Solubility of polar organic solutes in nonaqueous systems: Role of specific interactions

Anderson, Bradley D.; Rytting, J. Howard; Higuchi, Takeru

doi:10.1002/jps.2600690617

Cited by 38 publications

(12 citation statements)

References 15 publications

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“…While the partition coefficient measurements were carried out at very low concentrations (less than 10 −3 moles/liter) to prevent the possible participation of self‐association, the goodness of fit of Eq. (4) to the data provides additional evidence for the absence of such an effect 22–26. Moreover, as shown in Figure 4, no difference was seen in the tyramine partition coefficients at two different aqueous concentrations of 1 and 0.05 mM.…”

Section: Resultsmentioning

confidence: 58%

See 1 more Smart Citation

Substituent effects on the ionization and partitioning of p-(aminoethyl)phenols and structurally related compounds: Electrostatic effects dependent on conformation

Tejwani

Stouch

Anderson

2009

Journal of Pharmaceutical Sciences

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Section: Resultsmentioning

confidence: 58%

“…The concentration in each phase was then determined using a reversed phase HPLC method described previously 21. The operating concentration of 1 mM or lower was chosen for all the solutes to avoid possible contributions of self‐associated species22–26 to the measurement.…”

Section: Methodsmentioning

confidence: 99%

Substituent effects on the ionization and partitioning of p-(aminoethyl)phenols and structurally related compounds: Electrostatic effects dependent on conformation

Tejwani

Stouch

Anderson

2009

Journal of Pharmaceutical Sciences

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“…When plotted on a log-linear plot, near-linear relationships were obtained for all pressures, indicating an approximate exponential relationship between solubility and cosolvent concentration as shown in Figure 4. This is in contrast to liquid systems containing 1:l interactions (Anderson et al, 1980;Fung and Higuchi, 1971) where the solubility is a linear function of cosolvent concentration. This behavior may indicate that the greater free volume in a supercritical fluid compared to a liquid appears to allow cosolvent-solute interactions to alter the local composition to a greater extent and thus be manifested in a stronger dependency of solubility on cosolvent concentration.…”

Section: Resultsmentioning

confidence: 82%

Chemical-physical interpretation of cosolvent effects in supercritical fluids

Ting¹,

Tomasko²,

Foster³

et al. 1993

Ind. Eng. Chem. Res.

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Cosolvent effects in supercritical fluids can be considerable for systems where the cosolvent interacts strongly with the solute. It is shown in a companion paper that strong interactions occur between naproxen ((S)-6-methoxy-cy-methyl-2-naphthaleneacetic acid) and various polar cosolventa in supercritical C02. A chemical-physical model proposed by Ekart and Eckert that incorporates chemical equilibria into the Soave-Redlich-Kwong equation of state was used here to study these systems. The model was found to describe these systems well, and the associated equilibrium constants obtained could be correlated with the cosolvent cy, P, and ?r* solvatochromic parameters by a linear free energy relationship. This correlation suggests that both physical and chemical forces are important in the solvation process of naproxen in polar cosolvent-supercritical C02 mixtures.The model coupled with the correlation represents a step toward predicting solubilities in cosolventmodified supercritical fluids using nonthermodynamic data. This method of modeling cosolvent effects allows a more intuitive interpretation of the data than either a purely physical equation of state or ideal chemical theory can provide. IntroductionIt is believed that the relatively high solubilities of nonvolatile solutes in supercritical fluids result partially from clustering of solvent molecules around the solute molecules, creating a local density which is greater than the bulk (Kim and Johnston, 1987a;Kajimoto et al., 1988;Petache and Debenedetti, 1989;Cochran and Lee, 1989;Brennecke et al., 1990a). This effect has been found to be greatest close to the critical point. With the introduction of cosolventa, various workers (Kim and Johnston, 1987b;Yonker and Smith, 1988) have found that the cosolvent concentration in the vicinity of the solute is also greater than the bulk. Although direct evidence is yet required to confirm the existence of distinct species being formed between polar solutes and polar cosolvents in supercritical fluids, an excited-state naphthalene-triethylamine complex (an exciplex) was found to be formed in the naphthalene/triethylamine/COz system studied by Brennecke et al. (1990b). Donohue and co-workers (Walsh et al., 1987 have also used the concept of complex formation between the solute and cosolvent in supercritical fluid systems. However, spectroscopic analysis of synthetic liquid solution mixtures was used to provide evidence of the formation of separate species and to obtain the related equilibrium constant. Evidence of complexing was also inferred by Lemert and Johnston (1991) for the hydroquinoneln-tributyl phosphate/supercritical COz system.It is shown in a companion paper (Ting et al., 1993) that purely physical models like the Peng-Robinson (Peng and Robinson, 1976) and the Soave-Redlich-Kwong (Soave, 1972) equations of state together with a binary interaction parameter could be used to correlate the solubility of polar organics like naproxen in polar cosolvent-supercritical C02 mixtures. The binary interaction parame...

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“…Efforts to facilitate computational prediction of this property are therefore warranted and are expected to increase the throughput and lower the costs of lipid formulation development (2). As described by Anderson et al (17), ideal solubility theory and regular solution theory fail to give an accurate prediction of drug solubility in polar organic lipid solutes and solvents, due to the absence of molecular interactions in the calculations. Similarly, Thi et al (16) examined the solubility of ten compounds in ten LBF excipients, but were unable to find a clear link between the physicochemical properties of the drugs investigated and solubility in the excipients.…”

Section: Introductionmentioning

confidence: 99%

Computational Prediction of Drug Solubility in Lipid Based Formulation Excipients

et al. 2013

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PurposeTo investigate if drug solubility in pharmaceutical excipients used in lipid based formulations (LBFs) can be predicted from physicochemical properties.MethodsSolubility was measured for 30 structurally diverse drug molecules in soybean oil (SBO, long-chain triglyceride; TGLC), Captex355 (medium-chain triglyceride; TGMC), polysorbate 80 (PS80; surfactant) and PEG400 co-solvent and used as responses during PLS model development. Melting point and calculated molecular descriptors were used as variables and the PLS models were validated with test sets and permutation tests.ResultsSolvation capacity of SBO and Captex355 was equal on a mol per mol scale (R2 = 0.98). A strong correlation was also found between PS80 and PEG400 (R2 = 0.85), identifying the significant contribution of the ethoxylation for the solvation capacity of PS80. In silico models based on calculated descriptors were successfully developed for drug solubility in SBO (R2 = 0.81, Q2 = 0.76) and Captex355 (R2 = 0.84, Q2 = 0.80). However, solubility in PS80 and PEG400 were not possible to quantitatively predict from molecular structure.ConclusionSolubility measured in one excipient can be used to predict solubility in another, herein exemplified with TGMCversus TGLC, and PS80 versus PEG400. We also show, for the first time, that solubility in TGMC and TGLC can be predicted from rapidly calculated molecular descriptors.

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Solubility of polar organic solutes in nonaqueous systems: Role of specific interactions

Cited by 38 publications

References 15 publications

Substituent effects on the ionization and partitioning of p-(aminoethyl)phenols and structurally related compounds: Electrostatic effects dependent on conformation

Substituent effects on the ionization and partitioning of p-(aminoethyl)phenols and structurally related compounds: Electrostatic effects dependent on conformation

Chemical-physical interpretation of cosolvent effects in supercritical fluids

Computational Prediction of Drug Solubility in Lipid Based Formulation Excipients

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