Solubility and dissolution rate of progesterone-cyclodextrin-polymer systems

This contribution focused on the solubility improvement of the poorly water-soluble steroid hormone progesterone which, in its natural state, presents a reduced oral bioavailability. In the first part of this study, two simple, reproducible methods that were candidates for use in the preparation of inclusion complexes with cyclodextrins were investigated. Solubility capacities of the progesterone complex with hydroxypropyl-β-CD (HPβ-CD), hydoxypropyl-γ-CD (HPγ-CD), permethyl-β-CD (PMβ-CD), and sulfobutylether-β-CD (SBEβ-CD), prepared by the freeze-drying and precipitation methods, were evaluated by Higuchi phase solubility studies. The results showed that HPβ-CD and PMβ-CD were the most efficient among the four cyclodextrins for the solubilization of progesterone, with the highest apparent stability constants. Therefore, dissolution studies were conducted on these latest progesterone/cyclodextrin complexes and physical mixtures. Two additional natural cyclodextrins, β-CD and γ-CD, were taken as references. Hence, the influence of more highly soluble derivatives of β-CD (HPβ-CD, PMβ-CD) on the progesterone dissolution rate, in comparison to pristine β-CD, alongside an increase in the cavity width for γ-CD versus β-CD, were investigated. The dissolution kinetics of progesterone dissolved from HPβ-CD, PMβ-CD, and γ-CD revealed higher constant rates in comparison to β-CD. Therefore, the aim of the second part of this study was to investigate the possibility of improving the dissolution rate of progesterone/β-CD binary systems upon formation of ternary complexes with the hydrophilic polymer, PEG 6000, as β-CD had the smallest progesterone solubility and dissolution capacity among the four cyclodextrins studied (β-CD, HPβ-CD, HPγ-CD and PMβ-CD). The results indicated that dissolution constant rates were considerably enhanced for the 5% and 10% progesterone/β-CD complexes in PEG 6000.

The interaction of progesterone with the cyclodextrins of interest on the form of the binary physical mixtures, complexes, or ternary complexes were investigated by differential scanning calorimetry (DSC) and Fourier transformed-infrared spectroscopy (FT-IR). The results proved that progesterone was diffused into the cyclodextrin cavity, replacing the water molecules and, in case of ternary systems, that the progesterone β-cyclodextrin was well dispersed into PEG, thus improving progesterone bioavailability for subsequent oral delivery in the same way as derivatized cyclodextrins. The present work proves that ternary complexes are promising systems for drug encapsulation.     

Daidzein/cyclodextrin/hydrophilic polymer ternary systems

Objective: To evaluate the effect of different cyclodextrins (β-cyclodextrin [β-CD], methyl-β-cyclodextrin [Mβ-CD], or hydroxypropyl-β-cyclodextrin [HPβ-CD]) and/or hydrophilic polymers (carboxymethylcellulose, hydroxypropylmethylcellulose [HPMC], polyethyleneglycol, or polyvinylpyrrolidone [PVP]) on daidzein solubility in water.

Materials and methods: The corresponding associations were characterized in aqueous media using phase-solubility studies. The morphology of daidzein/cyclodextrin freeze-dried complexes was characterized using scanning electron microscopy, and their spatial configuration was proposed by means of nuclear magnetic resonance spectroscopy.

Results and discussion: In the presence of 6?mM of cyclodextrins, the solubility of daidzein in water was significantly enhanced: 5.7-fold (β-CD), 7.2-fold (Mβ-CD), and 9.4-fold (HPβ-CD). The analysis of the three solid complexes proved that the formation of inclusion complexes occurred through the insertion of the B and C rings of daidzein molecule into the cyclodextrins cavity. The association of daidzein/cyclodextrin complexes to the hydrophilic polymers HPMC or PVP (1%, w/w) was able to improve the solubility of daidzein even further.

Conclusion: The highest solubilizing effect was obtained for daidzein/HPβ-CD/PVP ternary system (12.7-fold).     

Inclusion complexes of bendamustine with β-CD,HP-β-CD and Epi-β-CD: in-vitro and in-vivo evaluation

Abstract

The objective of the present work was to investigate the inclusion behavior of bendamustine (BM) with β-cyclodextrin and its hydrophilic derivatives (HP-β-CD and Epi-β-CD) for the enhancement of aqueous solubility, dissolution and bioavailability. The supramolecular binary complexes were prepared by three different methods, viz. physical mixture (PM), kneading (KND) and co-evaporation (COE). Phase-solubility study revealed the higher solubilizing and complexing ability of polymerized cyclodextrin (K_s?=?645?M^?1) than parent cyclodextrin (K_s?=?43?M^?1) and chemically derived cyclodextrin (K_s?=?100?M^?1). Meanwhile, the solubility of BM was significantly enhanced in phosphate buffer of pH 6.8, which was 24.5 folds greater compared with the phosphate buffer pH 4.5 and four times greater than aqueous medium. The dissolution efficiency was found to be highest for BM: Epi-β-CD complex (87%) compared to BM: HP-β-CD complex (84%), BM: β-CD (79%) and pure drug (20%). In-vivo pharmacokinetic study revealed that the bioavailability of BM was enhanced 2.55 times on complexation with Epi-β-CD using KND method. The t_1/2 of BM was increased from 34.2?min to approximately 75.7?min, allowing the absorption for longer time. The order of increase in solubility, dissolution and bioavailability of BM was KND?>?COE?>?PM?>?pure drug. Thus, the strategy of host–guest inclusion was very effective and could be successfully used in the development of suitable pharmaceutical dosage form with enhanced therapeutic activity.     

In vitro and in vivo studies on the complexes of glipizide with water-soluble β-cyclodextrin-epichlorohydrin polymers

The purpose of this study was to evaluate the potential of a newly modified cyclodextrin derivative, water-soluble β-cyclodextrin-epichlorohydrin polymer (β-CDP), as an effective drug carrier to enhance the dissolution rate and oral bioavailability of glipizide as a poorly water-soluble model drug. Inclusion complexes of glipizide with β-CDP were prepared by the co-evaporation method and characterized by phase solubility, dissolution, and differential scanning calorimetry. The solubility curve was classified as type A(L), which indicated the formation of 1:1 complex between glipizide and β-CDP. β-CDP had better properties of increasing the aqueous solubility of glipizide compared with HP-β-CD. The dissolution rate of drug from the β-CDP complexes was significantly greater than that of the corresponding physical mixtures indicating that the formation of amorphous complex increased the solubility of glipizide. Moreover, the increment in drug dissolution rate from the glipizide/β-CDP systems was higher than that from the corresponding ones with HP-β-CD, which indicated that β-CDP could provide greater capability of solubilization for poorly soluble drugs. Furthermore, in vivo study revealed that the bioavailability of glipizide was significantly improved by glipizide /β-CDP inclusion complex after oral administration to beagle dogs.     

In vitro and in vivo studies on the complexes of glipizide with water-soluble β-cyclodextrin–epichlorohydrin polymers

The purpose of this study was to evaluate the potential of a newly modified cyclodextrin derivative, water-soluble β-cyclodextrin–epichlorohydrin polymer (β-CDP), as an effective drug carrier to enhance the dissolution rate and oral bioavailability of glipizide as a poorly water-soluble model drug. Inclusion complexes of glipizide with β-CDP were prepared by the co-evaporation method and characterized by phase solubility, dissolution, and differential scanning calorimetry. The solubility curve was classified as type A_L, which indicated the formation of 1:1 complex between glipizide and β-CDP. β-CDP had better properties of increasing the aqueous solubility of glipizide compared with HP-β-CD. The dissolution rate of drug from the β-CDP complexes was significantly greater than that of the corresponding physical mixtures indicating that the formation of amorphous complex increased the solubility of glipizide. Moreover, the increment in drug dissolution rate from the glipizide/β-CDP systems was higher than that from the corresponding ones with HP-β-CD, which indicated that β-CDP could provide greater capability of solubilization for poorly soluble drugs. Furthermore, in vivo study revealed that the bioavailability of glipizide was significantly improved by glipizide /β-CDP inclusion complex after oral administration to beagle dogs.     

Inclusion complexes of fluorofenidone with β-cyclodextrin and hydroxypropyl-β-cyclodextrin

Background: Fluorofenidone is a novel antifibrotic drug and its aqueous solubility is low. Aim: This study was to prepare and characterize inclusion complexes of fluorofenidone (AKF-PD) with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD). Method: The AKF-PD/cyclodextrins (CDs) inclusion complexes were prepared by coprecipitation and freeze-drying, respectively. The solubility enhancement of AKF-PD was evaluated by phase solubility method. Inclusion complexation in solid phase was studied by X-ray diffraction (XRD) and differential thermal analysis (DTA). The dissolution profiles of AKF-PD/CDs inclusion complexes were investigated and compared with those of their physical mixtures and AKF-PD alone. Results: The phase solubility diagrams of AKF-PD with β-CD and HP-β-CD were of A_L-types, and the solubility of AKF-PD could be increased by 51.5% for β-CD at 0.014 M and 794.0% for HP-β-CD at 0.254 M. The results from XRD and DTA suggested that AKF-PD could form inclusion complex with β-CD or HP-β-CD. The dissolution rate of AKF-PD from the inclusion complexes was much more rapid than AKF-PD alone. Conclusions: The formulation of AKF-PD/CDs inclusion complexes showed superior performance in improving dissolution properties of AKF-PD.     

Inclusion Complexation of Nimesulide with β-Cyclodextrins

Nimesulide (NM), a nonsteroidal anti-inflammatory drug (NSAID) has poor aqueous solubility. The present study describes the complexation of NM with β-cyclodextrin (β-CD) and its derivative hydroxypropyl β-cyclodextrin (HPβ-CD). The complexation was studied by phase solubility method, Fourier transformed infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffractometry (XRD). The complexes were prepared by a freeze-drying technique. The in vitro dissolution rate of drug–HPβ-CD complex was faster compared to the drug–β-CD complex and drug alone.     

Interaction of Antimalarial Agent Artemisinin with Cyclodextrins

To obtain an effective solution of the poorly water soluble antimalarial agent artemisinin, the use of several kinds of cyclodextrins (CDs) as solubilizers was examined. The following CDs were used in this study: α-CD, β-CD, γ-CD as parent CDs, 2-hydroxypropyl-β-CD (HP-β-CD), sulfobutyl ether β-CD (SBE7-β-CD), heptakis (2,6-di-O-methyl)-β-CD (DM-β-CD), 2,3,6-partially methylated-β-CD (PM-β-CD) as modified CDs, and glucosyl-β-CD (G1-β-CD), and maltosyl-β-CD (G2-β-CD) as branched CDs. The solubility curves of artemisinin with CDs can all be classified as type A_L. The apparent stability constants for artemisinin-parent CD complexes increased in the order of α- < γ- ≤ β-CD. The constants for artemisinin-β-CD derivative (and β-CD) complexes increased in the order of G2-β-CD ? G1-β-CD cong; PM-β-CD ? β-CD < HP-β-CD < SBE7-β-CD < DM-β-CD. These results suggest that the addition of CDs enables the solubilization of artemisinin.     

Interaction of Cyclomaltononaose (δ-CD) with Several Drugs

The effects of δ-cyclodextrin (δ-CD; cyclomaltononaose) on solubility of 14 drugs that are slightly soluble or insoluble in water were studied and compared with those of conventional cyclodextrins (CDs) such as α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), and γ-cyclodextrin (γ-CD). In general, δ-CD had a weak complex-forming ability with the drugs examined in comparison with β-CD and γ-CD. However, in the case of digitoxin, δ-CD enhanced solubility of the guest molecules. To determine the mechanism of inclusion complex formation of δ-CD with digitoxin, the interaction of both drugs was investigated by the solubility method and spectroscopic methods such as ultraviolet (UV) and ¹H-NMR (nuclear magnetic resonance). The changes in chemical shift (¹H) and hypsochromic shift of UV suggested that digitoxin was partially included in the cavity of δ-CD.     

Enhancement of dissolution rate and bioavailability of sulfamethoxazole by complexation with β-cyclodextrin

The purpose of this study was to improve the solubility and dissolution rate of sulfamethoxazole (SMZ) with inclusion compound of β-cyclodextrin (β-CD). The interaction between SMZ and β-CD in solution was studied by the phase-solubility method. The phase-solubility studies revealed the formation of inclusion complexes with poor solubility with an inclusion complex of 1:1 molar ratio and a stability constant of 122.3?M(-1). The solid complexes of SMZ with β-CD were prepared by using kneading and coprecipitation methods. The physical mixture of these chemicals was also prepared for comparison. Inclusion complexation was confirmed by the results from the studies of infrared spectoroscopy (IR) and differential scanning calorimetry (DSC). The effect of water-soluble polymers i.e., polyethylene glycol 20000 and non-ionic surfactants i.e., polysorbate 20 on the complexation of SMZ with β-CD was also investigated by the same methods. The rates of release of the active material from the complexes were determined from dissolution studies using USP XXII paddle method. The formulation, that provided delivery of active material near to the target value in six healthy volunteers and in vivo tests, clearly revealed that the bioavailability of active material was found to be enhanced by preparing ternary mixtures.     

Effect of hydrophilic polymers on isradipine complexation with hydroxypropyl β-cyclodextrin

Complexation of isradipine with hydroxypropyl β-cyclodextrin (HPβCD) 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 HPβCD and on the dissolution rate of isradipine from the HPβCD complexes. The phase solubility studies indicated the formation of isradipine-HPβCD 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 improved the complexation and solubilizing efficiencies of HPβCD. Solid inclusion complexes of isradipine-HPβCD 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 isradipine were significantly improved by complexation with HPβCD. The isradipine-HPβCD (1:2) inclusion complex yielded a 9.66-fold increase in the dissolution rate of isradipine. The addition of hydrophilic polymers also markedly improved the dissolution rate of isradipine from HPβCD complexes: a 11.72-, 17.01-, and 39.23-fold increase was observed with PVP, PEG, and HPMC respectively. X-ray diffractometry and differential scanning calorimetry indicated stronger drug amorphization and entrapment in HPβCD because of the combined action of HPβCD and the hydrophilic polymers.     

Evaluation of Stereoselective Dissolution of Racemic Salbutamol Matrices Prepared with Commonly Used Excipients and 1H-NMR Study

The purpose of this work was to examine the in vitro enantioselective dissolution of salbutamol from matrix tablets containing various chiral excipients, such as γ-cyclodextrin (γ-CD), heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD), sulfobutyl-β-cyclodextrin (SBE-β-CD), hydroxypropylmethylcellulose (HPMC), and egg albumin. In this study, two types of tablets were prepared; the coated tablet contained the complex of racemic salbutamol and cyclodextrin (γ-CD, DM-β-CD, and SBE-β-CD), and the uncoated tablet was composed of the drug with either HPMC or egg albumin. Subsequently, these formulations were evaluated for enantioselective release. The results revealed that the formulations containing either SBE-β-CD, HPMC, or egg albumin had no enantioselective release, while the formulation with DM-β-CD gave slightly different release of the two enantiomers at the end of the dissolution profile. The formulation containing γ-CD provided significant stereoselectivity throughout the dissolution profile. The release of the eutomer R-salbutamol was higher than that of the distomer S-salbutamol from the γ-CD tablet. In addition, the enantioselective interaction for the γ-CD inclusion complex was investigated by ¹H-NMR (nuclear magnetic resonance) spectroscopy and gave evidence to support the enantioselectivity obtained on dissolution.     

Gefitinib–cyclodextrin inclusion complexes: physico-chemical characterization and dissolution studies

Background: Gefitinib, an anticancer drug, has an extremely low aqueous solubility, and its oral absorption is limited by its dissolution rate. The solubility and dissolution of gefitinib can be improved by complexation with cyclodextrins (CDs). Methods: Phase solubility studies of gefitinib with hydroxypropyl βCD (HPβCD) and randomly methylated βCD (RMβCD) in n various aqueous systems was conducted to characterize the complexes in the liquid state. The inclusion complexes in the solid state were prepared by freeze-drying method and characterized by X-ray diffractometry (X-RD) and differential scanning calorimetry (DSC). Results: Gefitinib formed stable complexes with HPβCD and RMβCD in distilled water as indicated by the association rate constants (Ks) of 458.9 and 1096.2 M^?1 for HPβCD and RMβCD, respectively. The complexation of gefitinib with CDs in pH 4.5 acetate buffer indicated an A_N type of phase-solubility diagrams, whereas gefitinib and HPβCD in distilled water in the presence of polymers such as polyvinyl pyrrolidone K-30 (PVP) or hydroxypropyl methylcellulose E3 (HPMC) resulted in A_P-type phase-solubility diagrams. The solid-state amorphous complexes (as described by DSC and X-RD) showed substantial increases in the solubility and dissolution rate of gefitinib with both CDs. Further increases in the solubility and dissolution rate of the gefitinib-HPβCD freeze-dried complex were obtained by physically mixing the complex with PVP and HPMC. Conclusion: Gefitinib formed stable inclusion complexes with HPβCD and RMβCD, and the solubility and dissolution rate of the drug was significantly increased.     

Solubility enhancement of miconazole nitrate: binary and ternary mixture approach

Context: Enhancement of aqueous solubility of very slightly soluble Miconazole Nitrate (MN) is required to widen its application from topical formulation to oral/mucoadhesive formulations.

Objective: Aim of the present investigation was to enhance the aqueous solubility of MN using binary and ternary mixture approach.

Materials and methods: Binary mixtures such as solvent deposition, inclusion complexation and solid dispersion were adopted to enhance solubility using different polymers like lactose, beta-cyclodextrin (β-CD) and polyethylene-glycol 6000 (PEG 6000), respectively. Batches of binary mixtures with highest solubility enhancement potentials were further mixed to form ternary mixture by a simple kneading method. Drug polymer interaction and mixture morphology was studied using the Fourier transform infrared spectroscopy and the scanning electron microscopy, respectively along with their saturation solubility studies and drug release.

Results: An excellent solubility enhancement, i.e. up to 72 folds and 316 folds of MN was seen by binary and ternary mixture, respectively. Up to 99.5% drug was released in 2?h from the mixtures of MN and polymers.

Discussion: Results revealed that solubility enhancement by binary mixtures is achieved due to surface modification and by increasing wettability of MN. Tremendous increase in solubility of MN by ternary mixture could possibly be due to blending of water soluble polymers, i.e. lactose and PEG 6000 with β-CD which was found to enhance the solubilizing nature of β-CD.

Conclusion: Owing to the excellent solubility enhancement potential of ternary mixtures in enhancing MN solubility from 110.4?μg/ml to 57?640.0?μg/ml, ternary mixture approach could prove to be promising in the development of oral/mucoadhesive formulations.     

Etodolac and Solid Dispersion with P-Cyclodextrin

Abstract

Etodolac/β-cyclodextrin (Eto/β-CD) dispersions were prepared with a view to study the influence of β-CD on the solubility and dissolution rate of this poorly soluble drug. Two systems were used: physicai mixture of Eto/β-CD and kneading solid dispersion of Eto/β-CD. Physical characterization of the prepared systems was carried out by scanning electron microscopy (SEM), differential scanning calorimetric (DSC), x-ray, and IR studies. The solubility and dissolution rate of Eto were increased with β-CD physical mixture as well us with Eto/β-CD kneading solid dispersion. However, enhancement was not statistically different among various cyclodextrin dispersions.     

Designing and monitoring microstructural properties of oligosaccharide/co-solvent ternary complex particles to improve benznidazole dissolution

Benznidazole (BNZ) is the main drug used for the treatment of Chagas disease. However, its low aqueous solubility limits its efficacy. In this study, we have prepared host–guest inclusion complexes of BNZ with beta-cyclodextrin (β-CD) in solid phase and assessed the influence of the co-solvents triethanolamine (TEA) and 1-methyl-2-pyrrolidone (NMP) for improving the drug dissolution performance. The physicochemical properties of prepared spray-dried (SD) particles and physical mixtures (PM) were carefully monitored using FTIR, XRD and SEM images. The used co-solvents affected β-CD–drug interactions, the structural properties and drug dissolution behavior of particles. TEA did not improve the solubilizing effect of β-CD, while NMP was able to enhance drug dissolution performance in both SD and PM complexes. These promising results support the use of specific co-solvents with CD as a new raw material for insoluble compounds. The studied solid dispersions showed promising features to improve BNZ efficacy against Chagas disease.     

Percutaneous Absorption of Metopimazine and Effect of Cyclodextrins

Metopimazine (MPZ) is used to prevent emesis during chemotherapies. A transdermal delivery system of MPZ may present a great advantage in patients to improve compliance. Hydroxypropyl β cyclodextrin (HPβCD) and partially methylated β cyclodextrin (PMβCD) were tested to enhance the percutaneous absorption of MPZ through pig skin using Franz's cells. The MPZ hydrochloride flux was low with 0.176 ± 0.054 μg/h/cm² and no flux was detected with a suspension of MPZ (base). The used characterization analyses demonstrated the formation of an inclusion complex with cyclodextrin and this complex improved percutaneous absorption of MPZ. Flux was increased to 0.240 ± 0.032 μg/h/cm² and 0.566 ± 0.057 μg/h/cm² for HPβCD and PMβCD, respectively, with a concentration of 20%. This study has shown that HPβCD and PMβCD improved the percutaneous penetration of MPZ. Cyclodextrin complexes increased MPZ bioavailability at the skin surface and PMβCD was also able to extract cutaneous fatty acids.     

Fast-dissolving carvacrol/cyclodextrin inclusion complex electrospun fibers with enhanced thermal stability,water solubility,and antioxidant activity

Carvacrol is a known antioxidant molecule and commonly used in food and cosmetics as a flavor and fragrance agent; however, carvacrol has major issues such as high volatility, low water solubility, and stability. In this study, carvacrol/cyclodextrin inclusion complex fibers (carvacrol/CD-IC fibers) were produced via electrospinning in order to enhance thermal stability, water solubility and shelf-life of carvacrol having antioxidant activity. The phase solubility and computational modeling studies showed that carvacrol can form inclusion complexes with two types of modified CDs, hydroxypropyl-β-cyclodextrin (HPβCD) and hydroxypropyl-γ-cyclodextrin (HPγCD). The carvacrol/cyclodextrin inclusion complex electrospun fibers (carvacrol/HPβCD-IC fibers and carvacrol/HPγCD-IC fibers) were obtained as free-standing fibrous webs. Although pure carvacrol is highly volatile, the electrospun carvacrol/CD-IC fibers were quite effective to preserve high amount of carvacrol due to the inclusion complexation. In addition, carvacrol/CD-IC fibers have shown higher temperature stability for carvacrol. Moreover, carvacrol/CD-IC fibers showed more effective antioxidant activity as compared to pure carvacrol. The carvacrol/CD-IC fibrous webs have shown fast-dissolving character in water due to the enhanced water solubility of carvacrol/CD-IC and their ultrafine fiber structure. In short, encapsulation of carvacrol in electrospun CD-IC fibrous webs has shown potentials for food and oral care applications due to free-standing and fast-dissolving character along with high water solubility, high temperature stability and enhanced antioxidant by carvacrol/cyclodextrin inclusion complexation.     

An optimized commercially feasible milling technique for molecular encapsulation of meloxicam in β-cyclodextrin

Background: The practical applicability of solid dispersions (SD) for improvement of oral bioavailability of poorly water-soluble drugs has still remained limited because of lack of feasibility for scale-up of manufacturing processes. The present research work deals with the preparation of SDs of meloxicam (MLX) with β-cyclodextrin (β-CD) by the ball-milling technique to overcome the scale-up issues.

Methods: Phase-solubility studies were conducted to analyze the influence of β-CD on solubility of MLX. In vitro dissolution studies on various complexes as well as tablets prepared on pilot scale in an industrial set up were performed and compared with the marketed products. Physicochemical characterization of optimized complexes was done using various methods to study drug-β-CD interaction.

Results: Solubility of pure MLX in water at 25°C was found to be only 9.4 µg/mL. The AL type of phase-solubility profile of MLX with β-CD [stability constant (K_1:1)?=?22.056?M^?1 and Gibbs free energy (ΔF^o)?=?–7.665 KJ/mole] confirmed the solubility enhancement capability of β-CD. Milling time of 6?h was considered to be optimum and showed maximum enhancement of drug dissolution. The amorphous nature of the milled complex and mode of interaction of MLX with β-CD was confirmed by differential scanning calorimetry (DSC), x-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance spectrophotometry (¹HNMR). Tablets containing MLX-β-CD (1:1.5?M) milled complexes showed the best release (T_90%?=?10.94?min) compared to the marketed products (T_90% ≥ 450?min). Stability studies performed confirmed the integrity of the amorphous complex.

Conclusion: Stable inclusion complexes of MLX-β-CD with enhanced aqueous solubility and dissolution rate were prepared by a highly efficient and controlled large-scale milling technique.     

Development and evaluation of orally disintegrating tablets of cilostazol-β-cyclodextrin inclusion complexes

Context: The clinical applications of cilostazol (CLZ) are limited by its low aqueous solubility (<5?µg/ml) and high biovariability.

Objective: The aim of this study was to enhance the solubility of CLZ by forming inclusion complexes (ICs) with beta cyclodextrin (β-CD) and formulating them into oral disintegrating tablets.

Methods: Phase solubility study of CLZ with β-CD was performed in water. Job’s plot was constructed to determine the stoichiometry of ICs. ICs, prepared by spray-drying technique, were characterized using Fourier transform infrared spectroscopy, differential scanning calorimetry, hot stage microscopy, powder X-ray diffraction and nuclear magnetic resonance. Molecular modeling studies were performed to understand the mode of interaction of CLZ with β-CD. The formulation process was undertaken using a reproducible design of experiment generated model, attained by variation of diluents and disintegrants at three levels. Tablets were evaluated for drug content, hardness, friability, disintegration time (DT), wetting time (WT) and dissolution profiles.

Results and discussion: Phase solubility studies suggested an A_L type curve with stability constant (K_s) of 922.52?M^?1. Job’s plot revealed 1:2 stoichiometry. All analytical techniques confirmed inclusion complexation. Molecular modeling revealed dispersive van der Waals interaction energy as a major contributor for stabilization of complex. The spray-dried complexes showed higher solubility and faster dissolution compared to plain CLZ. The optimized formulation showed DT of 11.1?±?0.8?s, WT of 8.7?±?0.9?s and almost complete dissolution of CLZ in 15?min.

Conclusion: The prepared tablets with low DT and fast dissolution will prove to be a promising drug delivery system with improved bioavailability and better patient compliance.