Danazol-β-cyclodextrin binary system: A potential application in emergency contraception by the oral route

This study explored the potential of β-cyclodextrin to improve the aqueous solubility and dissolution of danazol, investigated a simple and less expensive method for preparation of a danazol-β-cyclodextrin binary system, and explored the potential application of a danazol-β-cyclodextrin binary system as a single-dose emergency contraceptive. Phase solubility analysis indicated formation of a first-order soluble complex with stability constant 972.03 M⁻¹, while Job's plot affirmed 1∶1 stoichiometry. The hyperchromic shift in the UV-Vis spectrum of danazol in the presence of β-cyclodextrin indicated solubilization capability of β-cyclodextrin for danazol. The extrinsic Cotton effect with a negative peak at 280.7 nm confirmed the inclusion of danazol in the asymmetric locus of β-cyclodextrin.¹H-nuclear magnetic resonance analysis suggested that the protons of the steroidal skeleton of danazol display favorable interactions with the β-cyclodextrin cavity. The danazol-β-cyclodextrin binary system was prepared by kneading, solution, freeze-drying, and milling methods. The extent of the enhancement of dissolution rate was found to be dependent on the preparation method. Dissolution studies showed a similar relative dissolution rate (2.85) of the danazol-β-cyclodextrin binary system prepared by the freeze-drying and milling (in the presence of 13% moisture) methods. In a mouse model, the danazol-β-cyclodextrin binary system at 51.2 mg/kg (equivalent to a 400-mg human dose) showed 100% inhibition of implantation when given postcoitally. Moreover, the danazol-β-cyclodextrin binary system is safe up to 2000 mg/kg in the mouse (15.52 g/70 kg human) as a single oral dose. Thus, the danazol-β-cyclodextrin binary system could serve as a new therapeutic application: an oral emergency contraceptive at a physiologically acceptable single dose. Published: May 11, 2007     

Diclofenac-β-cyclodextrin binary systems: Physicochemical characterization and in vitro dissolution and diffusion studies

The aim of this work was to study the influence of β-cyclodextrin (β-CD) on the biopharmaceutic properties of diclofenac (DCF). To this purpose the physicochemical characterization of diclofenac-β-cyclodextrin binary systems was performed both in solution and solid state. Solid phase characterization was performed using differential scanning calorimetry (DSC), powder x-ray diffractometry (XRD), and Fourier transform infrared spectroscopy (FTIR). Phase solubility analyses, and in vitro permeation experiments through a synthetic membrane were performed in solution. Moreover, DCF/β-CD interactions were studied in DMSO by¹H nuclear magnetic resonance (NMR) spectroscopy. The effects of different preparation methods and drug-to-β-CD molar ratios were also evaluated. Phase solubility studies revealed 1∶1 M complexation of DCF when the freeze-drying method was used for the preparation of the binary system. The true inclusion for the freeze-dried binary system was confirmed by¹H NMR spectroscopy, DSC, powder XRD, and IR studies. The dissolution study revealed that the drug dissolution rate was improved by the presence of CDs and the highest and promptest release was obtained with the freeze-dried binary system. Diffusion experiments through a silicone membrane showed that DCF diffusion was higher from the saturated drug solution (control) than the freeze-dried inclusion complexes, prepared using different DCF-β-CD molar ratios. However, the presence of the inclusion complex was able to stabilize the system giving rise to a more regular diffusion profile. Published: October 22, 2005     

Triamterene-beta-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 beta-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 beta-cyclodextrin--by cogrinding, kneading, and coevaporation, using low pH conditions--and their characterization, 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 167.67 M(-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 beta-cyclodextrin in the coevaporate. Remarkable improvement in in vitro drug release profiles in 0.1N 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 beta-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 Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe on Formulating with Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances

The purpose of this study was to improve the aqueous solubility, dissolution, and pharmacodynamic properties of a BCS class II drug, ezetimibe (Eze) by preparing ternary cyclodextrin complex systems. We investigated the potential synergistic effect of two novel hydrophilic auxiliary substances, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and l-ascorbic acid-2-glucoside (AA2G) on hydroxypropyl-β-cyclodextrin (HPBCD) solubilization of poorly water-soluble hypocholesterolemic drug, Eze. In solution state, the binary and ternary systems were analyzed by phase solubility studies and Job’s plot. The solid complexes prepared by freeze-drying were characterized by Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), nuclear magnetic resonance (NMR), and scanning electron microscopy (SEM). The log P values, aqueous solubility, dissolution, and antihypercholesterolemic activity of all systems were studied. The analytical techniques confirmed the formation of inclusion complexes in the binary and ternary systems. HPBCD complexation significantly (p?<?0.05) reduced the log P and improved the solubility, dissolution, and hypocholesterolemic properties of Eze, and the addition of ternary component produced further significant improvement (p?<?0.05) even compared to binary system. The remarkable reduction in log P and enhancement in solubility, dissolution, and antihypercholesterolemic activity due to the addition of TPGS or AA2G may be attributed to enhanced wetting, dispersibility, and complete amorphization. The use of TPGS or AA2G as ternary hydrophilic auxiliary substances improved the HPBCD solubilization and antihypercholesterolemic activity of Eze.     

Tablet formulation containing meloxicam and beta-cyclodextrin: mechanical characterization and bioavailability evaluation

The purpose of this research was to evaluate beta-cyclodextrin (beta-CD) as a vehicle, either singly or in blends with lactose (spray-dried or monohydrate), for preparing a meloxicam tablet. Aqueous solubility of meloxicam in presence of beta-CD was investigated. The tablets were prepared by direct compression and wet granulation techniques. The powder blends and the granules were evaluated for angle of repose, bulk density, compressibility index, total porosity, and drug content. The tablets were subjected to thickness, diameter, weight variation test, drug content, hardness, friability, disintegration time, and in vitro dissolution studies. The effect of beta-CD on the bioavailability of meloxicam was also investigated in human volunteers using a balanced 2-way crossover study. Phase-solubility studies indicated an A(L)-type diagram with inclusion complex of 1:1 molar ratio. The powder blends and granules of all formulations showed satisfactory flow properties, compressibility, and drug content. All tablet formulations prepared by direct compression or wet granulation showed acceptable mechanical properties. The dissolution rate of meloxicam was significantly enhanced by inclusion of beta-CD in the formulations up to 30%. The mean pharmacokinetic parameters (C(max), K(e), and area under the curve [AUC](0-infinity)) were significantly increased in presence of beta-CD. These results suggest that beta-CD would facilitate the preparation of meloxicam tablets with acceptable mechanical properties using the direct compression technique as there is no important difference between tablets prepared by direct compression and those prepared by wet granulation. Also, beta-CD is particularly useful for improving the oral bioavailablity of meloxicam.     

Nanosuspensions Containing Oridonin/HP-β-Cyclodextrin Inclusion Complexes for Oral Bioavailability Enhancement via Improved Dissolution and Permeability

Chemotherapy via oral route of anticancer drugs offers much convenience and compliance to patients. However, oral chemotherapy has been challenged by limited absorption due to poor drug solubility and intestinal efflux. In this study, we aimed to develop a nanosuspension formulation of oridonin (Odn) using its cyclodextrin inclusion complexes to enhance oral bioavailability. Nanosuspensions containing Odn/2 hydroxypropyl-β-cyclodextrin inclusion complexes (Odn-CICs) were prepared by a solvent evaporation followed by wet media milling technique. The nanosuspensions were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and dissolution. The resulting nanosuspensions were approximately 313.8 nm in particle size and presented a microcrystal morphology. Nanosuspensions loading Odn-CICs dramatically enhanced the dissolution of Odn. Further, the intestinal effective permeability of Odn was markedly enhanced in the presence of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and poloxamer. Bioavailability studies showed that nanosuspensions with Odn-CICs can significantly promote the oral absorption of Odn with a relative bioavailability of 213.99% (Odn suspensions as reference). Odn itself possesses a moderate permeability and marginal intestinal metabolism. Thus, the enhanced bioavailability for Odn-CIC nanosuspensions can be attributed to improved dissolution and permeability by interaction with absorptive epithelia and anti-drug efflux. Nanosuspensions prepared from inclusion complexes may be a promising approach for the oral delivery of anticancer agents.     

Effects of the Preparation Method on the Formation of True Nimodipine SBE-β-CD/HP-β-CD Inclusion Complexes and Their Dissolution Rates Enhancement

The aims of this study were to enhance the solubility and dissolution rate of nimodipine (ND) by preparing the inclusion complexes of ND with sulfobutylether-b-cyclodextrin (SBE-β-CD) and 2-hydroxypropyl-b-cyclodextrin (HP-β-CD) and to study the effect of the preparation method on the in vitro dissolution profile in different media (0.1 N HCl pH 1.2, phosphate buffer pH 7.4, and distilled water). Thus, the inclusion complexes were prepared by kneading, coprecipitation, and freeze-drying methods. Phase solubility studies were conducted to characterize the complexes in the liquid state. The inclusion complexes in the solid state were investigated with differential scanning calorimetry (DSC), X-ray diffractometry (X-RD), and Fourier transform infrared spectroscopy (FT-IR). Stable complexes of ND/SBE-β-CD and ND/HP-β-CD were formed in distilled water in a 1:1 stoichiometric inclusion complex as indicated by an A_L-type diagram. The apparent stability constants (Ks) were 1334.4 and 464.1 M⁻¹ for ND/SBE-β-CD and ND/HP-β-CD, respectively. The water-solubility of ND was significantly increased in an average of 22- and 8-fold for SBE-β-CD and HP-β-CD, respectively. DSC results showed the formation of true inclusion complexes between the drug and both SBE-β-CD and HP-β-CD prepared by the kneading method. In contrast, crystalline drug was detectable in all other products. The dissolution studies showed that all the products exhibited higher dissolution rate than those of the physical mixtures and ND alone, in all mediums. However, the kneading complexes displayed the maximum dissolution rate in comparison with drug and other complexes, confirming the influence of the preparation method on the physicochemical properties of the products.     

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.     

Prodrugs of the cancer cell selective anti-cancer agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131) are orally efficacious in a mouse model of resistant colon cancer

A131 (1) possesses a unique cancer cell selective dual mechanism of action where cancer cells are killed but normal cells only undergo growth arrest and are able to regrow after removal of 1. SAR studies of 1 indicate that only the specific structure of 1 elicits the full pharmacological effect. However, application of 1 in mouse models of cancer has been hampered by its low solubility and stability when given orally. In this work we describe the study of various prodrugs based on modification of the indole nitrogen. A range of acyl analogues were prepared as prodrugs which were shown to undergo degradation to the parent drug in plasma. A preferred prodrug fully elicited the pharmacological effects of 1 in cells and led to high aqueous solubility suitable for oral administration. In a mouse model of paclitaxel-resistant colon cancer, compound 10, as a TFA salt, showed 76% tumor growth inhibition when administered at an oral dose of 80?mg/kg twice a day.     

Co-Amorphous Combination of Nateglinide-Metformin Hydrochloride for Dissolution Enhancement

The aim of the present work was to prepare a co-amorphous mixture (COAM) of Nateglinide and Metformin hydrochloride to enhance the dissolution rate of poorly soluble Nateglinide. Nateglinide (120 mg) and Metformin hydrochloride (500 mg) COAM, as a dose ratio, were prepared by ball-milling technique. COAMs were characterized for saturation solubility, amorphism and physicochemical interactions (X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR)), SEM, in vitro dissolution, and stability studies. Solubility studies revealed a sevenfold rise in solubility of Nateglinide from 0.061 to 0.423 mg/ml in dose ratio of COAM. Solid-state characterization of COAM suggested amorphization of Nateglinide after 6 h of ball milling. XRPD and DSC studies confirmed amorphism in Nateglinide, whereas FTIR elucidated hydrogen interactions (proton exchange between Nateglinide and Metformin hydrochloride). Interestingly, due to low energy of fusion, Nateglinide was completely amorphized and stabilized by Metformin hydrochloride. Consequently, in vitro drug release showed significant increase in dissolution of Nateglinide in COAM, irrespective of dissolution medium. However, little change was observed in the solubility and dissolution profile of Metformin hydrochloride, revealing small change in its crystallinity. Stability data indicated no traces of devitrification in XRPD of stability sample of COAM, and % drug release remained unaffected at accelerated storage conditions. Amorphism of Nateglinide, proton exchange with Metformin hydrochloride, and stabilization of its amorphous form have been noted in ball-milled COAM of Nateglinide-Metformin hydrochloride, revealing enhanced dissolution of Nateglinide. Thus, COAM of Nateglinide-Metformin hydrochloride system is a promising approach for combination therapy in diabetic patients.     

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.     

Preparation and Evaluation of Diosgenin Nanocrystals to Improve Oral Bioavailability

Diosgenin (DSG), a well-known steroid sapogenin derived from Dioscorea nipponica Makino and Dioscorea zingiberensis Wright, has a variety of bioactivities. However, it shows low oral bioavailability due to poor aqueous solubility and strong hydrophobicity. The present study aimed to develop DSG nanocrystals to increase the dissolution and then improve the oral bioavailability and biopharmaceutical properties of DSG. DSG nanocrystals were prepared by the media milling method using a combination of pluronic F127 and sodium dodecyl sulfate as surface stabilizers. The physicochemical properties of the optimal DSG nanocrystals were characterized using their particle size distribution, morphology, differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy data, and solubility and dissolution test results. Pharmacokinetic studies of the DSG coarse suspension and its nanocrystals were performed in rats. The particle size and polydispersity index of DSG nanocrystals were 229.0?±?3.7 nm and 0.163?±?0.064, respectively. DSG retained its original crystalline state during the manufacturing process, and its chemical structure was not compromised by the nanonizing process. The dissolution rate of the freeze-dried DSG nanocrystals was significantly improved in comparison with the original DSG. The pharmacokinetic studies showed that the AUC_0–72h and C _max of DSG nanocrystals increased markedly (p?<?0.01) in comparison with the DSG coarse suspension by about 2.55- and 2.01-fold, respectively. The use of optimized nanocrystals is a good and efficient strategy for oral administration of DSG due to the increased dissolution rate and oral bioavailability of DSG nanocrystals.     

Characterization of beta-lapachone and methylated beta-cyclodextrin solid-state systems

The purpose of this research was to explore the utility of beta cyclodextrin (betaCD) and beta cyclodextrin derivatives (hydroxypropyl-beta-cyclodextrin [HPbetaCD], sulfobutylether-beta-CD [SBbetaCD], and a randomly methylated-beta-CD [RMbetaCD]) to form inclusion complexes with the antitumoral drug, beta-lapachone (betaLAP), in order to overcome the problem of its poor water solubility. RMbetaCD presented the highest efficiency for betaLAP solubilization and was selected to develop solid-state binary systems. Differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), Fourier transform infrared (FTIR) and optical and scanning electron microscopy results suggest the formation of inclusion complexes by both freeze-drying and kneading techniques with a dramatic improvement in drug dissolution efficiency at 20-minute dissolution efficiency (DE(20-minute) 67.15% and 88.22%, respectively) against the drug (DE(20-minute) 27.11%) or the betaCD/drug physical mixture (DE(20-minute) 27.22%). However, the kneading method gives a highly crystalline material that together with the adequate drug dissolution profile make it the best procedure in obtaining inclusion complexes of RMbetaCD/betaLAP convenient for different applications of betaLAP.     

Design,Optimization, and Evaluation of Lurasidone Hydrochloride Nanocrystals

The present investigation was carried out to design, optimize, and evaluate lurasidone hydrochloride nanocrystals for improving its solubility and dissolution characteristics. Nanocrystals were prepared by media milling technique using zirconium oxide beads with 0.1 mm diameter. Various stabilizers, viz. poloxamer 188, PVP K30, SLS, HPMC E15, and PVP S 630 D, were evaluated to stabilize the nanocrystals. The Pareto chart obtained through Plackett-Burman screening design revealed that HPMC E 15 showed the highest standardized effect (p value <0.05) on percent dissolution efficiency at 2 min. In subsequent studies, a 3² factorial design was employed to quantify the effect of two independent variables, namely amount of stabilizer and milling time on predetermined response variables mean particle size, saturation solubility, and percent dissolution efficiency at 2 min. Statistical analysis of the factorial design revealed that all predetermined response variables were significantly dependent (p value <0.05) on the independent variables. The observed response of the optimized batch prepared as per the desirability function was in close agreement with predicted response, and mathematical model generated was validated. The optimized batch was lyophilized, and X-ray powder diffraction studies indicated that there was no substantial change in crystallinity of the drug. The optimized formulation showed mean particle size of 228 nm and released almost all the drug within first 5 min. Since the crystallinity of the drug is maintained, improvement in saturation solubility and dissolution efficiency could be attributed to decrease in mean particle size of the drug.     

Binary and ternary inclusion complexes of finasteride in HPβCD and polymers: Preparation and characterization

The aim of this study was to determine whether inclusion complexes between 2-hydroxypropyl-β-cyclodextrin (HPβCD) and finasteride (FIN) are formed, and to characterize these. Equimolar FIN/HPβCD solid systems in the presence or absence of 0.1% (w/v) of polyvinylpyrrolidone K30 (PVP K30) or 0.3% of chitosan were prepared by coevaporation and freeze-drying methods. The systems were characterized by phase solubility, NMR, DSC, and XRD analysis. The results suggest that true binary and ternary inclusion complexes were formed.     

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.     

Assessment of Incremental Dosage Regimen of Combined Oestrogen-Progestogen Oral Contraceptive

Eighty-six women of proved fertility used an incremental dosage regimen of a combined oral contraceptive for a total of 570 cycles over one year. A daily tablet containing 50 μg of ethinyloestradiol and 50 μg D-norgestrel was taken for 11 days and a daily tablet containing 50 μg ethinyloestradiol and 125 μg D-norgestrel for the next 10 days. Withdrawal bleeding occurred during the tabletfree interval of seven days. The new preparation proved to be an efficient contraceptive, well tolerated, and with few side effects. Women who had gained weight while taking other oral contraceptives lost weight when they changed to the new preparation. The regimen allowed a significant reduction in the cycle dose of progestogen, and these results suggest that a further reduction in the cycle dose of both oestrogen and progestogen may be possible without losing contraceptive efficiency.     

Effect of Drug Solubility on Polymer Hydration and Drug Dissolution from Polyethylene Oxide (PEO) Matrix Tablets

The purpose of the study was to investigate the effect of drug solubility on polymer hydration and drug dissolution from modified release matrix tablets of polyethylene oxide (PEO). Different PEO matrix tablets were prepared using acetaminophen (ACE) and ibuprofen (IBU) as study compounds and Polyox WSR301 (PEO) as primary hydrophilic matrix polymer. Tablet dissolution was tested using the USP Apparatus II, and the hydration of PEO polymer during dissolution was recorded using a texture analyzer. Drug dissolution from the preparations was dependent upon drug solubility, hydrogel formation and polymer proportion in the preparation. Delayed drug release was attributed to the formation of hydrogel layer on the surface of the tablet and the penetration of water into matrix core through drug dissolution and diffusion. A multiple linear regression model could be used to describe the relationship among drug dissolution, polymer ratio, hydrogel formation and drug solubility; the mathematical correlation was also proven to be valid and adaptable to a series of study compounds. The developed methodology would be beneficial to formulation scientists in dosage form design and optimization.     

Cyclodextrin-facilitated bioconversion of 17 beta-estradiol by a phenoloxidase from Mucuna pruriens cell cultures.

After complexation with beta-cyclodextrin, the phenolic steroid 17 beta-estradiol could be ortho-hydroxylated into a catechol, mainly 4-hydroxyestradiol, by a phenoloxidase from in vitro grown cells of Mucuna pruriens. By complexation with beta-cyclodextrin the solubility of the steroid increased from almost insoluble to 660 microM. The bioconversion efficiency after 72 hr increased in the following order: freely suspended cells (0%), immobilized cells (1%), cell homogenate (6%), phenoloxidase preparation (40%). Mushroom tyrosinase converted 17 beta-estradiol, as a complex with beta-cyclodextrin, solely into 2-hydroxyestradiol, with a maximal yield of 30% after 6-8 hr. Uncomplexed 17 beta-estradiol was not converted at all in any of these systems.