Triamterene-β-cyclodextrin systems: Preparation,characterization and in vivo evaluation

The purpose of this research was to improve the solubility and therefore dissolution and bioavailability of triamterene, a poorly water soluble diuretic, by complexation with β-cyclodextrin. Triamterene has been reported to show low bioavailability after oral administration, with wide intersubject variation. This study presents the formulation of solid dispersions of triamterene with β-cyclodextrin—by cogrinding, kneading, and coevaporation, using low pH conditions—and their characterizations, evaluation of improvement in dissolution profiles, and in vivo advantage. Phase solubility studies indicated complex with possible stoichiometry of 1∶1 and a stability constant of 167.67M⁻¹. The solid dispersions were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance, x-ray diffraction, and differential scanning calorimetry studies. The characterization studies confirmed inclusion of the phenyl ring of triamterene within the nonpolar cavity of β-cyclodextrin in the coevaporate. Remarkable improvement in in vitro drug release profiles in 0.1 N HCl and pH 6.8 phosphate buffer was observed with all dispersions, especially the coevaporate. The coevaporate, when administered orally in rats, also exhibited improved in vivo activity, as measured by net sodium ion excretion, as compared with triamterene powder. Thus, coevaporation of the drug and β-cyclodextrin from acidified alcohol provide the optimum condition for inclusion complexation to give a binary system with remarkable improvement in in vitro drug release profile and in vivo performance.     

Improved Bioavailability of Poorly Water-Soluble Drug Curcumin in Cellulose Acetate Solid Dispersion

Curcumin (Cur), one of the most widely used natural active constituents with a great variety of beneficial biological and pharmacological activities, is a practically water-insoluble substance with a short biologic half-life. The aim of this study was to develop a sustained-release solid dispersion by employing water-insoluble carrier cellulose acetate for solubility enhancement, release control, and oral bioavailability improvement of Cur. Solid dispersions were characterized by solubility, in vitro drug release, Fourier transform infrared spectroscopy, X-ray diffractometry, and differential scanning calorimetry studies. The in vivo performance was assessed by a pharmacokinetic study. Solid-state characterization techniques revealed the amorphous nature of Cur in solid dispersions. Solubility/dissolution of Cur was enhanced in the formulations in comparison with pure drug. Sustained-release profiles of Cur from the solid dispersions were ideally controlled in vitro up to 12 h. The optimized formulation provided an improved pharmacokinetic parameter (C _max = 187.03 ng/ml, t _max = 1.95 h) in rats as compared with pure drug (C _max = 87.06 ng/ml, t _max = 0.66 h). The information from this study suggests that the developed solid dispersions successfully enhanced the solubility and sustained release of poorly water-soluble drug Cur, thus improving its oral bioavailability effectively.     

Formulation and Evaluation of Taste Masked Oral Reconstitutable Suspension of Primaquine Phosphate

The purpose of this research was to mask the intensely bitter taste of primaquine phosphate (PRM) and to formulate suspension powder (cachets) of the taste masked drug. Taste masking was done using beta-cyclodextrin. To characterize and formulate taste masked cachets of PRM, the 1:25 M physical mixture was selected based on bitterness score. Phase solubility studies, fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD) were performed to identify the physicochemical interaction between drug and carrier, hence its effect on dissolution. Cachets were evaluated for angle of repose, sedimentation characterization and pH. In vitro drug release studies for physical mixture and kneaded system were performed at pH, 1.2 and 6.8. Bitterness score was evaluated using gustatory sensation test. Phase solubility studies showed weak interaction between PRM and CD. The FTIR, DSC and XRPD studies indicated inclusion complexation in physical mixture and kneaded system. In addition, kneaded system and physical mixture exhibited better drug release at pH 1.2 and negligible effect at pH 6.8. Cachets prepared using physical mixture, (DS24), showed complete bitter taste masking and easy redispersibility. Taste evaluation of cachets in human volunteers rated tasteless with a score of 0 to DS24 and 3 to DS25. Thus, results conclusively demonstrated successful taste masking and formulation of cachets with taste masked drug.     

Physico-Chemical Characterization and In Vitro Dissolution Assessment of Clonazepam—Cyclodextrins Inclusion Compounds

The objectives of this research were to prepare and characterize inclusion complexes of clonazepam with β-cyclodextrin and hydroxypropyl-β-cyclodextrin and to study the effect of complexation on the dissolution rate of clonazepam, a water-insoluble lipid-lowering drug. The phase-solubility profiles with both cyclodextrins were classified as A_P-type, indicating the formation of 2:1 stoichiometric inclusion complexes. Gibbs free energy ( DG_tr^o ) \left( {\Delta {G_{tr}}^o} \right) values were all negative, indicating the spontaneous nature of clonazepam solubilization, and they decreased with increase in the cyclodextrins concentration, demonstrating that the reaction conditions became more favorable as the concentration of cyclodextrins increased. Complexes of clonazepam were prepared with cyclodextrins by various methods such as kneading, coevaporation, and physical mixing. The complexes were characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry studies. These studies indicated that complex prepared kneading and coevaporation methods showed successful inclusion of the clonazepam molecule into the cyclodextrins cavity. The complexation resulted in a marked improvement in the solubility and wettability of clonazepam. Among all the samples, complex prepared with hydroxypropyl-β-cyclodextrin by kneading method showed highest improvement in in vitro dissolution rate of clonazepam. Mean dissolution time of clonazepam decreased significantly after preparation of complexes and physical mixture of clonazepam with cyclodextrins. Similarity factor indicated significant difference between the release profiles of clonazepam from complexes and physical mixture and from plain clonazepam. Tablets containing complexes prepared with cyclodextrins showed significant improvement in the release profile of clonazepam as compared to tablet containing clonazepam without cyclodextrins.     

Preparation and Evaluation of Solid Dispersions of A New Antitumor Compound Based on Early-Stage Preparation Discovery Concept

Ensuring sufficient drug solubility is a crucial problem in pharmaceutical-related research. For water-insoluble drugs, various formulation approaches are employed to enhance the solubility and bioavailability of lead compounds. The goal of this study was to enhance the dissolution and absorption of a new antitumor lead compound, T-OA. Early-stage preparation discovery concept was employed in this study. Based on this concept, a solid dispersion system was chosen as the method of improving drug solubility and bioavailability. Solid dispersions of T-OA in polyvinylpyrrolidone (PVP) K30 were prepared by the solvent evaporation method. Dissolution testing determined that the ideal drug-to-PVP ratio was 1:5. X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry were employed to confirm the formation of solid dispersions. Scanning electron microscopy demonstrated that T-OA was converted into an amorphous form. Both in vitro dissolution testing and the in vivo studies demonstrated that the solubility and bioavailability of T-OA were significantly improved when formulated in a solid dispersion with PVP. The dissolution rate of the T-OA/PVP solid dispersion was greatly enhanced relative to the pure drug, and the relative bioavailability of T-OA solid dispersions was found to be 392.0%, which is 4-fold higher than the pure drug.     

Mucoadhesive, thermosensitive, prolonged-release vaginal gel for clotrimazole:beta-cyclodextrin complex

The purpose of this study was to achieve a better therapeutic efficacy and patient compliance in the treatment for vaginitis. Clotrimazole (1%) has been formulated in a vaginal gel using the thermosensitive polymer Pluronic F127 (20%) together with mucoadhesive polymers such as Carbopol 934 and hydroxypropylmethylcellulose (0.2% for both). To increase its aqueous solubility, clotrimazole was incorporated as its inclusion complex with 1:1 molar ratio with beta-cyclodextrin. The inclusion complex was thoroughly characterized using various techniques, including 1H NMR spectroscopy, FT IR spectrophotometry, differential scanning calorimetry, scanning electron microscopy, phase solubility studies, and determination of stability constant (k(1:1)). The gelation temperature and rheological behavior of different formulations at varying temperatures were measured. In vitro release profiles of the gels were determined in pH 5.5 citrate buffer. It was observed that complexation with cyclodextrin slowed down the release of clotrimazole considerably. Carbopol 934, on the other hand, was found to interact with beta-cyclodextrin, inducing precipitation. As far as rheological properties are concerned, thermosensitive in situ gelling was obtained with formulations containing drug:cyclodextrin complex rather than with free drug. Thus, the optimum formulation for a controlled-release thermosensitive and mucoadhesive vaginal gel was determined to be clotrimazole:beta-cyclodextrin 1% with 0.2% hydroxypropylmethylcellulose in Pluronic F127 gel (20%) providing continuous and prolonged release of active material above MIC values.     

Formulation and In Vivo Evaluation of Orally Disintegrating Tablets of Clozapine/Hydroxypropyl-β-cyclodextrin Inclusion Complexes

The aim of this study was to improve the solubility and oral bioavailability of clozapine (CLZ), a poorly water-soluble drug subjected to substantial first-pass metabolism, employing cyclodextrin complexation technique. The inclusion complexes were prepared by an evaporation method. Phase solubility studies, differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy were used to evaluate the complexation of CLZ with hydroxypropyl-β-cyclodextrin (HP-β-CD) and the formation of true inclusion complexes. Characterization and dissolution studies were carried out to evaluate the orally disintegrating tablets (ODTs) containing CLZ/HP-β-CD complexes prepared by direct compression. Finally, the bioavailability studies of the prepared ODTs were performed by oral administration to rabbits. The ODTs showed a higher in vitro dissolution rate and bioavailability compared with the commercial tablets. It is evident from the results herein that the developed ODTs provide a promising drug delivery system in drug development, owing to their excellent performance of a rapid onset of action, improved bioavailability, and good patient compliance.     

Preformulation Study of the Inclusion Complex Irbesartan-β-Cyclodextrin

The aim of the present work was to improve the solubility and dissolution profile of Irbesartan (IRB), a poorly water-soluble drug by formation of inclusion complex with β-cyclodextrin (βCD). Phase solubility studies revealed increase in solubility of the drug upon cyclodextrin addition, showing A_L—type of graph with slope less than one indicating formation of 1:1 stoichiometry inclusion complex. The stability constant (K _s) was found to be 104.39 M⁻¹. IRB–βCD binary systems were prepared by cogrinding, kneading using alcohol, kneading using aqueous alcohol, and coevaporation methods. Characterization of the binary systems were carried out by differential scanning calorimetry, Fourier transform infrared spectroscopy, scanning electron microscopy, X-ray diffraction, and proton nuclear magnetic resonance. The dissolution profiles of inclusion complexes were determined and compared with those of IRB alone and physical mixture. Among the various methods, coevaporation was the best in which the solubility was increased and dissolution rate of the drug was the highest. The study indicated the usefulness of cyclodextrin technology to overcome the solubility problem of IRB.     

Solubility Enhancement of Lovastatin by Modified Locust Bean Gum Using Solid Dispersion Techniques

The aim of the present study was to improve the solubility of poorly water soluble drug lovastatin (LS) by solid dispersion (SD) techniques using modified locust bean gum (MLBG) as a carrier. The locust bean gum (LBG) was modified by heating and there observed irreversible decrease in viscosity, whereas swelling property remains unaffected. The advantage of modification of LBG was illustrated by difference in dissolution profiles of their SD. Effect of polymer concentration and methods of preparation on solubility enhancement were studied using solubility and dissolution studies, respectively. The result of solubility study showed increase in solubility of LS with increase in concentration of MLBG. It was found that the dissolution rate of LS from its SD was dependent on the method of preparation of solid dispersions. Dissolution study revealed that the modified solvent evaporation is most convenient and effective method for solubility enhancement of poorly water soluble drug LS, among various methods of preparation of SD. The prepared SDs were characterized by differential scanning calorimetry, scanning electron microscopy, and X-ray diffraction study. In vivo study was performed by measuring 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG Co-A) reductase inhibition activity. Significant reduction in HMG Co-A reductase activity was observed in case of solid dispersions of LS than plain LS. In conclusion, MLBG could be used as a potential carrier in enhancing the dissolution rate and bioavailability of LS.     

Acyclovir-Polyethylene Glycol 6000 Binary Dispersions: Mechanistic Insights

The dissolution and subsequent oral bioavailability of acyclovir (ACY) is limited by its poor aqueous solubility. An attempt has been made in this work to provide mechanistic insights into the solubility enhancement and dissolution of ACY by using the water-soluble carrier polyethylene glycol 6000 (PEG6000). Solid dispersions with varying ratios of the drug (ACY) and carrier (PEG6000) were prepared and evaluated by phase solubility, in vitro release studies, kinetic analysis, in situ perfusion, and in vitro permeation studies. Solid state characterization was done by powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR) analysis, and surface morphology was assessed by polarizing microscopic image analysis, scanning electron microscopy, atomic force microscopy, and nuclear magnetic resonance analysis. Thermodynamic parameters indicated the solubilization effect of the carrier. The aqueous solubility and dissolution of ACY was found to be higher in all samples. The findings of XRD, DSC, FTIR and NMR analysis confirmed the formation of solid solution, crystallinity reduction, and the absence of interaction between the drug and carrier. SEM and AFM analysis reports ratified the particle size reduction and change in the surface morphology in samples. The permeation coefficient and amount of ACY diffused were higher in samples in comparison to pure ACY. Stability was found to be higher in dispersions. The results suggest that the study findings provided clear mechanical insights into the solubility and dissolution enhancement of ACY in PEG6000, and such findings could lay the platform for resolving the poor aqueous solubility issues in formulation development.     

A Menthol-Based Solid Dispersion Technique for Enhanced Solubility and Dissolution of Sulfamethoxazole from an Oral Tablet Matrix

A menthol-based solid dispersion was designed to improve the intrinsic solubility of the poorly soluble sulfamethoxazole- a class II drug molecule of Biopharmaceutics Classification System (BCS) displaying widespread antibacterial activity. Solid dispersions of menthol and sulfamethoxazole were compressed with hydroxypropyl methylcellulose (HPMC) into suitable sulfamethoxazole-loaded matrix tablets for oral drug delivery. The sulfamethoxazole-loaded solid dispersions and compressed tablets were characterized for their physicochemical and physicomechanical properties such as changes in crystallinity, melting point, molecular transitions, and textural analysis for critical analysis of their effects on the solubility and dissolution of sulfamethoxazole. The formulations were further evaluated for swelling, degradation, solubility, and in vitro drug release behavior. In vitro drug release from the sulfamethoxazole-loaded matrix tablets displayed a minimum and maximum fractional release of 0.714 and 0.970, respectively. The tablets further displayed different release rate profiles over the study periods of 12, 16, 48, and 56 h which were attributed to the varying concentrations of menthol within each formulation. Menthol was determined as a suitable hydrophilic carrier for sulfamethoxazole since it functioned as a solubilizing and release-retarding agent for improving the solubility and dissolution of sulfamethoxazole as well as controlling the rate at which it was released.KEY WORDS: crystallinity, menthol, oral solubility and dissolution, solid dispersion, sulfamethoxazole     

Polymeric surfactant based etodolac chewable tablets: formulation and in vivo evaluation

Etodolac (ET) is a nonsteroidal anti-inflammatory drug with proved potential antitumor and uric acid lowering effects. It shows dissolution rate-dependent bioavailability. This work was carried out to improve the dissolution rate of etodolac using three carriers of known potential to improve solubility and hence dissolution rate of poorly soluble drugs through coevaporation technique. The polymeric surfactant inutec, 2-hydroxypropyl-β-cyclodextrin, and tromethamine were used at three different drug/carrier ratios. The dissolution rate of ET at pH 1.2 and 6.8 is improved in all of the solid dispersion systems compared to that of the pure drug and physical mixtures. DSC of coevaporates at 1:5 drug/carrier ratio providing the fastest dissolution rate suggested loss of ET crystallinity which was further confirmed by X-ray diffraction. Inutec-based coevaporate was chosen for the formulation of ET chewable tablets. Chewable tablets (F3) that met the USP monograph specifications for ET tablets, with 86% dissolved amount within 15 min, was chosen for in vivo absorption study in comparison with pure ET-filled hard gelatin capsules. The results showed significantly higher mean C _max and shorter mean T _max (about 2 h earlier) and about 1.32-fold higher mean AUC_0–24 values for the F3 chewable tablets compared to ET-filled capsules.     

Dual Activity of Hydroxypropyl-β-Cyclodextrin and Water-Soluble Carriers on the Solubility of Carvedilol

Carvedilol (CAR) is a non-selective α and β blocker categorized as class II drug with low water solubility. Several recent studies have investigated ways to overcome this problem. The aim of the present study was to combine two of these methods: the inclusion complex using hydroxypropyl-β-cyclodextrin (HPβCD) with solid dispersion using two carriers: Poloxamer 188 (PLX) and Polyvinylpyrrolidone K-30 (PVP) to enhance the solubility, bioavailability, and the stability of CAR. Kneading method was used to prepare CAR-HPβCD inclusion complex (KD). The action of different carriers separately and in combination on Carvedilol solubility was investigated in three series. CAR-carrier and KD-carrier solid dispersions were prepared by solvent evaporation method. In vitro dissolution test was conducted in three different media: double-distilled water (DDW), simulative gastric fluid (SGF), and PBS pH 6.8 (PBS). The interactions between CAR, HPβCD, and different carriers were explored by Fourier transform infrared spectroscopy (FTIR), powder X-ray diffractometry (XRD), and differential scanning colorimetry (DSC). The results showed higher solubility of CAR in KD-PVP solid dispersions up to 70, 25, and 22 fold compared to pure CAR in DDW, SGF, and PBS, respectively. DSC and XRD analyses indicated an improved degree of transformation of CAR in KD-PVP solid dispersion from crystalline to amorphous state. This study provides a new successful combination of two polymers with the dual action of HPβCD and PLX/PVP on water solubility and bioavailability of CAR.     

Interaction of sulfadiazine with cyclodextrins in aqueous solution and solid state

The main objective of this work was to increase the solubility of sulfadiazine by formation of inclusion complexes with β-cyclodextrin, and methyl-β-cyclodextrin. The apparent stability constants have been determined by phase solubility studies in water and buffer solutions of pH values of 2 and 8. The stoichiometry of all complexes was found to be 1:1 but different relative affinities were found for each cyclodextrin. It was possible to obtain a greater overall solubility by using a combined approach of pH adjustment and complexation with cyclodextrins. Guest-host interactions have been investigated using nuclear magnetic resonance. Complexes were prepared in solid state by different methods and were characterized using differential scanning calorimetry, thermogravimetric analysis, Fourier-transform infrared spectroscopy, X-ray diffractometry and scanning electron microscopy. The dissolution rate of the drug from the inclusion complex made by freeze-dried was much faster than this of the pure drug.     

Physicochemical characterization and dissolution properties of nimesulide-cyclodextrin binary systems

The objective of this work is physicochemical characterization of nimesulide-cyclodextrin binary systems both in solution and solid state and to improve the dissolution properties of nimesulide (N) via complexation with α-, β, and γ-cyclodextrins (CDs). Detection of inclusion complexation was done in solution by means of phase solubility analysis, mass spectrometry, and ¹H nuclear magnetic resonance (¹H-NMR) spectroscopic studies, and in solid state using differential scanning calorimetry (DSC), powder x-ray diffractometry (X-RD), scanning electron microscopy (SEM), and in vitro dissolution studies. Phase solubility, mass spectrometry and ¹H-NMR studies in solution revealed 1∶1 M complexation of N with all CDs. A true inclusion of N with β-CD at 1∶2 M in solid state was confirmed by DSC, powder X-RD and SEM studies. Dissolution properties of N-CD binary systems were superior when compared to pure N.     

Preparation and Pharmacokinetic Study of Aprepitant–Sulfobutyl Ether-β-Cyclodextrin Complex

Aprepitant (APR), a neurokinin 1 receptor antagonist, is an approved treatment for chemotherapy-induced nausea and vomiting and for post-operative nausea and vomiting. However, it has poor water solubility. This study was performed to optimize the capsule formulation of an inclusion complex of APR with sulfobutyl ether-β-cyclodextrin (SBE-β-CD), and to evaluate its water solubility, dissolution rate, and bioavailability. The complex was prepared through the saturated-aqueous solution method and then characterized by Fourier transform infrared spectroscopy, x-ray powder diffraction, and differential scanning calorimetry. Subsequently, a pharmacokinetic study was performed using liquid chromatography–tandem mass spectrometry. Emend, which features an innovative formulation that incorporates drug nanoparticles with high bioavailability, was used as a reference for comparison with the optimized formulation. As a result, the dissolution rates and extent of release of the test formulation in various media were enhanced relative to those of Emend. The bioavailability of the drug complex was comparable to that of Emend. In summary, the SBE-β-CD complexation could provide a practical and cost-effective option for enhancing the solubility and bioavailability of APR according to our research.     

Cellulose-Based Matrix Microspheres of Prednisolone Inclusion Complex: Preparation and Characterization

The purpose of the present investigation was to encapsulate pure prednisolone (PRD) and PRD–hydroxypropyl-β-cyclodextrin (HPβCD) complex in cellulose-based matrix microspheres. The system simultaneously exploits complexation technique to enhance the solubility of low-solubility drug (pure PRD) and subsequent modulation of drug release from microspheres (MIC) at a predetermined time. The microspheres of various compositions were prepared by an oil-in-oil emulsion–solvent evaporation method. The effect of complexation and presence of cellulose polymers on entrapment efficiency, particle size, and drug release had been investigated. The solid-state characterization was performed by Fourier transform infrared spectroscopy, thermogravimetry, differential scanning calorimetry, and powder X-ray diffractometry. The morphology of MIC was examined by scanning electron microscopy. The in vitro drug release profiles from these microspheres showed the desired biphasic release behavior. After enhancing the solubility of prednisolone by inclusion into HPβCD, the drug release was easily modified in the microsphere formulation. It was also demonstrated that the CDs in these microspheres were able to modulate several properties such as morphology, drug loading, and release properties. The release kinetics of prednisolone from microspheres followed quasi-Fickian and first-order release mechanisms. In addition to this, the f ₂-metric technique was used to check the equivalency of dissolution profiles of the optimized formulation before and after stability studies, and it was found to be similar. A good outcome, matrix microspheres (coded as MIC5) containing PRD–HPβCD complex, showed sustained release of drug (95.81%) over a period of 24 h.     

Physicochemical Properties and Dissolution Studies of Dexamethasone Acetate-β-Cyclodextrin Inclusion Complexes Produced by Different Methods

Inclusion complexes between dexamethasone acetate (DMA), a poorly water soluble drug, and β-cyclodextrin (βCD) were obtained to improve the solubility and dissolution rate of this drug. Phase-solubility profile indicated that the solubility of DMA was significantly increased in the presence of βCD (33-fold) and was classified as A_L-type, indicating the 1:1 stoichiometric inclusion complexes. Solid complexes prepared by different methods (kneading, coevaporation, freeze drying) and physical mixture were characterized by differential scanning calorimetry, thermogravimetry, infrared absorption and optical microscopy. Preparation methods influenced the physicochemical properties of the products. The dissolution profiles of solid complexes were determined and compared with those DMA alone and their physical mixture, in three different mediums: simulated gastric fluid (pH 1.2), simulated intestinal fluid (pH 7.4) and distilled water. The dissolution studies showed that in all mediums DMA presented an incomplete dissolution even in four hours. In contrast, the complexes formed presented a higher dissolution rate in simulated gastric fluid (SGF pH 1.2), which indicate that these have different ionization characteristics. According to the results, the freeze–dried and kneaded products exhibited higher dissolution rates than the drug alone, in all the mediums.     

Influence of hydrophilic polymers on celecoxib complexation with hydroxypropyl beta-cyclodextrin

Complexation of celecoxib with hydroxypropyl beta-cyclodextrin (HPbetaCD) in the presence and absence of 3 hydrophilic polymers-polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), and polyethylene glycol (PEG)-was investigated with an objective of evaluating the effect of hydrophilic polymers on the complexation and solubilizing efficiencies of HPbetaCD and on the dissolution rate of celecoxib from the HPbetaCD complexes. The phase solubility studies indicated the formation of celecoxib-HPbetaCD inclusion complexes at a 1:1M ratio in solution in both the presence and the absence of hydrophilic polymers. The complexes formed were quite stable. Addition of hydrophilic polymers markedly enhanced the complexation and solubilizing efficiencies of HPbetaCD. Solid inclusion complexes of celecoxib-HPbetaCD were prepared in 1:1 and 1:2 ratios by the kneading method, with and without the addition of hydrophilic polymers. The solubility and dissolution rate of celecoxib were significantly improved by complexation with HPbetaCD. The celecoxib-HPbetaCD (1:2) inclusion complex yielded a 36.57-fold increase in the dissolution rate of celecoxib. The addition of hydrophilic polymers also markedly enhanced the dissolution rate of celecoxib from HPbetaCD complexes: a 72.60-, 61.25-, and 39.15-fold increase was observed with PVP, HPMC, and PEG, respectively. Differential scanning calorimetry and X-ray diffractometry indicated stronger drug amorphization and entrapment in HPbetaCD because of the combined action of HPbetaCD and the hydrophilic polymers.     

Evaluation of Drug Load and Polymer by Using a 96-Well Plate Vacuum Dry System for Amorphous Solid Dispersion Drug Delivery

It is well recognized that poor dissolution rate and solubility of drug candidates are key limiting factors for oral bioavailability. While numerous technologies have been developed to enhance solubility of the drug candidates, poor water solubility continuously remains a challenge for drug delivery. Among those technologies, amorphous solid dispersions (SD) have been successfully employed to enhance both dissolution rate and solubility of poorly water-soluble drugs. This research reports a high-throughput screening technology developed by utilizing a 96-well plate system to identify optimal drug load and polymer using a solvent casting approach. A minimal amount of drug was required to evaluate optimal drug load in three different polymers with respect to solubility improvement and solid-state stability of the amorphous drug-polymer system. Validation of this method was demonstrated with three marketed drugs as well as with one internal compound. Scale up of the internal compound SD by spray drying further confirmed the validity of this method, and its quality was comparable to a larger scale process. Here, we demonstrate that our system is highly efficient, cost-effective, and robust to evaluate the feasibility of spray drying technology to produce amorphous solid dispersions.