3.5.1 Effect of SLS on Dissolution Rate of NVP
The selection of an appropriate dissolution medium for assessing the dissolution rate of a sparingly soluble API is challenging, as it is often difficult to achieve sink conditions. Sink condition is defined as the volume of medium that is at least three times greater than that required to dissolve the total dose of an API in the product under investigation, for example this would be at least three times the volume required to dissolve 100 mg of NVP [173, 195, 203]. The addition of a small amount of surfactant to a dissolution test medium for testing poorly water soluble compounds has been suggested as an appropriate way to better simulate the GIT environment and to achieve sink conditions [195, 204]. However, the lowest possible concentration of surfactant to achieve 75-80% API release within a reasonable test time must be used [205].
The dissolution profiles depicting drug release in 50 mM phosphate buffer of pH 6.8 using different concentrations of SLS are depicted in Figure 3.1.
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Figure 3.1. NVP dissolution profiles in 50 mM phosphate buffer with different amounts of SLS (n= 6, dip rate = 8 dpm, pH = 6.8).
Increasing the amount of SLS in the dissolution medium resulted in an increased rate and extent of dissolution of NVP which has also been reported for other compounds [195, 203, 205]. The increase in the extent of drug release can be attributed to the increased solubilisation of NVP due to improved wetting of the dosage form and NVP particles.
Comparison of the f1 and f2 factors in Table 3.4 revealed that dissolution profiles from media with different concentrations of SLS were different except for those with 1 and 2 % SLS, although inspection of the two profiles showed that the rate of NVP release was higher in medium containing 2% SLS and the profiles were slightly different. Therefore 2.0% w/v was selected as it resulted in slightly higher rate of release and resulted in the requisite 80%
release from NVP tablets.
0 20 40 60 80 100 120
0 5 10 15 20 25 30
Cumulative % NVP release
Time (hours)
0%w/v SLS 0.25%w/v SLS 0.5%w/v SLS 1.0%w/v SLS 2%w/v SLS
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Table 3.4. Comparison of dissolution profiles of NVP release in medium with different concentrations of SLS
Profiles compared f1 f2
0 % vs. 0.25 % 47.1 44.4
0 % vs. 0.5 % 66.8 37.2
0 % vs. 1 % 105.6 28.2
0 % vs. 2 % 135.9 23.0
0.25 % vs. 0.5 %
0.25 % vs. 1 % 13.4
39.8 63.5
41.6
0.25 % vs. 2 % 60.4 32.8
0.5 % vs. 1 % 23.2 50.5
0.5 % vs. 1 % 41.4 38.2
1 % vs. 2% 14.7 54.8
Red = out of specifications
3.5.2 Effect of Agitation Rate on Dissolution Rate
The dissolution profiles generated using agitation rates of 5 dpm, 10 dpm, 15 dpm or 50 rpm are shown in Figure 3.2 and the f1 and f2 values calculated from the comparison of dissolution profiles using data from USP Apparatus 3 (Test) to that of USP Apparatus 2 (Reference) are listed in Table 3.5.
Figure 3.2. Dissolution profiles of NVP using different agitation rates in 50mM phosphate buffer, pH = 6.8.
0 20 40 60 80 100 120
0 5 10 15 20 25
Cumulative % drug release
Time (hours)
DPM =5 DPM =10 DPM=15 USP II= 50 rpm
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Table 3.5. Comparison of dissolution profiles obtained from different dip speeds in USP Apparatus 3 to USP Apparatus 2 at 50 rpm
Reciprocation rate (dpm) f1 f2
5 6.2 70.8
10 13.2 54.6
15 24.5 42.3
Red = out of specification.
These results indicate that the lower reciprocation rates of 5 and 10 dpm using USP Apparatus 3 produce dissolution profiles that are equivalent to a rotation speed of 50 rpm for USP Apparatus 2 and are in agreement with previously reported results [195]. Further inspection of the dissolution profiles generated using USP Apparatus 2 and 3 suggest that the f2 factor may improve if dissolution testing were to be performed using dip rates of between 5 and 10 dpm. Consequently a dissolution test using USP Apparatus 3 was performed at a dip rate of 8 dpm and yielded f1 and f2 factors of 2.4 and 88.9, respectively. Therefore, a dip rate of 8 dpm was selected for use for all NVP dissolution studies. The results reveal that NVP release from tablets increases with an increase in agitation rate and are in agreement with previously reported data [170, 173, 192, 195]. Analysis of the f1 and f2 factors revealed statistical differences in the dissolution profiles as shown in Table 3.6, and showed that large differences in agitation rates yielded very different dissolution profiles.
Table 3.6. Comparison of NVP dissolution profiles at different agitation rates
Profiles compared f1 f2
5 dpm vs. 10 dpm 15.7 50.5
5 dpm vs. 15 dpm 30.9 37.4
10 dpm vs. 15 dpm 13.1 50.8
8 dpm vs. 50 rpm 2.4 88.9
Red = out of specification
Most modified release dosage forms exhibit faster dissolution rates as agitation rates or speeds are increased. Mild agitation conditions are recommended for use during dissolution testing to permit use of the maximum discriminating power of a method in order to be able to detect products that may exhibit poor in vivo performance. Therefore, a desirable agitation rate or speed by rotation of the basket or paddle, dip rate of a reciprocating cylinder or flow rate for USP Apparatus 4 must be adjusted to yield a result for which 80% of the API is dissolved by the end of the specified test interval, as recommended in the FIP guidelines [206].
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3.5.3 Effect of Mesh Size (MS) on the Rate and Extent of NVP Dissolution
Studies have been undertake to investigate the effect of mesh size on the rate and extent of drug release from dosage forms [192, 198]. In general the extent of API release increases with an increase in the mesh size used [197]. The impact of API release rates whilst, dependent on the size of the mesh of the top screen, release does not appear to be affected by that of the bottom mesh size as studies on the effect of the bottom mesh screen size did not reveal any differences in percent drug released [192]. However the lack of difference in the results observed were attributed to the use of a high agitation rate of 30 dpm which offsets the effect of mesh size within the first two hours of commencing dissolution testing.
The dissolution profiles of NVP from tablets using different sizes of mesh screens are shown in Figure 3.3.
Figure 3.3. NVP dissolution profiles using mesh screens of different size in 50 mM phosphate buffer of pH 6.8 (n = 6, dip rate = 8 dpm).
The rate of NVP release increased with an increase in the mesh size, however the extent of API release from NVP tablets did not appear to be affected by the mesh size used. This may be attributed to the fact that complete drainage of the dissolution medium from the inner cylinders, regardless of the size of the mesh used occurred or may well be a consequence of hydrodynamic forces having a more pronounced effect on NVP release than the mesh size after a specific length of time during dissolution testing.
0 20 40 60 80 100 120
0 5 10 15 20 25 30
Cumulative % NVP release
Time (hours)
MSS 78 MSS 40 MSS 20
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An analysis of the f1 and f2 factors revealed that the dissolution profiles generated with the use of MS 20 and 40 were similar whereas those from MS 20 and 78 were different as shown in Table 3.7.
Table 3.7. Comparison of dissolution profiles of NVP generated from using different mesh screen sizes
Profiles compared f1 f2
20 vs. 40 11.5 67.1
20 vs. 78 32.9 44.9
40 vs. 78 19.2 53.7
Red = out of specification
A mesh of screen size 20 was selected for use as it appeared to produce better drainage which is an important aspect when using USP Apparatus 3.
3.5.4 Effect of Buffer Molarity on Dissolution Rate
The dissolution rate of NVP did not seem to be significantly affected by the molar strength of the buffer used, although a slight increase in the dissolution rate of NVP was observed with an increase in molarity up to 8 hours of dissolution testing as depicted in Figure 3.4.
However, after 8 hours of dissolution testing the molarity did not appear to affect the rate of NVP release to any great extent.
Figure 3.4. NVP dissolution profiles in media of different molarity (n = 6, dpm = 8, pH = 6.8).
0 10 20 30 40 50 60 70 80 90 100
0 5 10 15 20 25 30
Cumulative % NVP release
Time (hours)
25 mM 50 mM 75 mM
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Analysis of the f1 and f2 factors showed that dissolution profiles were similar but the f2 factor decreased with an increase in the difference in molarity, for example a comparison of the profiles for NVP release in dissolution media of 25 mM and 50 mM revealed that they were more similar to each other compared to profiles for buffers of 25 mM and 75 mM. A summary of the f1 and f2 analysis is shown in Table 3.8.
Table 3.8. Comparison of dissolution profile of NVP generated from use of different molarity media. Red = out of specification
Profiles compared f1 f2
25 mM vs. 50 mM 8.7 64.9
25 mM vs. 75 mM 15.5 53.0
50 mM vs. 75 mM 6.2 70.3
Red = out of specification
The studies revealed that any of the molarities studied could be used for dissolution testing and a 50 mM buffer was selected for all future experiments as it is the standard buffer used for dissolution studies in our laboratory.
Following evaluation of the dissolution parameters that may affect NVP release from tablets a specific set of dissolution conditions were selected for use and these are listed in Table 3.9.
Table 3.9. Summary of selected dissolution conditions
Parameter Settings
Medium 250 mL of 50 mM phosphate buffer containing 2.0% w/v SLS
Row pH Time in
medium (h) Formulation development
1 1.2 2
2 7.2 6
3 7.2 6
4 7.2 4
5 7.2 4
6 7.2 2
Optimised formulation
1 1.6 2
2 3.4 2
3 4.7 4
4 6.8 6
5 7.2 4
6 7.2 6
Agitation rate 8 dpm
Mesh screen size 20 (840 µm) top and bottom
Temperature 37 0.5 °C
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3.6. METHOD VALIDATION