The profiles of drug (paracetamol) release from the pellets produced and the results of the statistical moment analysis are presented in Figures 4.1-4.7 and Table 4.8. The results proved that for the pellets studied, paracetamol was released at least 90% or completely within 3 h, confirmed by the plateau occurring during the dissolution study. The burst effect (i.e. more than 60% of drug content was released within the first 5 min) were found for particular formulations (AP-03, AP-04, MP-03, HP-03, EP-03). Thus, low AUC and MDT values were obtained for these formulations. Their low VR values confirmed the steepness of the initial stage of the dissolution curves (Table 4.8). In common, these formulations were wetted with the binder liquids in which the proportions of ethanol were relatively high, having surface tension approximately 29 mN/m (Table 2.2). To identify the effect, the pellets were sputter coated with gold (Emitech K550, Kent, UK) and the surface structure of pellets was viewed using scanning electron microscopy (Philips XL20 scanning electron microscope, Eindhoven, The Netherlands). The micrographs of the surface of the pellet before and after the dissolution studies (Figure 4.8-4.9) proved the presence of a considerable amount of the drug on the surface of these pellets resulting in a rapid release in the initial stage. The deposition of the drug on the surface of pellets may be attributed to a relatively high migration of binder liquid between particles from the core to the surface of products which was accompanied by the migration of dissolved paracetamol during the process. In addition, as the proportions of ethanol in the system of binder liquid increased, the solubility of paracetamol increased and hence the amount of dissolved paracetamol in the migrating liquid increased. Thus, the lower solubility of paracetamol in the system which contained a relatively low proportion of ethanol, or did not contain ethanol, can explain a decrease in the amount of dissolved paracetamol migrating with the liquid to the surface, and hence the absence of such burst effect. The effect of the decrease in the surface tension of the binder liquid on an increase in the migration of liquid cannot be simply established, although it was possible that the reduced surface tension of the liquid could reduce the forces which hold the mass together. The solution of binders (MC or HPMC) which had relatively low surface tension, compared to that of water, was not in this case due to the binding properties of the additives. Conversely, it has been reported that for the formulation tested, lowering the surface tension by the addition of a surfactant
100 60 A P - 0 1 M P - 0 1 M P - 0 2 2 . 5 2 3 0 0 . 5 1 1 .5 T i m e ( h )
Figure 4.1 The influence of the addition of methylcellulose as a powder (MP-01) or a solution (MP-02) on drug (paracetamol) release from pellets. Formulation AP-01 contained no additive. 100 OU
1
" 4 0I
A P - 0 1 H P - 0 1 H P - 0 2 2 . 5 3 0 0 . 5 1 1.5 2 T i m e ( h )Figure 4.2 The influence of the addition of hydroxypropyl methylcellulose as a powder (HP-01) or a solution (HP-02) on drug (paracetamol) release from pellets. Formulation AP-01 contained no additive.
100
A P - 0 1 S P - 0 1
0 0 . 5 1 1.5 2 2 . 5 3
T i m e ( h )
Figure 4.3 The influence of the addition of Starch 1500 (SP-01) on drug (paracetamol) release from pellets. Formulation AP-01 contained no additive.
100
A P - 0 1 E P - 0 1
0 0 . 5 1 1 .5 2 2 . 5 3
T i m e ( h )
Figure 4.4 The influence of the addition of ethylcellulose as a powder on drug (paracetamol) release from pellets. Formulation AP-01 contained no additive.
100 4 0 A P - 0 1 S R P - 0 1 E U P - 0 1 0 0 . 5 1 1.5 2 2 . 5 3 T i m e ( h )
Figure 4.5 The influence of the addition of Surelease E-7-19010 (SRP-01) and Eudragit RS30D (EUP-01) on drug (paracetamol) release from pellets. Formulation AP-01 contained no additive. 100 "O A P - 0 4 M P - 0 3 H P - 0 3 0 0 . 5 1 1.5 2 2 . 5 3 T i m e ( h )
Figure 4.6 The influence of the addition of methylcellulose (MP-03) and hydroxypropyl methylcellulose (HP-03) on drug (paracetamol) release from pellets, when the mixture of ethanol and water (1:1, by volume) was used as a binder liquid. Formulation AP-04 contained no additive.
100 g
I
I
AP-02EP-02 AP-03 EP-03 0 0.5 1 1.5 2 2.5 3 T i m e ( h )Figure 4.7 The influence of the addition of ethylcellulose as a solution on drug (paracetamol) release from pellets. Formulation EP-02 contained 2% ethylcellulose. Formulation EP-03 contained 4% ethylcellulose. Formulations AP-02 and AP-03 contained no additive.
Table 4.8 Area under the dissolution curve, AUC; mean dissolution time, MDT; variance associated with the MDT, VR; relative dispersion of dissolution time, RD,
{mean and standard deviation, n = 6) and release model, RM, of drug release from pellets, in sieve fraction 1000-1400 pm, produced from the formulations used to investigate the influence of hydrophilic and hydrophobic polymers on the formation and
Formulation AUC (%-h) MDT (h) VR(h") RD RM* AP-01 54.3 (0.8) 0.57 (0.00) 0.36 (0.01) 1.097 (0.029) N AP-02 61.5 (0.8) 0 . 6 6 (0 .01 ) 0.51 (0.01) 1.191 (0.013) N AP-03 9.0 (0.3) 0 . 1 0 (0 .01 ) 0 . 0 2 (0 .0 1 ) 1.730 (0.040) N AP-04 7.7 (0.5) 0.08 (0 .00 ) 0 . 0 1 (0 .0 0 ) 2.032 (0.101) N MP-01 70.1 (4.0) 0.73 (0.04) 0.48 (0.03) 0.917 (0.044) 1 MP-02 65.3 (2.0) 0.69 (0.02) 0.39 (0.01) 0.828 (0.026) 2 MP-03 14.9 (0.4) 0.16 (0 .01 ) 0.09 (0.01) 3.605 (0.084) N HP-01 66.3 (0.7) 0 . 6 8 (0 .0 1) 0.38 (0.01) 0.825 (0.020) 2 HP-02 63.5 (2.9) 0.66 (0.03) 0.37 (0.01) 0.852 (0.041) 2 HP-03 14.5 (1.1) 0.16 (0 .0 1) 0.09 (0.01) 3.504 (0.070) N SP-01 46.4 (2.3) 0.50 (0.01) 0.16 (0 .0 1) 0.654 (0.011) 3 EP-01 39.1 (1.3) 0.41 (0.02) 0 . 2 0 (0 .0 1 ) 1.191 (0.051) N EP-02 61.9 (3.7) 0.66 (0.05) 0.48 (0.04) 1.100 (0.064) 1 EP-03 15.4 (1.2) 0.16 (0 .0 1 ) 0.06 (0 .0 1 ) 2.380 (0.078) N SRP-01 47.5 (1.7) 0.49 (0.02) 0 . 2 1 (0 .0 1 ) 0.896 (0.028) N EUP-01 71.9 (2.8) 0.76 (0.02) 0.55 (0.03) 0.964 (0.020) 1
* Release mode : 1, first order; 2, square root; 3, cube root; N, no simple kinetics (Table 1.1).
$
cc V Spot Maqn 00kV6 0 386x
Det WD I--- St 24 0 APOItA
(a) N o additive (b) No additive
Æ
(a) 3% Methylcellulose (b) 3% Methylcellulose
.'•'SO m V spot Maqn IOOkV4 0 38 6 x D e l WO I--- Sf 26 2 HPOltA
(3) 3% Hydroxypropyl methylcellulose (b) 3% Hydroxypropyl methylcellulose
figure 4.8 Scanning electron micrographs of the surface of pellets, formed by using water as the *^^er liquid, before (a) and after (b) the dissolution tests.
r
, t
%
# %
(a) No additive (b) No additive
cc V Spot Maqn
0 0 I V 4 0 386k
Del WD I- - - -
SE 24.4 MP4)3A
(a) 3% Methylcellulose (b) 3% Methylcellulose
V spot Magn l 0 0 k V 4 0 386k 3% Hydroxypropyl methylcellulose H h B (b) 3 % hydroxypropyl methylcellulose Del WD I--- SE 26 0 HP4WA
figure 4.9 Scanning electron micrographs of the surface of pellets, formed by using the mixture of ^^hanol and water ( : , by volume) as the binder liquid, before (a) and after (b) the dissolution tests.
resulted in a decrease in the migration of liquid to the surface of pellets (Chien and Nuessle, 1985). In this study, however, since the system contained ethanol, a rapid evaporation of this solvent, together with the effect of the centrifugal force, interparticle collision, or particle-spheronizer wall collision, could pull the liquid to the surfaces of the particle during spheronization and/or drying. The surfaces of these pellets after spheronization were found to be wetter than those of pellets produced from other formulations.
Using the aqueous binder liquid, there appeared to be a slight increase in the values of AUC and MDT when the hydrogel-forming polymers (MC and HPMC) were incorporated at a 3% level, while a slight decrease in these values was obtained for the formulation containing 30% swellable polymer ( Starch 1500), This may be due to the fact that the pellets containing Starch 1500 were swollen and partially disintegrated during the dissolution test. The pellets containing MC or HPMC, however, did not visibly change in size or form a gel barrier. This probably related to a relatively small quantity of the polymer in the pellets. The dissolution results observed for the formulations containing MC and Starch 1500 somewhat confirmed the results of Funck et al. (1991) who found that for the formulations tested, the pellets containing 2% Starch 1500 disintegrated, while the pellets containing 2% MC remained intact during the dissolution studies and that there was no marked influence of these materials on the drug release. The method of incorporating these polymers did not appear to affect the AUC and MDT values.
The incorporation of 30% EC into the formulation did not provide retardation of drug release. On the contrary, this decreased the values of AUC, MDT and VR, as opposed to the standard formulation. EC is a more hydrophobic material and has considerably less wettability (contact angle = 102.90°) than MCC (contact angle = 40.53 °). Thus, the presence of EC in the pellets should reduce the wettability of the surface of pellets in the dissolution medium. However, as the proportion of MCC (60%) was higher than that of EC (30%), it was possible that the surface of pellets still had good wetting properties; hence subsequent penetration of the dissolution medium could occur as the standard formulation. The disruption of an hydrophilic matrix by the presence of an hydrophobic material could contribute to the more rapid drug release, as opposed to the standard formulation.
The drug and EC, which both dissolve in ethanol, were expected to precipitate out together when water was subsequently added. Thus, this would result in a more hydrophobic surface of drug particle. An attempt was made to study this occurrence at two levels of EC. The dissolution results, however, show a marked difference for the two formulations studied. The formulation containing a higher quantity of EC (solid weight) provided a rapid drug release. Thus, the hydrophobicity of EC could not explain this effect. The proportion of ethanol to water and the migration of dissolved paracetamol to the surface contributed to the rapid drug release of the formulation containing lower EC content and a higher proportion of ethanol (EP-03), as discussed previously. On the other hand, the wet powder mass which contained a lower quantity of EC and lower proportion of ethanol (in EC solution) required more water to provide a correct consistency. As a result, paracetamol is less soluble in this liquid system and could precipitate out. The precipitation of paracetamol for the formulation EP-02 could cause a slight increase in the values of AUC, MDT and VR, as opposed to the standard formulation AP-01 studied on water as the binder liquid, but resulted in similar AUC, MDT and VR values, as compared to formulation AP-02 studied on the same amount of ethanol and water.
With the same solid content, the incorporation of Surelease E-7-19010 resulted in a decrease in the values of AUC, MDT and VR, while Eudragit RS30D could extend these values, when compared to the standard formulation (AP-01). Eudragit RS30D has been studied and appeared to give retardation of drug release from pellets which also contained Avicel RC 591, acid and plasticizer (Goskonda et al., 1994). In this study, however, with a simple system (drug, Avicel PH-101 and Eudragit RS30D), the presence of Eudragit RS30D up to 15% (solid weight) did not give appreciable retardation of drug release, although there was a reduction in the release of drug from the pellets greater than with the addition of other additives studied. As opposed to the addition of EC as a powder at 30%, the addition o f EC in the form of aqueous dispersion at 15% (solid content) gave slightly higher AUC and MDT values and equivalent VR values.
The kinetics of drug release, as predicted by the application of statistical moment analysis, was found to be associated with the additives and the method of incorporation.
Nonetheless, for some of the formulations studied, such as the pellets which exhibited a burst effect, no simple kinetics could be identified. This was, presumably, due to more
than one process of drug release occurring simultaneously. First order kinetics were obtained for the formulations containing 3% MC incorporated as a powdered ingredient (RD = 0.917 ± 0.044), 2% EC incorporated as a solution (RD = 1.100 ± 0.064), and for the formulation containing Eudragit RS30D (RD = 0.964 ± 0.020). Thus, the rate of drug release from these pellets was dependent on the amount of drug remaining in the pellets. The square root of time relationship was found for drug release from pellets containing 3% MC incorporated in the form of a solution (RD = 0.828 ± 0.026) and the formulations containing 3%HPMC incorporated as either a powder (RD = 0.825 ± 0.020) or a solution (RD = 0.852 ± 0.041). Overall, the drug release of pellets containing hydrogel-forming polymers was generally governed by the diffusion process. For the pellets containing Starch 1500 which partially disintegrated (RD = 0.654 ± 0.011), the cube root law dominated the kinetics of drug release, reflecting that the dissolution of drug particle was the rate-limiting step.
4.5 CONCLUSIONS
The main aim of this study was to establish the influence of a range o f additives which could provide a potential retardation of drug release. Paracetamol was used as the model drug at 10%. An attempt was made to incorporate the hydrophilic and hydrophobic polymers into the formulations of pellets at limiting levels o f each of the polymers.
When water was the binder liquid, the levels of 3% methylcellulose, 3% hydroxypropyl methylcellulose, 30% Starch 1500, or 30% ethylcellulose in the formulations of pellets were restricted with the feasibility of processing by extrusion/spheronization. The addition of the different hydrophilic polymers (methylcellulose, hydroxypropyl methylcellulose, or Starch 1500) and aqueous dispersion of hydrophobic polymers (ethylcellulose (Surelease E-7-19010) and acrylate-copolymers (Eudragit RS30D)) were found to aid the extrusion, giving a uniform extrudate. However, this did not improve the quality of pellets as the pellets produced appeared to be less round, when compared with pellets which did not contain additive. On the other hand, the addition of ethylcellulose at 30% gave a severe forced flow profile, yet variable extrudate possessed sufficient deformability and could be rounded to become spherical
pellets. The dissolution results of these formulations provided no distinct retardation of drug release from pellets, when compared to the formulation of pellets containing no additive. The application of statistical moments analysis identified the kinetics of drug release for some of the formulations studied. The kinetics of drug release from the pellets which remained intact was governed by either first order or diffusion process. For pellets containing Starch 1500 which partially disintegrated, the rate of drug release was controlled by the dissolution of drug particles.
The use of ethanol as a co-binder liquid with water markedly influenced the processability, the characteristics of the pellets produced, and drug release from these pellets. For the formulation containing methylcellulose or hydroxypropyl methylcellulose, the change of binder liquid from water to the mixture of ethanol and water resulted in the reduction of the amount of liquid required to form a good consistency o f the wet powder mass, the possibility of increasing the level of the polymer in the formulation, and the shorter time of spheronization. In general, when ethanol was present, a decrease in the size of pellets and an increase in their porosity was observed.
Despite the fact that none of the formulations of pellets studied provided substantial retardation of drug release, the influence of the presence of ethanol as a co- binder liquid on drug release was found to be dependent of the proportion of ethanol to water. The relatively high proportions of ethanol to water caused the deposition of paracetamol on the surface o f pellets and hence the burst effect at the initial stage of the dissolution tests.
The kinetics of drug release from pellets formed with ethanol and water was rarely identified with the defined kinetics.
Overall results signified that it was not possible to develop a prolonged drug release matrix pellet, prepared by the process of extrusion and spheronization, by the addition of the hydrophilic and hydrophobic polymers. A relatively small quantity of the polymeric additive which could be incorporated in the formulation of pellets could be one reason.