Partition Coefficient Log Research Articles

Validation of Dual-Action Chemo-Radio-Labeled Nanocarriers with High Efficacy against Triple-Negative Breast Cancer.

Identification and selectivity of molecular targets with prolonged action for difficult-to-target cancer such as triple-negative breast cancer (TNBC) represent a persisting challenge in the precision delivery of therapeutics. In the quest to target undruggable sites, this study validates the bioavailability of polydopamine-sealed mesoporous silica nanocarriers (PDA-mSiO2) for in vivo drug delivery to TNBC. For controlled transport and release, the chemotherapeutic drug doxorubicin was encapsulated in mSiO2 nanocarriers coated with a PDA layer serving as a stimuli-responsive gatekeeper or seal. For unifying targeting and treatment modalities, these nanocarriers were covalently conjugated to a macrocyclic chelator (DOTA) and folate (FA-mSiO2.) that enabled incorporation of radionuclides and identification of FR Alpha (FolRα) receptors present on TNBC cells. The robust chemical design of FA- and DOTA-functionalized PDA-coated mSiO2 nanocarriers constitutes mild reaction conditions to avoid the loss of surface-bound molecules. The radiolabeling studies with the theranostic pair 68Ga and 177Lu showed quantitative trends for radiochemical efficacy and purity. Nanocarriers equipped with both radiolabels and affinity ligands were optimally stable when incubated with human serum for up to 120 h (177Lu), demonstrating hydrophilicity with a partition coefficient (log P) of -3.29 ± 0.08. Specifically, when incubated with TNBC cells, the cells received significant FA-mSiO2 carriers, demonstrating efficient carrier internalization and time-dependent uptake. Moreover, in vivo results visualize the retention of drug-filled carriers at the tumor sites for a long time, which holds promise for therapeutic studies. This research work demonstrates for the first time the successful dual conjugation of nanocarriers through the colocation of radionuclides and anticancer drugs that is promising for both live molecular imaging and enhanced therapeutic effect for TNBC.

Elaborating the Occurrence and Distribution of Per- and Polyfluoroalkyl Substances in Rivers and Sediment around a Typical Aging Landfill in China.

Per- and polyfluoroalkyl substances (PFASs) are bioaccumulative and widely distributed persistent organic pollutants (POPs). Understanding the distribution of and ecological risks posed by PFASs is critical, particularly for PFAS emissions and accumulation from a common urban pollution source. The transformation characteristics and ecological risks of PFASs from a typical aging municipal landfill leachate were systematically monitored and assessed over five years in this study. The results showed that the total PFAS concentrations (ΣPFASs) in the rivers were between 26.4 and 464.3 ng/L, whereas in sediment, ΣPFASs ranged from 9.5 to 58.5 ng/g (w/w). The presence of perfluorooctanoic acid (PFOA) was the most prominent PFAS in both water (39.4-152.3 ng/L) and sediment (1.1-56.1 ng/g). In a five-year monitoring study, the concentration of PFASs in the aging landfill decreased by 23.3%, with higher mean concentrations observed during summer (307.6 ng/L) compared to winter (250.4 ng/L). As for the pollution distribution, the suspended particulate matter-water partition coefficient (log Kd) of carboxylic acid (PFCAs) and perfluoroalkane sulfonic acids (PFSAs) ranged from 1.53 to 2.65, and from 1.77 to 2.82, respectively. PFSAs and long-chain PFCAs exhibited a greater propensity for sediment association compared to short-chain PFCAs. An ecological risk assessment of four typical PFASs, PFOA, perfluorooctane sulfonate (PFOS), perfluorobutanoic acid (PFBA), and perfluorobutane sulfonic acid (PFBS), utilizing the hazard quotient method revealed that the rivers surrounding the typical aging landfill exhibited a low contamination risk for PFOA, while no ecological risks were associated with the other three FPASs. This study contributes to an enhanced comprehension of the occurrence, distribution, and risk of PFASs in the rivers in rivers and sediment surrounding a typical aging landfill site in China, thereby providing crucial reference information for ensuring water quality safety.

Gas–particle partitioning of organophosphate esters in indoor and outdoor air and its implications for individual exposure

The extensive utilization of organophosphate esters (OPEs) has resulted in their widespread presence in the environment, raising concerns about potential human health risks. In this study, 13 OPEs were analyzed in both gas and particle phases as well as in indoor and outdoor atmospheric environments. Moreover, human exposure to OPEs were investigated within a university environment, focusing on forehead contact and individual PM2.5 inhalation. The results showed similar distribution patterns of OPEs indoors and outdoors, although higher concentrations were found indoors. The average atmospheric concentration of ∑OPEs (combining particle and gaseous OPEs) was 1575 pg/m3 in the outdoor environment and 6574 pg/m3 ∑OPEs in the indoor microenvironments. The overwhelming majority of OPEs exhibit a pronounced propensity to adsorb onto PM2.5 particles. Notably, the concentration of OPEs on the forehead differed significantly from that in the atmospheric environment, whereas individual PM2.5 exposure was consistent with the concentration of indoor PM2.5. Intriguingly, some OPEs with high octanol–water partition coefficient (log Kow) were not detected in the environment but found on human foreheads. Gas-particle partitioning was predicted using the Harner–Bidleman and Li–Ma–Yang models and the results were in agreement with the monitoring data for approximately half of the OPE monomers. Correlations between OPEs exposure and gas-particle partitioning were found to be more significant for novel OPEs. No non-cancer risk to humans through individual exposure to OPEs was identified via forehead exposure or inhalation. The previously unreported relationship between individual exposure and the environmental occurrence of traditional and novel OPEs demonstrated in this study highlights the importance of evaluating the potential health risks associated with actual OPE exposure.

Cytotoxicity and bioavailability assessment from thiamin-phospholipid complexation loaded Ajwain oil based self nanoemulsifying system

Poor bioavailability (<5%) of thiamin hydrochloride (TH) primarily relates to its impaired permeability across gut mucosa. To modulate its permeability, a dual system based approach consisting of phospholipid complexation embedded into a self nanoemulsifying system was investigated. Thiamin-Phospholipid Complex (TPC) was developed and its Ajwain oil (AJO)-based self nanoemulsifying formulations (SNFs) were evaluated. Formation of TPC complexation was resulted from molecular interactions held between free bases of thiamin and phospholipid (PL). FTIR characterization reveals that the amino group (-NH2) in the free base of thiamin was physically interacted to phosphate linkage in PL. Single endothermic event in TPC & TH, reveals complexation between PL & free bases as interpreted from DSC data. Their corresponding melting point was 127 °C and 258 °C, respectively. Heat of fusion (ΔHf) in TPC was higher than TH or PL. TPC exhibits a poor conductive environment over TH when diluted with ethanol/Tween20 (T2) medium. Lipophilic character of TPC was confirmed from partition coefficient (log P). Exact combination where ternary components produced fully dilutable nanoemulsion system, was identified using ternary diagram drawn between AJO (incorporated with TPC) as oil phase, and Tween20/Polyethylene glycol 600 (PEG600) as Surfactant/co-surfactant (Smix) at ratios 1:1; 1:2 & 2:1. Seven TPC-loaded self nanoemulsifying formulations (SNFs) were designed which, upon subjected to aqueous phase dilution yielded nanoemulsion with droplet size range 95–190 nm with zeta potential −1.78 ± 0.10 mV. Conductivity and Refractive index (RI) data of SNFs were in the range of 98 ± 7.0 to 231 ± 27 μS/cm and 1.458 to 1.463 units, respectively. In vitro TH release from SNF was determined in hydrochloric (HCl) buffer at pH 1.2, and in phosphate buffer solution (PB) at pH 6.8, data interpretation reveals that TPC delayed the release pattern compared to TH and could be attributed to lipophilic behavior of TPC. Intestinal permeability of drug was assessed from optimized SNF (F1) vs. TH across intestinal gut sac model (Apical to basolateral A→B) resulted in a significant difference in permeability coefficient (1.09 × 10−5cm/h). Antioxidant potential of SNF was demonstrated in the DPPH method. MTT assay of TPC formulation conducted on MCF-7 and MDA-MB-231 (Breast cancer) cell lines showed the developed system from AJO possessed cytotoxicity effect. Pharmacokinetic assessment showed that optimized SNFs produced more than four-fold enhancement in bioavailability over control (TH solution) in the Wistar rat model. Meanwhile Area under curve (AUC) data obtained from TPC (in coarse emulsion) vs.TH produced a significant difference (p < 0.001). It can be concluded that developed SNFs via phospholipid complexation produced lipophilic transformation of TH and its SNFs modulated permeability as well as bioavailability enhancement of thiamin.

Occurrence, distribution, and environmental risk of 61 glucocorticoids in surface water of the Yellow River Delta, China

Glucocorticoids (GCs), as important endocrine disrupting compounds and emerging contaminants, could have irreversible adverse effects on aquatic organisms even at ng/L levels. However, previous studies have only focused on the dissolved concentrations of GCs in the water, and limited data are available for their occurrences in the solid phase. In this study, the occurrence, distribution, and environmental risks of 61 natural and synthetic GCs in surface water of the Yellow River Delta (YRD) were simultaneously analyzed by investigating water, suspended particulate matter (SPM) and sediment samples at 64 sites in six major rivers in the wet season. Overall, 51 GCs were detected in all samples from different matrices, and their concentrations were in the range of not detected (ND)−274 ng/L in water, ND−42 ng/g dry weight (dw) in SPM and ND−9.98 ng/g dw in sediment. Natural GCs were the dominant compounds in all samples, followed by synthetic halogenated esters. High concentrations of GCs were observed in discharge outlet samples from livestock farming, aquaculture and industrial production, and the composition differences of GCs between human/animal sources and industrial sources could be used as indicators to identify pollution sources. Most GCs were distributed in the water phase, while compounds with higher log octanol/water partition coefficients (log Kow) tended to be adsorbed to SPM and sediment. The spatial distribution of GCs was primarily affected by anthropogenic activities and hydrodynamic conditions. Four synthetic compounds (budesonide [BD], fluocinolone acetonide [FOA], fluticasone propionate [FP], and clobetasol propionate [CBSP]) were identified as the main contributors to GC activity with a combined contribution of 57 %–95 %. Risk assessment using the risk quotient revealed that low to moderate risks are posed to aquatic organisms in surface water.

Partitioning behavior of dyes in ionic liquids induced aqueous biphasic systems of PPG 725 & ammonium salts

ABSTRACT Polypropylene glycol (PPG) is one of the most utilized polymers in aqueous biphasic systems. The low polarity of the polymer-rich phase restricts the application of the ABSs. The applicability of polymer rich ABSs can be induced by adding little amount of ionic liquids as adjuvants. Therefore, an analysis involving the introduction of a small amount of imidazolium-based ILs to PPG 725 + ammonium salts ABSs was performed. The phase diagrams as well as the partitioning behavior of dyes: Orange II (OII), Eriochrome Black T (EBT) and Brilliant Green (BG) were investigated. The addition of 5% 1-butyl-3-methylimidazolium acetate, [BMIM][AC] modulates the partition behaviors of all the investigated dyes. The employed ILs and dyes partitioned preferentially into the polymer-rich phase. The partition coefficients (Kdye) for all the dyes follow the sequence: BG > EBT > OII in all investigated ABSs. The results obtained are in accordance with the logarithm of octanol-water partition coefficients (log Kow) of the respective dyes. The recovery of BG dye from polymer phase has been studied successfully by adsorption onto chitosan.

Modeling the Partitioning of Anionic Carboxylic and Perfluoroalkyl Carboxylic and Sulfonic Acids to Octanol and Membrane Lipid.

Perfluoroalkyl carboxylic and sulfonic acids (PFCAs and PFSAs, respectively) have low acid dissociation constant values and are, therefore, deprotonated under most experimental and environmental conditions. Hence, the anionic species dominate their partitioning between water and organic phases, including octanol and phospholipid bilayers which are often used as model systems for environmental and biological matrices. However, data for solvent-water (SW) and membrane-water partition coefficients of the anion species are only available for a few per- and polyfluoroalkyl substances (PFAS). In the present study, an equation is derived using a Born-Haber cycle that relates the partition coefficients of the anions to those of the corresponding neutral species. It is shown via a thermodynamic analysis that for carboxylic acids (CAs), PFCAs, and PFSAs, the log of the solvent-water partition coefficient of the anion, log KSW (A- ), is linearly related to the log of the solvent-water partition coefficient of the neutral acid, log KSW (HA), with a unity slope and a solvent-dependent but solute-independent intercept within a PFAS (or CA) family. This finding provides a method for estimating the partition coefficients of PFCAs and PFSAs anions using the partition coefficients of the neutral species, which can be reliably predicted using quantum chemical methods. In addition, we have found that the neutral octanol-water partition coefficient, log KOW , is linearly correlated to the neutral membrane-water partition coefficient, log KMW ; therefore, log KOW , being a much easier property to estimate and/or measure, can be used to predict the neutral log KMW . Application of this approach to KOW and KMW for PFCAs and PFSAs demonstrates the utility of this methodology for evaluating reported experimental data and extending anion property data for chain lengths that are unavailable. Environ Toxicol Chem 2023;00:1-12. © 2023 SETAC.

Transport and Attenuation of an Artificial Sweetener and Six Pharmaceutical Compounds in a Sequenced Wetland-Steel Slag Wastewater Treatment System

The occurrence of pharmaceutically active compounds (PhACs), nutrients, and an artificial sweetener acesulfame in wastewater, and subsequent removal in an engineered system comprising aerobic wetland, anaerobic wetland, and steel slag cells, were investigated. The PhACs evaluated in this study covered a range of octanol–water partition coefficients (log Kow = 0.07–2.45) and acid dissociation constants (pKa = 1.7–13.9) and included carbamazepine, caffeine, sulfamethoxazole, ibuprofen, and naproxen. The mean flow rate in the system was 0.89 m3 day−1 (0.02 to 4.27 m3 day−1), representing a hydraulic retention time of 5 days. The removal efficiencies of PO4-P, NH3-N, and cBOD5 in the treatment system were &gt;99, 82, and 98%. The removal efficiencies for the PhACs and acesulfame were classified into four groups, including those that were (a) efficiently removed (caffeine by &gt;75%); (b) moderately removed (ibuprofen by 50–75%); (c) poorly removed (sulfamethoxazole and naproxen by 25–50%); and (d) recalcitrant (carbamazepine and acesulfame by &lt;25%). Variability in concentrations and treatment efficiencies was observed in different sampling events, which may be due to variations in input concentrations or changes in the flow rate. The addition of a steel slag cell increased the overall removal efficiency of the studied compounds, except for carbamazepine.

Lipid emulsion therapy during management of the critically-ill poisoned patient: a prospective cohort study

Background Despite conflicting data, intravenous lipid emulsion has emerged as a potential antidote. The “lipid sink” theory suggests that following intravenous administration of lipid, lipophilic drugs are sequestered in the vascular compartment, thereby reducing their tissue concentrations. This study sought to determine if survival is associated with the intoxicant’s degree of lipophilicity. Methods We reviewed all cases in the Toxicology Investigators Consortium’s lipid sub-registry between May 2012 through December 2018. Information collected included demographics, exposure circumstances, clinical course, management, disposition, and outcome. The primary outcome was survival after lipid emulsion therapy. Survival was stratified by the log of the intoxicant’s octanol-water partition coefficient. We also assessed the association between intoxicant lipophilicity and an increase in systolic blood pressure after lipid emulsion administration. Results We identified 134 patients, including 81 (60.4%) females. The median age was 40 years (interquartile range 21-75). One hundred and eight (80.6%) patients survived, including 45 (33.6%) with cardiac arrest during their intoxication. Eighty-two (61.2%) were hypotensive, and 98 (73.1%) received mechanical ventilation. There was no relationship between survival and the log of the partition coefficient of the intoxicant on linear analysis (P = 0.89) or polynomial model (P = 0.10). Systolic blood pressure increased in both groups. The median (interquartile range) systolic blood pressure before lipid administration was 68 (60-78) mmHg for those intoxicants with a log partition coefficient < 3.6 compared with 89 (76-104) mmHg after lipid administration. Among those drugs with a log partition coefficient > 3.6, the median (interquartile range) was 69 (60-84) mmHg before lipid and 89 (80-96) mmHg after lipid administration. Conclusion Most patients in this cohort survived. Lipophilicity was not correlated with survival or the observed changes in blood pressure. The study did not address the efficacy of lipid emulsion.

Predicting the removal efficiency of pharmaceutical and personal care products using heated metal oxides as adsorbents based on their physicochemical characteristics

Pharmaceutical and personal care products (PPCPs) are emerging pollutants that are commonly found in the environment and exist predominantly in nondegradable forms. Several attempts have been made to remove PPCPs via conventional wastewater treatment processes; however, these processes have limitations, such as high costs and insufficient removal efficiencies. Adsorption is a promising alternative for removing PPCPs because it is inexpensive, highly reusable, and easy to operate. Therefore, this study aims to determine the contributing characteristics that can be used to predict the adsorption behaviour of PPCPs based on their physicochemical properties, with heated metal oxide adsorbents (HMOAs). HAOP (heated aluminium oxide particles) and HIOP (heated iron oxide particles) with particle sizes below 38 μm were used. Results from the Brunauer-Emmett-Teller (BET) analysis show that HIOP has higher surface area and smaller pore size (113.7 ± 26.3 m2/g and 5.4 ± 1.8 nm) than HAOP (14.5 ± 0.6 m2/g and 18.6 ± 3.1 nm), which suggest that HIOP would show superior adsorption rates compared to HAOP. The adsorption mechanism is identified based on three major physicochemical properties of PPCPs: molecular weight (M.W.), octanol–water partition coefficient (log Kow), and acid dissociation constant (pKa). The results suggest that the most dominant factor that contributes to the adsorption of PPCPs on to HMOAs is the M.W., where the larger the molecular size, the better the adsorption efficiency. The tests conducted with varying log Kow values revealed that the hydrophilicity of the adsorbent influences the adsorption performance. It was found that HIOP exhibits better removal efficiencies with hydrophilic PPCPs (up to 83%) than with hydrophobic PPCPs (48%), while HAOP exhibits better removal efficiencies with hydrophobic PPCPs (86%) than with hydrophilic PPCPs, with less than 10% removal. Unlike the M.W. and pKa values, the log Kow does not exhibit any visible trend. Therefore, the adsorption behaviour can be predicted with the M.W. and pKa values of the PPCPs, when HAOP and HIOP are used as adsorbents.

Lipophilicity of fentalogs: Comparison of experimental and computationally derived data.

Although fentanyl and a small number of derivatives used for medical or veterinary procedures are well characterized, physiochemical properties have not been determined for many of the newer fentanyl analogs. Partition coefficients (Log P) were determined for 19 fentalogs using the shake-flask method and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Experimentally determined partition coefficients were compared with computationally derived data using six independent software sources (ACD/LogP, LogKOWWIN v 1.69, miLogP 2.2, OsirisP, XLOGP 3.0, ALogPS 2.1). Fentalogs with a wide variety of structural modifications were intentionally selected, yielding Log P values ranging from 1.21 to 4.90. Comparison of experimental and computationally derived Log P values were highly correlated (R2 0.854-0.967). Overall, substructure-based modeling using fragmental methods or property-based topological approaches aligned more closely with experimentally determined Log P values. LC-MS/MS was also used to estimate pKa values for fentalogs with no previously reported data. Lipophilicity and pKa are important considerations for analytical detection and toxicological interpretation. In silico methods allow the determination of physicochemical information prior to certified reference materials being readily available for in vitro or in vivo studies. Computationally derived data can provide insight regarding physiochemical characteristics of future fentalogs and other classes of synthetic analogs that have yet to emerge.

Chemometrics as a valuable tool for evaluating interactions between antiretroviral drugs and food.

Clinically significant interactions with food occur for more than half of antiretroviral drugs. Different physiochemical properties deriving from the chemical structures of antiretroviral drugs may contribute to the variable food effect. Chemometric methods allow analysing a large number of interrelated variables concomitantly and visualizing correlations between them. We used a chemometric approach to determine the types of correlations among different features of antiretroviral drugs and food that may influence interactions. Thirty-three antiretroviral drugs were analysed: ten nucleoside reverse transcriptase inhibitors, six non-nucleoside reverse transcriptase inhibitors, five integrase strand transfer inhibitors, ten protease inhibitors, one fusion inhibitor and one HIV maturation inhibitor. Input data for the analysis were collected from already published clinical studies, chemical records and calculations. We constructed a hierarchical partial least squares (PLS) model with three response parameters: postprandial change of time to reach maximum drug concentration (ΔTmax ), albumin binding (%) and logarithm of partition coefficient (logP). Predictor parameters were the first two principal components of principal component analysis (PCA) models for six groups of molecular descriptors. PCA models explained 64.4% to 83.4% of the variance of the original parameters (average: 76.9%), whereas the PLS model had four significant components and explained 86.2% and 71.4% of the variance in the sets of predictor and response parameters, respectively. We observed 58 significant correlations between ΔTmax , albumin binding (%), logP and constitutional, topological, hydrogen bonding and charge-based molecular descriptors. Chemometrics is a useful and valuable tool for analysing interactions between antiretroviral drugs and food.

Exploring sorption of pesticides and PAHs in microplastics derived from plastic mulch films used in modern agriculture

The sorption and vector effect of microplastics on the transfer of pesticides and polycyclic aromatic hydrocarbons (PAHs), as well as its impact on agriculture remain largely unexplored. This comparative study is first to investigate the sorption behavior of different pesticides and PAHs at environmentally realistic concentrations by model microplastics and microplastics derived from polyethylene mulch films. Sorption was found to be up to 90% higher in the case of microplastics derived from mulch films as opposed to pure polyethylene microspheres. For microplastics from mulch films, the sorption percentages for pesticides in media containing CaCl2 were reported to be: pyridate (75.68% and 52.44%), fenazaquin (48.54% and 32.02%), pyridaben (45.04% and 56.70%), bifenthrin (74.27% and 25.88%), etofenprox (82.16% and 54.16%) and pyridalyl (97.00% and 29.74%) at 5 μg/L and 200 μg/L pesticide concentration levels respectively. For PAHs, the sorption amounts were: naphthalene (22.03% and 48.00%), fluorene (38.99% and 39.00%), anthracene (64.62% and 68.02%) and pyrene (75.65% and 86.38%) at 5 μg/L and 200 μg/L PAH concentration levels respectively. Sorption was influenced by the octanol-water partition coefficient (log Kow) and ionic strength. Kinetics of the process in the case of sorption of pesticides were best explained by pseudo-first order kinetic model (R2 between 0.90 and 0.98) while the best fitting isotherm model was Dubinin-Radushkevich (R2 between 0.92 and 0.99). Results suggest the presence of surface level physi-sorption through a micropore volume filling mechanism and the role of hydrophobic and electrostatic forces. Pesticide desorption data in polyethylene mulch films indicate that pesticides with high log Kow were almost completely retained in mulch films, while those with lower log Kow were desorbed rapidly into the surrounding media. Our study highlights the role of microplastics from plastic mulch films as vectors for pesticide and PAH transport at environmentally realistic concentrations and the factors that influence it.

Building Machine Learning Small Molecule Melting Points and Solubility Models Using CCDC Melting Points Dataset.

Predicting solubility of small molecules is a very difficult undertaking due to the lack of reliable and consistent experimental solubility data. It is well known that for a molecule in a crystal lattice to be dissolved, it must, first, dissociate from the lattice and then, second, be solvated. The melting point of a compound is proportional to the lattice energy, and the octanol-water partition coefficient (log P) is a measure of the compound's solvation efficiency. The CCDC's melting point dataset of almost one hundred thousand compounds was utilized to create widely applicable machine learning models of small molecule melting points. Using the general solubility equation, the aqueous thermodynamic solubilities of the same compounds can be predicted. The global model could be easily localized by adding additional melting point measurements for a chemical series of interest.

Evaluation of Membrane Permeability of Copper-Based Drugs

Membrane permeability of copper complexes with potential anti-inflammatory activity were measured using an artificial membrane in a modified Franz cell. Using CuCl2 as the control, all the ligands tested enhanced the diffusion of copper, with enhancement factors ranging from 2 to 7. Octanol/water partition coefficients (log Ko/w) were measured and correlated with the permeability coefficients (Kp). In addition, chemical speciation was used to determine the predominant complex in solution at physiological pH. No correlation was found between the measured permeability coefficients and either molecular weight (MW) or log Ko/w.

Characterization of piroctone olamine for topical delivery to the skin.

Dandruff and its more severe related condition, seborrheic dermatitis affects a high proportion of the population at some point in their life. Piroctone olamine, also known as Octopirox® (OPX) is the monoethanolamine salt of piroctone and is an antifungal agent widely used for the management of dandruff. The aim of the present work was to characterize the physicochemical properties of piroctone olamine and to conduct pre-formulation studies for the development of novel topical formulations of this active. An HPLC method was developed and validated for the analysis of OPX. The melting point was determined using the DSC Q2000 (TA Instruments, USA). The distribution coefficient (logD(O/PBS) ) and partition coefficient (log Po/w ) was determined in phosphate-buffered saline (PBS) AND deionized (DI) water using the shake flask method. All experiments were performed at room temperature. The solubility was determined experimentally by adding amount of active to a solvent. The samples were kept at 32° ± 1°C for 48 h in a water bath. The stability of the compound was determined in a range of solvents by preparing solutions of 1mg mL-1 in the relevant solvents. These solutions were kept and stirred throughout the experiment at 32 ± 1°C, and aliquots were taken at 24, 48 and 96 h. The HPLC method was developed successfully; however, samples at the lower end of the calibration curve showed lower degrees of precision and accuracy. Based on experiments with DSC, the melting point was observed at an onset temperature of 132.4°C. The LogD was determined to be 1.84. The compound had the highest solubility in methanol (278.4mg mL-1 ) and propylene glycol (PG), with a value of 248.8mg mL-1 . The lowest solubility for OPX was in dimethyl isosorbide (9.9mg mL-1 ), Labrafac™ (3.6mg mL-1 ) and isostearyl isostearate (0.5mg mL-1 ). Over the 4 days, OPX showed stability in ethanol and PG, while a notable decrease in OPX was observed in PBS and DI water at 32 ± 1°C. The physicochemical properties of OPX were characterized to find suitable excipients able to target the epidermis for topical delivery. Building on these findings, future work will focus on the development of novel topical formulation of OPX.

Computational study of physicochemical, optical, and thermodynamic properties of 2,2-dimethylchromene derivatives.

A large number of heterocyclic compounds are used as drugs, mainly due to the duality of lipophilicity playing in hydrophobic interactions and solubility with at least one hydrogen bond acceptor. The study of electronic properties is then important to better understand not only these charge distribution effects but also some other physicochemical properties involved in bioactivity to directly assess the bioavailability of these compounds and a possible classification in related applications. Phytomolecules such as chromenes are very accessible molecules exhibiting a bioactivity. Our study is focused on the impact of a number of functional groups acting on some 2,2-dimethylchromene derivatives, namely their global reactivity from the frontier molecular orbitals and local reactivity from the Fukui functions, where the carbonyl group acting as an electron withdrawal group has the most relevant effect, the solubility from the partition coefficient Log P strongly depending on the charge distribution and electronegative sites, the optical effects from the delocalization in the vinyl group, as well as the evaluation of the entropy associated with the molecular flexibility also acting on the bioactivity. Despite the effects of the wave function or density methods on the order of magnitude of these properties, these compounds are consistent with the rules for a potential oral drug candidate. The calculations of the electronic properties were performed through two levels of theory: Hartree-Fock level as a wave function-based method as an ab initio reference including some physically consistent eigenvalues and density functional theory DFT as a correlation consistent method using different functionals: hybrid or with a long-range correction. The basis set used is a 6-311++G(d,p) Pople basis set including diffuse and polarization basis functions. The basis set is adapted to the size of the molecules and consequently to the degree of electronic localization. Gaussian 09 software was used for the computation.

Enhancing Oil Solubility of BCS Class II Drug Phenytoin Through Hydrophobic Ion Pairing to Enable High Drug Load in Injectable Nanoemulsion to Prevent Precipitation at Physiological pH With a Potential to Prevent Phlebitis

This work investigates the micellar titration of phenytoin (a weakly acidic drug) with cetyltrimethylammonium hydroxide (CTAH) to form a hydrophobic ion-pair to enhance oil solubility of phenytoin, followed by an effort to formulate nanoemulsion that could potentially prevent precipitation of phenytoin at physiological pH. The ion-pair formulated in nanoemulsion was evaluated for in vitro precipitation during serial dilution at physiological pH. The formation of ion-pair during titration was explained in context of pH-solubility data. The mathematical model successfully integrated ionization and micellization equilibria to reflect on dominant mechanisms for solubilization. The micellar phenomenon during titration was confirmed using Dynamic Light Scattering (DLS). The phase changes of the excess undissolved solids during titration were evident from X-Ray Powder Diffraction (XRPD) and Fourier Transform Infrared Spectroscopy (FTIR). This analysis confirmed the conversion of phenytoin into ionized state and its subsequent ionic interaction with CTAH forming hydrophobic ion-pair complex (HIP). The complete ion pair formation was evident at pHmax (8.8 to 9.2), and its 1:1 stoichiometry was confirmed using HPLC (Phenytoin and CTAH) and H1 NMR, hence could also be called as a lipophilic salt. The ion-pair (salt) was insoluble in water and showed remarkably high partition coefficient (log P) in octanol/water. As characterized by Hot Stage Microscopy (HSM), the melting point of the ion-pair complex was lowered to 150.8⁰C compared to the free acid (> 300οC), this was even further lowered to 81.1 °C when evaluated in castor oil. This led to approximately eight-fold higher solubility of hydrophobic ion pair (HIP) in castor oil compared to the free acid form. The high miscibility in castor oil was suitable to formulate a high drug load injectable dispersed system. This was successfully achieved with lecithin and polysorbate as emulsifiers without leaching drug into continuous phase at pH 7.4. This nanoemulsion (<300 nm, and > +30 mV zeta potential) remain stable when evaluated over a period of one month. A serial dilution study of the nanoemulsion was performed in PBS buffer, microscopic observations suggested no birefringence despite incubation at 25°C for several hours. This result indicated that Phenytoin remained strongly partitioned within dispersed oily phase with a higher drug loading when ion-paired phenytoin was used. The higher drug load could enable a small volume slow bolus injection to meet 50 mg/min or lower delivery rate criteria for Phenytoin in the clinical set up. This provided a pathway to further explore potential injectable nano-emulsion formulations that could alleviate typical phlebitis issue associated with the injectable phenytoin solution administration at physiological pH.

Supersaturation maintenance of carvedilol and chlorthalidone by cyclodextrin derivatives: Pronounced crystallization inhibition ability of methylated cyclodextrin

Cyclodextrin (CD) is used to solubilize poorly water-soluble drugs by inclusion complex formation. In this study, we investigated the effect of CD derivatives on stabilizing the supersaturation by inhibiting the crystallization of two poorly water-soluble drugs, carvedilol (CVD) and chlorthalidone (CLT). The phase solubility test showed that β-CD and γ-CD derivatives enhanced the solubility of CVD to a greater extent, whereas the solubility of CLT was enhanced more by β-CD derivatives. The solubilization efficacy of CD derivatives was dependent on the size fitness between the drug molecule and the CD cavity. In the drug crystallization induction time measurement, the same initial drug supersaturation ratio (S) was employed in all the CD solutions, and the methylated CD derivatives greatly outperformed unmethylated CD derivatives in stabilizing the supersaturation of both CVD and CLT. The crystallization inhibition strength of CD derivatives was strongly affected by the CD derivative substituent. Moreover, the calculated logarithm of octanol/water partition coefficients (log P) of CD derivatives showed a good correlation with drug crystallization inhibition ability. Thus, the high hydrophobicity of methylated CD plays an essential role in inhibiting crystallization. These findings can provide a valuable guide for selecting appropriate stabilizing agents for drug-supersaturation formulations.

Using Machine Learning To Predict Partition Coefficient (Log P) and Distribution Coefficient (Log D) with Molecular Descriptors and Liquid Chromatography Retention Time.

During preclinical evaluations of drug candidates, several physicochemical (p-chem) properties are measured and employed as metrics to estimate drug efficacy in vivo. Two such p-chem properties are the octanol-water partition coefficient, Log P, and distribution coefficient, Log D, which are useful in estimating the distribution of drugs within the body. Log P and Log D are traditionally measured using the shake-flask method and high-performance liquid chromatography. However, it is challenging to measure these properties for species that are very hydrophobic (or hydrophilic) owing to the very low equilibrium concentrations partitioned into octanol (or aqueous) phases. Moreover, the shake-flask method is relatively time-consuming and can require multistep dilutions as the range of analyte concentrations can differ by several orders of magnitude. Here, we circumvent these limitations by using machine learning (ML) to correlate Log P and Log D with liquid chromatography (LC) retention time (RT). Predictive models based on four ML algorithms, which used molecular descriptors and LC RTs as features, were extensively tested and compared. The inclusion of RT as an additional descriptor improves model performance (MAE = 0.366 and R2 = 0.89), and Shapley additive explanations analysis indicates that RT has the highest impact on model accuracy.