and 1,4-dioxane-rich mixtures but preferentially solvated by 1,4-dioxane in those mixtures with intermediate compositions.

Solubility and preferential solvation of sulfadiazine in methanol + water mixtures at several temperatures

The solubility of sulfadiazine (SD) in some methanol+water cosolvent mixtures was measured at five temperatures from 293.15 to 313.15K in all the polarity range. The mole fraction solubility of this drug was maximal in neat methanol (δ=29.6MPa1/2) and minimum in pure water (δ=47.8MPa1/2) at all the temperatures studied. The thermodynamic functions Gibbs energy, enthalpy, and entropy of solution were obtained from these solubility data by using the van’t Hoff and Gibbs equations. Thermodynamic quantities of mixing were also calculated by using ideal solubility values reported in the literature. Non-linear enthalpy–entropy relationship was observed for SD in the plot of enthalpy vs. Gibbs energy of mixing, thus, ΔmixH° vs. ΔmixG° plot shows two different trends according to the slopes obtained when the mixtures composition changes. Accordingly, the driving mechanism for SD solution process in water-rich is the entropy; whereas, from 0.20 in mass fraction of methanol to neat methanol the process is enthalpy-driven. Additionally, the preferential solvation of this drug by the solvents was analyzed by means of the inverse Kirkwood–Buff integrals observing that it is preferentially solvated by water in water-rich mixtures but preferentially solvated by methanol in methanol-rich mixtures.

Solubility and Solution Thermodynamics of Some Sulfonamides in 1-Propanol + Water Mixtures

The solubilities of sulfadiazine (SD), sulfamerazine (SMR) and sulfamethazine (SMT) in some 1-propanol + water co-solvent mixtures were measured at five temperatures from 293.15 to 313.15 K over the polarity range provided by the aqueous solvent mixtures. The mole fraction solubility of all these sulfonamides was maximal in the 0.80 mass fraction of 1-propanol solvent mixture (δ solv = 28.3 MPa1/2) and minimal in water (δ = 47.8 MPa1/2) at all temperatures studied. The apparent thermodynamic functions Gibbs energy, enthalpy, and entropy of solution were obtained from these solubility data by using the van’t Hoff and Gibbs equations. Apparent thermodynamic quantities of mixing were also calculated by using the ideal solubilities reported in the literature. Nonlinear enthalpy–entropy relationships were observed for these drugs in the plots of enthalpy versus Gibbs energy of mixing. The plot of ∆mix H° versus ∆mix G° shows different trends according to the slopes obtained when the mixture compositions change. Accordingly, the mechanism for the solution process of SD and SMT in water-rich mixtures is enthalpy driven, whereas it is entropy driven for SMR. In a different way, in 1-propanol-rich mixtures the mechanism is enthalpy driven for SD and SMR and entropy driven for SMT. Ultimately, in almost all of the intermediate compositions, the mechanism is enthalpy driven. Nevertheless, the molecular events involved in the solution processes remain unclear.

Solution thermodynamics of sulfadiazine in some ethanol + water mixtures

The solubility of sulfadiazine (SD) in several cosolvent mixtures was measured at temperatures from 293.15 to 313.15K in all the polarity range provided by aqueous mixtures conformed by ethanol and water. The solubility was maximal in the mixture 0.80 in mass fraction of ethanol (δ=30.0MPa1/2) and minimum in pure water (δ=47.8MPa1/2) at all the temperatures. The thermodynamic functions Gibbs energy, enthalpy, and entropy of solution were obtained from these solubility data by using the van't Hoff and Gibbs equations. Thermodynamic quantities of mixing were also calculated by using calorimetric values related to a drug fusion process reported in the literature. A nonlinear enthalpy–entropy relationship was observed in a plot of enthalpy vs. Gibbs energy of mixing. The plot of ΔmixH° vs. ΔmixG° shows two different trends according to the slope obtained; that is, i) one with a negative slope from pure water up to 0.20 in mass fraction of ethanol and another one from the mixture 0.80 in mass fraction of ethanol up to pure ethanol; and ii) one with a positive slope from the mixture 0.20 in mass fraction of ethanol up to the mixture 0.80 in mass fraction of ethanol. Accordingly, the driving mechanism for SD solubility in water-rich and ethanol-rich mixtures is the entropy, whereas, between 0.20 and 0.80 mass fraction of ethanol the driving mechanism is the enthalpy. This behavior is similar to the one exhibited by the similar drug sulfapyridine.

Solubilities of Sulfadiazine in Methanol, Ethanol, 1-Propanol, 2-Propanol, Acetone, and Chloroform from (294.15 to 318.15) K

The solubilities of sulfadiazine in methanol, ethanol, 1-propanol, 2-propanol, acetone, and chloroform have been determined with temperatures from (294.15 to 318.15) K by a static equilibrium method. The experimental data were correlated with the modified Apelblat equation.

Solubilities of Sulfadiazine, Sulfamethazine, Sulfadimethoxine, Sulfamethoxydiazine, Sulfamonomethoxine, Sulfamethoxazole, and Sulfachloropyrazine in Water from (298.15 to 333.15) K

Using a static equilibrium method, the solubilities of sulfadiazine, sulfamethazine, sulfadimethoxine, sulfamethoxydiazine, sulfamonomethoxine, sulfamethoxazole, and sulfachloropyrazine in water have been determined experimentally from (298.15 to 333.15) K. The experimental data were correlated with the modified Apelblat equation. The calculated results show good agreement with the experimental data.

Extended Hildebrand Solubility Approach: Sulfonamides in Binary and Ternary Solvents

The extended Hildebrand solubility approach is used to estimate the solubility of sulfonamides in binary and ternary solvent systems. The solubility of sulfisomidine in the binary solvent, dioxane–water, shows a bell-shaped profile with a solubility maximum well above the ideal solubility of the drug. This is attributed to solvation of the drug with the dioxane–water solvent, and indicates that the solute–solvent interaction energy (W) is larger than the geometric mean (δ1δ2) of regular solution theory. The solubilities of sulfadiazine, sulfisomidine, sulfathiazole, and sulfamethoxazole were determined in mixtures of dimethylacetamide, glycerol, and water, and the solubility profiles were well reproduced by use of the extended Hildebrand solubility approach. Since the solubility parameter (δ1 = 11) of the solvent (dimethylacetamide) was approximately equal to the solubility parameters of the sulfonamides, and because of the powerful solvating power of dimethylacetamide, the solubility profiles did not exhibit peaks as observed for sulfisomidine in dioxane–water. When sulfisomidine was dissolved in a ternary mixture, i.e., butyl acetate (δ1 = 8.5), dimethylacetamide (δ1 ≃ 11), and methanol (δ1 = 14.5), a spike was produced in the solubility profile at the solubility parameter of dimethylacetamide. This sharply peaked profile suggests that the two branches be treated as separate solubility curves, which are then independently well reproduced by the extended Hildebrand solubility approach. None of the four sulfonamides yielded log-linear relationships in the ternary mixtures.

Solubilities of Sulfadiazine, Sulfisomidine, and Sulfadimethoxine in Several Normal Alcohols

The solubilities of sulfadiazine, sulfisomidine, and sulfadimethoxine in several normal alcohols were determined over a limited temperature range. For all solutes, the highest solubility occurred in methanol, a relatively polar solvent. The entropy of solution, as developed by Hildebrand, was used for interpretive purposes. Experimental results showed that in most cases the entropy quantity increased with decreasing solubility for any particular solute. Solutions of sulfonamides in 1-decanol yielded relatively small entropy values when compared with those for the other normal alcohol solvents. It appears that this diminishing entropy correlates with the substitutions on the pyrimidine moiety of the N1-substituted sulfanilamides.

Comparative Solubilities of Sulfadiazine, Sulfamerizine and Sulfamethazine and Their N4-Acetyl Derivatives at Varying pH Levels

SummaryComparative data are presented on the solubilities of sulfadiazine, sulfamerizine and sulfamethazine and their N4-aeetyl derivatives in buffer solutions at varying pH levels within the physiological range of urinary pH. The findings have been discussed briefly in reference to their possible bearing on renal complications from therapy with these drugs.

Prevention of Crystalluria During Sulfadiazine Therapy. Experimental and Clinical Studies

Conclusions1. The solubilities of sulfa-diazine and particularly of acetyl sulfadiazine, in buffers and in normal urine, increase markedly with increasing pH within the physi-ological pH range of urine. 2. Examination of urine specimens from patients receiving sulfadiazine has demonstrated that crystal-luria due to sulfadiazine can be prevented by maintaining the urine neutral or alkaline and the volume within limits generally considered optimum for patients with infection. 3. This study affords evidence that renal reactions due to the precipitation of sulfadiazine compounds can be prevented by appropriate alkali and fluid therapy. Our clinical findings to date accord with this assumption.