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Inclusion complexes require higher concentration of Beta cyclodextrins (βCD) resulting in increased formulation bulk, toxicity, and production costs. This systematic review offers a comprehensive analysis using Quality by design (QbD) as a tool to predict potential applications of Polyvinylpyrrolidone (PVP) as a ternary substance to address issues of inclusion complexes. We reviewed 623 documents from 2013 to 2023 and Eighteen (18) research papers were selected for statistical and meta-analysis using the QbD concept to identify the most critical factors for selecting drugs and effect of PVP on inclusion complexes. The QbD analysis revealed that Molecular weight (MW), Partition coefficient (Log P), and the auxiliary substance ratio directly affected complexation efficiency (CE), thermodynamic stability in terms of Gibbs free energy (ΔG), and percent drug release. However, Stability constant (K s ) remained unaffected by any of these parameters. The results showed that low MW (250), median Log P (6), and a βCD: PVP ratio of 2:3 would result in higher CE, lower G, and improved drug release. PVP improves drug solubility, enhances delivery and therapeutic outcomes, and counteracts increased drug ionization due to decreased pH. In certain cases, its bulky nature and hydrogen bonding with CD molecules can form non-inclusion complexes. The findings of the study shows that there is potential molecular interaction between PVP and β-cyclodextrins, which possibly enhances the stability of inclusion complexes for drug with low MW and log P values less than 9. The systematic review shows a comprehensive methodology based on QbD offers a replicable template for future investigations into drug formulation research., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Flavonoids are hydroxylated polyphenols that are widely distributed in plants with diverse health benefits. Despite their popularity, the bioavailability of flavonoids is often overlooked, impacting their efficacy and the comparison of products. The study discusses the bioavailability-related physicochemical properties of flavonoids, with a focus on the poorly soluble compounds commonly found in dietary supplements and herbal products. This review sums up the values of pKa, log P, solubility, permeability, and melting temperature of flavonoids. Experimental and calculated data were compiled for various flavonoid subclasses, revealing variations in their physicochemical properties. The investigation highlights the challenges posed by poorly soluble flavonoids and underscores the need for enabling formulation approaches to enhance their bioavailability and therapeutic potential. Compared to aglycones, flavonoid glycosides (with sugar moieties) tend to be more hydrophilic. Most of the reviewed aglycones and glycosides exhibit relatively low log P and high melting points, making them "brick dust" candidates. To improve solubility and absorption, strategies like size reduction, the potential use of solid dispersions and carriers, as well as lipid-based formulations have been discussed. [ABSTRACT FROM AUTHOR]

The Statistical Assessment of Modeling of Proteins and Ligands (SAMPL) challenges focuses the computational modeling community on areas in need of improvement for rational drug design. The SAMPL7 physical property challenge dealt with prediction of octanol-water partition coefficients and pKa for 22 compounds. The dataset was composed of a series of N-acylsulfonamides and related bioisosteres. 17 research groups participated in the log P challenge, submitting 33 blind submissions total. For the pKa challenge, 7 different groups participated, submitting 9 blind submissions in total. Overall, the accuracy of octanol-water log P predictions in the SAMPL7 challenge was lower than octanol-water log P predictions in SAMPL6, likely due to a more diverse dataset. Compared to the SAMPL6 pKa challenge, accuracy remains unchanged in SAMPL7. Interestingly, here, though macroscopic pKa values were often predicted with reasonable accuracy, there was dramatically more disagreement among participants as to which microscopic transitions produced these values (with methods often disagreeing even as to the sign of the free energy change associated with certain transitions), indicating far more work needs to be done on pKa prediction methods.

Partition coefficients describe the equilibrium partitioning of a single, defined charge state of a solute between two liquid phases in contact, typically a neutral solute. Octanol-water partition coefficients ([Formula: see text]), or their logarithms (log P), are frequently used as a measure of lipophilicity in drug discovery. The partition coefficient is a physicochemical property that captures the thermodynamics of relative solvation between aqueous and nonpolar phases, and therefore provides an excellent test for physics-based computational models that predict properties of pharmaceutical relevance such as protein-ligand binding affinities or hydration/solvation free energies. The SAMPL6 Part II octanol-water partition coefficient prediction challenge used a subset of kinase inhibitor fragment-like compounds from the SAMPL6 [Formula: see text] prediction challenge in a blind experimental benchmark. Following experimental data collection, the partition coefficient dataset was kept blinded until all predictions were collected from participating computational chemistry groups. A total of 91 submissions were received from 27 participating research groups. This paper presents the octanol-water log P dataset for this SAMPL6 Part II partition coefficient challenge, which consisted of 11 compounds (six 4-aminoquinazolines, two benzimidazole, one pyrazolo[3,4-d]pyrimidine, one pyridine, one 2-oxoquinoline substructure containing compounds) with log P values in the range of 1.95-4.09. We describe the potentiometric log P measurement protocol used to collect this dataset using a Sirius T3, discuss the limitations of this experimental approach, and share suggestions for future log P data collection efforts for the evaluation of computational methods.

The SAMPL Challenges aim to focus the biomolecular and physical modeling community on issues that limit the accuracy of predictive modeling of protein-ligand binding for rational drug design. In the SAMPL5 log D Challenge, designed to benchmark the accuracy of methods for predicting drug-like small molecule transfer free energies from aqueous to nonpolar phases, participants found it difficult to make accurate predictions due to the complexity of protonation state issues. In the SAMPL6 log P Challenge, we asked participants to make blind predictions of the octanol-water partition coefficients of neutral species of 11 compounds and assessed how well these methods performed absent the complication of protonation state effects. This challenge builds on the SAMPL6 p[Formula: see text] Challenge, which asked participants to predict p[Formula: see text] values of a superset of the compounds considered in this log P challenge. Blind prediction sets of 91 prediction methods were collected from 27 research groups, spanning a variety of quantum mechanics (QM) or molecular mechanics (MM)-based physical methods, knowledge-based empirical methods, and mixed approaches. There was a 50% increase in the number of participating groups and a 20% increase in the number of submissions compared to the SAMPL5 log D Challenge. Overall, the accuracy of octanol-water log P predictions in SAMPL6 Challenge was higher than cyclohexane-water log D predictions in SAMPL5, likely because modeling only the neutral species was necessary for log P and several categories of method benefited from the vast amounts of experimental octanol-water log P data. There were many highly accurate methods: 10 diverse methods achieved RMSE less than 0.5 log P units. These included QM-based methods, empirical methods, and mixed methods with physical modeling supported with empirical corrections. A comparison of physical modeling methods showed that QM-based methods outperformed MM-based methods. The average RMSE of the most accurate five MM-based, QM-based, empirical, and mixed approach methods based on RMSE were 0.92 ± 0.13, 0.48 ± 0.06, 0.47 ± 0.05, and 0.50 ± 0.06, respectively.

Flavonoids are hydroxylated polyphenols that are widely distributed in plants with diverse health benefits. Despite their popularity, the bioavailability of flavonoids is often overlooked, impacting their efficacy and the comparison of products. The study discusses the bioavailability-related physicochemical properties of flavonoids, with a focus on the poorly soluble compounds commonly found in dietary supplements and herbal products. This review sums up the values of pKa, log P, solubility, permeability, and melting temperature of flavonoids. Experimental and calculated data were compiled for various flavonoid subclasses, revealing variations in their physicochemical properties. The investigation highlights the challenges posed by poorly soluble flavonoids and underscores the need for enabling formulation approaches to enhance their bioavailability and therapeutic potential. Compared to aglycones, flavonoid glycosides (with sugar moieties) tend to be more hydrophilic. Most of the reviewed aglycones and glycosides exhibit relatively low log P and high melting points, making them “brick dust” candidates. To improve solubility and absorption, strategies like size reduction, the potential use of solid dispersions and carriers, as well as lipid-based formulations have been discussed.

Atorvastatin calcium (ATV) is an anti-hyperlipidemic agent with poor bioavailability. Several approaches were reported to improve the solubility of ATV. In this study ATV was prepared as a choline salt (ATV-C) and a complex of the prepared salt with hydroxy-propyl-beta-cyclodextrin (HPβCD) (ATV-C-CD) hoping to enhance ATV solubility, decrease the partition coefficient and improve its transdermal permeability. The pharmaceutical properties of the products were investigated. The prepared salts were characterized by FTIR, NMR and DSC, UV and HPLC. 2D NMR was successfully employed to unequivocally assign the protons of ATV, which was essential for better understanding of the structure of the formed salt. ATV-C showed higher solubility in phosphate buffer than ATV. Its log Po/phosphate buffer was found to be 1.1 while that for ATV 1.78. This change had an effect on the transdermal permeation where the ATV-C compound achieved a 4 times greater diffusion compared to ATV. Interestingly, ATV-C seemed to cause a tighter fitting of the drug into the HPβCD cavity leading to higher binding constant. However, the ATV-C-CD complex showed a negative effect on transdermal permeation. [ABSTRACT FROM AUTHOR]

Estimation of crystalline solute solubility is well documented throughout the literature. However, the anhydrous crystal form is typically considered with these models, which is not always the most stable crystal form in water. In this study, an equation which predicts the aqueous solubility of a hydrate is presented. This research attempts to extend the utility of the ideal solubility equation by incorporating desolvation energetics of the hydrated crystal. Similar to the ideal solubility equation, which accounts for the energetics of melting, this model approximates the energy of dehydration to the entropy of vaporization for water. Aqueous solubilities, dehydration and melting temperatures, and log P values were collected experimentally and from the literature. The data set includes different hydrate types and a range of log P values. Three models are evaluated, the most accurate model approximates the entropy of dehydration ( ΔS d ) by the entropy of vaporization ( ΔS vap ) for water, and utilizes onset dehydration and melting temperatures in combination with log P . With this model, the average absolute error for the prediction of solubility of 14 compounds was 0.32 log units. [ABSTRACT FROM AUTHOR]

Myricetin (MYR) is a natural compound that has been investigated as a chemopreventative agent. MYR has been shown to suppresses ultraviolet B (UVB)-induced cyclooxygenase-2 (COX-2) protein expression and reduce the incidence of UVB-induced skin tumors in mice. Despite MYR's promise as a therapeutic agent, minimal information is available to guide the progression of formulations designed for future drug development. Here, data is presented describing the solid-state and solution characterization of MYR. Investigation into the solid-state properties of MYR identified four different crystal forms, two hydrates (MYR I and MYR II) and two metastable forms (MYR IA and MYR IIA). From solubility studies, it was evident that all forms are very insoluble (<5 μg/ml) in pure water. MYR I was found to be the most stable form at 23, 35, and 56°C. Stability determination indicated that MYR undergoes rapid apparent first-order degradation under basic pH conditions, and that degradation was influenced by buffer species. Apparent first-order degradation was also seen when MYR was introduced to an oxidizing solution. Improved stability was achieved after introducing 0.1% antioxidants to the solution. MYR was found to have good stability following exposure to ultraviolet radiation (UVR), which is a consideration for topical applications. Finally, a partitioning study indicated that MYR possess a log P of 2.94 which, along with its solid-state properties, contributes to its poor aqueous solubility. Both the solid-state properties and solution stability of MYR are important to consider when developing future formulations. [ABSTRACT FROM AUTHOR]

Spectroscopic studies of ether rifamycins ( 1 – 9 ) have shown that all these compounds tend to be zwitterions with different localizations of intramolecularly transferred proton, which influences their solubility and log P values. According to ESI MS studies, rifamycins 3 and 4 form complexes with Li + or Na + , while the other ones ( 7 – 9 ) coordinate small organic molecules, which can be further replaced by Na + cation. Biological assays revealed that the use of 7 – 9 in the form of complexes with small organic molecules improves their antibacterial potency as a result of changed: log P , solubility and binding mode with bacterial RNA polymerases. [ABSTRACT FROM AUTHOR]

P-glycoprotein ( P-gp) regulates absorption of many drugs in the gastrointestinal tract and their accumulation in tumor tissues, but the basis of substrate recognition by P-gp remains unclear. Bitter-tasting phenylthiocarbamide, which stimulates taste receptor 2 member 38 ( T2 R38), increases P-gp activity and is a substrate of P-gp. This led us to hypothesize that bitterness intensity might be a predictor of P-gp-inhibitor/substrate status. Here, we measured the bitterness intensity of a panel of P-gp substrates and nonsubstrates with various taste sensors, and used multiple linear regression analysis to examine the relationship between P-gp-inhibitor/substrate status and various physical properties, including intensity of bitter taste measured with the taste sensor. We calculated the first principal component analysis score ( PC1) as the representative value of bitterness, as all taste sensor's outputs shared significant correlation. The P-gp substrates showed remarkably greater mean bitterness intensity than non- P-gp substrates. We found that Km value of P-gp substrates were correlated with molecular weight, log P, and PC1 value, and the coefficient of determination ( R2) of the linear regression equation was 0.63. This relationship might be useful as an aid to predict P-gp substrate status at an early stage of drug discovery. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2789-2794, 2015 [ABSTRACT FROM AUTHOR]

Thermodynamic analysis of the solubility of benzoylphenylurea ( BPU) derivatives was conducted to investigate the relative importance of crystal packing and hydration for improving solubility with minor structural modification. The contribution of crystal packing to solubility was evaluated from the change in Gibbs energy on the transition from the crystalline to liquid state. Hydration Gibbs energy was estimated using a linear free-energy relationship between octanol-water partition coefficients and gas-water partition coefficients. The established solubility model satisfactorily explained the relative thermodynamic solubility of the model compounds and revealed that crystal packing and hydration equally controlled solubility of the structural analogs. All hydrophobic substituents were undesirable for solubility in terms of hydration, as expected. On the other hand, some of these hydrophobic substituents destabilized crystal packing and improved the solubility of the BPU derivatives when their impact on crystal packing exceeded their negative influence on hydration. The replacement of a single substituent could cause more than a 10-fold enhancement in thermodynamic solubility; this degree of improvement was comparable to that generally achieved by amorphous formulations. Detailed analysis of thermodynamic solubility will allow us to better understand the true substituent effect and design drug-like candidates efficiently. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3524-3531, 2014 [ABSTRACT FROM AUTHOR]

The knowledge of physicochemical properties of organic compounds becomes increasingly important in pharmaceutical sciences, chemical engineering, and other fields. In this study, we developed UPPER ( Unified Physicochemical Property Estimation Relationships), a comprehensive model for the estimation of 20 physicochemical properties of organic compounds. UPPER is a system of thermodynamically sound relationships that relate the various phase-transition properties to one another, which includes transition heats, transition entropies, transition temperatures, molar volume, vapor pressure, solubilities and partition coefficients in different solvents, and so on. UPPER integrates group contributions with the molecular geometric factors that affect transition entropies. All of the predictions are directly based on molecular structure. As a result, the proposed model provides a simple and accurate prediction of the properties studied. UPPER is designed to predict industrially, pharmaceutically, and environmentally relevant physicochemical properties. It can be an aid for the efficient design and synthesis of compounds with optimal physicochemical properties. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2710-2723, 2014 [ABSTRACT FROM AUTHOR]

The effects of surfactant type and content on the kinetics of emulsion reconstitution and release of drugs differing in lipophilicity from self-emulsifying microcrystalline cellulose pellets were studied. Furosemide and propranolol were the drugs, medium-chain triglyceride was the oil, and Cremophors ELP, RH40, and RH60 were the surfactants. Pellets were prepared by extrusion/spheronization with emulsions (75% water and 25%, w/w, oil/surfactant/drug). Stability of the emulsions was evaluated from changes in the back-scattered light, and re-emulsification and drug release from light transmittance and UV spectroscopy, respectively. Emulsion stability increased because of the incorporation of the drugs. Re-emulsification depended only on the surfactant content and was expressed by a simple power equation ( [ABSTRACT FROM AUTHOR]

The binding constants ( Kbs) of 17 aryl propionic acid derivatives (APADs) and related compounds with polyvinylpyrrolidone (PVP K30) and vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64) in aqueous media were determined by affinity capillary electrophoreses (ACE). The Kbs of APAD to polymers increase with octanol-water partition coefficients of the compounds. Kollidon VA64 is a stronger binder than PVP K30 to APAD compounds. The Kbs are greater at pH 4 than at pH 9. Both hydrophobic interaction and hydrogen bonding may be involved. However, hydrophobic interaction appears to be dominant. The ACE method is simple and fast, which could be used to study drug-polymer interaction in aqueous media. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:960-966, 2013 [ABSTRACT FROM AUTHOR]

The new development of the bioconcentration factor (BCF) base-line model of Dimitrov et al. [SAR QSAR Environ. Res. 6 (2005), pp. 531–554] is presented. The model applicability domain was expanded by enlarging the training set of the model up to 705 chemicals. The list of chemical-dependent mitigating factors was expanded by including water solubility of chemicals. The original empirical term for estimating ionization of chemicals was mechanistically analysed using two different approaches. In the first one, the ionization potential of chemicals was estimated based on the acid dissociation constant (pKa ). This term was found to be less adequate for inclusion in the ultimate BCF model, due to overestimating ionization of chemicals. The second approach, estimating the ionization as a ratio between distribution and partition coefficients (log P and log D), was found to be more successful. The new ionization term allows modelling of chemicals with both acidic and basic functionalities and chemicals undergoing different degrees of ionization. The significance of the different mitigating factors which can reduce the maximum bioconcentration potential of the chemicals was re-formulated and model parameters re-evaluated. [ABSTRACT FROM AUTHOR]

Abstract: Furaneol is an important aroma compound. It is very difficult to extract furaneol from food matrices and separate it on a gas chromatography column due to its high polarity and instability. A new quantitative method was developed to quantify furaneol in aqueous samples by the use of derivatization/solid phase microextraction (SPME) coupled with gas chromatography/mass spectrometry (GC/MS). The derivatization was carried out by reacting pentafluorobenzyl bromide with furaneol in basic solutions at elevated temperatures. The derivative was stable and less polar so that SPME-GC/MS could be applied for extraction, separation and detection. The automated analytical method had a limit of detection (LOD) of 0.5ngmL−1, a limit of quantification (LOQ) of 2ngmL−1, a repeatability of 9.5%, and a linear range from 2 to 500ngmL−1. The method was applied to analyze fruit samples. And it was found that the concentrations of furaneol in tomato ranged from 95 to 173μgkg−1, in strawberries ranged from 1663 to 4852μgkg−1. The results were verified with a LC procedure. To facilitate analytical method development, some physico-chemical parameters for furaneol were determined in this work. Its solubility in water was determined as 0.315gmL−1 (25°C). Its Log D in water and Log P in 0.1M phosphate buffer were −0.133 and 0.95 (20°C), respectively. Its pK a was 8.56 (20°C). [Copyright &y& Elsevier]

NPC 1161C is a novel antimalarial drug of interest because of its superior curative and prophylactic activity, and favorable toxicity profile against in vivo and in vitro models of malaria, pneumocystis carinii pneumonia, and leishmaniasis. The preformulation studies performed included determination of pKs, aqueous and pH solubility, cosolvent solubility, log P, pH stability, thermal analysis, and preliminary hygroscopicity studies. The mean pK, pK, and pK were determined to be 10.12, 4.07, and 1.88, respectively. The aqueous solubility was found to be 2.4 × 10 M having a saturated solution pH of 4.3-5.0 and a low intrinsic solubility of 1.6 × 10 M. A mathematical model of the pH-solubility profile was derived from pH 2.2 to 8.0. An exponential decrease in solubility was observed with increasing pH. The excess solid phase in equilibrium with the solution in aqueous buffers was determined to be the free-base form of the drug. A significant increase in solubility was observed with all the cosolvents studied, in both unbuffered and buffered systems. Mean log P of the salt and the free base were estimated to be 2.18 and 3.70, respectively. The compound had poor stability at pH 7.0 at 37°C, with a t of 3.58 days. Thermal analysis of the drug using DSC and TGA revealed that the drug is present as a semi-crystalline powder, which transformed into the amorphous state after melting. The drug was also found to sublime at higher temperatures. Determination of physicochemical properties of NPC 1161C provided useful information for the development of a dosage form and preclinical evaluation. [ABSTRACT FROM AUTHOR]

The lipophilicity of some emerging pesticides is investigated by reversed-phase high performance thin-layer chromatography (RP-HPTLC) on RP-18, RP-8 and CN stationary phases. The mobile phases were mixtures of methanol-water in different proportions of volume. The lipophilicity indices taken in consideration during this study are: RM0, mean of RF and RM, b, φ0, scores corresponding to the first principal components of RM and RF. The obtained results are compared with the computed lipophilicity indices (Log P) in order to evaluate the suitability of the involved method in the lipophilicity estimation for the pesticides. The comparison is performed through correlation matrices and profiles. The obtained correlations are indicating a high statistical significance. [ABSTRACT FROM AUTHOR]

Creatine is widely used as a dietary supplement for body builders to enhance athletic performance. As the monohydrate, its low solubility in water and high dose lead to water retention and gastrointestinal discomfort. Hence, alternative creatine derivatives with enhanced water solubility and potential therapeutic advantages have been synthesized. As a zwitterionic compound, creatine can form salts at the N-methyl guanidinium or carboxylic acid functional groups. In this study, we determined the aqueous solubilities and partition coefficients of six N-methyl guanidinium salts of creatine compared to those of creatine monohydrate; two of these were new salts, namely, creatine mesylate and creatine hydrogen maleate. The aqueous solubilities of the salts were significantly more than that of creatine monohydrate with the hydrochloride and mesylate being 38 and 30 times more soluble, respectively. The partition coefficients of the creatine salts were very low indicating their relatively high polarity. Permeabilities of creatine pyruvate, citrate, and hydrochloride in Caco-2 monolayers were compared to that of creatine monohydrate. Aside from the creatine citrate salt form that had reduced permeability, there were no significant differences in permeability characteristics in Caco-2 monolayers. Typical of an amphoteric compound, creatine is least soluble in the pH region near the isoelectric point. [ABSTRACT FROM AUTHOR]

The reformulation of pressurized metered dose inhalers with HFAs from CFCs has given rise to many solubility challenges. Compounds and excipients previously used in CFCs were observed to have significantly different solubility values in HFA-134a. In this investigation, the solubility values of 36 solid organic solutes in HFA-134a were determined. The set of compounds display diverse physico-chemical properties and yielded solubility values that ranged over 4 orders of magnitude. The experimental solubilities were compared to calculated values obtained from ideal solubility theory as well as from regular solution theory. While the theoretical models did not offer absolute solubility estimations, a clear correlation with the ideal solubility (melting point) was noted. Further consideration utilizing multiple linear regression models afforded correlations based on molecular properties. Regression models, containing melting point and log P (or molar volume) resulted in promising correlations having average absolute errors of 0.43 log units, or a factor of 2.69. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:198–208, 2008 [ABSTRACT FROM AUTHOR]

Onychomycosis is a challenging fungal infection to treat topically, likely due to the unique properties of the nail plate. This seemingly impenetrable barrier has high resistance to the passage of antifungal drugs in sufficient concentrations to kill the causative fungi deep in the nail bed. Recently, a new class of antifungal agent was described, termed oxaboroles, which have broad-spectrum activity. These oxaboroles were designed with properties believed to be required to allow for easier transit through the nail plate. Herein, we report (i) the nail penetration results of four oxaboroles that led to the selection of AN2690, (ii) the results of the nail penetration of AN2690 from four vehicles, and (iii) the nail penetration of AN2690 in its chosen vehicle compared to a commercial control, ciclopirox. AN2690 has superior penetration compared to ciclopirox, and achieves levels within and under the nail plate that suggest it has the potential to be an effective topical treatment for onychomycosisand the American Pharmacists Association J Pharm Sci 96: 2622–2631, 2007 [ABSTRACT FROM AUTHOR]

A new bilinear function that accounts for the disparity between the log-linear and parabolic models for cosolvent solubilization is presented, where ethanol was used as the model cosolvent. This accounts for both the initial and terminal slopes in the ethanol/water solubility profiles of semi-polar solutes. The proposed model has only two fitted parameters σA and σB, which represent the initial and terminal asymptotes in the solubility profiles. The bilinear function can also model the ethanol/water solubility profile more accurately than the log-linear model and a general parabolic model. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:2731–2735, 2005 [ABSTRACT FROM AUTHOR]

Pharmaceutical profiling studies were conducted on a novel prototype γ-secretase inhibitor, to determine the potential of its oral absorption. Such compounds can be of use in the treatment of Alzheimer’s disease (AD). The studies included determination of solubility, dissociation constant (pKa), octanol/water partition coefficient (log P) and the capacity factor (kIAM′) on immobilized artificial membrane (IAM) chromatographic columns. The compound is very slightly solubility in water (120 ± 50 μg/mL) but the solubility increased considerably in basic medium (270 ± 60 μg/mL). The compound exhibited pKa of (10.36 ± 0.11); and log P of (3.36 ± 0.16) determined by shake-flask method and (3.31 ± 0.01) determined by high performance liquid chromatography (HPLC). The experimentally determined log P values correlated well with the calculated one of 3.44. The observed log kIAM′ value of (2.79 ± 0.04) indicates that the compound can reasonably be expected to have high membrane permeability, and therefore, good absorption profile if taken orally. This conclusion is also supported by other parameters determined. [Copyright &y& Elsevier]

Results from calculations of the logarithm of the octanol–water partition coefficient, log P, and the aqueous solubility, S, for a wide range of arylamine dyes and related structures are presented. Since many arylamine dyes have functional groups that easily form ions, the logarithm of the apparent partition coefficient for dissociative systems, log D, has also been calculated as a function of pH for some of these compounds. Correlations of the observed biological behavior of various dyes with log P and S are discussed. [Copyright &y& Elsevier]