Examination of the Solubilization of Drugs by Bile Salt Micelles

MINIREVIEW Examination of the Solubilization of Drugs by Bile Salt Micelles TIMOTHY SCOTT WIEDMANN, LAMYA KAMEL Department of Pharmaceutics, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455

Received 28 September 2001; revised 27 November 2001; accepted 18 February 2002

ABSTRACT: The purpose of this review is to provide a critical examination of the reported solubilization of drugs by bile salt micelles. The underlying premise is that with better information regarding the inherent biological complexity, efforts to predict the oral bioavailability of drug will be enhanced. The common means of comparing the reported values was chosen to be the solubilization ratio. This is equal to the moles of drug solubilized per mole of bile salt. The values were segregated according to bile salt type, temperature, ionic strength, and the presence and absence of added lipids. Only segregation by bile salt type was pairwise statistically significant. From the solubilization ratios and the reported values of the aqueous solubility, the logarithms of the mole fraction micelle partition coefficients, log Km/a, were calculated. The log Km/w was found to be correlated with the reported logarithm of the octanol/water partition coefficient. The rank order of slopes of the log Km/a as a function of log Ko/w was cholate & taurodeoxycholate > glycocholate & taurocholate & glycodeoxycholate, with deoxycholate not being statistically different from the other data sets. The slope and intercept for the bile salt mixed micelle systems were 0.600 and 2.44, respectively, which were statistically indistinguishable from glycocholate, taurocholate, and glycodeoxycholate bile salt data. The existence of statistically significant correlations suggests that predicting the solubilization in the intestine may be possible with in vitro measurements if additional information is gathered in the appropriate micellar solutions. ß 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1743–1764, 2002

Keywords: absorption

bile salts; micelle; solubilization; octanol water partition coefficient; drug

INTRODUCTION The ability to predict the extent of drug absorption from the gastrointestinal (GI) tract would be of great value for the drug development process. Presently, the specific steps required for a drug to reach the systemic circulation after ingestion are well known.1 Moreover, the factors influencing Correspondence to: Timothy Scott Wiedmann (Telephone: 612-624-5457; Fax: 612-626-2125; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 91, 1743–1764 (2002) ß 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association

each of these steps have been investigated. This includes gastric emptying, GI transit, dosage form disintegration, drug particle dissolution, membrane permeability, and enzymatic and chemical stability. However, despite these many efforts, the extent of absorption cannot be predicted primarily because of the inherent molecular and biological complexity. The focus of this review is the solubility of drugs in bile salt solutions. The underlying premise is that prediction of drug absorption requires more detailed information of each specific step. Therefore, a better characterization of the molecular

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

1743

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

10 2 2 11 4 7 GC (475-31-0) GDC (360-65-6) GCDC (640-79-9) 5 2 4 4 3 7 TC (81-24-3) TDC (516-50-7) TCDC (516-35-8) 13 3 4 11 5 9 Adapted from Cabral and Small.3

0.1 M Salt H2 O H2O

0.1 M Salt

Abbreviation

CMC (mM)

Abbreviation 0.1 M Salt

Tauro-Conjugated

CMC (mM) CMC (mM)

H2O Abbreviation

C DC CDC a

There are two main approaches for quantitatively describing the solubilization of drugs in micelles, cf.72 One approach uses a two-state model in which the micelles are considered a separate phase and the distribution of drug is treated in an analogous manner to the partitioning

Cholate (81-25-4) Deoxycholate (83-44-3) Chenodeoxycholate (474-25-9)

THEORY OF BILE SALT SOLUBILIZATION

Unconjugated Bile Salts (CAS # No.)

and biological complexity by direct measurement will facilitate predicting drug absorption. Although the solubility of drugs in aqueous solutions has received considerable attention, solubilization in the GI milieu is of greater relevance for drug absorption. Albeit, efforts have been made at developing predictive models for the solubilization with the full appreciation that perhaps the dissolution rate remains of greater importance.2 Cabral and Small3 have provided a detailed coverage of the physical chemistry of bile as it pertains to the physiology of the GI tract. Of particular importance is the discussion of the various types of bile salts (Table 1) in which the nature of their self-association is given as well as the specific values of the critical micelle concentration (CMC).3,4 The effects of temperature, pH, ionic strength, and concentration of bile salt on these parameters were also given. The first review of the solubilization of drugs by bile salt micelles was provided by Ekwall et al.5 in the early 1940s. Carey and Small6 also had an important contribution in the 1970s. More recently, Dressman and co-workers7 addressed the solubilization of drugs with the specific purpose of predicting drug solubilization in the GI tract. Finally, Zuman and Fini8 provided a rather extensive list along with a good discussion of the effects of the type of bile salt, ionic strength, and temperature on the extent of solubilization. Although these provided an excellent context for our effort, none has made use of all the data currently available for predicting the absorption of drugs from the GI tract. In this review, the available literature9–71 involving the measurements of the solubilization of drugs and other chemical entities in bile salt solutions has been reviewed. In addition, the data have been classified and a common quantitative basis has been used from which the extent of solubilization was compared. Finally, trends that may be useful for predicting the solubilization of drugs have been identified.

Glyco-Conjugated

WIEDMANN AND KAMEL

Table 1. Consensus Values of the CMC in Water and in 0.1 M Salt Solutionsa

1744

SOLUBILIZATION OF DRUGS BY BILE SALT MICELLES

between a bulk organic solvent and water. The approach provides simplicity, although Gibbs phase rule is ignored. Another approach, referred to as a mass action model, treats the micellar solution in the correct thermodynamic manner as a single phase. The solubilization is then considered as an equilibration among the micelles leading to a Poisson distribution. Although more rigorous, much of the bile salt solubilization data collected cannot be analyzed with this approach because of the inadequacy of the measurements.

Two-State Model For the two-state model, a common basis for comparing the solubilization of drugs is the solubilization ratio. The solubilization ratio is defined as follows: SR ¼ ND =NBS where ND is the moles of drug solubilized per mole of micellar bile salt, NBS. The mole fraction micelle solubilization, Xm, is calculated from the solubilization ratios as follows: Xm ¼ SR=ð1 þ SRÞ

1745

This has the inherent assumption that the solubilizate is present at the maximum allowable concentration, that is, at saturation. By writing explicit expressions for each micelle, Mi, and each solubilizate containing micelle, Rj, the total concentration of micelles, Mt, and solubilizate, Rt, may be found by summing overall i and j. Thus, Mt ¼ ½M expfK1 ½Rg Rt ¼ ½R þ K1 ½R½M expfK1 Rg where [R] is the concentration of solubilizate not associated with the micelle. [R] is assumed to be the aqueous solubility in the two-state model. The average number of solubilizate molecules per micelle is given by h Ri ¼ fRt  ½Rg=Mt ¼ K1 ½R For drugs that are poorly solubilized, only singly occupied micelles need to be considered. Thus, K1 ¼ ½MR=½M½R which can be rearranged to K1 ½R=n ¼ ½MR=ð½BSt  CMCÞ ¼ h Ri=n ¼ SR and thereby the two-state and mass action models can be related.

The micelle/aqueous partition coefficient on a mole fraction basis is defined as follows: Kx;m=a ¼ Xm =Xa where Xa is the aqueous solubility expressed as a mole fraction.

Ionized Solutes For ionizable solutes, there are simultaneous equilibria present that must be included.40 In the case of a weak acid, the dissociation of the micellar and aqueous solubilized species is given as:

Mass Action Model

þ HAm ! Hm þ A m

For the mass action model,42 monodispersed micelles, M, are formed by the aggregation of n bile salt molecules, S, as

þ HAw ! Hw þ A w

nS ! M The drug or solubilizate, R, is solubilized within the micelles as M þ R ! MR1 MR1 þ R ! MR2


MRm1 þ R ! MRm Each of the above steps has an associated equilibrium constant, Ki, where Ki ¼ K1 =i

where the subscript, m, refers to the micellar solution and subscript, w, refers to the aqueous solution. These expressions can be linked by the distribution of each component between a micellar solution and aqueous solution with the twostate model: HAw ! HAm  A w ! Am þ þ Hw ! Hm

Equilibrium constants may be defined for the ionization processes as well as for the distribution of each component between the micellar and JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

1746

WIEDMANN AND KAMEL

aqueous phases as follows: þ gfA Ka;m ¼ fHm m g=fHAm g þ Ka;w ¼ fHw gfA w g=fHAw g

KHA ¼ fHAm g=fHAw g  KA ¼ fA m g=fAw g KHþ ¼

þ þ fHm g=fHw g

where brackets have been used to represent activities to simplify the notation. Of these five expressions, only four are independent by the following relationship: 1 ¼ ðKa;m =Ka;w ÞðKHA =KA KHþ Þ It remains a challenge to predict or expect a simple correlation between the total amount of concentration of drug in solution, both ionized and nonionized, and some physical property such as the partition coefficient.

QUANTIFICATION OF BILE SALT SOLUBILIZATION The solubilization ratio can be used as the common value to express the micelle solubilization of drugs.39 In this review, if this value was not explicitly reported, it was calculated as the slope of a graph of the total concentration of drug in solution at saturation as a function of the total concentration of bile salt above the CMC in solution. It is noted that not all compounds yield a linear relationship. In these cases, the value corresponding to that obtained in the range of 10 to 50 mM bile salt was used because it most often provides a linear relation. In the case in which the micelle solubilization was determined as the total drug in solution, [D]t, at a specific total bile salt concentration, [BS]t, the SR was calculated as follows: SR ¼ ð½Dt  Cs Þ=ð½BSt  CMCÞ where Cs is the solubility of the drug in the absence of bile salts in molar concentration, and the CMC of the bile salt is under similar conditions of temperature, concentration of bile salt, and ionic strength. The literature values of the CMC provided by Cabral and Small3 were used. A two-state model for the micellar solubilization was assumed, and the micelle/aqueous partition coefficient was calculated from the mole fraction aqueous solubility and mole fraction JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

solubilization of drug in the micelle. The aqueous solubility was taken from the same article if provided, whereas other literature sources were used if necessary. The mole fraction aqueous solubility, Xa, was calculated as Xa ¼ Cs  1:8  105 where no correction for density was used. In cases in which mixtures of bile salts or mixtures of bile salts and other lipids were used, the solubilization ratio was calculated with the assumption that all of the lipid was in the micelle when the CMC was not available. If the measurements were made with different total lipid concentrations but with a constant lipid ratio, the CMC was assumed constant. That is, the slope of the plot of the total concentration of solute in solution as a function of the total lipid concentration was used as the solubilization ratio. The octanol/water partition coefficients were obtained from the same article if possible but most often values were obtained from detailed reviews.73 When the partition coefficient was not available, it was calculated from the most closely related compound using the group contribution method.74 Values of the partition coefficient obtained in different solvent systems are noted. Partition coefficients are reported on a concentration scale, that is, concentration of solute in octanol divided by the observed concentration in water, Kc,o/w. The mole fraction octanol/water partition coefficients were obtained using the relationship: log Kx;o=w ¼ log Kc;o=w þ 0:94 Finally, most partition coefficients were determined at 258C, whereas much of the solubilization data was obtained at 378C. For charged species, the ionization constant in the aqueous environment may be readily obtained. The ionization constant in the micellar environment, as defined above, cannot be directly obtained, because the activity of the proton in the micellar environment cannot be measured. Rather, the usual experimental approach is to measure the ionized and nonionized species associated with the micelle spectroscopically and the bulk pH potentiometrically. In no cases were the necessary measurements made of the solubilization ratio of both nonionized or ionized species. Thus, values are provided but are not included in the correlations.

SOLUBILIZATION OF DRUGS BY BILE SALT MICELLES

Data were plotted and linear regression was performed using Microsoft Excel. Each observed data point was compared with the calculated and if the difference was greater than 1 (i.e., a factor of 10 on the common logarithm scale), the data point was considered an outlier. The outlier was removed from the data set, and the process repeated until all of the data fell within one logarithm unit. The standard t test was used to compare the slopes and intercepts in a pair-wise manner for statistical differences at 95% confidence. In addition, the error sum of squares of the regressed data and total sum of squares are provided.

BILE SALT SOLUBILIZATION RESULTS An alphabetical listing of the solubilization ratios is given in Tables 2–9. Table 2 provides a listing of compounds determined in more than one bile salt. The listing of compounds determined in only one bile salt is given in Tables 3–8, and Table 9 provides the results from the mixed systems. In addition, the molecular weight, melting point, aqueous solubility, and octanol/water partition coefficient are provided as well as the pKa if applicable. The taurocholate (TC) system has been the most extensively studied. This is a result of the relative insensitivity of the aggregation number of the TC micelle to changes in pH, ionic strength, and temperature. Many older measurements were made with the cholate (C) system as well, probably because of the early availability of this bile salt. Fewer data are available for the taurodeoxycholate (TDC) and deoxycholate (DC) systems, and little is available for the remaining systems of glycine-conjugated bile salts and the chenodeoxycholates and ursodeoxycholates. This is perhaps unfortunate because about two-thirds of bile salts in the human bile are conjugated with glycine. A striking feature resulting from economic considerations is that there are essentially no data available for the most abundant bile salt in bile, glycochenodeoxycholate. The data were first classified by bile salt, and then further grouped by temperature, ionic strength, and presence of ionization on the solute. For the effect of temperature, the data were grouped into a 378C group that had temperatures, T, 32 < T < 408C and a 258C group, 20 < T < 318C. Almost all of the measurements were performed at 378 or 258C. The results were categorized by

1747

ionic strength into two groups of those determined in water and those determined in the presence of a buffer and/or sodium chloride solution that typically was near the physiological ionic strength. In no case were these categories found pairwise statistically different. The first and foremost driving force for micelle solubilization is the hydrophobicity of the solubilizate. Therefore, in searching for a means to predict the extent of solubilization, a measure of the drug’s hydrophobicity was needed. In this regard, the octanol/water partition coefficient was deemed the best choice because of its widespread use.75,76 Thus, the micelle/aqueous partition coefficients of drugs in TC, TDC, C, DC, glycocholate (GC), and glycodeoxycholate (GDC) systems were plotted as a function of the octanol/water partition coefficients. A summary of the equations for the trend lines is given in Table 10. TC Beginning with the most abundant data set, TC (Fig. 1), the correlation coefficient for the data was 0.97. The slope and intercept were 0.587 and 2.33, respectively, in which 64 compounds were included, and there were five outliers. A potential complication is that the octanol/water partition coefficients are typically determined near infinite dilution whereas the micelle/aqueous partition coefficients were determined at saturation. Thus, differences in the ideality of these solutions would also give rise to a non-zero intercept and a slope that differs from unity. Focusing on the correlation, the slope was significantly lower than unity, and the intercept was significantly greater than zero. Although still debated, partition coefficients determined in a different bulk solvent have been correlated with the octanol/water partition coefficients.56 In these cases, the slope may be related to the discriminating power of the solvent relative to octanol, and the intercept may be related inversely to the amount of water in the solvent. In this context, the TC micelles were considerably less discriminating than octanol with respect to the hydrophobicity of the solutes. Specifically, the discrimination power of the TC micelle was more comparable to pentanol than it was to octanol. The positive intercept may indicate that the TC micelle has considerably less water than octanol. It should be noted that the intercept has a contribution from the use of the concentration-based partition coefficients in octanol as compared with JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

83-46-5

641-77-0

b-Sitosterol

11b,17a-Dihydroxy-4-

2.356

2.79

11b-Hydroxyprogesterone 600-57-7

19-Nortestosterone

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

7.43

6.70

7.21

7.55

6.10

5.90

6.75

5.60

5.50

6.42

7.9

7.78

8.09

5.37

5.30

5

2,2,3,3,4,5,5,6 PCBb

2,2,3,3,6,6 PCBb

2,2,3,4,4,5,5 PCBb

2,2,4,4,6,6 PCBb

2,2,4,5 PCBb

2,3,4,5 PCBb

2,3,4,5,6 PCBb

2,4,5 PCBb

2,4,6 PCBb

20-Methylcholanthrene

22-Dehydrocholesterol

24-Dehydrocholesterol

24-Methylenecholesterol

3,5 PCBb

4,4 PCBb

5,10-Dimethyl-1,2-

2.13

1.94

71-43-2

71-43-2

378-44-9

Benzene

Benzene

b-methasone

9.31

474-62-4

80-97-7

57-88-5

57-88-5

Campesterol

Cholestanol

Cholesterol

Cholesterol

8.53

7.38

8.53

8.56

Brassicasterol

2.13

103-33-3

Azobenzene

3.82

7.00

2,2,3,3,4,4 PCBb

benzanthracene

5.60

2,2,3,3 PCBb

434-22-0

2.356

11a-Hydroxyprogesterone 80-75-1

1.937

9.63

50-28-2

a-Estradiol

pregene-3,20 dione

2.58

CAS

Substance

Log Ko/w

149

149

141

158

148

233

6

279

68

144

117

135

179-80

334.2

363.8

124

185.1

185.4

288.7

140

220-23

Mp

386.7

386.7

388.7

400.7

398.7

392.5

78.12

78.12

182.2

150.2

222.9

222.9

398.7

384.7

384.7

268.3

257.4

257.4

326.3

291.9

291.9

360.8

295.2

360.8

429.6

360.8

291.9

279.4

330.5

330.5

346.5

414.7

272.4

MW

3.2 E-5

3.2 E-5

3.95 E-5

1.81 E-6

7.43 E-5

0.16

22.9

22.9

0.1

1.50 E-5

3.21 E-4

2.9 E-4

5.10 E-5

2.28 E-4

1.04 E-4

1.10 E-5

1.14 E-3

6.42 E-4

1.2 E-5

5. E-5

2.8 E-5

3.74 E-6

2.34 E-6

7.85 E-6

7.2 E-7

5.2 E-6

8.52 E-5

0.959

0.09324

0.3519

0.236

1.38 E-6

0.37

Aq

1.55

0.5

0.0159

0.0011

0.0621

0.0786

C

1

0.0278

0.0033

0.1632

0.00857

DC

0.03

0.001

GC

0.0435

0.037

0.00862

0.00300

0.06

0.0179

0.0385

0.05

0.0026

0.00621

GDC

0.036

0.0015

GCDC

0.00901

1.47

0.00781

0.00260

0.00220

0.0113

0.024

0.0009

0.0004

0.00901

0.0133

0.01

0.0015

0.0023

0.0022

0.00080

0.0010

0.0009

2 E-03

0.00031

0.00138

2.7 E-05

0.00020

0.0012

0.00791

0.0418

0.00806

0.0038

TC

0.19

0.04

0.0026

TDC

1.96

0.04

0.0015

TCDC

0.06

UDC

Table 2. Solubilization Ratios for Solutes That Have Been Determined in More Than One Bile Salt Systema

0.0113

0.00116

0.00494

0.00289

0.306

0.00125

0.00135

0.0014

0.00032

0.00551

3.13 E-4

5.8 E-4

0.00302

0.00172

0.0113

0.0287

0.00865

Mix

pKa

37

37

37

37

37

37

25

30

37

40

25

25

37

37

37

40

25

25

25

25

25

25

25

25

25

25

25

30

37

37

37

37

40

T

0.1 M NaCl, pH 7

0.13 M Na, pH 6.7

0.1 M NaCl, pH 7

0.1 M NaCl, pH 7

0.1 M NaCl, pH 7

NaCl TC/EPC, 20 M

0 mM HEPES, 150 M

Water

D2O

0.15 M Naþ , pH 6.3

Water

PBS, 10 mM TC/0.5 mM OA

PBS, 10 mM TC/0.5 mM OA

0.1 M NaCl, pH 7

0.1 M NaCl, pH 7

0.1 M NaCl, pH 7

Water

PBS, 10 mM TC/0.5 mM OA

PBS, 10 mM TC/0.5 mM OA

PBS, 10 mM TC/0.5 mM OA

PBS, 10 mM TC/0.5 mM OA

PBS, 10 mM TC/0.5 mM OA

PBS, 10 mM TC/0.5 mM OA

PBS, 10 mM TC/0.5 mM OA

PBS, 10 mM TC/0.5 mM OA

PBS, 10 mM TC/0.5 mM OA

PBS, 10 mM TC/0.5 mM OA

PBS, 10 mM TC/0.5 mM OA

7.2–8.6 in DC

pH 7.0–7.8 in C and

NaCl TC/EPC, 20 mM

10 mM HEPES, 150 mM

NaCl TC/EPC, 20 mM

0 mM HEPES, 150 mM

NaCl TC/EPC, 20 mM

10 mM HEPES, 150 mM

0.1 M NaCl, pH 7

Water

Comments

10

19

10

10

10

11

18

17

16

15

13

13

10

10

10

14

13

13

13

13

13

13

13

13

13

13

13

12

11

11

11

10

9

Ref.

1748 WIEDMANN AND KAMEL

2.82

2.82

50-22-6

7261-97-4

7261-97-4

64-85-7

439-14-5

439-14-5

56-53-1

20830-75-5

474-77-1

54350-48-0

65646-68-6

127-31-1

462-06-6

17605-67-3

25812-30-0

77-21-4

77-21-4

77-21-4

77-21-4

77-21-4

77-21-4

77-21-4

36167-63-2

84-16-2

84-16-2

84-16-2

84-16-2

50-23-7

53-86-1

Corticosterone

Dantrolene

Dantrolene

Deoxycorticosterone

Diazepam

Diazepam

Diethylstilbestrol

Digoxin

Epicholesterol

Etretinate

Fenretinide

Fludrocortisone

Fluorobenzene

Fucosterol

Gemfibrozil

Glutethimide

Glutethimide

Glutethimide

Griseofulvin

Griseofulvin

Griseofulvin

Griseofulvin

Halofantrine-HCl

Hexestrol

Hexestrol

Hexestrol

Hexestrol

Hydrocortisone

Indomethacine

1.38

1.552

5.37

5.37

5.37

5.37

8.5

2.11

2.18

2.18

2.18

2.11

2.11

2.11

2.80

8.67

2.73

1.682

9.81

8.48

8.15

0.238

5.07

2.902

1.70

1.7

1.937

1.937

152-58-9

Cortexolone

4.39

2030-63-9

Clofazimine

155

221.2

220

220

220

220

203-4

220

220

220

220

84

84

84

61-3

357.8

362.5

352.8

352.8

352.8

352.8

536.9

353

352.8

352.8

352.8

217.3

217.3

217.3

250.4

412.7

96.1

41 124

380.5

391.3

354.5

386.7

780.9

268.3

284.7

284.7

330.5

314.3

314.3

346.5

346.5

473.4

253.8

175

106

142

230

169-72

133

133

414.4

279-80

279-80

184.2

214.7

210-2

0.0788

0.187

0.195

0.197

0.0054

0.0062

0.0068

0.0962

0.0598

0.104

0.9

0.0439

0.033

0.0090

2.62 E-3 0.247

0.8547

0.037

0.037

0.037

0.037

2.42 E-3

0.038

0.038

0.038

0.038

5.52

5.52

5.52

67.89

2.18 E-5

16.2

0.241

1.28 E-5

3.40 E-6

3.88 E-5

0.0232

0.0391

0.229

0.229

0.458

0.023

0.023

0.694

0.127

0.0010

0.271

0.0277

0.164

0.167

0.179

0.0047

0.0062

0.0075

0.119

0.13

0.163

0.81

0.0439

0.0393

0.213

0.221

0.231

0.251

0.0039

0.0051

0.0063

0.092

0.0543

0.0718

0.13

8 E-04

0.2

0.0309

0.0332

0.0227

0.0145

0.234

0.043

0.22

0.225

0.223

0.0932

0.003

0.0038

0.0049

0.0062

0.1

0.0612

0.108

0.00943

0.0286

0.00848

0.00036

0.0060

6.6 E-4

0.2

0.0358

0.0505

0.0035

0.01501

0.0072

0.00891

0.0412

0.258

0.00187

0.105

0.00882

0.00795

0.00815

0.04382

0.0657

0.00206

0.0451

0.0141

4.5

4.5

4.5

3.4

7.5

8.51

37

37

40

27

37

45

37

37

27

37

45

37

27

45

37

37

25

37

37

37

37

37

37

30

25

37

37

37

37

37

37

coefficient

31

11

9

29

29

29

30

22

29

29

29

29

29

29

28

10

27

11

26

26

10

5

25

24

23

11

22

21

11

11

20

(Continued)

Cyclohexane partition

NaCl TC/EPC, 20 mM

10 mM HEPES, 150 mM

Water

Water

Water

Water

TC/EPC, 1–30 mM

20 mM NaAc pH 5.5,

PBS, 6.5, 10/5 mM TC/OA

Water

Water

Water

Water

Water

Water

10/2.5 mM

20 mM acetate, 5.9 GC/MO

0.1 M NaCl, pH 7

0.1 M phos/D2O

NaCl TC/EPC, 20 mM

10 mM HEPES, 150 mM

0.15 M NaCl 10/2 TC/PC

0.15 M NaCl 10/10 TC/PC

0.1 M NaCl, pH 7

Decomposition pH 6.4

0.15 M phosphate

H2O pH 7.5–8.3

0.50–169 mM

0.067 M phos, 7.4 GC/EPC

NaCl TC/EPC, 20 mM

10 mM HEPES, 150 mM

PBS, 6.5, 10/5 mM TC/OA

pH 6.5 PBS

NaCl TC/EPC, 20 mM

10 mM HEPES, 150 mM

NaCl TC/EPC, 20 mM

10 mM HEPES, 150 mM

NaCl, pH 7.2

pKa 8.51, 150 mM

SOLUBILIZATION OF DRUGS BY BILE SALT MICELLES

1749

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

58-18-4

3443-84-3

3443-84-3

846-49-1

91-20-3

33631-41-3

112-80-1

103-90-2

445-27-2

459-60-9

352-32-9

83833-14-1

Methyltestosterone

Monoolein

Monoolein

Motretinid

Naphthalene

N-ethyl retinamide

Oleic acid

Paracetamol

p-Fluoro-acetophenone

p-Fluoro-anisole

p-Fluoro-toluene

Phenylazo-b-naphthyla-

4264-83-9

50-24-8

57-83-0

57-83-0

83-48-7

58-22-0

57-85-2

12001-79-5

p-nitrophenyl-phosphate

Prednisolone

Progesterone

Progesterone

Stigmasterol

Testosterone

Testosterone propionate

Vitamin K

3.8

3.292

8.97

3.87

3.870

1.617

1.93

3.83

2.83

2.24

1.71

0.2

9.38

8.50

3.37

7.75

8.19

8.19

110.1

57

62-3

118-22

155

170

121

121

232.9

8

450.7

344.5

288.4

412.7

314.5

314.5

360.4

308.4

126.1

45

105

138.1

151

282.4

327.2

308.4

353.5

302.4

321.2

498.3

386.7

531

531.4

MW

45

4

Dec

80.2

161-6

166-8

122

146

146

Mp

0.006

0.06

2.96 E-6

0.0352

0.0352

0.469

2.27

6.20

8.88

114

4.10 E-5

2.35 E-5

0.255

6.5 E-6

0.102

0.1494

2.01 E-4

2.36 E-5

1.3

0.013

Aq

0.021

0.0066

0.023

0.023

0.0042

0.45

0.5

0.8

0.1

0.0162

0.022

C

0.029

0.0342

0.0253

0.0389

0.085

0.011

0.76

0.72

0.96

0.12

0.0305

DC

0.018

0.006

1.4

0.0236

0.058

GC

0.041

0.0189

1.7

0.0476

GDC

1.7

GCDC

0.004

0.00798

0.105

0.17

0.085

0.011

0.004

1.5

0.00360

0.00204

1.4

1.63

0.046

0.12

0.0071

0.007

TC

0.183

1.04

1.7

1.17

TDC

1.5

1.6

1.63

TCDC

UDC

0.75

0.0431

0.0251

0.0543

0

0.18

0.0016

0.0262

0.00453

Mix

4.5

4.5

9.5

11.5

1.3,

4.5

6.5

2.94

6.51,

pKa

25

30

40

37

37

37

37

22

37

25

25

25

25

37

37

37

23

37

37

37

30

25

37

37

37

37

T

GC/EPC 20/20 mM

Phos pH 7.5, 0.2 ionic,

7.2–8.6 in DC

pH 7.0–7.8 in C and

Water

0.1 M NaCl, pH 7

Water DC/PC 0–16 mM

NaCl TC/EPC, 20 mM

10 mM HEPES, 150 mM

NaCl TC/EPC, 20 mM

10 mM HEPES, 150 mM

pH 7 Tris, 0.1 M NaCl

1/15 M phos pH 7.3

Water, pH 8–9

0.1 M phos/D2O

0.1 M phos/D2O

0.1 M phos/D2O

PBS, 6.5, 10/5 mM TC/OA

0.13 M Na, pH 6.7

0.15 M NaCl 10/2 TC/PC

Water

0.15 M NaCl 10/10 TC/PC

37

12

9

10

36

11

11

35

31

34

27

27

27

22

19

26

17

26

19 16

0.15 M Naþ, pH 6.3

12

33

32

10

0.13 M Na, pH 6.7

7.2–8.6 in DC

pH 7.0–7.8 in C and

0.067 M phos pH 7.4

40:0–40:40

pH 9, TC/MO,

10 mM phos pH 7.8, bicarb

0.1 M NaCl, pH 7

22

21

Log Kow in pH 11.8

PBS, 6.5, 10/5 mM TC/OA

Ref.

Comments

Data presented are logarithm of the octanol/water partition coefficient, log Ko/w; melting point in 8C, Mp; molecular weight, MW; aqueous solubility in millimolar concentration units, Aq; temperature at which the solubility was determined; and solution compositions under Comments. b Polychlorinated biphenyl derivatives.

a

50-33-9

Phenylbutazone

mine

1.86

846-49-1

Lorazepam

3.8

6.65

Leukotriene

1.5

8.66

65277-42-1

Ketoconazole

3.73

Log Ko/w

Lathosterol

65277-42-1

CAS

Ketoconazole

Substance

Table 2. (Continued)

1750 WIEDMANN AND KAMEL

17230-88-5 56-47-3 439-14-5

Danazol Dexamethasone Diazepam

57-41-0

Phenytoin

5.55 1.025

1.92

2.18 1.552 4.03

2.18

235.2

296

220 217-20 148

220

225 270 133

233 170-0.3 150

180

Mp

265.7 394.5

352.3

352.8 362.5 285.4

352.8

337.5 392.5 284.75

392.5 252.3 1203

268.4 256.4

MW

0.57

0.0769

0.0306 0.88 0.157

0.038

0.00155 0.258 0.229

0.16 6.50E-6 0.0055

1.10E-5 1.50E-5

Aq (mM)

0.009 0.0060

0.002

0.00429 0.0311 2.69

0.0071

0.0027 0.0090 0.018

0.0055 0.01 0.0016

0.01 0.0096

TC

8.06

8.95

3.3

pKa

37 37

37

37 37 37

37

37 37 37

37 37 37

37 37

T

0.1 M NaCl 0.1 M phos McIlavaine buffer, pH 5.5, 0.1 M ionic strength 0.1 M NaCl 0.1 M NaCl McIlavaine buffer, pH 5.5, 0.1 M ionic strength McIlavaine buffer, pH 5.5, 0.1 M ionic strength pH 8–9, NSS 0.1 M NaCl McIlavaine buffer, pH 5.5, 0.1 M ionic strength McIlavaine buffer, pH 5.5, 0.1 M ionic strength 0.1 M phos 0.1 M NaCl

0.1 M phos 0.1 M phos

Comments

38 39

8

40 39 8

8

39 39 8

39 38 8

38 38

Ref.

a Data presented are logarithm of the octanol/water partition coefficient, Log Ko/w; melting point in 8C, Mp; molecular weight, MW; aqueous solubility in millimolar concentration units, Aq; temperature at which the solubility was determined; and solution compositions under Comments. b Not sufficiently defined in original text. c Polychlorinated biphenyl with 42% chlorine by weight. d Mixture of compounds.

124-94-7

d

126-07-8 50-23-7 359-83-1

Griseofulvin Hydrocortisone Pentazocine

PCB-Clc Triamcinolone

126-07-8

Griseofulvin

4.53 1.83 2.82

1.94 5.38 3.00

378-44-9 50-32-8 59865-13-3

b

6.42 5

Log Ko/w

56-49-5

CAS

3-Methylcholanthrene 7,12-Dimethylbenzanthracene b-methasone Benzo(a)pyrene Cyclosporine A

Substance

Table 3. Solubilization Ratios for Taurocholate (TC)a

SOLUBILIZATION OF DRUGS BY BILE SALT MICELLES

1751

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

a Data presented are logarithm of the octanol/water partition coefficient, log Ko/w; melting point in 8C, Mp; molecular weight, MW; aqueous solubility in millimolar concentration units, Aq; temperature at which the solubility was determined; and solution compositions under Comments.

93.13 93.13 122.12 122.12 149.2 149.2 178.2 178.2 121.2 121.2 150.18 150.18 178.6 178.6 194.1 194.1 6.3 6.3 122.4 122.4 14.4 14.4 164.5 164.5 4.87 4.87 113.5 113.5

Aniline Aniline Benzoic acid Benzoic acid 4-Butylaniline 4-Butylaniline 4-Butylbenzoic acid 4-Butylbenzoic acid 4-Ethylaniline 4-Ethylaniline 4-Ethylbenzoic acid 4-Ethylbenzoic acid 4-Hexylaniline 4-Hexylaniline 4-Hexylbenzoic acid 4-Hexylbenzoic acid

62-53-3 62-53-3 65-85-0 65-85-0 104-13-2 104-13-2 20651-71-2 20651-71-2 589-16-2 589-16-2 619-64-7 619-64-7 33228-45-4 33228-45-4 21643-38-9 21643-38-9

0.94 0.94 1.87 1.87 3.58 3.58 3.87 3.87 1.94 1.94 2.87 2.87 3.94 3.94 4.87 4.87

97-9 97-9

MW

75.6 195.2 23.97 12.3 2.66 2.46 0.6 0.827 29.4 65 2.57 3.01 0.294 0.266 0.224 0.224

3.0 3 0.31 0.29 1.0 0.98 0.22 0.2 2.3 0.86 0.2 0.17 1.3 0.9 0.17 0.16

22 22 22 22 22 22 22 22 22 22 22 22 22 22 22 22

150 mM NaCl Water 150 mM NaCl Water 150 mM NaCl Water 150 mM NaCl Water 150 mM NaCl Water 150 mM NaCl Water 150 mM NaCl Water 150 mM NaCl Water

40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40

WIEDMANN AND KAMEL

Mp Log Ko/w CAS Substance

Table 4.

Solubilization Ratios for Taurodeoxycholate (TDC)a

Aq (mM)

TDC

T

Comments

Ref.

1752

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

mole fraction-based partition coefficients in the micelles. Nevertheless, reducing the intercept by 0.94 to adjust for this difference would still leave a positive intercept. It has been established that there are about 20 water molecules of hydration for each TC molecule in the micelle.77 This is more than the solubility of water in octanol. However, there still may be less water associated with the solubilizate in the micelle in comparison with octanol. The more likely explanation lies in the difference in the solubilization in a micelle relative to a bulk solvent. Specifically, a correction for the restrictive environment arising from the small size of the micelle should be applied relative to a bulk solvent. This has been treated as a Laplace effect78 as well as an entropic effect.42 This correction would lead to a negative intercept. In this regard, no direct means of correcting for the effect of molecular weight on the observed solubilization was found, although further detailed work is certainly warranted. Another factor, and perhaps the most likely, is that a positive intercept will arise from the interfacial activity of the solutes. That is, many of the solutes would be expected to reside at the bile salt/ water interface. Given the low aggregation number of the TC micelle and the relatively large size of the solubilizates, this factor almost certainly contributes to the large positive intercept that is observed. In an examination of the outliers, the four compounds that had significantly positive deviations were benzo(a)pyrene, cholesterol, 7,12dimethylbenzanthracene, and 3-methylcholanthrene. The main purpose of bile is to assist in the solubilization of cholesterol, so it is perhaps not unexpected to find a positive deviation for cholesterol that may arise from specific interactions. The other three compounds are large, planar, polyaromatic solutes. Such solutes are capable of self-associating but also would fit well between two TC molecules. Brassicasterol, a cholesterol derivative, exhibited negative deviations. There is no obvious rationale why such a minor structural change would cause such a dramatic change in the solubilization. Finally, with respect to TC, the solubilization ratio was also plotted as a function of the logarithm of the octanol/water partition coefficient.39 However, no statistically significant correlation coefficient was found. In summary, there was a strong positive correlation for drugs between the TC micelle/aqueous partition coefficient and the octanol/water partition coefficient.

98-86-2 100-66-3 120-12-7 71-43-2 71-43-2 64-85-7 64-85-7 50-28-2 100-41-4 392-56-3 84-16-2 108-67-8 42200-33-9 91-20-3 91-20-3 91-20-3 104-51-8 1077-16-3 98-95-3 538-68-1 103-65-1 129-00-0 100-42-5 58-22-0 119-64-2 108-88-3 108-88-3 873-66-5 91-16-7

43178-07-0 53-70-3 56-49-5 56-49-5 50-32-8

CAS

3.37 3.37 3.37 4.13 5.13 1.8 4.63 3.63 4.8 2.83 3.29 4.13 2.7 2.7 3.35 2.09

5 7.11 6.42 6.42 6.38 7.58 1.58 2.11 4.45 2.13 2.13 2.902 2.902 2.58 3.13 2.22 5.37 3.63

Log Ko/w

20.5 37.5 215 5.5 6 414.4 414.4 220-23 95 5.3 220 45 124-36 80.2 80.2 80.2 88.5 61 2.79 78.25 99.2 149-51 30 155 36 95 95 27 22

205-7 179-180 179-180

Mp

256.4 120.2 108.1 178.13 78.12 78.12 330.5 330.5 272.37 106.13 186.06 352.8 120.2 309.42 308.4 308.4 308.4 134.13 152.13 123.1 148.13 120.13 204.13 104.2 288.4 132.2 92.13 92.13 118.2 138.2

278.36 268.3 286.3

MW

0.037 0.0166 32 0.255 0.255 0.255 0.082 0.0059 16.2 0.022 0.43 1.30E-8 2.97 0.06 0.35 3.71 3.71 0.44 70

1.30E-8 5.70E-6 1.10E-5 1.10E-5 6.50E-6 1.50E-5 51 14 0.00024 23 23 0.46 0.46 0.37 1.59

Aq (mM) 0.0081 0.0036 0.00260 0.0019 0.00714 0.0038 1.0 0.4 0.00138 1.55 0.0041 0.0058 0.0016 0.0013 0.0319 0.45 0.0375 0.25 0.25 0.0625 0.044 0.068 0.156 0.075 0.5 0.106 0.362 0.011 0.45 0.026 0.35 0.55 0.156 0.6 1.3

C

25 25 25 25 25 25 25 40 25 25 25 25 25

40 40 40 40 40 40 25 25 25 25 25 40 40 40 25 25 40 25 37 25 25

T Water Water Water Water Water Water 0.1 M phos/D2O 0.1 M phos/D2O Water 0.1 M phos/D2O Water Water Water Water Water 0.1 M phos/D2O Water 0.1 M phos/D2O pH 11 Water pH 8–9 pH 8–9 Water Water 0.1 M phos/D2O Water Water Water 0.1 M phos/D2O Water 0.1 M phos/D2O 0.1 M phos/D2O Water 0.1 M phos/D2O 0.1 M phos/D2O

Comments 15 41 15 41 15 41 27 27 42 27 42 9 9 9 42 27 9 27 43 42 44 45 42 42 27 42 42 42 27 9 27 27 42 27 27

Ref.

a Data presented are logarithm of the octanol/water partition coefficient, log Ko/w; melting point in 8C, Mp; molecular weight, MW; aqueous solubility in millimolar concentration units, Aq; temperature at which the solubility was determined; and solution compositions under Comments.

1,2 Benzanthracene 1,2:5,6 Dibenzanthracene 20-Methylcholanthrene 20-Methylcholanthrene Benzo[a]pyrene 9,10-Dimethylbenzanthracene Acetophenone Anisole Anthracene Benzene Benzene Deoxycorticosterone Deoxycorticosterone Estradiol Ethylbenzene Hexafluorobenzene Hexestrol Mesitylene Nadolol Naphthalene Naphthalene Naphthalene n-Butylbenzene n-Hexylbenzene Nitrobenzene n-Pentylbenzene n-Propylbenzene Pyrene Styrene Testosterone Tetralin Toluene Toluene trans-Propenylbenzene Veratrole

Substance

Table 5. Solubilization Ratios for Cholate (C)a

SOLUBILIZATION OF DRUGS BY BILE SALT MICELLES

1753

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

1249-75-8 1912-56-7 5405-42-5 28050-38-6 73465-45-9 100596-78-9 91-75-8 298-46-4 152-58-9 50-04-4 64-85-7 56-47-3 50-23-7 137-58-6 57-42-1 91-80-5 57-27-2 53-16-7 59-46-1 50-55-5 58-22-0 91-81-6

68-96-2 2603-77-2 1448-36-8 3057-04-3

CAS

3.292

0.73 3.45

1.937 2.68 2.902 3.08 1.552

2.9 4.41 4.13 4.41 5.29 6.45 5.29 6.45 5.29 5.29

Log Ko/w

197 251-54 61 264dec 155

120-2 190-3 214.7 235 414.4 154-60 221.2 68-9 186-9

Mp

285.33 270.36 236.3 608.7 288.4 255.35

311.42 265.3 236.26 346.5 402.2 330.5 372.51 362.5 234.33 247.35

330.5

MW

0.06

0.01

0.4584 0.02846 0.8547

0.00186 0.1271

0.04

Aq (mM) 0.0066 0.075 0.6 0.075 0.038 0.019 0.022 0.03 0.038 0.038 0.013 0.08 0.18 0.0429 0.01 0.176 0.0014 0.079 0.36 0.66 0.35 0.02 0.0076 1.18 0.0003 0.01 0.4

DC

6.6

9.85

pKa

37 37 30 37 40 37 30 30 30 30 37 30 30 30 30

37 23 23 23 23 23 23 23 23 23 30

T

Water NS Water Water Water NS NS NS NS Water NS NS NS NS

Water Water Water Water Water Water Water Water Water Water NS NS

Comments

36 46 46 46 46 46 46 46 46 46 44 44 47 36 36 36 9 36 44 44 44 44 36 44 44 44 44

Ref.

a Data presented are logarithm of the octanol/water partition coefficient, log Ko/w; melting point in 8C, Mp; molecular weight, MW; aqueous solubility in millimolar concentration units, Aq; temperature at which the solubility was determined; and solution compositions under Comments.

17a-Hydroxy progesterone 3a,12a-Dihydroxy-5b-cholan-24-ol Methyl 3a,7a,12a-trihydroxy-5b-cholan-24-oate Methyl 3a,7a-dihydroxy-5b-cholan-24-oate Methyl 3a,12a-dihydroxy-5b-cholan-24-oate Methyl 3a-hydroxy-5b-cholan-24-oate Methyl 3b,12a-dihydroxy-5b-cholan-24-oate Methyl 3b-hydroxy-5b-cholan-24-oate Methyl 3b,7a-dihydroxy-5b-cholan-24-oate Methyl 3b,7b-dihydroxy-5b-cholan-24-oate Adiphene Antazoline Carbamazepine Cortexolone Cortisone acetate Deoxycorticosterone Deoxycorticosterone-acetate Hydrocortisone Lidocaine Meperidine Metapyrilene Morphine Oestrone Procaine Reserpine Testosterone Tripelenamine

Substance

Table 6. Solubilization Ratios for Deoxycholate (DC)a

1754 WIEDMANN AND KAMEL

SOLUBILIZATION OF DRUGS BY BILE SALT MICELLES

1755

Table 7. Solubilization Ratios for Glycocholate (GC)a

Substance

CAS

Decane 124-18-5 Decanol 112-30-1 Phosphatidylcholine 2644-64-6 Testosterone 58-22-0 Testosterone 58-22-0

Log Ko/w

Mp

MW

Aq (mM)

4.01

7

158.3

0.251

3.292 3.292

155 155

288.4 288.4

0.06 0.06

GC

T

Comments

Ref.

0.0001 3 2 0.022 0.019

37 37 37 25 25

0.15 M NaCl 0.15 M NaCl 0.15 M NaCl Water 0.1 M NaCl

48 48 48 49 49

a

Data presented are logarithm of the octanol/water partition coefficient, log Ko/w; melting point in 8C, Mp; molecular weight, MW; aqueous solubility in millimolar concentration units, Aq; temperature at which the solubility was determined; and solution compositions under Comments.

TDC

aggregation is sensitive to pH. Many measurements were made at a pH in excess of 9 to avoid this complication. The C data set had a slope of 0.86 and an intercept of 1.3 as shown in Figure 2. The data set included 47 compounds with 11 outliers. The solutes exhibiting positive deviations were hexestrol, estradiol, deoxycorticosterone, 5,10-dimethyl-1,2 benzanthracene, and 9,10dimethyl-1,2-benzanthracene, whereas those with negative deviations included ethylbenzene, benzene, pyrene, and mesitylene. For the correlation, the data had a slope even higher and an intercept even lower than TC, although the C set was not statistically different from the TDC set. This indicates that the trihydroxy, nonconjugated bile salt yields solubilization data comparable to the dihydroxy, conjugated bile salt. Thus, equivalent arguments may be made concerning the discriminatory power and hydration.

For TDC, a dihydroxy, conjugated bile salt, the only possible means of classifying the data would have been by ionic strength, but there was no significant difference. Thus, with pooled data, the slope and intercept were 0.773 and 1.43, respectively. This was based on 19 compounds with only cholesterol as the single outlier exhibiting a positive deviation. The slope for TDC was significantly higher than that obtained with TC, and the intercept was significantly lower. This suggests that the dihydroxy bile salt is more discriminating than the trihydroxy TC with respect to hydrophobicity. What is perhaps noteworthy of this group is that all but three of the compounds reported were para-alkyl benzoic acid or aniline derivatives. Despite the structural similarity of this series, the correlation was the same as that of TC at 0.97. Moreover, with this series, significant surface activity would be expected, yet the intercept was not particularly large.

DC, GC, GDC, and Ursodeoxycholate (UDC) For DC, the data had an intermediary slope at 0.68 and an intercept at 2.01. The correlation coefficient was relatively low, 0.87, which included 30 solutes. The two outliers were 5,10dimethyl-1,2 benzanthracene and hexestrol.

C Sodium C is a trihydroxy bile salt but is not conjugated. The effective pKa of the NaC in the aggregate is near 7,3 and so the extent of

Table 8. Solubilization Ratios for Ursodeoxycholate (UDC)a Substance Anthracene Ethylbenzene Naphthalene n-Butylbenzene Pyrene

CAS

Log Ko/w

Mp

MW

Aq (mM)

UDC

TC

Comments

Ref.

120-12-7 100-41-4 91-20-3 104-51-8 129-00-0

4.45 3.13 3.37 4.13 4.8

215 95 80.2 88.5 149-51

178.13 106.13 308.4 134.13 204.13

0.00024 1.59 0.255 0.082 1.30E-8

0.03 0.21 0.15 0.21 0.01

25 25 25 25 25

Water Water Water Water Water

18 18 18 18 18

a Data presented are logarithm of the octanol/water partition coefficient, log Ko/w; melting point in 8C, Mp; molecular weight, MW; aqueous solubility in millimolar concentration units, Aq; temperature at which the solubility was determined; and solution compositions under Comments.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

25812-30-0

25812-30-0

25812-30-0

25812-30-0

50-23-7

846-49-1

846-49-1

846-49-1

846-49-1

846-49-1

846-49-1

846-49-1

846-49-1

846-49-1

33631-41-3

57-41-0

21616-46-6

Gemfibrozil

Gemfibrozil

Gemfibrozil

Gemfibrozil

Hydrocortisone

Lorazepam

Lorazepam

Lorazepam

Lorazepam

Lorazepam

Lorazepam

Lorazepam

Lorazepam

Motretinid

N-ethyl retinamide

Phenytoin

3-(Hydroxy-methyl)

phenytoin

3-Propyloxy-methyl-

phenytoin

3-Acetoxymethyl-

b

27506-79-2

25812-30-0

Gemfibrozil

phenytoin

25812-30-0

Gemfibrozil

54350-48-0

Etretinate

25812-30-0

50-28-2

Estradiol

Gemfibrozil

20830-75-5

Digoxin

65646-68-6

20830-75-5

Digoxin

25812-30-0

56-53-1

Diethylstilbestrol

Gemfibrozil

56-53-1

Diethylstilbestrol

Fenretinide

439-14-5

3.34

2.80

2.23

2.21

8.50

7.75

1.86

1.86

1.86

1.86

1.86

1.86

1.86

1.86

1.55

2.80

2.80

2.80

2.80

2.80

2.80

2.80

2.80

9.81

8.48

2.58

0.238

0.238

5.07

5.07

2.82

2.82

131

171

158

297

Dec

169-185

166-8

166-8

166-8

166-8

166-8

166-8

166-8

166-8

217-20

61-3

61-3

61-3

61-3

61-3

61-3

61-3

61-3

175

106

220-3

230dec

230dec

169-72

169-72

133

133

352.4

338.4

324.3

252.3

327.22

353.51

321.2

321.2

321.2

321.2

321.2

321.2

321.2

321.2

362.5

250.4

250.4

250.4

250.4

250.4

250.4

250.4

250.4

391.26

354.49

272.37

780.9

780.9

268.3

268.3

284.75

284.75

0.0085

0.0124

0.034

0.05

2.4E-5

6.5E-5

0.149

0.149

0.149

0.149

0.149

0.149

0.149

0.149

0.85

67.9

67.9

67.9

67.9

67.9

67.9

67.9

67.9

1.3E-5

3.4E-5

0.37

0.0232

0.0232

0.039

0.039

0.229

0.229

0.258

439-14-5

392.5

Diazepam

270

0.0027

0.0026

0.0054

0.0108

0.0386

0.0014

0.0276

0.0294

0.0374

0.0394

0.0537

0.0544

0.058

0.058

0.969

0.126

0.134

0.134

0.143

0.143

0.148

0.148

0.26

0.0435

0.0027

0.0057

5.4E-4

6.7E-4

0.18

0.19

0.0458

0.046

0.0099

0.0079

Diazepam

1.83

0.3

50-02-2

315.72

Dexamethasone

238

1622-61-3

Clonazepam

2.04

4.3E-4

7235-40-7

b-Carotene

Mix

5.3E-4

Aq (mM) 5.8E-4

MW

7235-40-7

Mp

7235-40-7

Log Ko/w

b-Carotene

CAS

b-Carotene

Substance

Table 9. Solubilization Ratios in Mixed Bile Salt/Lipid Systemsa

1.3, 11.5

1.3, 11.5

1.3, 11.5

1.3, 11.5

1.3, 11.5

1.3, 11.5

1.3, 11.5

1.3, 11.5

4.5

4.5

4.5

4.5

4.5

4.5

4.5

4.5

3.4

3.4

1.5, 10.5

pKa

25

25

25

25

37

37

25

25

25

25

25

25

25

25

37

37

37

37

37

37

37

37

37

37

37

25

37

37

37

37

25

25

37

25

37

37

37

TC

Phos pH 6.4, mix/EPC, 0.051 M

Phos pH 6.4, mix/EPC, 0.051 M

Phos pH 6.4, mix/EPC, 0.051 M

Phos pH 6.4, mix/EPC, 0.051 M

0.15 M NaCl, 10/10 TC/PC

0.15 M NaCl, 10/2 TC/PC

Phos pH 7.4, DC/SPC 0.5, 5% w/w

Phos pH 7.4, DC/SPC 0.5, 10% w/w

Phos pH 7.4, GC/SPC 0.3, 5% w/w

Phos pH 7.4, C/SPC 0.3, 5% w/w

Phos pH 7.4, 0–169 mM GC/SPC 0.55% w/w

0.067 M phos, pH 7.9, GC/SPC 0.5, 0–169 mM

Phos pH 7.4, 0–169 mM, C/SPC 0.5, 5% w/w

Phos pH 7.4, C/SPC 0.5, 10% w/w

1–15 mM TC/EPC

20 mM acetate, pH 5.9, GC/PC: 10/2.0

20 mM acetate, pH 5.9, GC/MO: 10/4.55

20 mM acetate, pH 5.9, GC/MO: 10/4.55

20 mM acetate, pH 5.9, GC/PC/MO: 10/2/2.55

20 mM acetate, pH 5.9, GC/PC/MO: 10/2/2.55

20 mM acetate, pH 5.9, GC/PC/MO: 10/2/2.55

20 mM acetate, pH 5.9, GC/PC/MO: 10/2/2.55

20 mM acetate, pH 5.9, GC/PC, 10/4.55

0.15 M NaCl, 10/10 TC/PC

0.15 M NaCl, 10/2 TC/PC

0.067 M phos, pH 7.10, GC/SPC 0.5, 0–169 mM

0.15 M phos, TC/PC 40/2.6

0.15 M phos, GC/PC 40/2.6

0.15 M phos, GC/PC 40/2.6

0.15 M phos, TC/PC 40/2.6

0.067 M phos, pH 7.6, DC/EPC 0.5, 0–169 mM

0.067 M phos, pH 7.5, C/EPC 0.5, 0–169 mM

10 mM HEPES, NSS, TC/EPC, 20 mM

0.067 M phos, pH 7.7, GC/SPC 0.5, 0–169 mM

tri/diOH BS ratio 2.6, 1.13 TO/2.5 MO/7.5 OA/0.68 PC

tri/diOH BS ratio 1.32, 1.13 TO/2.5 MO/7.5 OA/0.68 PC

tri/diOH BS ratio 0.66, 1.13 TO/2.5 MO/7.5 OA/0.68 PC

Commentsc

50

50

50

50

26

26

33

33

33

33

33

23

33

33

54

53

53

53

53

53

53

53

53

26

26

23

58

58

48

48

23

23

11

23

57

57

57

Ref.

1756 WIEDMANN AND KAMEL

68-26-8

68-26-8

33069-62-4

33069-62-4

33069-62-4

33069-62-4

29767-20-2

29767-20-2

29767-20-2

29767-20-2

29767-20-2

29767-20-2

29767-20-2

29767-20-2

29767-20-2

10379-14-3

12001-79-5

12001-79-5

12001-79-5

Retinol

Retinol

Taxol

Taxol

Taxol

Taxol

Teniposide

Teniposide

Teniposide

Teniposide

Teniposide

Teniposide

Teniposide

Teniposide

Teniposide

Tetrazepam

Vitamin K

Vitamin K

Vitamin K

3.87

3.87

1.62

6.70

6.14

5.58

5.02

4.46

3.90

Log Ko/w

62-3

62-3

62-3

242-6

242-6

242-6

242-6

242-6

242-6

242-6

242-6

242-6

213-6

213-6

213-6

213-6

121

121

232.9

50

81

65

86

106

91

Mp

450.68

450.68

450.68

288.8

656.67

656.67

656.67

656.67

656.67

656.67

656.67

656.67

656.67

859.9

859.9

859.9

859.9

286.2

286.2

286.2

314.5

314.5

360.44

436.5

422.5

408.5

394.5

380.4

366.4

MW

0.368

0.368

0.368

0.368

0.368

0.368

0.368

0.368

0.368

0.0117

0.0117

0.0117

0.0117

0.0352

0.0352

0.469

0.00054

0.00012

0.0003

0.0005

0.0013

0.021

Aq (mM)

0.65

0.67

0.73

0.0378

0.0189

0.019

0.02

0.023

0.0232

0.0249

0.0321

0.03291

0.034

0.0205

0.0212

0.0219

0.0229

0.0048

0.0067

0.0075

0.0179

0.0427

0.0234

0.0119

0.0066

0.0106

0.0041

0.0037

0.0084

Mix

pKa

25

25

25

25

10

10

10

10

10

10

10

10

10

25

25

25

25

37

37

37

25

37

25

25

25

25

25

25

25

T *C

Phos pH 7.5, DC/EPC, 20/20 mM

Phos pH 7.5, C/EPC 20/20 mM

Phos pH 7.5, GDC/EPC 20/20 mM

0.067 M phos, pH 7.8, GC/SPC 0.5

20 mM Tris, 0.15 M salt, GC/EPC, ratio 1.0, 50 mg/mL

20 mM Tris, 0.15 M salt, TC/EPC, ratio 1.0, 50 mg/mL

20 mM Tris, 0.15 M salt, C/EPC, ratio 1.0, 50 mg/mL

20 mM Tris, 0.15 M salt, CDC/EPC, ratio 1.0, 50 mg/mL

20 mM Tris, 0.15 M salt, GCDC/EPC, ratio 1.0, 50 mg/mL

20 mM Tris, 0.15 M salt, TCDC/EPC, ratio 1.0, 50 mg/mL

20 mM Tris, 0.15 M salt, DC/EPC, ratio 1.0, 50 mg/mL

20 mM Tris, 0.15 M salt, GDC/EPC, ratio 1.0, 50 mg/mL

20 mM Tris, 0.15 M salt, TDC/EPC, ratio 1.0, 50 mg/mL

20 mM Tris pH 7.5, C/PC, 0.8 ratio, 25 mg/mL

20 mM Tris pH 7.5, DC/PC, 0.8 ratio, 25 mg/mL

20 mM Tris pH 7.5, TC/EPC, 0.8 ratio, 25 mg/mL

20 mM Tris pH 7.5, TDC/EPC, 0.8 ratio, 25 mg/mL

tri/diOH BS ratio 2.6, 1.13 TO/2.5 MO/7.5 OA/0.68 PC

tri/diOH BS ratio 1.32, 1.13 TO/2.5 MO/7.5 OA/0.68 PC

tri/diOH BS ratio 0.66, 1.13 TO/2.5 MO/7.5 OA/0.68 PC

0.067 M phos, pH 7.11, GC/SPC 0.5, 0–169 mM

Water DC/LPC, 0–16 mM, PC const DC

0.067 M phos, pH 7.12, GC/SPC 0.5, 0–169 mM

Phos pH 6.4, mix/EPC, 0.051 M

Phos pH 6.4, mix/EPC, 0.051 M

Phos pH 6.4, mix/EPC, 0.051 M

Phos pH 6.4, mix/EPC, 0.051 M

Phos pH 6.4, mix/EPC, 0.051 M

Phos pH 6.4, mix/EPC, 0.051 M

Comments

37

37

37

23

55

55

55

55

55

55

55

55

55

56

55

55

55

57

57

57

23

36

23

50

50

50

50

50

50

Ref.

Data presented are logarithm of the octanol/water partition coefficient, log Ko/w; melting point in 8C, Mp; molecular weight, MW; aqueous solubility in millimolar concentration units, Aq; temperature at which the solubility was determined; and solution compositions under Comments. b Not reported in CAS. c Abbreviations: MO: mono oleate; OA: oleic acid; SPC: sphingomyelin; TO: tridein.

a

57-83-0

68-26-8

Retinol

57-83-0

Progesterone

50-24-8

Progesterone

b

b

b

b

Prednisolone

phenytoin

3-Nonyloxy-methyl-

phenytoin

3-Octyloxy-methyl-

phenytoin

3-Heptyloxy-methyl-

phenytoin

3-Hexyloxy-methyl-

phenytoin

3-Pentyloxy-methyl-

b

27512-04-5

3-Butyloxy-methyl-

phenytoin

CAS

Substance

Table 9. Solubilization Ratios in Mixed Bile Salt/Lipid Systemsa

SOLUBILIZATION OF DRUGS BY BILE SALT MICELLES

1757

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

1758

WIEDMANN AND KAMEL

Table 10. Intercepts and Slopes ( 95% Confidence Limits) From Linear Regression of Plots of the Log Mole Fraction Micelle/Aqueous Partition Coefficient as a Function of the Log Octanol/Water Partition Coefficienta

GDC TC M GC DC TDC C

Intercept

Slope

r2

n

Outliers

SSE

SSTO

2.5  1.2 2.33  0.20 2.44  0.18 2.22  0.49 2.01  0.49 1.43  0.39 1.30  0.30

0.56  0.15 0.587  0.036 0.600  0.036 0.62  0.13 0.68  0.15 0.773  0.096 0.86  0.08

0.92 0.97 0.98 0.92 0.87 0.97 0.96

12 64 53 19 30 19 47

2 5 5 0 2 1 11

1.53 9.70 5.43 3.31 6.13 2.81 7.03

9.89 177 124 21.6 24.7 45.6 80.0

a Included are the correlation coefficient, r2; number of points in the correlation, n; the error sum of squares, SSE; and the total sum of squares, SSTO.

Because of the poor correlation and intermediary nature of the slope and intercept, these data were not statistically different from any of the other data sets. Two additional data sets were obtained with two glycine-conjugated bile salts, GC, a trihydroxy, and GDC, a dihydroxy bile salt. These data were not statistically different from TC, although neither data set was large. Finally, no

correlation was attempted with the small data set obtained with UDC.

Figure 1. Logarithm of the micelle/aqueous partition coefficient given as a function of the logarithm of the octanol/water partition coefficient for observations made in TC (outliers excluded). The solid line represents a best fit of a limited data using linear regression.

Figure 2. Logarithm of the micelle/aqueous partition coefficient given as a function of the logarithm of the octanol/water partition coefficient for observations made in C (outliers excluded). The solid line represents a best fit of the limited data using linear regression.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

RANK ORDER OF BILE SALT SOLUBILIZATION For the above solubilizations and the molecular weights, the data were also examined for the

SOLUBILIZATION OF DRUGS BY BILE SALT MICELLES

correlation between the micelle/aqueous partition coefficient and octanol/water partition coefficient based on a mass rather than mole fraction. The correlation coefficients were not changed, and slopes were modestly increased (< 5%). However, the intercepts were displaced one unit to the positive and their range of values was reduced from about 1.9 to 1.5. This latter aspect suggests that further efforts may yield a correction factor for the effect of molecular size in micelle solubilization. Although the solubilization is inversely related to the melting point in an analogous manner as is the aqueous solubility, the correlation is poor. However, this may represent a fertile ground for additional work. Overall, the rank order of slopes was C & TDC > GC & TC & GDC, with DC not being statistically different from the other data sets. This rank order does not correlate with hydrophobicity of the bile salt, aggregation number, or CMC, and neither could the rank order of the intercepts be reconciled with any of these parameters. Thus, as was noted early on by Bates et al.,29 the effect of bile salt type on the solubilization of specific solutes does not reveal a consistent correlation. This is evident despite the repeated assertion in the literature that bile salt micelles with larger aggregation numbers should provide greater solubilization. What perhaps was not always fully appreciated is the unique nature of the aggregation of bile salt micelles in comparison with the traditional micelles composed of surfactants with flexible alkyl chains.3 That is, bile salts are believed to form small, back-to-back associations. These are referred to as simple micelles. The larger aggregates or secondary micelles are thought to arise from association of the primary micelles through hydrogen bonding. Therefore, a large aggregation number does not necessarily create a larger hydrophobic domain. It would, however, create a distinct interfacial region between the hydrophobic pockets and the hydrogen-bonded region between the simple micelles. Moreover, the back-to-back association of the bile salt may provide an especially favorable environment that leads to the positive deviations observed with the large planar polyaromatic solutes. In addition, a number of cholesterol derivatives are known to form adducts with DC.46 This also suggests a strong association with rigid compounds. Whereas little can be said of the interaction of charged solutes, several planar charged compounds are noteworthy.31,51 The first

1759

is chlorpromazine. This solute carries a positive charge and can form insoluble complexes with the negatively charged bile salts. Thus, chlorpromazine bears some resemblance to the adduct formation of the cholesterol derivatives. The other compounds are phenylbutazone and indomethacin.31 These nonsteroidal antiinflammatory drugs are planar but carry a negative charge at neutral pH. The presence of bile salts in solution leads to a reduction in the total amount of phenylbutazone in solution. A closer examination reveals that the charge resides near the center of the molecule. As such, micelle solubilization would require the charge be located near the center of the hydrophobic area of a back-to-back association of bile salts. The companion molecule, indomethacin has its charge near the periphery. Consistent with this change in molecular structure, it has a reasonable solubilization within bile salt micelles.

SOLUBILIZATION IN MIXED MICELLES Solubilization data collected with the mixed micellar lipid are found in Tables 2 and 9. With this data set, the inherently diverse structures of the bile salts are further complicated by the more diverse possibilities of added lipid. Studies have included the phospholipids, egg and soy phosphatidylcholine, and soy phosphatidylethanolamine. In addition, there have been studies with fatty acids, monoglycerides, and triglycerides, each of which can vary in acyl chain composition. Nevertheless, most of the data were taken from three studies that used the following compositions: 10 mM TC/0.5 mM oleic acid,13 10 mM TC/10 mM egg PC,11 and a mixed bile salt system/egg PC with a total lipid concentration of 51 mM.50 Interestingly, these three systems span the micellar solution region of the phase diagram from the bile-rich portion of simple bile salt micelles with a few mixed micelles to large mixed micelles that approach the phase divergence line. Whereas most solutes were found to have a larger solubilization as the lipid-to-bile salt ratio increased, these data could not be separated in a statistically significant manner. In pooling the data, a remarkably good correlation was found where the r2 was 0.98 encompassing 53 different solutes with only five outliers (Fig. 3). Hydrocortisone and N-ethyl retinamide displayed positive deviations, and estradiol and three of the polychlorinated biphenyls exhibited negative JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

1760

WIEDMANN AND KAMEL

MEASUREMENTS IN HUMAN GASTRIC AND INTESTINAL ASPIRATES

Figure 3. Logarithm of the micelle/aqueous partition coefficient given as a function of the logarithm of the octanol/water partition coefficient for micelles observations made in mixtures of bile salts and lipids (outliers excluded). The solid line represents a best fit of the limited data using linear regression.

deviations. The slope and intercept were 0.600 and 2.44, respectively. As such, the slope and intercept were statistically indistinguishable from TC, GDC, and GC bile salt data. In keeping with the discussion, the slope indicates that the mixed bile salt system has a low discrimination to the solute’s hydrophobicity. In a closer examination of the three mixed systems used, much of the data was obtained with either TC or a mixture of bile salts that were largely conjugated. Therefore, because the slope of the mixed system was not different from TC, GDC, and GC, it would appear that the addition of lipid to the conjugated bile salts does not affect the discriminating power of the micelle. Related work with fluorescent probes indicated that the environment of nonconjugated bile salts became more polar with the addition of egg phosphatidylcholines.79 This is consistent with the larger slopes observed with TDC and C in comparison with the mixed system. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

The most significant work to date is that of Pedersen et al.70,71 These investigators have determined the solubilization and dissolution rates of hydrocortisone and danazol in human gastric and intestinal aspirates. For hydrocortisone, the solubilization ratio was 0.19 based on the assayed concentration of bile salts of 2 mM. This may be compared with the solubilization ratios that ranged from 0.03 to 0.067 for model systems composed of GC and TC alone and in combination with egg phosphatidylcholine and the lipids of oleic acid and glyceryl monooleate. The discrepancy may be related to the presence of lipids in addition to the bile salt that provided for the large solubilization. Similar results were observed with danazol where the solubilization in intestinal and gastric aspirates were about one order of magnitude greater than that observed in model systems.71 It is perhaps interesting to also note that the solubilization of danazol in the sodium dodecyl sulfate system was more than an order of magnitude larger, 0.043 versus 0.0025 than that observed with the human aspirates. Certainly, additional measurements coupled with a better characterization of the composition of the aspirate would be of tremendous value in understanding the solubilization of drugs in the intestine.

PREDICTING INTESTINAL DRUG SOLUBILIZATION The underlying premise of this work was that prediction of drug absorption requires more detailed information of the specific steps involved. To this end, the solubilization of drugs by bile salt micelles was investigated, and this report provides the most comprehensive review of the solubilization of drugs by bile salt micelles. It was found that statistically significant correlations exist between the micelle/aqueous partition coefficient and the octanol/water partition coefficient of specific bile salts. These correlations suggest that, in general, there are two, or possibly three, distinct types of solubilization by bile salts. No effect of temperature, ionic strength, or molecular weight was found. This suggests that these factors represent minor contributions if at all to the overall solubilization. Presently, there are few or no data on a physiological mixture of bile salts

SOLUBILIZATION OF DRUGS BY BILE SALT MICELLES

in the intestine.70,71 Therefore, it would be unwise at this time to use a single bile salt to predict the extent of solubilization of drug in the intestine where a diverse mixture of bile salts exists. In principle, it should be possible to predict the extent of solubilization in the GI tract from the aqueous solubility and the octanol/water partition coefficient. This prediction is contingent upon finding a correlation for solutes solubilized in the physiological relevant bile salt system. In this prediction, the total concentration of drug in solution is approximated by the sum of aqueous solubility and the concentration of drug associated with the micelle:

1761

of compounds are needed in a mixture of bile salts that is more typical of the intestinal composition. First, this would provide a more appropriate means of predicting the solubilization of drug in the intestine. Second, the results may be correlated with the existing set of data from which it may be possible to determine whether a simpler bile salt composition may suffice for predicting drug absorption. Finally, because the vast majority of approved drugs on the market carry a charge, additional work should be directed at characterizing the interaction of charged solutes with bile salt micelles.

½Dt ¼ ½Daq þ ½Dm The micelle solubilized drug concentration is related to the mole fraction solubilized and bile salt concentration as follows: ½Dm ¼ fð1  Xm Þ=Xm g½BS which, in turn, is related to the octanol/water partition coefficient through the micelle/water partition coefficient, Km/a, Xm ¼ bðKo=w Þa ½Daq

ACKNOWLEDGMENTS We acknowledge the research support of LK as part of a summer fellowship program from Scripps College, Claremont, CA. We enthusiastically thank Dr. Christopher A. Lipinski, Senior Research Fellow, Pfizer Global Research and Development, who as an anonymous reviewer, provided most of the CAS numbers in the Tables, and thereby has facilitated the use of these results by the scientific community.

yielding the following ½Dt ¼ ½Daq þ f½BS=bðKo=w Þa ½Daq g  ½BS Overall, this will generally provide a positive contribution to the total amount of drug in solution, because the product of the partition coefficient and aqueous solubility is generally less than unity.

FUTURE DIRECTIONS The bile salts in human bile are essentially all conjugated, and the glycine-to-taurine conjugation exists at a ratio of two to one.3 The reasonably close correlation between GC and TC suggest the nature of the conjugation may not be significant in determining the extent of the solubilization. Nevertheless, there are significant differences between TDC and TC suggesting that the number of hydroxyl groups is an important factor in determining the solubilization. Thus, caution is needed, because nearly 60% of the bile salts in human bile are dihydroxy.3 Certainly, better characterizations of the composition of the intestinal contents would be of value. Clearly, measurements of a diverse array

REFERENCES 1. Curatolo W. 1998. Physical chemical properties of oral drug candidates in the discovery and exploratory development settings. Pharm Sci Technol Today 1:387–393. 2. Horter D, Dressman JB. 1997. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv Drug Del Rev 25:3–14. 3. Cabral DJ, Small DM. 1989. Physical chemistry of bile. In: Schultz SG, Forte JG, Rauner BB, editors. Handbook of physiology: The gastrointestinal system III, Section 6. Baltimore, MD: Waverly Press. pp 621–661. 4. Coello A, Meijide F, Nunez ER, Tato JV. 1996. Aggregation behavior of bile salts in aqueous solution. J Pharm Sci 85:9–16. 5. Ekwall P, Fontell K, Sten A. 1967. Micelle formation in bile salt solutions. In: Schulman JH, editor. Proceedings of the 2nd International Congress on Surface Activity, Vol. 1. London: Butterworth Scientific Publications, p 357. [Cited in Carey MC, Small DM. 1970. The characteristics of mixed micellar solutions with particular reference to bile. Am J Med 49:590–608.] 6. Carey MC, Small DM. 1970. The characteristics of mixed micellar solutions with particular reference to bile. Am J Med 49:590–608. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

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7. Mithani SD, Bakatselou V, TenHoor CN, Dressman JB. 1996. Estimation of the increase in solubility of drugs as a function of bile salt concentration. Pharm Res 13:163–167. 8. Zuman P, Fini A. 2000. Solubilization of organic compounds in the presence of bile salts and related phenomena. In: Hinze WL, editor. Organized assemblies in chemical analysis, Vol. 2. New York: JAI Press Inc. pp 117–145. 9. Ekwall P, Sjoblom L. 1950. Aqueous solutions of steroid hormones. Acta Endocrinol 4:179–191. 10. Armstrong MJ, Carey MC. 1987. Thermodynamic and molecular determinants of sterol solubilities in bile salt micelles. J Lipid Res 28:1144–1155. 11. Cai X, Grant DJW, Wiedmann TS. 1997. Analysis of the solubilization of steroids by bile salt micelles. J Pharm Sci 86:372–377. 12. Thakkar AL. 1970. Solubilization of some steroid hormones in aqueous solutions of bile salts. J Pharm Sci 59:1499–1501. 13. Dulfer WJ, Groten JP, Govers HAJ. 1996. Effect of fatty acids and the aqueous diffusion barrier on the uptake and transport of polychlorinated biphenyls in caco-2 cells. J Lipid Res 37:950–961. 14. Norman A. 1960. The beginning solubilization of 20-methylcholanthrene in aqueous solutions of conjugated and unconjugated bile acid salts: Bile acids and steroids 79. Acta Chem Scand 14:1295– 1299. 15. Ekwall P, Setala K, Sjoblom L. 1951. Further investigations on the solubilization of carcinogenic hydrocarbons by association colloids. Acta Chem Scand 5:175–189. 16. Hoffman AF. 1962. The function of bile salts in fat absorption. Biochem J 89:57–68. 17. Fung BM, Thomas L Jr. 1979. The motion of aromatic molecules in bile acid micelles. Chem Phys Lipids 25:141–148. 18. Moroi Y, Okabe M. 2000. Micelle formation of sodium ursodeoxycholate and solubilization into micelle. Colloids Surf 169:75–84. 19. Montet JC, Reynier MO, Montet AM, Gerolami A. 1979. Distinct effects of three bile salts on cholesterol solubilization by oleate-monoolein-bile salt micelles. Biochim Biophys Acta 575:289–294. 20. O’Reilly JR, Corrigan OI, O’Driscoll CM. 1994. The effect of simple micellar systems on the solubility and intestinal absorption of clofazimine (G663) in the anesthetized rat. Int J Pharm 105:137–146. 21. Poelma FGJ, Breas R, Tukker JJ. 1990. Intestinal absorption of drugs. IV. The influence of taurocholate and L-cysteine on the barrier function of mucus. Int J Pharm 64:161–169. 22. Poelma FGJ, Breas R, Tukker JJ, Crommelin DJA. 1990. Intestinal absorption of drugs: The influence of mixed micelles on the disappearance kinetics of drugs from the small intestine of the rat. J Pharm Pharmacol 43:317–324.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

23. Hammad MA, Muller BW. 1998. Increasing drug solubility by means of bile salt-phosphatidylcholine-based mixed micelles. Eur J Pharm Biopharm 46:361–367. 24. Rosoff M, Serajuddin ATM. 1980. Solubilization of diazepam in bile salts and in sodium cholatelecithin-water phases. Int J Pharm 6:137–146. 25. Mattha AG, Omar SM, Kassem MA. 1982. Study of the influence of sodium taurocholate (STC) and sodium glycocholate (SGC) on the mass transfer of certain drugs. Diethylstilbestrol. Int J Pharm 11:27–34. 26. Li C-Y, Zimmerman CL, Wiedmann TS. 1996. Solubilization of retinoids by bile salt/phospholipid aggregates. Pharm Res 13:907–913. 27. Kolehmainen E. 1989. Solubilization of aromatics in aqueous bile salts. II. Benzene and some substituted benzenes in sodium deoxycholate and cholate: 1H and 19F NMR studies. J Colloid Interface Sci 127:301–309. 28. Luner PE, Babu SR, Radebaugh GW. 1994. The effects of bile salts and lipids on the physicochemical behavior of gemfibrozil. Pharm Res 11:1755– 1760. 29. Bates TR, Gibaldi M, Kanig JL. 1966. Solubilizing properties of bile salt solutions. I. Effect of temperature and bile salt concentration on the solubilization of glutethimide, griseofulvin, and hexestrol. J Pharm Sci 55:191–199. 30. Humberstone AJ, Porter CJH, Charman WN. 1996. A physicochemical basis for the effect of food on the absolute oral bioavailability of halofantrine. J Pharm Sci 85:525–529. 31. Miyazaki S, Yamahira T, Morimoto Y, Nadai T. 1981. Micellar interaction of indomethacin and phenylbutazone with bile salts. Int J Pharm 8: 303–310. 32. Kararli TT, Gupta VW. 1992. Solubilization and dissociation properties of a leucotriene-D4 antagonist in micellar solutions. J Pharm Sci 81:483–485. 33. Hammad MA, Muller BW. 1999. Solubility and stability of lorazepam in bile salt/soya phosphatidylcholine-mixed micelles. Drug Dev Ind Pharm 25: 409–417. 34. McBain JW, Merrill RC Jr, Binograd JR. 1944. The solubilization of water-insoluble dye in dilute solutions of aqueous detergents. J Am Chem Soc 63:670–676. 35. Rouard M, Sari H, Nurit S, Entressangles B, Desnuelle P. 1978. Inhibition of pancreatic lipase by mixed micelles of diethyl p-nitrophenyl phosphate and bile salts. Biochem Biophys Acta 530: 227–235. 36. Martin GP, Kellaway IW, Marriott C. 1978. The solubilization of progesterone by mixed bile saltphospholipid sols. Chem Phys Lipids 22:227–238. 37. Nagata M, Yotsuyanagi T, Ikeda K. 1988. Solubilization of vitamin K1 by bile salts and

SOLUBILIZATION OF DRUGS BY BILE SALT MICELLES

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

phosphatidylcholine-bile salts mixed micelles. J Pharm Pharmacol 40:85–88. Laher JM, Barrowman JA. 1983. Polycyclic hydrocarbon and polychlorinated biphenyl solubilization in aqueous solutions of mixed micelles. Lipids 18:216–222. Bakatselou V, Oppenheim RC, Dressman JB. 1991. Solubilization and wetting effects of bile salts on the dissolution of steroids. Pharm Res 8:1461– 1469. Wiedmann TS, Kvanbeck K, Han C-H, Roongta V. 1997. Ionization and solubilization of 4-alkyl benzoic acids and 4-alkyl anilines in sodium taurodeoxycholate solutions. Pharm Res 14:1571– 1582. Ekwall P, Setala K. 1948. On the solubilization of carcinogenic hydrocarbons by association colloids. Acta Chem Scand 2:733–739. Sugioka H, Moroi Y. 1998. Micelle formation of sodium cholate and solubilization into micelle. Biochim Biophys Acta 1394:99–110. Yamaguchi T, Ikeda C, Sekine Y. 1986. Intestinal absorption of a b-adrenergic blocking agent nadolol. II. Mechanism of the inhibitory effect on the intestinal absorption of nadolol by sodium cholate in rats. Chem Pharm Bull 34:3836–3843. Stella VJ, Martodihardjo S, Terada K, Rao VM. 1998. Some relationships between the physical properties of various 3-acyloxymethyl prodrugs of phenytoin to structure: Potential in vivo performance implications. J Pharm Sci 87:1235–1241. Mukerjee P, Cardinal JR. 1976. Solubilization as a method for studying self-association: Solubility of naphthalene in the bile salt sodium cholate and the complex pattern of its aggregation. J Pharm Sci 65:882–886. Kano K, Tatemoto S, Hashimoto S. 1991. Specific interactions between sodium deoxycholate and its water-insoluble analogues: Mechanisms for premicelle and micelle formation of sodium deoxycholate. J Phys Chem 95:966–970. Samaha MW, Gadalla MAF. 1987. Solubilization of carbamazepine by different classes of nonionic surfactants and a bile salt. Drug Dev Ind Pharm 13:93–112. Carey MC, Small DM. 1970. The characteristics of mixed micellar solutions with particular reference to bile. Am J Med 49:590–608. Martis L, Hall NA, Thakkar AL. 1972. Micelle formation and testosterone solubilization by sodium glycocholate. J Pharm Sci 61:1757–1761. Stella VJ, Martodihardjo S, Terada K, Rao VM. 1998. Some relationships between the physical properties of various 3-acyloxymethyl prodrugs of phenytoin to structure: Potential in vivo performance implications. J Pharm Sci 87:1235–1241. Carey MC, Hirom PC, Small DM. 1976. A study of the physicochemical interactions between biliary

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

1763

lipids and chlorpromazine hydrochloride. Biochem J 153:519–531. Ekwall P, Setala K. 1948. On the solubilization of carcinogenic hydrocarbons by association colloids. Acta Chem Scand 2:733–739. del Estal JL, Alvarez AI, Villaverde C, Prieto JG. 1993. Comparative effects of anionic, natural bile acid surfactants and mixed micelles on the intestinal absorption of the anthelmintic albendazole. Int J Pharm 91:105–109. Naylor LJ, Bakatselou V, Dressman JB. 1993. Comparison of the mechanism of dissolution of hydrocortisone in simple and mixed micelle systems. Pharm Res 10:865–870. Alkan-Onyuksel H, Son K. 1992. Mixed micelles as proliposomes for the solubilization of teniposide. Pharm Res 9:1556–1562. Alkan-Onyuksel H, Ramakrishnan S, Chai H-B, Pezzuto JM. 1994. A mixed micellar formulation suitable for the parenteral administration of Taxol. Pharm Res 11:206–212. El-Gorab M, Underwood BA. 1973. Solubilization of b-carotene and retinol into aqueous solutions of mixed micelles. Biochim Biophys Acta 306:58–66. Kassem MA, Mattha AG, El-Nimr AEM, Omar SM. 1982. Study of the influence of sodium taurocholate (STC) and sodium glycocholate (SGC) on the mass transfer of certain drugs. Digoxin. Int J Pharm 11: 1–9. Hammad MA, Muller BW. 1998. Solubility and stability to tetrazepam in mixed micelles. Eur J Pharm Biopharm 7:49–55. Kolehmainen E. 1985. Solubilization of aromatics in aqueous bile salts. I. Benzene and alkylbenzenes in sodium cholate: 1H study. J Colloid Interface Sci 105:273–277. Mukerjee P, Moroi Y, Murata M, Yang AYS. 1984. Bile salts as atypical surfactants and solubilizers. Hepatology 4:61S–65S. Bates TR, Gibaldi M, Kanig JL. 1966. Solubilizing properties of bile salt solutions. II. Effect of inorganic electrolyte, lipids, and a mixed bile salt system on the solubilization of glutethimide, griseofulvin, and hexestrol. J Pharm Sci 55:901–906. Sjovall J. 1959. On the concentration of bile acids in the human intestine during absorption: Bile acids and steroids 74. Acta Physiol Scand 46:339–345. Cantarow A, Paschkis KE, Rakoff AE, Hansen LP. 1944. Solubility of certain steroids and other water-insoluble substances in aqueous solutions of sodium dehydrocholate. Endocrinology 35:129– 131. Ekwall P, Sjoblom L. 1950. On the solubilization of steroid hormones by association colloids. Acta Chem Scand 3:1179–1180. Miyazaki S, Inoue H, Yamahira T, Nadai T. 1979. Interaction of drugs with bile components. I. Effects of bile salts on the dissolution behavior of

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

1764

67.

68.

69.

70.

71.

72.

73.

WIEDMANN AND KAMEL

indomethacin and phenylbutazone. Chem Pharm Bull 27:2468–2472. Moroi Y, Okabe M. 2000. Micelle formation of sodium ursodeoxycholate and solubilization into the micelle. Colloids Surf A 169:75–84. de Castro B, Gameiro P, Guimaraces C, Lima JLFC, Reis S. 2001. Study of partition of nitrazepam in bile salt micelles and the role of lecithin. J Pharm Biomed Anal 24:595–602. Freeman CP. 1969. Properties of fatty acids in dispersions of emulsified lipid and bile salt and the significance of these properties in fat absorption in the pig and the sheep. Br J Nutr 23:249–263. Pedersen BL, Brondsted H, Lennernas H, Christensen FN, Mullertz A, Kristensen HG. 2000. Dissolution of hydrocortisone in human and simulated intestinal fluids. Pharm Res 17:183–189. Pedersen BL, Mullertz A, Brondsted H, Kristensen HG. 2000. A comparison of the solubility of danazol in human and simulated gastrointestinal fluids. Pharm Res 17:891–894. Couper A. 1984. Thermodynamics of surfactant solutions. In: Tadros TF, editor. Surfactants. New York: Academic Press, pp 19–52. Leo A, Hansch C, Elkins D. 1971. Partition coefficients and their uses. Chem Rev 71:525–616.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 8, AUGUST 2002

74. Davis SS, Higuchi T, Rytting JH. 1974. Determination of thermodynamics of functional groups in solutions of drug molecules. In: Bean HS, Beckett AH, Carless JE, editors. Advances in pharmaceutical sciences. New York: Academic Press. pp 74– 261. 75. Hansch C, Leo A. 1979. Substituent constants for correlation analysis in chemistry and biology. John Wiley & Sons. pp 171–336. 76. Rekker RF. 1977. The hydrophobic fragmental constant. In: Nauta WT, Rekker RF, editors. Pharmacochemistry library, Vol I. Amsterdam: Elsevier Scientific Publishing. pp 25–36. 77. O’Connor CJ, Wallace RG. 1985. Physico-chemical behavior of bile salts. Adv Colloid Interface Sci 22:1–111. 78. King AD Jr. 1995. Solubilization of gases. In: Christian SD, Scamehorn JF, editors. Solubilization in surfactant aggregates. New York: Marcel Dekker. pp 35–58. 79. Matsuzaki K, Yokoyama I, Komatsu H, Handa T, Miyajima K. 1989. A fluorescent probing study on microenvironments in bile salt micelles and bile salt/phosphatidylcholine mixtures in the absence and presence of cholesterol. Biochim Biophys Acta 980:371–376.