Abstract：
:AZD1175 and AZD2207 are 2 highly lipophilic compounds with a significant risk of not achieving therapeutic plasma concentrations due to solubility-limited absorption. The compounds have the same molecular weight and minimal structural differences. The aim of the present work was to investigate whether salts could be applied to improve the intestinal absorption, and the subsequent in vivo exposure. Drug solubilities, dissolution rates, and degree of supersaturation and precipitation were determined in biorelevant media. Dog studies were performed, in the absence and presence of a precipitation inhibitor (hydroxypropyl methylcellulose). Finally, a human phase I study was performed. For AZD1175, there was a good agreement between dissolution rates, in vivo exposure in dog, and the obtained exposure in human with the selected hemi-1,5-naphthalenedisulfonate of the compound. For AZD2207, the picture was more complex. The same counter ion was selected for the study in man. In addition, the chloride salt of AZD2207 showed promising data in the presence of a precipitation inhibitor in vitro and in dog that, however, could not be repeated in man. The differences in observations between the 2 compounds could be attributed to the difference in solubility and to the degree of supersaturation in the gastric environment rather than in the intestine.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Tannergren C,Karlsson E,Sigfridsson K,Lindfors L,Ku A,Polentarutti B,Carlert Sdoi
10.1016/j.xphs.2016.07.016subject
Has Abstractpub_date
2016-11-01 00:00:00pages
3314-3323issue
11eissn
0022-3549issn
1520-6017pii
S0022-3549(16)41605-9journal_volume
105pub_type
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