An investigation into the structure and properties of Carbopol 934 gels using dielectric spectroscopy and oscillatory rheometry

journal of

cam&ll.ld ELSEVIER

Journal of Controlled Release 30 ( 1994) 2 13-223

An investigation into the structure and properties of Carbopo1934 gels using dielectric spectroscopy and oscillatory rheometry Duncan Q.M. Craig *, Slobodanka Tamburic, Graham Buckton, J. Michael Newton Centre for Materials Science, School of Pharmacy, University of London, 29-39 Brunswick Square, London

WCIN lAX, England, UK

(Received 27 May 1993; accepted in revised form 5 November 1993)

Abstract Carbopols are polyacrylic acid polymers which may be used as bioadhesive vehicles for drug delivery. In order to have a greater understanding of the factors affecting drug release from these gels, it is necessary to develop methods of studying their physical properties. In this investigation, Carbopol 934 gels have been studied using dielectric spectroscopy and oscillatory rheometry. The effect of a number of variables on the dielectric and rheological behaviour have been studied; these include the presence of a gelling agent (triethanolamine), changing the concentration of polymer, the addition of propylene glycol and the addition of a model drug (chlorhexidine gluconate). The results are interpreted in terms of the structure of the gel network and suggest that the use of these two techniques in conjunction provides an effective means of assessing the properties of gel systems. In particular, the presence of both propylene glycol and chlorhexidine gluconate were shown to have a marked effect on the gel structure, although the results indicated that the mechanisms involved were different. Keywords: Dielectric spectroscopy; Rheology; Gel; Carbopol; Chlorhexidine gluconate

1. Introduction

Carbopols are polyacrylic acid polymers, crosslinked with ally1 sucrose [l-3]. These materials are available in a number of grades, depending largely on the molecular weight of the polymer chains. In addition, Carbopols are believed to be highly polydisperse, with considerable variation in the molecular weight of supposedly identical grades having been reported [3]. These polymers contain acidic carboxyl groups which partially dissociate in water, producing a flexible coil structure. It has been suggested that gel formation is dependent on the electrostatic repulsion between the anionic groups, resulting in the molecules becoming extended and rigid. On addition of basic materials, the *Corresponding author. 0168-3659/94/$07.00 0 1994 Elsevier Science B.V. All rights reserved ssDfOl68-3659 (93)EOl63-A

dissociation of the carboxyl groups is enhanced and hence the viscosity of the systems increases, although on addition of further quantities of base the viscosity may decrease due to screening of the carboxyl groups [4]. An alternative hypothesis for gel formation in hydrophilic non-aqueous solvents involves hydrogen bonding of the solvent molecules to the polymer chains, resulting in extended, rigid molecules [ 51, although Barry and Meyer [ 31 have argued that this mechanism is not likely to be relevant to aqueous dispersions due to the water molecules being too small to have a significant effect on the polymer flexibility. It has also been suggested that the gel consists of regions of concentrated polymer similar to a series of swollen particles in close proximity to each other [ 6-81. Carbopols have been used extensively within the pharmaceutical industry due to their high viscosity at

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D.Q.M. Craig et al. /Journal of Controlled Release 30 (1994) 213-223

low concentrations, good patient acceptability and low toxicity profile. They were initially used as alternative thickening agents to natural gums. Subsequent uses include bases for wound dressings [9], ophthalmic vehicles [ lo] and transdermal systems [ 111. Furthermore, there has been considerable interest in the use of Carbopols as bioadhesive systems [ 12-141. In the present study, Carbopol 934 has been studied as a potential vehicle for an oral bioadhesive system containing chlorhexidine gluconate for dental use. Previous studies [ 11,151 have indicated that the release rate of drugs from these systems is sensitive to a number of formulation variables, hence it is desirable to have a greater knowledge of the gel structure in order to understand the release behaviour. There is therefore a need to develop techniques with which to study these gel systems. Carbopo1934 gels have been used as models for the use of two techniques which have not previously been used in conjunction to study pharmaceutical gels, namely oscillatory rheometry and dielectric spectroscopy. As these techniques are not widely used, a brief introduction to the theories involved will be given.

2. Theories of oscillatory rheometry and dielectric spectroscopy

As detailed explanations of the theoretical basis of oscillatory rheology [ 16-181 and dielectric spectroscopy [ 191 have been given elsewhere, only a brief resume will be given here. The theoretical implications of using the two techniques in conjunction will be discussed in more detail. Oscillatory rheometry involves the application of an oscillatory shear stress to a sample and the subsequent measurement of the shear strain. As the measuring method is dynamic rather than static, many systems (especially gel systems) will respond differently as the frequency changes, i.e., the materials show viscoelasticity. In particular, at high frequencies gel systems may behave as elastic solids, whereby recovery is complete after removal of the applied stress. At low frequencies, however, the samples show viscous behaviour, whereby irreversible deformation occurs on application of the stress (i.e., the sample flows). At intermediate frequencies, the samples show components of both types of behaviour. Analysis of this behaviour yields information on the structure of the sample, particularly

in terms of the rigidity and deformability of the system. The frequency dependent behaviour of these systems may not be reliably expressed in terms of a single quantity, as it is necessary to state the elastic and viscous components separately in order to characterise the material fully. These two components are most simply expressed in terms of a complex variables, with one component relating to the elastic behaviour and the other referring to the viscous behaviour. While a number of mathematically equivalent variables may be chosen to describe the system, the response is usually expressed in terms of the complex shear stress G* where G*(w) =G’(w) +iG”(o)

(1)

where (w) denotes the angular frequency of measurement, i is the square root of - 1, G’ is the real component of the response and reflects the elastic nature of the response, while G” is the imaginary component which represents the viscous component. The ratio between the two is the tan8 value, given by tan6 = G”/ G’

(2)

hence the value of tan6 shows the relative proportions of the two components, although it should be remembered that this value will itself be frequency dependent for viscoelastic materials. Dielectric analysis involves the application of an oscillatory electric field to a sample, again resulting in a response which is dependent on frequency. These two components are most easily envisaged by considering the energy put into the system by the application of the field to be partially stored by processes such as dipole reorientation and partially lost due to collisions caused by charge movement through the system. The energy stored in the system is given by the capacitance C, while the energy lost as heat is given by the dielectric loss, G/w, where G is the conductance of the system. By studying both the absolute values and the relationship between these two components over a range of frequencies, it is possible to derive information on the structure of the sample, as has been demonstrated in a number of studies on pharmaceutical systems [ 20-23 I. The dielectric behaviour may be measured by enclosing the sample between two parallel plate electrodes of area A and separation distance d. The application of an electric field will cause the establishment of induced charges and the reorientation of dipoles,

D.Q.M. Craig et al. /Journal of Controlled Release 30 (1994) 213-223

both of which will lead to a polarisation, P, defined as the dipole moment per unit volume of sample. The overall charge on the plates (Q) is related to the applied voltage V, i.e., Q=CV

(3)

where C is the capacitance which describes the ability of the sample to store charge. On the application of an oscillating field to a dielectric material, the dipolar response becomes frequency dependent as the different polarisation mechanisms exhibit varying degrees of inertia with respect to the field. The capacitance must now be considered to be a complex number, as both the magnitude and phase behaviour of the sample must be considered, hence C*(w) =C’(w)

-C(w)

(4)

where C’ and C’ are the real and imaginary components respectively (as in Eq. 1) . While the real component is usually (and not entirely accurately) simply referred to as the capacitance, the imaginary component is referred to as the dielectric loss (G/w) , where G is the conductance of the system. The dielectric loss may be considered to consist of two components. Firstly, the term includes the movement of fixed charges around an axis under the influence of an electric field and secondly the loss includes the direct current conductivity due to charges moving freely through the system. In aqueous systems such as those studied here, the latter is likely to predominate. As dielectric behaviour is related to the structure of a material, measurement of the capacitance and loss over a range of frequencies yield spectra which are characteristic of the properties of that sample. The present study concerns the use of low frequency dielectric analysis, whereby the frequency range under examination is between lo-* and IO4 Hz. The interpretation of such spectra is based on a theoretical approach suggested by Hill and Pickup [ 241 which has been supported by a number of experimental studies on gels [ 22,25,26], emulsions [ 271, liposome suspensions [ 19,201 and drug dispersions in self-emulsifying systems [28]. At high frequencies, the response is dominated by charge movement through the system, as indicated by the dielectric loss. At lower frequencies, however, the response is indicative of an adsorbed barrier layer on the electrodes which, in the case of gels, represents a layer of polymer [ 221. Analysis of this

215

layer gives an indication of the behaviour of the polymer molecules, whereas the high frequency conductivity gives an indication of the movement of molecules through the gel. It is therefore possible to gain information on both the gel network and the movement of smaller molecules (such as drugs) by examining different regions of the spectra. While it is not necessary to give a full explanation of the interpretation here, two points in particular are of relevance to the present study. Firstly, the slope of the capacitance at low frequencies gives an indication of the ease with which charges may move through the system, as a horizonal slope will indicate a perfect barrier, i.e., the polymer molecules are not allowing any charges through the system. The extent of deviation from the horizontal indicates the ‘leakiness’ of the barrier. By measuring the low frequency slope, therefore, one may gain information regarding the porosity of the gel. Secondly, the absolute value of the capacitance is a measure of the thickness of the layer, as the capacitance is given by qw>

=y!

where C(w) refers to the real part of the complex capacitance, E,,is the permittivity of free space, er is the relative permittivity (dielectric constant) of the sample, A is the area of the sample (which will be equivalent to the electrode area) and d is the thickness of the layer is question (i.e., the barrier layer at low frequenties). There are several parallels between oscillatory rheology and dielectric spectroscopy. Firstly, in both cases an oscillatory stimulus is applied to the sample and the response measured in terms of the phase behaviour of the system, the difference being that one technique involves a mechanical force and the other an electrical one. Furthermore, the type of information which may be obtained is similar. Neither technique is a direct atomic probe in the same manner as NMR or IR, although it is often possible to explain the response in terms of specific molecular movements. However, it is reasonable to state that the techniques are ultimately more useful as means of assessing the material properties of samples, particularly when they are complex, such as in the present case. In a previous study on alginate gels [ 221, low frequency dielectric analysis was used in conjunction with linear viscosity measurements. While the latter tech-

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D.Q.M. Craig et al. /Journal of Controlled Release 30 (1994) 213-223

nique inevitably yields incomplete information on viscoelastic systems, the study provided a useful insight into how dielectric measurements may be used in conjunction with viscosity data. The study indicated that the viscosity measurements gave information concerning the most rigid component of the system, i.e., the polymer chains themselves, while the dielectric analysis showed the movement of small charges (and drugs) through the system, as well as also yielding data on the structure of the polymer chain network. This study therefore indicated that there is considerable potential in using the two techniques in conjunction. By using the dielectric technique with oscillatory rheological measurements, it is intended that not only will information on the Carbopol systems be obtained, but the potential uses of the concurrent application of the two techniques will be further explored.

3. Materials and methods

Carbopol 934 (Goodrich Chemicals, UK) was added in small aliquots to mixtures containing triethanolamine and propylene glycol (where stated) and made up to volume using double distilled water to give final concentrations of 2.5% w/v Carbopol 934, 4% w/v triethanolamine and 5 or 15% w/v propylene glycol, as described in a previous study [ 151. In the case of gels containing 5% w/v Carbopol934, the triethanolamine content was 8% w/v in order to maintain a constant polymer/amine ratio. Chlorhexidine gluconate (CHG) 1% solution (Sigma) was used as received. Oscillatory rheometry was performed using a Carimed Controlled Stress Rheometer (Carri-med Ltd., UK) over a frequency range of 0.01-10 Hz at 298 K. Measurements were performed using a torque of 1350 PN. m and an amplitude of 3 mrad, which is within the range of the values used in a previous study on neutralised carbopol gels [ 181. Dielectric studies were conducted using a Dielectric Spectrometer (Dielectric Instrumentation Ltd., Herts) over a frequency range of lo-* to 10“Hz at 298 K. Platinum electrodes were used (area 0.5 cm*, separation distance 1 mm) and a voltage of 1 V r.m.s. applied.

4. Results and discussion 4.1. Effect of added base (triethanolamine) on the behaviour of 5% w/v Carbopol934 system.

Fig. 1 shows the oscillatory response of 5% w/v gels with and without 8% trietbanolamine, with selected values being given in Table 1. The presence of triethanolamine caused a substantial increase in both the elastic and viscous components of the response, although the tan8 value showed a much smaller change. This indicates that while the absolute values of the response have increased, the relative elasticity remains largely unchanged. The phase angle varied from 8.37 to 9.80 and 7.45 to 11.03 for samples with and without triethanolamine, respectively, over the frequency range studied. These values are similar to those reported for Carbopo194 1 gels although somewhat larger than those reported for Carbopol940 systems [ 161. In both cases, the curves are comparatively flat, indicating that the systems may be in the plateau region of response. Over this frequency range, the cross-links or entanglements within the gel prevent any substantial rearrangement of the molecules, hence both moduli remain largely unchanged [ 16,181. The width of the plateau reflects the degree of association within the gel, with a plateau region that extends into the low frequency region reflecting a highly cross-linked structure. As the frequency range observed here is comparatively limited, it is not possible to ascertain the width of the plateau

1

10000

-is

10

!

0.01

0.1 Frequency

1 (Hz)

Fig. 1. Effect of triethanolarnine addition on the rheological properties of 5% Carbopol 934. n, +: G’,G” 5% Carbopol 934 (no TEA), q,O: G’,G” 5% Carbopol934 ( 8% TEA).

D.Q.M. Craigetal./JoumalofControlledRelease30(1994)213-223

217

Table 1 Parameters characterising the rheological behaviour of Carbopol gel systems at a representative frequency of 0.5456 Hz G’ (N/m*)

G’ (N/m*)

7Pa.S)

1036

170.4

49.71

0.1645

14.00

0.1413

117.5

34.27

0.1527

141.7

41.33

0.1720

2.5% w/v Carbopol934 147.4 875.9 (4% triethanolamine, 15% propylene glycol)

42.99

0.1682

2.5% w/v Carbopo1934 851.8 164.3 (4% triethanolamine, 0.1% chlorhexidine gluconate)

47.92

0.1906

Sample

5% w/v Cakmpol934 (8% triethaoolamine) 5% w/v carbopo1934 (0% triethanolamine)

339.7

2.5% w/v Carbopo1934 (4% triethaoolamine)

769.1

2.5% w/v Carbopo1934 823.5 (4% triethanolamine, 5% propylene glycol)

47.99

tans

-3

2.5% w/v Carbopol934 832.9 142.9 41.68 0.1715 (4% w/v triethanolamine, 5% propylene glycol, 0.05% chlorhexidine gluconate) 2.5% w/v Carbopol934 806.1 147.4 43.00 (4% triethanolamine, 5% propylene glycol, 0.1% chlorhexidine gluconate)

0.1828

region in this case. Furthermore, the polydispcrsity of the polymers may play a role in determining the ease with which the polymer chains move past each other in addition to the degree of entanglement or crosslinking. The dielectric response of the gels with and without triethanolamine is shown in Fig. 2 and the characteristic parameters given in Table 2. These spectra show a similar response to that described by Binns et al. [ 221, whereby a bulk process is seen at higher frequencies ( 103-Iti Hz) dominated by a conductance process in series with a barrier layer of polymer that has been adsorbed at the electrodes. These two regions are of interest because the bulk conductance gives an indication of the mobility of charges within the system, while the barrier layer gives an indication of the bchaviour of the polymer molecules themselves. The high frequency dielectric loss (G/w) increases in the presence of the triethanolamine, reflecting an increase in conductivity due to the presence of additional mobile charges within the system. The low frequency response, however, shows comparatively little change, indicating that the adsorbed layer remains largely unchanged.

-1 Log

3

1

Frequency

(Log

5

Hz1

Fig. 2. Effect of the addition of triethanolamine on the dielectric response of Carbopol 934. n, +: C,G/o 5% Carbopol 934 (no TEA). 0, 0: C,G/o 5% Carbopol934 (8% TEA).

Clearly, therefore, the presence of triethanolamine is increasing the moduli of the gel system, possibly due to a greater degree of ionisation of the carboxyl groups. The dielectric data indicated that at least a significant proportion of the triethanolamine is in a free state, as shown by the increase in conductance. However, the similarities between the low frequency responses for the systems with and without base indicate that the ease with which charges move through the gel layer remains largely unchanged. Similar results were found on adding calcium to alginate gels [ 221, i.e., the viscosity of the system showed a substantial increase but the low frequency response remained largely unchanged. It is thought that the dielectric response reflects the movement of small molecules through the system, while the rheological bchaviour reflects the flexibility of the polymer network itself. In this case, therefore, despite the increase in viscosity, the movement of smaller molecules (probably residual ions in the polymer of trace ionic impurities in the water) has not been significantly altered. 4.2. The effect of Carbopo1934 concentration The effect of changing the concentration on the rheological properties of Carbopo1934 is indicated in Fig. 3, which shows the response of 2.5 and 5% w/v systems. Again, the response is relatively flat, with both the storage and loss moduli being lower for the 2.5% w/v system. However, the proportionality of the two moduli (as shown by the tans value) is similar for both

218

D.Q.M. Craig etal. /Joloumai of Controlled Release 30 (1994) 213-223

Table 2 Parameters characterising the dielectric response of Carbopol gel systems Sample

G(Mho) at 1~ Hz

G( Mho) at 0.1 Hz

C(P) at 1000 Hz

Log capacitance slope (l-0.1 Wz)

C(P) at 0.1 Hz

5% w/v carbopo1934 (8% triethanolamine)

5.884X lo-*

3.693 x IO+

3.834X lo-’

0.131

1.369X IO-’

5% w/v Carbopo1934 (0% t~e~anolamine)

6.738X lo-’

5.070x lo+

7.127x lo-’

0.120

1.396x IO-”

2.5% w/v Carbopo1934 (4% triethanolamine)

2.891 x IO-*

6.524 X IO+

8.512x lo-*

0.153

1.207X 1O-5

2.5% w/v carbopo1934 2.155 x 10-2 (4% t~e~~ol~ne, 5% propylene glycol)

3.157x 1ov

1.375x 10-1

0.203

9.104x lo-”

2.5% w/v Carbopol934 1.899x lO-2 (4% trietbanolamine, 15% propylene glycol)

3.833 X lO+

9.267X 10-s

0.190

9.528X 1o-6

2.5% wlv Carbopol934 1.640x lo-2 (4% triethanolamine, 0.1% chlorhexidine gluconate)

4.913x 1o-6

1.839x IO-’

0.222

6.968 x 1o-6

2.5% w/v Carbopo1934 3.599 x 10-2 2.126X lO-6 2.099x 10-7 (4% w/v triethanolamine, 5% w/v propylene glycol, 0.05% chlorhexidine gluconate)

0.075

1.052x lo-’

2.5% w/v Carbopol934 4.711X 10-2 2.599x lo+ 3.341 x 10-7 (4% w/v trietbanolamine, 5% w/v propylene glycol, 0.1% chlorhexidine gfuconate)

0.124

1.219x 10-5

systems, indicating that the mechanism of mechanical relaxation is similar for both concen~ations. The dielectric response of the two systems is shown in Fig. 4. As may be expected, the high frequency conductance is lower for the 2.5% w/v system, as the number of charge carriers within the gel is reduced. The low frequency response is similar between the two samples, with a slight decrease in capacitance and increase in loss seen for the 2.5% gels.

the low frequency capacitance, indicating that the barrier layer is becoming more permeable to the movement of charge through the system, although the actual amount of charge moving through the system decreases on adding propylene glycol. This latter effect could be due to the substitution of water for propylene glycol which in turn may result in a decrease in the total content of trace ionic impurities within the system. It appears that the propylene glycol is interacting with the polymer network in a way which increases

4.3. The effects of added propylene glycol 10000,

The effects of adding 5% and 15% wiv propylene glycol to the 2.5% w/v Carbopo1934 gels on the rheological response are shown in Fig. 5a and b. Both the storage and loss moddi of the gels increased on adding propylene glycol, despite the molecular weight of the additive being considerably smaller than that of the polymer. Furthermore, the tan8 value increased on addition of propylene glycol, implying a proportionately greater viscous com~nent for these gels. For the systems containing 15% w/v propylene glycol, there was a further marked increase in the storage modulus, al~ough the effect on the loss modulus was less well defined. The dielectric response is shown in Fig. 6a and b. The presence of propylene glycol is clearly altering

5

cn 10

I

f

/

0.01

0.1 Frequency

I

1

10

B-k1

Fig. 3. Rheological properties of 2.5% and 5% Carbopol934. II, + : G’,G” 2.5% Carbopol934.0,0: G’,G’ 5% Carbopol934.

D.Q.M. Craig et al. /Journal of Controlled Release 30 (1994) 213-223

-2

-1

0

1

Log Frequency

2

3

4

(Log Hz)

Fig. 4. Dielectric properties of 2.5% and 5% Carbopol934. C,G/o 2.5% Carbopol934.0,O: C, G/o 5% Carbopol934.

n, + :

both the storage and loss moduli, although the mechanisms involved are not yet clear. However, examination of the rheological and dielectric data together indicates that while the rigidity of the chains may be increasing, the effective porosity may also be increasing. The addition of propylene glycol therefore appears to result in a more rigid but more open structure. It is also interesting to note that in three out of the four parameters studied, the changes seen on adding propylene glycol do not appear to be particularly concentration dependent, as the 5 and 15% systems gave similar results compared to the gels containing no propylene glycol. A similar trend was noted for the diffusion coefficients of chlorhexidine gluconate through the gels [ 151. 4.4. The effects of adding chlorhexidine gluconate Given the fact that the gel systems already contain a significant quantity of base, the addition of 0.1% CHG may be expected to have little effect on the gel structure, despite the presence of basic groups within this molecule. However, inspection of the rheological data (Fig. 7) indicates that at low frequencies, the presence of the drug has a profound effect on both the storage and loss moduli, with a peak being seen in the latter. At high frequencies, an increase in the storage modulus was seen on addition of the drug. However, the tani3 value increases from 0.1766 at 10 Hz to 1.092 at 0.01 Hz, indicating a large increase in the preponderance of the viscous behaviour of the sample at low frequencies. While it is possible to use one of a number of spring/ dashpot models to describe rheological behaviour, it is

219

nevertheless difficult to directly relate these models to the precise molecular behaviour of the gels. It may be speculated, however, that the addition of CHG may result in ‘thinning’ of the gel due to the screening of the anionic groups on the polymer chains, although the mechanism is likely to be complex. In addition, Fu Lu et al. [ 301 have reported the formation of complexes between erythromycin and claithromycin and Carbopol 934, hence a similar phenomenon may be occurring here. In either case, the rigidity of the bonds between adjacent polymer chains has clearly been altered. The marked changes seen in the rheological data are mirrored by equally marked changes in the dielectric response, as shown in Fig. 8. The barrier layer is considerably less well defined in the presence of the CHG (seen by the higher negative slope of the low frequency capacitance given in Table 2)) indicating that the barrier function of the gel layer has been profoundly disrupted, i.e., charge may move in and out of the gel structure comparitively easily. This correlates with the rheological data, in that the gel structure has become considerably more open in the presence of the CHG. Both the dielectric and rheological profiles of the gels containing 5% propylene glycol were also altered on addition of the model drug at two concentration levels, as shown in Figs. 9a and b and 10a and b. The storage modulus showed a decrease in the low frequency modulus for samples containing 0.05% drug, while the effect on the loss modulus was very marked, particularly for the 0.05% drug sample. Again, therefore, the presence of CHG causes an increase in the loss modulus at low frequencies, indicating an increase in the viscous properties of the system. It is interesting to note that the presence of 0.05% drug had a greater effect on the low frequency loss modulus than did the 0.1% system, although the other parameters (storage modulus, capacitance and dielectric loss) seemed to show little change between the 0.05 and 0.1% systems compared to the responses seen for the gels containing no drug. Overall, the effects on the dielectric response were not as marked as for the systems without propylene glycol, possibly due to the gel structure having already been to some extent disrupted by the propylene glycol itself. Moreover, Figure 10a and Table 2 indicates that the integrity of the barrier layer is increased in the presence of the drug (indicated by the slope of the low frequency capacitance), hence some synergistic effect may be present between the drug and the

220

D.Q.M. Craig et al. /Journal of Controlled Release 30 (1994) 213-223

5a

1400

?

1

250 1

-

1220

i

5b

220 -E

z

E

L-

190-

z

1040-

4 9

660 -

zk : ci

660

500

! 0.01

I 0.1

I 1

Frequency

1

70

10

!

H

0.01

0.1

(Hz)

1

Frequency

10

(Hz1

Fig. 5. Effect of propylene glycol on (a) the storage modulus and (b) the loss modulus of Carbopol 934. W: 2.5% Carbopol 934. + 2.5% Carbopo1934 with 5% propylene glycol. 0 2.5% Carbopo1934 with 15% propylene glycol. 6a

6b

-4

-3 G:

iz

1 ! 0" -'

-4

2

s

.p

-5

t; u

;

0" -I

0

-6

-6

-7

-2

-1

0

1

Log Frequency

2

3

4

5

-3

-2

(Log Hz)

-1

0

1

Log Frequency

2

3

4

(Log Hz)

Fig. 6. Effect of propylene glycol on (a) the capacitance and (b) the dielectric loss of Carbopol934. Cl: 2.5% Carbopol934.0 934 with 5% propylene glycol. 0 2.5% Carbopo1934 with 15% propylene glycol.

2.5% Carbopol

10000 -E ti 2 %

1000

B I 2 <

100

zil m ii cii 10 0.01

0.1

Frequency

1

10

(Hz1

Fig. 7. Effect of chlorhexidine gluconate on the rheological properties of Catbopol934. W, + : G’S Carbopol934. Cl, 0: G’.G’ Carbopol 934 with 0.1% CHG.

-2

-1

0

1

Log Frequency

2

3

[Log

4

5

Hz1

Fig. 8. Effect of chlorhexidine gluconate on the dielectric properties of Carbopol934. H, 0: C,G/o Carbopol934.0,O: CC/o Carbopo1934 with 0.1% CHG.

D.Q.M. Craig et al. /Journal of Controlled Release 30 (1994) 213-223

400; 0.01

0.1

Frequency

1

10

0.01

221

0.1

(H-4

1

Frequency

10

[Hz)

Fig. 9. Effect of chlorhexidine gluconate and propylene glycol on (a) the storage modulus and (b) the loss modulus of Carbopol934.0: Carbopol934 with 5% propylene glycol. 0 0.05% CHG. 0 0.1% CHG added.

2.5%

lob

-3

Log Frequency

[Log

Hz)

I

,

I

I

1

I

-2

-1

0

1

2

3

Log Frequency

I

4

5

(Log Hz]

Fig. 10. Effect of chlorhexidine gluconate and propylene glycol on (a) the capacitance and (b) the dielectric loss of Carbopol934. 0: 2.5% Carbopol934 with 5% propylene glycol. 0 0.05% CHG added. 0 0.1% CHG added.

propylene glycol. However, the most important conclusions from this study is that the data clearly shows that the presence of relatively small quantities of CHG may have a profound effect on the structure of the gel.

5. Conclusions

The study has indicated the potential of using dielectric and rheological measurements in conjunction, particularly in terms of analysing gel systems. The results shown here support the suggestion made in a previous study [ 221 that rheological studies may give information on the behaviour of the polymer chains, while dielectric analysis may give information on the movement of charges through the system. This there-

fore allows a much more complete analysis of not only gel systems, but also of drug dispersions ion gels. It would clearly be desirable to be able to make more exact predictions of gel structure from the data, particularly in terms of using the dielectric data to predict porosity and diffusion coefficients and the rheological data to predict the degree of entanglement. However, this study has suggested that by using the two techniques in conjunction, such an analysis is indeed feasible. The change in properties observed on adding propylene glycol correspond to the alteration in release rate from the gels noted in a previous study [ 151. The rheological and dielectric data indicated that the propylene glycol caused the gel structure to become more open, while the dissolution data indicated that the dif-

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D.Q.M. Craig et al. /Journal of Controlled Release 30 (1994) 213-223

fusion coefficient through the gel increased with increasing concentration of propylene glycol. While this observation would broadly support the conclusions drawn from the rheological and dielectric studies, caution is required when relating the two studies, as, by definition, the dissolution studies are examining the release of a drug from the gel systems while the studies examining the effect of propylene glycol addition contained no drug. This conclusion is especially pertinent as this investigation showed that the presence of a drug may itself have a profound effect on the gel structure. On the basis of the dielectric and rheological effects observed here, it is not necessarily valid to correlate the dissolution behaviour of one drug with that of another as the drug itself may alter the gel structure. Furthermore, while the dissolution behaviour from the gel is reported to obey the Higuchi equation [ 151, it is important to note that the calculated apparent diffusion coefficients should not be used on anything other than a comparitive basis if the drug is interacting with the matrix. Simple diffusion models may not be applicable in such cases and care must be taken in trying to calculate the true diffusion coefficients from such drug release studies. Overall, therefore, the study has demonstrated that the use of rheological and dielectric studies in conjunction provides a powerful means of material characterisation for gel systems and that, in this particular case, the effects of including various additives, such as a model drug, may have a profound effect on the structure of the gel. It is arguably necessary to have a much greater understanding of such interactions in order to fully understand, and hence predict, the release behaviour of drugs from gel systems. The datadescribed here, when considered in combination with dissolution data given in a previous study [ 151, indicates that the use of these two techniques in combination provides an effective means of characterising the physical properties of gel systems and that these properties are pertinent to the understanding the mechanism of release of drugs from Carbopol and other gels.

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