2-[N-(2,4-Difluoro­phen­yl)carbamo­yl]-3,4,5,6-tetra­fluoro­benzoic acid

The title compound, C14H5F6NO3, was synthesized by condensation of tetra­fluoro­phthalic anhydride and 2,4-difluoro­aniline. It was then recrystallized from hexane to give a nonmerohedral twin with two crystallographically unique mol­ecules in the asymmetric unit. The refined twin fraction is 0.460 (3). Torsional differences between the aryl rings and the central amide group account for the presence of two unique mol­ecules. The compound packs as double tapes formed by O—H⋯O and N—H⋯O hydrogen-bonding inter­actions between each unique mol­ecule and its symmetry equivalents

Solvent-induced micelle formation in a hydrophobic interaction model

We investigate the aggregation of amphiphilic molecules by adapting the two-state Muller-Lee-Graziano model for water, in which a solvent-induced hydrophobic interaction is included implicitly. We study the formation of various types of micelle as a function of the distribution of hydrophobic regions at the molecular surface. Successive substitution of non-polar surfaces by polar ones demonstrates the influence of hydrophobicity on the upper and lower critical solution temperatures. Aggregates of lipid molecules, described by a refinement of the model in which a hydrophobic tail of variable length interacts with different numbers of water molecules, are stabilized as the length of the tail increases. We demonstrate that the essential features of micelle formation are primarily solvent-induced, and are explained within a model which focuses only on the alteration of water structure in the vicinity of the hydrophobic surface regions of amphiphiles in solution.Comment: 11 pages, 10 figures; some rearrangement of introduction and discussion sections, streamlining of formalism and general compression; to appear in Phys. Rev.

Estimation of drug solubility in water, PEG 400 and their binary mixtures using the molecular structures of solutes

With the aim of solubility estimation in water, polyethylene glycol 400 (PEG) and their binary mixtures, quantitative structure-property relationships (QSPRs) were investigated to relate the solubility of a large number of compounds to the descriptors of the molecular structures. The relationships were quantified using linear regression analysis (with descriptors selected by stepwise regression) and formal inference-based recursive modeling (FIRM). The models were compared in terms of the solubility prediction accuracy for the validation set. The resulting regression and FIRM models employed a diverse set of molecular descriptors explaining crystal lattice energy, molecular size, and solute-solvent interactions. Significance of molecular shape in compound's solubility was evident from several shape descriptors being selected by FIRM and stepwise regression analysis. Some of these influential structural features, e.g. connectivity indexes and Balaban topological index, were found to be related to the crystal lattice energy. The results showed that regression models outperformed most FIRM models and produced higher prediction accuracy. However, the most accurate estimation was achieved by the use of a combination of FIRM and regression models. The results also showed that the use of melting point in regression models improves the estimation accuracy especially for solubility in higher concentrations of PEG. Aqueous or PEG/water solubilities can be estimated by these models with root mean square error of below 0.70. © 2010 Elsevier B.V

Some micellar properties of long-chain acylcarnitines

The acid dissociation constants of long-chain esters of carnitine ([beta]-hydroxy-[gamma]-trimethylammonium-butyrate) above the critical micelle concentration were determined potentiometrically at several concentrations of added KCl. As the degree of protonation [beta] increases the apparent pK values decrease owing to the increased positive charge on the micelle. The difference in pK between the neutral (zwitterionic) micelle and the value at any given [beta] was used to determine the surface potential of the micelle [Psi] at that degree of protonation. At each degree of protonation the measured surface potential was related to the surface charge density [sigma] with the aid of the calculations of Loeb, Wiersema, and Overbeek for a spherical impenetrable particle. The surface potentials and surface charge densities of lauryl-, myristyl-, and palmitylcarnitine are nearly identical at a given degree of protonation and ionic strength, and, as expected, increasing the ionic strength produces a decrease in the surface potential. From the partial molal volume of each surfactant in the micelle and the calculated surface charge density it was possible to calculate the aggregation number n of the micelle. Good agreement was found between the calculated values of n and values obtained from light-scattering experiments at several ionic strengths and degrees of protonation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32652/1/0000016.pd

Application of the Henderson-Hasselbalch equation to solubility determination: NSC-639829 Case Study

A number of publications which challenge the applicability of the Henderson-Hasselbalch equation to saturated solutions have appeared in the last few years (Avdeef [1-3], Butcher et al. [4], and Volgyi et al. [5]). In the most recent of these, Butcher et al. [4] suggested “the Henderson-Hasselbalch equation may not always be an accurate predictor of the pH dependence of solubility.” They claimed that the pKa of 4.70 determined by Jain et al. [6] for NSC-639829 is incorrect and that the value of 3.76, which they obtained by extrapolation of spectrophotometrically determined pKa values in 22, 30, and 41 percent methanol-water solutions, is the correct value. We believe that 4.70 is the correct value and that there are several serious flaws in their analysis. These are described below

3D printing of medicines: Engineering novel oral devices with unique design and drug release characteristics

YesThree dimensional printing (3DP) was used to engineer novel oral drug delivery devices, with specialised design configurations loaded with multiple actives, with applications in personalised medicine. A filament extruder was used to obtain drug-loaded - paracetamol (acetaminophen) or caffeine - filaments of polyvinyl alcohol with characteristics suitable for use in fused-deposition modelling 3D printing. A multi-nozzle 3D printer enabled fabrication of capsule-shaped solid devices, containing paracetamol and caffeine, with different internal structures. The design configurations included a multilayer device, with each layer containing drug, whose identity was different from the drug in the adjacent layers; and a two-compartment device comprising a caplet embedded within a larger caplet (DuoCaplet), with each compartment containing a different drug. Raman spectroscopy was used to collect 2-dimensional hyper spectral arrays across the entire surface of the devices. Processing of the arrays using direct classical least squares component matching to produce false colour representations of distribution of the drugs showed clearly the areas that contain paracetamol and caffeine, and that there is a definitive separation between the drug layers. Drug release tests in biorelevant media showed unique drug release profiles dependent on the macrostructure of the devices. In the case of the multilayer devices, release of both drugs was simultaneous and independent of drug solubility. With the DuoCaplet design it was possible to engineer either rapid drug release or delayed release by selecting the site of incorporation of the drug in the device, and the lag-time for release from the internal compartment was dependent on the characteristics of the external layer. The study confirms the potential of 3D printing to fabricate multiple-drug containing devices with specialized design configurations and unique drug release characteristics, which would not otherwise be possible using conventional manufacturing methods.The full-text of this article will be released for public view at the end of the publisher embargo on 10 Oct 2016

The influence of heat capacity assumptions on the estimation of solubility parameters from solubility data

Regular solution theory indicates that solubility parameters of crystalline organic compounds can be estimated from solubilities in London solvents. The equation for this purpose is: where X2 is the mole fraction solubility of a compound in a solvent with a solubility parameter of [delta]1. With the exception of [Delta]Cp, all parameters in the equation necessary to estimate the solute parameter, [delta]2, can either be suitably approximated or readily determined experimentally. In order to use the equation, simplifying assumptions have been made concerning [Delta]Cp, namely: [Delta]Cp = 0 or [Delta]Cp = [Delta]Sf, the entropy of fusion. In the present work, we have considered the extent to which these assumptions influence the magnitude of solubility parameters estimated from solubilities in n-hexane, n-heptane, n-dodecane, cyclohexane, carbon tetrachloride, toluene and benzene. Using n-alkyl p-aminobenzoates as test compounds, it is shown that solubility-based solubility parameters are relatively insensitive to the form of the equation used to calculate [delta]2. Specifically, solubility parameter estimations based on the two simplifying assumptions differ by no more than 0.2 (cal/ml)1/2, an increment of the order of the presumed inherent error of estimation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28068/1/0000511.pd

A water-gated organic thin film transistor as a sensor for water-borne amines

The p-type semiconducting polymer Poly(2,5-bis(3-hexadecylthiophen-2-yl)thieno[3,2-b]thiophene) (PBTTT) displays innate sensitivity to water-borne amines. We demonstrate this with the help of water- gated PBTTT thin film transistors (TFTs). When octylamine is added to the gating water, TFTs respond with a significantly reduced saturated drain current. Underlying TFT drift is minimised by initial conditioning, and remaining drift can be accounted for by normalising current response to the current level under purge immediately before exposure. Normalised current response vs. amine concentration is reproducible between different transistors, and can be modelled by a Langmuir surface adsorption isotherm, which suggests physisorption of analyte at the PBTTT surface, rather than bulk penetration. Same PBTTT transistors do not respond to 1- octanol, confirming the specific affinity between amines and thiophene- based organic semiconductors

Percutaneous drug penetration: Choosing candidates for transdermal development

There is currently a high level of interest in using the skin as a route for delivering drugs. One hears the questions: What are the attributes of a drug that make it a serious candidate for transdermal delivery? By what a priori analysis might one zero in on the best transdermal candidate within a family of drugs? Answers to these questions lie in understanding the molecular factors that make a drug a facile permeant of the skin. Among other properties, it must have a high absolute affinity for the skin's phases, which provide for its diffusive conduction. Other factors in evaluation are the potency of the drug and the relative efficiency of the drug's systemic presentation once it has gained access to the body. One also considers the potential for the drug to elicit adverse responses in the skin. Fortunately, parallels between the drug's ability to partition between oil and water and its ease of mass transfer across the skin can be used to ferret out a working mass transfer coefficient. If not already known, solubilities are easily experimentally deduced. The extent of first-pass metabolism by the oral route, presumed to be a known quantity, is compared with the relative amount of metabolism of the drug in the course of its diffsion through the skin, an experimentally determined quantity, in order to set the transdermal dose. These bits of information can then be used to form an early, reasonably faithful picture of the feasibility of delivering a particular drug transdermally and to make a first estimate of the size of patch required for the drug.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50213/1/430130209_ftp.pd

QSPR Studies on Aqueous Solubilities of Drug-Like Compounds

A rapidly growing area of modern pharmaceutical research is the prediction of aqueous solubility of drug-sized compounds from their molecular structures. There exist many different reasons for considering this physico-chemical property as a key parameter: the design of novel entities with adequate aqueous solubility brings many advantages to preclinical and clinical research and development, allowing improvement of the Absorption, Distribution, Metabolization, and Elimination/Toxicity profile and “screenability” of drug candidates in High Throughput Screening techniques. This work compiles recent QSPR linear models established by our research group devoted to the quantification of aqueous solubilities and their comparison to previous research on the topic