Solid-state characterization and dissolution properties of ezetimibe–cyclodextrins inclusion complexes

Patel, Rakesh P.; Bhimani, Dipen B.; Patel, Jay; Patel, Deepa

doi:10.1007/s10847-007-9371-7

Cited by 46 publications

(38 citation statements)

References 10 publications

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“…With respect to the binary E-CD system, the altered pH could be the possible reason for the higher stability constant obtained in this study (statistically significant, p<0.05) compared to the value reported earlier (1316 M −1 ) by Patel et al [5]. We performed all the liquid-state analyses using 4.5 pH acetate buffer in contrast to the distilled water used by Patel et al [5] because our dissolution studies were conducted using the same pH media.…”

Section: Discussioncontrasting

confidence: 63%

“…Attempts were made in the past to study the benefits of Eze-CD complexation. Patel et al was the first to prepare incompletely amorphous complexes of Eze with β-CD and HPBCD by coevaporation and kneading methods and pointed out the influence of method of complex preparation on solubility and dissolution behaviors [5]. Taupitz et al also prepared incompletely amorphous Eze-HPBCD binary complex by freeze-drying method and clearly stated that incomplete amorphous state relates to incomplete complexation of the sample [6].…”

Section: Introductionmentioning

confidence: 99%

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Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe on Formulating with Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances

Srivalli

Mishra

2015

AAPS PharmSciTech

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Abstract. 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.

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Section: Discussioncontrasting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe on Formulating with Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances

Srivalli

Mishra

2015

AAPS PharmSciTech

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“…EZE, being practically insoluble in water, exhibits a low dissolution profile in gastrointestinal fluids with variable bioavailability. Thus, researchers have investigated different approaches to ameliorate the dissolution characteristics of EZE (7)(8)(9) and optimize bioavailability with a less variable pharmacokinetic profile.…”

Section: Introductionmentioning

confidence: 99%

Studies in Dissolution Enhancement of Ezetimibe by Solid Dispersions in Combination with a Surface Adsorbent

Parmar¹,

Shah²,

Sheth³

2011

Dissolution Technol.

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The aim of this investigation was to improve the dissolution properties of the water-insoluble drug ezetimibe (EZE) and potentially improve bioavailability. A combination of melt and adsorption techniques was employed for the preparation of solid dispersions. PEG 4000, PEG 6000, and Gelucire 44/14 were used as hydrophilic carriers, and lactose monohydrate was used as an adsorbent. Phase solubility curves are of A L type, indicating a linear relationship between drug solubility and carrier concentration. Dissolution studies reveal an improvement of in vitro drug release. Mathematical modeling indicates that drug release data are best described by the Korsmeyer-Peppas model, with Fickian diffusion as the possible drug-release mechanism. Physicochemical characterization of solid dispersions by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) suggests a reduction in drug crystallinity following dissolution enhancement. Hence, the present investigation reveals that the dissolution characteristics of EZE could be ameliorated in a solid dispersion.

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“…Ezetimibe has a highly irregular and very slow dissolution rate in GI fluids due to its hydrophobic character, 5 resulting in reduced and highly unpredictable bioavailability. 6,7,35 In this study, the solubility, dissolution, and bioavailability of ezetimibe-loaded solid SNEDDS, SMSD, and SESD were compared, leading to the selection of the best drug delivery system with the highest oral bioavailability.…”

Section: Discussionmentioning

confidence: 99%

“…It has a fast first-pass metabolism and P-glycoprotein efflux. Moreover, due to its hydrophobic character, this drug has an extremely irregular and very low dissolution profile in the gastrointestinal (GI) fluids, 5 resulting in highly unpredictable bioavailability. 6,7 The bioavailability of orally administered drugs can be improved by using lipid-based formulations.…”

mentioning

confidence: 99%

Comparative study on solid self-nanoemulsifying drug delivery and solid dispersion system for enhanced solubility and bioavailability of ezetimibe

Rashid¹,

Kim²,

Yousaf³

et al. 2015

IJN

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Background The objective of this study was to compare the physicochemical characteristics, solubility, dissolution, and oral bioavailability of an ezetimibe-loaded solid self-nanoemulsifying drug delivery system (SNEDDS), surface modified solid dispersion (SMSD), and solvent evaporated solid dispersion (SESD) to identify the best drug delivery system with the highest oral bioavailability. Methods For the liquid SNEDDS formulation, Capryol 90, Cremophor EL, and Tween 80 were selected as the oil, surfactant, and cosurfactant, respectively. The nanoemulsion-forming region was sketched using a pseudoternary phase diagram on the basis of reduced emulsion size. The optimized liquid SNEDDS was converted to solid SNEDDS by spray drying with silicon dioxide. Furthermore, SMSDs were prepared using the spray drying technique with various amounts of hydroxypropylcellulose and Tween 80, optimized on the basis of their drug solubility. The SESD formulation was prepared with the same composition of optimized SMSD. The aqueous solubility, dissolution, physicochemical properties, and pharmacokinetics of all of the formulations were investigated and compared with the drug powder. Results The drug existed in the crystalline form in SMSD, but was changed into an amorphous form in SNEDDS and SESD, giving particle sizes of approximately 24, 6, and 11 µm, respectively. All of these formulations significantly improved the aqueous solubility and dissolution in the order of solid SNEDDS ≥ SESD > SMSD, and showed a total higher plasma concentration than did the drug powder. Moreover, SESD gave a higher area under the drug concentration time curve from zero to infinity than did SNEDDS and SMSD, even if they were not significantly different, suggesting more improved oral bioavailability. Conclusion Among the various formulations tested in this study, the SESD system would be strongly recommended as a drug delivery system for the oral administration of ezetimibe with poor water solubility.

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Solid-state characterization and dissolution properties of ezetimibe–cyclodextrins inclusion complexes

Cited by 46 publications

References 10 publications

Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe on Formulating with Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances

Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe on Formulating with Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances

Studies in Dissolution Enhancement of Ezetimibe by Solid Dispersions in Combination with a Surface Adsorbent

Comparative study on solid self-nanoemulsifying drug delivery and solid dispersion system for enhanced solubility and bioavailability of ezetimibe

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