Dissociation Constants and OctanolâWater ... - ACS Publications

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Dissociation Constants and Octanol−Water Partition Equilibria for Several Fluoroquinolones Gina-Mabel Cárdenas-Youngs and José-Luis Beltrán* Departament de Química Analítica, Universitat de Barcelona, Avinguda Diagonal 645, 08028 Barcelona, Spain S Supporting Information *

ABSTRACT: The octanol/water partition and acid−base dissociation equilibria for a set of six fluoroquinolones have been studied by the shake-flask method at 25 °C and at 0.15 M NaCl ionic strength, determining the partition coefficient (logD) in the pH range 3 to 9. The substances studied are ciprofloxacin (CIP), danofloxacin (DAN), difloxacin (DIF), enrofloxacin (ENR), marbofloxacin (MAR), and sarafloxacin (SAR). After the partition equilibrium, the remaining fluoroquinolone concentration is determined in aqueous phase by liquid chromatography with fluorescence detection. The pKa values obtained are in accordance with the previously published data, ranging between 5.59 and 6.50 for pKa1 and between 7.99 and 8.96 for pKa2. The lipophilicity of the substances is low, with logKOW ranging between −1.09 to 0.68. Additionally, we have determined the octanol/water partition coefficient for the cationic species in all cases. subsuperficial water,9 being used also to estimate the organic carbon partition coefficient10 and the water solubility.11 However, despite being used for about 40 years, there are some differences between the equilibrium constants reported for dissociation and octanol−water distribution of fluoroquinolones. Table 1 indicates these properties for the group of substances studied in this work. It can be observed that the maximum variation for a single substance in pKa1 and pKa2 values, apart from the last pKa values for sarafloxacin) are about 0.4 (enrofloxacin) and 1.0 (difloxacin) pKa units, respectively. These variations can be owed to the different experimental procedures in the pKa determination. They include potentiometric,13,14,17 spectrophotometric,16,17,21 or electrophoretic16 procedures. The ionic strength is, in some cases, not specified,16,17 corrected to ionic strength 0.01 M17 or pHcorrected.14 The temperature is 25 °C in general, but it was 23 °C in the last case. So, these different procedures and experimental conditions can lead to different results. Regarding logKOW values, the difference between published data can be higher than 2.4 logKOW units (sarafloxacin); this means more than 250 times in the KOW value. These higher differences can be owed to the fact that in some cases, the partition constants are predicted values, obtained from structure−property relationships; depending on the descriptors and the algorithm used in the calculation method, it can give different values.22 So, the use of these parameters as input data to predict the behavior of these drugs in biochemistry and environmental studies can lead to large prediction errors because of the uncertainness of the data supplied.

1. INTRODUCTION Quinolones are a class of synthetic antimicrobial agents widely used against a variety of bacterial infections.1 Derivatives containing one or more fluoride atoms in their molecular structure are named fluoroquinolones. Their antibacterial activity is based on the inhibition of the DNA gyrase,2,3 required for synthesis of bacterial mRNAs (transcription) and DNA replication. Its molecular structure confers the characteristic of being zwitterionic drugs, which in turn makes them to present a broad antibacterial activity spectrum against Gram-positive, Gram-negative, and mycobacterial pathogens as well as anaerobes. As zwitterionic substances, they may exist in four different species in solution: as cation, neutral, anion, and zwitterion, depending on the pH of the medium and the dissociation constants (pKa). The octanol/water partition constant (KOW) is defined as the ratio of the equilibrium concentrations of a substance between an octanol phase and the corresponding in aqueous phase. The concentrations being expressed in terms of the mass or moles of chemical per unit volume of liquid.4,5 The lipophilicity of a drug can be measured as the octanol−water partition constant and is usually presented in the literature in logarithm form (logKOW). This parameter is very useful in medicinal chemistry and biochemistry studies,4 and also in environmental chemistry. For example, logKOW is used in simulation models for the prediction of tissue drug residues,6 in the prediction of membrane penetration of drug7 or in the study of dermal penetration of amphiphilic compounds in aqueous solution.8 Moreover, logKOW is highly related with the behavior, mobility, and the fate in the environment, as this parameter is one of the most important input for the application of transport-diffusion models in soils and sediments, and in superficial and © 2015 American Chemical Society

Received: July 6, 2015 Accepted: October 20, 2015 Published: October 30, 2015 3327

DOI: 10.1021/acs.jced.5b00556 J. Chem. Eng. Data 2015, 60, 3327−3332

Journal of Chemical & Engineering Data

Article

general, the authors determine the logD at discrete pH values (e.g., 5, 7, and 9). The aim of this work is the determination of the octanol− water partition and the dissociation constants of a series of fluoroquinolones, by studying the partition equilibria by the shake-flask method in a wide pH range (approximately from 3 to 9.5) at 25 °C and ionic strength 0.15 mol L−1 NaCl. Most of the substances studied in this work are fluoroquinolones used in veterinary therapy: danofloxacin (DAN), difloxacin (DIF), enrofloxacin (ENR), marbofloxacin (MAR), and sarafloxacin (SAR). Ciprofloxacin (CIP), although used in human therapy, is included here because of it is a metabolite of ENR. The structures of the studied drugs are given in Figure 1.

Table 1. Literature Values for Dissociation Constants and Octanol−Water Partition Coefficients of Several Fluoroquinolones fluoroquinolone

pKa1

pKa2

6.08 6.14 5.9 5.86 6.33 6.16 6.18

8.58 8.7 8.89 8.24 8.84 8.62 8.73

logKOWa

CIP

logD (pH)a

reference

−0.99 (7.0) −1.13 (7.4)

12 13 14 15 16 16 17 18 19 16 16 20 12 16 16 20 14 15 16 16 19 20 16 16 20 16 16 17 21 19 20

0.4

−0.78 (7.4) −1.36b

DAN

6.07 6.32

8.56 8.73 0.44

b

DIF

0.76 (7.0) 5.66 5.8

7.24 8.26

6.19 6.27 5.88 6.09

7.59 ca. 8.3 7.74 7.91

1.28b ENR

1.1

0.24b 0.7b MAR

5.69 5.51

8.02 8.38 −1.11b

SAR

5.62 5.87 5.89 4.12

8.18 8.88 8.59 6.78

−0.89 (7.0) −1.36b 1.07b

a b

2. EXPERIMENTAL SECTION 2.1. Reagents and Apparatus. VETRANAL-grade CIP, DAN, DIF hydrochloride, ENR, MAR, and SAR hydrochloride trihydrate were purchased from Fluka−Sigma-Aldrich (Buchs, Switzerland). All other chemicals used were analytical grade. Fluoroquinolone stock standard solutions (100 mg L−1) in 0.15 mol L−1 NaCl were prepared by dissolving the corresponding compound in deionized water. Solutions were stored at 4 °C in amber glass bottles and used within 1 week. Working solutions were prepared daily by dilution of the stock solutions. Sodium hydroxide, hydrochloric acid, anhydrous sodium hydrogen phosphate, and sodium chloride were purchased from Merck (Darmstadt, Germany); sodium tetraborate decahydrate and oxalic acid dihydrate were purchased from Sigma-Aldrich (Buchs, Switzerland). Solvents used were n-octanol HPLCgrade (Panreac, Barcelona, Spain), acetonitrile (ACN) HPLCgrade (Merck, Darmstadt, Germany), and deionized water with a resistivity of 18.2 MΩ cm−1 (Milli-Q Plus system, Millipore, Molheim, France). 2.2. Apparatus. The liquid chromatographic equipment consisted of an Agilent 1200 series HPLC system, equipped with a degasser (G1322A), automatic injector (G1329A), quaternary pump (G1311A), and fluorescence detector (G1321A). The chromatographic column was a Phenomenex Kinetex C18 (150 mm × 4.60 mm, 2.6 μm), with a Phenomenex Kinetex precolumn. The HPLC system was controlled with the Agilent ChemStation software (v. 2001− 2010; Rev B.04.02 SP1) running in a PC under Windows XP.

LogKOW or logD, at indicated pH, as given in the references. Predicted values.

When available, experimental logKOW values are determined by the shake-flask method, but some aspects differ: in some cases, the lipophilicity/pH profile is measured,18,20 but in

Figure 1. Structures of the fluoroquinolones studied in this work. 3328



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The mobile phase consisted of 0.01 mol L−1 oxalic acid at pH 2.5 and ACN (77:23 v:v). The flow rate was 1.0 mL min−1. MAR was monitored at 297/507 nm (excitation/emission wavelengths) and the other substances (CIP, DAN, DIF, ENR, and SAR) at 280/450 nm. pH was measured using a CRISON GLP21 pH-meter (precision ± 0.01 pH units), equipped with a combined glass electrode (pH 52-02). Other instruments were a Heraeus Labofuge 400 centrifuge and a SBS MRH-4 rotary mixer. 2.3. Procedures. A solution containing 0.01 mol L−1 Na2HPO4 and 0.01 mol L−1 Na2B4O7 was prepared, adjusting the ionic strength to 0.15 mol L−1 by the addition of NaCl. Then, it was saturated in n-octanol. About 16 samples were prepared in amber vials with equal volume of this solution and n-octanol, adjusting the pH in the range 3 to 9, by the addition of the adequate volume of 0.15 mol L−1 HCl and 0.15 mol L−1 NaCl to obtain the same volume of aqueous phase in all samples (6 mL). At each sample were added the same amount of standard solution of respective quinolone to give an initial concentration in aqueous phase about 3 mg L−1. The total volume of aqueous phase was 6.0 mL, whereas the watersaturated n-octanol volume was 50 mL. This volume ratio (6:50 water:octanol) has been selected to get a significant fluoroquinolone concentration change in the aqueous phase, because of the low lipophilicity of fluoroquinolones. All flasks were shaken at 25 °C (± 1) for 3 h to obtain the equilibrium. Then, each bottle was centrifuged and the aqueous and organic phases were separated. An aliquot of aqueous phase was filtered to obtain the concentration of fluoroquinolone in this phase, and another aliquot was separated to measure the pH solution at equilibrium. 2.4. Determination of Partition Constants. The apparent partition constants were determined as a function of pH by the shake-flask approach in n-octanol/buffer system at 25 °C and 0.15 M NaCl ionic strength. The concentration of fluoroquinolone in aqueous phase was measured by HPLC with fluorescence detection. The concentration of the drugs in the octanol (COCT) phase was obtained by mass balance, from the initial concentration in aqueous phase (C0,W), the remaining concentration in equilibrium (CW), and the volumes of octanol and aqueous phase (VOCT and VW, respectively) COCT =

C0,W − C W VOCT

octanol phase, the partition coefficient defined in eq 2 can be written as D=

COCT CW

(3)

[HQ app]W [H+]

K a1 =

[H 2Q+]W −

K a2 =

(4)

+

[Q ]W [H ] [HQ app]W

(5)

[H 2Q+]OCT [H 2Q+]W

(6)

KD + =

K OW =

[HQ app]OCT [HQ app]W

(7)

By substituting the concentrations of the different species in eq 3 as a function of the hydrogen ion concentration in aqueous phase ([H+]) and the equilibrium constants of eqs 4−7 we obtain D=

K D +[H+] K a1

+ K OW

+

[H ] K a1

+1+

K a2 [H+]

(8)

Equation 8 indicates the relationships between the partition coefficient, the pH of solution and the different equilibrium constants. Thus, from the experimental data pairs D/pH, we can obtain an estimate of these constants. The [H+] values are calculated from the measured pH and the mean activity coefficient.24 As there is not a direct equation to obtain the constants, we use a nonlinear least-squares (NNLS) procedure to refine a set of guessed constants. First, we define an objective function (U) based on the squared differences between experimental and calculated values of logD n

∑ (logDEXP, i − logDCALC,i )2 i=1

(1)

= f (pH, DEXP , Ka1 , Ka2 , KD + , K OW )

and the apparent partition coefficient (D) is defined by the ratio

D=

[H 2Q+]W + [HQ app]W + [Q−]W

On the other hand, the constants corresponding to the dissociation and partition equilibria are defined as

U= VW

[H 2Q+]OCT + [HQ app]OCT

(9)

where n is the number of data pairs D/pH, and logDEXP,i and logDCALC,i the experimental and calculated values for the i data point. As the logDCALC,i values are calculated from the measured pH of the solution and the set of guessed equilibrium constants, the U function depends on the experimental data pairs pH/D and the set of guessed constants, which are refined iteratively until a minimum in the U function is obtained. Using the Solver function of the MS Excel worksheet makes the refinement process; the estimated errors in the equilibrium constants are calculated by the SolvStat macro.25

(2)

The values COCT and CW indicate the total concentrations of the different species in octanol and aqueous phases, respectively. As noted before, these species can be protonated (H2Q+), neutral (HQ), zwitterionic (HQ±), or anionic (Q−) depending on the pH of the solution. For practical purposes, from here, we will consider in this work the sum of the neutral and zwitterionic species as the “apparent neutral species” (HQapp). Moreover, several authors indicated the possibility of extraction in octanol of the ion pair formed in acidic medium between the protonated species of fluoroquinolones and chloride.18,23 Taking into account this possibility, and being [H2Q+]OCT the concentration of the ion pair H2Q+·Cl− in

3. RESULTS AND DISCUSSION To determinate the equilibrium constants, we plot the experimental data as logD/pH, and the maximum value for logD is used as the initial guess for logKOW; the initial guessed values for pKa1 and pKa2 are taken 3.0 and 9.0, respectively. Figure 2 shows the procedure used for the determination of the 3329



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that, in general, the pKa1 and pKa2 values are in good agreement (the higher differences correspond to pKa1 of CIP and pKa2 of MAR), with differences about 0.1−0.2 pH units. This fact indicates that the procedure used is a valid alternative to determine the dissociation constants of fluoroquinolones. The case for KOW data is different, as there is not an agreement between the literature values: in some cases, the partition equilibria are studied at a single pH value (7.0 or 7.4); on the other hand, in some fluoroquinolones (DAN, MAR), the data reported are obtained only by prediction from the structure. As noted in the introductory part, the differences in the reported data from several authors can be up two magnitude orders in logKOW. Our results indicate a narrower range for logKOW values, as they are in the interval −1.09 (CIP) to 0.68 (DIF). On the other hand, if we compare the pKa2 with logKOW values, it seems that the most acidic substances (DIF and ENR, with pKa2 equal to 7.99 and 8.25, respectively) are also the most lipophilic (logKOW values are 0.68 and 0.39, respectively). Additionally, in this work, we have determined the partition constants for the cationic species for all six fluoroquinolones; in this case, the values are very similar for all substances, ranging from −1.37 (DAN) to −0.83 (DIF), as logKD+ in NaCl 0.15 M medium. With the set of equilibrium constants we have calculated the partition coefficients (as logD) in octanol/water, in the pH range 3 to 9. The data are given in Table 3.

Figure 2. logD/pH data for ciprofloxacin: □, experimental data; lines, the calculated data for the different models (see text).

equilibrium constants in the case of CIP: taken these pKa values and −1.09 (the higher experimental logD value) as logKOW as starting constants, we obtain the calculated logD values indicated as the dotted line, which approaches the experimental data only for pH > 7 (Model I). A first refinement of logKOW, pKa1, and pKa2, simultaneously, applied to the experimental data points between about one pH unit below and over the corresponding to maximum logD, gave the following values: pKa1 = 5.51, pKa2 = 8.87, and logKOW = −1.07 (Model II). The dashed line indicates the calculated logD values in this case. By comparison with the experimental data, a clear lack of fit is noted in the acidic pH range, indicating the necessity of adding new species to the equilibrium model. Similar evidence have been obtained in the literature,18,23 showing a distorted logD/ pH plot in acidic medium, due to higher than expected logD values and attributed to the extraction of the H2Q+·Cl− ionpair. So, we postulate the extraction of the protonated species, according the eq 6. A new refinement, including the equilibria described by the eqs 4 to 7, and applied to all the experimental data gave the following values: pKa1 = 5.51, pKa2 = 8.96, logKOW = −1.07, and logKD+ = −1.36 (Model III). This model, represented by the continuous line in Figure 2, presented a good fit to experimental data, and was used as the definite model. This calculation procedure has been applied to the fluoroquinolones studied in this work, and the results are given in Table 2. The experimental data logD/pH for all Fluoroquinolones studied are given in Tables 1A and 1B of Supporting Information. In nearly all cases, the extraction of the neutral and protonated (cationic) species are sufficient to explain the variation of the distribution coefficient as a function of pH. Only in the case of SAR a small deviation was observed at pH > 9. By comparison of the results obtained in this work (Table 2) with those given in the literature (Table 1), it can be observed

4. CONCLUSIONS We have determined the apparent dissociation and octanol/ water partition equilibria constants for a set of six fluoroquinolones (CIP, DAN, DIF, ENR, MAR, and SAR), by using the shake-flask procedure at 25 °C and I = 0.15 M in NaCl. The results obtained for the acid−base dissociation constants are in general in accordance with the previously published data. The octanol/water partition equilibrium is somewhat difficult to compare with the literature data because they are only available for CIP, ENR, DIF, and SAR. Nevertheless, our results are similar to the published data when available. For example, in the case of CIP, the logD literature values at pH 712 and 7.413,18 are −0.99, −1.13, and −0.78, respectively. They are compatible with the logKOW value obtained in this work (−1.09); however, it is different to given in ref 15: logKOW = 0.4. In the case of DIF, our value logKOW = 0.68 is similar to the logD = 0.76 at pH = 7 given in ref 12. For SAR the logD value given in ref 21 at pH = 7 (−0.89) is close to our logKOW value (−0.69). However, the literature value given for logKOW of ENR (1.1, ref 15) is very different to our value (0.39). In the case of logKOW values predicted by structureproperties relationships (refs 19 and 20), some values are close

Table 2. Equilibrium Constants for the Octanol−Water Partition of the Studied Fluoroquinolonesa substance ciprofloxacin danofloxacin difloxacin enrofloxacin marbofloxacin sarafloxacin a

pKa1 5.59 6.50 5.60 6.02 5.86 5.92

(0.08) (0.04) (0.14) (0.02) (0.09) (0.11)

pKa2 8.96 8.94 7.99 8.25 8.80 9.09

(0.02) (0.06) (0.05) (0.02) (0.05) (0.06)

logKOW −1.09 −0.23 0.68 0.39 −0.94 −0.69

(0.01) (0.02) (0.03) (0.01) (0.02) (0.02)

logKD+ −1.36 −1.37 −0.83 −1.02 −1.81 −1.18

(0.01) (0.02) (0.05) (0.01) (0.02) (0.04)

At 25°C, I = 0.15 M NaCl). The estimated standard deviations are given between parentheses. 3330



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Table 3. Calculated logD Values for Octanol−Water Partition of the Studied Fluoroquinolones at Selected pH Values substance ciprofloxacin danofloxacin difloxacin enrofloxacin marbofloxacin sarafloxacin

pH 3.00

4.00

5.00

6.00

7.00

7.40

8.00

9.00

−1.36 −1.37 −0.80 −1.01 −1.81 −1.18

−1.35 −1.36 −0.63 −0.95 −1.78 −1.18

−1.30 −1.26 −0.05 −0.59 −1.60 −1.11

−1.16 −0.83 0.50 0.04 −1.18 −0.88

−1.10 −0.37 0.63 0.32 −0.98 −0.73

−1.10 −0.30 0.60 0.33 −0.97 −0.71

−1.13 −0.28 0.43 0.23 −0.99 −0.72

−1.35 −0.50 −0.26 −0.33 −1.28 −0.90

(6) Haritova, A. M.; Fink-Gremmels, J. A simulation model for the prediction of tissue: plasma partition coefficients for drug residues in natural casings. Vet. J. 2010, 185, 278−284. (7) Mazák, K.; Noszál, B. Zwitterions can be predominant in membrane penetration of drugs: experimental proof. J. Med. Chem. 2012, 55, 6942−6947. (8) Korinth, G.; Wellner, T.; Schaller, K. H.; Drexler, H. Potential of the octanol−water partition coefficient (log P) to predict the dermal penetration behaviour of amphiphilic compounds in aqueous solutions. Toxicol. Lett. 2012, 215, 49−53. (9) Mackay, D.; Fraser, A. Bioaccumulation of persistent organic chemicals: mechanisms and models. Environ. Pollut. 2000, 110, 375− 391. (10) Seth, R.; Mackay, D.; Muncke, J. Estimating the organic carbon partition coefficient and its variability for hydrophobic chemicals. Environ. Sci. Technol. 1999, 33, 2390−2394. (11) Mackay, D.; Bobra, A.; Shiu, W. Y.; Yalkowsky, S. H. Relationships between aqueous solubility and octanol-water partition coefficients. Chemosphere 1980, 9, 701−711. (12) Ross, D. L.; Elkinton, S. K.; Riley, C. M. Physicochemical properties of the fluoroquinolone antimicrobials. IV. 1-Octanol/water partition coefficients and their relationships to structure. Int. J. Pharm. 1992, 88, 379−389. (13) Montero, M. T.; Freixas, J.; Hernández-Borrell, J. Expression of the partition coefficients of a homologous series of 6-fluoroquinolones. Int. J. Pharm. 1997, 149, 161−170. (14) Qiang, Z.; Adams, C. Potentiometric determination of acid dissociation constants (pKa) for human and veterinary antibiotics. Water Res. 2004, 38, 2874−2890. (15) Tolls, J. Sorption of Veterinary Pharmaceuticals in Soils: A Review. Environ. Sci. Technol. 2001, 35, 3397−3406. (16) Jiménez-Lozano, E.; Marqués, I.; Barrón, D.; Beltrán, J. L.; Barbosa, J. Determination of pKa values of quinolones from mobility and spectroscopic data obtained by capillary electrophoresis and a diode array detector. Anal. Chim. Acta 2002, 464, 37−45. (17) Bermejo, M.; Avdeef, A.; Ruiz, A.; Nalda, R.; Ruell, J. A.; Tsinman, O.; González, I.; Fernández, C.; Sánchez, G.; Garrigues, T. M.; Merino, V. PAMPAa drug absorption in vitro model 7. Comparing rat in situ, Caco-2, and PAMPA permeability of fluoroquinolones. Eur. J. Pharm. Sci. 2004, 21, 429−441. (18) Sun, J.; Sakai, S.; Tauchi, Y.; Deguchi, Y.; Chen, J.; Zhang, R.; Morimoto, K. . Determination of lipophilicity of two quinolone antibacterials, ciprofloxacin and grepafloxacin, in the protonation equilibrium. Eur. J. Pharm. Biopharm. 2002, 54, 51−58. (19) Cabrera Pérez, M. A.; González Díaz, H.; Fernández Teruel, C.; Plá-Delfina, J. M.; Bermejo Sanz, M. A novel approach to determining physicochemical and absorption properties of 6-fluoroquinolone derivatives: experimental assessment. Eur. J. Pharm. Biopharm. 2002, 53, 317−325. (20) Grabowski, T.; Jaroszewski, J. J.; Piotrowski, W. Correlations between no observed effect level and selected parameters of the chemical structure for veterinary drugs. Toxicol. In Vitro 2010, 24, 953−959. (21) Caço, A. I.; Tomé, L. C.; Dohrn, R.; Marrucho, I. M. Protonation Equilibria and Lipophilicity of Sarafloxacin. J. Chem. Eng. Data 2010, 55, 3160−3163.

to our results (CIP, MAR), but this is not a clear trend, as in SAR the results have serious discrepancies between both references. The results indicate that the studied fluoroquinolones are rather hydrophilic, as four of them (CIP, DAN, MAR, and SAR) have negative values for logKOW, and only two of them (DIF and ENR) have positive values. Moreover, the partition equilibria for the cationic species have been also determined in order to explain the extraction behavior in acidic medium. In all cases, the proposed distribution models are in good accordance with the experimental data, providing a good fit, as shown Figure 2 for CIP.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.5b00556. Experimental data (pH/logD) obtained in the octanol− water partition equilibria for the fluoroquinolones. (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: + 3493 403 9120. Fax: + 3493 402 1233. Present Address

́ ́ (G.-M. C.-Y.) Departamento de Quimica Analitica, Facultad de Ciencias Naturales, Exactas y Tecnologia.́ Ciudad Universitaria Octavio Méndez Pereira. Universidad de Panamá. Estafeta Universitaria ap. 3366. Panamá 4, Panamá. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS G.-M. C.-Y. thanks to the Secretaria Nacional de Ciencia y Tecnologiá de Panamá (SENACYT) for the Ph.D. scholarship for the development of this research

■

REFERENCES

(1) Emmerson, A. M.; Jones, A. M. The quinolones: decades of development and use. J. Antimicrob. Chemother. 2003, 51 (Suppl.1), 13−20. (2) Sárközy, G. Quinolones: a class of antimicrobial agents. Vet. Med.−Czech. 2001, 46, 257−274. (3) Paton, J. H.; Reeves, D. S. Fluoroquinolone antibiotics. Microbiology, pharmacokinetics and clinical use. Drugs 1988, 36, 193−228. (4) Mazák, K.; Kökösi, J.; Noszál, B. Lipophilicity of zwitterions and related species: a new insight. Eur. J. Pharm. Sci. 2011, 44, 68−73. (5) Takács-Novák, K.; Józan, M.; Szász, G. Lipophilicity of amphoteric molecules expressed by the true partition coefficient. Int. J. Pharm. 1995, 113, 47−55. 3331



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(22) Hughes, L. D.; Palmer, D. S.; Nigsch, F.; Mitchell, J. B. O. Why are some properties more difficult to predict than others? A study of QSPR models of Solubility, Melting Point, and Log P. J. Chem. Inf. Model. 2008, 48, 220−232. (23) Sun, J.; Sakai, S.; Tauchi, Y.; Deguchi, Y.; Chen, G.; Chen, J.; Morimoto, K. Protonation equilibrium and lipophilicity of olamufloxacin (HSR-903), a newly synthesized fluoroquinolone antibacterial. Eur. J. Pharm. Biopharm. 2003, 56, 223−229. (24) Perrin, D. D.; Dempsey, B. Buffers for pH and Metal Ion Control; Chapman and Hall: London, 1974. (25) Billo, E. J. Excel for Chemists: A Comprehensive Guide, 2nd ed.; John Wiley & Sons: New York, 2001.

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