Article pubs.acs.org/JPCB
Enhancement of the 1‑Octanol/Water Partition Coefficient of the Anti-Inflammatory Indomethacin in the Presence of Lidocaine and Other Local Anesthetics Ryo Tateuchi,†,‡,§,∥ Naoki Sagawa,† Yohsuke Shimada,†,‡,§,∥ and Satoru Goto*,†,‡,§,∥ †
Faculty of Pharmaceutical Sciences, ‡Center for Drug Delivery Research, §Center for Physical Pharmaceutics, Research Institute for Science and Technology, and ∥Division of Colloid and Interface Science Research Institute for Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan ABSTRACT: Side effects and excessive potentiation of drug efficacy caused by polypharmacy are becoming important social issues. The apparent partition coefficient of indomethacin (log P′IND) increases in the presence of lidocaine, and this is used as a physicochemical model for investigating polypharmacy. We examined the changes in log P′IND caused by clinically used local anestheticslidocaine, tetracaine, mepivacaine, bupivacaine, and dibucaineand by structurally similar basic drugs procainamide, imipramine, and diltiazem. The quantitative structure− activity relationship study of log P′IND showed that the partition coefficient values (log PLA) and the structural entropic terms (ΔSobs, log f) of the additives affect log P′IND. These results indicate that the local anesthetics and structurally similar drugs function as phase-transfer catalysts, increasing the membrane permeability of indomethacin via heterogeneous intermolecular association. Therefore, we expect that the potency of indomethacin, an acidic nonsteroidal anti-inflammatory drug, will be increased by concurrent administration of the other drugs.
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through intermolecular interactions.5 These techniques are used for improving the membrane permeability and transitivity of drugs to target tissues. This shows that intermolecular interactions can regulate the effect of a drug, and thus the intramolecular interactions between drugs and concurrently administered components should also be considered in polypharmacy. Indomethacin (IND), an acidic nonsteroidal anti-inflammatory drug, increases renal dysfunction in combination with triamterene, a basic potassium-sparing diuretic.6 The combination of various counterions increases the apparent partition coefficient of acidic drugs;7−9 therefore, the increase in the apparent partition coefficient of IND (log P′IND) may be caused by concurrent administration with triamterene. The widely used local anesthetic (LA) lidocaine (xylocaine, LID) also increases log P′IND. A mixture of IND and LID forms a relatively stable amorphous complex, which has a low melting point of around room temperature. The aqueous solubility of the mixture is increased compared with that of IND or LID alone.10 Tomono and colleagues investigated the optimum constitution of a stable mixture quantitatively, and prepared a cocrystal of IND/LID with a molar ratio of 2:1 by evaporation of an ethanol solution of the drugs.11 In addition, Hough et al. reported a stable ionic
INTRODUCTION Polypharmacy of antipsychotic medications is defined as the concurrent administration of two or more antipsychotic drugs,1 and it is common in the treatment of patients with psychiatric disorders. Selective serotonin reuptake inhibitors (SSRIs) are antidepressants mainly used to treat major depression and anxiety. They are also used to treat depersonalization disorder, and remission is occasionally observed. However, patients with bipolar disorder taking SSRIs are at risk of a manic switch;2 thus, administration of SSRIs alone is not recommended, and this is a common example of polypharmacy. Furthermore, withdrawal symptoms are often observed when a valid SSRI treatment is abruptly interrupted,3 meaning that if an SSRI does not improve a patient’s symptoms, the dose must be tapered, and it will be used in combination with the newly started drug, also resulting in polypharmacy. Hence, polypharmacy is necessary for treating many conditions, although the risk of drug−drug interactions may increase as a result, and this is a difficult problem to address. Drug−drug interactions through drug-metabolizing enzymes or drug-binding proteins have been extensively investigated, because most psychotropic drugs are metabolized by cytochromes and other enzymatic systems.4 Physicochemical interactions that affect the pharmacokinetics and pharmacology of individual drugs are well-known. However, possible physicochemical interactions between multiple drugs have not been investigated thoroughly. Solid dispersions and nanosuspensions increase the apparent hydrophilicity of drugs © XXXX American Chemical Society
Received: April 27, 2015 Revised: June 29, 2015
A
DOI: 10.1021/acs.jpcb.5b03984 J. Phys. Chem. B XXXX, XXX, XXX−XXX
Article
The Journal of Physical Chemistry B
additives, CIND and C LA, respectively. The equilibrated concentration, C0, in the octanolic phase was calculated from the equilibrated concentration, Cw, in the aqueous layer, and the initial concentration, Ctot, in the octanolic layer before the partition equilibration procedure, according to eq 3.
liquid at room temperature, consisting of LID and the laxative dioctyl sulfosuccinate (docusate).12 Generally, the concurrent administration of an acidic or basic drug with a counterion increases the apparent partition coefficient. Although this improves the membrane permeability and bioavailability of the drug, this polypharmacy may also increase the risk of unexpected overflow beyond lipid barriers or the accumulation of the drug in adipose tissue. Previously, we found that log P′IND was increased by mixing it with LID.10 In the present study, we examined the change in log P′IND caused by the LAs tetracaine (TET), mepivacaine (MEP), bupivacaine (BUP), and dibucaine (DIB), and the structurally similar basic drugs, procainamide (PRA), imipramine (IMI), and diltiazem (DTZ). Then, we analyzed the quantitative structure− activity relationship study of these LAs and other basic drugs on log P′IND. We obtained a regression equation of the apparent hydrophobicity of IND in terms of the logarithm of the partition coefficient values (log PLA) and the structural entropy of the additive drugs. According to the method of Yalkowsky and colleagues, the structural entropic termthe molecular flexibility factor, log fwas predicted by the fragment parameters of the molecules.13,14 To obtain the experimental value of the structural entropic term, we derived the entropy of fusion, ΔSobs, from the change in the enthalpy of fusion observed by differential scanning calorimetry (DSC).
Co = C tot − Cw
Because C0 is proportional to Cw for IND, the regression slope corresponded to log P′IND in the absence or presence of an additive (Figure 1).
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EXPERIMENTAL SECTION Materials. IND, LID, TET hydrochloride, and DIB hydrochloride were purchased from Wako Pure Chemical Industries, Osaka, Japan. MEP hydrochloride and IMI hydrochloride were obtained from Sigma-Aldrich Co., St. Louis, MO, USA. DTZ hydrochloride and BUP hydrochloride were supplied from Tokyo Chemical Industry Co., Tokyo, Japan, and PRA hydrochloride came from Kanto Chemical Co., Inc., Tokyo, Japan. Other reagents were of the highest grade commercially available. Measurement of 1-Octanol/Water Partition Coefficient. The aqueous phase was 0.1 mol/L phosphate buffer (pH 6.45) that was equilibrated with 1-octanol. A mixture of 1octanol containing IND with the aqueous phase in the absence or presence of an additive (LID, MEP, BUP, TET, DIB, PRA, IMI, or DTZ) was shaken for 6 h at 298 K, and then it was left to stand for 16 h at the same temperature. The aqueous and octanolic phases were spectrophotometrically analyzed. If the absorption spectrum of an additive overlapped with that of IND, then the concentration of IND was calculated by eqs 1 and 2. A1 = εIND1C IND + εLA2C LA
(1)
A 2 = εIND2C IND + εLA2C LA
(2)
(3)
Figure 1. Apparent partition coefficient of IND at 298 K. (a) Octanolic spectra and (b) aqueous spectra after partition equilibration of 0, 0.6, 1.2, and 1.8 mmol/L IND diluted 10-fold with octanol in the absence of an LA. Concentrations of IND in the equilibrated octanolic phase were estimated from differences in the spectra. The horizontal and vertical axes respectively show the aqueous and octanolic concentration of IND after partition equilibration. Regression analysis gave a correlation coefficient of 0.999.
Effect of Additive on the Apparent Partition Coefficient of Indomethacin. Log P′IND changed depending on the concentration of the additive. We define κ as the effect of an additive on log P′IND. κ=
log P′IND − log P 0 IND [LA]
(4)
Here, log P′IND and log P0IND are observed partition coefficient of IND in the presence and absence of the additive, respectively, [LA] is the concentration of the additive, and log P′IND − log P 0 IND is the increase of log P for the acidic drug IND in the presence of the additive relative to log P0IND. Differential Scanning Calorimetry and Estimating the Entropy of Fusion. The observed enthalpy change of fusion, ΔHobs, was determined by DSC (DSC8230, Rigaku Co., Tokyo, Japan). The sample (10 mg) was put into a closed aluminum pan. Measurements were carried out at a scanning speed of 10 K/min under a flow of nitrogen gas (30 mL/min). We calculated the enthalpy change of fusion of the sample from the DSC curve, and then calculated the entropy change of fusion, ΔSobs, according to eq 5.14
Here, A1 and A2 are the observed absorbances at wavelengths λ1 and λ2, respectively. λ1 and λ2 were wavelengths where the differences between the absorption intensity of IND and that of the additives were large. Wavelengths λ1 and λ2 were measured at 300 and 323 nm for IND and DIB; 236 and 323 nm for IND and DTZ; and 249 and 350 nm for IND and PRA or TET. A wavelength of 350 nm was used for IND and IMI because this additive is transparent at this wavelength. Similarly, 323 nm was used for IND with the other additives. Regression coefficients εIND1 and εLA1 are the molar absorption coefficients of IND and of the additive, respectively, at wavelength λ1, and regression coefficients εIND2 and εLA2 are those at wavelength λ2. By using eqs 1 and 2, we obtained concentrations of IND and the
ΔSobs = B
ΔHobs Tm
(5) DOI: 10.1021/acs.jpcb.5b03984 J. Phys. Chem. B XXXX, XXX, XXX−XXX
Article
The Journal of Physical Chemistry B Calculation of Yalkowski’s Molecular Flexibility Factor. Yalkowski’s molecular flexibility factor, log f, was calculated for the drugs by using eqs 6 and 7. log f = log 2.85τ
(6)
τ = SP3 + 0.5 × SP2 + 0.5 × RING − 1
(7)
presence of the LAs and other basic drugs at 298 K are listed in Table 1. The κ value for DIB (106 L/mol) was much greater than those for LID (24.0 L/mol) and MEP (45.8 L/mol), suggesting that the κ values depend on the molecular size or related properties of the LAs. In contrast, the low κ value for DTZ (46.8 L/mol), which has a much higher molecular weight (414.52 g/mol), indicated that this is not the case. However, the κ values also appeared to show a linear correlation with the pKa values of the LAs. The κ value for PRA (11.0 L/mol), which has a higher pKa (9.32), showed that this was also not the case. We quantitatively analyzed the relationships between the κ values of IND and the physicochemical parameters of the basic drugs. Thus, we observed a relationship between the κ values and the log PLA in their neutral form. For example, IMI has a κ value of 102 L/mol, and a log PLA value of 4.80, confirming the relationship between the κ values and the hydrophobicity of basic additives (Figure 3). The relationship between κ of IND and log PLA, DTZ, PRA, and IMI at 298 K was obtained by eq 8.
Here, SP3 is the number of sp3 chain atoms, SP2 is the number of sp2 chain atoms, and RING is the number of fused-ring systems.13 Measurement of 13C NMR Spectra. 13C NMR spectra were recorded on a 400 MHz spectrometer (JNM-LA400, JEOL Ltd., Tokyo, Japan). IND and LA were dissolved in chloroform-d containing tetramethylsilane as an internal standard. The deuterated solvent provided the lock signal.
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RESULTS AND DISCUSSION We analyzed log P′IND in the absence and presence of BUP and the other basic drugs. The spectra of IND at final concentrations of 0, 0.6, 1.2, and 1.8 mmol/L in octanol before the partition experiments are shown in Figure 1a, and the corresponding spectra of IND in the equilibrated aqueous phase are shown in Figure 1b. The absorbance calibration was obtained at all wavelengths in these spectra, so that the concentration of IND in the equilibrated aqueous phase, Cw, and the initial concentration of IND, Ctot, could be calculated from the observed absorbance. The concentration of IND in the equilibrated octanolic phase, C0, was calculated by using eq 3. The correlation coefficient of >0.999 indicated that the concentration of IND in the equilibrated aqueous phase was proportional to that in the equilibrated octanol phase (Figure 1), and the slope of the regression line was determined as log P′IND. Log P′IND linearly depended on the concentration of BUP, and the intercept was 1.857 on the log P scale for IND (Figure 2). In the presence of various concentrations of BUP, log P′IND increased with a slope of 41.9 on the log P scale of BUP, which was defined as the κ value for BUP, according to eq 4. For the other basic drugs, the log P of IND also increased proportionally to the drug concentration. The values of κ for IND in the
κ = 23.875 log PLA − 14.254 (±4.965)
n = 8,
r = 0.894,
(±15.665)
(8)
s = 16.737
Here, n is the number of LAs and other basic drugs, r is the correlation coefficient, and s is the standard error of the estimate. The numbers in parentheses are the standard errors of the regression coefficients. Next, we consider the chemical structures of LID, MEP, and BUP, which share a common anilide moiety. The solvent accessible surface (Connolly surface) and the polar surface of LID are 423.96 and 32.34 Å2, respectively, and those of MEP are similar.17 Although this suggests that the log P value of MEP may be similar to that of LID, their log P values are different. LID probably has a greater log P value than MEP because the polar portion of LID is hidden through its intermolecular interactions, as the molecular structure of LID is flexible enough to become entangled. The structure of MEP, which contains an aliphatic ring, would be too rigid to do this. In addition, BUP also has a hydrocarbon chain connected to the corresponding ring, increasing its flexibility. According to Leo’s fragment constant approach for predicting hydrophobicity, a methylene increases the log P by 0.66.18 If this were valid for the hydrophobicity of the LAs, the log P value of BUP would be 5.08 based on that of LID, or 3.1 based on that of MEP. The reported value of log P value of BUP is 3.41, which is much more hydrophilic than that calculated from LID. Thus, it is thought that LID becomes too hydrophobic, and BUP becomes slightly hydrophilic. We assumed that the hydrocarbon chains of BUP would associate with each other to decrease their hydrophobicity. The values of log PLA would depend on the groups present in the structure (e.g., methylene and anilide) and on the molecular flexibility and conformational diversity. We used Yalkowsky’s molecular flexibility factor, log f, to describe the flexibility of the structure, which would also reflect the degree of the intermolecular interaction.13 We conducted multiple regression analysis for κ by using log f of the additive LAs and basic drugs. κ = 23.059 log PLA + 4.277 log f − 21.351 (±5.352)
Figure 2. Changes in the apparent partition coefficient of IND with the concentration of BUP. The slope of the regression line in the inset shows the apparent partition coefficient of IND in the presence of 0.4, 0.8, 1.2, and 1.6 mmol/L BUP. Error bars show estimated errors from regression analysis.
n = 8,
r = 0.900,
(±19.571)
(±6.399)
(9)
s = 17.566
Although eq 9 does not show a statistical improvement compared with the single regression in eq 8, the relationship of C
DOI: 10.1021/acs.jpcb.5b03984 J. Phys. Chem. B XXXX, XXX, XXX−XXX
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The Journal of Physical Chemistry B Table 1. Values of κ, log P, log f, and ΔSobs of LAs and the Other Drugs LA
κ (L/mol)
log Pa
log f b
BUP MEP LID PRA DIB TET IMI DTZ
41.9 45.8 24.0 11.0 106 66.4 102 46.8
3.41 1.95 2.44 0.88 4.40 2.79 4.80 2.70
1.82 0.455 2.05 2.50 3.87 3.41 1.59 2.04
ΔHc (kJ/mol)
Tmc (K)
341 441 338 412 445
ΔSd (J/mol/K)
15.1 26.1 27.7 46.2 29.7
Mw (g/mol)
pKaa
288.43 246.35 234.34 235.33 343.46 264.36 280.41 414.52
8.1 7.7 8.01 9.32 8.85 8.39 9.4 8.06
44.2 59.1 93.0 112 66.7
a
Data taken from refs 15−18. The pKa for a basic drug is the value of its conjugate acid. bCalculated values from eqs 6 and 7. cExperimental values obtained by DSC. dCalculated values from eq 5.
have high structural symmetry or structural flexibility do not follow this rule. When organic compounds are complex and asymmetric, the entropy change of fusion increases with molecular flexibility factor (log f) according to Yalkowsky’s hypothesis.13 This suggests that log f is the main contributor to the observed entropy change of fusion, when we compare organic compounds that are asymmetric, with similar physicochemical properties, and a limited range of molecular weight. The conformational flexibility could be estimated more quantitatively by DSC than by log f. Next, we performed DSC on the additive drugs to estimate the observed enthalpy change of fusion, ΔHobs, and the melting point, Tm, and we calculated the observed entropy change of fusion, ΔSobs, with eq 5. The entropy of fusion (ΔSobs) of MEP, BUP, and DTZ could not be measured, because these compounds decomposed at their melting points. Simple and multiple linear regression analysis were conducted for κ, as shown in eqs 10, 11, and 12.
Figure 3. Log P of the additive LAs and κ of IND determined at 298 K. Error bars show estimated errors from regression analysis.
the κ value with log P and log f produced lower deviation for DIB, TET, LID, DTZ, PRA, and BUP. Log f is usually used to describe the thermodynamic contribution of conformational diversity during the transition from the solid to the liquid phase. According to Walden’s rule, nonspherical rigid molecules that do not associate in the liquid state have an average entropy change of fusion of 56.5 J/K/mol.13,14 However, molecules that
κ = 26.143 log PLA − 17.962
(±16.295)
(±4.838)
n = 5,
r = 0.952,
(10)
s = 15.363
κ = 25.827 log PLA + 4.749 log f − 45.015 (±3.996)
(±3.060)
(±22.010)
(11)
Table 2. 13C NMR Chemical Shifts of IND and LID IND no.
a
1 2 3 4 5 6 7 8 9 10 11, 15 12, 14 13 16 17 18 19
δ
b
136.24 111.78 130.76 101.25 156.05 111.68 114.98 130.44 168.27 133.78 131.16 129.11 139.32 13.26 29.99 176.82 55.70
δ(IND/LID) 135.71 113.25 130.81 101.37 155.92 111.38 114.87 130.76 168.21 133.55 131.08 129.01 139.08 13.27 30.72 175.62 55.53
LID c
Δδ
d
no.
−0.53 1.47 0.04 0.12 −0.13 −0.30 −0.11 0.33 −0.06 −0.23 −0.08 −0.10 −0.24 0.00 0.73 −1.20 −0.17
a
1 2, 6 3, 5 4 7, 8 9 10 11, 12 13, 14
δ
δ(IND/LID)c
Δδd
135.06 133.94 128.18 127.03 18.52 170.29 57.51 48.92 12.63
134.98 133.95 128.14 127.13 18.40 168.79 56.08 48.55 11.71
−0.08 0.01 −0.04 0.10 −0.12 −1.50 −1.43 −0.37 −0.92
b
a Carbon atoms as numbered in Scheme 1. bChemical shifts of IND or LID individually. cChemical shift of IND or LID in solution at a 1:1 molar ratio. dΔδ = δ(IND/LID) − δ.
D
DOI: 10.1021/acs.jpcb.5b03984 J. Phys. Chem. B XXXX, XXX, XXX−XXX
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The Journal of Physical Chemistry B Table 3. 13C NMR Chemical Shifts of IND and DIB IND
DIB
no.a
δb
δ(IND/DIB)c
Δδd
no.a
δb
δ(IND/DIB)c
Δδd
1 2 3 4 5 6 7 8 9 10 11, 15 12, 14 13 16 17 18 19
136.24 111.78 130.44 101.25 156.05 111.68 114.98 131.16 168.27 133.78 130.76 129.11 139.32 13.26 176.82 29.99 55.70
135.01 114.76 130.83 101.74 155.77 111.51 115.33 131.35 168.17 134.19 130.97 128.91 138.81 13.22 177.05 30.99 55.53
−1.22 2.97 0.40 0.49 −0.28 −0.16 0.36 0.19 −0.10 0.41 0.21 −0.20 −0.51 −0.05 0.23 1.00 −0.17
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17, 18 19, 20
161.61 111.18 145.14 121.53 125.27 124.53 129.90 127.56 147.33 65.97 31.01 19.29 13.87 167.01 37.34 51.15 46.56 11.75
161.53 110.97 144.13 121.55 125.35 124.44 129.76 127.49 147.13 65.93 32.10 19.25 13.82 167.68 35.54 50.82 46.34 8.86
−0.08 −0.20 −1.01 0.03 0.08 −0.09 −0.14 −0.07 −0.20 −0.04 1.09 −0.03 −0.04 0.67 −1.79 −0.33 −0.22 −2.90
a
Carbon atoms as numbered in Scheme 1. bChemical shifts of IND or DIB individually. cChemical shifts of IND or DIB in solution at a 1:1 molar ratio. dΔδ = δ(IND/DIB) − δ.
Scheme 1. Structures of the Drugs Used in This Study
n = 5,
r = 0.978,
s = 12.673
κ = 23.765 log PLA + 0.439ΔSobs − 43.636 (±3.247)
n = 5,
r = 0.987,
(±0.189)
(±15.163)
hydrophobicity of the counterions and their conformational flexibility. Tables 2 and 3 show the 13C NMR chemical shifts of IND and LAs (see Scheme 1 for structures of the drugs used in this study). In the mixtures of IND and LID and IND and DIB, characteristic chemical shifts were observed for the carboxylic acid group of IND and the amino group of the LAs. This suggests ionic interaction between IND and these LAs. An ionic liquid is a salt in which the ions are too asymmetric or flexible to form a crystal at room temperature, meaning it forms a liquid.19 Ionic liquids are neither water nor oil, and are bound with intermolecular interactions that are stronger than hydro-
(12)
s = 9.786
We analyzed five of the compounds, excluding MEP, BUP, and DTZ. Multiple regression eq 11, that expresses κ in terms of log PLA and log f, was more significant than single regression eq 10. Furthermore, using ΔSobs in eq 12 improved the relationship between κ and the physicochemical parameters. The regression analyses of this study showed that the increase in log P′IND by addition of LAs and other basic drugs depends on the E
DOI: 10.1021/acs.jpcb.5b03984 J. Phys. Chem. B XXXX, XXX, XXX−XXX
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The Journal of Physical Chemistry B phobic or hydrophilic interactions.20 However, if the cationic and anionic components contained large hydrophobic regions, then the van der Waals interactions between the counterions would increase, and a pair of hydrophobic ions could disperse as a discontinuous phase in a hydrophobic solvent. For example, the phase-transfer catalyst, potassium-crown ether, carries permanganate anions or superoxide anions in organic solvents.21,22 In our further research, we examine the interaction between IND and LAs in aqueous solution. Direct interactions between IND and any basic drug would create a dispersion of a discontinuous phase enclosing both acidic and basic components. The LAs and other basic drugs in the present paper may act as a phase-transfer catalyst promoting the transit of IND from the aqueous phase to the octanolic phase. The most hydrophobic basic drugs, DIB and IMI, would facilitate the condensation of the acidic IND into the hydrophobic phase most efficiently. If the molecular flexibility of these basic drugs mainly affects the affinity with acidic IND, then this acid−base interaction would allow the drugs to travel through the blood− brain barrier, which usually prevents compounds in the blood from entering the central nervous system. These results may play an important role in understanding of the effects of using combinations of acidic and basic antipsychotic drugs.
(9) Takács-Novák, K.; Szász, G. Ion-Pair Partition of Quaternary Ammonium Drugs: The Influence of Counter Ions of Different Lipophilicity, Size, and Flexibility. Pharm. Res. 1999, 16, 1633−1638. (10) Shimada, Y.; Goto, S.; Uchiro, H.; Hirabayashi, H.; Ymaguchi, K.; Hirota, K.; Terada, H. Features of Heat-Induced Amorphous Complex between Indomethacin and Lidocaine. Colloids Surf., B 2013, 102, 590− 596. See also: Correction: Colloids Surf., B, 2014, 103, 664−665. . (11) Umeda, Y.; Nagase, H.; Makimura, M.; Tomono, K.; Shiro, M.; Ueda, H. Crystal Structure of 2:1 Complex of Indomethacin and Lidocaine. Anal. Sci.: X-Ray Struct. Anal. Online 2007, 23, x15−x16. (12) Hough, W. L.; Smiglak, M.; Rodriguez, H.; Swatloski, R. P.; Spear, S. K.; Daly, D. T.; Pernak, J.; Grisel, J. E.; Carliss, R. D.; Soutullo, M. D.; et al. The Third Evolution of Ionic Liquids: Active Pharmaceutical Ingredients. New J. Chem. 2007, 31, 1429−1436. (13) Dannenfelser, R. M.; Yalkowsky, S. H. Estimation of Entropy of Melting from Molecular Structure: A Non-Group Contribution Method. Ind. Eng. Chem. Res. 1996, 35, 1483−1486. (14) Goto, S. QSAR study for transdermal delivery of drugs and chemicals. In Colloid and Interface Science in Pharmaceutical Research and Development; Ohshima, H., Makino, K., Eds.; Elsevier: Amsterdam, 2014; pp 121−129. (15) DRUG BANK. http://www.drugbank.ca/drugs/ (accessed April 17, 2015). (16) CHEMICALIZE.ORG beta. http://www.chemicalize.org/ (accessed April 17, 2015). (17) Virtual Computational Chemistry Laboratory. http://www. vcclab.org/ (accessed April 17, 2015). (18) Hansch, C.; Leo, A.; Hoekman, D. Exploring QSAR Hydrophobic, Electronic, and Steric Constants; American Chemical Society: Washington DC, 1995; pp 1−348. (19) Eike, D. M.; Brennecke, J. F.; Maginn, E. J. Predicting Melting Points of Quaternary Ammonium Ionic Liquids. Green Chem. 2003, 5, 323−328. (20) Wasserscheid, P. Chemistry: Volatile Times for Ionic Liquids. Nature (London, U. K.) 2006, 439, 797. (21) Sam, D. J.; Simmons, H. E. Crown Polyether Chemistry. Potassium Permanganate Oxidations in Benzene. J. Am. Chem. Soc. 1972, 94, 4024−4025. (22) Valentine, J. S.; Curtis, A. B. Convenient Preparation of Solutions of Superoxide Anion and the Reaction of Superoxide Anion with a Copper (II) Complex. J. Am. Chem. Soc. 1975, 97, 224−226.
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CONCLUSION We have investigated the increase in log P′IND caused by LAs and other basic drugs. The effects of hydrophobicity (log PLA), molecular flexibility (log f), and entropy changes of fusion (ΔSobs) of the basic drugs suggest that the basic drugs function as phase-transfer catalysts for IND through these interactions. Understanding these interactions, especially three-dimensional specificity, would help in addressing some of the problems encountered in polypharmacy.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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REFERENCES
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DOI: 10.1021/acs.jpcb.5b03984 J. Phys. Chem. B XXXX, XXX, XXX−XXX
