A Review on Progress in QSPR Studies for Surfactants

This paper presents a review on recent progress in quantitative structure-property relationship (QSPR) studies of surfactants and applications of various molecular descriptors. QSPR studies on critical micelle concentration (cmc) and surface tension (γ) of surfactants are introduced. Studies on charge distribution in ionic surfactants by quantum chemical calculations and its effects on the structures and properties of the colloids of surfactants are also reviewed. The trends of QSPR studies on cloud point (for nonionic surfactants), biodegradation potential and some other properties of surfactants are evaluated

Micellar chromatographic partition coefficients and their application in predicting skin permeability

The major goal for physicochemical screening of pharmaceuticals is to predict human drug absorption, distribution, elimination, excretion and toxicity. These are all dependent on the lipophilicity of the drug, which is expressed as a partition coefficient i.e. a measure of a drug’s preference for the lipophilic or hydrophilic phases. The most common method of determining a partition coefficient is the shake flask method using octanol and water as partitioning media. However, this system has many limitations when modeling the interaction of ionised compounds with membranes, therefore, unreliable partitioning data for many solutes has been reported. In addition to these concerns, the procedure is tedious and time consuming and requires a high level of solute and solvent purity. Micellar liquid chromatography (MLC) has been proposed as an alternative technique for measuring partition coefficients utilising surfactant aggregates, known as micelles. This thesis investigates the application of MLC in determining micelle-water partition coefficients (logPMW) of pharmaceutical compounds of varying physicochemical properties. The effect of mobile phase pH and column temperature on the partitioning of compounds was evaluated. Results revealed that partitioning of drugs solely into the micellar core was influenced by the interaction of charged and neutral species with the surface of the micelle. Furthermore, the pH of the mobile phase significantly influenced the partitioning behaviour and a good correlation of logPMW was observed with calculated distribution coefficient (logD) values. More interestingly, a significant change in partitioning was observed near the dissociation constant of each drug indicating an influence of ionised species on the association with the micelle and retention on the stationary phase. Elevated column temperatures confirmed partitioning of drugs considered in this study was enthalpically driven with a small change in the entropy of the system because of the change in the nature of hydrogen bonding. Finally, a quantitative structure property relationship was developed to evaluate biological relevance in terms of predicting skin permeability of the newly developed partition coefficient values. This study provides a better surrogate for predicting skin permeability based on an easy, fast and cheap experimental methodology, and the method holds the predictive capability for a wider population of drugs. In summary, it can be concluded that MLC has the ability to generate partition coefficient values in a shorter time with higher accuracy, and has the potential to replace the octanol-water system for pharmaceutical compounds

Modified aqueous mobile phases: A way to improve retention behavior of active pharmaceutical compounds and their impurities in liquid chromatography

Most commonly used analytical technique for determination of active pharmaceutical ingredients and their impurities in quality control throughout all phases of drug research, development and manufacture is definitely reversed-phase high performance liquid chromatography (RP-HPLC). However, pharmaceutical industry professionals are often faced with various challenges in RP mode, which cannot be resolved with common variations in the composition of the mobile phase. These challenges often occur when analyzing compounds that contain basic ionizable groups, possess large differences in polarities and require consumption of high amounts of toxic organic solvents. Among available strategies for addressing the aforementioned issues, the most convenient one includes RP-HPLC mobile phase modifications by an addition of the proper chemical compounds. In that respect, RP-HPLC method can be easily adapted to the needs of the analysis without time-consuming and expensive equipment procurement. In this review the chaotropic chromatography, micellar liquid chromatography, and cyclodextrin modified RP-HPLC systems are presented and discussed in details. Special attention is devoted to the theoretical background, the possibility of retention modeling and applications in various fields of pharmacy, as well as their prospective in further research

Experimental and Computational Modeling of Microemulsion Phase Behavior

The phase behavior of microemulsions formed in a surfactant-brine-oil system for a chemical Enhanced Oil Recovery (EOR) application is complex and depends on a range of parameters. Phase behavior indicates a surfactant solubilization. Phase behavior tests are simple but time-consuming especially when it involves a wide range of surfactant choices at various concentrations. An efficient and insightful microemulsion formulation via computational simulation can complement phase behavior laboratory test. Computational simulation can predict various surfactant properties, including microemulsion phase behavior. Microemulsion phase behavior can be predicted predominantly using Quantitative Structure-Property Relationship (QSPR) model. QSPR models are empirical and limited to simple pure oil system. Its application domain is limited due to the model cannot be extrapolated beyond reference condition. Meanwhile, there are theoretical models based on physical chemistry of microemulsion that can predict microemulsion phase behavior. These models use microemulsion surface tension and torque concepts as well as with solution of bending rigidity of microemulsion interface with relation to surface solubilization and interface energy

Modeling the Behavior of Amphiphilic Aqueous Solutions

Two types of predictive models based on artificial neural networks (ANN) and quadratic regression model developed in our laboratory will be summarized in this book chapter. Both models were developed to predict the density, speed of sound, kinematic viscosity and surface tension of amphiphilic aqueous solutions. These models were developed taking into account the concentration, the number of carbons and the molecular weight values. The experimental data were compiled from literature and included different surfactants: i) hexyl, ii) octyl, iii) decyl, iv) tetradecyl and v) octadecyl trimethyl ammonium bromide. Neural models present better adjustment values, with R2 values above 0.902 and AAPD values under 2.93% (for all data), than the quadratic regression models. Finally, it is concluded that the quadratic regression and the neural models can be powerful prediction tools for the physical properties of surfactants aqueous solutions

Poly(2-oxazoline)-based polymeric micelle platform for drug delivery

Polymeric micelles (PMs) have been extensively utilized as drug delivery platform. Particularly, potent hydrophobic small molecules were encapsulated in the PMs to alleviate toxicity issues and improve therapeutic outcomes. We attempt to provide detailed information on PMs for hydrophobic small molecules, such as the design of block copolymers (BCP) and current clinical outcomes from PMs. In particular, we aim to describe advanced analytical approaches for elucidating molecular interactions for effective solubilization. This dissertation includes a novel computer-aided strategy for rational design of PMbased delivery systems for poorly soluble drugs. We have developed novel descriptors of drug polymer complexes that were employed to build models to predict both drug loading efficiency (LE) and loading capacity (LC). These models were used for virtual screening of drug libraries and eight drugs for the experimental validation. Three putative true positive as well as three putative negative hits were confirmed (implying 75% prediction accuracy). The success of the computational strategy suggests its broad utility for rational design of drug delivery systems. This dissertation involves the study of poly(2-oxazoline) micelles (POx) for treatment of medulloblastoma. For patients with SHH-subgroup medulloblastoma, SHH-pathway inhibition may be more effective and less toxic than current non-targeted therapy. We successfully solubilized SHH-pathway inhibitor, vismodegib, in POx micelles (POx-vismo) and showed the PM formulation improved drug efficacy, demonstrated in the treatment of medulloblastoma animal model. Mechanistic studies revealed that POx-vismo decreased vismodegib binding to serum proteins and improved brain and tumor drug penetration without penetration of the nanoparticle carrier into the CNS. This dissertation also includes the development of novel poly(2-oxazoline)-based block copolymer with the aromatic heterocyclic side chains and demonstration of its application as a drug delivery platform. The copolymer was synthesized via the condensation of N,N dimethylbiguanide with the methyl ester side chain in poly(2-methoxycarboxyethyl-2-oxazoline) block (PMestOx). Successful encapsulation into these micelles has been demonstrated for several poorly soluble drugs. The capability of this new copolymer to solubilize a uniquely diverse set of active pharmaceutical ingredients suggests potential applications in drug delivery. In summary, poly(2-oxazoline)-based PM platforms are versatile drug delivery platform and exhibit the broad potential for ideal drug delivery of therapeutic small molecules.Doctor of Philosoph

Molecular surface area measures of polarity and hydrogen bonding for QSAR

Modifications were made to the traditional PSA descriptor by decoupling it into its H-bond acidic and basic components. The PSA based descriptors were also scaled according to the known hydrogen bonding characteristics of common functional groups to make them more realistic measures of a molecules hydrogen bonding capacity. Three other surface area descriptors total surface area, total halogen atom surface area and total aromatic carbon surface area were also defined. Various routes to the calculation of these descriptors were explored and it was concluded the best descriptors were those obtained from a single structure generated using the semi empirical-method AMI. It was also shown that descriptors obtained from a vdw surface were more suitable than those obtained from solvent accessible surface area. The scaled PSA descriptors were initially tested against octanol-water, chloroform-water, and cyclohexane-water partition coefficients of 110 organic and drug-like molecules. All of the models produced were seen to be statistically accurate and followed known characteristics of the partition coefficients considered. The scaled PSA descriptors were then applied successfully to a number of important biological processes such as cellular uptake and intestinal absorption models were also produced for important industrial processes such as Fluorophilicity and CMC. The surface area descriptors were also seen to be equally capable of modelling inorganic molecules and excellent models were produced for octanol-water and chloroform-water partitions for a number of platinum containing drugs.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Molecular surface area measures of polarity and hydrogen bonding for QSAR

Modifications were made to the traditional PSA descriptor by decoupling it into its H-bond acidic and basic components. The PSA based descriptors were also scaled according to the known hydrogen bonding characteristics of common functional groups to make them more realistic measures of a molecules hydrogen bonding capacity. Three other surface area descriptors total surface area, total halogen atom surface area and total aromatic carbon surface area were also defined. Various routes to the calculation of these descriptors were explored and it was concluded the best descriptors were those obtained from a single structure generated using the semi empirical-method AMI. It was also shown that descriptors obtained from a vdw surface were more suitable than those obtained from solvent accessible surface area. The scaled PSA descriptors were initially tested against octanol-water, chloroform-water, and cyclohexane-water partition coefficients of 110 organic and drug-like molecules. All of the models produced were seen to be statistically accurate and followed known characteristics of the partition coefficients considered. The scaled PSA descriptors were then applied successfully to a number of important biological processes such as cellular uptake and intestinal absorption models were also produced for important industrial processes such as Fluorophilicity and CMC. The surface area descriptors were also seen to be equally capable of modelling inorganic molecules and excellent models were produced for octanol-water and chloroform-water partitions for a number of platinum containing drugs