Abstract

Hydrophobic drugs are facing a significant challenge in dissolution rate enhancement and solubility in aqueous solutions; therefore, a variety of methods have been applied to improve dissolution rate and solubility. Accordingly, hydrophobic drugs can be formulated in suitable dosage forms. Three diuretic drugs were used in this research (bendroflumethiazide, furosemide and indapamide). Solid dispersions via lyophilisation technique and self-emulsifying drug delivery systems (SEDDS) were employed to enhance drugs’ dissolution rates. Furthermore, for solid dispersions, dissolution-enhancing excipients were added to the chosen drugs at different concentrations, those excipients were gluconolactone, hydroxypropyl-γ-cyclodextrin, and trehalose (used in three different ratios 1:1, 1:2, 1:5 drug: excipient). Regarding SEDDS, the drugs were mixed with oils (Labrafil®M1944CS) and surfactants (Labrasol®, CapryolTM90 and Solutol®HS15) in different ratios to form emulsifying systems. Nevertheless, all prepared formulations were investigated using the following techniques: dissolution testing (to determine drug release from solid dispersion and SEDD systems), high-performance liquid chromatography (to determine drugs’ contents), Fourier transform infrared spectroscopy (to investigate the drugs’ structural changes after processing), differential scanning calorimetry (to test thermal characteristics of the formulations), scanning electron microscopy (for testing particle morphology), and transmission electron microscopy and zeta sizer (for investigating SEDDS).

The results showed that the physical mixing and solid dispersions via the freeze-drying process meaningfully, p < 0.05, increased the percentage of bendroflumethiazide released with time. For example, the drug dissolution in the aqueous medium was enhanced from less than 20% to 99.79% within 90 min for physically mixed drug:hydroxypropyl-γ-cyclodextrin (1:5). The lyophilisation process enhanced the drug release rate, and the highest drug dissolution was obtained for drug:gluconolactone (1:1) with 98.98% drug release within 90 min. All furosemide lyophilised samples presented significant improvements, for drug dissolution, p < 0.05, with superior effects for hydroxypropyl-γ-cyclodextrin and trehalose over gluconolactone.
Regarding SEDDS, drugs’ samples formed negatively charged dispersions of 170-250nm and achieved rapid and significantly, p<0.05, higher drug release, which was maintained over 90min when compared to that of the unprocessed drug powders. Dissolution improvement and nano-size distribution characteristics for samples stored at 25 and 40ºC were preserved due to the formation of stable nano-sized SEDDS dispersions with high drug release, e.g. Indapamide, solubility and low CMC results.
The dissolution enhancement of the used hydrophobic drugs, using various sugar molecules is mainly referred to known sugars’ ability to enhance the dissolution of lipophilic drugs, owing to their ability to upsurge the external area, improving drug wettability and polar effects as they contain polar groups in their structure, hence superior solubility due to the possibility of the intermolecular hydrogen bonding development. However, SEDDS contributed to the drug dissolution enhancement by the spontaneous formation of small globules (in a nano-size range) containing drugs in solubilised forms; consequently, the surface area was increased, and dissolution rate was improved. Accordingly, SEDDS is a promising technique to be used for the dissolution augmentation of other hydrophobic drugs.