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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: michal.nachajski@umed.lodz.pl
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
550 MICHA£ J. NACHAJSKI et al.
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
Surface-active agents from the group of polyoxyethylated glycerol esters... 551
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
552 MICHA£ J. NACHAJSKI et al.
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
Surface-active agents from the group of polyoxyethylated glycerol esters... 553
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
554 MICHA£ J. NACHAJSKI et al.
(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.
Surface-active agents from the group of polyoxyethylated glycerol esters... 555
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