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This project aims to study the nature of interaction and orientation of selected drugs such as dexamethorphan HBr (DXM), diphenhydramine HCl (DPH), and lidocaine HCl (LDC) inclusion complexes with hydroxyl-propyl s-cyclodextrin (HP-s-CD) using 1HNMR spectroscopy, 2D-NMR ROESY and molecular-modeling techniques. Freeze-drying technique was used to formulate the inclusion complexes between DXM, DPH and LDC with HP-s-CD (1:1 M ratio) in solid state. Inclusion complex formation was initially characterized by Fourier transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM) techniques. Further characterization of inclusion complexes to determine the interaction of DXM, DPH and LDC with HP-β-CD was performed using the 1HNMR spectroscopy, 2D-NMR ROESY and molecular modeling techniques. Inclusion complexes of DXM, DPH and LDC with HP-s-CD were successfully prepared using the freeze-drying technique. Preliminary studies with FT-IR, DSC, XRD and SEM indicated the formation of inclusion complexes of DXM, DPH and LDC with HP-β-CD at 1:1 M ratio. 1HNMR study showed a change in proton chemical shift upon complexation. 2D-NMR ROESY (two-dimensional) spectroscopy gave an insight into the spatial arrangement between the host and guest atoms. 2D-ROESY experiments further predicted the direction of orientation of guest molecules, indicating the probability that amino moieties of DXM, DPH and LDC are inside the hydrophobic HP-s-CD cavity. Cross-peaks of inclusion complexes demonstrated intermolecular nuclear Overhauser effects (NOE) between the amino protons in DXM, DPH and LDC and H-atoms of HP-s-CD. Molecular modeling studies further confirmed the NMR data, providing a structural basis of the individual complex formations. Microsecond time-level molecular dynamics and metadynamics simulations indicate much stronger binding of DXM to HP-s-CD and more dynamic behavior for DPH and LDC. In particular, LDC can exhibit multiple binding modes, and even spent some time (∼1-2%) out of the carrier, proving the dynamic nature of the complex. To conclude, 2D-NMR and molecular dynamic simulations elucidate the formation of inclusion complexes and intermolecular interactions of DXM, DPH and LDC with HP-s-CD.

The availability of suppositories in Hungary, especially in clinical pharmacy practice, is usually provided by extemporaneous preparations. Due to the known advantages of rectal drug administration, its benefits are frequently utilized in pediatrics. However, errors during the extemporaneous manufacturing process can lead to non-homogenous drug distribution within the dosage units. To determine the root cause of these errors and provide corrective actions, we studied suppository samples prepared with exactly known errors using both cerimetric titration and HPLC technique. Our results show that the most frequent technological error occurs when the pharmacist fails to use the correct displacement factor in the calculations which could lead to a 4.6% increase/decrease in the assay in individual dosage units. The second most important source of error can occur when the molding excess is calculated solely for the suppository base. This can further dilute the final suppository drug concentration causing the assay to be as low as 80%. As a conclusion we emphasize that the application of predetermined displacement factors in calculations for the formulation of suppositories is highly important, which enables the pharmacist to produce a final product containing exactly the determined dose of an active substance despite the different densities of the components.

Organogels have emerged as an alternative carrier for small and macromolecules via transdermal, oral, rectal and ophthalmic routes. Pluronic lecithin organogels (PLO gels) are lecithin-based organogels widely used in compounding pharmacies as a vehicle for enhancing the transdermal permeability of many therapeutic drugs. However, the scientific and systematic evidence in support of how well PLO gels help in transdermal delivery is scanty. Recently, some clinical studies have reported nearly complete lack of bioavailability of certain topically administered drugs from PLO gels. The present review aims at summarizing gels and organogels, with a focus on the use of PLO gels in transdermal drug delivery. A special emphasis is placed on controversies looming over the use of PLO gels as a delivery platform for drugs via transdermal route. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

A water-insoluble complex between diltiazem HCl and Na deoxycholate was prepared to achieve sustained release dosage forms. Physicochemical characterization of the drug complex was carried out with differential scanning calorimetry, (1)H-nuclear magnetic resonance, and Fourier transform infrared spectroscopy. These techniques showed that the characteristic peaks in both the drug and the complexing agent (protonated amine and carboxylate) disappeared and new peaks appeared upon formation of the ionic complex. The release of diltiazem from drug-complex tablets was sustained for a long period of time (24 h) and was dependent on the pH of the dissolution medium. However, the dependence of drug release on pH was eliminated at pH 6-8 and minimized at pH 1.5 when drug-complex powders were incorporated in hydroxypropylmethylcellulose (HPMC) drug carriers. Unlike the release of diltiazem HCl from HPMC drug carriers, drug release from drug-complex/HPMC tablets was linear or near linear irrespective of the viscosity grade of the polymer (E15 to K4M). This is due to a shift in the controlling mechanism of drug release from drug diffusion to erosion of polymer. Also, drug release kinetics was not significantly affected by the water solubility of cationic drugs (diltiazem HCl, verapamil HCl, propranolol HCl, and labetalol HCl) ranging from 1.6 to 62% and the type of amine (i.e., secondary or tertiary). The same release characteristics were observed from the complexes between anionic drugs (Na salicylate, naproxen Na, and tolmetin Na) and benzathine diacetate as found from the complexes between cationic drugs and Na deoxycholate.

Industrial manufacturing of solid oral dosage forms require quality tests, such as friability, hardness, and disintegration. The United States Pharmacopeia (USP) disintegration test uses 900mL of water. However, recent studies of orally disintegrating tablets (ODTs) have shown that this volume does not accurately portray the oral environment. In our study, various tests were conducted with a more moderate amount of water that accurately resembles the oral environment. A simulated wetting test was performed to calculate the water absorption ratio. Results showed that wetting was comparable to disintegration. Although the wetting test worked for most types of ODTs, it had limitations that produced inaccurate results. This led to the use of a modified shaking water bath test. This test was found to work for all types of ODT products and was not subject to the limitations of the wetting test. The shake test could provide disintegration times rather than water permeation times; however, it could not be used to calculate the water absorption ratio. A strong correlation was observed between the standardized shake test and the USP disintegration times for the tablets. This shake test could be used during the development stages and quality tests for ODTs with relative ease.

Granulations of dimenhydrinate (DMH) were prepared using various concentrations of ethyl cellulose (EC) by the solid dispersion technique. Characterization was done using thermal analysis, powder X-ray diffraction, infrared spectroscopy, optical microscopy and dissolution studies. Humidity studies were performed to investigate the effect of moisture on the drug and solid dispersions. It was seen that the crystalline drug was converted into its amorphous form in all the granulations. There was no chemical interaction between the DMH and EC. The thermal decomposition of drug in the granules was not affected. Dissolution studies revealed that the drug release from the granulations was significantly reduced as compared to the pure drug. As the amount of ethyl cellulose increased, the drug release rate decreased and the drug release kinetics showed a better fit to zero-order kinetics. Humidity studies showed that the drug and granulations remained stable in conditions not exceeding 70%RH. At high humidity of 100%RH, there was formation of the hydrate crystal forms of the drug in the pure drug samples and granules with 1:1 DMH-EC content whereas the granules with higher polymer content did not show any significant changes indicating better drug stability in the granules.

Solid-state interaction between ibuprofen and nicotinamide was studied using thermal, spectroscopic, and microscopic techniques. Solubility enhancement was calculated by high-performance liquid chromatography and suspension was found to be the suitable choice of formulation. Ibuprofen-nicotinamide binary mixtures were prepared by solvent evaporation method. Differential scanning calorimetry was used to investigate the stoichiometry and thermal properties of the complex between ibuprofen and nicotinamide. A sharp, single endotherm was observed between the melting endotherms of the individual components at a composition of 60% ibuprofen and 40% nicotinamide (w/w). Several spectroscopic techniques such as ultraviolet-visible, Fourier transform infrared, nuclear magnetic resonance, and powder X-ray diffraction were used to investigate the type of interaction between the two components. Optical microscopy was performed to observe changes with regard to particle size and crystal habit. It was concluded that the interaction that occurred was Pi donor-Pi acceptor in nature and too weak to sustain the integrity of the complex in the liquid state. The solubility of ibuprofen was enhanced by 62 times in the suspension when the concentration of nicotinamide was 13.3 mg/mL. The suspension prepared in this study has potential of being a better medication for pain relief in patients with osteoarthritis.

The possibility of obtaining tolbutamide polymorphs was investigated using the solvents acetonitrile and 1-octanol. Tolbutamide is an oral hypoglycemic agent that exists in four polymorphic forms. Characterization of the various polymorphs was carried out by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), infrared spectroscopy (FTIR), optical microscopy and dissolution studies. Form A, crystallized from acetonitrile, resembled the form I polymorph, while form O, crystallized from 1-octanol, resembled the form III polymorph. Tablets of both form A and form O were produced at compression pressures of 2500 lbs and 5000 lbs using cornstarch and talc and were exposed to 40%, 75% and 95% RH conditions. DSC and PXRD studies did not show any significant drug-excipient interaction. Moreover, the change in the crystalline state of either form upon exposure to humidity was not evident. Dissolution studies showed a significantly lower drug release rate from form O tablets compressed at 5000 lbs pressure and exposed to 95% RH. Pressure and humidity had no significant effect on the dissolution profiles on the form A tablets. It was concluded that form A was the robust choice for further formulation development.

A rapid and sensitive high‐performance liquid chromatographic method was developed for the determination of propylthiouracil. The chromatographic system utilized a C8 column with the detector wavelength set at 276 nm. The mobile phase was composed of water and methanol in a 70:30 (v/v) ratio and was delivered at a flow rate of 0.5 mL/minute. The analytical run time was less than 7 min. The standard curves were linear over a range of 1–100 µg/mL with a correlation coefficient of 0.9958. The limit of quantification was assessed to be 15 ng and the limit of detection 4.5 ng. The RSD values for the intra‐ and inter‐day precision studies were 0.11–1.28% and 1.65%, respectively. The accuracy was ≤5% over the concentration range 1–100 µg/mL. The stability‐indicating nature of the assay method was determined by subjecting a stock solution of propylthiouracil to extremes of acidic and basic degradation. It was found that the method was specific for propylthiouracil. Hence, a simple, rapid, sensitive, stab...

The present study evaluates the effects of excipients, compression pressure, and relative humidity (RH) on the stability of sulfamerazine polymorphs (referred here as SMZ I and SMZ II) and their release from directly compressed tablets using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and dissolution analysis. SMZ I and SMZ II tablets were compressed with magnesium stearate (MGST), and microcrystalline cellulose (MCC) at 5000, 7500, and 10,000 lbs. pressures and stored at 40, 75, 95, and 100% RH conditions for 5 weeks. There were indications of possible drug-excipient interaction in the binary mixtures under different relative humidity conditions from the DSC data, but they could not be confirmed by PXRD because the crystal structures of the drug and excipients remained unaltered. The crystal structures of the polymorphs in the tablet also remained unaltered under the above conditions. There were, however, significant differences observed in the drug release properties of the two polymorphs. SMZ II was found in general to have a higher rate of drug release than SMZ I. Extensive gelation of MCC under higher moisture conditions, compression pressure during tableting, and inherent tabletability of the sulfamerazine crystals were factors that affected drug release. All these factors contributed towards prolonging the disintegration and deaggregation of the tablet particles and were therefore concluded to be the rate limiting steps for the dissolution process.

Four non-polymeric plasticizers, propylene glycol, diethyl phthalate, triacetin, and glycerin have been subjected to rising temperature thermogravimetry for kinetic analysis and vaporization-based thermal stability evaluation. Since volatile loss of a substance is a function of its vapor pressure, the thermal stability of these plasticizers has been analyzed by generating vapor pressure curves using the Antoine and Langmuir equations. Unknown Antoine constants for the sample compounds, triacetin and glycerin have been derived by subjecting the vapor pressure curves to nonlinear regression. For the first time, the entire process of obtaining the unknown Antoine constants through thermogravimetry has been validated by developing an approach called the 'double reference method.' Based on this method, it has been possible to show that this technique is accurate even for structurally diverse compounds. Kinetic analysis on the volatilization of compounds revealed a predominant zero order process. The activation energy values for vaporization of propylene glycol, diethyl phthalate, triacetin, and glycerin, as deduced from the Arrhenius plots, have been determined to be 55.80, 66.45, 65.12, and 67.54 kJ/mol, respectively. The enthalpies of vaporization of the compounds have been determined from the Clausius-Clapeyron plots. Rising temperature thermogravimetry coupled with nonlinear regression analysis has been shown to be an effective and rapid technique for accurately predicting the vapor pressure behavior and thermal stability evaluation of volatile compounds.

The objective of this study was to develop and analyze an analytical method in order to evaluate preformulation candidates by their thermodynamic parameters and evaporation characteristics. Ortho, meta and tere-phthalic acids were chosen as model compounds. The relative advantages and disadvantages of a rapid thermogravimetric method have been studied in detail, which would aid in the preformulation characterization for pharmaceuticals. Methyl paraben was taken as the model compound for calibration, as its evaporation characteristics are well known. Using the Antoine and the Langmuir equation for evaporation conjointly, the parameter k, known as the coefficient of evaporation was determined. The value for this constant was validated by three methods simultaneously. Previously the use of such methods for compounds having uninhibited zero order evaporation has been documented. In the present study, phthalic acid was chosen as the model compound since its evaporation is a two-step overlapping phenomenon. In this study we have shown the use of Pressure Differential Scanning Calorimetry in separating such simultaneous endothermic processes. The Clausius-Clapeyron equation seemingly has anomalous behavior for vapor pressure over high temperature ranges. In this study a modification of the equation has been suggested to take into account the changes in the heat capacities that result due to high temperature effects. This study aims at documenting a concise method for rapid pharmaceutical characterization and suggests modifications for some basic thermodynamic parameters over higher temperature ranges.

Characterization of formulation components in pre-formulation and formulation studies will be made easier if a rapid method to evaluate the evaporation characteristics of an ingredient in the formulation is developed. This study aims at providing a simple and rapid thermogravimetric method for estimating the vapor pressure characteristics using the Antoine equation as the analytical tool. The heat treatment for the majority of benzoic acid derivatives follows zero-order rate processes that are in good correlation with their evaporation process. The optimum conditions for the rising temperature experiments were found when the heating rate was 10 degrees C/min in an atmosphere of dry nitrogen (100 ml/min). Methyl paraben was taken as the calibration compound since its Antoine constants are reported in the literature, and its selected thermodynamic parameters were evaluated using the Langmuir equation. The coefficient of vaporization (k macro) was determined to be 124,525+/-0.8, with units being reported in the S.I. system. The corresponding vapor-pressure plots were obtained for the remaining compounds and their Antoine constants calculated.

This study prepared an extemporaneously formulated liquid suspension dosage form (5 mg/ml) from commercially available 25 mg tablets. Stability-indicating HPLC assay procedures were established and utilized to analyze the concentration of the drug. The method proved to be a simple model since it does not contain a buffer system. The mobile phase used was the same as that suggested by the manufacturer for the storage of the column. Therefore, the solvent system saves analytical processing time, since it does not require a change in the mobile phase before or after the analysis. The analytical method has been shown to be stability-indicating. The results have shown that there is no interference from any of the degradation products obtained from stressing spironolactone by heat and extremes in pH or with the internal standard, hydrocortisone 21-acetate.

Purpose: Polymeric nanosuspension was prepared from an inert polymer resin (Eudragit® RL100) with the aim of improving the availability of sulfacetamide at the intraocular level to combat bacterial infections. Methods: Nanosuspensions were prepared by the solvent displacement method using acetone and Pluronic® F108 solution. Drug to polymer ratio was selected as formulation variable. Characterization of the nanosupension was performed by measuring particle size, zeta potential, Fourier Transform infrared spectra (FTIR), Differential Scanning Calorimetry (DSC), Powder X-Ray Diffraction (PXRD), drug entrapment efficiency and in vitro release. In addition, freeze drying, redispersibility and short term stability study at room temperature and at 40C were performed. Results: Spherical, uniform particles (size below 500 nm) with positive zeta potential were obtained. No significant chemical interactions between drug and polymer were observed in the solid state characterization of the freeze dried nanosuspension (FDN). Drug entrapment efficiency of the selected batch was increased by changing the pH of the external phase and addition of polymethyl methacrylate in the formulation. The prepared nanosuspension exhibited good stability after storage at room temperature and at 40C. Sucrose and Mannitol were used as cryoprotectants and exhibited good water redispersibility of the FDN. Conclusion: The results indicate that the formulation of sulfacetamide in Eudragit® RL100 nanosuspension could be utilized as potential delivery system for treating ocular bacterial infections.

Sedimentation of dilute pharmaceutical suspensions obeys Stokes's law, which assumes that there is no interaction between particles. The behavior of concentrated pharmaceutical suspensions is generally interpreted by use of modifications of Stokes's law that do not consider chemical interaction between particles. Properties of the medium itself, such as dielectric constant and surface tension, have not been included in the established equations. The present work shows that the dielectric constant of the medium has a distinct effect on the rate of sedimentation of the systems investigated.

A high performance liquid chromatographic (HPLC) method for the quantitation of acetazolamide in a suspension dosage form is described. The method is simple, accurate, and precise. Acetazolamide was extracted from the suspension using a mobile phase which contained 65% phosphate buffer and 35% methanol and separated from other components by reversed-phase high performance liquid chromatography. The separation was carried out using a C18 column (250 × 4.5 mm i.d.). The photometric detector was set at 254 nm. The excipients present in the tablets from which the suspension was compounded did not interfere with the assay procedure. Sixteen replicate injections of 10.5 mg/mL samples resulted in a percent relative standard deviation of 2.02.

The purpose of this study was to investigate a rapid method for the evaluation of vaporization characteristics for selected benzoic acid derivatives. The compounds studied in this context were the ortho -, meta - and para -derivatives of hydroxy and amino benzoic acids. Calculations for the order of reaction were first carried out for each of the compounds using methyl paraben as the calibration standard. Those compounds undergoing zero order, non-activated evaporation processes, were analyzed by the Antoine and Langmuir equations, conjointly. The coefficient of vaporization was obtained as 1.2×10 5 ±0.8 Pa kg 0.5 mol 0.5 s −1 m −2 K −0.5 . The vapor pressure values were used to determine the Antoine constants using the SPSS 10.0 software. This study attempts to outline a comprehensive thermogravimetric technique for vapor pressure characterization of single-component systems.

The analysis used yohimbine HCl solution prepared from commercially available yohimbine HCl powder. Stability-indicating high-performance liquid chromatographic (HPLC) assay procedures were established and utilized to analyze the concentration of the drug. The method proved to be a simple model since it does not contain a buffer system. The mobile phase used, a methanol:water 70:30 ratio, was similar to that suggested by the manufacturer for the storage of the column. Therefore, the solvent system saves analytical processing time since it does not require a change in the mobile phase before and after the analysis. The analytical method has been shown to be stability indicating. The assay method showed a retention time for yohimbine of 4.2 min; for caffeine, the internal standard, it was 2.3 min. The standard deviation and the coefficient of variation were under acceptable limits of 2% and were specifically 1.51% and 1.35% for within-day and between-day samples, respectively. The results showed that the degradation products obtained from stressing yohimbine HCl by heat and extremes in pH did not interfere with the yohimbine HCl peak, although the internal standard, caffeine, did show some interference due to having a retention time similar to the degradation products.

Many pharmaceutical formulations are produced in the form of concentrated suspensions. Calcium carbonate suspensions are used in this study and interpreted as the “model” for the behavior of such suspensions. The behavior of concentrated suspensions of powders in a liquid medium cannot be treated by the simple application of the normal principles of free fall and the use of Stokes Law pertaining to the viscous resistance offered by the surrounding fluid to fall. A single particle operating by the Stokes principle obeys this relationship. This law applies to the behavior of particles at low concentration in a liquid medium and is the basis for particle size distribution methods. At higher concentrations, however, the particles do not enjoy the freedom of unhindered fall. The system subsides “en bloc” and it is common practice to offer a modification to the Stokes equation which takes into consideration some function of the porosity of the system. There have been a considerable number of equations developed and modified based on this principle. However, an alternative method is to approach the problem by dealing with the permeability of a bed of powders in a liquid in which the bed is slowly altering with time. This is best achieved by the use of the permeability equation developed and presented by Kozeny–Carmen. This equation, as well as the Richardson–Zaki expression, are related to show that the Kozeny parameter K varies with the suspension porosity under sedimentation conditions. The values of K are often larger than the value normally reported (i.e., ~5). The data and treatment outlined here are extended to include not only the calcium carbonate suspensions, but other systems previously mentioned in the literature.

The solubility of a series of compounds was determined in a wide polarity spectrum of normal aliphatic alcohols over a limited temperature range. The solutes chosen were the methyl through n ‐butyl p ‐hydroxybenzoates, several of these being useful preservatives. Solubility profiles were determined for these compounds and the effect of temperature upon their solubility behavior was investigated. The solubility of the solutes is expressed in several concentration notations; mole fraction plots showed a variable twin peak array as a function of the dielectric constant for the solutes studied. Since heats of fusion were available and data were generated as a function of temperature, ther‐modynamic parameters for these systems could be calculated. The relationship of these parameters to multiple solubility peak array is discussed.

The solubilities of several sulfonamides were studied at three temperatures over a wide spectrum of polarity of normal alcohols. The sulfonamides chosen for study were sulfasoxaeole, sulfadimethoxine, sulfasomidine and sulfadiazine and their solubility behavior in various alcohols such ae methanol through 1-decanol at 25°. 30° and 37°.Solubility in alcohols was found to increase with temperature and the rank order of solubility at any temperature wae found to be in the general order of sulfasoxizole, sulfadimethoxine, sulfasomidine and sulfadiaeine. Solubility was found to be highest in methanol and diminished with increasing chain length of the alcohol.The solubility magnitude for several of the sulfonamides gave an interesting reversal in 1-decanol and all the results obtained are discussed further in this communication.

The effect of flocculant materials on kaolin-water suspensions is reported using two kaolins. One of these is a pharmaceutical-grade kaolin and the other an industrial kaolin. These two systems serve as a model in a broader investigation which will systematically study the ancillary ingredients of pharmaceutical kaolin-based suspensions. These studies are based on concentrated suspensions where fall of particles is hindered and characterized by sedimentation “en bloc” with a sludge line serving as interface between the supernatent liquid and the settling suspension. It is shown that there is an optimum concentration of macromolecular flocculant which causes maximum flocculation. At higher concentrations of flocculant the system is stabilized. Two approaches are used to explain the results. The first represents the phenomenon as a modification of Stokes Law results. A correlation is found between the parameter A used as a characterization constant in Steinour's empirical relationship and the Richar...

Molecular orbital calculations were carried out on the series benzoic acid, p -hydroxybenzoic acid, methylparaben, and ethylparaben. The characteristic trends of this entire series of preservatives are demonstrated by these members. The computer program used was Iterated Extended Huckel Theory. These systems were characterized in terms of atomic charge distributions, effect of hydroxyl and ester groups (both sterically and electronically), preferred molecular conformations, and distinguishing features of molecular orbitals. Through this approach, it was hoped that a common mode of action for all members of this series could be detected and that the trend(s) in this feature would correlate with known trends in activity of members of this series.

The solubilities of a series of chemically related barbiturates, including some medically useful ones as well as phenobarbital, were determined at 25 degrees in the straight-chain alcohols methanol through butanol. The solubility values are given in both milligrams per milliliter and the mole fraction notation. The solubility in methanol was the highest and decreased nonlinearly for the solubility in 1-butanol. In several cases, mole fraction solubility gave shouldering or peaking as a function of the carbon number of the solvent. This series of barbiturates was broken down into two subsets of straight-chain and branched alkyl barbiturates, and solubility ratios in these subsets were considered.

It has been shown that the degradation of aspirin in mixtures may be monitored by thermal analytical techniques. The methodology employed differential scanning calorimetry and thermal gravimetric analysis by standard techniques providing simple and rapid analysis for screening the stability of aspirin in mixtures. The degradation was found to depend on the nature of the additive but, in particular, the presence of acidic or basic groups within its structure.

The solubility of a related series of parabens was determined in water at four temperatures. The parabens chosen were the methyl through n-butyl p-hydroxybenzoates, and the temperature variations were 5 degrees increments from 25 to 40 degrees. These solutes are useful preservatives, especially combinations of the methyl and propyl ester derivatives. The chemical relationship of these compounds varied by successive linear methylene additions on the ester portion of the molecules. The thermodynamic values obtained for these aqueous systems could be related to these molecular variants since the remainder of the molecule was constant. For the overall thermodynamics, the free energy functions such as the ideal, actual, and excess were found to be smooth, nonlinear functions of the number of carbon atoms in the alkyl portion of the paraben esters. A linear relationship with the number of carbon atoms in the ester portion of these esters was found with the partial excess free energy of the solute.