Exploring the Impact of Intestinal Fluid Components on the Solubility and Supersaturation of Danazol
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Exploring the Impact of Intestinal Fluid Components on the Solubility and Supersaturation of Danazol. / Madsen, Cecilie Maria; Plum, Jakob; Hens, Bart; Augustijns, Patrick; Mullertz, Anette; Rades, Thomas.
In: Journal of Pharmaceutical Sciences, Vol. 110, No. 6, 2021, p. 2479-2488.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Exploring the Impact of Intestinal Fluid Components on the Solubility and Supersaturation of Danazol
AU - Madsen, Cecilie Maria
AU - Plum, Jakob
AU - Hens, Bart
AU - Augustijns, Patrick
AU - Mullertz, Anette
AU - Rades, Thomas
PY - 2021
Y1 - 2021
N2 - Eleven simulated intestinal fluids (SIF) were designed using a Design of Experiment (DoE) approach. The DoE SIF covered a range of compositions of fasted state human intestinal fluid (FaHIF) with regard to pH, bile salt (BS), and phospholipid (PL). Using the model compound danazol, the apparent crystalline solubility (aCS) and apparent amorphous solubility (aAS), as well as the supersaturation propensity was determined in the DoE SIF media. The aCS of danazol was dependent on the composition of the SIF, with PL as the main factor, and a small effect from BS and an interaction between BS and PL. From the DoE solubility data a model was derived, which could predict aCS in commercially available SIF (FaSSIF-V1 and -V2) and in a range of FaHIF. The aAS of danazol was differently affected by the SIF composition than the aCS; PL was again the main factor influencing the aAS, but interactions between BS and pH, as well as pH and PL were also important. The supersaturation propensities of danazol in the DoE SIF media were affected by the same factors as the aCS. Hence, the supersaturation behaviour and aCS of danazol, were found to be closely related.
AB - Eleven simulated intestinal fluids (SIF) were designed using a Design of Experiment (DoE) approach. The DoE SIF covered a range of compositions of fasted state human intestinal fluid (FaHIF) with regard to pH, bile salt (BS), and phospholipid (PL). Using the model compound danazol, the apparent crystalline solubility (aCS) and apparent amorphous solubility (aAS), as well as the supersaturation propensity was determined in the DoE SIF media. The aCS of danazol was dependent on the composition of the SIF, with PL as the main factor, and a small effect from BS and an interaction between BS and PL. From the DoE solubility data a model was derived, which could predict aCS in commercially available SIF (FaSSIF-V1 and -V2) and in a range of FaHIF. The aAS of danazol was differently affected by the SIF composition than the aCS; PL was again the main factor influencing the aAS, but interactions between BS and pH, as well as pH and PL were also important. The supersaturation propensities of danazol in the DoE SIF media were affected by the same factors as the aCS. Hence, the supersaturation behaviour and aCS of danazol, were found to be closely related.
KW - Developability
KW - Gastrointestinal tract
KW - Oral drug delivery
KW - Poorly water-soluble drug(s)
KW - Preformulation
KW - Solubility
KW - Supersaturation
U2 - 10.1016/j.xphs.2020.12.039
DO - 10.1016/j.xphs.2020.12.039
M3 - Journal article
C2 - 33428916
VL - 110
SP - 2479
EP - 2488
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
SN - 0022-3549
IS - 6
ER -
ID: 271609414