Effect of Solubility Improvement <i>via</i> Formation of an Amorphous Composite of Indomethacin and Sulindac on Membrane Permeability

Abstract

The importance of permeability as well as solubility of the drug has been recognized in improving the solubility of poorly water-soluble drugs. This study investigated the impact of amorphous composites of indomethacin (IMC) and sulindac (SLD) on the membrane permeability of drugs. The IMC/SLD (1/1) formulation prepared by dry grinding was amorphous with a single glass transition temperature. The Fourier transform IR spectra and Raman spectra revealed formation of hydrogen bonds between the OH group of IMC and the carbonyl group of SLD. These results suggest that an amorphous composite was formed between IMC and SLD through hydrogen bonding. The amount of dissolved IMC and SLD from the amorphous composite of IMC/SLD (1/1) was higher than that of the untreated IMC or SLD in the dissolution test. The permeated amounts and permeation rates of both drugs were enhanced by increasing the solubility of the amorphous composite. Conversely, the apparent membrane permeability coefficients (P app ) were almost same for untreated drugs and amorphous composites. In the case of hydroxypropyl-β-cyclodextrin and sodium dodecyl sulfate, P app of the drugs decreased with the addition of these compounds, although the drug solubility was enhanced by the solubilization effect. This study revealed that an amorphous composite formed through hydrogen bonding is an attractive pharmaceutical way to enhance the permeated amount and permeation rate without changing the P app of both the drugs.

Designing a Novel Coamorphous Salt Formulation of Telmisartan with Amlodipine to Enhance Permeability and Oral Absorption

“…The P app of TMS and AML from the ground TMS/AML (1:1) was 3.8 × 10 –6 cm/s at TMS concentrations of 79 μg/mL and 8.0 × 10 –9 cm/s at an AML concentration of 74 μg/mL, respectively. In our previous study, the coamorphous formation between indomethacin and sulindac did not affect the P app of the drugs, even with improved solubility via supersaturation . Indomethacin–sulindac coamorphous formation via hydrogen bonds could dissociate into free drugs in an aqueous solution before membrane permeation and increase membrane-permeable drugs on the surface of the membrane in proportion to solubility.…”

“…19,20 The membrane permeability of drugs in the coamorphous state via hydrogen bonding between indomethacin and sulindac has been previously reported. 21 The coamorphous formation between indomethacin and sulindac simultaneously enhanced the permeated amount and flux of both drugs without changing their P app . This indicates that the hydrogen bonds formed in the solid state were broken after dispersing in the aqueous solution, and membrane-permeable free drugs were supplied from the coamorphous formation on the membrane surface.…”

“…Laitinen et al concluded that coamorphous salt formation was more effective than non-salt coamorphous systems for stabilizing supersaturation . However, there have been few reports on the effects of coamorphous formation on drug membrane permeation. , The membrane permeability of drugs in the coamorphous state via hydrogen bonding between indomethacin and sulindac has been previously reported . The coamorphous formation between indomethacin and sulindac simultaneously enhanced the permeated amount and flux of both drugs without changing their P app .…”

“…In our previous study, the coamorphous formation between indomethacin and sulindac did not affect the P app of the drugs, even with improved solubility via supersaturation. 21 Indomethacin−sulindac coamorphous formation via hydrogen bonds could dissociate into free drugs in an aqueous solution before membrane permeation and increase membrane-permeable drugs on the surface of the membrane in proportion to solubility. Based on this phenomenon, two reasons may be considered for the decreased P app of drugs: coamorphous salt formation between TMS and AML.…”