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Dissolution of Danazol Amorphous Solid Dispersions: Supersaturation and Phase Behavior as a Function of Drug Loading and Polymer Type.
Mol Pharm. 2016 Jan 04; 13(1):223-31.MP

Abstract

Amorphous solid dispersions (ASDs) are of great interest as enabling formulations because of their ability to increase the bioavailability of poorly soluble drugs. However, the dissolution of these formulations under nonsink dissolution conditions results in highly supersaturated drug solutions that can undergo different types of phase transitions. The purpose of this study was to characterize the phase behavior of solutions resulting from the dissolution of model ASDs as well as the degree of supersaturation attained. Danazol was chosen as a poorly water-soluble model drug, and three polymers were used to form the dispersions: polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), and hydroxypropylmethyl cellulose acetate succinate (HPMCAS). Dissolution studies were carried out under nonsink conditions, and solution phase behavior was characterized using several orthogonal techniques. It was found that liquid-liquid phase separation (LLPS) occurred following dissolution and prior to crystallization for most of the dispersions. Using flux measurements, it was further observed that the maximum attainable supersaturation following dissolution was equivalent to the amorphous solubility. The dissolution of the ASDs led to sustained supersaturation, the duration of which varied depending on the drug loading and the type of polymer used in the formulation. The overall supersaturation profile observed thus depended on a complex interplay between dissolution rate, polymer type, drug loading, and the kinetics of crystallization.

Authors+Show Affiliations

Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University , West Lafayette, Indiana 47907, United States.Bristol-Myers Squibb Company , New Brunswick, New Jersey 08903, United States.Bristol-Myers Squibb Company , New Brunswick, New Jersey 08903, United States.Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University , West Lafayette, Indiana 47907, United States.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26618718

Citation

Jackson, Matthew J., et al. "Dissolution of Danazol Amorphous Solid Dispersions: Supersaturation and Phase Behavior as a Function of Drug Loading and Polymer Type." Molecular Pharmaceutics, vol. 13, no. 1, 2016, pp. 223-31.
Jackson MJ, Kestur US, Hussain MA, et al. Dissolution of Danazol Amorphous Solid Dispersions: Supersaturation and Phase Behavior as a Function of Drug Loading and Polymer Type. Mol Pharm. 2016;13(1):223-31.
Jackson, M. J., Kestur, U. S., Hussain, M. A., & Taylor, L. S. (2016). Dissolution of Danazol Amorphous Solid Dispersions: Supersaturation and Phase Behavior as a Function of Drug Loading and Polymer Type. Molecular Pharmaceutics, 13(1), 223-31. https://doi.org/10.1021/acs.molpharmaceut.5b00652
Jackson MJ, et al. Dissolution of Danazol Amorphous Solid Dispersions: Supersaturation and Phase Behavior as a Function of Drug Loading and Polymer Type. Mol Pharm. 2016 Jan 4;13(1):223-31. PubMed PMID: 26618718.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dissolution of Danazol Amorphous Solid Dispersions: Supersaturation and Phase Behavior as a Function of Drug Loading and Polymer Type. AU - Jackson,Matthew J, AU - Kestur,Umesh S, AU - Hussain,Munir A, AU - Taylor,Lynne S, Y1 - 2015/12/09/ PY - 2015/12/1/entrez PY - 2015/12/1/pubmed PY - 2016/10/1/medline KW - amorphous solid dispersion KW - amorphous solubility KW - crystallization KW - dissolution KW - polymers KW - supersaturation SP - 223 EP - 31 JF - Molecular pharmaceutics JO - Mol Pharm VL - 13 IS - 1 N2 - Amorphous solid dispersions (ASDs) are of great interest as enabling formulations because of their ability to increase the bioavailability of poorly soluble drugs. However, the dissolution of these formulations under nonsink dissolution conditions results in highly supersaturated drug solutions that can undergo different types of phase transitions. The purpose of this study was to characterize the phase behavior of solutions resulting from the dissolution of model ASDs as well as the degree of supersaturation attained. Danazol was chosen as a poorly water-soluble model drug, and three polymers were used to form the dispersions: polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), and hydroxypropylmethyl cellulose acetate succinate (HPMCAS). Dissolution studies were carried out under nonsink conditions, and solution phase behavior was characterized using several orthogonal techniques. It was found that liquid-liquid phase separation (LLPS) occurred following dissolution and prior to crystallization for most of the dispersions. Using flux measurements, it was further observed that the maximum attainable supersaturation following dissolution was equivalent to the amorphous solubility. The dissolution of the ASDs led to sustained supersaturation, the duration of which varied depending on the drug loading and the type of polymer used in the formulation. The overall supersaturation profile observed thus depended on a complex interplay between dissolution rate, polymer type, drug loading, and the kinetics of crystallization. SN - 1543-8392 UR - https://www.unboundmedicine.com/medline/citation/26618718/Dissolution_of_Danazol_Amorphous_Solid_Dispersions:_Supersaturation_and_Phase_Behavior_as_a_Function_of_Drug_Loading_and_Polymer_Type_ L2 - https://doi.org/10.1021/acs.molpharmaceut.5b00652 DB - PRIME DP - Unbound Medicine ER -