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

Substituent effects on the mutagenicity of phenyl glycidyl ethers in Salmonella typhimurium

Phenyl glycidyl ether and 6 para-substituted derivatives, the methoxy, tert-butyl, methyl, chloro, bromo and nitro compounds, were tested in the Ames' test for mutagenicity. With the exception of the tert-butyl derivative in TA1535, all 7 compounds were mutagenic in both strains TA100 and TA1535. Electron-donating groups in the para position decreased mutagenicity while electron-withdrawing groups increased this mutagenicity. The mutagenicity of the series of compounds in both strains could be correlated to the Hammett substituent constants for the para-substituent groups. The glycidyl ether results might best be considered in terms of a normal reaction with bionucleophiles as compared to the literature report for the correlation of mutagenicity with abnormal product formation for a styrene oxide series.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24019/1/0000268.pd

Effect of methyl branching of C8H18 alkanes and water activity on lipase-catalyzed enantioselective esterification of ibuprofen

The purpose of this research was to study the effect of the methyl branching of a high log P alkane solvent and the water activity in the organic medium on the initial rate and the enantioselectivity of ibuprofen esterification catalyzed by Candida rugosa lipase. Resolution of ibuprofen is important because S-(+)-ibuprofen has the desired pharmacological activity, whereas the R-(-)-enantiomer causes much of the side effects. The Candida rugosa lipase-catalyzed reaction in isooctane at 40\ub0C and 0.73 water activity gave the best results, both in terms of the initial reaction rate and the enantioselectivity of the reaction. An increase in water activity allowed a higher reaction rate and enantiomeric excess in each of the four solvents. An increase in methyl branching did not necessarily increase the initial reaction rate, but it allowed a higher enantioselectivity, evidenced by an increase in the substrate enantiomeric excess

Investigation of the in vitro performance difference of drug-Soluplus® and drug-PEG 6000 dispersions when prepared using spray drying or lyophilization

AbstractPurpose: To evaluate the physicochemical and in vitro characteristics of solid dispersions using BCS II model drugs with Soluplus® and one of its component homopolymers, PEG 6000. Methods: Nifedipine (NIF) and sulfamethoxazole (SMX) of 99.3% and 99.5% purity, respectively, were selected as BCS II model drugs, such that an improved dissolution rate and concentration in the gastrointestinal tract should increase oral bioavailability. Soluplus® is an amorphous, tri-block, graft co-polymer with polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol (PCL:PVAc:PEG6000) in the ratio 57:30:13. PEG 6000 (BASF) is a waxy material with melting point of about 60°C. Solid dispersions were prepared using lyophilization or spray drying techniques. Dissolution study, crystallinity content, and analysis for new chemical bond formation have been used to evaluate the dispersed materials. Results: Although each polymer improved the drug dissolution rate, dissolution from Soluplus® was slower. Enhanced dissolution rates were observed with NIF solid dispersions, but the dissolution profiles were quite different due to the selected technique, polymer, and dissolution medium. For SMX, there was similarity across the dissolution profiles despite the medium, polymer, or applied technique. Each polymer was able to maintain an elevated drug concentration over the three hour duration of the dissolution profile, i.e., supersaturation was supported by the polymer. DSC thermograms revealed no melting endotherm, suggesting that the drug is amorphous or molecularly dispersed. Conclusion: NIF and SMX solid dispersions were successfully prepared by spray drying and lyophilization using Soluplus® or PEG 6000. Each polymer enhanced the drug dissolution rate; NIF dissolution rate was improved to a greater extent. Dispersions with PEG 6000 had a faster dissolution rate due to its hydrophilic nature. DSC analysis showed that no crystalline material exists in the dispersions

Solid and Liquid Heat Capacities of n -Alkyl Para-aminobenzoates Near the Melting Point

The expression that relates the ideal mole fraction solubility of a crystalline compound to physico-chemical properties of the compound includes a term involving the difference in the heat capacities of the solid and liquid forms of the solute, Δ C P . There are two alternate conventions which are employed to eliminate this term. The first assumes that the term involving Δ C P , or Δ C P itself, is zero. The alternate assumption assigns the value of the entropy of fusion to the differential heat capacity. The relative validity of these two assumptions was evaluated using the straight-chain alkyl para-aminobenzoates as test compounds. The heat capacities of the solid and liquid forms of each of the para-aminobenzoates, near the respective melting point, were determined by differential scanning calorimetry. The data lead one to conclude that the assumption that the differential heat capacity is not usually negligible and is better approximated by the entropy of fusion.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41542/1/11095_2004_Article_305879.pd

Lipase-catalyzed enantioselective esterification of flurbiprofen with n-butanol

The influences of water activity and solvent hydrophobicity on the kinetics of the lipase-catalyzed enantioselective esterification of flurbiprofen with n-butanol were investigated. The solvent effect was not similar for lipases from Candida rugosa (Crl), Mucor javanicus (Mjl), and porcine pancreas (Ppl). The lipase-catalyzed reaction rates in different solvents across a wide range of water activities revealed that the Ppl-catalyzed reaction exhibited no enantioselectivity and no substantial water activity or solvent dependence. The Mjl-catalyzed reaction proceeded faster, preferring the R-enantiomer reaction over that of its antipode, but had little solvent or water activity dependence. The Crl-catalyzed reactions in n-heptane and n-nonane had similar water activity dependence, but the reaction was considerably faster and more enantioselective (preferring the S-enantiomer reaction) in isooctane, a solvent whose hydrophobicity is intermediate between that of the other two alkanes. Substrate enantiomeric excess, for the Crl-catalyzed reaction at 96 hours and at a water activity of 0.65, in n-heptane, isooctane, and n-nonane was 40.9, 93.0, and 50.0%, respectively. Since the three solvents possess similar physical properties, the explanation for this anomalous behavior might be the effect of the solvent structural characteristics on Crl, since isooctane is the only branched alkane