Biopharmaceutic Profiling of Salts to Improve Absorption of Poorly Soluble Basic Drugs

Tannergren, Christer; Karlsson, Εva; Sigfridsson, Kalle; Lindfors, Lennart; Ku, Angela; Polentarutti, Britta; Carlert, Sara

doi:10.1016/j.xphs.2016.07.016

Cited by 6 publications

(1 citation statement)

References 40 publications

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“…However, the ratio [AUC 0-tlast of the highest dose/AUC 0tlast of the lowest dose] was close to the ratio of the two doses, i.e., 11 and 12, respectively. This was in line with previous estimations on the linearity of AUC with the dose up to 100 mg (11) and implies problematic absorption rates but not extent of absorption for highest dose. Slower absorption at the highest dose could be related with increased precipitation in upper small intestine at higher doses.…”

Section: Azd2207 Eq Capsulessupporting

confidence: 92%

The BioGIT System: a Valuable In Vitro Tool to Assess the Impact of Dose and Formulation on Early Exposure to Low Solubility Drugs After Oral Administration

Kourentas

Vertzoni

Barmpatsalou

et al. 2018

AAPS J

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The purpose of this study was to evaluate the usefulness of the in vitro biorelevant gastrointestinal transfer (BioGIT) system in assessing the impact of dose and formulation on early exposure by comparing in vitro data with previously collected human plasma data of low solubility active pharmaceutical ingredients. Eight model active pharmaceutical ingredients were tested; Lu 35-138C (salt of weak base in a HP-beta-CD solution, three doses), fenofibrate (solid dispersion, tablet, two doses), AZD2207 EQ (salt of weak base, capsule, three doses), posaconazole (Noxafil® suspension, two doses), SB705498 (weak base, tablets vs. capsules), cyclosporine A (Sandimmun® vs. Sandimmun® Neoral), nifedipine (Adalat® capsule vs. Macorel® tablet), and itraconazole (Sporanox® capsule vs. Sporanox® solution). AUC values were calculated from the apparent concentration versus time data in the duodenal compartment of the BioGIT system. Differences in AUC values were evaluated versus differences in AUC and in AUC values calculated from previously collected plasma data in healthy adults. Ratios of mean AUC, mean AUC, and mean AUC values were estimated using the lowest dose or the formulation with the lower AUC value as denominator. The BioGIT system qualitatively identified the impact of dose and of formulation on early exposure in all cases. Log-transformed mean BioGIT AUC ratios correlated significantly with log-transformed mean plasma AUC ratios. Based on this correlation, BioGIT AUC ratios between 0.3 and 10 directly reflect corresponding plasma AUC ratios. BioGIT system is a valuable tool for the assessment of the impact of dose and formulation on early exposure to low solubility drugs.

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Section: Azd2207 Eq Capsulessupporting

confidence: 92%

The BioGIT System: a Valuable In Vitro Tool to Assess the Impact of Dose and Formulation on Early Exposure to Low Solubility Drugs After Oral Administration

Kourentas

Vertzoni

Barmpatsalou

et al. 2018

AAPS J

Self Cite

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Salt Screening and Selection

Tian

Reid

Semin

2021

Burger's Medicinal Chemistry and Drug Discovery

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The stability, processability, and in vivo performance of active pharmaceutical ingredients (APIs) are significantly affected by their salt forms. The appropriate salt can improve the overall therapeutic and pharmaceutical performance of an API. Salt screening and selection is integrated into the drug discovery and development, and the desired attributes are impacted by multiple factors, including API chemistry, the intended dosage form, pharmacokinetics, and pharmacodynamics. Counterion, solvent, and crystallization are three key elements affecting screening outcomes and selection of the final salt form. Common applications of pharmaceutical salts, general considerations for using salt forms, and a brief acid–base theory related to solubility estimation for salt forms are introduced. A strategy to select counterions and solvents for salt formation is articulated in detail as well as crystallization methodology to harvest highly pure and crystalline salt forms. Three different salt‐screening approaches ( in situ , rational, and high throughput) are discussed with respect to resource required, project timelines, and the purpose of the study. A four‐tier salt selection strategy is presented, and the desired attributes to meet the target product profile for a typical oral drug are included to guide selection of an appropriate salt from the very initiation of form screen.

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Preformulation investigation and challenges; salt formation, salt disproportionation and hepatic recirculation

Sigfridsson

Nilsson

Ahlqvist

et al. 2017

European Journal of Pharmaceutical Sciences

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Biopharmaceutic Profiling of Salts to Improve Absorption of Poorly Soluble Basic Drugs

Cited by 6 publications

References 40 publications

The BioGIT System: a Valuable In Vitro Tool to Assess the Impact of Dose and Formulation on Early Exposure to Low Solubility Drugs After Oral Administration

The BioGIT System: a Valuable In Vitro Tool to Assess the Impact of Dose and Formulation on Early Exposure to Low Solubility Drugs After Oral Administration

Salt Screening and Selection

Preformulation investigation and challenges; salt formation, salt disproportionation and hepatic recirculation

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