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J Pharm Sci

Differences in Food Effects for 2 Weak Bases With Similar BCS Drug-Related Properties: What Is Happening in the Intestinal Lumen?

Differences in Food Effects for 2 Weak Bases With Similar BCS Drug-Related Properties: What Is Happening in the Intestinal Lumen?

J Pharm Sci. 2016 Feb 23;

Authors: Cristofoletti R, Patel N, Dressman JB

Abstract
Ketoconazole and posaconazole are both Biopharmaceutics Classification System class 2 drugs (highly permeable, poorly soluble), are structurally similar, and are administered at the same doses. Nevertheless, the duodenal concentration profile and the magnitude of the positive food effect observed for these 2 drugs are markedly different. The aim of this study was to investigate, by means of in silico models, the likely mechanism(s) behind such differences. On the basis of the simulations presented here, it seems highly likely that the balance between the degree of supersaturation in the intestinal lumen and the drug flux across enterocyte membrane can explain the massive difference in the relevance of in vivo precipitation for these 2 drugs, when administered in the fasted state. In the fed state, it appears that the slower gastric emptying together with the higher solubility combines to effect better absorption in the case of posaconazole.

PMID: 26921120 [PubMed – as supplied by publisher]

Supersaturation and Precipitation of Posaconazole upon Entry in the Upper Small Intestine in Humans.

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Supersaturation and Precipitation of Posaconazole upon Entry in the Upper Small Intestine in Humans.

J Pharm Sci. 2015 Oct 27;

Authors: Hens B, Brouwers J, Corsetti M, Augustijns P

Abstract
The purpose of this study was to explore gastrointestinal dissolution, supersaturation and precipitation of the weakly basic drug posaconazole in humans, and to assess the impact of formulation pH and type on these processes. In a cross-over study, two posaconazole suspensions (40 mg dispersed in 240 mL water at pH 1.6 and pH 7.1, respectively) were intragastrically administered; subsequently, gastric and duodenal fluids were aspirated. In parallel, blood samples were collected. Additionally, posaconazole was intragastrically administered as a solution (20 mg in 240 mL water, pH 1.6). When posaconazole was administered as an acidified suspension, supersaturated duodenal concentrations of posaconazole were observed for approximately 45 min. However, extensive intestinal precipitation was observed. Administration of the neutral suspension resulted in subsaturated concentrations with a mean duodenal AUC0-120 min and Cmax being approximately twofold lower than for the acidified suspension. The mean plasma AUC0-8 h of posaconazole was also twofold higher following administration of the acidified suspension. Similar to the acidified suspension, significant intestinal precipitation (up to 92%) was observed following intragastric administration of the posaconazole solution. This study demonstrated for the first time the gastrointestinal behavior of a weakly basic drug administered in different conditions, and its impact on systemic exposure. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.

PMID: 26505884 [PubMed – as supplied by publisher]

Full Characterization of Linezolid and Its Synthetic Precursors by Solid-State Nuclear Magnetic Resonance Spectroscopy and Mass Spectrometry.

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Full Characterization of Linezolid and Its Synthetic Precursors by Solid-State Nuclear Magnetic Resonance Spectroscopy and Mass Spectrometry.

J Pharm Sci. 2015 Sep 7;

Authors: Wielgus E, Paluch P, Frelek J, Szczepek WJ, Potrzebowski MJ

Abstract
In this work, for the first time we report complementary structural and spectral studies of linezolid and its synthetic precursors (R)-N-{3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl}methanol and (R)-N-{3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxooxazolidin-5-yl}methyl azide employing solid-state nuclear magnetic resonance (SS NMR) spectroscopy and electron ionization mass spectrometry. Each technique provides unique and specific set of information. Through high-resolution SS NMR using (13) C, (15) N, and (19) F as structural probes, we revealed dynamic molecular disorder in the crystal lattice for polymorphs II and III of linezolid, never reported before. Utilizing variable temperature (13) C cross-polarization magic-angle spinning technique, we proved that the disorder has a local character. Only morpholine residue of linezolid is under fast regime exchange at room temperature. This process slows down at a lower temperature and stopped at 213 K. The mass spectrometry revealed that chemical modification at oxazolidinone end of linezolid has a significant influence on fragmentation pathways of studied drug and its synthetic precursors. In particular, the compound that has azide group at the methyl substituent in the position C5 of the oxazolidinone ring is characterized by the most complicated fragmentation pattern, probably caused by thermal decomposition, which was taking place before ionization. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.

PMID: 26344859 [PubMed – as supplied by publisher]