Abstract
Purpose: Hydrophobic drugs are facing a major challenge in dissolution rate enhancement and solubility in aqueous solutions; therefore, a variety of methods have been used to improve dissolution rate and/or solubility of bendroflumethiazide as a model hydrophobic drug. Methods: In this study, two main methods (physical mixing and lyophilisation) were used with gluconolactone, hydroxyl propyl γ-ccyclodextrin, and trehalose to explore this challenge. Bendroflumethiazide, practically insoluble in water, was mixed with one of the three excipients gluconolactone, hydroxyl propyl γ-cyclodextrin, and trehalose in three different ratios 1:1, 1:2, 1:5. To the best of our knowledge, the dissolution of the drug has not been previously enhanced by using either these methods or any of the used excipients. Samples containing drug and each of the excipients were characterized via dissolution testing, Fourier Transform infra-red spectroscopy, differential scanning calorimetry, and scanning electron microscopy. Results: The used methods showed a significant enhancement in dug dissolution rate; physical mixing significantly, p < 0.05, increased the percentage of the drug released with time; for example, bendroflumethiazide dissolution in distilled water was improved from less than 20% to 99.79% within 90 min for physically mixed drug-cyclodextrin 1:5. The lyophilisation process was enhanced and the drug dissolution rate and the highest drug dissolution was achieved for (drug-gluconolactone 1:1) with 98.98% drug release within 90 min. Conclusions: the physical mixing and freeze drying processes significantly increased the percentage of drug release with time.
Highlights
For the pharmaceutical industry, one of the greatest challenges in the hydrophobic drug development process is the water solubility, which is the key controlling dissolution rate, and bioavailability [1]
Drug must be dissolved in the gastric fluids to be absorbed into the systemic circulation following oral administration, incomplete absorption from the gastrointestinal tract leads to disruption in drug distribution, reduced bioavailability and therapeutic failure [2]; solubility enhancement for hydrophobic drugs is essential
There were attempts in the past to enhance this drug solubility/dissolution including spray drying process [12,23], using solid dispersion formulations with polymers such as polyvinylpyrrolidone, polyethylene glycols [24]; these polymers have certain limitations, such as a tendency to crystallise and an inability to stabilise some active ingredients in the solid phase [25]
Summary
One of the greatest challenges in the hydrophobic drug development process is the water solubility, which is the key controlling dissolution rate, and bioavailability [1]. There were attempts in the past to enhance this drug solubility/dissolution including spray drying process [12,23], using solid dispersion formulations with polymers such as polyvinylpyrrolidone, polyethylene glycols [24]; these polymers have certain limitations, such as a tendency to crystallise and an inability to stabilise some active ingredients in the solid phase [25]. In this current study, bendroflumethiazide with various sugar molecules-based dissolution enhancing carriers (namely, hydroxyl-propyl gamma cyclodextrin, gluconolactone and trehalose) were processed by the lyophilisation and physical mixing techniques. The aim of this study was to evaluate the effectiveness of the above-mentioned excipients with physical mixing and lyophilisation techniques on dissolution performance of bendroflumethiazide, by tracking morphological and physicochemical drug characteristics during this enhancement process
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