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There is a growing interest in the use of dry powder inhalers (DPIs) for administering high-dose drugs with low potency to the lungs as carrier-free formulations to treat both local pulmonary and systemic diseases. The main purpose of particle engineering and formulation design in the development of high-dose DPIs without carrier is to reduce the cohesive property of the particles and overcome the large inter-particulate interaction while enhancing powder dispersion and lung delivery upon inhalation and maintaining stability without agglomeration during storage. In particular, the cohesive property of high-dose DPIs can induce several physiological and physicochemical problems that must be improved. This review describes various particle surface modification methods, including sophisticated particle engineering (such as micronization) and formulation techniques, which are utilized to overcome the problems associated with high-dose DPIs. Currently, changing the cohesive property of particles through various micronization processes and improving the surface properties of particles through co-processing with limited excipients have been mainly used as efficient methods for particle surface modification. Using these technological principles, novel approaches have been attempted to develop inhalable drug particles, such as high-dose antibiotics and high-value biopharmaceuticals. The research on high-dose DPIs has expanded widely, and consequently, the drugs that received recent regulatory approvals have been successful based on the research results. Thus, it is expected that the next generation of DPIs will be safer and have higher therapeutic efficacy beyond the limitations of traditional high-dose DPIs.

Dry powder inhaler (DPI) formulations are highly efficient in pulmonary drug delivery because devices for their delivery are portable and aerosolization does not require a propellant. The performance of DPIs depends on various physical properties of particles for their manufacture, including aerodynamic diameter, density, particle shape, surface composition, morphology, roughness, and energy. Among these, particle surface properties are the most important factors in determining the interparticulate interactions, which affect the aerosolization efficiency, physicochemical stability, and subsequent in vivo lung deposition efficiency. For a better understanding of the correlation between surface properties and the performance of DPI, there is the need to perform surface characterization of the DPI. This review focuses on analysis of the technology used in the design of DPIs. Thus, the surface crystallinity and polymorphism, surface energy, surface roughness, and changes in solid-state properties of the particles used in DPI formulation will be determined. The commonly used solid-state techniques may not be appropriate for the characterization of DPIs because their detection is mainly limited to the fine changes in physicochemical surface properties such as partial amorphous contents generated on the drug particle surface. Thus, sophisticated technologies with higher detection limits and superior spatial resolutions are required for in-depth characterization. Data obtained from surface analytical techniques can lead to an in-depth understanding of inhalable dry powder at the particle surface. This can provide unique predictive insights into rationally designing inhalable particles with optimal surface properties to provide optimal aerosolization performance for a given DPI formulation.

In this study, supercritical fluid-assisted spray-drying (SA-SD) was applied to achieve the micronization of fenofibrate particles possessing surface-active additives, such as d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), sucrose mono palmitate (Sucroester 15), and polyoxyethylene 52 stearate (Myrj 52), to improve the pharmacokinetic and pharmacodynamic properties of fenofibrate. For comparison, the same formulation was prepared using a spray-drying (SD) process, and then both methods were compared. The SA-SD process resulted in a significantly smaller mean particle size (approximately 2 μm) compared to that of unprocessed fenofibrate (approximately 20 μm) and SD-processed particles (approximately 40 μm). There was no significant difference in the effect on the particle size reduction among the selected surface-active additives. The microcomposite particles prepared with surface-active additives using SA-SD exhibited remarkable enhancement in their dissolution rate due to the synergistic effect of comparably moderate wettability improvement and significant particle size reduction. In contrast, the SD samples with the surface-active additives exhibited a decrease in dissolution rate compared to that of the unprocessed fenofibrate due to the absence of particle size reduction, although wettability was greatly improved. The results of zeta potential and XPS analyses indicated that the surface-active additive coverage on the surface layer of the SD-processed particles with a better wettability was higher than that of the SA-SD-processed composite particles. Additionally, after rapid depletion of hydrophilic additives that were excessively distributed on the surfaces of SD-processed particles, the creation of a surface layer rich in poorly water-soluble fenofibrate resulted in a decrease in the dissolution rate. In contrast, the surface-active molecules were dispersed homogeneously throughout the particle matrix in the SA-SD-processed microparticles. Furthermore, improved pharmacokinetic and pharmacodynamic characteristics were observed for the SA-SD-processed fenofibrate microparticles compared to those for the SD-processed fenofibrate particles. Therefore, the SA-SD process incorporating surface-active additives can efficiently micronize poorly water-soluble drugs and optimize their physicochemical and biopharmaceutical characteristics.

Micro-/nanoparticle formulations containing drugs with or without various biocompatible excipients are widely used in the pharmaceutical field to improve the physicochemical and clinical properties of the final drug product. Among the various micro-/nanoparticle production technologies, emulsion-based particle formation is the most widely used because of its unique advantages such as uniform generation of spherical small particles and higher encapsulation efficiency (EE). For this emulsion-based micro-/nanoparticle technology, one of the most important factors is the extraction efficiency associated with the fast removal of the organic solvent. In consideration of this, a technology called supercritical fluid extraction of emulsions (SFEE) that uses the unique mass transfer mechanism and solvent power of a supercritical fluid (SCF) has been proposed to overcome the shortcomings of several conventional technologies such as solvent evaporation, extraction, and spray drying. This review article presents the main aspects of SFEE technology for the preparation of micro-/nanoparticles by focusing on its pharmaceutical applications, which have been organized and classified according to several types of drug delivery systems and active pharmaceutical ingredients. It was definitely confirmed that SFEE can be applied in a variety of drugs from water-soluble to poorly water-soluble. In addition, it has advantages such as low organic solvent residual, high EE, desirable release control, better particle size control, and agglomeration prevention through efficient and fast solvent removal compared to conventional micro-/nanoparticle technologies. Therefore, this review will be a good resource for determining the applicability of SFEE to obtain better pharmaceutical quality when researchers in related fields want to select a suitable manufacturing process for preparing desired micro-/nanoparticle drug delivery systems containing their active material.

Dutasteride, an analog of testosterone, a 5α-reductase inhibitor is widely used in the treatment of moderate to severe symptomatic benign prostatic hyperplasia. The aim of this study was to compare the pharmacokinetic characteristics of dutasteride in beagle dogs after oral administration of a conventional soft gelatin capsule (Avodart®) and a novel solid-supersaturatable soft-microemulsifying drug delivery system (SMEDDS) tablet. In this comparative dissolution study, the dissolution of dutasteride was pH-independent for both formulations. Noncompartmental analysis and modeling approaches were carried out to determine the pharmacokinetic parameters of dutasteride. Approximately 90% of the drug dissolved in all media within 15 min, indicating that there was little difference in the dissolution rate of the solid-supersaturatable SMEDDS tablets and that of the commercial soft gelatin capsules. Using t test analysis, no statistically significant difference was detected in the pharmacokinetic parameters of the two formulations. The test/reference geometric mean ratios were 1.087 (90% confidence intervals 0.8529–1.3854) for the area under the plasma concentration versus time curve from 0 to the last time point (48 h) with a measurable concentration and 1.094 (90% confidence intervals 0.8909–1.3454) for maximum plasma concentration. Unfortunately, the bioequivalent criterium (0.8–1.25) was not met due to the small sample size, but the results of this study suggest a possible bioequivalence of dutasteride in the two formulations. Based on the results of this study, the development of a tablet dosage form of dutasteride using a solid-supersaturatable SMEDDS should be considered for humans.

Diethylene glycol monoethyl ether (DEGEE) is produced via the O-alkylation of ethanol with two ethylene oxide units, followed by distillation. It has a long history of safe use in food and personal-care products, and is used as an effective strong solubilizer in oral, topical, transdermal, and injectable human and veterinary pharmaceutical products. It has been used as a pharmaceutical solvent for many years under the trade name transcutol. DEGEE, a hydroalcoholic solvent, is gaining interest as a penetration/permeation enhancer, solubilizer, and surfactant for drug delivery systems. The physicochemical properties of DEGEE, the solubility data for drugs in DEGEE or DEGEE-water mixtures, and the applications of DEGEE in the solubilization of poorly water-soluble drugs are summarized in this review. DEGEE is a promising excipient as a solubilizer for many pharmaceutical products with enhanced drug absorption via oral, parenteral, and topical administration, as well as cosmetic products.

The solubility of trans-resveratrol in the solvent mixture of Transcutol HP + water was determined experimentally by using the solid-liquid equilibrium method within the temperatures range 288.15–313.15 K. The mole fraction solubility of trans-resveratrol increased with increasing temperature of the mixture or fraction of Transcutol HP. The highest mole fraction solubility (1.61 × 10−1) of trans-resveratrol was observed in pure Transcutol HP at 313.15 K, whereas the lowest value (1.29 × 10−6) was found in pure water at 288.15 K. The measured solubility data were correlated with van't Hoff, Jouyban-Acree, and Jouyban-Acree-van't Hoff computational models. Thermodynamic analysis suggested an endothermic and spontaneous dissolution behavior of trans-resveratrol in the studied solvents. When the formulation composed of hydroxypropyl methylcellulose/polyvinylpyrrolidone K12/sodium lauryl sulfate (1.0%/0.5%/0.1%, w/w) was used, the formulation prepared at 0.1 mass fraction resulted in an average particle size of 234.8 to 754.6 nm and the smallest particle size was observed for the formulation prepared using concentration of drug solution with 0.025. It was confirmed that the nanosuspension was produced at the ratio determined to be suitable on the basis of the measured solubility data. Therefore, the experimental solubilities and computational model can be useful for formulation studies using trans-resveratrol.

Objective Eperisone hydrochloride is used in the treatment of musculoskeletal disorders as a muscle relaxant via blocking of calcium channels. In this study, we aimed to investigate the within-subject variability (CVwR) of reference eperisone formulation for highly-variable drugs and to perform bioequivalence study of two oral formulations (sugar- and film-coated tablets) of eperisone hydrochloride 50 mg in healthy subjects by reference-replicated crossover study. Materials and methods 36 healthy Korean male subjects were recruited, and 33 subjects completed the study. A randomized, single-dose, open-label, three-way, three-sequence, reference formulation-replicated, crossover bioequivalence study was conducted to determine the bioequivalence of eperisone. Blood samples were collected before dosing and at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after dosing. The plasma concentration of eperisone was determined using liquid chromatography-tandem mass spectrometry. Results The CVwR of eperisone reference product was 33.17% for AUCt and 50.21% for Cmax. The acceptance limit for Cmax was scaled to 0.6984 - 1.4319 according to CVwR. The 90% confidence intervals for the test/reference geometric mean ratio were 0.8275 - 1.1692 for AUCt and 0.7587 - 1.1652 for Cmax, which were within the accepted bioequivalence limits. Single oral doses of eperisone hydrochloride 50 mg were generally well tolerated in healthy adult subjects in this study. Conclusion The newly developed film-coated tablet can be interchanged with the original sugar-coated tablet of eperisone. In addition, the reference scaling methods are more effective and economical than the classical method for assessing BE of HVDs. .

This study was aimed to develop a fixed dose combination (FDC) tablet containing a low dose of evogliptin tartrate (6.87 mg) for immediate release combined with a high dose (1000 mg) of sustained-release (SR) metformin HCl appropriate for once daily dosing the treatment of type 2 diabetes. To prepare the FDC tablets, an active coating was used in this study, whereby evogliptin tartrate film was layered on a matrix core tablet containing metformin HCl. To overcome the problem caused by a low-dose drug in combination with a relatively large matrix tablet containing high-dose drug, it was also aimed to confirm the formulation and coating operation for satisfactory content uniformity, and to describe the chemical stability during storage of the amorphous active coating layer formulation in relation to molecular mobility. Furthermore, the in vitro release and in vivo pharmacokinetic profiles of metformin HCl and evogliptin tartrate in the FDC active coating tablet were compared to those of the commercially marketed reference drugs, Diabex XR® (Daewoong, Seoul, Korea) containing metformin HCl and Suganon® (Donga ST, Seoul, Korea) containing evogliptin tartrate. In conclusion, the newly developed FDC active coating tablet in this study was confirmed to be bioequivalent to the reference marketed products in beagle dogs, with satisfactory content uniformity and stability.

A fixed dose combination (FDC) bilayer tablet, consisting of high-dose metformin HCl in a sustained release layer and low-dose evogliptin tartrate in an immediate release layer, was developed based on a quality by design (QbD) approach. To implement QbD approach, the bilayer tableting process parameters judged as high risk through risk analysis were optimized by a central composite face-centered design as a design of experiment (DOE) methodology. Using DOE, the optimized conditions of the tableting process for drug products that satisfy the established quality target product profiles were obtained. The content uniformity of low-dose evogliptin tartrate in the optimized bilayer tablet prepared on a large scale was confirmed by at-line transmittance Raman spectroscopy as a process analytical technology. In addition, the in vitro drug release and in vivo pharmacokinetic studies showed that metformin HCl and evogliptin tartrate in the bilayer tablet is bioequivalent to those of the respective reference drugs. Furthermore, the physicochemical stability of the optimized bilayer tablet during storage under long-term and accelerated conditions was also confirmed. Therefore, it can be concluded that the QbD approach is an effective way to develop a new FDC bilayer tablet that is easy to scale up for successful commercialization.

In this study, we designed amorphous solid dispersions based on Eudragit E/HCl (neutralized Eudragit E using hydrochloric acid) to maximize the dissolution of trans-resveratrol. Solid-state characterization of amorphous solid dispersions of trans-resveratrol was performed using powder X-ray diffraction, scanning electron microscopy, and particle size measurements. In addition, an in vitro dissolution study and an in vivo pharmacokinetic study in rats were carried out. Among the tested polymers, Eudragit E/HCl was the most effective solid dispersion for the solubilization of trans-resveratrol. Eudragit E/HCl significantly inhibited the precipitation of trans-resveratrol in a pH 1.2 dissolution medium in a dose-dependent manner. The amorphous Eudragit E/HCl solid dispersion at a trans-resveratrol/polymer ratio of 10/90 exhibited a high degree of supersaturation without trans-resveratrol precipitation for at least 48 h by the formation of Eudragit E/HCl micelles. In rats, the absolute oral bioavailability (F%) of trans-resveratrol from Eudragit E/HCl solid dispersion (10/90) was estimated to be 40%. Therefore, trans-resveratrol-loaded Eudragit E/HCl solid dispersions prepared by spray drying offer a promising formulation strategy with high oral bioavailability for developing high-quality health supplements, nutraceutical, and pharmaceutical products.

Orlistat, an anti-obesity drug, has two critical issues—the first is its low efficacy due to low water solubility and the second is side effects such as oily spotting due to its lipase inhibition. The present study was designed to propose a solution using a formulation with mesoporous silica to simultaneously overcome two issues. Orlistat was loaded onto mesoporous silica by the supercritical melt-adsorption (SCMA) method, using carbon dioxide (CO2). Various types of mesoporous silica were used as adsorbents, and the effects of the pore volume, diameter and particle size of mesoporous silica on the pharmaceutical characteristics were evaluated by various solid-state characterization methods and in vitro and in vivo studies in relation to pharmacological efficacy and the improvement of side effects. The results showed that the pore volume and diameter determine loadable drug amount inside pores and crystallinity. The dissolution was significantly influenced by crystallinity, pore diameter and particle size, and the inhibition of lipase activity was in proportion to the dissolution rate. In vivo studies revealed that the serum triglyceride (TG) concentration was significantly decreased in the group administered amorphous orlistat-loaded Neuisilin®UFL2 with the highest in vitro dissolution rate and lipase activity inhibition in comparison to the commercial product. Furthermore, oily spotting tests in rats revealed that undigested oil was adsorbed onto mesoporous silica after orlistat was released in the gastro-intestinal tract, and it correlated with in vitro result that oil adsorption capacity was dependent on the surface area of empty mesoporous silica. Therefore, it was concluded that mesoporous silica type plays a major role in determining the pharmaceutical characteristics of orlistat formulation prepared using SCMA with CO2 for improving the low solubility and overcoming the side effects.

The glimepiride/L-arginine (GA) binary systems were prepared at various molar ratios by using a supercritical antisolvent (SAS) process. For comparison, the GA system was also prepared by physical mixing (PM), melt quenching (MQ), and solvent evaporation (SE) methods. Analyses by DSC and PXRD showed that only the GA binary mixture at 1:1 M ratio prepared by the SAS process was a pure co-amorphous mixture with an excellent content uniformity. On the other hand, GA mixture prepared by PM and SE were not pure co-amorphous systems and contained crystalline eutectic mixture, and MQ method at 170 °C induced the decrease in drug content due to decomposition of glimepiride. The positive deviation of experimentally measured glass transition temperature (Tg) compared to predicted Tg by the Gordon Taylor equation suggests specific molecular interactions between glimepiride and L-arginine in solid-state GA co-amorphous (GACA) mixture. The intermolecular interactions between glimepiride and L-arginine in GACA system were characterized by FT-IR and solid-state NMR analyses. Improved glimepiride dissolution rate of GACA formulation were confirmed using the solubility test, contact angle measurement, and dissolution test. Furthermore, the evaluation of pharmacodynamic hypoglycemic effect demonstrated that GACA prepared by the SAS process significantly improved the therapeutic efficacy of glimepiride.

In this study, the solubility data of the solid–liquid equilibrium of efinaconazole in acetone, acetonitrile, 1-butanol, diethylene glycol monoethyl ether (DEGME), dichloromethane, dimethylformamide (DMF), ethanol, ethyl acetate, methanol, 1-propanol, 2-propanol, propylene glycol, polyethylene glycol 400 (PEG 400), tetrahydrofuran, water, and three binary mixed solvents (DEGME + water, ethanol + water, and PEG 400 + water) were measured at five different temperatures (288.15–308.15 K) using the shake-flask technique. The solubility of efinaconazole in the fifteen mono solvents was highest in dichloromethane, followed by tetrahydrofuran, DMF, and acetone, and lowest in water. In the binary mixtures, the solubility of efinaconazole increased with an increase in the DEGME, ethanol, and PEG 400 mass fraction at a defined temperature, respectively. According to the Kamlet-Taft linear solvation energy relationship model analysis, the self-cohesiveness of the solvent indicating solvent–solvent interaction was the main factor affecting the solubility of efinaconazole, which resulted in decreased solubility. Nine models, including the van’t Hoff, modified Apelblat, Buchowski-Ksiazczak λh, simplified CNIBS/R-K, Jouyban-Acree, Jouyban-Acree-van’t Hoff, Jouyban-Acree-modified Apelblat, Sun, and Ma models, were used to regress the experimental solubility data of efinaconazole in fifteen mono solvents and the three binary mixtures. In addition, the dissolution thermodynamic properties of efinaconazole were estimated using a modified van’t Hoff analysis. The experimental solubility data and correlated models of efinaconazole in fifteen mono solvents and the three binary mixed solvents could be useful for the crystallization, purification, and development of liquid dosage forms such as topical solutions during drug development.

A solid–liquid equilibrium technique was used to measure the solubility of oxcarbazepine in a mono-solvent and a solvent mixture in the temperature range of 288.15–308.15 K under atmospheric pressure. Oxcarbazepine in N-methyl-2-pyrrolidone (NMP) showed the highest solubility. The KAT-LSER model was applied to determine solvent effect on the solubility of oxcarbazepine in mono-solvents at 298.15 K; the dipolarity–polarizability and cohesive energy density, as the Hildebrand solubility parameter, of the solvent had a greater effect on oxcarbazepine solubility than other parameters. The solubility results of oxcarbazepine in the mono-solvents and mixed (NMP + water) solvents were correlated by applying various models. The oxcarbazepine dissolution in the mono-solvents and mixed (NMP + water) solvents was endothermic and spontaneous. Oxcarbazepine nanosuspensions were prepared based on these solubility results of oxcarbazepine in a mono-solvent and mixed (NMP + water) solvent; the average particle size of all oxcarbazepine nanosuspensions was smaller than 200 nm. The experimental and calculated solubility results of oxcarbazepine may be utilized in drug development through the application of solubilization techniques to increase the bioavailability of poorly water-soluble drugs.

In this study, the solubility of lifitegrast was measured at various temperatures ranging from 288.15–308.15 K in four green solvents + water mixtures through a solid-liquid equilibrium via the shake-flask method. The experimental mole fraction solubility of lifitegrast increased with increasing temperature. The mole fraction solubility of lifitegrast increased as the mass fraction of green solvents increased at a constant temperature, except in diethylene glycol monoethyl ether (DEGME) + water mixtures. The mole fraction solubility of lifitegrast in neat polyethylene glycol 400 (PEG 400), which was approximately 33,600 times higher than in neat water at 298.15 K, was the highest solubility overall binary composition. Five models, including the van’t Hoff model, modified Apelblat model, simplified CNIBS/R-K model, Sun model, and Ma model were used to correlate and fit the experimental solubility data of lifitegrast in four green solvents + water mixtures. The thermodynamic parameters during the dissolution process of lifitegrast in four green solvents + water mixtures, such as enthalpy (ΔH°), Gibbs free energy (ΔG°), and entropy (ΔS°), were estimated using the modified van’t Hoff equation. The solubility data and correlation models could be useful for developing formulations during drug product development, such as eye drops based on these results.

The purpose of this study was to evaluate the effects of cyclodextrins (CyDs) to stabilize exnatide in the microencapsulation medium and influence on the pharmaceutical properties of exenatide loaded PLGA microsphere. Three CyDs interacted differently with exenatide by investigation using ultraviolet, fluorescence and circular dichroism spectroscopy. The binding affinities of CyDs to the hydrophobic tryptophan residues of exenatide increased in following order: α-CyD β-CyD γ-CyD. It was consistent with orders of W/O interface stabilizing and anti-adsorption effects. However, the stabilizing effect of β-CyD on liquid-state and freeze-drying of exenatide was greater than that of γ-CyD. The negative values of ΔH

The solubilities of cilostazol in aqueous solutions containing polyethylene glycol 4000 (PEG 4000), polyethylene glycol 6000 (PEG 6000), polyvinylpyrrolidone K30 (PVP K30), and poly(1-vinylpyrrolidone-co-vinyl acetate) (PVP/VA) are measured at temperatures ranging from 298.15 to 318.15 K. It increased with the increase in the hydrophilic carrier concentration and temperature. PVP/VA was the most effective polymer to solubilize cilostazol. The transfer Gibbs free energy (Δ tr G °) and enthalpy (Δ tr H °) values were negative, indicating that the transfer of cilostazol from only water to an aqueous hydrophilic polymer solution is spontaneous and energetically favorable. Furthermore, the Δ tr G ° and Δ tr H ° values decreased with the increase in the hydrophilic polymer concentration, indicating that solubilization is more favorable with the increase in the hydrophilic polymer concentrations. In particular, the Δ tr G ° values considerably decreased for PVP/VA compared to PEG 4000, PEG 6000, and PVP K30. This result indicated that PVP/VA is an effective solubilizing additive for developing oral solid formulations of cilostazol.

In this study, the solubility of sarpogrelate hydrochloride in methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, acetone, acetonitrile, and tetrahydrofuran was determined at temperatures ranging from 288.15 K to 308.15 K under atmospheric pressure by using a solid-liquid equilibrium method. The obtained experimental solubility data of sarpogrelate hydrochloride were correlated with the modified Apelblat model, Buchowski-Ksiazczak λ h model and ideal model. The mole fraction solubility of sarpogrelate hydrochloride in the selected pure solvents increased with the increase in temperature. The maximum mole fraction solubility of sarpogrelate hydrochloride was observed in methanol (1.16 × 10 − 2 at 308.15 K), followed by that in ethanol (4.76 × 10 − 3 at 308.15 K), 1-propanol (6.98 × 10 − 3 at 308.15 K), 1-butanol (4.12 × 10 − 4 at 308.15 K), acetonitrile (3.13 × 10 − 4 at 308.15 K), acetone (2.75 × 10 − 4 at 308.15 K), 2-propanol (1.86 × 10 − 4 at 308.15 K), and tetrahydrofuran (9.92 × 10 − 5 at 308.15 K). The correlation and curve fitting results indicated good correlation of the experimental solubility data of sarpogrelate hydrochloride with the modified Apelblat model. Therefore, the experimental solubility and correlation equations established in this study can be useful in the crystallization/purification, preformulation, and formulation stages of sarpogrelate hydrochloride production or testing in laboratories and related industries.

In this study, the solubility of oxcarbazepine in pure methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, acetone, acetonitrile, and tetrahydrofuran was analysed across the temperature range of 288.15–308.15 K under atmospheric pressure by using a solid-liquid equilibrium method. The experimental values obtained data were correlated using the modified Apelblat model at each temperature. The mole fraction solubility of oxcarbazepine in all eight pure solvents increased gradually in a temperature-dependent manner. The highest mole fraction solubility of 3.08 × 10−3 at 308.15 K was observed for tetrahydrofuran, followed by acetone (1.82 × 10−3 at 308.15 K), acetonitrile (1.22 × 10−3 at 308.15 K), methanol (1.11 × 10−3 at 308.15 K), ethanol (6.17 × 10−4 at 308.15 K), 1-butanol (6.17 × 10−4 at 308.15 K), 1-propanol (6.16 × 10−4 at 308.15 K), and 2-propanol (4.13 × 10−4 at 308.15 K). The experimental solubility in all solvents correlated well with that calculated using the modified Apelblat equation across the temperature range of (288.15–308.15) K. Therefore, the experimental solubility and correlation equations established in this study could be useful during the crystallization/purification, pre-formulation, and formulation stages of oxcarbazepine production in laboratories and related industries.

In this study, the solubility of pranlukast hemihydrate in methanol, ethanol, 1-propanol, 2-propanol, and 1-butanol was determined at temperatures ranging from 298.15 to 323.15 K by a solid-liquid equilibrium method. The measured solubility data of pranlukast hemihydrate were correlated with the modified Apelblat and Van't Hoff models. The maximum mole fraction solubility of pranlukast hemihydrate in 1-butanol was observed to be 26.39 × 10 − 5 at 323.15 K, followed by that in 1-propanol (9.63 × 10 − 5 at 323.15 K), ethanol (6.18 × 10 − 5 at 323.15 K), 2-propanol (5.71 × 10 − 5 at 323.15 K), and methanol (3.96 × 10 − 5 at 323.15 K). Interestingly, the solubility of pranlukast hemihydrate increases with a decrease in dielectric constant of the primary alcohols. The measured solubility data of pranlukast hemihydrate correlated well with the modified Apelblat equation. In addition, thermodynamic analysis indicated an endothermic and spontaneous dissolution behavior of pranlukast hemihydrate in the studied solvents. Therefore, these experimental solubilities and correlation equations can be useful in the purification/crystallization and formulation study of pranlukast hemihydrate in laboratories and related industries.

The aim of this study was to investigate the effects of various stabilizers on the encapsulation efficiency and release of exenatide-loaded PLGA (poly(lactic-co-glycolic acid)) microspheres prepared by the water-in-oil-in-water (W/O/W) solvent evaporation (SE) method. It was shown that the stabilizers affected exenatide stability in aqueous solutions, at water/dichloromethane interfaces, on PLGA surfaces, or during freeze-thawing and freeze-drying procedures. Sucrose predominantly reduces instability generated during freeze-thawing and freeze-drying. Phenylalanine prevents the destabilization at the water&ndash, dichloromethane (DCM) interface through decreased adsorption. Poloxamer 188 enhances stability in aqueous solutions and prevents adsorption to PLGA. Proline and lysine decrease adsorption on PLGA surfaces. Fourier transform infra-red spectroscopy (FT-IR) was used to find the molecular interaction of additives with exenatide or PLGA. Additives used in stability assessments were then added stepwise into the inner or outer water phase of the W/O/W double emulsion, and exenatide-loaded microspheres were prepared using the solvent evaporation method. The effect of each stabilizer on the encapsulation efficiency and release behavior of microspheres correlated well with the stability assessment results, except for the negative effect of poloxamer 188. Particle size analysis using laser diffractometry, scanning electron microscopy (SEM), water vapor sorption analysis, differential scanning calorimetry (DSC), and circular dichroism (CD) spectroscopy were also employed to characterize the prepared exenatide-loaded PLGA microsphere. This study demonstrated that an adequate formulation can be obtained by the study about the effect of stabilizers on peptide stability at the preformulation step. In addition, it can help to overcome various problems that can cause the destabilization of a peptide during the microsphere-manufacturing process and sustained drug release.

The purpose of this study was to develop a resveratrol nanosuspension with enhanced oral bioavailability, based on an understanding of the formulation and process parameters of nanosuspensions and using a quality by design (QbD) approach. Particularly, the antisolvent method, which requires no solvent removal and no heating, is newly applied to prepare resveratrol nanosuspension. To ensure the quality of the resveratrol nanosuspensions, a quality target product profile (QTPP) was defined. The particle size (z-average, d90), zeta potential, and drug content parameters affecting the QTPP were selected as critical quality attributes (CQAs). The optimum composition obtained using a 3-factor, 3-level Box&ndash, Behnken design was as follows: polyvinylpyrrolidone vinyl acetate (10 mg/mL), polyvinylpyrrolidone K12 (5 mg/mL), sodium lauryl sulfate (1 mg/mL), and diethylene glycol monoethyl ether (DEGEE, 5% v/v) at a resveratrol concentration of 5 mg/mL. The initial particle size (z-average) was 46.3 nm and the zeta potential was &minus, 38.02 mV. The robustness of the antisolvent process using the optimized composition conditions was ensured by a full factorial design. The dissolution rate of the optimized resveratrol nanosuspension was significantly greater than that of the resveratrol raw material. An in vivo pharmacokinetic study in rats showed that the area under the plasma concentration versus time curve (AUC0&ndash, 12h) and the maximum plasma concentration (Cmax) respectively, than those of the resveratrol raw material. Therefore, the prepara values of the resveratrol nanosuspension were approximately 1.6- and 5.7-fold higher,tion of a resveratrol nanosuspension using the QbD approach may be an effective strategy for the development of a new dosage form of resveratrol, with enhanced oral bioavailability.

We created composite nanoparticles containing hydrophilic additives using a supercritical antisolvent (SAS) process to increase the solubility and dissolution properties of trans-resveratrol for application in oral and skin delivery. Physicochemical properties of trans-resveratrol-loaded composite nanoparticles were characterized. In addition, an in vitro dissolution&ndash, permeation study, an in vivo pharmacokinetic study in rats, and an ex vivo skin permeation study in rats were performed. The mean particle size of all the composite nanoparticles produced was less than 300 nm. Compared to micronized trans-resveratrol, the trans-resveratrol/hydroxylpropylmethyl cellulose (HPMC)/poloxamer 407 (1:4:1) nanoparticles with the highest flux (0.792 &mu, g/min/cm2) exhibited rapid absorption and showed significantly higher exposure 4 h after oral administration. Good correlations were observed between in vitro flux and in vivo pharmacokinetic data. The increased solubility and flux of trans-resveratrol generated by the HPMC/surfactant nanoparticles increased the driving force on the gastrointestinal epithelial membrane and rat skin, resulting in enhanced oral and skin delivery of trans-resveratrol. HPMC/surfactant nanoparticles produced by an SAS process are, thus, a promising formulation method for trans-resveratrol for healthcare products (owing to their enhanced absorption via oral administration) and for skin application with cosmetic products.