Solubility Of Ketoconazole Research Articles

Randomly Methylated β-Cyclodextrin Inclusion Complex with Ketoconazole: Preparation, Characterization, and Improvement of Pharmacological Profiles.

As a powerful imidazole antifungal drug, ketoconazole's low solubility (0.017 mg/mL), together with its odor and irritation, limited its clinical applications. The inclusion complex of ketoconazole with randomly methylated β-cyclodextrin was prepared by using an aqueous solution method after cyclodextrin selection through phase solubility studies, complexation methods, and condition selection through single factor and orthogonal strategies. The complex was confirmed by FTIR (Fourier-transform infrared spectroscopy), DSC (differential scanning calorimetry), TGA (thermogravimetric analysis), SEM (scanning electron microscope images), and NMR (Nuclear magnetic resonance) studies. Through complexation, the water solubility of ketoconazole in the complex was increased 17,000 times compared with that of ketoconazole alone, which is the best result so far for the ketoconazole water solubility study. In in vitro pharmacokinetic studies, ketoconazole in the complex can be 100% released in 75 min, and in in vivo pharmacokinetic studies in dogs, through the complexation, the Cmax was increased from 7.56 μg/mL to 13.58 µg/mL, and the AUC0~72 was increased from 22.69 μgh/mL to 50.19 μgh/mL, indicating that this ketoconazole complex can be used as a more efficient potential new anti-fungal drug.

Unraveling hydrogen bond interactions between ketoconazole and imidazolium-based ionic liquids: An experimental and theoretical study

The solubility and solvation mechanism of the Biopharmaceutical Classification System class II insoluble drug, ketoconazole (KCZ), were investigated in eight different types of imidazolium-based ionic liquids (ILs). An in vitro cytotoxicity test was conducted on Human immortalized keratinocytes cells to evaluate the potential toxicity of these ILs. The results showed no cytotoxicity for any of the imidazolium-based ILs tested. The solubility of KCZ was then examined in the eight imidazolium-based ILs at temperatures ranging from 298.15 K to 338.15 K. The findings revealed that the solubility of KCZ followed a specific order among the imidazolium-based ILs tested. The imidazolium-based IL [BMIM][Tf2N] exhibited the highest solubility of KCZ, followed by [HMIM][PF6], [EMIM][Tf2N], [BMIM][TfO], [BMIM][PF6], [EMIM][TfO], [BMIM][BF4], and [EMIM][BF4] in decreasing order. To understand the interaction mechanism between the imidazolium-based ILs and KCZ, the cations, anions and KCZ were analyzed using σ-profiles computed from both the COSMO-RS model and quantum chemical calculations. The results indicated that KCZ had strong hydrogen bond (HB) acceptors, particularly the oxygen atom of the carbonyl group and the nitrogen atom of the imidazole ring. These HB acceptors contributed to the formation of stronger HBs with the hydrogen atoms of cations compared to the oxygen atoms of the anions. The trend of HB strength followed [Emim]+ > [Bmim]+ > [Hmim]+ > [Tf2N]− > [TfO]− > [PF6]− > [BF4]−. Based on these findings, it can be concluded that [BMIM][Tf2N], which has a strong HB donor cation and a strong HB acceptor anion, displayed the most effective dissolution of KCZ.

Enhancing Solubility and Dissolution Rate of Antifungal Drug Ketoconazole through Crystal Engineering.

To improve the solubility and dissolution rate of the BCS class II drug ketoconazole, five novel solid forms in 1:1 stoichiometry were obtained upon liquid-assisted grinding, slurry, and slow evaporation methods in the presence of coformers, namely, glutaric, vanillic, 2,6-dihydroxybenzoic, protocatechuic, and 3,5-dinitrobenzoic acids. Single-crystal X-ray diffraction analysis revealed that the hydroxyl/carboxylic acid. . .N-imidazole motif acts as the dominant supramolecular interaction in the obtained solid forms. The solubility of ketoconazole in distilled water significantly increased from 1.2 to 2165.6, 321.6, 139.1, 386.3, and 191.7 μg mL-1 in the synthesized multi-component forms with glutaric, vanillic, 2,6-dihydroxybenzoic, protocatechuic, and 3,5-dinitrobenzoic acid, respectively. In particular, the cocrystal form with glutaric acid showed an 1800-fold solubility increase in water concerning ketoconazole. Our study provides an alternative approach to improve the solubility and modify the release profile of poorly water-soluble drugs such as ketoconazole.

Natural Oils Enhance the Topical Delivery of Ketoconazole by Nanoemulgel for Fungal Infections.

Nanoemulgel (NEG) pharmaceutical formulations are gaining popularity because of their ability to serve both as a nanoemulsion and as a gel. These products are well-known for their ease of use, spreadability, controlled release, and ability to hydrate dry skin. Natural essential oils have been shown to promote the cutaneous permeability of topical formulations, enhancing medication safety and efficacy. Herein, we developed NEG for the enhanced permeation of ketoconazole against candidiasis using clove oil (clove-oil-NEG) or eucalyptus oil (eucalyptus-oil-NEG), using the gelling agents carbopol 943 and hydroxypropyl methylcellulose (HPMC). We tested various excipients to increase the solubility of ketoconazole and formulate a nanoemulsion (NE). We measured the NE droplet particle size, shape, entrapment efficiency, and drug release. Furthermore, the physicochemical properties of the optimized nanoemulsion formulation were characterized by techniques such as Fourier transform infrared (FT-IR) spectroscopy and X-ray diffraction (XRD) analysis. The NEs were loaded into gels to form NEGs. NEGs were characterized for drug content, homogeneity, rheology, spreadability, and antifungal activity against Candida albicans, both in vitro and in vivo. Optimized ketoconazole NEG preparations consisted of either 15% clove oil or 20% eucalyptus oil. Droplet sizes in the optimized NEs were <100 nm, and the polydispersity indexes were 0.24 and 0.26. The percentages of ketoconazole released after 24 h from the clove-oil-NEG and eucalyptus-oil-NEGs were 91 ± 4.5 and 89 ± 7%, respectively. Scanning electron microscopy (SEM) showed that the NEGs had a smooth, uniform, and consistent shape and internal structural organization. The drug contents in the clove-oil-NEG and eucalyptus-oil-NEG were 98.5 ± 2.2 and 98.8 ± 3.4%, respectively. Permeation values of ketoconazole from clove-oil-NEG and eucalyptus-oil-NEG were 117 ± 7 and 108.34 ± 6 μg cm-2, respectively. The ketoconazole NEG formulations also had higher levels of fungal growth inhibition than a marketed formulation. Finally, in vivo studies showed that the NEGs do not irritate the skin. Ketoconazole NEG with either 15% clove oil or 20% eucalyptus oil is stable with better efficacy than ketoconazole alone due to excellent dispersion, drug dissolution, and permeability and thus might be recommended for the effective and safe treatment of candidiasis.

Solubility of Ketoconazole in Ethylene Glycol + Water Mixtures at Different Temperatures

Solubility of Ketoconazole in Ethylene Glycol + Water Mixtures at Different Temperatures

Inclusion complex of ketoconazole and p-sulfonic acid calix[6]arene improves antileishmanial activity and selectivity against Leishmania amazonensis and Leishmania infantum

Many previous studies presented the effectiveness of ketoconazole (KTZ) against leishmaniasis. However, the bioavailability and therapeutic efficacy of free KTZ are limited due to its low aqueous solubility. In this study, an inclusion complex (IC6HKTZ) was prepared with p-sulfonic acid calix[6]arene (CX6SO3H) to improve the solubility and efficacy of KTZ against Leishmania amazonensis and Leishmania infantum promastigotes. A linear increase in KTZ solubility as a function of CX6SO3H concentration was verified using the phase-solubility diagram. The resulting diagram was classified as AL-type and a 1:1 host–guest stoichiometry was assumed to prepare IC6HKTZ by freeze-drying. FTIR, TG/DSC, XRD, and solid-state 13C NMR spectroscopy analyses were performed to confirm the formation of IC6HKTZ. The solubility enhancement of KTZ by 120.00 μM CX6SO3H was about 95 times. The IC50 values of IC6HKTZ and free KTZ were 3.95 and 14.35 μM for Leishmania amazonensis and 6.74 and 17.47 μM for Leishmania infantum, respectively. The viability of DH82 macrophages was not affected by CX6SO3H. These results show that CX6SO3H is a new supramolecular carrier system that improves antileishmanial activities to KTZ for the treatment of cutaneous and visceral leishmaniasis.

Determination of Saturated Ketoconazole Solubility Using Spectrophotometry Uv-Vis Method

Ketoconazole is a weakly basic drug that has lower solubility at higher pH. Determination of solubility of ketoconazole in the base solution is not easy due to the poor solubility. The simple, low cost, efficient, accurate spectrophotometry methods in UV/VIS region have been developed for the determination of ketoconazole. The wavelengths were selected at 230 nm using solvent buffer phosphate pH 6.8. The Beers’ law was obeyed in the concentration range 5-50 ppm. According to ICH guidelines the parameters such as linearity, accuracy, precision, the limit of detection, and the limit of quantification were studied. The regression equation of calibration curve was found to be y=0.0448x-0.13. All concentrations were linear, with the absorbance having a correlation coefficient 0.9994. The accuracy was found between 93.84-95.95%. The % Relative Standard Deviation (RSD) of Ketoconazole was found to be 0.112-1.237 for intraday and 0.008-0.792 for interday precision. The result of the limit of detection (LOD) for ketoconazole was 0.988 that could be reliably detected and the limit of quantification (LoQ) for ketoconazole was 3.294 ppm. The result of ketoconazole solubility was 21.044±0.759 ppm that indicating ketoconazole was a poorly soluble drug in the intestine. The proposed methods could be applied to the determination solublity ketoconazole in buffer phosphate pH 6.8 with good accuracy, good precise, and simple.

Validation of RP-HPLC method for determination of pHdependent solubility of ketoconazole in phosphate buffer pH 6.8

Validation of RP-HPLC method for determination of pHdependent solubility of ketoconazole in phosphate buffer pH 6.8

Experimental Solubility of Ketoconazole, Validation Models, and In vivo Prediction in Human Based on GastroPlus.

The study aimed to identify a suitable cosolvent + water mixture for subcutaneous (sub-Q) delivery of ketoconazole (KETO). The solubility was assessed for several dimethyl acetamide (DMA) + water mixtures at T = 293.2 to 318.2 K and pressure P = 0.1 MPa. The experimental solubility (xe) was validated using the Van 't Hoff and Yalkowsky models and functional thermodynamic parameters (enthalpy ΔsolH°, entropy ΔsolS°, and Gibbs free energy ΔsolG°). The in vitro drug release study was performed at physiological pH, and the data served as the input to GastroPlus, which predicted the in vivo performance of KETO dissolved in a DMA + water cosolvent mixture for sub-Q delivery in human. The maximum solubility (mole fraction) of KETO (9.81 × 10-1) was obtained for neat DMA at 318.2 K whereas the lowest value (1.7 × 10-5) was for pure water at 293.2 K. An apparent thermodynamic analysis based on xe gave positive values for the functional parameters. KETO dissolution requires energy, as evidenced by the high positive values of ΔsolH° and ΔsolG°. Interestingly, ΔsolG° progressively decreased with increasing concentration of DMA in the DMA + water mixture, suggesting that the DMA-based molecular interaction improved the solubilization. Positive values of ΔsolG° and ΔsolS° for each DMA + water cosolvent mixture corroborated the endothermic and entropy-driven dissolution. GastroPlus predicted better absorption of KETO through sub-Q delivery than oral delivery. Hence, the DMA + water mixture may be a promising system for sub-Q delivery of KETO to control topical and systemic fungal infections.

Solubility study of ketoconazole in propylene glycol and ethanol mixtures at different temperatures: A laser monitoring method

The solubility of ketoconazole in the mixtures of propylene glycol and ethanol is measured by a laser monitoring technique in the temperature range of 293.2–313.2 K. The generated solubility data are fitted to some linear and non-linear cosolvency models and the accuracy of each model is investigated by calculating the mean relative deviations (MRD%) for the back-calculated data. The apparent thermodynamic parameters of ketoconazole dissolution are also computed according to the van’t Hoff and Gibbs equations.

Solubility of Ketoconazole (antifungal drug) in SC-CO2 for binary and ternary systems: measurements and empirical correlations

One of the main steps in choosing the drug nanoparticle production processes by supercritical carbon dioxide (SC-CO2) is determining the solubility of the solid solute. For this purpose, the solubility of Ketoconazole (KTZ) in the SC-CO2, binary system, as well as in the SC-CO2-menthol (cosolvent), ternary system, was measured at 308–338 K and 12–30 MPa using the static analysis method. The KTZ solubility in the SC-CO2 ranged between 0.20 × 10–6 and 8.02 × 10–5, while drug solubility in the SC-CO2 with cosolvent varied from 1.2 × 10–5 to 1.96 × 10–4. This difference indicated the significant effect of menthol cosolvent on KTZ solubility in the SC-CO2. Moreover, KTZ solubilities in the two systems were correlated by several empirical and semiempirical models. Among them, Sodeifian et al., Bian et al., MST, and Bartle et al. models can more accurately correlate experimental data for the binary system than other used models. Also, the Sodeifian and Sajadian model well fitted the solubility data of the ternary system with AARD% = 6.45, Radj = 0.995.

A laser monitoring technique for solubility study of ketoconazole in propylene glycol and 2-propanol mixtures at various temperatures

In the current study, ketoconazole solubility profile is determined in the mixtures of propylene glycol and 2-propanol at temperature range of 293.2–313.2 K by employing a laser-based monitoring setup followed by a gravimetric measurement. The generated solubility data for ketoconazole are correlated with various reported mathematical solubility models and the mean relative deviations of the back-calculated solubility data obtained from the mentioned models are calculated and used for the investigation of models' accuracies. Furthermore, the apparent thermodynamic properties of ketoconazole dissolution process are computed by using the van't Hoff and Gibbs equations. The automated monitoring of ketoconazole solubility in the mixed solvent can be a helpful method for the pharmaceutical industry and obtained solubility data extend the solubility database of ketoconazole.

Simultaneous improvement of ketoconazole solubility, antifungal and antibiofilm activity by multicomponent complexation.

Background: A novel multicomponent complex (MC) of ketoconazole (KET) with β-cyclodextrin (β-CD) and N-acetylcysteine (NAC) was developed with the purpose of improving the solubility as well as the antifungal and antibiofilm activity of KET against Candida albicans. Results & methodology: The interactions among the components were studied using nuclear magnetic resonance, thermal analysis, powder x-ray diffraction, infrared spectroscopy and scanning electron microscopy. Phase-solubility studies demonstrated a considerable increase in the solubility of the MC. An enhancement in antibiofilm and antifungal activity of MC was determined against C. albicans by XTT assay and microbiological studies. Conclusion: This MC, with improvements in the drug pharmaceutical performance, might have an important potential in the development of new pharmaceutical formulations of KET.

Dissolution thermodynamics and preferential solvation of ketoconazole in some {ethanol (1) + water (2)} mixtures

In this research, the equilibrium mole fraction solubility of ketoconazole in some aqueous-ethanolic mixtures was calculated from previously measured solubility data reported in molarity scale at temperatures from 298.2 to 313.2 K. Experimental mole fraction solubility values were adequately correlated with the Jouyban-Acree and Jouyban-Acree-van't Hoff models. The respective apparent thermodynamic functions (Gibbs energy, enthalpy, and entropy of the dissolution processes) were computed using the van't Hoff and Gibbs equations. The enthalpy–entropy relationship for ketoconazole was non-linear in the plot of enthalpy vs. Gibbs energy of solution with negative slope in the composition region 0.00 ≤ w1 ≤ 0.20 but positive slope in the region 0.20 ≤ w1 ≤ 0.70. Beyond this composition, the behavior is more complex. Therefore, the driving mechanism for ketoconazole dissolution process is the entropy in water-rich mixtures and the enthalpy in mixtures 0.20 ≤ w1 ≤ 0.70. In addition, the inverse Kirkwood-Buff integrals were used to investigate the preferential solvation of ketoconazole which is preferentially solvated by water molecules in water-rich and also in ethanol-rich mixtures but preferentially solvated by ethanol molecules in mixtures 0.24 ≤ x1 ≤ 0.75. Dissolution thermodynamics and preferential solvation computations were carried out employing whole experimental solubility data points and the simulated data using a minimum number of seven data points as training set, in which there were no significant differences in the obtained numerical values except for enthalpy-entropy compensation data.

Solubility of ketoconazole in 1,4-dioxane + water mixtures at T = (293.2 to 313.2) K

Abstract The solubility of ketoconazole was measured in aqueous mixtures of 1,4-dioxane at T = (293.2 to 313.2) K using the shake flask method. To mathematically represent the generated solubility data, combined nearly ideal binary solvent/Redlich-Kister (CNIBS/R-K), van't Hoff, Jouyban-Acree, Jouyban-Acree-van't Hoff, UNIQUAC, and NRTL models were applied. Differences of experimental and predicted values were expressed as the percentage of averaged relative deviation (% ARD). Apparent thermodynamic quantities of ketoconazole dissolution and mixing were reported at harmonic temperature. Moreover, the dissolution mechanism of ketoconazole was studied in 1,4-dioxane + water mixtures. Based on the inverse Kirkwood-Buff integrals, the preferential solvation parameters were calculated and it is observed that ketoconazole is preferentially solvated by water in water-rich and 1,4-dioxane-rich mixtures.

Solubility of ketoconazole in the binary mixtures of 2-propanol and water at different temperatures

In the present study, the solubility of ketoconazole is measured by a shake – flask method in the binary solvent mixtures of 2-propanol + water at different temperatures. The experimental solubility data are correlated/back-calculated by some cosolvency models i.e. van't Hoff, Yalkowsky, Jouyban-Acree, Jouyban-Acree-van't Hoff, the mixture response surface and the modified Wilson models. Moreover, the density of ketoconazole saturated solutions is fitted by Jouyban-Acree model and the obtained equation is reported. The accuracy of these models is investigated by calculation of the corresponding MRD%. The apparent thermodynamic parameters including dissolution standard enthalpy change (ΔH∘), standard entropy change (ΔS∘), Gibbs free energy change (ΔG∘) for ketoconazole dissolution are calculated by using van't Hoff and Gibbs equations. Moreover, the preferential solvation analysis demonstrates that ketoconazole is preferentially solvated by water in water-rich and in 2-propanol-rich mixtures, but preferentially solvated by 2-propanol in mixtures of composition 0.19 < x1 < 0.58.

The solubility of ketoconazole in binary carbitol + water mixtures at T = (293.2–313.2) K

The solid-liquid equilibrium of ternary {ketoconazole + carbitol + water} systems was studied by a shake-flask technique at T = (293.2–313.2) K and atmospheric pressure. The temperature and solvent composition dependency models of Jouyban-Acree, Jouyban-Acree-van't Hoff, NRTL, UNIQUAC and Wilson as well as solvent composition dependency models of combined nearly ideal binary solvent/Redlich-Kister (CNIBS/R-K) and modified Wilson were utilized for modeling the experimental solubility data. To predict the solubility data, Yalkowsky and extended Yalkowsky models were utilized. It was observed that the solubility of ketoconazole was increased with the enhancement in temperature and concentration of carbitol. According to the % ARD values, order of performance of the models with temperature and solvent composition dependencies are Jouyban-Acree-van't Hoff > NRTL > Jouyban-Acree > UNIQUAC > Wilson. The % ARD values indicate that in comparison between the models with solvent composition dependency, CNIBS/R–K model has a better consistency with the experimental data. Further, the computed thermodynamic properties of dissolution for ketoconazole in aqueous carbitol solutions suggest that except in neat water, enthalpy has the main contribution to standard Gibbs free energies of dissolution. Finally, preferential solvation analysis based on the inverse Kirkwood-Buff integrals demonstrates that ketoconazole is preferentially solvated by water in water-rich mixtures but preferentially solvated by carbitol in mixtures of 0.12 < x1 < 1.00.

Ketoconazole solubility in aqueous binary mixtures of 1‑propanol at various temperatures

The aim of this work is to have a brief overview on various solubilization methods reported for ketoconazole and using a commonly used method, i.e. cosolvency for enhancement of ketoconazole in binary mixtures of 1‑propanol and water at different temperatures. The generated data are correlated with eight cosolvency mathematical models including the van't Hoff, the double log-log, the mixture response surface, Yalkowsky, Jouyban-Acree, Jouyban-Acree-van't Hoff, modified Jouyban-Acree-van't Hoff, and the modified Wilson models. The mean relative deviations (MRD%) of the back-calculated solubility for each investigated models are calculated as an accuracy criterion. Density of the ketoconazole saturated solutions as another physico-chemical properties is also fitted by the Jouyban-Acree model. Moreover, standard enthalpy, entropy and Gibbs free energy change for ketoconazole dissolution process were obtained by using van't Hoff and Gibbs equations. Finally, preferential solvation analysis based on the inverse Kirkwood-Buff integrals demonstrates that ketoconazole is preferentially solvated by water in water-rich mixtures but preferentially solvated by 1‑propanol in mixtures of 0.19 < x1 < 1.00.

Measurement and mathematical modeling of ketoconazole solubility in propylene glycol + water mixtures at various temperatures

The aim of this work was to study the solubilization behavior and thermodynamics of ketoconazole solubility in the binary mixtures of propylene glycol (PG) and water at five different temperatures ranging T = 293.2–313.2 K. Some cosolvency mathematical models including van't Hoff equation, Yalkowsky model, Jouyban-Acree model, Jouyban-Acree-van't Hoff model, modified Jouyban-Acree-van't Hoff model, the modified Wilson model, the double log-log model and the mixture response surface model were fitted to the experimental results, and the mean relative deviations (MRD%) of the back-calculated solubilities were calculated. Density of the solutions saturated with ketoconazole over the entire solvent composition and temperature range was also determined and the obtained density values were correlated/back-calculated with the Jouyban–Acree model, resulting in a very accurate calculation of the densities with MRD% of 0.1%. Moreover, apparent thermodynamic properties of ketoconazole dissolution process in the investigated mixed solvents including entropy, enthalpy and Gibbs free energy were computed using van't Hoff and Gibbs equations. Furthermore, preferential solvation analysis demonstrates that ketoconazole is preferentially solvated by water in water-rich mixtures but preferentially solvated by PG in the other mixtures.

Solubility of ketoconazole in N-methyl-2-pyrrolidone + water mixtures at T = (293.2 to 313.2) K

The aim of this investigation was to study the solubility behavior of ketoconazole in the binary mixed solvents of N-methyl-2-pyrrolidone (NMP) and water within the temperature range of 293.2–313.2 K and develop mathematical models using five cosolvency models; i.e. van't Hoff equation, Yalkowsky model, Jouyban-Acree model, Jouyban-Acree-van't Hoff model and modified Wilson model. In addition, density of the solutions saturated with ketoconazole in various solvent compositions and temperatures was measured and the results were correlated according to the Jouyban–Acree model. Moreover, apparent thermodynamic quantities of ketoconazole dissolution process in the NMP/water mixtures, including entropy, enthalpy and Gibbs free energy were computed using van't Hoff and Gibbs equations. The modeling showed that the mean relative deviation (MRD%) of the back-calculated solubility data using the above mentioned models were 2.9%, 55.4%, 13.6%, 8.6% and 21.8% respectively.