5.4 RESULTS AND DISCUSSION
5.4.2 In Vitro API Release Studies
The dissolution profile generated for batch NVP001 revealed that the rate of NVP release was very low and incomplete after 24 hours of testing with only 16.7 % of NVP released as shown in Figure 5.6.
Figure 5.6. Dissolution profile of NVP release from tablets of batch NVP001 and Viramune® XR (n = 6).
The incomplete drug release from the tablets of batch NVP001 was attributed to the use of a high percentage (30%) of HPMC in the formulation. It has been observed that regardless of the physicochemical properties of the polymer and API, drug release generally decreases with an increase in the percent composition of the release controlling polymer used to form the matrix. Large quantities of polymer correspond to low porosity in the matrix resulting in a slower rate and extent of API release [331]. The use of a high proportion of polymer also promotes a greater degree of cross-linking, an increase in the gel layer thickness and tortuosity of the matrix, which are characteristics that impede API diffusion through the gel layer thereby altering API release [332].
0 20 40 60 80 100 120
0 5 10 15 20 25 30
Cumulative % drug release
Time (hours)
REF NVP001
153 | P a g e
The percent HPMC in batch NVP002 was reduced by 5% in an effort to improve the rate and extent of drug release from the tablets, as it has been reported that an increase in the percent polymer from 3.5% to 19.2% resulted in a decrease in the release rate of an API [333].
Therefore, it was anticipated that a decrease in the amount of polymer used in the matrix would result in an increase in NVP release from the tablets. However, the resultant increase in NVP release was minimal and a total of only 19.64% NVP was released after 24 hours of dissolution testing as depicted in Figure 5.7.
Figure 5.7. Dissolution profile of NVP release from tablets of batch NVP002 and Viramune® XR (n = 6).
The percent HPMC in batch NVP003 was reduced by a further 10 % in an effort to increase the rate and extent of NVP release, however the resultant increase in NVP release was also minimal with only 34.9 % NVP released after 24 hours of dissolution testing as shown in Figure 5.8.
0 20 40 60 80 100 120
0 5 10 15 20 25 30
Cumulative % drug release
Time (hours)
REFNVP002
154 | P a g e
Figure 5.8. Dissolution profile of NVP release from tablets of batch NVP003 and Viramune® XR (n = 6).
The slow rate of release of NVP from tablets of batches NVP002 and NVP003 was attributed to the presence of DCP in the matrices as it is insoluble and has been shown to retard API release from matrix tablets by blocking the diffusion of the API from the matrix and by decreasing the erosion of the polymer matrix [334, 335]. It has been reported that the use of DCP can have a significant impact on API release from matrix formulations, particularly if the API is poorly water soluble, as NVP is. DCP makes the matrix less accessible to water thereby reducing the degree of matrix erosion, which is an important factor in determining the rate and extent of release of poorly water soluble compounds [336]. Consequently DCP was not included in subsequent formulations in an attempt to improve the rate and extent of release of NVP.
In an attempt to improve the rate and extent of NVP release, batch NVP004 was manufactured using 10% w/w HPMC, however the tablets exhibited rapid release and a high extent of NVP release with approximately 98% of the NVP released within two hours of commencing testing as shown in Figure 5.9.
0 20 40 60 80 100 120
0 5 10 15 20 25 30
Cumulative % drug release
Time (hours)
REFNVP003
155 | P a g e
Figure 5.9. Dissolution profile of NVP release from tablets of batch NVP004 and Viramune® XR (n = 6).
The rapid rate of release and high extent of NVP release from tablets of batch NVP004 was more likely due to the fact that DCP was not used in the formulation and insufficient HPMC was included. This resulted in a decrease in the gel strength and a high porosity that favours NVP diffusion out of the matrix [336]. Furthermore the rapid release observed may also be a function of an increase in the amount of lactose used in the formulation. This effect of lactose may be attributed to the dissolution of lactose on hydration of the tablet, which may result in an increase in the porosity and a reduction of the gel strength of the matrix [335].
The formulation of Batch NVP005 was modified by increasing amount of HPMC by 10%
and decreasing the amount of lactose by 10 % with a view to decreasing the rate of NVP release from the tablets. The release of NVP decreased appreciably but was still more rapid than that observed for the reference product with approximately 53.5% released within the first two hours of commencing dissolution testing as shown in Figure 5.10.
0 20 40 60 80 100 120
0 10 20 30
Cumulative % drug release
Time (hours)
REF NVP004
156 | P a g e
Figure 5.10. Dissolution profile of NVP release from tablets of batch NVP005 and Viramune® XR (n = 5).
The amount of HPMC was then increased by a further 10% and the spray dried lactose content was reduced from 30% to 20% to produce batch NVP006. The rate of release of NVP decreased significantly and the dissolution profile was observed to be similar to that of the reference product as shown in Figure 5.11. Calculation of the f1 and f2 values to permit comparison of the dissolution profiles yielded f1 and f2 values of 14.1 and 52.1, respectively and indicates that the tablets from batch NVP006 could release NVP similar to the profile observed for the reference tablets. Consequently the formulation for batch NVP006 was selected for further development and optimisation.
0 20 40 60 80 100 120
0 10 20 30
Cumulative % drug release
Time (hours)
REFNVP005
157 | P a g e
Figure 5.11. Dissolution profile of NVP release from tablets of batch NVP006 and Viramune® XR (n = 6).
A combination of polymers with different chemistries or viscosities can be used to optimise drug release from hydrophilic matrices manufactured using HPMC as the primary release controlling polymer [337, 338] and carbomers to modulate drug release from matrices [339, 340]. This combination has been reported to produce a synergistic increase in the viscosity of a matrix due to strong hydrogen bonding between the carbomer and HPMC [340]. The stronger cross-link between the two polymers produces a more rigid structure through which diffusion must take place and the interaction results in increased stability of API release profiles compared to matrices manufactured with HPMC alone [340].
The combination of anionic polymers and HPMC can influence drug release in basic dissolution media by lowering the micro-environment pH of the matrix and can also decrease API release in acidic media through formation of an insoluble matrix [339, 340].
Batches NVP007, NVP008 and NVP009 were formulated using combinations of Methocel® K4M and Carbopol® 71G NF, with the HPMC content fixed at 10% and the amount of Carbopol® 71G NF ranging between 5% and 15%. Tablets from batch NVP007 produced rapid release of NVP with 100% being released within the first two hours of commencing dissolution testing as shown in Figure 5.12.
0 20 40 60 80 100 120
0 5 10 15 20 25 30
Cumulative % drug release
Time (hours)
REF NVP006
158 | P a g e
Figure 5.12. Dissolution profile of NVP release from tablets of batch NVP007 and Viramune® XR (n = 6).
Increasing the amount of Carbopol® 71G NF from 5% to 10% and then 20% of the total polymer content resulted in significant retardation of NVP release from the tablets of batch NVP008 as shown in Figure 5.13.
Figure 5.13. Dissolution profile of NVP release from tablets of batch NVP008 and Viramune® XR (n = 8).
0 20 40 60 80 100 120 140
0 5 10 15 20 25 30
Cumulative % drug release
Time (hours)
REFNVP007
-20 0 20 40 60 80 100 120 140
0 5 10 15 20 25 30
Cumulative % drug release
Time (hours)
REFNVP008
159 | P a g e
Tablets from batch NVP008 had a comparable dissolution profile to that of the reference product and yielded f1 and f2 values of 13.5 and 52.4, respectively. However NVP release at selected time points were highly variable and this may well be due to the inclusion of Carbopol® 71G. Performance of carbomers has been reported to be variable with large fluctuations in API release [340] and therefore this formulation was not developed further.
A further increase in the amount of Carbopol® 71G NF to 15% and the total polymer content to 25% resulted in much slower NVP release with a total of only 52.9% of the NVP released after 24 hours of commencing testing as shown in Figure 5.14.
Figure 5.14. Dissolution profile of NVP release from tablets of batch NVP009 and Viramune® XR (n = 6).
These studies indicate that appropriate modulation of NVP release can be readily achieved with a combination of carbomer and HPMC at lower total polymer levels than if the polymers were used individually, which has been observed with other data [338-340].
Combinations of HPMC and methacrylic acid copolymers have been studied extensively and adequate control over drug release rates have been reported with these combinations [341- 344]. An attempt to modulate NVP release using a polymer mixture of Methocel® K4M and Eudragit® RS PO was attempted and batches NVP010, NVP011 and NVP012 were produced
0 20 40 60 80 100 120
0 10 20 30
Cumulative % drug release
Time (hours)
REFNVP009
160 | P a g e
using these polymers. This polymer combination did not retard NVP release at the total polymer concentrations used as the tablets released 100% NVP within 2 hours of commencing testing. It was evident that the use of this polymer combination would require large amounts of Eudragit® RS PO which would result in a more expensive product compared to if HPMC or combinations of HPMC and Carbopol® 71G NF were used.
Therefore this approach was not pursued further. The dissolution profiles of NVP release from batches NVP010, NVP011, NVP012 and Viramune® XR are shown in Figures 5.15- 5.17.
Figure 5.15. Dissolution profile of NVP release from tablets of batch NVP010 and Viramune® XR (n = 6).
0 20 40 60 80 100 120 140
0 10 20 30
Cumulative % drug release
Time (hours)
REFNVP010
161 | P a g e
Figure 5.16. Dissolution profile of NVP release from tablets of batch NVP011 and Viramune® XR (n = 6).
Figure 5.17. Dissolution profile of NVP release from tablets of batch NVP012 and Viramune® XR (n = 6).
0 20 40 60 80 100 120 140
0 10 20 30
Cumulative % drug release
Time (hours) REF NVP011
0 20 40 60 80 100 120 140
0 10 20 30
Cumulative % drug release
Time (hours)
REFNVP012
162 | P a g e