Abstract：
PURPOSE:Nine common excipients were examined to determine their ability to cause disproportionation of the HCl salt of a a weakly basic compound. The goal was to determine which excipients were problematic and correlate the results to known properties such as surface pH, slurry pH, or molecular structure. Such a correlation enables a general, simple excipient selection process. METHODS:Binary compacts and "pseudo formulations" are studied after stressing at 40°C/75%RH and 40°C/35% RH for up to 28 days. Near-Infrared (NIR) and X-Ray powder diffraction (XRPD) measurements monitored the conversion of the HCl salt to the free base. RESULTS:The excipients which induced measureable disproportionation were magnesium stearate, sodium croscarmellose, and sodium stearyl fumarate. Magnesium stearate induced the most extensive and rapid disproportionation at 40°C/75%RH and 40°C/35%RH. Samples containing magnesium stearate showed a unique and significant water uptake above 31%RH. CONCLUSIONS:The problematic excipients are best explained by the proton accepting capacity of excipient carboxylate groups which have pK(a)'s higher than the pH(max) of the drug salt. Alternative lubricants and disintegrants are suggested and a simple excipient screening process is proposed. Magnesium stearate was the most deleterious excipient for HCl salts due to the formation of the deliquescent salt magnesium chloride.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
John CT,Xu W,Lupton LK,Harmon PAdoi
10.1007/s11095-013-1002-ysubject
Has Abstractpub_date
2013-06-01 00:00:00pages
1628-41issue
6eissn
0724-8741issn
1573-904Xjournal_volume
30pub_type
杂志文章abstract：PURPOSE:Changes in drug absorption and first-pass metabolism have been reported throughout the pediatric age range. Our aim is to characterize both intestinal and hepatic CYP3A-mediated metabolism of midazolam in children in order to predict first-pass and systemic metabolism of CYP3A substrates. METHODS:Pharmacokinet...
journal_title：Pharmaceutical research
pub_type： 杂志文章
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journal_title：Pharmaceutical research
pub_type： 杂志文章
doi：10.1023/a:1016226024587
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journal_title：Pharmaceutical research
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journal_title：Pharmaceutical research
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doi：10.1023/a:1011087012826
更新日期：2001-01-01 00:00:00
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journal_title：Pharmaceutical research
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journal_title：Pharmaceutical research
pub_type： 杂志文章
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journal_title：Pharmaceutical research
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journal_title：Pharmaceutical research
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更新日期：2013-06-01 00:00:00
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journal_title：Pharmaceutical research
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doi：10.1007/s11095-012-0815-4
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更新日期：2014-06-01 00:00:00
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journal_title：Pharmaceutical research
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更新日期：1998-07-01 00:00:00
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journal_title：Pharmaceutical research
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更新日期：2002-08-01 00:00:00
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更新日期：1999-08-01 00:00:00
