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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.

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.

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.

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.

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. .

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 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.

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.

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.

Silybin (SBN) is a major active constituent of silymarin, a mixture of flavonoids found in fruits and seeds of milk thistle. The aim of this study was to describe a simple bioanalytical method for quantifying SBN in rat plasma. A simple protein deproteinization procedure with acetonitrile (ACN) was employed for plasma sample preparation. A reversed column and gradient elution of a mobile phase (mixture of phosphate buffer (pH 5.0) and ACN) were used for chromatographic separation. The selectivity, linearity (50–5000 ng/mL), precision, accuracy, recovery, matrix effect, and stability for this method were validated as per the current Food and Drug Administration (FDA) guidelines. Our method for SBN was applied to a comparative pharmacokinetic study on four different commercial silymarin products. This in vivo rat study demonstrated that product #4 significantly enhanced the relative oral bioavailability of SBN, as compared to product #1–3. Therefore, the bioanalytical method proposed herein could serve as a promising alternative for preclinical pharmacokinetic studies on silymarin products and, by extension, clinical use after partial modification and validation.

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

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.

In this study, colloidal silica microparticles containing solubilizing excipient were prepared using the spray-drying process to enhance dissolution and oral absorption of lercanidipine hydrochloride. Several measurements including scanning electron microscopy, powder X-ray diffraction, particle size determination, in vitro dissolution, and pharmacokinetic study were conducted in rats. Among the tested solubilizing excipients, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) dramatically enhanced the solubility of lercanidipine hydrochloride through micelle solubilization. In addition, TPGS-colloidal silica microparticles at the ratio of 1:10:10 (drug:TPGS:colloidal silica) showed rapid dissolution rate in all dissolution media and displayed higher area under the curve and maximum plasma concentration values compared with raw lercanidipine hydrochloride. Therefore, amorphous TPGS-colloidal silica microparticles fabricated using the spray-drying process have great potential in the clinical application of lercanidipine hydrochloride.

The aim of this study was to measure the mole fraction solubility of dronedarone hydrochloride in six pure solvents across a temperature range of 298.15–323.15 K. The experimental solubility of dronedarone hydrochloride correlated with the Apelblat equation. The maximum mole fraction solubility of dronedarone hydrochloride was observed to be 0.119 in methanol at 323.15 K followed by ethanol (3.62 × 10− 2 at 323.15 K), 1-propanol (1.59 × 10− 2 at 323.15 K), 1-butanol (8.05 × 10− 3 at 323.15 K), 2-propanol (2.93 × 10− 3 at 323.15 K), and water (6.11 × 10− 5 at 323.15 K). Based on these results, dronedarone hydrochloride can be considered freely soluble in methanol, soluble in ethanol, and slightly soluble in 1-propanol, 2-propanol, 1-butanol, and water. These data could be important for the recrystallization and formulation development of dronedarone hydrochloride.

The solubility of trans-resveratrol in a solvent of primary alcohols (methanol, ethanol, n-propanol, n-butanol) + dichloromethane prepared at various mass fractions was measured at different temperatures (283.15–303.15 K) under atmospheric pressure. The solubility profile of trans-resveratrol in the solvent mixture was markedly dependent on temperature and solvent composition. The solubility increased as temperature and the mass fraction of the primary alcohol increased. The maximum solubility in each solvent mixture was in the following order: ethanol > methanol > n-propanol > n-butanol. The mass fraction of the primary alcohol reached the highest solubility at 1.0, and the slope gradually decreased as the mass fraction increased. Several computational models, such as van't Hoff, modified Apelblat, simplified CNIBS/R-K, Jouyban–Acree, Jouyban–Acree–van't Hoff, Jouyban–Acree–modified Apelblat, Ma, and Sun models were employed to analyze the experimental solubility data. The dissolution of trans-resveratrol in the primary alcohol + dichloromethane mixture was confirmed to be endothermic and spontaneous according to the obtained thermodynamic parameters. The solubility data for the primary alcohol + dichloromethane binary mixtures obtained herein could be used to obtain the solvent composition that can dissolve the drug and specific excipient. Therefore, experimental solubility data and computational models for trans-resveratrol could be employed in future formulation studies, such as in the design and development of dosage forms.

The solubility of bisacodyl at 288.15–308.15 K was determined by solid-liquid equilibrium in fourteen solvents commonly used in pharmaceutical production. The lowest solubility is in water, and the highest is in N-methyl-2-pyrrolidone (NMP) and other solvents that have high dielectric constants and large dipole moments. According to the Kamlet-Taft linear solvation energy relationship model, the solubility of bisacodyl decreases with increasing hydrogen bond acidity (α) of the solvent. Experimental solubility data for the fourteen mono solvents and NMP + water binary mixtures were fitted to various theoretical models. In all considered cases, the dissolution of bisacodyl is endothermic and spontaneous. Based on solubility data in the NMP + water binary mixtures, water and NMP were respectively used as antisolvent and solvent to prepare bisacodyl nanosuspensions using liquid antisolvent precipitation. A nanosuspension with mean particle size below 100 nm can be prepared by adjusting the concentration of bisacodyl in NMP and the mass fraction of NMP in the mixed solvent. These solubility data and parametric models established for bisacodyl in mono solvents and mixtures could be very useful for the purification, crystallization, particle size control, as well as dosage form development of bisacodyl.

In this study, glimepiride and l -arginine (GA) binary mixtures at various molar ratios were prepared to evaluate whether they could improve the poor water solubility and dissolution characteristics of glimepiride. It was shown that glimepiride and arginine form a eutectic mixture, a type of crystalline solid dispersions, at a 1:1 M ratio and eutectic temperature of 426.9 K using a phase diagram constructed using differential scanning calorimetry (DSC) and thermo-microscopy. The preserved characteristic powder X-ray diffraction (PXRD) patterns and infrared (IR) spectra of each material in those of GA binary mixtures confirmed the formation of eutectic mixture without molecular interaction in solid state. The formation of GA eutectic mixture (GAEM) resulted in the improvement of solubility through pH modification and the intermolecular interaction of glimepiride and l -arginine in aqueous mediums, thereby wettability and dissolution rate of glimepiride were also enhanced. The intermolecular interaction between glimepiride and l -arginine at a 1:1 stoichiometry of the complex in solution state was identified by phase solubility, stoichiometric determination, and solution state nuclear magnetic resonance (NMR) spectroscopy. Specific molecular interactions such as hydrogen bonding and hydrophobic interaction were suggested as main mechanisms of GA complexation in solution. Therefore, this study concludes that the GAEM could be an effective way to improve the solubility and dissolution rate of glimepiride.

Self-emulsifying drug delivery systems (SEDDSs) are a vital strategy to enhance the bioavailability (BA) of formulations of poorly water-soluble compounds. However, these formulations have certain limitations, including in vivo drug precipitation, poor in vitro in vivo correlation due to a lack of predictive in vitro tests, issues in handling of liquid formulation, and physico-chemical instability of drug and/or vehicle components. To overcome these limitations, which restrict the potential usage of such systems, the supersaturable SEDDSs (su-SEDDSs) have gained attention based on the fact that the inclusion of precipitation inhibitors (PIs) within SEDDSs helps maintain drug supersaturation after dispersion and digestion in the gastrointestinal tract. This improves the BA of drugs and reduces the variability of exposure. In addition, the formulation of solid su-SEDDSs has helped to overcome disadvantages of liquid or capsule dosage form. This review article discusses, in detail, the current status of su-SEDDSs that overcome the limitations of conventional SEDDSs. It discusses the definition and range of su-SEDDSs, the principle mechanisms underlying precipitation inhibition and enhanced in vivo absorption, drug application cases, biorelevance in vitro digestion models, and the development of liquid su-SEDDSs to solid dosage forms. This review also describes the effects of various physiological factors and the potential interactions between PIs and lipid, lipase or lipid digested products on the in vivo performance of su-SEDDSs. In particular, several considerations relating to the properties of PIs are discussed from various perspectives.

The purpose of the present study was to fabricate ezetimibe-hydroxypropyl cellulose (HPC) solid dispersion nanoparticles with enhanced dissolution and oral bioavailability using the supercritical antisolvent (SAS) process. We investigated the influence of SAS process parameters (pressure, temperature, and solute concentration) on the formation of ezetimibe-HPC solid dispersion particles. Physico-chemical properties of solid dispersion nanoparticles were characterized by scanning electron microscopy, differential scanning calorimeter, powder X-ray diffraction, a particle size analyzer, and measurements of the specific surface area. The mean particle size of ezetimibe-HPC solid dispersions could be controlled by the solute concentration. Physico-chemical analysis demonstrated that ezetimibe is amorphous in all solid dispersions. The dissolution rate of the solid dispersion nanoparticles was inversely proportional to the mean particle size. Ezetimibe administered in the form of 150.6-nm HPC solid dispersion nanoparticles demonstrated rapid dissolution of up to 95 % of the total amount within 10 min, as well as higher oral bioavailability than the drug introduced in the physical mixture. We also observed 3.2- and 2.0-fold increases in Cmax and AUC0→24 h values, respectively, for ezetimibe administered in the nanoparticle form compared to the drug within the physical mixture. Therefore, these results demonstrated that dissolution and oral absorption of ezetimibe can be enhanced by formulating it in the form of amorphous HPC solid dispersion nanoparticles manufactured using the SAS process.

The aim of this study was to investigate the effects of various parameters at each control strategy in drug product degradation on the stability of pemetrexed in injectable aqueous solution. A forced degradation study confirmed that oxidation is the main mechanism responsible for the degradation of pemetrexed in aqueous solutions. As control strategies, the antioxidant levels, drug concentration, pH of the control formulation, dissolved oxygen (DO) levels in the control process, and headspace oxygen levels in the control packaging were varied, and their effects on the stability of pemetrexed were evaluated. Sodium sulfite was found to be particularly effective in preventing the color change, and N-acetylcysteine (NAC) had a significant effect in preventing chemical degradation. The sulfite and NAC were found to stabilize pemetrexed in the aqueous solution by acting as sacrificial reductants. A pH below 6 caused significant degradation. The stability of pemetrexed in the solution increased as the concentration of the drug increased from 12.5 to 50 mg/mL. In addition, the DO levels in the solution were controlled by nitrogen purging, and the oxygen levels in headspace were controlled by nitrogen headspace, which also had significant positive effects in improving the stability of the pemetrexed solution, thus, it was confirmed that molecular oxygen is involved in the rate-limiting oxidation step. Based on these results obtained by observing the effects of various control strategies, the optimal formulation of an injectable solution of pemetrexed is suggested as follows: sodium sulfite at 0.06 mg/mL, as an antioxidant for prevention of color change, NAC at 1.63 mg/mL, as an antioxidant for prevention of chemical degradation, pH range 7&ndash, 8, DO levels below 1 ppm, and headspace oxygen levels below 1%. In conclusion, it can be suggested that this study, which includes well-designed control strategies, can lead to a better understanding of the complex degradation mechanism of pemetrexed, thus, it can lead to the development of an injectable solution formulation of pemetrexed, with improved stability.

The aim of this study was to develop a novel valsartan-loaded spray-dried emulsion based on hydroxypropylmethyl cellulose (HPMC) with enhanced oral absorption. The valsartan-loaded redispersible dry emulsion was prepared by using a high-pressure homogenization and spray-drying process with water, Capryol 90, HPMC, and different surfactants, based on the results of the solubility study. The spray-dried emulsions formed small and homogeneous emulsions with a mean droplet emulsion size ranging from 133.5 to 152.5nm at the dispersion state in water. The valsartan-loaded redispersible dry emulsion with HPMC/poloxamer 407 showed enhanced pH-independent valsartan release, resulting in a dramatically enhanced oral bioavailability of valsartan compared to the raw material and commercial product. Therefore, a formulation strategy using the redispersible dry emulsion with HPMC/poloxamer 407 is very effective for the development of a new dosage form containing valsartan.

In this study, the mole-fraction solubility data for telmisartan in dichloromethane + primary alcohol (methanol, ethanol, n-propanol or n-butanol) mixtures were measured at five different temperatures by employing a solid-liquid equilibrium using the shake-flask technique. In addition, the melting temperature and enthalpy of telmisartan were determined by differential scanning calorimetry, while powder X-ray diffraction analysis was used to evaluate the crystal form of telmisartan obtained before and after the solubility experiments. The solid state characterization confirmed no transformation of telmisartan into polymorphs. The solvent synergistic effect was observed in all binary mixtures. In particular, the telmisartan solubility in the mass fraction values of dichloromethane (w) of 0.8 at 298.15 K was found to be approximately 90.77 and 4.98 times higher than that in pure methanol and pure dichloromethane, respectively. The experimental solubility data for telmisartan were correlated and fitted to the van't Hoff, modified Apelblat, simplified CNIBS/R-K, Jouyban-Acree, Jouyban-Acree-van't Hoff, Jouyban-Acree-Apelblat, Ma, and Sun models. The thermodynamic parameters, such as the dissolution enthalpy (∆H°), Gibbs free energy (∆G°), and dissolution entropy (∆S°), confirmed that the dissolution of telmisartan in the mixtures was an endothermic process. Furthermore, dichloromethane and primary alcohol mixtures (w = 0.8) were used as the solvent in the preparation of telmisartan nanoparticles using the supercritical antisolvent (SAS) technique. The smallest particle size (630.8 nm) of the telmisartan nanoparticle obtained from a solvent mixture of dichloromethane and methanol was obtained. Results confirmed that the solubility data and estimated equations for telmisartan in the dichloromethane + primary alcohol mixtures with a strong synergistic solvation are useful in research and development for the purification and preparation of nanoparticles as well as in future studies on telmisartan to design and develop dosage forms.

In recent years, various polymorphic forms have been identified, including solvates of carvedilol. In this study, the solubility values of a thermodynamically stable form (Form I) of carvedilol in acetone, 1-butanol, dichloromethane, ethanol, ethyl acetate, glycerol, methanol, 1-propanol, 2-propanol, propylene glycol, polyethylene glycol (PEG) 400, and tetrahydrofuran were measured at temperatures ranging from 288.15 K to 308.15 K through a solid-liquid equilibrium by using the shake-flask technique. The solubility of carvedilol was lowest in glycerol and greatest in PEG 400, followed by tetrahydrofuran. Based on KAT-LSER model analysis, the sensitivity of the solute-solvent interaction was higher than the solvent-solvent interaction. The specific hydrogen bonding interactions were more important than nonspecific dipolarity/polarizability interactions. The experimentally determined solubility data of carvedilol was well regressed by the modified Apelblat model and the Buchowski-Ksiazczak λh model. The dissolution process of carvedilol was endothermic and spontaneous in the experimental temperature range. Tetrahydrofuran was used as the solvent for the preparation of carvedilol nanoparticles using supercritical antisolvent precipitation. The average particle size of carvedilol nanoparticles (550.8–903.5 nm) was varied using the initial drug concentration in tetrahydrofuran. The solubility data and estimated equations for carvedilol (Form I) in the twelve pure solvents require research and development for the purification and production of micro/nanoparticles.

Process simulation using mathematical modeling tools is becoming more common in the pharmaceutical industry. A mechanistic model is a mathematical modeling tool that can enhance process understanding, reduce experimentation cost and improve product quality. A commonly used mechanistic modeling approach for powder is the discrete element method (DEM). Most pharmaceutical materials have powder or granular material. Therefore, DEM might be widely applied in the pharmaceutical industry. This review focused on the basic elements of DEM and its implementations in pharmaceutical manufacturing simulation. Contact models and input parameters are essential elements in DEM simulation. Contact models computed contact forces acting on the particle-particle and particle-geometry interactions. Input parameters were divided into two types—material properties and interaction parameters. Various calibration methods were presented to define the interaction parameters of pharmaceutical materials. Several applications of DEM simulation in pharmaceutical manufacturing processes, such as milling, blending, granulation and coating, were categorized and summarized. Based on this review, DEM simulation might provide a systematic process understanding and process control to ensure the quality of a drug product.

In this study, the solid-liquid equilibrium of rebamipide was determined in pure methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, acetone, acetonitrile, ethyl acetate, glycerol, polyethylene glycol (PEG) 400, propylene glycol, and water over the temperature range from 288.15 K to 308.15 K by using the shake-flask method. The mole fraction solubility of rebamipide was highest in PEG 400, followed by propylene glycol, ethanol, and methanol, and lowest in water. Analysis using the KAT-LSER model revealed that the solvent-solute interactions related to hydrogen bond formation and nonspecific dipolarity/polarizability of solvent resulted in the increased solubility of rebamipide. In contrast, the solubility of rebamipide decreased as the self-cohesiveness of the solvent increased. Based on the curve fitting and correlation results, the experimental solubility data of rebamipide in twelve solvents were described mathematically by using the modified Apelblat model. The dissolution process of rebamipide in all twelve solvents was endothermic and spontaneous. From the solubility data, ethanol and methanol were selected as the most suitable solvents, and rebamipide particles with a mean particle size of 1 μm were prepared by using a supercritical antisolvent process. The experimental solubility data and mathematically correlated equations of rebamipide estimated in this work may be useful for studies on the crystallization process of the final step of rebamipide synthesis, for the purification rebamipide of pharmaceutical applications, and the preformulation and formulation development stages for rebamipide dosage forms.

The aim of the present study was to investigate the effect of Soluplus® on the solubility of atorvastatin calcium and to develop a solid dispersion formulation that can improve the oral bioavailability of atorvastatin calcium. We demonstrated that Soluplus® increases the aqueous solubility of atorvastatin calcium. Several solid dispersion formulations of atorvastatin calcium with Soluplus® were prepared at various drug : carrier ratios by spray drying. Physicochemical analysis demonstrated that atorvastatin calcium is amorphous in each solid dispersion, and the 2 : 8 drug : carrier ratio provided the highest degree of sustained atorvastatin supersaturation. Pharmacokinetic analysis in rats revealed that the 2 : 8 dispersion significantly improved the oral bioavailability of atorvastatin. This study demonstrates that spray-dried Soluplus® solid dispersions can be an effective method for achieving higher atorvastatin plasma levels.

This study was undertaken to improve the solubility and dissolution of a poorly water-soluble drug, celecoxib, by surface modification with a hydrophilic polymer and a surfactant by using a spray-drying technique. Based on the preliminary solubility tests, hydroxypropylmethyl cellulose (HPMC) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were selected as the polymer and the surfactant, respectively. A novel surface-modified celecoxib microparticle was successfully fabricated using a spray-drying process with water, HPMC, and TPGS, and without the use of an organic solvent. The physicochemical properties of the surface-modified celecoxib microparticle were characterized using scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), a particle size analyzer, and contact angle determination. The formulation with drug/HPMC/TPGS at the weight ratio of 1:0.5:1.5 was determined to be the most effective composition in the preparation of the surface-modified celecoxib microparticle, based on the results of wettability, solubility, and dissolution studies. We found that the surface modification of microparticles with HPMC and TPGS can be an effective formulation strategy for new dosage forms of poorly water-soluble active pharmaceutical ingredients (APIs) to provide higher solubility and dissolution.

The objective of this study was to develop lercanidipine–hydroxypropylmethyl cellulose (HPMC) nanoparticles with high oral bioavailability. The lercanidipine–HPMC nanoparticles with/without surfactants were manufactured using a supercritical antisolvent (SAS) process. Gelucire 44/14, poloxamer 407, and d -α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were evaluated as surfactants. Spherical lercanidipine–HPMC nanoparticles with a mean particle size less than 400 nm were successfully prepared using a SAS process. The dissolution and oral bioavailability of lercanidipine was significantly increased by addition of surfactants. Especially lercanidipine–HPMC nanoparticles with TPGS showed a 2.47-fold higher oral bioavailability than raw material. Furthermore, the dissolution efficiency was strongly correlated to the in vivo Cmax and AUC0 → 24 h. Therefore, the preparation of HPMC nanoparticles with TPGS using a SAS process is a highly effective formulation strategy for enhanced oral bioavailability of lercanidipine.