A General Treatment of Solubility 4. Description and Analysis of a PCA Model for Ostwald Solubility Coefficients

Article discussing a general treatment of solubility and a description and analysis of a principal component analysis (PCA) model for Ostwald solubility coefficients

A General Treatment of Solubility. 3. Principal Component Analysis (PCA) of the Solubilities of Diverse Solutes in Diverse Solvents

Article discussing a general treatment of solubility and principle component analysis (PCA) of the solubilities of diverse solutes in diverse solvents

The calculation of physicochemical descriptors and their application in predicting properties of drugs and other compounds.

The work presented may be divided into two main sections: The first section focuses on the important aspect of compound descriptor determination. The method by which descriptors are obtained indirectly through compound solubility in organic solvents and direct water-solvent partition measurements is illustrated by example for drug compounds. This approach is extended through the derivation of gas-water and water-solvent partition equations for the n-alcohols which in the future will be available for use in descriptor determination. Importantly, the equation coefficients are also interpreted to deduce various physicochemical properties of the homologous series of alcohols. An alternative method to assign descriptors is probed through reversed-phase HPLC. Measurements are recorded for a series of solutes on several bonded phases and multivariate analysis is used to investigate the interrelationship between columns in an effort to isolate the most suitable phases. The second section is concerned with application of the Abraham General Solvation Equation to examine processes of special interest in drug design; aqueous solubility and intestinal absorption. An algorithm to predict water solubility is obtained containing an additional cross-term which is found to compensate at least partly for a melting point correction term. The amended equation is shown to be comparable in accuracy to commercially available packages for a test set of 268 structurally diverse compounds. Of further importance in drug delivery is the process of intestinal absorption. An extensive literature search provides evaluated absorption data for a large set of drug compounds and forms a strong basis for subsequent QSAR analysis. Intestinal absorption is found to be comparable in humans and rat, and predominantly dependent on the hydrogen-bonding capability of the drug. The mechanism of absorption is considered through transformation of the percent absorption data to an overall rate constant

The inhibition of calcium carbonate precipitation in water softening

The cold-lime water softening reaction was simulated by the precipitation of calcium carbonate following the addition of lime water, to prepared solutions of calcium bicarbonate. A laboratory batch crystalliser was used. The overall rate of calcium ion removal was followed using an ion selective electrode and samples were removed for Coulter Counting to enable the variation in crystal size with time to be studied. The effect on the crystallisation rate due to some organic materials likely to be present in raw water or added during processing was studied. These experiments were done with and without added calcium carbonate to simulate conditions in a retained sludge type of reactor. The calcium ion measurements enabled the induction period before precipitation, the half-life of the precipitation and the precipitation rate to be determined. High molecular weight polyacrylamides of anionic, cationic and nonionic type, had no significant effects whereas an extract of water humic substance and low molecular weight polyacrylate had a marked effect on the induction period, half life and precipitation rate. A starch was intermediate in its effects. The optimum does and the adsorption isotherms of the flocculants on calcium carbonate were also determined. The crystal size distribution over the range 2-37 um was determined by Coulter Counter for several runs. Although high product recovery was obtained attempts to use the population balance method for a detailed study of the nucleation kinetics were less successful. From the results obtained-possible reasons for the observed differences in inhibition behaviour were discussed, with particular reference to the solution diffusivity of the species concerned

Development of Multivariate Powder X-ray Diffraction Techniques and Total Scattering Analyses to Enable Informatic Calibration of Solid Dispersion Potential

The objective of this work was to introduce a novel method for predicting solid dispersion potential enabled by the ability to differentiate phase-separated co-solidified products from amorphous molecular solid dispersions. The central hypothesis states that a combination of materials properties exists that defines the propensity of an active pharmaceutical ingredient to form a binary amorphous molecular solid dispersion with polyvinylpyrrolidone:vinyl acetate copolymer using a melt-quench procedure. Testing this hypothesis required execution of specific aims directed to address issues inherent to characterizing amorphous materials. The work herein is presented with respect to two separate subjects: (1) analytical development and (2) theoretical applications. In the first few chapters, advanced powder X-ray diffraction data processing techniques are explored and adapted to composite pharmaceutical systems. Specific emphasis will be placed ontotal scattering data manipulations and their benefits over traditional practices. The concluding part of this work is devoted to illustrating the use of materials informatics in modeling solid dispersion potential, ultimately afforded by implementing the materials characterization methodologies developed in the initial stages. Molecular descriptors, commonly employed in quantitative structure-property relationship assessment, were tested for correlation to dispersion potential across a library of small molecule organic compounds. The final model accurately predicted dispersion potential for all 12 calibration compounds and three test compounds

The prediction of chemosensory effects of volatile organic compounds in humans

An introduction to indoor air pollution is given, and the chemosensory effects in humans of volatile organic compounds (VOCs), singly and in binary mixtures, are described, together with the bioassays already developed to quantify the effects of VOCs. The need for predictive models that can take over the bioassays is emphasised. Attention is drawn to the establishment of mathematical models to predict the chemosensory effects of VOCs in humans. Nasal pungency threshold (NPT), eye irritation threshold (EIT) and odour detection threshold (ODT) values are available for a series of VOCs that cover a large range of solute properties. Each of these sets of biological data are regressed against the corresponding solute descriptors, E, S, A, B and L to obtain quantitative structure activity relationships (QSARs) for log(l/NPT), log(l/ODT) and log(l/EIT) taking on the form: LogSP = c + e.E + s.S + a.A + b.B + l.L The availability of solute descriptors is investigated. It is shown that solute descriptors, E an excess molar refraction, S the solute dipolarity/polarizability, A the solute overall hydrogen-bond acidity, B the solute overall hydrogen-bond basicity and L the logarithmic value of the solute Ostwald solubility coefficient in hexadecane at 298K, can be obtained through the use of various thermodynamic measurements. In this way descriptors for some 300 solutes have been obtained. A headspace gas chromatographic method is also devised to determine the 1:1 complexation constant, K, between hydrogen bond donors and hydrogen bond acceptors in octan-1-ol. The 30 complexation constants measured are then correlated with α2H*, β2H, a combination of the solute 1:1 hydrogen bond acidity and basicity, respectively, to give: Log K1:1 = 2.950. α2H*β2H - 0.74

Evaluation of the availability and applicability of computational approaches in the safety assessment of nanomaterials: Final report of the Nanocomput project

This is the final report of the Nanocomput project, the main aims of which were to review the current status of computational methods that are potentially useful for predicting the properties of engineered nanomaterials, and to assess their applicability in order to provide advice on the use of these approaches for the purposes of the REACH regulation. Since computational methods cover a broad range of models and tools, emphasis was placed on Quantitative Structure-Property Relationship (QSPR) and Quantitative Structure-Activity Relationship (QSAR) models, and their potential role in predicting NM properties. In addition, the status of a diverse array of compartment-based mathematical models was assessed. These models comprised toxicokinetic (TK), toxicodynamic (TD), in vitro and in vivo dosimetry, and environmental fate models. Finally, based on systematic reviews of the scientific literature, as well as the outputs of the EU-funded research projects, recommendations for further research and development were also made. The Nanocomput project was carried out by the European Commission’s Joint Research Centre (JRC) for the Directorate-General (DG) for Internal Market, Industry, Entrepreneurship and SMEs (DG GROW) under the terms of an Administrative Arrangement between JRC and DG GROW. The project lasted 39 months, from January 2014 to March 2017, and was supported by a steering group with representatives from DG GROW, DG Environment and the European Chemicals Agency (ECHA).JRC.F.3-Chemicals Safety and Alternative Method

The Physical Chemistry of pMDI Formulations Derived from Hydrofluoroalkane Propellants. A Study of the Physical Behaviour of Poorly Soluble Active Pharmaceutical Ingredients; Bespoke Analytical Method Development Leading to Novel Formulation Approaches for Product Development.

Embargoed until July 2016.Active Pharmaceutical Ingredients (APIs) are frequently prepared for delivery to the lung for local topical treatment of diseases such as Chronic Obstructive Pulmonary Disease (COPD) and asthma, or for systemic delivery. One of the most commonly used devices for this purpose is the pressurised metered dose inhaler (pMDI) whereby drugs are formulated in a volatile propellant held under pressure. The compound is aerosolised to a respirably sized dose on actuation, subsequently breathed in by the user. The use of hydrofluoroalkanes (HFAs) in pMDIs since the Montreal Protocol initiated a move away from chlorofluorocarbon (CFC) based devices has resulted in better performing products, with increased lung deposition and a concomitant reduction in oropharyngeal deposition. The physical properties of HFA propellants are however poorly understood and their capacity for solubilising inhaled pharmaceutical products (IPPs) and excipients used historically in CFCs differ significantly. There is therefore a drive to establish methodologies to study these systems in-situ and post actuation to adequately direct formulation strategies for the production of stable and efficacious suspension and solution based products. Characterisation methods have been applied to pMDI dosage systems to gain insight into solubility in HFAs and to determine forms of solid deposits after actuation. A novel quantitative nuclear magnetic resonance method to investigate the physical chemistry of IPPs in these preparations has formed the centrepiece to these studies, accessing solubility data in-situ and at pressure for the first time in HFA propellants. Variable temperature NMR has provided thermodynamic data through van’t Hoff approaches. The methods have been developed and validated using budesonide to provide limits of determination as low as 1 μg/mL and extended to 11 IPPs chosen to represent currently prescribed inhaled corticosteroids (ICS), β2-adrenoagonists and antimuscarinic bronchodilators, and have highlighted solubility variations between the classes of compounds with lipophilic ICSs showing the highest, and hydrophilic β2- agonist / antimuscarinics showing the lowest solubilities from the compounds under study. To determine solid forms on deposition, a series of methods are also described using modified impaction methods in combination with analytical approaches including spectroscopy (μ-Raman), X-ray diffraction, SEM, chromatography and thermal analysis. Their application has ascertained (i) physical form / morphology data on commercial pMDI formulations of the ICS beclomethasone dipropionate (QVAR® / Sanasthmax®, Chiesi) and (ii) distribution assessment in-vitro of ICS / β2-agonist compounds from combination pMDIs confirming co-deposition (Seretide® / Symbicort®, GlaxoSmithKline / AstraZeneca). In combination, these methods provide a platform for development of new formulations based on HFA propellants. The methods have been applied to a number of ‘real’ systems incorporating derivatised cyclodextrins and the co-solvent ethanol, and provide a basis for a comprehensive study of solubilisation of the ICS budesonide in HFA134a using two approaches: mixed solvents and complexation. These new systems provide a novel approach to deliver to the lung, with reduced aerodynamic particle size distribution (APSD) potentially accessing areas suitable for delivery to peripheral areas of the lung (ICS) or to promote systemic delivery

Polymorphic Crystallization Process Development

Ph.DDOCTOR OF PHILOSOPH