Controlling the Solubility, Release Rate and Permeation of Riluzole with Cyclodextrins.

Riluzole (RLZ), a sodium channel-blocking benzothiazole anticonvulsant BCS class II drug, is very slightly soluble in aqueous medium. To improve aqueous solubility and modulate dissolution rate and membrane permeability, complex formation of RLZ with two cyclodextrin, α-cyclodextrin (α-CD) and sulfobutylether-ß-cyclodextrin (SBE-ß-CD), was studied. The stability constants demonstrated a greater affinity of SBE-ß-CD towards RLZ compared to α-CD. A solubility growth of 1.7-fold and 3.7-fold with α-CD and SBE-ß-CD, respectively, was detected in the solutions of 1% cyclodextrins and accompanied by the permeability reduction. For 1% CD solutions, several biopolymers (1% w/v) were tested for the membrane permeability under static conditions. The synergistic positive effect of α-CD and polymer on the solubility accompanied by unchanged permeability was revealed in RLZ/α-CD/PG, RLZ/α-CD/PEG400, and RLZ/α-CD/PEG1000 systems. Solid RLZ/CD complexes were prepared. Dynamic dissolution/permeation experiments for the solid samples disclosed the characteristic features of the release processes and permeation rate through different artificial membranes. The maximal permeation rate was determined across the hydrophilic semi-permeable cellulose membrane followed by the lipophilic PermeaPad barrier (model of intestinal and buccal absorption) and polydimethylsiloxane-polycarbonate membrane (simulating transdermal delivery way). Different mode of the permeation between the membranes was estimated and discussed.

Mechanistic Insight in Permeability through Different Membranes in the Presence of Pharmaceutical Excipients: A Case of Model Hydrophobic Carbamazepine.

The present study reports the effects of two pharmaceutical excipients of differing natures-non-ionic surfactant pluronic F127 (F127) and anionic sulfobutylether-ß-cyclodextrin (SBE-ß-CD)-on the permeation of the model compound, carbamazepine (CBZ). The permeability coefficients of CBZ at three concentrations of the excipients were measured through two different artificial barriers: hydrophilic cellulose membrane (RC) and lipophilic polydimethylsiloxane-polycarbonate membrane (PDS). The equilibrium solubility of CBZ in F127 and SBE-ß-CD solutions was determined. The micellization, complexation, and aggregation tendencies were investigated. Systemically increasing the solubility and the reduction of permeation upon the excipients' concentration growth was revealed. The quantitative evaluation of the permeability tendencies was carried out using a Pratio parameter, a quasi-equilibrium mathematical mass transport model, and a correction of permeability coefficients for the free drug concentration ("true" permeability values). The results revealed the mutual influence of the excipient properties and the membrane nature on the permeability variations.

Cyclodextrin's Effect on Permeability and Partition of Nortriptyline Hydrochloride.

Cyclodextrin-based delivery systems have been intensively used to improve the bioavailability of drugs through the modification of their pharmaceutically relevant properties, such as solubility, distribution and membrane permeation. The present work aimed to disclose the influence of HP-ß-CD and SBE-ß-CD on the distribution and permeability of nortriptyline hydrochloride (NTT•HCl), a tricyclic antidepressant drug. To this end, the distribution coefficients in the 1-octanol/buffer and n-hexane/buffer model systems and the coefficients of permeability through the cellulose membrane and lipophilic PermeaPad barrier were determined at several cyclodextrin concentrations. The results demonstrated a dramatic decrease in both the distribution and the permeability coefficients as the cyclodextrin concentration rose, with the decrease being more pronounced in SBE-ß-CD due to the charge-charge attraction and electrostatic interactions between NTT and SBE-ß-CD. It is these interactions that were shown to be responsible for the greater value of the constant of NTT's association with SBE-ß-CD than that with HP-ß-CD. The findings of this study revealed similar trends in the 1-octanol/buffer 6.8 pH distribution and permeability through the PermeaPad barrier in the presence of CDs. These results were attributed to the determinative role of the distribution coefficient (serving as a descriptor) in permeation through the PermeaPad barrier modeling the lipophilic nature of biological barriers.

Polymorphism of Carbamazepine Pharmaceutical Cocrystal: Structural Analysis and Solubility Performance.

Polymorphism is a common phenomenon among single- and multicomponent molecular crystals that has a significant impact on the contemporary drug development process. A new polymorphic form of the drug carbamazepine (CBZ) cocrystal with methylparaben (MePRB) in a 1:1 molar ratio as well as the drug's channel-like cocrystal containing highly disordered coformer molecules have been obtained and characterized in this work using various analytical methods, including thermal analysis, Raman spectroscopy, and single-crystal and high-resolution synchrotron powder X-ray diffraction. Structural analysis of the solid forms revealed a close resemblance between novel form II and previously reported form I of the [CBZ + MePRB] (1:1) cocrystal in terms of hydrogen bond networks and overall packing arrangements. The channel-like cocrystal was found to belong to a distinct family of isostructural CBZ cocrystals with coformers of similar size and shape. Form I and form II of the 1:1 cocrystal appeared to be related by a monotropic relationship, with form II being proven to be the thermodynamically more stable phase. The dissolution performance of both polymorphs in aqueous media was significantly enhanced when compared with parent CBZ. However, considering the superior thermodynamic stability and consistent dissolution profile, the discovered form II of the [CBZ + MePRB] (1:1) cocrystal seems a more promising and reliable solid form for further pharmaceutical development.

Modulation of Distribution and Diffusion through the Lipophilic Membrane with Cyclodextrins Exemplified by a Model Pyridinecarboxamide Derivative.

The main aims of the study were to disclose the influence of the structure on the solubility, distribution and permeability of the parent substances, iproniazid (IPN), isoniazid (INZ) and isonicotinamide (iNCT), at 310.2 K and to evaluate how the presence of cyclodextrins (2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and methylated ß-cyclodextrin (M-ß-CD)) affects the distribution behavior and diffusion properties of a model pyridinecarboxamide derivative, iproniazid (IPN). The following order of decreasing the distribution and permeability coefficients was estimated: IPN > INZ > iNAM. A slight reduction of the distribution coefficients in the 1-octanol/buffer pH 7.4 and n-hexane/buffer pH 7.4 systems (more pronounced in the first system) was revealed. The extremely weak IPN/cyclodextrins complexes were estimated from the distribution experiments: KC(IPN/HP-ß-CD) > KC(IPN/M-ß-CD). The permeability coefficients of IPN through the lipophilic membrane-the PermeaPad barrier-were also measured with and without cyclodextrins in buffer solution. Permeability of iproniazid was increased in the presence of M-ß-CD and reduced by HP-ß-CD.

Virtual Screening, Structural Analysis, and Formation Thermodynamics of Carbamazepine Cocrystals.

In this study, the existing set of carbamazepine (CBZ) cocrystals was extended through the successful combination of the drug with the positional isomers of acetamidobenzoic acid. The structural and energetic features of the CBZ cocrystals with 3- and 4-acetamidobenzoic acids were elucidated via single-crystal X-ray diffraction followed by QTAIMC analysis. The ability of three fundamentally different virtual screening methods to predict the correct cocrystallization outcome for CBZ was assessed based on the new experimental results obtained in this study and data available in the literature. It was found that the hydrogen bond propensity model performed the worst in distinguishing positive and negative results of CBZ cocrystallization experiments with 87 coformers, attaining an accuracy value lower than random guessing. The method that utilizes molecular electrostatic potential maps and the machine learning approach named CCGNet exhibited comparable results in terms of prediction metrics, albeit the latter resulted in superior specificity and overall accuracy while requiring no time-consuming DFT computations. In addition, formation thermodynamic parameters for the newly obtained CBZ cocrystals with 3- and 4-acetamidobenzoic acids were evaluated using temperature dependences of the cocrystallization Gibbs energy. The cocrystallization reactions between CBZ and the selected coformers were found to be enthalpy-driven, with entropy terms being statistically different from zero. The observed difference in dissolution behavior of the cocrystals in aqueous media was thought to be caused by variations in their thermodynamic stability.

Revisiting the Solubility-Permeability Relationship with Hydrophobic Drug Umifenovir in Pluronic Solutions: Impact of pH and Co-Solvent.

This study describes the influence of pluronic F-127 (F-127) and ethanol (EtOH) on the solubility of umifenovir (UMF) in buffer solutions of pH 2.0 and pH 7.4, and its permeability through cellulose membranes. A 44.4-fold greater UMF solubility in acidic medium as compared to an alkaline one was estimated at 310.15 K. The concentration of UMF in the saturated solution was enhanced by the interaction with F-127 micelles. The combined positive effect of EtOH and F-127 on the solubility was estimated. The aggregation number of F-127 micelles in the presence of 10% and 20% ethanol appeared to be reduced by 2.1-fold and 4.1-fold, respectively, as compared to buffer pH 7.4. The presence of ethanol in buffer pH 7.4 solution provided better solvent conditions but inhibited the formation of F-127 micelles. The impact of UMF on the aggregation number of F-127 was not pronounced and was expressed only by a slight increase of 1 and 3 units in 10% and 20% EtOH, respectively. According to the values of zeta potential, addition of EtOH reduced the stability of the system. The permeation of UMF in buffer pH 7.4 measured through the cellulose membrane MWCO 12-14 kDa was increased 1.4-fold by 10% EtOH. An increase in EtOH content to 20% reduced this effect to 1.2-fold. Decreasing effect of 1.5% F-127 on the permeability was inhibited by using 10% EtOH. The solution containing 1.5% F-127 and 10% EtOH was shown to be an advantageous system for UMF in view of the solubility-permeability balance. The authors suppose the findings of the study to be useful for the design of pharmaceutical formulations based on UMF antiviral drugs.

Influence of Co-amorphization on the Physical Stability and Dissolution Performance of an Anthelmintic Drug Flubendazole.

In this work, the co-amorphization approach was applied to flubendazole (FluBZ), resulting in the formation of two novel solid forms of FluBZ with l-phenylalanine (Phe) and l-tryptophan (Trp). A variety of physicochemical techniques have been used to describe new systems, including powder X-ray diffraction, thermal methods, infrared spectroscopy, and scanning electron microscopy. Co-amorphization has been shown to suppress crystallization tendency and considerably increase the shelf-life storage of amorphous flubendazole solid across a wide range of relative humidities. The dissolution behavior of the amorphous forms in biorelevant media at pH = 1.6, pH = 6.5, and 37 °C has been studied in terms of Cmax (maximum FluBZ concentration), Tmax (time to attain peak drug concentration), and AUC (concentration area under the curve during dissolution). At pH = 6.5, a continuous supersaturation and the highest AUC value of all examined systems were observed for the FluBZ-Phe (1:1) system. The phase solubility diagrams revealed that the reason for the better dissolution performance of FluBZ-Phe (1:1) at pH = 6.5 is a complexation between the components in a solution. This work highlights the applicability of co-amorphous systems in improving the physical stability and dissolution performance of drug compounds with poor biopharmaceutical characteristics.

Permeability of New Antifungal Fluconazole Derivatives through a Lipophilic Membrane: Experiment and Modeling.

Relationships between the structures of molecules and their properties form the basis of modern chemistry and lay the foundation for structure-based drug design. Being the main two determinants of bioavailability, solubility and permeability of drugs are widely investigated experimentally and predicted from physicochemical parameters and structural descriptors. In the present study, we measure the passive diffusion permeability of a series of new fluconazole derivatives with triazole and thiazolo-pyrimidine moieties connected by different linker bridges through the PermeaPad barrier-a relatively new biomimetic lipophilic membrane that has been increasingly used in recent years. The permeability coefficients of new derivatives are shown to be dependent both on the structure of the linker fragment and on the substituent in the phenyl ring of the thiazolo-pyrimidine moiety. The impact of the compound ionization state on the permeability is revealed. Reliable correlations of the permeability with the antifungal activity and distribution coefficient are found. In addition, the solubility-diffusion approach is shown to be able to successfully predict the permeability of the studied derivatives. The obtained results can be considered another step in the development of permeability databases and design of schemes for in vitro permeability prediction.

Correction: Volkova et al. Cyclodextrin's Effect on Permeability and Partition of Nortriptyline Hydrochloride. Pharmaceuticals 2023, 16, 1022.

In the original publication [...].

New Solid Forms of Nitrofurantoin and 4-Aminopyridine Salt: Influence of Salt Hydration Level on Crystal Packing and Physicochemical Properties.

The crystallization of the poorly soluble drug nitrofurantoin (NFT) with 4-aminopyridine (4AmPy) resulted in three multicomponent solid forms with different hydration levels: anhydrous salt [NFT+4AmPy] (1:1), salt monohydrate [NFT+4AmPy+H2O] (1:1:1), and salt tetrahydrate [NFT+4AmPy+H2O] (1:1:4). Each salt was selectively prepared by liquid-assisted grinding in the presence of acetonitrile or ethanol/water mixture at a specific composition. The NFT hydrated salts were characterized using single crystal X-ray diffraction. The [NFT+4AmPy+H2O] salt (1:1:1) crystallized as an isolated site hydrate, while the [NFT+4AmPy+H2O] salt (1:1:4) crystallized as a channel hydrate. The dehydration processes of the NFT salt hydrates were investigated using differential scanning calorimetry and thermogravimetric analysis. A powder dissolution experiment was carried out for all NFT multicomponent solid forms in pH 7.4 phosphate buffer solution at 37 °C.

Experimental Examination of Solubility and Lipophilicity as Pharmaceutically Relevant Points of Novel Bioactive Hybrid Compounds.

The important physicochemical properties of three novel bioactive hybrid compounds with different groups (-CH3, -F and -Cl) were studied, including kinetic and thermodynamic solubility in pharmaceutically relevant solvents (buffer solutions and 1-octanol) as well as partition coefficient in system 1-octanol/buffer pH 7.4. The aqueous solubility of these chemicals is poor and ranged from 0.67 × 10-4 to 1.98 × 10-3 mol·L-1. The compounds studied are more soluble in the buffer pH 2.0, simulating the gastrointestinal tract environment (by an order of magnitude) than in the buffer pH 7.4 modelling plasma of blood. The solubility in 1-octanol is significantly higher; that is because of the specific interactions of the compounds with the solvent. The prediction solubility behaviour of the hybrid compounds using Hansen's three-parameter approach showed acceptable results. The experimental solubility of potential drugs was successfully correlated by means of two commonly known equations: modified Apelblat and van't Hoff. The temperature dependencies of partition coefficients of new hybrids in the model system 1-octanol/buffer pH 7.4 as a surrogate lipophilicity were measured by the shake flask method. It was found that compounds demonstrated a lipophilic nature and have optimal values of partition coefficients for oral absorption. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than fluconazole. In addition, the thermodynamic aspects of dissolution and partition processes have been examined. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than the reference drug.

Synthesis, Neuroprotective Effect and Physicochemical Studies of Novel Peptide and Nootropic Analogues of Alzheimer Disease Drug.

Glutamate is an excitatory neurotransmitter in the nervous system. Excessive glutamate transmission can lead to increased calcium ion expression, related to increased neurotoxicity. Memantine is used for treating patients with Alzheimer's disease (AD) due to its protective action on the neurons against toxicity caused by over activation of N-methyl-D-aspartate receptors. Nootropics, also called "smart drugs", are used for the treatment of cognitive deficits. In this work, we evaluate the neuroprotective action of four memantine analogues of glycine derivatives, including glycyl-glycine, glycyl-glycyl-glycine, sarcosine, dimethylglycine and three conjugates with nootropics, modafinil, piracetam and picamilon. The new structural memantine derivatives improved cell viability against copper-induced neurotoxicity in APPswe cells and glutamate-induced neurotoxicity in SH-SY5Y cells. Among these novel compounds, modafinil-memantine, piracetam-memantine, sarcosine-memantine, dimethylglycine-memantine, and glycyl-glycine-memantine were demonstrated with good EC50 values of the protective effects on APPswe cells, accompanied with moderate amelioration from glutamate-induced neurotoxicity. In conclusion, our study demonstrated that novel structural derivatives of memantine might have the potential to develop promising lead compounds for the treatment of AD. The solubility of memantine analogues with nootropics and memantine analogues with glycine derivatives in buffer solutions at pH 2.0 and pH 7.4 simulating the biological media at 298.15 K was determined and the mutual influence of the structural fragments in the molecules on the solubility behavior was analyzed. The significative correlation equations relating the solubility and biological properties with the structural HYBOT (Hydrogen Bond Thermodynamics) descriptors were derived. These equations would greatly simplify the task of the directed design of the memantine analogues with improved solubility and enhanced bioavailability.

Formation Thermodynamics of Carbamazepine with Benzamide, Para-Hydroxybenzamide and Isonicotinamide Cocrystals: Experimental and Theoretical Study.

Formation thermodynamic parameters for three cocrystals of carbamazepine (CBZ) with structurally related coformers (benzamide (BZA), para-hydroxybenzamide (4-OH-BZA) and isonicotinamide (INAM)) were determined by experimental (cocrystal solubility and competitive reaction methods) and computational techniques. The experimental solubility values of cocrystal components at eutectic points and solubility product of cocrystals [CBZ + BZA], [CBZ + 4-OH-BZA], and [CBZ + INAM] in acetonitrile at 293.15 K, 298.15 K, 303.15 K, 308.15 K, and 313.15 K were measured. All the thermodynamic functions (Gibbs free energy, enthalpy, and entropy) of cocrystals formation were evaluated from the experimental data. The crystal structure of [CBZ + BZA] (1:1) cocrystal was solved and analyzed by the single crystal X-ray diffractometry. A correlation between the solubility products and pure coformers solubility values has been found for CBZ cocrystals. The relationship between the entropy term and the molecular volume of the cocrystal formation has been revealed. The effectiveness of the estimation of the cocrystal formation thermodynamic parameters, based on the knowledge of the melting temperatures of active pharmaceutical ingredients, coformers, cocrystals, as well as the sublimation Gibbs energies and enthalpies of the individual components, was proven. A new method for the comparative assessment of the cocrystal stability based on the H-bond propensity analysis was proposed. The experimental and theoretical results on the thermodynamic parameters of the cocrystal formation were shown to be in good agreement. According to the thermodynamic stability, the studied cocrystals can be arranged in the following order: [CBZ + 4-OH-BZA] > [CBZ + BZA] > [CBZ + INAM].

Another Move towards Bicalutamide Dissolution and Permeability Improvement with Acetylated ß-Cyclodextrin Solid Dispersion.

The complex formation of antiandrogen bicalutamide (BCL) with methylated (Me-ß-CD) and acetylated (Ac-ß-CD) ß-cyclodextrins was investigated in buffer solution pH 6.8. A two-fold strongly binding of BCL to Ac-ß-CD as compared to Me-ß-CD was revealed. The solid dispersion of BCL with Ac-ß-CD was prepared by the mechanical grinding procedure to obtain the complex in the solid state. The BCL/Ac-ß-CD complex was characterized by DSC, XPRD, FTIR, and SEM techniques. The effect of Ac-ß-CD in the BCL solid dispersions on the non-sink dissolution/permeation simultaneous processes was disclosed using the side-by-side diffusion cell with the help of the cellulose membrane. The elevated dissolution of the ground complex, as compared to the raw drug as well as the simple physical mixture, accompanied by the supersaturation was revealed. Two biopolymers-polyvinylpyrrolidone (PVP, Mn = 58,000) and hydroxypropylmethylcellulose (HPMC, Mn ~ 10,000)-were examined as the precipitation inhibitors and were shown to be useful in prolonging the supersaturation state. The BCL/Ac-ß-CD complex has the fastest dissolution rate in the presence of HPMC. The maximal concentration of the complex was achieved at a time of 20, 30, and 90 min in the pure buffer, with PVP and with HPMC, respectively. The effectiveness of the BCL dissolution (release) processes (illustrated by the AUCC(t) parameter) was estimated to be 7.8-, 5.8-, 3.0-, and 1.8-fold higher for BCL/Ac-ß-CD (HPMC), BCL/Ac-ß-CD (PVP), BCL/Ac-ß-CD (buffer), and the BCL/Ac-ß-CD physical mixture, respectively, as compared to the BCL_raw sample. The excipient gain factor (EGF), calculated for the dissolution of the BCL complex, was shown to be 2.6 in the presence of HPMC, which is 1.3-fold greater as compared to PVP. From the experimental dissolution results, it can be concluded that the formation of BCL ground complex with Ac-ß-CD enhances the dissolution rate of the compound. The permeation was also shown to be advantageous in the presence of the polymers, which was demonstrated by the elevated fluxes of BCL through the membrane. The comparison of the dissolution/permeation processes was illustrated and discussed. The conclusion was made that the presence of HPMC as a stabilizer of the supersaturation state is promising and seems to be a useful tool for the optimization of BCL pharmaceutical formulations manufacturing.

Simultaneous Improvement of Dissolution Behavior and Oral Bioavailability of Antifungal Miconazole via Cocrystal and Salt Formation.

Miconazole shows low oral bioavailability in humans due to poor aqueous solubility, although it has demonstrated various pharmacological activities such as antifungal, anti-tubercular and anti-tumor effects. Cocrystal/salt formation is one of the effective methods for solving this problem. In this study, different methods (liquid-assisted grinding, slurrying and lyophilization) were used to investigate their impact on the formation of the miconazole multicomponent crystals with succinic, maleic and dl-tartaric acids. The solid state of the prepared powder was characterized by differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopy. It was found that lyophilization not only promotes partial amorphization of both salts but also allows obtaining a new polymorph of the miconazole salt with dl-tartaric acid. The lyophilized salts compared with the same samples prepared by two other methods showed better dissolution rates but low stability during the studies due to rapid recrystallization. Overall, it was determined that the preparation method of multicomponent crystals affects the solid-state characteristics and miconazole physicochemical properties significantly. The in vivo studies revealed that the miconazole multicomponent crystals indicated the higher peak blood concentration and area under the curve from 0 to 32 h values 2.4-, 2.9- and 4.6-fold higher than the pure drug. Therefore, this study demonstrated that multicomponent crystals are promising formulations for enhancing the oral bioavailability of poorly soluble compounds.

Chiral Recognition R- and RS- of New Antifungal: Complexation/Solubilization/Dissolution Thermodynamics and Permeability Assay.

Novel potential antifungal of 1,2,4-triazole class have been synthesized as pure enantiomer (R-98) and racemic (RS-186). The effect of 2-hydroxypropyl-ß-cyclodextrin (CD) on the solubility and permeability of RS-186 and R-98 in terms of chiral recognition was investigated. Phase solubility studies were carried out at 4 temperatures in 0-0.05 M CD concentration range for pH 2.0 and pH 7.4. AL- and AL--type phase-solubility profiles were obtained for both compounds in pH 2.0 and pH 7.4. The racemic formed more stable complexes with CD as compared to R-isomer. Disclosing of chiral discrimination was facilitated using the approach based on the complex consideration of the derived complexation/solubilization/inherent dissolution thermodynamic functions, including the differential parameters between the racemic compound and R-enantiomer. The differences in the thermodynamic parameters determined by the chirality were discussed in terms of the driving forces of the processes and the main interactions of the compounds with CD in solution. The membrane permeability of both samples in the presence of CD was accessed in order to evaluate the specificity of enantioselective transport through the lipophilic membrane. The solubility/permeability interrelation was disclosed. The investigated compounds were classified as medium permeable in pure buffers and low permeable in the presence of 0.01 M CD. The obtained results can be useful for the design of pharmaceutical products in the form of liquid formulations based on the investigated substances.

Physicochemical Profile of Antiandrogen Drug Bicalutamide: Solubility, Distribution, Permeability.

The pharmacologically relevant physicochemical properties of the antiandrogen drug bicalutamide (BCL) have been determined for the first time. Solubility in aqueous solution, 1-octanol, n-hexane, and ethanol was measured by the shake flask method in the temperature range of 293.15−313.15 K. The compound was shown to be poorly soluble in aqueous medium and n-hexane; at the same time, an essentially higher solubility in the alcohols was revealed. The following order of molar solubility was determined: ethanol > 1-octanol > water ≈ n-hexane. The solubility was correlated with the Van't Hoff and Apelblat equations. Evaluation of the Hansen solubility parameters and the atomic group contribution approach of Hoftyzer and Van Krevelen demonstrated consistency with the experimental data and good potential adsorption of bicalutamide. The temperature dependences of the distribution coefficients in the 1-octanol/water and n-hexane/water two-phase systems were measured and discussed in the framework of the thermodynamic approach. The ∆logD parameter determined from the distribution experiment clearly demonstrated the preference of the lipophilic delivery pathways for the compound in the biological media. The overall thermodynamic analysis based on the solubility and distribution results of the present study and the sublimation characteristics published previously has been performed. To this end, the thermodynamic parameters of the dissolution, solvation, and transfer processes were calculated and discussed in view of the solute-solvent interactions. The permeation rate of BCL through the PermeaPad barrier was measured and compared with PAMPA permeability.

New Antifungal Compound: Impact of Cosolvency, Micellization and Complexation on Solubility and Permeability Processes.

Poor solubility of new antifungal of 1,2,4-triazole class (S-119)-a structural analogue of fluconazole in aqueous media was estimated. The solubility improvement using different excipients: biopolymers (PEGs, PVP), surfactants (Brij S20, pluronic F-127) and cyclodextrins (α-CD, ß-CD, 2-HP-ß-CD, 6-O-Maltosyl-ß-CD) was assessed in buffer solutions pH 2.0 and pH 7.4. Additionally, 2-HP-ß-CD and 6-O-Maltosyl-ß-CD were proposed as promising solubilizers for S-119. According to the solubilization capacity and micelle/water partition coefficients in buffer pH 7.4 pluronic F-127 was shown to improve S-119 solubility better than Brij S20. Among biopolymers, the greatest increase in solubility was shown in PVP solutions (pH 7.4) at concentrations above 4 w/v%. Complex analysis of the driving forces of solubilization, micellization and complexation processes matched the solubility results and suggested pluronic F-127 and 6-O-Maltosyl-ß-CD as the most effective solubilizing agents for S-119. The comparison of S-119 diffusion through the cellulose membrane and lipophilic PermeaPad barrier revealed a considerable effect of the lipid layer on the decrease in the permeability coefficient. According to the PermeaPad, S-119 was classified as a highly permeated substance. The addition of 1.5 w/v% CDs in donor solution moves it to low-medium permeability class.

Isavuconazole: Thermodynamic Evaluation of Processes Sublimation, Dissolution and Partition in Pharmaceutically Relevant Media.

A temperature dependence of saturated vapor pressure of isavuconazole (IVZ), an antimycotic drug, was found by using the method of inert gas-carrier transfer and the thermodynamic functions of sublimation were calculated at a temperature of 298.15 K. The value of the compound standard molar enthalpy of sublimation was found to be 138.1 ± 0.5 kJ·mol-1. The IVZ thermophysical properties-melting point and enthalpy-equaled 302.7 K and 29.9 kJ mol-1, respectively. The isothermal saturation method was used to determine the drug solubility in seven pharmaceutically relevant solvents within the temperature range from 293.15 to 313.15 K. The IVZ solubility in the studied solvents increased in the following order: buffer pH 7.4, buffer pH 2.0, buffer pH 1.2, hexane, 1-octanol, 1-propanol, ethanol. Depending on the solvent chemical nature, the compound solubility varied from 6.7 × 10-6 to 0.3 mol·L-1. The Hansen s approach was used for evaluating and analyzing the solubility data of drug. The results show that this model well-described intermolecular interactions in the solutions studied. It was established that in comparison with the van't Hoff model, the modified Apelblat one ensured the best correlation with the experimental solubility data of the studied drug. The activity coefficients at infinite dilution and dissolution excess thermodynamic functions of IVZ were calculated in each of the solvents. Temperature dependences of the compound partition coefficients were obtained in a binary 1-octanol/buffer pH 7.4 system and the transfer thermodynamic functions were calculated. The drug distribution from the aqueous solution to the organic medium was found to be spontaneous and entropy-driven.