ABSTRACT
Purpose
This study focuses on the formulation optimization, in vitro and in vivo performance of differently sized nano-crystalline liquid suspensions and spray-dried powders of a poorly soluble BCS class II compound i.e. Danazol.
Methods
A DoE approach was utilized to optimize stabilizer concentration and formulate danazol (BCS class II) nano-crystalline suspensions and dry powders via wet milling followed by spray drying. Solubility studies were performed to select best stabilizers. Particle size, PXRD, contact angle measurement and in vitro dissolution were utilized in characterization of the liquid and spray-dried powder formulations.
Results
The liquid nano-crystalline suspensions followed particle size-dependent dissolution rates i.e. faster dissolution for smaller crystals. The spray-dried nano-crystal powders did not show fast dissolution profiles compared to the liquid nano-crystalline suspension. The poor dissolution of the spray-dried powder correlated to its high LogP value (i.e. LogP 4.53) and poor wetting (or polar surface-area). In vivo bioavailability studies showed superior performance of the liquid nano-crystalline suspensions compared to other milled and un-milled formulations.
Conclusion
Wet-milling and spray-drying optimization for danazol nano-crystalline suspension was performed. This study indicates that drug candidates with high LogP values and low polar surface area may not be suitable for formulation as dry nano-crystals.
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Abbreviations
- AUC:
-
Area under the curve
- BCS:
-
Biopharmaceutics classification system
- Cmax:
-
Maximum concentration
- DoE:
-
Design of experiment
- NS:
-
Nanosuspensions
- PSA:
-
Polar surface area
- PXRD:
-
Powder X-ray diffraction
- SD:
-
Spray drying
- Tmax:
-
Time to reach maximum concentration
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ACKNOWLEDGMENTS AND DISCLOSURES
The authors are grateful to Dr. Anson Ma (Associate Professor, University of Connecticut) and Dr. Xiuling Lu (Assistant professor, University of Connecticut) for use of the contact angle goniometer and HPLC-Fluorescence, respectively.
Funding
This current research was funded and supported by FDA/CDER/OPS (Contract number HHSF223201110077A).
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Kumar, S., Jog, R., Shen, J. et al. Formulation and Performance of Danazol Nano-crystalline Suspensions and Spray Dried Powders. Pharm Res 32, 1694–1703 (2015). https://doi.org/10.1007/s11095-014-1567-0
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DOI: https://doi.org/10.1007/s11095-014-1567-0