surface-active agents from the group of …

Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 70 No. 3 pp. 547ñ555, 2013 ISSN 0001-6837Polish Pharmaceutical Society

Modern technology of drug forms applied onskin, cosmetics and solid oral dosage forms ofpreparations (tablets, capsules, implants) searchesfor new classes of excipients which would not bexenobiotics in relation to the human enzymatic sys-tem (1-5).

After fragmentary biodegradation on the sur-face of the skin or after biotransformation in the ali-mentary canal, fatty acids (6), vitamins (7-9) andsterols (10) compatible with sebum or nourishmentare also expected to appear. They would also per-form the function of promoters of mass exchange atthe phase boundary (11).

The conducted chromatographic analysis(HPLC and GC ) of the products of catalyticoxyethylation of lardís fractions (6), and above all

the research on the structural level of hydrophilic-lipophilic balance as well as the viscosity of theiraqueous solutions (12, 13), served as a basis for pre-formulation research on surface activity and theprocess of equilibrium micellar solubilization oflipophilic therapeutic agents (14).

Making use of the results of research conduct-ed so far on the process of equilibrium solubilizationof selected classes of lipophilic therapeutic agents ofBCS class II and IV by aqueous solutions of theproducts of oxyethylation of lanolin (15), fatty acidmethyl esters of rape-seed oil (16), cholesterol (17),cholic acid (18) and ursodeoxycholic acid (19),comparative experimental research was conductedon surface activity and micellar solubilization oflipophilic therapeutic agents and rutin (rutoside)

SURFACE-ACTIVE AGENTS FROM THE GROUP OF POLYOXYETHYLATEDGLYCEROL ESTERS OF FATTY ACIDS. PART III. SURFACE ACTIVITY

AND SOLUBILIZING PROPERTIES OF THE PRODUCTS OF OXYETHYLATION OF LARD (ADEPS SUILLUS, F.P. VIII) IN THE

EQUILIBRIUM SYSTEM IN RELATION TO LIPOPHILIC THERAPEUTICAGENTS (CLASS II AND III OF BCS)

MICHA£ J. NACHAJSKI1*, JOWITA B. PIOTROWSKA2, MICHA£ K. KO£ODZIEJCZYK1, MAREK LUKOSEK3 and MARIAN M. ZGODA1

1Department of Drug Form Technology, Chair of Applied Pharmacy, Faculty of Pharmacy, Medical University in Lodz, MuszyÒskiego 1, 90-151 £Ûdü, Poland

2Hospital Pharmacy ñ Cytotoxic Drug Laboratory, M. Kopernik Provincial Specialist Hospital in Lodz,Pabianicka 62 93-513 £Ûdü, Poland

3Institute of Heavy Organic Synthesis ICSO Ñ Blachowniaî in KÍdzierzyn Koüle, Poland

Abstract: Research was conducted into the solubilization processes of diclofenac, ibuprofen, ketoprofen andnaproxen in equilibrium conditions in the environment of aqueous solutions of oxyethylated lardís fractions(Adeps suillus, Polish Pharmacopoeia VIII). The determined thermodynamic (cmc, ∆Gm

0) and hydrodynamic(R0, Robs, Ω, Mη) parameters characterizing the micelle of the solubilizer and the adduct demonstrate thatlipophilic therapeutic agents are adsorbed in a palisade structure of the micelle due to a topologically createdso-called ìlipophilic adsorption pocketî. This shows that the hydrophilicity of the micelle and the adsorptionlayer decreases at the phase boundary , which is confirmed by the calculated values of coefficients Am and r∑A. The results obtained indicate the possibility of making use of the class of non-ionic surfactants which are notksenobiotics for the modification of the profile of solid oral dosage forms with lipophilic therapeutic agentsfrom the II class of Biopharmaceutics Classification System (BCS).

Keywords: Surface activity, micellar solubilization, products of oxyethylation, lard, diclofenac, naproxen,ketoprofen, ibuprofen

547

* Corresponding author: e-mail: [email protected]

548 MICHA£ J. NACHAJSKI et al.

(20) by the products of oxyethylation of lardístriglycerides fractions (6, 12).

The results of the research will serve as a basisfor the modification of selected absorption and cos-metic bases with a possibility of creating modelpreparations applied on skin in the form of emulsiveointment preparations and cosmetics.

MATERIALS AND METHODS

Materials

Diclofenac, 2-(2,6-dichloranilino) phenyl-acetic acid, SIGMA, Germany, D 6899; ibuprofen,α-methyl-4-(2-methylpropyl)phenylacetic acid,(ibuprofen powder USP/Eph), MalinckrodtChemical, Lot. B14188; ketoprofen, 3-benzoyl-α-methyl-2-naphthaleneacetic acid, SIGMA, USPGrade.

Some physicochemical and thermodynamicvalues of selected non-steroidal anti-inflammatoryand analgesic drugs associated with their solubilityin water (21) were juxtaposed in Table 1.

Basic values characterizing the products of cat-alytic oxyethylation of lardís fractions were includ-ed in publications (6, 12). Fractions with thedeclared content of nTE = 40 and high solubility inwater were selected for research on the process ofequilibrium solubilization of lipophilic therapeuticagents (6, 12).

Surface activity of aqueous solutions of the prod-

ucts of oxyethylation of lardís triglycerides

The numerical value of the surface tensioncoefficient - γ25, was determined in accordance withthe Polish Standard (PN/ISO) by means of the sta-lagmometric method (22). It served as a basis to esti-mate the critical micellar concentration (cmc) for the

solubilizer and its adducts with lipophilic therapeu-tic agents on the basis of the following equation:

γ25 = f (c, log c; g ◊ 100 cm-3) (Table 1)The line equations at p = 0.05 and r2 ≥ 0.9980

were used to describe the relationship between thecoefficient of surface tension - γ25 and log c withinthe range of low concentrations (y = a1 ◊ log c + b1)and higher concentrations (y2 = a2 ◊ log c + b2) ñ(Fig. 1), which were juxtaposed in Table 2.

Both lines intersect at the identity point of sol-ubilizer and its adductís concentration range, whichcorresponds with the critical micellar concentration(cmc) and it is calculated on the basis of the follow-ing equation:

log cmc = b2 ñ b1/a1 ñ a2

The numerical values of cmc (mol/dm3)enabled also calculation of the thermodynamicpotential for micelle formation (∆Gm

0 ) on the basis ofthe equation:

∆Gm0 = 2.303 RT ◊ log cmc

of a complex system - solubilizer and its adductswith lipophilic therapeutic agents.

The numerical value of a decrease of the sur-face tension coefficient -γcmc

25 in the critical area wasused to estimate the surface occupied by lyophilicsegments of the solubilizer and the adduct - Am atthe phase boundary (water/air) on the basis of thesurface state equation (23):

f ◊ Am = k ◊ T, where: f = γH2O

25 ñ γcmc25 .

The results obtained in the course of researchare presented in Table 3.

Solubilization of lipophilic therapeutic agents

By means of the spectrophotometric method, inanalogy to publications (15, 18, 19), the amount ofthe surfactant: diclofenac, ibuprofen, ketoprofen and

Table 1. Practical solubility S(prac.)(25), experimental S(exp.)(25) and theoretical SW (25) of NSAIDs in water, the calculated melting entropy∆Hf(1) and the mole fraction of the ideal solubility logxfor their structures.

Therapeutic agent TmOK* SW S(exp.) S(prac.) logP** ∆Sf(1) ∆Hf(1) -logx

i

2 (1)

mg/dm3 mg/dm3 mg/dm3

Diclofenac 557.15 4.47 0.82 19.39 3.9 8.9235 4971.73 2.590

Ibuprofen 349.15 68.40 49.00 55.33 3.6 2.4832 867.03 0.510

Ketoprofen 367.15 21.30 51.00 129.21 3.2 3.1198 1145.46 0.690

Naproxen 426.15 51.00 15.9 63.83 2.8 5.0505 2152.28 1.280

Acetylsalicylic acid 408.15 1.46◊103 4.6◊103 - 1.4 4.4801 1828.58 1.100

Salicylic acid 431.15 1.13◊103 2.24◊103 - - 5.2066 2244.86 1.330

* TmOK = 273.15 + t∞C, ** logP ñ partition coefficient logarithm

Surface-active agents from the group of polyoxyethylated glycerol esters... 549

Tab

le 2

. Phy

sico

chem

ical

val

ues

char

acte

rizi

ng s

urfa

ce a

ctiv

ity o

f th

e pr

oduc

ts o

f ox

yeth

ylat

ion

of la

rdís

trig

lyce

ride

s fr

actio

ns a

nd th

eir

mic

ella

r ad

duct

s w

ith n

on-s

tero

idal

ant

i-in

flam

mat

ory

drug

s [N

SAID

].

Oxy

ethy

latio

n pr

oduc

t A

ppro

xim

atio

n eq

uatio

n -γ

25=f

(log

c)

log

cmc

cmc

cmc

×10

-4∆G

0 mγ25 cm

cA

m×

10-1

9 m2

ríA

1×

The

rape

utic

age

nt

y 1=

a 1x

+ b 1

y 2

= a 2

x+b 2

g ×

100c

m-3

mol

×dm

-3

kJ/d

m3

mJ

×m

-2

1.Fr

isol

37R

◊ n

TE

= 4

0 y 1

= -

8.61

17x

+ 44

.206

y 2 =

-3.

0736

x +

47.6

06-0

.613

0.24

325.

9116

-18.

4304

49.5

01.

8311

2.41

85D

iclo

fena

cy 1

= -

12.0

09x

+ 34

.105

y 2 =

-3.

3656

x +

41.1

04-0

.809

60.

1550

3.76

77-1

9.54

7344

.47

1.50

172.

1869

Ibup

rofe

ny 1

= -

17.2

79x

+ 22

.071

y 2 =

-3.

8348

x +

34.9

79-0

.922

70.

1114

2.70

78-2

0.36

6238

.70

1.23

681.

9846

Ket

opro

fen

y 1 =

-11

.792

x +

36.2

24y 2

= -

3.44

65x

+ 43

.099

-0.8

238

0.15

013.

6486

-1

9.62

6946

.54

1.61

802.

2699

Nap

roxe

n y 1

= -

9.89

86x

+ 39

.836

y 2 =

-3.

8487

x +

43.6

52-0

.631

30.

2337

5.

6807

-1

8.52

9245

.49

1.55

392.

2245

2. 3. 4. 5. 6. 7.

Fris

ol 5

0i ◊

nT

E=

40D

iclo

fena

cIb

upro

fen

Ket

opro

fen

Nap

roxe

nFr

isol

50i

◊ n

TE

=20

y 1 =

-8.

1698

x +

51.8

39y 1

= -

16.3

640x

+ 2

3.74

4y 1

= -

17.0

101x

+ 2

2.36

5y 1

= -

11.0

540x

+ 4

0.07

1y 1

= -

10.8

330x

+ 3

8.37

4y 1

= -

10.6

210X

+ 5

1.81

2

y 2 =

-3.

6370

x +

54.2

27y 2

= -

2.23

71x

+ 39

.745

y 2 =

-2.

6200

x +

36.4

84y 2

= -

3.42

18x

+ 45

.610

y 2 =

-4.

2830

x +

43.7

37y 2

= -

2.42

92X

+ 5

4.81

2

-0.5

268

-1.1

326

-0.9

812

-0.7

257

-0.8

188

-0.3

021

0.29

730.

0736

70.

1044

0.18

810.

1517

0.49

88

9.93

972.

4630

3.49

046.

2888

5.07

18

-17.

1421

-20.

6012

-19.

7368

-18.

2771

-18.

8103

55.8

841

.80

39.4

347

.59

46.5

055

.18

2.55

671.

3639

1.26

461.

6877

1.61

55

2.85

342.

0841

2.00

682.

3183

2.26

82

Frio

lehi

na F

L6

◊ n T

E =

40

Dic

lofe

nac

Ibup

rofe

nK

etop

rofe

nN

apro

xen

y 1 =

-15

.806

0x +

40.

273

y 1 =

-13

.265

0x +

32.

542

y 1 =

-16

.196

0x +

25.

058

y 1 =

-14

.512

0x +

28.

963

y 1=

-12.

7710

x +

34.2

31

y 2 =

-6.

0126

x +

50.0

72y 2

= -

3.36

64x

+ 41

.109

y 2 =

-4.4

540x

+ 3

4.54

4y 2

= -

2.20

18x

+ 40

.450

y 2 =

-3.

6896

x +

43.2

38

-1.0

006

-0.8

655

-0.8

078

-0.9

331

0.99

19

0.09

987

0.13

630.

1556

0.11

660.

1018

4.41

996.

0319

6.88

605.

1601

4.50

51

-19.

1516

-18.

3805

-18.

0521

-18.

7675

-19.

1041

53.3

044

.46

39.4

342

.65

46.4

4

2.20

241.

4957

1.26

461.

5057

1.64

65

2.64

832.

1825

2.00

682.

1879

2.28

98

Frio

lehi

na F

L12

i ◊ n

TE

= 40

Dic

lofe

nac

Ibup

rofe

nK

etop

rofe

nN

apro

xen

y 1 =

-11

.369

0x +

46.

710

y 1 =

-14

.243

9x +

30.

174

y 1 =

-16

.066

0x +

25.

649

y 1 =

-14

.371

0x +

29.

958

y 1=

ñ 13

.211

0x +

31.

472

y 2 =

-6.

7895

x +

49.6

25y 2

= -

3.36

55x

+ 41

.104

y 2 =

-3.

725

5x +

34.

694

y 2 =

-2.

2989

x +

41.2

45y 2

= -

3.51

59x

+ 41

.923

0.63

65-0

.993

1-0

.732

9-0

.934

9-1

.077

9

0.23

090.

1016

0.18

490.

1162

0.08

356

8.16

153.

5912

6.53

554.

0928

2.94

31

-17.

6308

-19.

6662

-18.

1816

-19.

3421

-20.

159

6 53

.29

44.4

636

.08

43.5

445

.43

2.20

251.

4957

1.14

661.

4474

1.55

04

2.64

842.

1825

1.91

092.

1469

2.22

20

Frio

lehi

na F

L 12

N ◊

nTE

= 4

0D

iclo

fena

cIb

upro

fen

Ket

opro

fen

Nap

roxe

n

y 1 =

-10

.932

0x +

47.

343

y 1 =

-11

.353

0x +

35.

518

y 1 =

-17

.238

0x +

21.

941

y 1 =

-14

.371

0x +

29.

718

y 1 =

-12

.732

0x +

33.

099

y 2 =

-4.

1441

x +

50.6

36y 2

= -

2.54

08x

+ 41

.684

y 2 =

-3.

7249

x +

34.6

97y 2

= -

2.49

62x

+ 41

.280

y 2=

-3.7

471x

+ 4

1.46

1

-0.4

851

-0.7

002

-0.9

441

-0.9

736

-0.9

441

0.32

720.

1995

0.11

370.

1063

0.11

38

10.6

476

6.49

213.

7001

3.45

914.

2761

-16.

9715

-18.

1982

-19.

5922

-19.

7591

-19.

2335

53.2

944

.46

38.7

043

.59

43.6

0

2.20

251.

4957

1.21

031.

4035

1.61

23

2.64

842.

1825

1.96

332.

1142

2.26

59

Cur

toil

◊ n T

E =

40

Dic

lofe

nac

Ibup

rofe

nK

etop

rofe

nN

apro

xen

y 1 =

-11

.145

0x +

39.

315

y 1 =

-12

.324

0x +

34.

967

y 1 =

-17

.134

0x +

17.

604

y 1=

-12.

3460

x +

31.9

21y 1

= -1

2.99

61x

+ 34

.073

y 2 =

-5.

6554

x +

44.6

68y 2

= -

1.70

60x

+ 44

.708

y 2 =

-2.

8138

x +

33.8

76y 2

= -

3.09

21x

+ 39

.557

y 2 =

-1.

8653

x +

44.5

17

-0.9

751

-0.9

174

-1.1

362

-0.8

251

-0.9

383

0.10

590.

1209

0.07

306

0.14

960.

1153

4.27

614.

8817

2.95

016.

0406

4.65

56

-19.

2335

-18.

9051

-20.

1538

-18.

3769

-19.

0226

49.7

046

.44

37.9

742

.65

46.4

5

1.84

751.

6117

1.21

031.

4028

1.61

23

2.42

562.

2655

1.96

322.

1136

2.26

60


Tab

le 3

. Bas

ic v

isco

sity

val

ues

char

acte

rizi

ng th

e pr

oces

s of

mic

ella

r so

lubi

lizat

ion

by o

xyet

hyla

ted

lard

ís f

ract

ions

at n

TE

= 40

in e

quili

briu

m s

yste

m.

Solu

biliz

er

GL

LM

ηn S

* R

o◊

10-7

Rob

s.◊

10-8

Ω◊

10-2

0c S

Km w

The

rape

utic

age

nt

[η]

cm

cm

cm3

mg

dm3

1. 2. 3. 4. 5. 6.

Mh

ñ M

cz. s

o lu

b.n s

∑ = ñ

ññññ

ññññ

ñññ

295.

11

1. 2. 3. 4. 5. 6.

Mh

ñ M

cz. s

o lu

b.n s

∑ = ñ

ññññ

ññññ

ñññ

206.

3

1. 2. 3. 4. 5. 6.

Mh

ñ M

cz. s

o lu

b.n s

∑ = ñ

ññññ

ññññ

ñññ

254.

3

1. 2. 3. 4. 5. 6.

Mh

ñ M

cz. s

o lu

b.n s

∑ = ñ

ññññ

ññññ

ñññ

230.

3

Frio

lehi

na F

L6

◊ n T

E =

40

+ D

iclo

fena

cFr

iole

hina

FL

12i

◊ n

TE

= 4

0 +

Dic

lofe

nac

Frio

lehi

na F

L 1

2N ◊

nT

E =

40

+ D

iclo

fena

cFr

isol

37R

◊ n

TE

= 4

0 +

Dic

lofe

nac

Fris

ol 5

0i ◊

nT

E =

40

+ D

iclo

fena

cC

urto

il ◊

n TE

= 4

0 +

Dic

lofe

nac

0.10

1813

0.18

9333

0.11

1681

0.10

5614

0.09

8506

0.10

3533

2513

.58

7021

.07

2929

.93

2671

.11

2380

.11

2580

.55

2.62

17.8

93.

953.

152.

152.

85

4.20

857.

2886

4.56

794.

3475

4.08

744.

2716

3.43

625.

9510

3.72

953.

5496

3.38

763.

4876

1.69

958.

8283

2.17

311.

8735

1.55

711.

7771

117.

0956

118.

6844

244.

2008

125.

0397

134.

5726

296.

6317

5.03

895.

1209

11.5

941

5.44

865.

9403

14.2

981

Frio

lehi

na F

L6

◊ n T

E =

40

+ Ib

upro

fen

Frio

lehi

na F

L 1

2i ◊

nT

E =

40

+ Ib

upro

fen

Frio

lehi

na F

L 1

2N ◊

nT

E =

40

+ Ib

upro

fen

Fris

ol 3

7R ◊

nT

E =

40

+ Ib

upro

fen

Fris

ol 5

0i ◊

nT

E =

40

+ Ib

upro

fen

Cur

toil

◊ n T

E =

40

+ Ib

upro

fen

0.24

1138

0.25

7767

0.27

0672

0.37

3193

0.30

9748

0.21

8134

1047

8.72

1170

1.96

1268

7.72

2159

3.74

1586

1.57

8876

.00

42.3

548

.28

52.9

496

.23

68.4

334

.59

9.02

879.

5778

10.0

011

6.16

8611

.269

18.

2619

7.37

177.

8201

8.16

5610

.850

99.

2009

6.74

57

16.7

811

20.0

324

22.8

073

53.5

191

32.6

288

12.8

584

3042

.801

530

81.7

120

3859

.922

033

54.0

856

3431

.906

637

82.1

011

53.9

937

54.6

969

68.7

618

59.6

196

61.0

261

67.3

553

Frio

lehi

na F

L6

◊ n T

E =

40

+ K

etop

rofe

nFr

iole

hina

FL

12i

◊ n

TE

= 4

0 +

Ket

opro

fen

Frio

lehi

na F

L 1

2N ◊

nT

E =

40

+ K

etop

rofe

nFr

isol

37R

◊ n

TE

= 4

0 +

Ket

opro

fen

Fris

ol 5

0i ◊

nT

E =

40

+ K

etop

rofe

nC

urto

il ◊

n TE

= 4

0 +

Ket

opro

fen

0.10

2719

0.13

0523

0.14

5734

0.15

0378

0.13

1167

0.11

8721

2550

.98

3792

.76

4552

.14

4794

.80

3823

.76

3241

.94

3.18

8.07

10.9

612

.01

8.18

5.91

5.24

385.

2438

5.78

135.

9441

5.26

674.

8218

3.46

334.

2815

4.72

034.

8532

4.30

013.

9369

1.74

023.

2876

4.40

584.

7882

3.33

092.

5561

687.

6574

675.

0629

648.

2997

890.

6028

951.

9911

712.

8463

4.32

204.

2245

4.01

745.

8926

6.36

774.

5169

Frio

lehi

na F

L6

◊ n T

E =

40

+ N

apro

xen

Frio

lehi

na F

L 1

2i ◊

nT

E =

40

+ N

apro

xen

Frio

lehi

na F

L 1

2N ◊

nT

E =

40

+ N

apro

xen

Fris

ol 3

7R ◊

nT

E =

40

+ N

apro

xen

Fris

ol 5

0i ◊

nT

E =

40

+ N

apro

xen

Cur

toil

◊ n T

E =

40

+ N

apro

xen

0.12

4591

0.14

4681

0.12

2105

0.14

6479

0.14

9507

0.15

0295

3511

.65

4497

.78

3396

.37

4590

.71

4748

.91

4790

.43

7.69

11.9

77.

0812

.37

13.0

513

.25

5.03

235.

7443

4.94

335.

8075

5.91

365.

9412

4.10

884.

6901

4.03

614.

7416

4.82

834.

8508

2.90

564.

3219

2.75

424.

4658

4.71

524.

7815

365.

8559

355.

3648

335.

3356

446.

9241

454.

5541

436.

4329

4.73

174.

5673

4.25

356.

0017

6.12

135.

8374


naproxen, solubilized in equilibrium conditions inaqueous solutions was determined.

Approximation equations describing the rela-tionship between the concentration - cexp and themeasured value of absorbance ñ A for testedlipophilic therapeutic agents ñ included in publica-tions (15, 18, 19) after transformation to the form ñcS = A ñ a/b made it possible to calculate the amountof the solubilized agent.

The obtained results served as a basis for cal-culation of the numerical value of the micellar parti-tion coefficient - Km

W (Table 3).

Viscosity of aqueous solutions of the product of

oxyethylation of lardís triglycerides and their

adducts after equilibrium micellar solubiliza-

tion

The limiting viscosity number GLL, [η] ofaqueous solutions of solubilizers and their adductsafter equilibrium micellar solubilization was deter-mined according to the Polish Standard by means ofan Ubbelohdeís viscosimeter (24).

The value served as a basis, as in publications(16-19), for calculating some viscosity values: Mη,Ro, Robs, Ω and the solubilization indexes - nS.

DISCUSSION

The research results presented in Table 2 indi-cate that in aqueous micellar solutions of Frisol 37R◊ nTE = 40, Frisol 50i ◊ nTE = 40, Friolehina FL12i ◊nTE = 40 and Friolehina FL12N ◊ nTE = 40, the ther-modynamic potential for the adductís micelle for-mation - ∆Gm

0 (add.) is lower by 2-3 kJ in relation tothe solubilizerís ∆Gm

0 . This experimental fact supports the increase of

thermodynamic stability of the adduct withlipophilic therapeutic agents (II class of BCS) inrelation to the solubilizerís micelle:

∆Gm0 (add.) < ∆Gm

0 (solubilizerís micelle).However, in the case of the Curtiolís*nTE = 40

and Friolehinaís FL6* nTE = 40 micelles, the thermo-dynamic stability of the micelle of the adduct withdiclofenac, ketoprofen, ibuprofen and naproxen is

Figure 1 The relationship between the coefficient of surface tension γ25 [mN/m] and the concentration [mg/100 mL] of solubilizers (nTE =40) and their micellar adducts with diclofenac, ibuprofen, ketoprofen and naproxen


considerably diverse; ∆Gm0 (add.) > ∆Gm

0 (solubilizerísmicelle). The exception in those systems is the ibupro-fen adduct with the Curtiolís micelle × nTE = 40.

In addition, on the basis of the research resultsincluded in Table 3, it should be stated that afterequilibrium solubilization of NSAIDs the calculatedeffective volume of the adduct is basically higher(while maintaining the order of magnitude) than theeffective volume of the solubilizerís micelle:Ω(add.) > Ω(solub.).

In this situation, regardless of the processmechanisms (including its complexity), it appearsthat the adsorption in a topological niche of themicelle of lyophilic therapeutic agent molecules (IIclass of BCS) results in the increase of the adductíshydrophilicity. It is reflected in the regression of thenumerical value of Am coefficient (while maintain-ing the order of magnitude) (Fig. 2).

In order to define the preferences of theNSAIDsí structure for a topological space and the

Figure 2. Calculated Am values for micellar solubilizers (nTE = 40) and their adducts with diclofenac, ibuprofen, ketoprofen and naproxen

Figure 3. The relationship between the partition coefficient Kmw and the soluble value of HLBrequ


adsorption layers of the solubilizerís micelle, thecourse of dependence between Km

W (micellar, solublepartition coefficient) and HLBRequ.: Km

W = f (HLBRequ.)was investigated on the basis of the data juxtaposedin Tables 3, 4 and Figure 3.

Taking into account the small number of theclass (n = 4), the course of dependence between Km

W (y)and HLBRequ.(x) for the process of equilibrium solu-bilization in the environment of non-ionic surfac-

tants ñ fig. 3, was drawn as a trend line and at p =0.05, r2 ≥ 0.9920 described with quadratic polynomi-al equations of the type: y = cx2 ñ bx + a for: (1) Aqueous solution of Friolehina FL6 nTE = 40

y = 0.145x2 - 14.256x + 308.10(2) Aqueous solution of Friolehina FL12i nTE = 40

y = 0.147x2 - 14.458x + 312.44(3) Aqueous solution of Friolehina FL12 nTE = 40

y = 0.178x2 - 17.577x + 382.81

Figure 4. Relationship between ríA1and ∆Gm

0

Figure 5. Model of solubilizing space of the products of oxyethylation of lardís fractions at nTE = 40 at the phase boundary


(4) Aqueous solution of Curtiol nTE = 40y = 0.159x2 - 15.590x + 337.45

(5) Aqueous solution of Frisol R37R nTE = 40y = 0.161x2 - 15.844x + 343.44

(6) Aqueous solution of Frisol 50i nTE = 40y = 0.169x2 - 16.735x + 366.45The course of the above dependences shows

that the solubilizing preferences of the surfactantísmicelle result not only from the type of fatty acids(particularly those with double bonds ñHC=CH-(cis/trans isomerism)) in a triglycerideís molecule,but they are also the consequence of the thermody-namic value of HLBRequ. of a therapeutic agent.

The ideal surface state equation (23) in anapplication version ñ f(π)A1 = kT enables calcula-tion of the A1 value i.e., the mean surface per onesurfactantís molecule at the phase boundary.

Simultaneously, at low surface pressure values,the surfactantís ñ solubilizerís molecule ñ behavesas two-dimensional ideal gas at the phase boundary.Thus, the A1 value enables estimating from the rela-tionship A1 = πr2; ríA1

∑ √A/π - the mean radius of thetopological volume occupied by lipophilic fragmentof a surfactantís molecule (ìfishing float ruleî ñuplift over the phase boundary), which determinesefficiency of the solubilization process (an increaseof the actual solubility). Calculated numerical val-ues of ríA1

are presented in Table 2. This situation through the investigation of the

relationship between () and for the micelle of thesolubilizerís adduct with diclofenac, ibuprofen,ketoprofen and naproxen enables estimating (Fig. 4)the solubilization mechanism including applicationdurability of the adduct .

The course of the above dependence at p = 0.05was described with quadratic polynomial equationsof the type y = cx2 + bx + c for: (7) Micellar solution of Frisol 37R nTE = 40 at r2 =0.7521 (r = 0.8672)

y = -0.0984x2 - 3.6451x - 3.4360(8) Micellar solution of Frisol 50i nTE = 40 at r2 =0.9801 (r = 0.9900)

y = 0.0920 x2 + 3.6982x + 39.2240(9) Micellar solution of Friolehina FL6 nTE= 40 at r2

= 0.7160 (r = 0.8461)y = 0.3294 x2 + 11.8550x + 108.6800

(10) Micellar solution of Friolehina FL12i nTE = 40at r2 = 0.5527 (r = 0.7430)

y = 0.2718 x2 + 10.3390 + 100.3200(11) Micellar solution of Friolehina FL12N nTE = 40at r2 = 0.8180 (r = 0.9040)

y = 0.0741 x2 + 2.9140x + 30.7560(12) Micellar solution of Curtiol nTE = 40 at r2 =0.8836 (r = 0.9400)

y = -0.37988 x2 - 14.5660x - 137.3300 From the course of the above relationships it

appears that in the environment of micellar solutionsof Frisol 37R nTE = 40, Frisol 50i nTE = 40 andFriolehina FL12i nTE = 40 with the increase of thestability of a micellar adduct ∆Gm

0 (of the adduct) <∆Gm

0 (H2O) the numerical value decreases. However,in the environment of the micellar solution ofFriolehina FL6 nTE = 40, a case in which ∆Gm

0 (of theadduct) > ∆Gm

0 (H2O) is noted with the regression ofríA1

value, analogical as in the solubilization processmentioned above

For micellar solutions of Friolehina FL12, nTE

= 40 and Curtiol nTE = 40 an asymptotically regres-sive character of the changes between ríA1

and ∆Gm0

was noted. Supplementing the above with the analysis of

hydrodynamic parameters of the solubilizerísmicelle and its micellar adduct with diclofenac,ibuprofen, ketoprofen and naproxen (R0, RObs., Ω andMη) it should be emphasized ñ despite the complex-ity of the problem ñ that essentially in the environ-ment of all tested oxyethylated derivatives, the reg-ularity R0, RObs.,Ω (of the adduct) > R0, RObs.,Ω (ofthe solubilizer) is observed.

Concluding the research results and calcula-tions, it can be stated that the effective micellar sol-ubilization of lipophilic therapeutic agents from theII class of BCS is accompanied with the increase ofhydrodynamic parameters (Table 3) together withthe increase of hydrophilic structure of the micelle,which is observed as the A1 and ríA1

numerical valuedecrease.

This situation is influenced by the content ofunsaturated fatty acids in a molecule of oxyethylat-ed triglyceride (cis-trans isomerism) which wasdetermined as the numerical value of an iodine num-ber L(I2) (12).

CONCLUSIONS

1. The products of oxyethylation of lardís frac-tions with the declared content of oxyethylated seg-ments ñ nTE = 40 turned out to be selective solubiliz-ers in relation to lipophilic therapeutic agents fromthe II class of BCS: diclofenac, ibuprofen, ketoprofenand naproxen. Ibuprofen is solubilized by the micel-lar solution of a surfactant in the most effective way ,which is confirmed by the numerical value of themicellar partition coefficient Km

W . In the quantitativeapproach, the solubilization process of diclofenac,ketoprofen and naproxen also enables the preformu-lation research on forming model solid dosage formswith modified pharmaceutical availability.


2. The estimation of a trend line between KmW

and the thermodynamic value of HLB requ enablesidentification of the relationship between the levelof HLB balance of the structure of the lipophilictherapeutic agent (diclofenac, ibuprofen, ketoprofenand naproxen), as well as properties of the structureof the solubilizersí micelle, which influences quan-titive preferences in solubility progression. Theresults of the preformulation research indicate thepossibility of using the products of oxyethylatedlardís fractions at nTE = 40 for creating a solid oraldosage form of the drug with ibuprofen (because ofhigh Km

W values) with an expected pharmaceuticalavailability profile.

3. Hydrodynamic parameters of the micelle ofthe surfactant and the adduct with diclofenac,ibuprofen, ketoprofen and naproxen, as well as cal-culated Am and ríA1

coefficients together with theequation of ideal surface state indicate that theadsorption of a therapeutic agent takes place in apalisade layer of the micelle ñ Fig. 5 at the increaseof R0, Robs, Ω values of the micelle and with simul-taneous decrease of its lipophilicity. However, it hasan individual reference to its thermodynamic stabil-ity ñ ∆Gm

0 .

Acknowledgment

The research project with a registration numberN N209 145736 reported here was financed byMinistry of Science and Higher Education (DecisionNo. 1457/B/H03/2009/36).

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Received: 04. 04. 2012

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