Solubility Of Itraconazole Research Articles

Particle design of itraconazole by supercritical anti-solvent technology: Processing-microstructure-solubility relationship

Particle design in recent years has attempted to overcome solubility limitations in drug development. In this work, the particle microstructures of itraconazole (ITZ) were designed by a supercritical anti-solvent (SAS) process, with or without hydroxypropyl methylcellulose (HPMC) as the dispersing material, where the processing-microstructure-solubility relationship was investigated. The results showed that ITZ particles with different shapes and crystal forms were obtained, which enhanced the ITZ solubility from 4.4 μg/mL to 108.5 μg/mL. For the optimal sample, ITZ crystal transformed into amorphous state, resulting in high solubility and fast dissolution rate. Moreover, hydrogen bond interaction was formed between HPMC and ITZ, which could hinder the recrystallization of dissolved ITZ, resulting in its complete dissolution. Also, the production efficiency was increased to 38.5 mg ITZ/min, which laid a foundation for the scale-up. These results show the great potential of SAS process on the particle design of poorly soluble drugs for solubility enhancement.

Efficient Enhancement in Itraconazole Solubility through its Cyclodextrin-Water Soluble Polymer Ternary Inclusion Complexes

The aim of this work is the enhancement of the hydrosolubility behaviour of a poorly soluble, weakly basic drug, using itraconazole (ITZ) as a case example. Binary inclusion complexes of ITZ with β-cyclodextrin (β-CD) are prepared in 1:2 molar ratios of ITZ to β-CD by co-evaporation method. Both solubility and dissolution behaviour are compared with that of the pure drug. Ternary complexes can be obtained by adding the polyvinylpirrolidone (PVP) which is a highly water soluble polymer, in the ITZ/ β-CD complex formation. Actually, Solid state analysis is performed for all formulations and for pure ITZ applying the Fourier transforms infrared (FT-IR) spectroscopy, powder X-ray diffraction (pX-RD) and differential scanning calorimetry (DSC). Solubility tests indicate that with all formulation, the solubility of ITZ formed with β-CD or β-CD and PVP proved to be increased. The obtained results show that the pure drug has a poor dissolution property, and the ternary inclusion complexes resulted in fast and extensive release of ITZ.
 Keywords: Itraconazole, β-cyclodextrin, polyvinylpyrrolidone.

Extended Hildebrand Solubility Approach: Prediction and Correlation of the Solubility of Itraconazole in Triacetin: Water Mixtures at 298.15°K.

The aim of the study is to explore the suitability of an empirical approach for the extended Hildebrand solubility approach (EHSA) to predict and correlate the solubility of the crystalline drug itraconazole (ITRA) in triacetin: water mixtures. The physicochemical properties of ITRA like fusion enthalpy, solubility parameter, and ideal mole fraction solubility were estimated. The solubilities of ITRA in mixed solvent blends comprising triacetin: water were determined at 298.15°K. Theoretical solubilities were back calculated using a polynomial regression equation of the interaction energy parameter W as a function of the solubility parameter (δ1) of the solvent mixture. Similarly, the solubilities were predicted by direct method based on the use of logarithmic experimental solubilities (logX2 ) against the solubility parameter (δ1) of the solvent mixture. The predictive capabilities of both EHSA and the direct method were compared using mean percent deviations. The solubility of ITRA was increased in all the triacetin: water blends and was highest in the blend in which the solubility parameter of ITRA equaled that of the solvent mixture. The prediction capacities of the direct method (mean % deviation was -1.89%) were better than those of EHSA (mean % deviation was 9.76%) in the fifth order polynomial. The results indicated that the solubility of any crystalline solute can be adequately predicted and correlated with the mere knowledge of physicochemical properties and EHSA. The information could be of help in process and formulation development.

Solubilization of itraconazole by surfactants and phospholipid-surfactant mixtures: interplay of amphiphile structure, pH and electrostatic interactions

Although surfactants are frequently used in enabling formulations of poorly water-soluble drugs, the link between their structure and drug solubilization capacity is still unclear. We studied the solubilization of the “brick-dust” molecule itraconazole by 16 surfactants and 3 phospholipid:surfactant mixtures. NMR spectroscopy was used to study in more details the drug-surfactant interactions. Very high solubility of itraconazole (up to 3.6 g/L) was measured in anionic surfactant micelles at pH = 3, due to electrostatic attraction between the oppositely charged (at this pH) drug and surfactant molecules. 1H NMR spectroscopy showed that itraconazole is ionized at two sites (2+ charge) at these conditions: in the phenoxy-linked piperazine nitrogen and in the dioxolane-linked triazole ring. The increase of amphiphile hydrophobic chain length had a markedly different effect, depending on the amphiphile type: the solubilization capacity of single-chain surfactants increased, whereas a decrease was observed for double-chained surfactants (phosphatidylglycerols). The excellent correlation between the chain melting temperatures of phosphatidylglycerols and itraconazole solubilization illustrated the importance of hydrophobic chain mobility. This study provides rules for selection of itraconazole solubilizers among classical single-chain surfactants and phospholipids. The basic physics underpinning the described effects suggests that these rules should be transferrable to other “brick-dust” molecules.

Investigation of Within-Tablet Dynamics for Extended Release of a Poorly Soluble Basic Drug from Hydrophilic Matrix Tablets Using ATR-FTIR Imaging.

Hydrophilic matrices are an effective option for oral controlled release but can face challenges in terms of bioavailability and efficacy when used in conjunction with poorly soluble, weakly basic drugs. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) imaging provides dynamic information relating to the location and chemical nature of both the sustained release matrix and the active pharmaceutical ingredient (API) during hydration/dissolution. In this study, we have identified a model system combining itraconazole (IT), a poorly soluble, weakly basic API that has pKa in the physiological range, and hydroxypropyl methylcellulose, which is a commonly used oral tablet matrix. This system was investigated to determine the swelling kinetics at different pH values at a fixed ionic strength and to facilitate the study of the influence of hydrating media pH on the drug particle movement (translocation). Using ATR-FTIR imaging, we were able to show that gel layer formation and swelling were independent of pH but highly dependent on the ionic strength of the hydrating medium in placebo tablets. When the ionic strength was fixed, gel layer formation and radial swelling were both shown to be pH-dependent when IT was incorporated into the matrix. This was verified using optical imaging. The chemical specificity of ATR-FTIR imaging permitted the observation of transformational changes of IT from the free base to the ionized form in the tablet core during hydration. This phenomenon was shown to be greater at pH 1.5 than at pH 7. ATR-FTIR imaging was able to follow drug particle translocation at both pH 1.5 and pH 7; however, the extent of migration away from the tablet core was shown to be greater at lower pH. The location of the translocated particles within the gel layer was different between the two studied pH values, with particles being located close to the swelling front at pH 7 and within the diffusion front at pH 1.5. In both pH environments, the translocated IT particles were shown to be predominantly in the free base form. No evidence of fully solubilized IT was observed in the surrounding medium because of the inherent aqueous solubility of IT being below the instrument detection limits. This work highlighted the value of utilizing a chemically specific spectroscopic tool to increase the understanding of the nature of the factors affecting the release of a pH-dependent, poorly soluble drug from a hydrophilic matrix at different pH values and permitted greater insights into what happens inside the polymer matrix during drug release.

Solubilization and determination of solution thermodynamic properties of itraconazole in different solvents at different temperatures

The solubility of itraconazole (ITRA) in thirteen pure solvents including water, dimethyl sulphoxide, acetonitrile, methanol, 1,4-butanediol, ethanol, isopropyl alcohol, n-butanol, octanol, ethyl acetate, toluene, benzene, 1,4-dioxane were estimated at the temperatures ranging from 293.15 K to 318.15 K under atmospheric pressure (0.1 MPa). The results reflected that the solubility of ITRA was a function of temperature and was increased with a rise in temperature in each solvent. Moreover, the solubility in polar solvents was less and found to be increased in non-polar solvents. Furthermore, the results of solubilization were correlated by the Van’t Hoff equation, the modified Apelblat equation, the Buchowski − Ksiazaczak λh equation, and the polynomial empirical equation. The polynomial empirical equation proved to be more accurate and suitable for the correlation of solubilities of ITRA in studied solvents at various temperatures. Besides, theoretical ideal solubilities, activity coefficients, and thermodynamic properties of the solution process including standard molar enthalpy, entropy, Gibbs free energy, and excess enthalpy were calculated from the experimental solubility data. These thermodynamic parameters indicated that the solubilization process was not spontaneous, endothermic, and enthalpy driven. Such thermodynamic based solubility data of ITRA will be of immense help in solubilization, synthesis, process development, preformualtion, and dosage form development in pharmaceuticals.

Estimation and Correlation of Solubility of Practically Insoluble Drug Itraconazole in 1,4-Butanediol + Water Mixtures Using Extended Hildebrand Solubility Approach

Extended Hildebrand solubility approach (EHSA) was applied to estimate and correlate the solubilities of itraconazole in 1,4-butanediol + water mixtures at 298.15 K. Experimental solubilities and properties like entropy of fusion and ideal mole fraction solubilities were determined. EHSA was applied to estimate interaction parameter ′W′ to understand the solute solvent interaction. Theoretical solubilities were calculated by using ′W′ as a function of solubility parameter of solvent blend (δ1) and by direct method using logarithmic experimental solubilities (logX2) against solubility parameter of solvent mixture (δ1). Prediction capacities of EHSA and direct method were compared using mean percent deviations obtained while comparing theoretical solubilities with experimental ones. Itraconazole solubility was increased in all the proportions of solvent mixtures and was found to be highest at 0.9 mass fraction of 1,4-butanediol where solubility parameter of drug matched with solvent mixture. Prediction capacity of EHSA was found to be better with regular polynomial equation of order 5 with mean deviation of − 1.69%. Using EHSA, the solubility of any solute can be adequately predicted with the knowledge of few physicochemical properties.

Liposomal itraconazole formulation for the treatment of glioblastoma using inclusion complex with HP-β-CD

Itraconazole, which has been widely used as an antifungal-agent, is revisited as an anticancer drug but its low solubility still remains a major hurdle. Inclusion complex was used to enhance the solubility of itraconazole, followed by encapsulating into liposome for glioblastoma. Itraconazole-inclusion complex was well formed at 1:1, 1:2 and 1:3 molar ratios of itraconazole: hydroxypropyl-β-cyclodextrin (HP-β-CD) as determined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR) analyses. Itraconazole-HP-β-CD inclusion complex was then encapsulated in liposome and its size was 120.5 ± 53.1 nm in diameter with 50% encapsulation efficiency. Stem cell-like property, as determined by the population ratio of CD90+/CD133+, was decreased from 3.38 to 1.46% when the U87-MG-TL cells were treated with 100 µM itraconazole/HP-β-CD-loaded liposome. Anti-proliferative effect of itraconazole/HP-β-CD-loaded liposome on U87-MG-TL cells was slightly better than that of free itraconazole (IC50 of 17 µM vs. 26 µM). Moreover, anti-proliferative effect of Itraconazole/HP-β-CD-loaded liposome on U87-MG-TL cells was higher than that of free itraconazole when the cells were co-treated with temozolomide (IC50 of 1.58 mM vs. 2.35 mM). Therefore, itraconazole/HP-β-CD-loaded liposomal formulation could serve as a promising strategy for targeting the glioblastoma multiforme.

Epsilon-poly-l-lysine decorated ordered mesoporous silica contributes to the synergistic antifungal effect and enhanced solubility of a lipophilic drug

The emergence of drug-resistant fungal strains remains a severe threat for the public health, which prompts strict restrictions on the uses of antifungal drugs. However, the majority of lipophilic fungistatic agents are poorly water soluble with a low oral adsorption characteristic posing challenges for the precise prescriptions. In this study, a natural antimicrobial cationic peptide of epsilon-poly-l-lysine (EPL) decorated ordered mesoporous silica (SBA-15) was facilely prepared for the efficient loading of antifungal itraconazole (ITZ) drugs. The characterized mesoporous SBA-15/EPL/ITZ composite exhibited remarkable antifungal performance against Aspergillus fumigatus as a model mold, which was attributed to synergistic antifungal activities of ITZ and EPL in the mesopores. Moreover, the in vitro release behaviors of ITZ in the composite nanoexcipients both in simulated gastric fluid and fasted state simulated intestinal fluid were studied. The observed release kinetics of ITZ demonstrated a contributing role of SBA-15/EPL to enhance the solubility of ITZ and thereby may promote its flux across the gastrointestinal epithelium, which is beneficial for the absorption of drugs. Additionally, SBA-15/EPL/ITZ composites showed desirable biocompatibility toward mammalian red blood cells, human cervical cancer cells (Hela) and human embryonic kidney cells (HEK-293T). Furthermore, the pharmacokinetic profiles of obtained nano-formulations were assessed in rats, among which the improved adsorption of SBA-15/EPL/ITZ composites (AUC0–24h sum: 8381.7 nM·h) was identified compared with that of pure ITZ (525.1 nM·h) and the commercial drug of Sporanox (7516.6 nM·h). Collectively, the prepared SBA-15/EPL/ITZ provides an ecofriendly and integrated nanocomposite with enhanced solubility of lipophilic drugs to combat proliferations of infectious fungi.

Floating drug delivery system of itraconazole: Formulation, in vitro and in vivo studies

A multiple unit oral floating drug delivery system of itraconazole was developed to prolong gastric residence time, target stomach mucosa and increase drug bioavailability. To prepare non-effervescent floating microspheres/beads, ionotropic gelation method was used. Since the solubility of itraconazole is low at pH 1.2, it was attempted to increase the solubility by preparing inclusion complexes using randomly methylated beta-cyclodextrin and with polyvinylpyrrolidone cross linked and starch. In this study, the effects of formulation parameters like, concentration and types of polymer, crosslinking agent and the excipients, the floating ability, surface characteristics and drug release profiles were investigated. Optimum formulation (NG17) was used for Caco-2 cell culture studies. In permeability studies, at pH 5, 6 and 7.4, the formulation NG17 at pH 5, which is the pH of the proximal region of small intestine (absorption window of itraconazole), showed the highest permeability value which is 5.88 × 10−6 cm/s. NG17 was also used for in vivo imaging studies. It was conducted in rabbits by using gamma scintigraphy and obtained that NG17 floated for 6.5 h in the stomach. As a result, it was found that, with non-effervescent floating bead formulations, the bioavailability of itraconazole can be improved.

Mechanistic Assessment of the Effect of Omeprazole on the In Vivo Pharmacokinetics of Itraconazole in Healthy Volunteers.

SUBA-itraconazole and Sporanox are two oral formulations of itraconazole. Drug-drug interactions with omeprazole have been previously reported; however, mechanistic understanding of the pharmacological and physiological interactions of omeprazole with orally administered itraconazole within a population modeling paradigm is lacking. The objective of this analysis was to mechanistically describe and quantify the effect of omeprazole on the pharmacokinetics of itraconazole and its major metabolite, hydroxyitraconazole from the SUBA itraconazole and Sporanox formulations. An in vitro-in vivo (IVIV) pharmacokinetic model of itraconazole and hydroxyitraconazole was developed including data from an omeprazole interaction study with SUBA itraconazole. Meta-models of gastric pH for healthy subjects and subjects receiving omeprazole were integrated into the IVIV model to capture omeprazole-mediated gastric pH changes on itraconazole dissolution and absorption. Omeprazole influenced the kinetics of itraconazole through altering the dissolution and absorption due to the pH-dependent solubility of itraconazole, inhibition of efflux transporters, and inhibiting the metabolism of itraconazole and hydroxyitraconazole. The model-predicted population effects of omeprazole on itraconazole from SUBA-itraconazole were to increase the area under the concentration-time curve (AUC0-24) and maximum concentration (Cmax) by 35 and 31%, respectively, and to decrease AUC0-24 and Cmax from Sporanox by 68 and 76%, respectively. Unlike SUBA itraconazole, which requires basic pH for itraconazole release, the omeprazole-induced pH-mediated reduction in Sporanox dissolution overrides any increased exposure from the drug-drug interaction at hepatic metabolizing enzymes or efflux transporters. The model presented here is the most complete quantitative description of the pharmacokinetics of itraconazole and hydroxyitraconazole currently available.

SOLID-STATE PROPERTIES AND SOLUBILITY STUDIES OF NOVEL PHARMACEUTICAL COCRYSTAL OF ITRACONAZOLE

Objective: Pharmaceutical cocrystal is a promising method to improve the solubility of active pharmaceutical ingredients (APIs). Itraconazole (ITZ) is a BCS class II antifungal drug with poor aqueous solubility, therefore an attempt was made to improve the solubility of ITZ using cocrystallization technique. In this work, six novel pharmaceutical cocrystals of ITZ with various coformers, including 4-hydroxybenzoic acid (4HBA), trans-cinnamic acid (TCA), suberic acid (SUB), sebacic acid (SBC), 1-hydroxy-2-naphthoic acid (1H2N), and benzamide (BZD) were prepared.Methods: ITZ cocrystals was prepared by solvent evaporation process. The cocrystals produced were characterized using powder x-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and fourier transform infrared (FTIR) spectroscopy. Solubility analysis was performed to evaluate the cocrystals.Results: PXRD and DSC analysis revealed that the pattern of all ITZ cocrystals was distinguishable from the individual compounds which indicates the formation of new phase. The solubility of ITZ and its cocrystals from highest to lowest after 24 h in 0.1 N HCl solution (pH 1.2) follows the order ITZ-TCA (1.97-fold), ITZ-SBC (1.09-fold), ITZ, ITZ-1H2N (0.58-fold) and ITZ-4HBA (0.46-fold).Conclusion: This study demonstrates that the selection of coformers has pronounced an impact on the physicochemical properties of ITZ. Based on this study, it can be concluded that cocrystallization offers a valuable way to improve the solubility of ITZ.

Linking the concentrations of itraconazole and 2-hydroxypropyl-β-cyclodextrin in human intestinal fluids after oral intake of Sporanox®

In a previously performed small-scale clinical study, healthy volunteers were asked to ingest an oral solution of itraconazole (Sporanox®) containing 40% 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) (i) with or (ii) without a standardized volume of water (240 mL) after which gastrointestinal and blood samples were collected. Although omitting water during the administration of Sporanox® resulted in noticeably higher duodenal concentrations of itraconazole, systemic exposure was almost unaffected. It is assumed that this discrepancy can be explained by differences in the extent of entrapment of itraconazole in the duodenum caused by differential complexation depending on the concentration of cyclodextrins. To further substantiate this hypothesis, the quantification of HP-β-CD concentrations in the aspirated intestinal fluids was performed by LC-MS/MS. When comparing the intestinal concentrations of itraconazole and HP-β-CD for one single healthy volunteer (HV02) in both test conditions, an excellent correlation was observed (Spearman’s rank coefficient of 0.96). Moreover, the data suggest that, similar to aqueous buffer media, also in human intestinal fluids a non-linear relationship exists between itraconazole solubility and HP-β-CD concentration (Ap-type profile; Spearman’s rank coefficient of 0.78), indicating that higher order complexes are formed at higher concentrations of HP-β-CD. This difference in extent of entrapment in the inclusion complexes helps to understand the observed impact of water intake on precipitation and permeation behavior of itraconazole in man. Without water intake, higher HP-β-CD concentrations resulted in less precipitation and increased duodenal concentrations of itraconazole. On the other hand, the stronger interaction at higher HP-β-CD concentrations reduced the free fraction of the drug explaining that increased intraluminal concentrations of itraconazole were not translated into an enhanced uptake. In conclusion, quantifying the concentrations of the solubilizing agent HP-β-CD in human intestinal fluids appeared to be of crucial importance to interpret the intraluminal behavior of an orally administered cyclodextrin-based solution.

Investigation of Polymer/Surfactant Interactions and Their Impact on Itraconazole Solubility and Precipitation Kinetics for Developing Spray-Dried Amorphous Solid Dispersions.

Methods were developed to systematically screen different polymer-surfactant combinations for the purpose of enhancing amorphous active pharmaceutical ingredient (API) solubility while maintaining its physical stability. Itraconazole (ITZ) was chosen as the model API mostly due to its low aqueous solubility. Special attention was paid to determine the effect of a reduction in the critical micelle concentration (CMC) by specific polymer/surfactant combinations on the ITZ solubility and physical stability. However, only a slight correlation was actually found. Only the polymer/surfactant combinations with the smallest effect on CMC improved solubility and stability of ITZ in simulated intestinal fluids (SIF). Surfactants were found to negate the stabilizing effects of polymers. ITZ crystallization tendency generally depended on the degree of supersaturation and the type of polymer/surfactant combinations used. In general, we found that instead of focusing solely on reducing the CMC, a systematic screening of systems that maintain high ITZ supersaturation proved to be a successful approach.

Synergistic Effect of Polyvinyl Alcohol and Copovidone in Itraconazole Amorphous Solid Dispersions.

The first objective is to evaluate the feasibility of melt-extruding polyvinyl alcohol-based amorphous solid dispersions for oral drug delivery. The second objective is to investigate the miscibility between polyvinyl alcohol 4-88 and copovidone, and to characterize the properties of ternary itraconazole amorphous solid dispersions comprising both polymers. Samples were prepared using a co-rotating, twin-screw extruder. A solution precipitation study was conducted to compare the precipitation inhibition of polyvinyl alcohol against other commonly used polymers for amorphous solid dispersions. Miscibility between polyvinyl alcohol 4-88 and copovidone was determined using DSC and XRD analyses. All extrudates were characterized using DSC, XRD, and non-sink dissolution. Polyvinyl alcohol demonstrated the highest capacity for inhibiting the precipitation of itraconazole. Itraconazole was found to be more soluble in copovidone (>30%) than in polyvinyl alcohol 4-88 (<5%) in binary extrudates. Polyvinyl alcohol and copovidone are miscible when the proportion of polyvinyl alcohol 4-88 does not exceed 30% (w/w). Compared to binary extrudates, the ternary extrudate demonstrated a higher degree of supersaturation and more sustained supersaturation of itraconazole in purified water and phosphate buffer pH6.8 solution. As a surface-active material, polyvinyl alcohol was effective in inhibiting precipitation of itraconazole in aqueous media. Solubility of itraconazole in polyvinyl alcohol in solid state was limited because of the high polarity of the polymer. Ternary systems comprising a mixture of polyvinyl alcohol and copovidone demonstrated better supersaturation in aqueous media than binary systems. Ternary systems benefited from both the high solubilizing capacity of copovidone and high precipitation inhibition capacity of polyvinyl alcohol.

Formulation and evaluation of Itraconazole mucoadhesive tablets for sustained release

The aim of this research was to prepare and evaluate sustain release mucoadhesive tablet ofitraconazole, in order to overcome its poor biopharmaceutical property and therapeutical efficacy. Itraconazole have low aqueous solubility and high permeability, hence in order to improve its solubility in both HCl and water it is formulated as solid dispersion by using solvent evaporation method. Solid dispersion was formulated using with itraconazole PEG 6000 in the ratio of 1: 2. Solid dispersion was then formulated in matrix of hydrophilic mucoadhesive polymers Carbopol 934P (CP) and HPMC E5LV into mucoadhesive sustained release tablet. Further, formulation were optimized for various amounts of CP and HPMC. Various amount of HPMC and Carbapol were taken as formulation variables for optimizing response variables i.e. dissolution parameters. Solid dispersion leads to enhancement in solubility of itraconazole in water up to 5.95% and in HCl it was 6.43%. In addition to enhancement of solubility in HCl and water they also lead to the slow release of drug up to 1.44% in 1 hour. Optimum combination of mucoadhesive polymers Carbopol 934P (CP) and HPMC E5LV provided adequate fairly regulated release profile. The experimental and predicted results for optimum formulations were found to be in close agreement. The formulation showed percentage drug release upto 86% for 9hour.

Development of fine solid-crystal suspension with enhanced solubility, stability, and aerosolization performance for dry powder inhalation

Dry powder for inhalation (DPI) is an attractive approach for the treatment of local lung diseases. However, the application of drugs with poor water solubility is often limited due to the dissolution obstacles in the fluid layer of the lung lining. In this study, fine solid-crystal suspension (FSCS) was proposed as a solvent-free method to improve the solubility of a drug with poor solubility (itraconazole) and achieve high deposition efficiency simultaneously. The FSCS, in which the crystalline drug particle was highly dispersed in the crystalline excipient, was initially prepared as drug-excipient extrudate by hot melt extrusion, followed by jet milling into fine particles. Unlike the amorphous solid dispersion in the high-energy state, which is liable to recrystallize and aggregate, the FSCS was expected not only to improve the solubility of itraconazole, but also to maintain excellent physical stability. As evidenced in the solubility and stability studies, the solubility of itraconazole in the FSCS was approximately 145-fold greater than that of the raw material, and the crystalline form of itraconazole in the FSCS was also unchanged after storage in the accelerated condition for 6 months (40°C and 75% relative humidity [RH]). The improved solubility might be ascribed to the reduced crystal size and increased wettability, as confirmed by the particle size and contact angle test. The FSCS also showed an encouragingly high fine-particle fraction of 50.59±0.67%, which might have benefited from the appropriate particle size. Therefore, the FSCS was suggested as a promising DPI for delivery of drugs with poor water solubility.

Microemulsion Based Bioadhesive Gel of Itraconazole Using Tamarind Gum: In-vitro and Ex-vivo Evaluation

The current study was aimed to formulate and evaluate bioadhesive gel containing microemulsion (ME) of itraconazole (ITZ) and an attempt was made to investigate suitability of tamarind gum (TG) as a gelling agent. The solubility of ITZ in oils, surfactants and co-surfactant was evaluated for the selection of appropriate component. The ratio of surfactant and co-surfactant was optimized by constructing pseudoternary phase diagram. Ternary phase diagram was constructed using isopropyl myristate (IPM) and oleic acid (OA) as oil phase, tween 80 as surfactant and isopropyl alcohol (IPA) as cosurfactant in order to obtain ME region. The optimized ME of ITZ was characterized by its qualitative and quantitative tests and incorporated into polymeric gels of carbopol (CBP), xanthan gum (XG) and TG. The ME based ITZ gels were evaluated for pH, drug content, viscosity, ex-vivo bioadhesion, spreadability and in vitro drug release. Furthermore, antifungal activity of the gels was performed by agar cup diffusion technique using cultures of Candida albicans. ITZ showed maximum solubility in mixture of IPM and OA (1:1). Stable ME was obtained when IPM and OA was taken in the ratio of 1:1 as oil phase, Tween 80 as surfactant and isopropyl alcohol (IPA) as cosurfactant at the weight ratio of 10:45:45. The optimized ME based gels showed pH in the range of 6.11 to 6.48, spreadability in the range of 4.1 to 7.1gm.cm/sec and ex vivo bioadhesion in the range of 65 to 84gm. The viscosity study indicated pseudoplastic behaviour of all ME based gel formulations. Amongst the studied ME gels, TG containing gels exhibited fast and complete drug release at the end of 24h. Formulation F7 containing TG showed wide zone of inhibition and found to be stable for three months. These results indicate that the TG containing ME gel may be a used as vehicle for topical delivery of drugs.

Solid liquid equilibrium of an antifungal drug itraconazole in different neat solvents: Determination and correlation

The information regarding thermodynamic parameters on solid-liquid equilibrium (SLE) of itraconazole (ITR) in different neat solvents is essential for its pharmaceutical and industrial applications. The SLE of ITR in different neat solvents had not been studied previously in literature. Hence, in this study, the SLE of ITR in various neat solvents including “water, ethanol, isopropanol (IPA), ethylene glycol (EG), propylene glycol (PG), n-butanol, ethyl acetate (EA), dimethyl sulfoxide (DMSO), polyethylene glycol-400 (PEG-400) and Transcutol®” was determined and correlated at temperatures “T=298.2K to 318.2K” and pressure “p=0.1MPa”. The experimental solubilities of ITR in mole fraction were determined by shake flask method and correlated with “Van't Hoff and Apelblat models”. The measured solubility values of ITR in mole fraction were correlated well with “Van't Hoff and Apelblat models” with root mean square deviation values of <5.0%. The mole fraction solubility values of ITR were increasing with increase in temperature in all neat solvents investigated. The solubility of ITR was obtained highest in Transcutol (9.80×10−4) followed by DMSO (8.79×10−4), PEG-400 (4.62×10−4), EA (3.35×10−4), ethanol (4.84×10−5), n-butanol (4.46×10−5), IPA (3.58×10−5), PG (2.12×10−5), EG (9.85×10−6) and water (8.12×10−8) at T=318.2K. The solubilities of ITR were obtained in similar magnitude in Transcutol and DMSO, PEG-400 and EA and ethanol, IPA and n-butanol. The results of “apparent thermodynamic analysis” showed an “endothermic and entropy-driven dissolution” of ITR in each solvent evaluated.

Biopharmaceutical Properties of Tubeimoside-1: A Cytotoxic Amphipathic Cyclic Bisdesmoside

Background: Biopharmaceutical properties of tubeimoside-1, a cytotoxic amphipathic cyclic bisdesmoside, were evaluated to search for the usefulness of tubeimoside-1. Methods: Using tubeimoside-1, the solubilizing activity to itraconazole, effect on oral absorption of itraconazole in rats, stability in aqueous solution and intestinal homogenate, cytotoxicity to Caco- 2 cells, and membrane permeability across rat intestine and Caco-2 cell monolayers were evaluated. Concentrations of tubeimoside-1 were analyzed by LC-MS. Results: The solubility of itraconazole was 38.0 μg/mL in water containing 2.5% propylene glycol. Tubeimoside-1 and hydroxypropyl-β-cyclodextrin at a concentration of 10% increased itraconazole solubility to 6.5 mg/mL and 0.72 mg/mL, respectively. In rats, coadministration of tubeimoside-1 (10%) significantly increased the oral absorption of itraconazole, however, the enhancing effect was almost half of hydroxypropyl-β-cyclodextrin (10%). Tubeimoside-1 was gradually degraded under acidic condition and in S9 fraction of intestinal mucosal homogenates. The cytotoxicity of tubeimoside-1 was observed in Caco-2 cells. The membrane permeability of tubeimoside-1 was almost negligible in rat intestine in situ and Caco-2 cell monolayers in vitro. Conclusions: Greater solubilizing activity and biodegradability of tubeimoside-1, in addition to cytotoxicity, were observed. Further study is necessary to search for the usefulness of tubeimoside-1 as a strong solubilizer by forming inclusion complex with lipophilic compounds.