Interlaboratory study of log {ce:inline-formula}P{/ce:inline-formula} determination by shake-flask and potentiometric methods

doi:10.1016/0731-7085(96)01773-6

Journal of Pharmaceutical and Biomedical Analysis

Volume 14, Issue 11, August 1996, Pages 1405-1413

https://doi.org/10.1016/0731-7085(96)01773-6 Get rights and content

Abstract

The {ce:inline-formula}pK _a{/ce:inline-formula} and log {ce:inline-formula}P{/ce:inline-formula} values of 23 structurally diverse compounds, including well known drugs and two pharmacons under development, were determined by potentiometry. Also, the log {ce:inline-formula}P{/ce:inline-formula} data were measured by the shake-flask method. Many of the samples were investigated at both of the participating laboratories in order to evaluate the reproducibility of the pH-metric log {ce:inline-formula}P{/ce:inline-formula} technique. The interlaboratory evaluation of {ce:inline-formula}pK _a{/ce:inline-formula} and log {ce:inline-formula}P{/ce:inline-formula} data obtained by potentiometry showed excellent agreement ({ce:inline-formula}averageΔpK _a = ± 0.02andΔlogP = ± 0.07{/ce:inline-formula}). The log {ce:inline-formula}P{/ce:inline-formula} values obtained by the two different methods, ranging from {ce:inline-formula}−1.84to5.80{/ce:inline-formula} (nearly eight orders of magnitude), were in very good concordance, as shown by the linear regression analysis: log {ce:inline-formula}P _pH-metric = 0.9794logP _shake-flask −0.0397 (r = 0.9987, s = ± 0.091, F = 8153{/ce:inline-formula}). The advantages of potentiometric log {ce:inline-formula}P{/ce:inline-formula} determination are discussed.

Reference (31)

TomlinsonE.
J. Pharm. Sci.
(1982)
BrookeD. et al.
Chemosphere
(1990)
El TayarN. et al.
J. Chromatogr.
(1991)
DanielssonL.-R. et al.
J. Pharm. Biomed. Anal.
(1994)
AvdeefA.
J. Pharm. Sci.
(1993)
Taka´cs-Nova´kK. et al.
J. Pharm. Biomed. Anal.
(1994)
AvdeefA. et al.
J. Pharm. Sci.
(1995)
SlaterB. et al.
J. Pharm. Sci.
(1994)
Taka´cs-Nova´kK. et al.
Int. J. Pharm.
(1992)
Taka´cs-Nova´kK. et al.
Int. J. Pharm.
(1995)

AsueroA.G.

Int. J. Pharm.

(1989)

RossD.L. et al.

J. Pharm. Biomed. Anal.

(1994)

TaylorP.J.

LeoA. et al.

Chem. Rev.

(1971)

TomlinsonE. et al.

Cited by (138)

Avoid missing pK<inf>a</inf>s: High-throughput workflow using solution pH-metric in tandem with UV-metric measurements
2023, Journal of Pharmaceutical and Biomedical Analysis
We describe a new high-throughput automated pK_a workflow using potentiometry starting with 10 mM DMSO stock (solution pH-metric). Two approaches using either neat DMSO stock solution or removal of DMSO were evaluated with different sample amounts and cosolvent schemes. These were validated against traditional potentiometric measurements for optimal conditions. Further, we detail how high throughput solution pH-metric experiments are performed in tandem with established UV-metric measurements to capitalize on the advantages of both approaches. This new workflow maintains the sample and time savings required for measuring a large number of samples in a drug discovery setting, while avoiding “missing pK_as” due to lack of sufficient UV chromophores. The combination of the two assays is key to tackle the challenges of low solubility, overlapping pK_as, and preliminary assignment of pK_as for Structure-Activity Relationship (SAR) understanding.
Electrochemical sensor for tricyclic antidepressants with low nanomolar detection limit: Quantitative Determination of Amitriptyline and Nortriptyline in blood
2022, Talanta
Amitriptyline and its metabolite, Nortriptyline are commonly used tricyclic antidepressant (TCA) drugs that are electrochemically active. In this work, the performance characteristics of a plasticized PVC membrane-coated glassy carbon (GC) electrode are described for the voltammetric quantification of Amitriptyline and Nortriptyline in whole blood. The highly lipophilic Amitriptyline and Nortriptyline preferentially partition into the plasticized PVC membrane where the free drug is oxidized on the GC electrode. The concentrations of the drugs in the membrane are orders of magnitude larger than in the sample solution, resulting in superb limit of detection (LOD) of the membrane-coated voltammetric sensor: 3 nmol/L for Amitriptyline and 20 nmol/L for Nortriptyline. Conversely, hydrophilic components of the sample solution, e.g., proteins, the protein-bound fraction of the drugs, and electrochemically active small molecules are blocked from entering the membrane, which provides exceptional selectivity for the membrane-coated sensor and feasibility for the measurements of Amitriptyline in whole blood. In this work, the concentrations of Amitriptyline and Nortriptyline were determined in whole blood using the sensor and the results of our analysis were compared to the results of the standard HPLC-MS method. Based on our experience, the one-step voltammetric methods with the membrane-coated sensor may become a real alternative to the significantly more complex HPLC-MS analysis.
Biosafety-inspired structural optimization of triazolium ionic liquids based on structure-toxicity relationships
2022, Journal of Hazardous Materials
Ionic liquids (ILs), owing to their low vapor pressure and excellent solvating ability, are being increasingly applied in various industries to replace highly toxic organic solvents. They mainly pollute aquatic environment and soils, directly endangering eco-environment and human health. Therefore, it is critical to understand and optimize structural motifs of ILs with reduced toxicity. Considering human oral exposure is the major route, our investigations employed a human cell panel (modeling oral exposures) including human stomach (GES-1), intestinal (FHC), liver (HepG2) and kidney (HEK293) cells using a series of experimental and computational approaches to explore the cytotoxicity and molecular mechanism of ILs. We discovered that the cytotoxicity of triazolium and imidazolium ILs was human cell line-dependent with cytotoxicity in an order of FHC > GES-1 > HepG2 > HEK293. For this reason, a toxicity assay using a single cell line was highly inappropriate. Compared to anions (Br^-, OTs^-, OTMBS^-) we tested, the cation of ILs played a major role in causing cytotoxicity. Ionic liquids with cations having longer hydrophobic sidechains (IL09 vs. IL01) readily insert into cell membranes with enhanced membrane and lipidomic perturbations, induce cytotoxicity by triggering cell cycle arrest and apoptosis. Reducing sidechain length and incorporating three nitrogen atoms (triazolium) instead of two (imidazolium) in the cation core alleviated cytotoxicity by reducing cell membrane perturbations and cell function interference. These findings provide important guiding principles for the design of the next-generation of “green” and safe ILs.
Lipophilicity study of different cephalosporins: Computational prediction of minimum inhibitory concentration using salting-out chromatography
2021, Journal of Pharmaceutical and Biomedical Analysis
The chromatographic and lipophilicity characters of seven cephalosporins of different four classes (cephradine, cefaclor, cefprozil, cefixime, cefotaxime, ceftazidime and cefepime) were examined by salting out thin-layer chromatography (SOTLC). SOTLC using ammonium sulfate salt was employed to predict the lipophilicity of the proposed drugs via their retention behavior. The calculated R_M0 values showed liner relationship with the molar concentration of ammonium sulfate in mobile phase in the range of 0.5–2.5 mol/L. Additionally, quantitative structure retention relationship (QSRR) was generated to figure out the relationship between the calculated chromatographic parameters (R_M0 and C₀) and log P of the studied cephalosporins. Good correlations were found between the chromatographically obtained retention parameters (R_M0 and C₀) and some molecular descriptors of the examined drugs. Furthermore, an efficient QSAR model was carried out using the calculated chromatographic parameters (R_M0 and C₀) and log P of the studied cephalosporins to predict minimum inhibitory concentration (MIC) and blood brain barrier (BBB) penetration of the examined drugs. The study was extended to separate and quantify the selected antibiotics in their pure forms and pharmaceutical formulations. Normal phase thin layer chromatographic (NP-TLC) method using a usable developing system of acetone: methanol: water: ammonium hydroxide: glacial acetic acid (90: 10: 18: 3: 2, by volume) was successfully applied to resolve the studied cephalosporins. Linearity was achieved in the range of 0.2–3 µg/mL for most of the studied antibiotics. The developed SOTLC method can be considered as a good start alternative to reversed phase thin layer chromatography (RP-TLC) for prediction of the lipophilic properties of examined cephalosporins. Moreover, the proposed NP-TLC densitometric method can be easily applied for quality control analysis of the chosen drugs and other structurally related components.
Polymeric membrane-modified voltammetric sensors for lipophilic analytes with nanomolar detection limit: Key parameters influencing the response characteristics
2021, Analytica Chimica Acta
Thin plasticized PVC membrane-coated glassy carbon working electrodes have been used for the voltammetric measurement of highly lipophilic, electroactive drugs. Compared to conventional working electrodes, these membrane-coated electrodes exhibit remarkable detection limit and selectivity and are less prone to electrode fouling. The unique performance characteristics of these sensors are related to the large partition coefficient of the analyte in the membrane coating where it is oxidized in a non-aqueous membrane phase. To analyze the influence of the key parameters of the response of membrane-coated sensors, we derived theoretical expressions on the voltammetric response of the sensors. In our analysis we considered 1) the partition coefficient ( $P_{m w}$ ) of the analyte between the aqueous sample and the organic membrane, 2) the membrane volume to sample volume ratio ( $V_{m} / V_{w}$ ), and 3) the binding constant of constituents in the sample that bind the analyte ( $K$ ). The results of our theoretical analysis have been tested through voltammetric measurement of highly lipophilic analytes with $l o g P_{o w}$ values (logarithm of the partition coefficient between octanol and water) ranging between 0.3 and 7.5. By understanding of the influence of the sensor design parameters on the overall sensor response, these parameters can be tuned for optimized response slope, detection limit, etc., for solving specific analytical tasks.
Structure-activity relationships for osmium(II) arene phenylazopyridine anticancer complexes functionalised with alkoxy and glycolic substituents
2020, Journal of Inorganic Biochemistry
Twenty-four novel organometallic osmium(II) phenylazopyridine (AZPY) complexes have been synthesised and characterised; [Os(η⁶-arene)(5-RO-AZPY)X]Y, where arene = p-cym or bip, AZPY is functionalized with an alkoxyl (O-R, R = Me, Et, ⁿPr, ⁱPr, ⁿBu) or glycolic (O-{CH₂CH₂O}_nR*, n = 1–4, R* = H, Me, or Et) substituent on the pyridyl ring para to the azo-bond, X is a monodentate halido ligand (Cl, Br or I), and Y is a counter-anion (PF₆⁻, CF₃SO₃⁻ or IO₃⁻). X-ray crystal structures of two complexes confirmed their ‘half-sandwich’ structures. Aqueous solubility depended on X, the AZPY substituents, arene, and Y. Iodido complexes are highly stable in water (X = I ⋙ Br > Cl), and exhibit the highest antiproliferative activity against A2780 (ovarian), MCF-7 (breast), SUNE1 (nasopharyngeal), and OE19 (oesophageal) cancer cells, some attaining nanomolar potency and good cancer-cell selectivity. Their activity and distinctive mechanism of action is discussed in relation to hydrophobicity (RP-HPLC capacity factor and Log P_o/w), cellular accumulation, electrochemical reduction (activation of azo bond), cell cycle analysis, apoptosis and induction of reactive oxygen species (ROS). Two complexes show ca. 4× higher activity than cisplatin in the National Cancer Institute (NCI) 60-cell line five-dose screen. The COMPARE algorithm of their datasets reveals a strong correlation with one another, as well as anticancer agents olivomycin, phyllanthoside, bouvardin and gamitrinib, but only a weak correlation with cisplatin, indicative of a different mechanism of action.

View all citing articles on Scopus

¹: Contribution No. 9 in the pH-metric log {ce:inline-formula}P{/ce:inline-formula} series from Sirius.

View full text

Interlaboratory study of log {ce:inline-formula}P{/ce:inline-formula} determination by shake-flask and potentiometric methods

Abstract

J. Pharm. Sci.

Chemosphere

J. Chromatogr.

J. Pharm. Biomed. Anal.

J. Pharm. Sci.

J. Pharm. Biomed. Anal.

J. Pharm. Sci.

J. Pharm. Sci.

Int. J. Pharm.

Int. J. Pharm.

Int. J. Pharm.

J. Pharm. Biomed. Anal.

Chem. Rev.