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The properties of solid dispersions of clofibrate in polyethylene glycols
PHARMACEUTICA ACTA HELVETIAE ELSEVIER
Pharmaceutics
Acta Helvetiae
70 (1995) 57-66
The properties of solid dispersions of clofibrate in polyethylene glycols S. Anguiano-Igea
*,
F.J. Otero-Espinar,
J.L. Vila-Jato, J. Blanco-Mhdez
Departamento de Farmacologia, Farmacia y Tecnologia Fannachica, Laboratorio de Galthica, Facultad de Farmacia, Universidad de Santiago de Compostela, Avda. de las Ciencias s/n, Santiago de Compostela, Spain Received
7 April 1994; accepted
23 September
1994
Abstract The effect of molecular weight of polyethylene glycols (PEGS) and drug/PEG ratio on the structure and dissolution rates of the solid dispersions with clofibrate have been examined. The differential scanning calorimetry curves showed a possible evidence for the presence of interstitial solid solution. Infra-red spectra suggested that little or no interaction is present between the drug and carrier. The dissolution rates of clofibrate increased as the molecular weight of PEG increased, but the best results were obtained with PEG 20000. Although the dissolution rate increased with the drug ratio, solid dispersions containing more than 20% of the drug were not real solid products and therefore these dispersions could not be prepared. Keywords: dispersion
Clofibrate;
Differential
scanning
calorimetry;
Dissolution
1. Introduction
Most of the orally administered liquid drugs are prepared in solutions or emulsion forms. It might sometimes be advantageous, as regards formulation, handling or administration, to produce solid dosage forms from these liquid products. The inclusion of liquid drugs in solids generally requires mechanical mixing of the liquid with solid components or their being formulated in soft gelatine capsules. These methods, however, may often cause a number of problems concerning the homogeneity of the active principle in the mixture, its stability and even technological and economic aspects arising from the specificity of the equipment used in their formulation. It would be an advantage to have a system or process permitting formulation of a solid product for oral administration inside a conventional dosage form (tablets, capsules).
* Corresponding
author.
0031-6865/95/$09.50 0 1995 Elsevier SSDI 0031-6865(94)00051-4
Science
B.V. All rights reserved
rate;
IR
spectroscopy;
Molecular
weight;
Polyethylene
glycol;
Solid
Clofibrate (ethyl 2-(-p-chlorophenoxyj-2-methylpropionate) is used to treat anomalies in the lipid metabolism, particularly hypercholesterolemia. It is a bitter-tasting, oily liquid of very reduced solubility in water. In use, its liquid nature creates technological and dosage-related problems. Since 1961, when Sekiguchi and Obi proposed the use of solid dispersion systems to improve the solubility and bioavailability of drugs of low aqueous solubility, the notion has been extensively treated in the literature. Solid dispersions can actually stabilize unstable drugs (Thakkar et al., 1977; Ford, 19861, facilitate the homogeneous distribution of a product present in small proportions in a mixture (Vadnere, 1990) and can also lead to sustained drug-release when sparingly soluble carriers are used (Hasegawa et al., 1985; 0th and Miies, 1989). Chiou and Smith (1971) studied the possibility of using these systems to formulate liquid drugs using PEG 6000. The purpose of this work was to study the feasibility of solid dispersion for the formulation of clofibrate, using polyethylene-glycol of various molecular weights,
S. Anguiano-Igea et al. /Pharmaceutics
58
100°C with constant stirring. The clofibrate was miscible in the PEG melt in all proportions. The melts were allowed to cool and solidify at room temperature and then stored at 4°C. The solid product was ground in a mortar at room temperature and then sieved (105-250 pm). For dissolution assays, a sufficient amount of molten material (about 2.5 g) was poured into aluminium discs (2 cm internal diameter) so that an excess existed.
with a view to obtaining a solid product and improve the solubility. The influence of the molecular weight of the polymer on the rate of release of clofibrate was also studied.
2. Experimental
Acta Hehetiae 70 (1995) 57-66
procedures
2.1. Materials Clofibrate (ICI Farma Espaiia) is a clear, almost colourless liquid (density: 1.138-1.1141, generally considered as insoluble in water (Hassan and Elazzouny, 1982) and with a boiling range from 158 to 160°C. The polyethylene glycols (PEGS, MerckR) of nominal molecular weight 10000, 20000 and 35000 were used as supplied. All materials and reagents were analytical grade.
2.3. Differential scanning calorimetry (DSC) Studies were conducted using a Perkin Elmer DSC-4 differential scanning calorimeter using aluminium sample pans for volatiles. Samples (about 5 mg) were heated at lO”C/min using nitrogen as the purging gas. 2.4. Infrared spectroscopy
2.2. Preparation of solid dispersions IR spectra were obtained using a Perkin Elmer Model 1330 IR Spectrophotometer using KBr discs for the dispersions and direct determination for the clofibrate in NaCl crystal windows.
Solid dispersions of clofibrate and PEG were obtained by the melt method. Clofibrate/PEG mixtures containing 2.5-20% w/w of clofibrate were heated to
PEG 35000
PEG 20000
SL-----,,h
Q
80
120
160
L?Ob
ib
80
120
160
200
40
80
120
160
200
(OC) Fig. 1. DSC
20% clofibrate
CumS
in
of (A)
PEGS.
PEGS untreated
and melts containing
(B) 2.5%, (C) 5%, (D) 7.5%, (E) IO%, (F) 12.5%, (G) 15%, (H) 17.5% and (I)
S. Anguiano-Igea et al. / Phannaceutica Acta Helvetiae 70 (1995) 57-66
59
2.6. Dissolution studies
8
40
1
60
80
loo
l20
140
160
Fig. 2. DSC curves of PEG 10000 (A) in a volatile a standard sample pan and (C) sealed in nitrogen
180
200°C
sample pan, (B) in atmosphere.
Before dissolution measurements, two hours after preparation, the excess dispersion was sliced away to produce constant surface area discs as proposed by Ford and Rubinstein (1977, 1978). The discs were placed in the central stirring axis of the dissolution apparatus (Prolabo) such that only the dispersion surface was available for dissolution. Deionized water (1000 ml) maintained at 37°C was used as the dissolution medium and the discs were rotated at 100 r.p.m. The clofibrate dissolved was determined spectrophotometrically at 225 nm. Dissolution rate constants, K (mg/min) were calculated by linear regression from the data provided by the apparently linear segments of the dissolution profiles. For each formulation a minimum of four replicates was obtained. Dissolution rate of pure clofibrate could not be studied in comparable conditions to those of the dispersions due to the liquid nature of the drug. Nevertheless a dissolution test of the drug was carried out by simply adding 50 mg of clofibrate to the same volumen of deionized water. Cumulative dissolved clofibrate at 30 min was 12 k 0.83 mg. 3. Results and discussion
2.5. X-ray diffraction
X-ray diffraction patterns were obtained in a Siemens D500 Diffractometer using Cu-K, radiation and a rate of 2”/min.
Fig. 3. IR spectra
3.1. Differential scanning calorimetry
The DSC curves obtained for the dispersions of clofibrate with PEGS 10000, 20000 and 35000 displayed
of pure PEG 10000 (top) and fused PEG 10000 (bottom).
60
S. Anguiano-Igea et al. /Pharmaceutics
similar characteristics (Fig. 1). The three PEGS gave single melting endotherms at about 62-63°C (Fig. 1A). At approximately 140°C there is a small exothermic peak, which also arises in the samples of pure PEG. It is related to the use of sealed aluminium pans for the experiment. Fig. 2 shows that the exotherm disappears when the sample is placed in a standard aluminium pan or when the capsules are sealed under nitrogen.
Acta Helvetiae 70 (I 995) 57-66
When they are sealed in air, some air is trapped and cannot be removed by the purging gas. The presence of air leads to oxidation of the PEG at that temperature. Incorporation of clofibrate into the PEGS (Fig. 1) resulted initially in a displacement of the peaks to lower temperatures, together with a broadening of the endotherms with increasing proportion of clofibrate in the mixture. In the dispersions prepared with PEG
PEG 10000 PEG 20000
b)
PEG 35000
d)
Fig. 4. IR spectra in the 1500-2000 cm-l (PEG 10000, 20000 and 35000) and 500-1000 lo%, (d) 15%, (e) 20% clofibrate in PEG and (f) pure clofibrate.
cm-’
(PEG
10000) regions
of. (a) pure PEG, (b) 5%, Cc)
S. Anguiano-Igea et al. /Pharmaceutics
10000 for small proportions of clofibrate the endotherms are slightly split. With PEG 20000 and 35000 no splitting is present, though the endotherm is slightly broadened, which appears to indicate the possible formation of a solid solution between the drug and the carrier, this being in keeping with results obtained by Chiou and Smith (1971) for the clofibrate-PEG 6000 system.
Acta Helvetiae 70 (1995) 57-66
61
becomes more intense as the proportion of drug increases. The band characteristic of clofibrate at 670 cm-’ corresponding to the C-Cl group absorption is seen in formulations of this carrier with 5% or more of clofibrate. In clofibrate-PEG 35000 formulations, the C = 0 band appears in the spectra for low proportions of clofibrate, though it is less intense than in the case of PEG 10000. The behavior of this band in solid
3.2. IR spectroscopy Although IR spectroscopy has been used to quantify the interaction in solid dispersion between drug and carrier, few pharmaceutical studies have attempted to interpret the modifications produced by the preparation method in the PEGS IR spectra. Fusion only induced marginal changes in the IR spectra of the PEG samples. Fig. 3 shows these changes in the PEG 10000, for the PEGS of higher molecular weight are similar though less accentuated. Ford et al. (1986) attribute these changes to a modification in the crystallinity of the polymer, which generally decreases after melting. Nevertheless, an increase in the degree of crystallinity may occur depending on the molecular weight of the PEG and the solidification process. In our case, the most significant changes take place in the bands at 948 and 962 cm-’ (CH, rock, CH, twist), the increase in the intensity of the peak at 948 cm-’ with respect to that at 962 cm-’ indicating an increase in the crystalline fraction (Nadeau, 1967). The modification of the band at 842 cm-’ is related to the crystallinity too, a decrease being related to an increase in the amorphous fraction. We never observed it to decrease, finding it to occasionally increase. The solidification at room temperature employed may have increased the ordered fraction (Craig and Newton, 1991). Fusion-solidification of the PEGS also led to the appearance of two new bands, one in the region 30003500 cm-’ and the other in the region 1400-1500 cm-‘. These new peaks may result from the absorption of water by the PEGS, which are hydroscopic, since heating was carried out in open containers in a water bath at 100°C. The spectrum of clofibrate was similar to that described in the literature (Hassan and Elazzouny, 1982). When clofibrate is incorporated into the PEGS (Fig. 4), in addition to the spectral changes produced by the fusion and crystallization, an absorption band appears at 1734 cm-‘, corresponding to the stretching vibration of the carbonyl group in the drug; in the dispersions prepared with PEG 10000 this band starts to appear when clofibrate makes up 2.5% of the formulation, and
-
b)
u-,-4
cl
Fig. 5. X-ray diffraction patterns obtained for (a) pure PEG 10000, (b) fused PEG and the solid dispersion containing (c) 5%, (d) lo%, (e) 15% and (f) 20% of clofibrate.
S. Anguiano-Igea et al. /Pharmaceutics
62
Acta Heluetiae 70 (1995) 57-66 l
dispersions prepared with PEG 20000 is different: the C = 0 stretching band is weak and appears when the proportion of drug is above 10%. The presence of clofibrate did not dramatically modify the spectra from those of PEGS and these results may indicate no strong interaction exists between the polymer and the drug.
2.5%
l
0 5%
12.5%
0 15%
T
A 7.5% -
AlO%
3.3. X-ray diffraction The powder X-ray diffraction patterns were obtained for the untreated PEGS, heat-treated and for the solid dispersions (Fig. 5). The peak characteristics of the carriers are unchanged after fusion, thus the increase in crystallinity indicated by the IR studies must occur in a very reduced way. The liquid nature of clofibrate makes it impossible to obtain a X-ray diffraction pattern, impeding the confirmation of the existence of an interstitial solid solution, which the thermal results seemed to suggest. 3.4. Dissolution
(u
2 b ;s 0
15
-
10
-
5
-
o1-B”““““’ 0
studies
5
10
15
20
25
30
Time (mid
Dissolution profiles of the clofibrate-PEG dispersions are shown in Figs. 6-8. With PEG 10000 (Fig. 61,
l
25
20
-
2.5%
0 5%
l
12.5%
0
15%
A 7.5%
*
17.5%
A 10%
*
20%
-
01 0
’
’ 5
’
’ 10
n ’
’
’
15
20
’
’ 25
’
’ 30
Time (mid Fig. 6. Dissolution profiles of the dispersions amount of clofibrate in PEG 10000.
containing
different
Fig. 7. Dissolution profiles of the dispersions amount of clofibrate in PEG 20000.
containing
different
the profiles are linear for all proportions of clofibrate during the first 30 min, after which the rate decreases and they become biphasic and irregular. This irregularity increases with the proportion of drug. The dissolution rate reaches a maximum at a proportion of 10% and remains more or less constant at higher proportions (Fig. 9). In all cases, drops of the free drug were observed in the dissolution medium at the end of the assays, and even sooner for the systems formed with the higher percentages of clofibrate; dissolution would hence be controlled by the drug once released from the dispersion, and not by the polymer. It is postulated that dissolution is rapid at first as the PEG 10000, present on the surface of the disc, dissolves, and is then depressed by the large quantity of drug already in the dissolution medium. Release from PEG 20000 (Fig. 7) formulations containing the lowest proportions of drug (2.5 and 5%) were linear for the entire assay time (1 h); using higher proportions of drug, linear release was maintained for a maximum of 40 min and biphasic profiles being obtained. At the end of all assays droplets of drug were observed in the dissolution medium, as for PEG 10000, depressing the release rate, though release rates with PEG 20000 are greater than with PEG 10000 (Fig. 9).
S. Anguiano-Igea
et al. /Pharmaceutics
The dissolution profiles of the dispersion prepared with PEG 35000 (Fig. 8) lie in three separate bands. For 2.5-10% of clofibrate the rate stays constant, increases for 12.5% and increases again for 15-20%. Table 1 The effect dispersions % clofibrate
of composition
and PEG
molecular Dissolution
weight
7.5
10
12.5
15
17.5
Though dissolution rates for the lower proportions of drug are higher for PEG 35000 than for PEG 20000, they become equal thereafter (Fig. 9). The initial dissolution rates calculated from the lin-
on the dissolution
rates
(mg min -‘I
of clofibrate
from clofibrate-PEG
PEG 20000
PEG 35000
0.2093 0.1872 0.2131 0.2063
0.3634 0.3738 0.3745 0.4347
0.6190 0.6431 0.5482 0.6158
x = 0.2040 Vn_l = 0.0115 0.3247 0.3266 0.3084 0.3130
0.3866 0.0325 0.4599 0.4564 0.4322 0.4486
0.6065 0.0407 0.6174 0.6659 0.6595 0.6844
52 = 0.3182 pn _ 1 = 0.0088 0.3721 0.3395 0.4229 0.3344
0.4493 0.0123 0.6882 0.5556 0.6215 0.6134
0.6568 0.0283 0.6086 0.5894 0.5910 0.6164
x = 0.3672 on _ 1 = 0.0407 0.5295 0.4234 0.4432 0.4373
0.6197 0.0543 0.8046 0.7635 0.7847 0.7573
0.6014 0.0133 0.5966 0.6475 0.6032 0.6111
x = 0.4584 gn _ , = 0.0482 0.5975 0.6009 0.4857 0.4131
0.7775 0.0215 0.7582 0.7814 0.9459 0.8917
0.6146 0.0227 0.8712 0.7676 0.7734 0.7857
R = 0.5614 on_ 1 = 0.0656 0.4477 0.6221 0.3990 0.4166
0.8443 0.0893 0.8801 0.885 1 0.8907 0.8848
0.7995 0.0484 1.0030 1.2757 1.0682 1.1218
x = 0.4714 ~~n-~ = 0.1025 0.6904 0.6314 0.4635 0.4948
0.8852 0.0043 0.9995 0.9258 0.9062 0.8742
1.1172 0.1163 1.1550 0.9836 1.0714 1.0748
x = 0.5700 = 0.1084 0.4410 0.7692 0.5890 0.6808
0.9264 0.0532 1.0446 1.1941 1.1705 1.2986
1.0712 0.0700 1.2773 1.2302 1.1273 1.1012
!? = 0.6200 u,_, = 0.1402
1.1770 0.1043
1.1840 0.0830
a,-, 20
63
rates (mg min-‘)
PEG 10000 2.5
5
variation
Acta Helvetiae 70 (1995) 57-66
solid
S. Anguiano-Igea
40
-
.
2.5%
l
12.5%
0
5%
0
15%
A 7.5%
10%
* 35
-
30
-
*
17.5%
*
20%
et al. /Pharmaceutics
Acta Helvetiae
70 (1995) 57-66
by linear regression on the straight section of the dissolution profiles. The weight of each of these variables on the dissolution rate was evaluated using stepwise multiple linear regression. The regression equation (Eq. 1) was then used to plot a response surface (Fig. 10). K = 0.000058
W + 0.021591
%drug
+ 5.549793 . lop7
W %drug
- 1.071196.
W2 - 0.33203
2 -0 z z s a, z & z G
25
-
20
-
15
-
10
-
r2 = 0.8756,
5-
01 0
’
’ 5
n
’
10
’
’
’
15
Time
’
n ’
n ’
20
25
30
(mid
Fig. 8. Dissolution profiles of the dispersions amount of clofibrate in PEG 35000.
containing
different
lo-”
F = 160.13, (Y< 0.01
(1)
where K is the dissolution rate in mg/min, W the molecular weight of PEG and %drug the proportion of clofibrate in percentage. For other drug/carrier systems using PEGS, the influence of the molecular weight of the carrier on the dissolution characteristics of the drug varies widely. In solid dispersions formed by sulphamethoxydiazine and PEG 6000 and 20000, Salib and Ebian (1978) observed the dissolution rate to increase with the molecular weight of the polymer for concentrations of drug not exceeding 5%, there being little difference between the polymers above this concentration. Coprecipitates of meprobamate with PEG 4000 and 20000 also showed increasing dissolution rates with increasing molecular weight (Draguet-Brughmans et al., 1979), which may be 1.4
ear portions of the dissolution profiles are plotted as a function of clofibrate concentration for disc containing PEG 10000, 20000 and 35000 in Fig. 9. For PEG 10000 and 20000 solid dispersions a linear relationship existed between dissolution rate and disc composition among O-12.5% (r = 0.9931) and O-20% (r = 0.9788) of clofibrate respectively. They indicate that the dissolution rate of the dispersions was proportional at the drug concentration on the discs and not reveals any changes in the dissolution mechanism. A number of other studies using constant surface area disc have shown a similar increase in dissolution rate with drug concentration at high carriers contents (Ford and Rubinstein, 1977, 1978; Ford, 1986; Craig and Newton, 1992). The variable dissolution rate of clofibrate-PEG 35000 systems was unexpected. It may due because the PEG 35000 solid dispersions were not sufficiently homogeneous due the high viscosity of moltens. The Friedman test (Siegel and Castellan, 1988) showed a statistically significant influence ((Y < 0.01) of both the molecular weight and the proportion of drug on the dissolution rate (Table 11, which was obtained
1.2
f
.
PEG
10000
0
PEG
20000
T
I
t 01
0
I
I
I
I
5
10
15
20
% clofibrate
Fig. 9. Dissolution melts.
rate
composition
profiles
of clofibrate-PEGS
S. Anguiano-Igea et al. /Pharmaceutics
Acta Hebetiae 70 (1995) 57-66
65
molecular weight, and the proportion of drug in the dispersion. Nevertheless two remarks must be added: First, the proportion of clofibrate is limited to 20%; exceeding this level gives formulations which cannot be properly treated as solids. In the work of Chiou and Smith (1971) with various liquid drugs and PEG 6000 the proportion of drug was limited to 10% in order for sufficiently solid products to be obtained; we have obtained better results by using PEG of higher molecular weight. Second, though the dissolution rate increases on increasing the molecular weight of PEG, for PEG 35000 this increase is limited by the irregular control the polymer affords over the release of the clofibrate. Presumably the dispersions prepared with PEG 35000 were not sufficiently homogenous due to the high viscosity of moltens. The most reproducible releases were obtained from PEG 20000 dispersions. Fig. 10. Response surface plotting dissolution rate (mg min-‘).
corresponding
to the parameter
Acknowledgements
due to inhibition of the crystalline growth of the meprobamate by the high viscous solution formed by the PEG 20000. Mura et al. (1987) postulate likewise for systems of ibuprofen with PEGS 4000, 6000 and 20000, and justify that formation of an interstitial solid solution would be simpler for the PEG 20000. In other cases, such as hydroflumethiazide (Corrigan and Timoney, 1976), sulphadimidine (Kassem et al., 19801, and tolbutamide (Miralles et al., 19821, dissolution rates decrease with increasing molecular weight; generally accepted in explanation is the fact that the PEGS of higher molecular weight dissolve more slowly than those of lower molecular weight, or eutectic mixtures with melting points below 37°C are produced with PEGS of lower molecular weight, so that melting may precede dissolution. No change in the dissolution rate was found for glibenclamide dispersed in PEGS 4000 or 6000 (Geneidi et al., 1980) and for griseofulvine with PEGS 4000, 6000 and 20000 (Chiou and Riegelman, 1969). It is noted that there are considerable discrepancies between the nominal and measured molecular weights of the PEG samples (Craig and Newton, 19911, which can vary within lots, and much more so between lots or commercial brands, implying that care must be taken when using PEG molecular weights in these kinds of studies. Our results show that the dissolution rate increases with both the molecular weight, more effective drug dispersion being produced in the carriers of higher
The authors are grateful to ICI Farma Espaiia for supplying clofibrate. This work was supported by a grant from the Xunta de Galicia (XUGA 20305A91).
References Chiou, W.L. and Riegelman, S. (1969) Preparation and dissolution characteristics of several fast release solid dispersions of griseofulvin. J. Pharm. Sci. 58, 1505-1509. Chiou, W.L. and Smith, L.D. (1971) Solid dispersions approach to the formulation of organic liquid drugs using polyethylene glycol 6000 as a carrier. J. Pharm. Sci. 60, 125-127. Corrigan, 0.1. and Timoney, R.F. (1976) The influence of polyethylene glycols on the dissolution properties of hydroflumethyazide. Pharm. Acta Helv. 51, 268-271. Craig, D.Q.M. and Newton, J.M. (1991) Characterization of polyetylene glycols using differential scanning calorimetry. Int. J. Pharm. 74, 33-41. Craig, D.Q.M. and Newton, J.M. (1992) The dissolution of nortriptyline HCl from polyetylene glycols solid dispersions. Int. J. Pharm. 78, 175-182. Draguet-Brughmans, M., Azibi, M. and Bouche, R. (1979) Solubilite et vitesse de dissolution du meprobamate; des cas significatifs. J. Pbarm. Belg. 34, 267-271. Ford, J.L. (1986) The current status of solid dispersions. Pharm. Acta Helv. 61, 66-88. Ford, J.L. and Rubinstein, M.H. (1977) The effect of composition and ageing on the dissolution rates of chlorpropamide-urea solid dispersions. J. Pharm. Pharmacol. 29, 688-694. Ford, J.L. and Rubinstein, M.H. (1978) Phase equilibria and dissolution rates of indomethacin-polyethylene glycol 6000 solid dispersions. Pharm. Acta Helv. 53, 327-332.
66
S. Anguiano-lgea
et al. /Pharmaceutics
Ford, J.L., Stewart, A.F. and Dubois, J.L. (1986) The properties of solid dispersions of indomethacin or phenylbutazone in polyethylene glycol. Int. J. Pharm. 28, 11-22. Geneidi, AS., Adel, M.S. and Shehate, E. (1980) Preparation and in vitro dissolution characteristics of various fast releases solid dispersions of glibenclamide. Can. J. Pharm. Sci. 15, 78-80. Hasegawa, A., Nakagawa, H. and Sugimoto, I. (1985) Application of solid dispersions of nifedipine with enteric coating agent to prepare a sustained-release dosage form. Chem. Pharm. Bull. 33, 1615-1619. Hassan, M.H.A. and Elazzouny, A.A. (1982) Clofibrate. In: Florey K. (Ed.), Analytical Profiles of Drug Substances, Vol. 11. Academic Press, New York, pp. 197-224. Kassem, A.A., Zaki, S.A., Mursi, N.M. and Tayel, S.A. (1980) Sulfadimidine solid dispersion systems. Part 2. Pharm. Ind. 42, 202-20s. Miralles, M.J., MC Ginity, J.W. and Martin, A. (1982) Combined water-soluble carriers for coprecipitated of tolbutamide. J. Pharm. Sci. 71, 302-304. Mura, P., Liguori, A. and Bramanti, G. (1987) Preparation and dissolution characteristics of solid dispersions of ibuprofen in various polyethylene glycols. II Farmaco Ed. Prac. 42, 149-156.
Acta Heluetiae 70 (1995) 57-66 Nadeau, H.G. (1967) Instrumental methods of analysis. In: Martin J. Schick (Ed.), Nonionic Surfactants. Marcel Dekker, New York, pp. 860-892. Oth, M.P. and Moes, A.J. (1989) Sustained-release solid dispersions of indomethacin with eudragit R RS and RL. Int. J. Pharm. 55, 157-164. Salib, N.H. and Ebian, A.R. (1978) Enhancing dissolution rate of sulfamethoxydiazine via solid dispersion in polyethylene glycol 6000 and 20000. Pharm. Ind. 40, 262-265. Sekiguchi, K. and Obi, N. (1961) Studies on absorption of eutectic mixture. I. A comparison of the behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man. Chem. Pharm. Bull. 9, 8666872. Siegel, S. and Castellan, N.J. (1988) Non-parametric Statistics for the Behavioral Sciences. McGraw Hill Inc., New York, pp. 174-181. Thakkar, A., Hirsch, C.A. and Page, J.G. (1977) Solid dispersion approach for overcoming bioavailability problems due to polymorphism of nabilone, a cannabinoid derivative. J. Pharm. Pharmacol. 29, 783-784. Vadnere, M.K. (1990) Coprecipitates and melts. In: Swarbrick K.J. and Boylan J. (Eds.), Encyclopedia of Pharmaceutical Technology, Vol. 3. Marcel Dekker, New York and Basel, pp. 337-352.
Pharmaceutics
Acta Helvetiae
70 (1995) 57-66
The properties of solid dispersions of clofibrate in polyethylene glycols S. Anguiano-Igea
*,
F.J. Otero-Espinar,
J.L. Vila-Jato, J. Blanco-Mhdez
Departamento de Farmacologia, Farmacia y Tecnologia Fannachica, Laboratorio de Galthica, Facultad de Farmacia, Universidad de Santiago de Compostela, Avda. de las Ciencias s/n, Santiago de Compostela, Spain Received
7 April 1994; accepted
23 September
1994
Abstract The effect of molecular weight of polyethylene glycols (PEGS) and drug/PEG ratio on the structure and dissolution rates of the solid dispersions with clofibrate have been examined. The differential scanning calorimetry curves showed a possible evidence for the presence of interstitial solid solution. Infra-red spectra suggested that little or no interaction is present between the drug and carrier. The dissolution rates of clofibrate increased as the molecular weight of PEG increased, but the best results were obtained with PEG 20000. Although the dissolution rate increased with the drug ratio, solid dispersions containing more than 20% of the drug were not real solid products and therefore these dispersions could not be prepared. Keywords: dispersion
Clofibrate;
Differential
scanning
calorimetry;
Dissolution
1. Introduction
Most of the orally administered liquid drugs are prepared in solutions or emulsion forms. It might sometimes be advantageous, as regards formulation, handling or administration, to produce solid dosage forms from these liquid products. The inclusion of liquid drugs in solids generally requires mechanical mixing of the liquid with solid components or their being formulated in soft gelatine capsules. These methods, however, may often cause a number of problems concerning the homogeneity of the active principle in the mixture, its stability and even technological and economic aspects arising from the specificity of the equipment used in their formulation. It would be an advantage to have a system or process permitting formulation of a solid product for oral administration inside a conventional dosage form (tablets, capsules).
* Corresponding
author.
0031-6865/95/$09.50 0 1995 Elsevier SSDI 0031-6865(94)00051-4
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B.V. All rights reserved
rate;
IR
spectroscopy;
Molecular
weight;
Polyethylene
glycol;
Solid
Clofibrate (ethyl 2-(-p-chlorophenoxyj-2-methylpropionate) is used to treat anomalies in the lipid metabolism, particularly hypercholesterolemia. It is a bitter-tasting, oily liquid of very reduced solubility in water. In use, its liquid nature creates technological and dosage-related problems. Since 1961, when Sekiguchi and Obi proposed the use of solid dispersion systems to improve the solubility and bioavailability of drugs of low aqueous solubility, the notion has been extensively treated in the literature. Solid dispersions can actually stabilize unstable drugs (Thakkar et al., 1977; Ford, 19861, facilitate the homogeneous distribution of a product present in small proportions in a mixture (Vadnere, 1990) and can also lead to sustained drug-release when sparingly soluble carriers are used (Hasegawa et al., 1985; 0th and Miies, 1989). Chiou and Smith (1971) studied the possibility of using these systems to formulate liquid drugs using PEG 6000. The purpose of this work was to study the feasibility of solid dispersion for the formulation of clofibrate, using polyethylene-glycol of various molecular weights,
S. Anguiano-Igea et al. /Pharmaceutics
58
100°C with constant stirring. The clofibrate was miscible in the PEG melt in all proportions. The melts were allowed to cool and solidify at room temperature and then stored at 4°C. The solid product was ground in a mortar at room temperature and then sieved (105-250 pm). For dissolution assays, a sufficient amount of molten material (about 2.5 g) was poured into aluminium discs (2 cm internal diameter) so that an excess existed.
with a view to obtaining a solid product and improve the solubility. The influence of the molecular weight of the polymer on the rate of release of clofibrate was also studied.
2. Experimental
Acta Hehetiae 70 (1995) 57-66
procedures
2.1. Materials Clofibrate (ICI Farma Espaiia) is a clear, almost colourless liquid (density: 1.138-1.1141, generally considered as insoluble in water (Hassan and Elazzouny, 1982) and with a boiling range from 158 to 160°C. The polyethylene glycols (PEGS, MerckR) of nominal molecular weight 10000, 20000 and 35000 were used as supplied. All materials and reagents were analytical grade.
2.3. Differential scanning calorimetry (DSC) Studies were conducted using a Perkin Elmer DSC-4 differential scanning calorimeter using aluminium sample pans for volatiles. Samples (about 5 mg) were heated at lO”C/min using nitrogen as the purging gas. 2.4. Infrared spectroscopy
2.2. Preparation of solid dispersions IR spectra were obtained using a Perkin Elmer Model 1330 IR Spectrophotometer using KBr discs for the dispersions and direct determination for the clofibrate in NaCl crystal windows.
Solid dispersions of clofibrate and PEG were obtained by the melt method. Clofibrate/PEG mixtures containing 2.5-20% w/w of clofibrate were heated to
PEG 35000
PEG 20000
SL-----,,h
Q
80
120
160
L?Ob
ib
80
120
160
200
40
80
120
160
200
(OC) Fig. 1. DSC
20% clofibrate
CumS
in
of (A)
PEGS.
PEGS untreated
and melts containing
(B) 2.5%, (C) 5%, (D) 7.5%, (E) IO%, (F) 12.5%, (G) 15%, (H) 17.5% and (I)
S. Anguiano-Igea et al. / Phannaceutica Acta Helvetiae 70 (1995) 57-66
59
2.6. Dissolution studies
8
40
1
60
80
loo
l20
140
160
Fig. 2. DSC curves of PEG 10000 (A) in a volatile a standard sample pan and (C) sealed in nitrogen
180
200°C
sample pan, (B) in atmosphere.
Before dissolution measurements, two hours after preparation, the excess dispersion was sliced away to produce constant surface area discs as proposed by Ford and Rubinstein (1977, 1978). The discs were placed in the central stirring axis of the dissolution apparatus (Prolabo) such that only the dispersion surface was available for dissolution. Deionized water (1000 ml) maintained at 37°C was used as the dissolution medium and the discs were rotated at 100 r.p.m. The clofibrate dissolved was determined spectrophotometrically at 225 nm. Dissolution rate constants, K (mg/min) were calculated by linear regression from the data provided by the apparently linear segments of the dissolution profiles. For each formulation a minimum of four replicates was obtained. Dissolution rate of pure clofibrate could not be studied in comparable conditions to those of the dispersions due to the liquid nature of the drug. Nevertheless a dissolution test of the drug was carried out by simply adding 50 mg of clofibrate to the same volumen of deionized water. Cumulative dissolved clofibrate at 30 min was 12 k 0.83 mg. 3. Results and discussion
2.5. X-ray diffraction
X-ray diffraction patterns were obtained in a Siemens D500 Diffractometer using Cu-K, radiation and a rate of 2”/min.
Fig. 3. IR spectra
3.1. Differential scanning calorimetry
The DSC curves obtained for the dispersions of clofibrate with PEGS 10000, 20000 and 35000 displayed
of pure PEG 10000 (top) and fused PEG 10000 (bottom).
60
S. Anguiano-Igea et al. /Pharmaceutics
similar characteristics (Fig. 1). The three PEGS gave single melting endotherms at about 62-63°C (Fig. 1A). At approximately 140°C there is a small exothermic peak, which also arises in the samples of pure PEG. It is related to the use of sealed aluminium pans for the experiment. Fig. 2 shows that the exotherm disappears when the sample is placed in a standard aluminium pan or when the capsules are sealed under nitrogen.
Acta Helvetiae 70 (I 995) 57-66
When they are sealed in air, some air is trapped and cannot be removed by the purging gas. The presence of air leads to oxidation of the PEG at that temperature. Incorporation of clofibrate into the PEGS (Fig. 1) resulted initially in a displacement of the peaks to lower temperatures, together with a broadening of the endotherms with increasing proportion of clofibrate in the mixture. In the dispersions prepared with PEG
PEG 10000 PEG 20000
b)
PEG 35000
d)
Fig. 4. IR spectra in the 1500-2000 cm-l (PEG 10000, 20000 and 35000) and 500-1000 lo%, (d) 15%, (e) 20% clofibrate in PEG and (f) pure clofibrate.
cm-’
(PEG
10000) regions
of. (a) pure PEG, (b) 5%, Cc)
S. Anguiano-Igea et al. /Pharmaceutics
10000 for small proportions of clofibrate the endotherms are slightly split. With PEG 20000 and 35000 no splitting is present, though the endotherm is slightly broadened, which appears to indicate the possible formation of a solid solution between the drug and the carrier, this being in keeping with results obtained by Chiou and Smith (1971) for the clofibrate-PEG 6000 system.
Acta Helvetiae 70 (1995) 57-66
61
becomes more intense as the proportion of drug increases. The band characteristic of clofibrate at 670 cm-’ corresponding to the C-Cl group absorption is seen in formulations of this carrier with 5% or more of clofibrate. In clofibrate-PEG 35000 formulations, the C = 0 band appears in the spectra for low proportions of clofibrate, though it is less intense than in the case of PEG 10000. The behavior of this band in solid
3.2. IR spectroscopy Although IR spectroscopy has been used to quantify the interaction in solid dispersion between drug and carrier, few pharmaceutical studies have attempted to interpret the modifications produced by the preparation method in the PEGS IR spectra. Fusion only induced marginal changes in the IR spectra of the PEG samples. Fig. 3 shows these changes in the PEG 10000, for the PEGS of higher molecular weight are similar though less accentuated. Ford et al. (1986) attribute these changes to a modification in the crystallinity of the polymer, which generally decreases after melting. Nevertheless, an increase in the degree of crystallinity may occur depending on the molecular weight of the PEG and the solidification process. In our case, the most significant changes take place in the bands at 948 and 962 cm-’ (CH, rock, CH, twist), the increase in the intensity of the peak at 948 cm-’ with respect to that at 962 cm-’ indicating an increase in the crystalline fraction (Nadeau, 1967). The modification of the band at 842 cm-’ is related to the crystallinity too, a decrease being related to an increase in the amorphous fraction. We never observed it to decrease, finding it to occasionally increase. The solidification at room temperature employed may have increased the ordered fraction (Craig and Newton, 1991). Fusion-solidification of the PEGS also led to the appearance of two new bands, one in the region 30003500 cm-’ and the other in the region 1400-1500 cm-‘. These new peaks may result from the absorption of water by the PEGS, which are hydroscopic, since heating was carried out in open containers in a water bath at 100°C. The spectrum of clofibrate was similar to that described in the literature (Hassan and Elazzouny, 1982). When clofibrate is incorporated into the PEGS (Fig. 4), in addition to the spectral changes produced by the fusion and crystallization, an absorption band appears at 1734 cm-‘, corresponding to the stretching vibration of the carbonyl group in the drug; in the dispersions prepared with PEG 10000 this band starts to appear when clofibrate makes up 2.5% of the formulation, and
-
b)
u-,-4
cl
Fig. 5. X-ray diffraction patterns obtained for (a) pure PEG 10000, (b) fused PEG and the solid dispersion containing (c) 5%, (d) lo%, (e) 15% and (f) 20% of clofibrate.
S. Anguiano-Igea et al. /Pharmaceutics
62
Acta Heluetiae 70 (1995) 57-66 l
dispersions prepared with PEG 20000 is different: the C = 0 stretching band is weak and appears when the proportion of drug is above 10%. The presence of clofibrate did not dramatically modify the spectra from those of PEGS and these results may indicate no strong interaction exists between the polymer and the drug.
2.5%
l
0 5%
12.5%
0 15%
T
A 7.5% -
AlO%
3.3. X-ray diffraction The powder X-ray diffraction patterns were obtained for the untreated PEGS, heat-treated and for the solid dispersions (Fig. 5). The peak characteristics of the carriers are unchanged after fusion, thus the increase in crystallinity indicated by the IR studies must occur in a very reduced way. The liquid nature of clofibrate makes it impossible to obtain a X-ray diffraction pattern, impeding the confirmation of the existence of an interstitial solid solution, which the thermal results seemed to suggest. 3.4. Dissolution
(u
2 b ;s 0
15
-
10
-
5
-
o1-B”““““’ 0
studies
5
10
15
20
25
30
Time (mid
Dissolution profiles of the clofibrate-PEG dispersions are shown in Figs. 6-8. With PEG 10000 (Fig. 61,
l
25
20
-
2.5%
0 5%
l
12.5%
0
15%
A 7.5%
*
17.5%
A 10%
*
20%
-
01 0
’
’ 5
’
’ 10
n ’
’
’
15
20
’
’ 25
’
’ 30
Time (mid Fig. 6. Dissolution profiles of the dispersions amount of clofibrate in PEG 10000.
containing
different
Fig. 7. Dissolution profiles of the dispersions amount of clofibrate in PEG 20000.
containing
different
the profiles are linear for all proportions of clofibrate during the first 30 min, after which the rate decreases and they become biphasic and irregular. This irregularity increases with the proportion of drug. The dissolution rate reaches a maximum at a proportion of 10% and remains more or less constant at higher proportions (Fig. 9). In all cases, drops of the free drug were observed in the dissolution medium at the end of the assays, and even sooner for the systems formed with the higher percentages of clofibrate; dissolution would hence be controlled by the drug once released from the dispersion, and not by the polymer. It is postulated that dissolution is rapid at first as the PEG 10000, present on the surface of the disc, dissolves, and is then depressed by the large quantity of drug already in the dissolution medium. Release from PEG 20000 (Fig. 7) formulations containing the lowest proportions of drug (2.5 and 5%) were linear for the entire assay time (1 h); using higher proportions of drug, linear release was maintained for a maximum of 40 min and biphasic profiles being obtained. At the end of all assays droplets of drug were observed in the dissolution medium, as for PEG 10000, depressing the release rate, though release rates with PEG 20000 are greater than with PEG 10000 (Fig. 9).
S. Anguiano-Igea
et al. /Pharmaceutics
The dissolution profiles of the dispersion prepared with PEG 35000 (Fig. 8) lie in three separate bands. For 2.5-10% of clofibrate the rate stays constant, increases for 12.5% and increases again for 15-20%. Table 1 The effect dispersions % clofibrate
of composition
and PEG
molecular Dissolution
weight
7.5
10
12.5
15
17.5
Though dissolution rates for the lower proportions of drug are higher for PEG 35000 than for PEG 20000, they become equal thereafter (Fig. 9). The initial dissolution rates calculated from the lin-
on the dissolution
rates
(mg min -‘I
of clofibrate
from clofibrate-PEG
PEG 20000
PEG 35000
0.2093 0.1872 0.2131 0.2063
0.3634 0.3738 0.3745 0.4347
0.6190 0.6431 0.5482 0.6158
x = 0.2040 Vn_l = 0.0115 0.3247 0.3266 0.3084 0.3130
0.3866 0.0325 0.4599 0.4564 0.4322 0.4486
0.6065 0.0407 0.6174 0.6659 0.6595 0.6844
52 = 0.3182 pn _ 1 = 0.0088 0.3721 0.3395 0.4229 0.3344
0.4493 0.0123 0.6882 0.5556 0.6215 0.6134
0.6568 0.0283 0.6086 0.5894 0.5910 0.6164
x = 0.3672 on _ 1 = 0.0407 0.5295 0.4234 0.4432 0.4373
0.6197 0.0543 0.8046 0.7635 0.7847 0.7573
0.6014 0.0133 0.5966 0.6475 0.6032 0.6111
x = 0.4584 gn _ , = 0.0482 0.5975 0.6009 0.4857 0.4131
0.7775 0.0215 0.7582 0.7814 0.9459 0.8917
0.6146 0.0227 0.8712 0.7676 0.7734 0.7857
R = 0.5614 on_ 1 = 0.0656 0.4477 0.6221 0.3990 0.4166
0.8443 0.0893 0.8801 0.885 1 0.8907 0.8848
0.7995 0.0484 1.0030 1.2757 1.0682 1.1218
x = 0.4714 ~~n-~ = 0.1025 0.6904 0.6314 0.4635 0.4948
0.8852 0.0043 0.9995 0.9258 0.9062 0.8742
1.1172 0.1163 1.1550 0.9836 1.0714 1.0748
x = 0.5700 = 0.1084 0.4410 0.7692 0.5890 0.6808
0.9264 0.0532 1.0446 1.1941 1.1705 1.2986
1.0712 0.0700 1.2773 1.2302 1.1273 1.1012
!? = 0.6200 u,_, = 0.1402
1.1770 0.1043
1.1840 0.0830
a,-, 20
63
rates (mg min-‘)
PEG 10000 2.5
5
variation
Acta Helvetiae 70 (1995) 57-66
solid
S. Anguiano-Igea
40
-
.
2.5%
l
12.5%
0
5%
0
15%
A 7.5%
10%
* 35
-
30
-
*
17.5%
*
20%
et al. /Pharmaceutics
Acta Helvetiae
70 (1995) 57-66
by linear regression on the straight section of the dissolution profiles. The weight of each of these variables on the dissolution rate was evaluated using stepwise multiple linear regression. The regression equation (Eq. 1) was then used to plot a response surface (Fig. 10). K = 0.000058
W + 0.021591
%drug
+ 5.549793 . lop7
W %drug
- 1.071196.
W2 - 0.33203
2 -0 z z s a, z & z G
25
-
20
-
15
-
10
-
r2 = 0.8756,
5-
01 0
’
’ 5
n
’
10
’
’
’
15
Time
’
n ’
n ’
20
25
30
(mid
Fig. 8. Dissolution profiles of the dispersions amount of clofibrate in PEG 35000.
containing
different
lo-”
F = 160.13, (Y< 0.01
(1)
where K is the dissolution rate in mg/min, W the molecular weight of PEG and %drug the proportion of clofibrate in percentage. For other drug/carrier systems using PEGS, the influence of the molecular weight of the carrier on the dissolution characteristics of the drug varies widely. In solid dispersions formed by sulphamethoxydiazine and PEG 6000 and 20000, Salib and Ebian (1978) observed the dissolution rate to increase with the molecular weight of the polymer for concentrations of drug not exceeding 5%, there being little difference between the polymers above this concentration. Coprecipitates of meprobamate with PEG 4000 and 20000 also showed increasing dissolution rates with increasing molecular weight (Draguet-Brughmans et al., 1979), which may be 1.4
ear portions of the dissolution profiles are plotted as a function of clofibrate concentration for disc containing PEG 10000, 20000 and 35000 in Fig. 9. For PEG 10000 and 20000 solid dispersions a linear relationship existed between dissolution rate and disc composition among O-12.5% (r = 0.9931) and O-20% (r = 0.9788) of clofibrate respectively. They indicate that the dissolution rate of the dispersions was proportional at the drug concentration on the discs and not reveals any changes in the dissolution mechanism. A number of other studies using constant surface area disc have shown a similar increase in dissolution rate with drug concentration at high carriers contents (Ford and Rubinstein, 1977, 1978; Ford, 1986; Craig and Newton, 1992). The variable dissolution rate of clofibrate-PEG 35000 systems was unexpected. It may due because the PEG 35000 solid dispersions were not sufficiently homogeneous due the high viscosity of moltens. The Friedman test (Siegel and Castellan, 1988) showed a statistically significant influence ((Y < 0.01) of both the molecular weight and the proportion of drug on the dissolution rate (Table 11, which was obtained
1.2
f
.
PEG
10000
0
PEG
20000
T
I
t 01
0
I
I
I
I
5
10
15
20
% clofibrate
Fig. 9. Dissolution melts.
rate
composition
profiles
of clofibrate-PEGS
S. Anguiano-Igea et al. /Pharmaceutics
Acta Hebetiae 70 (1995) 57-66
65
molecular weight, and the proportion of drug in the dispersion. Nevertheless two remarks must be added: First, the proportion of clofibrate is limited to 20%; exceeding this level gives formulations which cannot be properly treated as solids. In the work of Chiou and Smith (1971) with various liquid drugs and PEG 6000 the proportion of drug was limited to 10% in order for sufficiently solid products to be obtained; we have obtained better results by using PEG of higher molecular weight. Second, though the dissolution rate increases on increasing the molecular weight of PEG, for PEG 35000 this increase is limited by the irregular control the polymer affords over the release of the clofibrate. Presumably the dispersions prepared with PEG 35000 were not sufficiently homogenous due to the high viscosity of moltens. The most reproducible releases were obtained from PEG 20000 dispersions. Fig. 10. Response surface plotting dissolution rate (mg min-‘).
corresponding
to the parameter
Acknowledgements
due to inhibition of the crystalline growth of the meprobamate by the high viscous solution formed by the PEG 20000. Mura et al. (1987) postulate likewise for systems of ibuprofen with PEGS 4000, 6000 and 20000, and justify that formation of an interstitial solid solution would be simpler for the PEG 20000. In other cases, such as hydroflumethiazide (Corrigan and Timoney, 1976), sulphadimidine (Kassem et al., 19801, and tolbutamide (Miralles et al., 19821, dissolution rates decrease with increasing molecular weight; generally accepted in explanation is the fact that the PEGS of higher molecular weight dissolve more slowly than those of lower molecular weight, or eutectic mixtures with melting points below 37°C are produced with PEGS of lower molecular weight, so that melting may precede dissolution. No change in the dissolution rate was found for glibenclamide dispersed in PEGS 4000 or 6000 (Geneidi et al., 1980) and for griseofulvine with PEGS 4000, 6000 and 20000 (Chiou and Riegelman, 1969). It is noted that there are considerable discrepancies between the nominal and measured molecular weights of the PEG samples (Craig and Newton, 19911, which can vary within lots, and much more so between lots or commercial brands, implying that care must be taken when using PEG molecular weights in these kinds of studies. Our results show that the dissolution rate increases with both the molecular weight, more effective drug dispersion being produced in the carriers of higher
The authors are grateful to ICI Farma Espaiia for supplying clofibrate. This work was supported by a grant from the Xunta de Galicia (XUGA 20305A91).
References Chiou, W.L. and Riegelman, S. (1969) Preparation and dissolution characteristics of several fast release solid dispersions of griseofulvin. J. Pharm. Sci. 58, 1505-1509. Chiou, W.L. and Smith, L.D. (1971) Solid dispersions approach to the formulation of organic liquid drugs using polyethylene glycol 6000 as a carrier. J. Pharm. Sci. 60, 125-127. Corrigan, 0.1. and Timoney, R.F. (1976) The influence of polyethylene glycols on the dissolution properties of hydroflumethyazide. Pharm. Acta Helv. 51, 268-271. Craig, D.Q.M. and Newton, J.M. (1991) Characterization of polyetylene glycols using differential scanning calorimetry. Int. J. Pharm. 74, 33-41. Craig, D.Q.M. and Newton, J.M. (1992) The dissolution of nortriptyline HCl from polyetylene glycols solid dispersions. Int. J. Pharm. 78, 175-182. Draguet-Brughmans, M., Azibi, M. and Bouche, R. (1979) Solubilite et vitesse de dissolution du meprobamate; des cas significatifs. J. Pbarm. Belg. 34, 267-271. Ford, J.L. (1986) The current status of solid dispersions. Pharm. Acta Helv. 61, 66-88. Ford, J.L. and Rubinstein, M.H. (1977) The effect of composition and ageing on the dissolution rates of chlorpropamide-urea solid dispersions. J. Pharm. Pharmacol. 29, 688-694. Ford, J.L. and Rubinstein, M.H. (1978) Phase equilibria and dissolution rates of indomethacin-polyethylene glycol 6000 solid dispersions. Pharm. Acta Helv. 53, 327-332.
66
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et al. /Pharmaceutics
Ford, J.L., Stewart, A.F. and Dubois, J.L. (1986) The properties of solid dispersions of indomethacin or phenylbutazone in polyethylene glycol. Int. J. Pharm. 28, 11-22. Geneidi, AS., Adel, M.S. and Shehate, E. (1980) Preparation and in vitro dissolution characteristics of various fast releases solid dispersions of glibenclamide. Can. J. Pharm. Sci. 15, 78-80. Hasegawa, A., Nakagawa, H. and Sugimoto, I. (1985) Application of solid dispersions of nifedipine with enteric coating agent to prepare a sustained-release dosage form. Chem. Pharm. Bull. 33, 1615-1619. Hassan, M.H.A. and Elazzouny, A.A. (1982) Clofibrate. In: Florey K. (Ed.), Analytical Profiles of Drug Substances, Vol. 11. Academic Press, New York, pp. 197-224. Kassem, A.A., Zaki, S.A., Mursi, N.M. and Tayel, S.A. (1980) Sulfadimidine solid dispersion systems. Part 2. Pharm. Ind. 42, 202-20s. Miralles, M.J., MC Ginity, J.W. and Martin, A. (1982) Combined water-soluble carriers for coprecipitated of tolbutamide. J. Pharm. Sci. 71, 302-304. Mura, P., Liguori, A. and Bramanti, G. (1987) Preparation and dissolution characteristics of solid dispersions of ibuprofen in various polyethylene glycols. II Farmaco Ed. Prac. 42, 149-156.
Acta Heluetiae 70 (1995) 57-66 Nadeau, H.G. (1967) Instrumental methods of analysis. In: Martin J. Schick (Ed.), Nonionic Surfactants. Marcel Dekker, New York, pp. 860-892. Oth, M.P. and Moes, A.J. (1989) Sustained-release solid dispersions of indomethacin with eudragit R RS and RL. Int. J. Pharm. 55, 157-164. Salib, N.H. and Ebian, A.R. (1978) Enhancing dissolution rate of sulfamethoxydiazine via solid dispersion in polyethylene glycol 6000 and 20000. Pharm. Ind. 40, 262-265. Sekiguchi, K. and Obi, N. (1961) Studies on absorption of eutectic mixture. I. A comparison of the behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man. Chem. Pharm. Bull. 9, 8666872. Siegel, S. and Castellan, N.J. (1988) Non-parametric Statistics for the Behavioral Sciences. McGraw Hill Inc., New York, pp. 174-181. Thakkar, A., Hirsch, C.A. and Page, J.G. (1977) Solid dispersion approach for overcoming bioavailability problems due to polymorphism of nabilone, a cannabinoid derivative. J. Pharm. Pharmacol. 29, 783-784. Vadnere, M.K. (1990) Coprecipitates and melts. In: Swarbrick K.J. and Boylan J. (Eds.), Encyclopedia of Pharmaceutical Technology, Vol. 3. Marcel Dekker, New York and Basel, pp. 337-352.