Using measured pKa, LogP and solubility to investigate supersaturation and predict BCS class.

Ionization, lipophilicity and solubility have a profound influence on the transport properties of drug molecules. We will present an overview of why physicochemical properties are important, before discussing how the properties are related to each other. Findings are based on research in our own laboratories using our commercial instruments and software to measure the pKa, lipophilicity (LogP) and intrinsic solubility (LogS0) of 84 marketed ionizable drugs. In general, the most lipophilic molecules were the least soluble in water. Plots of LogP vs. LogS0 show results for these drugs clustered according to other properties, including melting point, number of H-bond donors and acceptors, ability to supersaturate, and BCS class. Molecules with high melting point tended to have a larger number of H-bond donors and acceptors, and to be less soluble than predicted from their LogP. Molecules with low melting point tended to have little H-bond donor capacity, and tended to be more soluble than predicted from their LogP. Molecules that could form supersaturated solutions tended to have higher melting points, and to be less soluble than predicted from their LogP. Molecules in BCS Classes I-III tended to cluster in different parts of the plot. It is proposed that comparing measured LogP and LogS0 of new molecules with these plots will facilitate a quick assessment of their likely BCS Class.

Characterisation of selected active agents regarding pKa values, solubility concentrations and pH profiles by SiriusT3.

The aim of this work was to determine pKa values and solubility properties of 34active agents using the SiriusT3 apparatus. The selected drug substances belong to the groups of ACE-inhibitors, ß-blockers, antidiabetics and lipid lowering substances. Experimentally obtained pKa and intrinsic solubility values were compared to calculated values (program ACD/ChemSketch) and pKa values to published data as well. Solubility-pH profiles were generated to visualise the substance solubility over the gastrointestinal pH range. The relationship between the solubility characteristic of a substance, its bioavailability and categorisation according to the Biopharmaceutics Classification System (BCS) was examined as well. The results showed a good agreement between experimentally obtained, calculated and published pKa values. The measured and calculated intrinsic solubility values indicated several major deviations. All solubility-pH profiles showed the expected shape and appearance for acids, bases or zwitterionic substances. The obtained results for the pKa and solubility measurements of the examined active agents may help to predict their physicochemical behaviour in vivo, and to understand the bioavailability of the substances according to their BCS categorisation. The easy and reproducible determination of pKa and solubility values makes the SiriusT3 apparatus a useful tool in early stages of drug and formulation development.

pH-metric log P. 6. Effects of sodium, potassium, and N-CH3-D-glucamine on the octanol-water partitioning of prostaglandins E1 and E2.

The pH-dependent octanol-water partition behavior of prostaglandins (Pg) E1 and E2 was studied by an automated potentiometric titration method. In 0.15 M KCl at 25 degrees C, the log P values of PgE1 and PgE2 are 3.20 +/- 0.02 and 2.90 +/- 0.02, respectively. The partition parameter also was determined in 0.15 M NaCl, 0.10 M NaCl, and 0.0003 M KCl for PgE1; no ionic strength dependence was observed. In contrast, the Pg anion partitioning, described by the extraction constant, log Ke (= [X+Pg-]OCT/[X+]AQ[Pg-]AQ, where X = Na or K), showed dependence on the nature and concentration of the background salt. For PgE1, the log Ke values are 0.50 +/- 0.08 (0.15 M KCl), 0.18 +/- 0.16 (0.15 M NaCl), 0.86 +/- 0.08 (0.10 M NaCl), and 1.80 +/- 0.09 (0.0003 M KCl); for PgE2, the log Ke value is 0.20 +/- 0.29. The extraction of the Pg anion into octanol by N-methyl-D-glucamine (glucamine) was also studied. In 0.15 M KCl, the log Ke value is 1.82 +/- 0.07. The extraction of the prostaglandin-glucamine complex into octanol maximizes at about pH 8.8. Due to the low aqueous solubility of the prostaglandins, the aqueous pKa values were determined by extrapolation from methanol-water solutions by the Yasuda-Shedlovsky technique. The Debye-Hückel theory was applied to predict the ionic strength dependence of the octanol-water ion-pair extraction constants (log Ke).

Determination of protonation macro- and microconstants and octanol/water partition coefficient of the antiinflammatory drug niflumic acid.

The drug niflumic acid is an amphoteric substance with overlapping pKa values. The acid-base chemistry of the molecule has been characterized in terms of protonation macroconstants (with reference to stoichiometric ionizations) and microconstants (with reference to ionizations of individual species). The proton-binding sites were assigned using 1H and 13C NMR spectroscopy. Due to the very poor water solubility of niflumic acid, the aqueous pKa values were determined from the apparent ionization constants in methanol-water solutions of various proportions by extrapolation to zero co-solvent using the Yasuda-Shedlovsky procedure. The kz tautomerization microconstant of the equilibrium unionized form<-->zwitterionic form was determined from mixtures of organic solvent (dioxane or methanol) with aqueous buffer (at the pH of isoelectric point) by UV spectroscopy, and used for calculation of the other protonation microconstants. The zwitterionic form of the molecule predominates over the uncharged form, the concentration being maximal at the isoelectric pH. The apparent partition coefficients (Papp) of niflumic acid were measured in octanol/water solution by the shake-flask method over a wide pH range. The lipophilicity profile (logPapp vs pH) shows a parabolic shape near its maximum at the isoelectric point. A relationship derived between Papp, PXH0(micropartition coefficient of the uncharged microspecies) and PX-(partition coefficient of the anion) is valid for amphoteric drugs, in cases where the partition of the unionized form and the ion-pair partition of anion can be confirmed. The logP values of microspecies indicate the high lipophilicity of niflumic acid, which is consistent with its good skin penetration and absorption.

Multiwavelength spectrophotometric determination of acid dissociation constants of ionizable drugs.

A multiwavelength spectrophotometric approach has been developed to determine acid dissociation constants (pKa values) of sparingly soluble drug compounds. UV absorption spectra of the drug solution are acquired using a versatile device based on a fiber optics dip probe, a light source and a photodiode array (PDA) detector while the PH and the ionic strength of the chemical system is manipulated precisely by means of a commercially available titrator. Target factor analysis (TFA) has been applied to deduce the pKa values from the multiwavelength UV absorption data recorded at different pH values. We have called this multiwavelength approach the WApH technique because the pKa results are determined from changes in Wavelength and Absorbance as a function of pH (WApH). The WApH technique is exemplified by using several pure drugs, namely, niflumic acid, nitrazepam, pyridoxine, quinine and terbutaline. The pKa values obtained agree well with those derived from pH-metric titrations. It has been demonstrated that the WApH technique is able to deduce pKa values with high accuracy even if the absorption spectra of the reacting species are very similar.

PH-metric log P 11. pKa determination of water-insoluble drugs in organic solvent-water mixtures.

The apparent acid dissociation constants (p(s)Ka) of two water-insoluble drugs, ibuprofen and quinine, were determined pH-metrically in acetonitrile water, dimethylformamide water, dimethylsulfoxide water, 1,4-dioxane-water, ethanol water, ethylene glycol-water, methanol water and tetrahydrofuran water mixtures. A glass electrode calibration procedure based on a four-parameter equation (pH = alpha + SpcH + jH[H+]+jOH[OH-]) was used to obtain pH readings based on the concentration scale (pcH). We have called this four-parameter method the Four-Plus technique. The Yasuda Shedlovsky extrapolation (p(s)Ka + log [H2O] = A/epsilon + B) was used to derive acid dissociation constants in aqueous solution (pKa). It has been demonstrated that the pKa values extrapolated from such solvent water mixtures are consistent with each other and with previously reported measurements. The suggested method has also been applied with success to determine the pKa values of two pyridine derivatives of pharmaceutical interest.

pH-metric logP 10. Determination of liposomal membrane-water partition coefficients of ionizable drugs.

PURPOSE: To investigate a novel approach for the determination of liposomal membrane-water partition coefficients and lipophilicity profiles of ionizable drugs. METHODS: The measurements were performed by using a pH-metric technique in a system consisting of dioleylphosphatidylcholine (DOPC) unilamellar vesicles in 0.15 M KCl at 25 degrees C. The DOPC unilamellar vesicle suspension was prepared via an extrusion process. RESULTS: The liposomal membrane-water partition coefficients of eight ionizable drugs: ibuprofen, diclofenac, 5-phenylvaleric acid, warfarin, propranolol, lidocaine, tetracaine and procaine were determined and the values for neutral and ionized species were found to be in the ranges of approximately 4.5 to 2.4 and 2.6 to 0.8 logarithmic units, respectively. CONCLUSIONS: It has been shown that the liposomal membrane-water partition coefficients as derived from the pH-metric technique are consistent with those obtained from alternative methods such as ultrafiltration and dialysis. It was found that in liposome system, partitioning of the ionized species is significant and is influenced by electrostatic interaction with the membranes. We have demonstrated that the pH-metric technique is an efficient and accurate way to determine the liposomal membrane-water partition coefficients of ionizable substances.