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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.

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.

Eun-Sol Ha,1 In-hwan Baek,2 Jin-Wook Yoo,1 Yunjin Jung,1 Min-Soo Kim1 1College of Pharmacy, Pusan National University, 2College of Pharmacy, Kyungsung University, Busan, Republic of Korea Abstract: The present study was carried out to develop an oral formulation of pranlukast hemihydrate with improved dissolution and oral bioavailability using a surface-modified microparticle. Based on solubility measurements, surface-modified pranlukast hemihydrate microparticles were manufactured using the spray-drying method with hydroxypropylmethyl cellulose, sucrose laurate, and water and without the use of an organic solvent. The hydrophilicity of the surface-modified pranlukast hemihydrate microparticle increased, leading to enhanced dissolution and oral bioavailability of pranlukast hemihydrate without a change in crystallinity. The surface-modified microparticles with an hydroxypropylmethyl cellulose/sucrose laurate ratio of 1:2 showed rapid dissolution of up to 85% within 30 minutes in dissolution medium (pH 6.8) and oral bioavailability higher than that of the commercial product, with approximately 2.5-fold and 3.9-fold increases in area under the curve (AUC0→12 h) and peak plasma concentration, respectively. Therefore, the surface-modified microparticle is an effective oral drug delivery system for the poorly water-soluble therapeutic pranlukast hemihydrate. Keywords: solubility, wettability, sucrose laurate, cellulose

The aim of this study was to develop celecoxib-polyvinylpyrrolidone (PVP) solid dispersion nanoparticles with and without surfactant using the supercritical antisolvent (SAS) process. The effect of different surfactants such as gelucire 44/14, poloxamer 188, poloxamer 407, Ryoto sugar ester L1695, and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) on nanoparticle formation and dissolution as well as oral absorption of celecoxib-PVP K30 solid dispersion nanoparticles was investigated. Spherical celecoxib solid dispersion nanoparticles less than 300 nm in size were successfully developed using the SAS process. Analysis by differential scanning calorimetry and powder X-ray diffraction showed that celecoxib existed in the amorphous form within the solid dispersion nanoparticles fabricated using the SAS process. The celecoxib-PVP-TPGS solid dispersion nanoparticles significantly enhanced in vitro dissolution and oral absorption of celecoxib relative to that of the unprocessed form. The area under the concentration-time curve (AUC0→24 h) and peak plasma concentration (Cmax) increased 4.6 and 5.7 times, respectively, with the celecoxib-PVP-TPGS formulation. In addition, in vitro dissolution efficiency was well correlated with in vivo pharmacokinetic parameters. The present study demonstrated that formulation of celecoxib-PVP-TPGS solid dispersion nanoparticles using the SAS process is a highly effective strategy for enhancing the bioavailability of poorly water-soluble celecoxib.

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.

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.

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.

In-hwan Baek,1,* Eun-Sol Ha,2,* Jin-Wook Yoo,2 Yunjin Jung,2 Min-Soo Kim21College of Pharmacy, Kyungsung University, 2College of Pharmacy, Pusan National University, Busan, Republic of Korea*These authors contributed equally to this workAbstract: In this study, a gelatin microparticle-containing self-microemulsifying formulation (SMF) was developed using a spray-drying method to enhance the oral delivery of the poorly water-soluble therapeutic dutasteride. The effect of the amount of gelatin and the type and amount of hydrophilic additives, namely, Gelucire® 44/14, poloxamer 407, sodium lauryl sulfate, Soluplus®, Solutol™ HS15, and D-α-tocopheryl polyethylene glycol 1000 succinate, on the droplet size, dissolution, and oral absorption of dutasteride from the SMF was investigated. Upon dispersion of the gelatin microparticle-containing SMF in water after spray-drying, the mean droplet size of the aqueous dispersion was in the range of 110–137 nm. The in vitro dissolution and recrystallization results showed that gelatin could be used as a solid carrier and recrystallization inhibitor for the SMF of dutasteride. Furthermore, combination of the gelatin microparticle-containing SMF and Soluplus enhanced the dissolution properties and oral absorption of dutasteride. The results of our study suggest that the gelatin microparticle-containing SMF in combination with Soluplus could be useful to enhance the oral absorption of dutasteride.Keywords: dissolution, solubility, bioavailability, dutasteride

The present study aimed to investigate the effect of Eudragit® E/HCl (E-SD) on the degradation of sirolimus in simulated gastric fluid (pH 1.2) and to develop a new oral formulation of sirolimus using E-SD solid dispersions to enhance oral bioavailability. Sirolimus-loaded solid dispersions were fabricated by a spray drying process. A kinetic solubility test demonstrated that the sirolimus/E-SD/TPGS (1/8/1) solid dispersion had a maximum solubility of 196.7 μg/mL within 0.5 h that gradually decreased to 173.4 μg/mL after 12 h. According to the dissolution study, the most suitable formulation was the sirolimus/E-SD/TPGS (1/8/1) solid dispersion in simulated gastric fluid (pH 1.2), owing to enhanced stability and degree of supersaturation of E-SD and TPGS. Furthermore, pharmacokinetic studies in rats indicated that compared to the physical mixture and sirolimus/HPMC/TPGS (1/8/1) solid dispersion, the sirolimus/E-SD/TPGS (1/8/1) solid dispersion significantly improved oral absorption of sirolimus. E-SD significantly inhibited the degradation of sirolimus in a dose-dependent manner. E-SD also significantly inhibited the precipitation of sirolimus compared to hydroxypropylmethyl cellulose (HPMC). Therefore, the results from the present study suggest that the sirolimus-loaded E-SD/TPGS solid dispersion has great potential in clinical applications.

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.