Abstract
Purpose
The purpose of this study was to develop an amorphous solid dispersion (SD) of an extremely water-insoluble and very weakly basic drug, itraconazole (ITZ), by interaction with weak organic acids and then drying that would enhance dissolution rate of drug and physical stability of formulation.
Methods
Aqueous solubility of ITZ in concentrated solutions of weak organic acids, such as glutaric, tartaric, malic and citric acid, was determined. Solutions with high drug solubility were dried using vacuum oven and the resulting SDs having 2 to 20% drug load were characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. The dissolution of SDs was initially studied in 250 mL of 0.1 N HCl (pH 1.1), and any undissolved solids were collected and analyzed by PXRD. The pH of the dissolution medium was then changed from 1.1 to 5.5, particle size of precipitates were measured, and drug concentrations in solution were determined by filtration through membrane filters of varying pore sizes.
Results
The aqueous solubility of ITZ was greatly enhanced in presence of weak acids. While the solubility of ITZ in water was ~4 ng/ mL, it increased to 25–40 mg per g of solution at 25°C and 200 mg per g of solution at 65°C at a high acid concentration leading to extremely high solubilization. PXRD of SDs indicated that ITZ was present in the amorphous form, wherein the acid formed a partially crystalline matrix. ATR-FTIR results showed possible weak interactions, such as hydrogen bonding, between drug and acid but there was no salt formation. SDs formed highly supersaturated solutions at pH 1.1 and had superior dissolution rate as compared to amorphous drug and physical mixtures of drug and acids. Following the change in pH from 1.1 to 5.5, ITZ precipitated as mostly nanoparticles, providing high surface area for relatively rapid redissolution.
Conclusions
A method of highly solubilizing an extremely water-insoluble drug, ITZ, in aqueous media and converting it into an amorphous form in a physically stable SD was successfully investigated. The dissolution rate and the extent of supersaturation of the drug in dissolution media improved greatly, and any precipitate formed at high pH had very small particle size.
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Abbreviations
- ATR-FTIR:
-
Attenuated total reflectance-Fourier transform infrared spectroscopy
- DSC:
-
Differential scanning calorimetry
- HPMC:
-
Hydroxypropylmethyl cellulose
- HPMCAS:
-
Hydroxypropylmethyl cellulose acetate succinate
- ITZ:
-
Itraconazole
- PXRD:
-
Powder X-ray diffractometry
- SD:
-
Solid dispersion
- TGA:
-
Thermogravimetric analysis
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ACKNOWLEDGMENTS AND DISCLOSURES
The authors would like to acknowledge the support of chemistry department at St. John’s University for providing the equipment to conduct FTIR studies.
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The views and opinions expressed in this article are those of the authors and do not reflect the official policy or position of Food and Drug Administration or any other agency of the U.S. government.
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Parikh, T., Sandhu, H.K., Talele, T.T. et al. Characterization of Solid Dispersion of Itraconazole Prepared by Solubilization in Concentrated Aqueous Solutions of Weak Organic Acids and Drying. Pharm Res 33, 1456–1471 (2016). https://doi.org/10.1007/s11095-016-1890-8
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DOI: https://doi.org/10.1007/s11095-016-1890-8