PH-metric log P 11. p K a determination of water-insoluble drugs in organic solvent–water mixtures

Avdeef, Alex; Box, Karl; Comer, John; Gilges, Martin; Hadley, Mark R.; Hibbert, C; Patterson, William Hamilton; Tam, Kin Yip

doi:10.1016/s0731-7085(98)00235-0

Cited by 222 publications

(151 citation statements)

References 21 publications

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“…electrode used is largely unidentified. In contrast, attention to such detail is the norm in pK a determination practice, where specialized calibration methods are well developed [22,27,44,45,[111][112][113]. Researchers who determine pK a values using commercial analyzers are well acquainted with the four-parameter electrode standardization procedure, described in Appendix C. Those using the Sirius Analytical titrators will recognize the procedure as the "Four-Plus" method, and those using the Pion titrators will recognize it as the "ABC" method.…”

Section: Recommendation For Reporting Ionic Strengthmentioning

confidence: 99%

Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

et al. 2016

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Section: Recommendation For Reporting Ionic Strengthmentioning

confidence: 99%

Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

et al. 2016

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“…The used pH-metric method is described more detailed elsewhere. 31,32 Distribution Coefficient. Distribution coefficients of the prodrugs were determined by the pH-metric technique using a Sirius PCA200 titrator.…”

Section: Mono-[3-(trans-4-tert-butyl-cyclohexylmethyl)-14-dioxo-14-mentioning

confidence: 99%

Synthesis, in Vitro Evaluation, and Antileishmanial Activity of Water-Soluble Prodrugs of Buparvaquone

et al. 2003

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Water-soluble phosphate prodrugs of buparvaquone (1), containing a hydroxynaphthoquinone structure, were synthesized and evaluated in vitro for improved topical and oral drug delivery against cutaneous and visceral leishmaniasis. The successfull prodrug synthesis involved a strong base; e.g., sodium hydride. Buparvaquone-3-phosphate (4a) and 3-phosphonooxymethylbuparvaquone (4b) prodrugs possessed significantly higher aqueous solubilities (>3.5 mg/mL) than the parent drug (e0.03 µg/mL) over a pH range of 3.0-7.4. Moreover, 4a and 4b maintained adequate lipophilicity as indicated by distribution coefficients (log D) between 0.5 and 3.0 over this pH range. Both 4a and 4b were also shown to be substrates for alkaline phosphatase in vitro and thus are promising bioreversible prodrugs for the improved topical and oral bioavailability of 1. Buparvaquone and its prodrugs showed nanomolar or lowmicromolar ED 50 activity values against species that cause cutaneous leishmaniasis, e.g., L. major, L. amazonensis, L. aethiopica, L. mexicana, and L. panamensis and also L. donovani, which is the causative agent of visceral leishmaniasis. From these results, the human skin permeation of the prodrugs 4a and 4b were studied in vitro. While no buparvaquone permeated across post mortem skin in vitro during 72 h of experiments, both prodrugs 4a and 4b permeated readily through the skin. In addition, 4b easily released the parent drug in human skin homogenate and, therefore, is a promising prodrug candidate to deliver buparvaquone through the skin for the treatment of cutaneous leishmaniasis.

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“…Log P values were determined by potentiometric titration using a PCA 200 instrument (Sirius analytical instruments, Forrest Row, UK) according to the equation logP¼ logð10 ðpk a Àpk aðoÞ Þ À 1Þ À logðrÞ, where pk a(o) is the pk a in an octanol/water mixture and (r) is the volume ratio octanol/ water (Takacs-Novak and Avdeef, 1996;Avdeef et al, 1999). Log D (7.4) was calculated from logD ð7:4Þ ¼ logP À logð1þ 10 pk a ÀpH Þ and assessed by the shake-flask technique (Leo, 1987) by measuring the distribution of the ionized+ nonionized form between 1-octanol and an HBSS/HEPES buffer (pH 7.4).…”

Section: High-performance Liquid Chromatography (Hplc) Analysismentioning

confidence: 99%

How Does the Benzamide Antipsychotic Amisulpride get into the Brain?—An In Vitro Approach Comparing Amisulpride with Clozapine

Härtter¹,

Hüwel

Lohmann

et al. 2003

Neuropsychopharmacol

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This study evaluated the disposition of the two atypical antipsychotics, amisulpride (AMS) and clozapine (CLZ), and its main metabolite N-desmethylclozapine (DCLZ), to their target structures in the central nervous system by applying an in vitro blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier based on monolayers of porcine brain microvessel endothelial cells (PMEC) or porcine choroid plexus epithelial cells (PCEC). Permeation studies through PMEC-and PCEC-monolayers were conducted for 60 min at drug concentrations of 1, 5, 10, and 30 mM applied to the donor compartment. PMEC were almost impermeable for AMS (permeation coefficient, Po1 Â 10 À7 cm/s) in the resorptive direction, whereas transport in the secretory direction was observed with a P ( 7 SD) of 5.2 7 3.6 Â 10 À6 cm/s. The resorptive P of CLZ and DCLZ were 2.3 7 1.2 Â 10 À4 and 9.6 7 5.0 Â 10 À5 cm/s, respectively. For the permeation across PCEC in the resorptive direction, a P of 1.7 7 2.5 Â 10 À6 cm/s was found for AMS and a P of 1.6 7 0.9 Â 10 À4 and 2.3 7 1.3 Â 10 À5 cm/s was calculated for CLZ and DCLZ, respectively. Both, CLZ and DCLZ, could easily pass both barriers with about a five-fold higher permeation rate of CLZ at the PCEC. The permeation of AMS across the BBB was restricted partly due to an efflux transport. It is thus suggested that AMS reaches its target structures via transport across the blood-CSF barrier.

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PH-metric log P 11. p K a determination of water-insoluble drugs in organic solvent–water mixtures

Cited by 222 publications

References 21 publications

Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

Synthesis, in Vitro Evaluation, and Antileishmanial Activity of Water-Soluble Prodrugs of Buparvaquone

How Does the Benzamide Antipsychotic Amisulpride get into the Brain?—An In Vitro Approach Comparing Amisulpride with Clozapine

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