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CHAPTER-VI
6.1 STUDIES ON ENHANCEMENT OF DISSOLUTION RATE OF
RITONAVIR BY SOLID DISPERSION TECHNOLOGIES
Among the various methods of enhancement of the dissolution rate and oral
bioavailability, solid dispersion technologies 1-5 were found to be very successful
with a number of drugs. In the present investigation, studies were carried out on
enhancement of dissolution rate and oral bioavailability of ritonavir by solid
dispersion technologies employing various water soluble and water dispersible
carriers. New classes of tablet excipients called superdisintegrants were evaluated as
carriers for solid dispersions and for enhancing the dissolution rate and oral
bioavailability of ritonavir. The feasibility of formulating the solid dispersions
developed into compressed tablets was also investigated.
Experimental
Materials
Ritonavir gift sample from (M/s Hetero Drugs Ltd., Hyderabad)
Polyvinyl Pyrrolidone (Mfg.: BASF, PVPK-30) (Sigma)
Hydroxy propyl cellulose - L (NISSO, having a viscosity of 3.0 - 5.9 cps in 2% by
weight aqueous solution at 20°C, HPC-L)
Hydroxy propyl methyl cellulose (having a viscosity of 50 cps in a 2% by weight
aqueous solution at 20°C) (HPMC).
Primogel gift sample from (M/s Natco Pharma Ltd., Hyderabad)
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Crospovidone gift sample from (M/s Natco Pharma Ltd., Hyderabad)
Croscarmellose sodium gift sample from (M/s Natco Pharma Ltd., Hyderabad)
Prosolve gift sample from (M/s Orchid Health Care Ltd., Chennai)
methanol (Qualigens)
Lactose I.P.
Potato starch I.P.
Talc IP.
Magnesium stearate I.P
Acacia (Loba Chemie)
All other materials were used of pharmacopoeial grade.
Methods
Preparation of Solid Dispersions Employing Soluble Carriers
Solid dispersions of ritonavir in water soluble carriers (HPMC, PVP and
HPC-L) were prepared by common solvent method employing methanol as solvent.
The required quantities of drug and carrier were weighed and dissolved in the
solvent in a round bottom flask to get a clear solution. The solvent was then removed
by evaporation under reduced pressure (vacuum) at 60°C with constant mixing. The
mass obtained was crushed, pulverized and shifted through mesh No. 100. The solid
dispersions were prepared at different ratios of drug carrier namely 95: 5, 90: 10 and
80: 20 respectively (Table 6.1).
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Preparation of Solid Dispersions Employing Super disintegrants
Solid dispersions of ritonavir in water insoluble carriers (Prosolve, Primogel,
crospovidone and croscarmellose sodium) were prepared by solvent evaporation
method. The required quantity of drug was dissolved in the solvent to get a clear
solution in a dry mortar. methanol was used as solvent. The water insoluble carrier
(passed through 120 mesh) was then added to clear drug solution and dispersed. The
solvent was removed by continuous trituration. Trituration was continued until a dry
mass was obtained. The mass obtained was further dried at 50°C for 4 h in a oven.
The dried product was crushed, pulverized and shifted through mesh No. 100. In
each case solid dispersions in the insoluble carriers were prepared at three different
ratios of drug: excipient namely 3:1,1:1 and 1 : 2 or 25%, 50%, 66% concentration
of the excipient respectively.
Estimation of Drug Contents of Solid Dispersions
From each batch, 4 samples of 100 mg each were taken and analysed for the
drug ritonavir. 100 mg of the dispersion was weighed in to a 100 ml volumetric
flask. Solvent (60 ml) was added and mixed the contents thoroughly to dissolve the
drug from the dispersion. Methanol was used as solvent for ritonavir. The solution
was then filtered and collected carefully into another 100ml volumetric flask. The
solution was made upto volume with the solvent. The solution was suitably diluted
with 0.1N hydrochloric acid at 210 nm for ritonavir. The results are given in
Table 6.2
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Dissolution Rate Study:
Dissolution rate of ritonavir as such and from various ritonavir solid
dispersions was studied using Disso-2000 (Labindia) 8 station dissolution rate test
apparatus with paddle stirrer. The dissolution rate was studied in 900ml 0.1N
hydrochloric acid ritonavir (100mg) or solid dispersion equivalent to 100 mg of
ritonavir, a speed of 50 rpm and a temperature of 370C±10C were used in each test.
Samples of dissolution medium (5ml) were withdrawn through a filter (0.45µ) at
different time intervals, suitably diluted, and assayed for ritonavir by measuring
absorbance at 210 nm. The dissolution experiments were conducted in triplicate. The
results are given in Tables 6.3 and given in Figs. 6.1 – 6.3 and 6.7 – 6.10.
X- Ray Diffration Study
X – Ray powder diffraction patterns of ritonavir and its solid dispersions
were obtained using X-ray powder diffractometer (Philips model) employing FC –
Ka radiation. The diffractograms were run at 2.40 / min in terms of 2θ angle. The
diffractograms are shown in Figs. 6.15 - 6.17
FT-IR Spectra
The FT-IR spectra were recorded by using KBr disc as reference on a FTIR
spectrophotometer (SHIMADZU). The FTIR spectra of ritonavir and its solid
dispersions are shown in Figs. 6.18 - 6.19
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Differential Scanning Calorimetry (DSC)
DSC thermograms of ritonavir and its solid dispersions in PVP, Prosolve and
Croscarmellose sodium were recorded on NETZSCH DSC 204. Samples 9.6 mg
were sealed into aluminium pans (Crucible) and scanned at a heating rate of 100C
min-1 over a temperature range of 200 – 1400C. The DSC thermograms are shown in
Figs. 6.20 - 6.22
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Table 6.1
List of Ritonavir Solid Dispersions Prepared and their Composition
S.No. Composition
Drug Carrier SD Code
1 Ritonavir (9.5) HPMC(0.5) SDF1
2 Ritonavir (9.0) HPMC(1.0) SDF2
3 Ritonavir (8.0) HPMC (2.0) SDF3
4 Ritonavir (9.5) PVP (0.5) SDF4
5 Ritonavir (9.0) PVP(1.0) SDF5
6 Ritonavir (8.0) PVP (2.0) SDF6
7 Ritonavir (9.5) HPC-L (0.5) SDF7
8 Ritonavir (9.0) HPC-L(1.0) SDF8
9 Ritonavir (8.0) HPC-L(2.0) SDF9
10 Ritonavir (3.0) Prosolve(1.0) . SDF10
11 Ritonavir (1.0) Prosolve(1.0) SDF11
12 Ritonavir (1.0) Prosolve (2.0) SDF12
13 Ritonavir (3.0) Primogel(1.0) SDF13
14 Ritonavir (1.0) Primogel(1.0) SDF14
15 Ritonavir (1.0) Primogel (2.0) SDF15
16 Ritonavir (3.0) Crospovidone (1.0) SDF16
17 Ritonavir (1.0) Crospovidone (1.0) SDF17
18 Ritonavir (1.0) Crospovidone (2.0) SDF18
19 Ritonavir (3.0) Croscarmellose (1.0) SDF19
20 Ritonavir (1.0) Croscarmellose (1.0) SDF20
21 Ritonavir (1.0) Croscarmellose (2.0) SDF21
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Table 6.2
Ritonavir Content of Various Solid Dispersions Prepared
Sample
No.
Percent Ritonavir Content
SD
F1
SD
F2
SD
F3
SD
F4
SD
F5
SD
F6
SD
F7
SD
F8
SD
F9
SD
F10
SD
F11
SD
F12
SD
F13
SD
F14
SD
F15
SD
F16
SD
F17
SD
F 1
8
SD
F19
SD
F20
SD
F21
1 94.9 89.4 80.4 94.6 90.2 80.0 94.2 89.5 80.6 74.9 48.6 32.6 74.8 49.3 33.2 74.6 49.4 33.0 74.8 49.8 32.0
2 94.5 88.6 79.2 94.3 89.5 79.2 94.8 89.0 79.5 74.2 49.5 32.9 74.9 49.6 33.0 74.9 48.8 32.6 74.3 49.5 31.8
3 94.7 89.6 80.5 94.8 88.9 78.5 94.6 89.7 79.2 74.5 49.2 33.0 74.4 49.5 33.2 74.4 49.2 32.5 74.6 49.7 32.6
4 94.5 88.8 79.0 74.5 89.4 79.6 94.9 88.5 78.9 74.7 49.3 32.8 74.6 49.5 32.8 74.8 49.7 32.0 74.5 49.8 32.9
X 94.7 89.1 79.7 94.6 89.5 79.3 94.6 89.1 79.5 74.6 49.2 32.8 74.7 49.4 33.0 74.7 49.3 32.5 74.6 49.7 32.3
s.d 0.19 0.47 0.78 0.20 0.53 0.63 0.31 0.53 0.74 0.30 0.39 0.28 0.22 0.12 0.19 0.22 0.38 0.41 0.21 0.14 0.51
c.v 0.20 0.52 0.97 0.22 0.59 0.80 0.33 0.59 0.93 0.40 0.79 1.46 0.30 0.25 0.58 0.30 0.77 1.26 0.28 0.28 1.58
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Table 6.3
Dissolution Profiles of Ritonavir and its Solid Dispersions in Water Soluble Polymers
Time
(min)
Percent Ritonavir Dissolved (x ± s.d.) (n=3)
Rito SDF1 SDF2 SDF3 SDF4 SDF5 SDF6 SDF7 SDF8 SDF9
5
18.00
±1.05
26.87
± 1.07
26.35
± 1.56
23.38
± 1.09
41.98
± 1.57
75.80
± 1.41
68.71
± 1.23
70.92
± 1.51
85.42
± 1.17
69.80
± 1.11
10 21.59
±1.20
28.80
± 1.41
36.24
± 1.07
28.78
± 1.21
47.90
± 1.17
84.38
± 1.19
78.45
± 1.31
75.36
± 1.04
88.28
± 1.63
72.29
± 1.71
20
26.42
± 1.09
34.47
± 1.19
45.92
± 1.15
38.48
± 1.89
55.33
± 1.46
91.97
± 1.77
88.51
± 1.42
79.30
± 1.14
90.83
± 1. 23
76.05
± 1.47
30
29.20
± 1.25
39.33
± 1.19
51.24
± 1.54
49.30
± 1.44
61.09
± 1.22
94.29
± 1.12
97.96
± 1.47
82.59
± 1.51
94.14
± 1.74
78.07
± 1.18
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Fig 6.1: Dissolution Profile of Ritonavir-HPMC Solid Dispersions
Fig. 6.2: Dissolution Profile of Ritonavir-PVP Solid Dispersions
0
20
40
60
80
100
120
0 10 20 30 40
Percent Ritonavir Dissolved
Time (min)
Rito
SDF4
SDF5
SDF6
0
10
20
30
40
50
60
0 5 10 15 20 25 30 35
Percent Ritonavir Dissolued
Time (min)
Rito
SDF1
SDF2
SDF3
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Fig. 6.3: Dissolution Profile of Ritonavir-HPC-L Solid Dispersions
Fig. 6.4: First order Plots of Dissolution Profiles of Ritonavir and its Dispersions in WaterSoluble Carrier (HPMC)
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40
percent Ritonavir Dissolved
Time(min)
Rito
SDF7
SDF8
SDF9
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Fig. 6.5: First order Plots of Dissolution Profiles of Ritonavir and its
Dispersions in Water Soluble Carrier (PVP K-30)
Fig. 6.6: First order Plots of Dissolution Profiles of Ritonavir and its
Dispersions in Water Soluble Carrier (HPC-L)
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Table 6.4
Dissolution Profiles of Ritonavir and its Solid Dispersions in Water Dispersible Carriers
Time (min)
Percent of Ritonavir dissolved ( x ± s.d. ) (n=3)
Rito SDF10 SDF11 SDF12 SDF13 SDF14 SDF15 SDF16 SDF17 SDF18 SDF19 SDF20 SDF21
5 18.00
± 1.05
78.33
± 1.41
79.42
± 1.07
68.88
± 1.09
68.60
± 1.56
76.23
± 1.14
87.14
± 1.74
83.99
± 1.79
81.52
± 1.11
82.74
± 1.07
70.36
± 1.32
74.58
± 1.64
78.86
±1.25
10 21.59
± 1.20
80.48
± 1.75
84.14
± 1.46
77.99
± 1.64
70.58
± 1.47
77.18
± 1.17
87.80
± 1.54
85.68
± 1.34
97.53
± 1.59
85.56
± 1.47
76.89
± 1.64
101.39
± 1.27
84.86
±1.78
20 26.42
±1.09
84.64
± 1.20
85.21
± 1.48
82.14
± 1.74
71.46
± 1.31
75.91
± 1.87
88.13
± 1.14
84.92
± 1.11
96.78
± 1.54
97.81
± 1.17
81.46
± 1.64
102.25
±1.55
86.01
±1.44
30 29.20
± 1.25
86.42
± 1.05
86.28
± 1.08
85.01
± 1.08
71.60
± 1.09
75.12
± 1.06
88.95
± 1.04
84.60
± 1.06
100.24
±1.03
99.65
± 1.07
83.26
± 1.08
101.91
±1.09
90.44
± 1.01
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Fig. 6.7: Dissolution Profile of Ritonavir-Prosolve Solid Dispersions
Fig. 6.8: Dissolution Profile of Ritonavir-Primogel Solid Dispersions
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40
Percent Ritonavir Dissolved
Time (min)
Rito
SDF10
SDF11
SDF12
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40
Percent Retonavir Dissolved
Time(min)
Rito
SDF13
SDF14
SDF15
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Fig. 6.9: Dissolution Profile of Ritonavir-Crospovidone Solid Dispersions
Fig. 6.10: Dissolution Profile of Ritonavir-Croscarmellose Solid Dispersions
0
20
40
60
80
100
120
0 10 20 30 40
Percent Ritonavir Dissolved
Time(min)
Rito
SDF16
SDF17
SDF18
0
20
40
60
80
100
120
0 10 20 30 40
Percent Ritonavir Dissolved
Time(min)
Rito
SDF19
SDF20
SDF21
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Fig. 6.11: First order Plots of Dissolution Profiles of Ritonavir and its Solid Dispersions in Water Dispersible Carrier (Prosolve)
Fig. 6.12: First order Plots of Dissolution Profiles of Ritonavir and its Solid Dispersions in Water Dispersible Carrier (Primogel)
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Fig. 6.13: First order Plots of Dissolution Profiles of Ritonavir and its Solid Dispersions in Water Dispersible Carrier (Crospovidone)
Fig. 6.14: First order Plots of Dissolution Profiles of Ritonavir and its Solid Dispersions in Water Dispersible Carrier (Croscarmellose sodium)
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Table 6.5
Correlation Coefficient (r) Values in the Analysis of Dissolution Data as per Zero order and First order Models
Solid Dispersion
Correlation Coefficient ( r ) Value
Zero order First order
SDF 1 09974 0.9968
SDF 2 0.9382 0.9623
SDF 3 0.9994 0.9947
SDF 4 0.9815 0.9933
SDF 5 08833 0.9676
SDF 6 0.9789 0.9392
SDF 7 0.9589 0.9826
SDF 8 09818 09849
SDF 9 0.9702 0.9819
SDF 10 0.9661 0.9803
SDF 11 0.7402 0.7821
SDF 12 0.8411 0.9093
SDF 13 0.7417 0.7504
SDF 14 0.6243 0.6138
SDF 15 0.9561 0.9584
SDF 16 0.9801 0.9864
SDF 17 0.5706 0.8074
SDF 18 0.9152 0.9776
SDF 19 0.8676 0.9134
SDF 20 0.8373 09143
SDF 21 0.8757 0.9160
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Table 6.6
Dissolution Parameters of Ritonavir and its Solid Dispersions in Water Soluble dispersible Carriers
Solid Dispersion
Carrier and Concentration
( % )
T50 (min)
K1
(min-1)
DE30
(%)
Percent Drug
Dissolved in 10 min
Increase in K1
(no. of folds)
Ritonavir
SDF 1
SDF 2
SDF 3
SDF4
SDF5
SDF6
SDF7
SDF 8
SDF9
--
HPMC (5)
HPMC (10)
HPMC(20 )
PVP ( 5 )
PVP (10 )
PVP (20 )
HPC – L (5 )
HPC – L ( 10 )
HPC – L (20 )
>30
>30
28
30
15
3.2
4.0
3.0
2.5
4.0
0.0058
0.0076
0.0160
0.0163
0.0157
0.0576
0.0562
0.0197
0.0350
0.0128
22.07
29.72
37.29
32.13
47.59
80.01
76.89
70.85
82.27
68.06
21.59
28.80
36.24
28.78
47.90
84.38
78.45
75.36
88.28
72.29
--
1.31
2.75
2.81
2.70
9.93
9.68
3.39
6.03
2.20
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Table 6.7
Dissolution Parameters of Ritonavir and its Solid Dispersions in
Water Dispersible Carriers
Solid
Dispersion
Carrier and Concentration
T50
(min) K1(min-1) DE30(%)
Percent drug dissolved in 10
min
Increase in K1 (no. of
folds)
Ritonavir -- >30 0.0058 22.07 21.59±1.20 -
SDF10 Prosolve (25) 03 0.0191 73.79 80.48±1.75 3.29
SDF11 Prosolve (50) 03 0.0270 77.05 84.14±1.46 4.65
SDF12 Prosolve (66) 3.6 0.0210 72.52 77.99±164. 3.62
SDF13 Primogel(25) 3.6 0.0250 64.83 70.58±1.47 4.31
SDF14 Primogel(50) 3.4 0.0295 69.82 77.18±1.17 5.08
SDF15 Primogel(66) 03 0.0550 80.67 87.80±1.54 9.45
SDF16 Crospovidone(25) 3.1 0.0420 77.82 85.68±1.34 7.24
SDF17 Crospovidone(50) 03 0.1633 86.93 97.53±1.59 28.15
SDF18 Crospovidone(66) 03 0.1723 84.39 85.56±1.47 29.70
SDF19 Croscarmelose Sodium (25)
3.4 0.0218 71.97 76.89±1.64 3.75
SDF20 Croscarmelose Sodium (50)
3.2 0.2740 88.84 101.39±1.27 47.24
SDF21 Croscarmelose Sodium (66)
03 0.0481 78.10 84.86±1.78 8.29
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Fig. 6.15: XRD of Ritonavir
Fig. 6.16: XRD of Ritonavir-PVP (9:1) SD
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150
Fig. 6.17: XRD of Ritonavir-Croscarmelose sodium (1:1) SD
Fig. 6.18: FTIR Spectra of (A) Ritonavir and (B) Ritonavir-PVP (9:1) SD
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151
Fig. 6.19: FTIR Spectra of (A) Ritonavir and (B) Ritonavir-Croscarmelose sodium (1:1) SD
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F
Fig. 6
Fig. 6.21: D
6.20: DSC T
DSC Thermo
Thermogram
ogram of Ri
m of Ritona
itonavir-PV
avir
VP(9:1)SD
Page 24
Fig. 6.22: DDSC Thermmogram of R
Ritonavir- C
Croscarmeloose sodium (1:1) SD
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154
RESULTS AND DISCUSSION
Solid dispersions of ritonavir in three water soluble polymers namely
HPMC, PVP and HPC-L were prepared by common solvent method employing
methanol as solvent. In each case solid dispersions were prepared at three
different ratios of drug: carrier namely 95:5, 90:10 and 80:20. Solid dispersions of
ritonavir in four water dispersible superdisintegrants namely Prosolve, Primogel,
crospovidone and croscarmellose sodium were prepared by solvent evaporation
method employing methanol as solvent for the drug. In each case solid dispersions
in superdisintegrants were prepared at three different ratios of drug: carrier
namely 3:1, 1:1 and 1:2. A total of 21 solid dispersions of ritonavir in water
soluble and water dispersible carriers were prepared and evaluated.
All the solid dispersions prepared were found to be fine and free flowing
powders. Drug content of the solid dispersions was estimated by the UV
spectrophotometric method described in Chapter IV. The percent drug content
values of various solid dispersions prepared are given in Table 6.2. There was no
loss of drug during the preparation and all the solid dispersions contained the drug
equal to the theoretical drug content based on the proportion drug and carrier
taken. Low s.d and c.v (< 2.0) in the percent drug content values (Table 6.2)
indicated that the drug content was uniform in a batch of solid dispersion prepared
in all the cases.
Dissolution Rate Characteristics
The dissolution rate of ritonavir as pure drug and from various solid
dispersions was studied in 0.1N hydrochloric acid. The dissolution data and
profiles are given in Tables 6.3 and 6.4 and Figs. 6.1 - 6.3 and 6.7 -6.10.
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155
The dissolution of ritonavir from all solid dispersions was rapid
and several times higher than the dissolution of ritonavir as such. The dissolution
data were fitted into zero order and first order kinetic models to assess the kinetics
and mechanism of dissolution. The kinetic model that fits the dissolution data was
evaluated by comparing the correlation coefficient (r) values obtained in various
models. The model that gave higher 'r' value is considered as the best fit model
(Table 6.5). The correlation coefficient (r) values obtained in the analysis of
dissolution data as per zero order and first order model are given in Table 6.5. The
'r' values are found to be higher in the first order model than those in zero order
model with all the solid dispersions as well as the pure drug. These results
indicated that the dissolution of ritonavir as such and from all solid dispersions
followed first order kinetics. Plots of log percent remaining versus time (Figs. 6.4
- 6.6 and 6.11 -6.14) were found to be linear with all the products. First order rate
constant (K1 min-1) was calculated in each case from the slope of first order linear
plots. The K1 min-1values of various products are given in Table 6.6 and 6.7.
The DE30 values were calculated in each case as per Khan et al6. and the
DE30 values are given in Table 6.6 and 6.7. T50 (time for 50% dissolution) values
and percent dissolved in 10 minutes were recorded from the dissolution data
profiles and are given in Table 6.6 and 6.7.
All the dissolution parameters (T50, percent dissolved in 10 min, DE30 and
K1 values) given in Table 6.6 and 6.7 indicated rapid and higher dissolution of
ritonavir from solid dispersions than that of ritonavir as such. Among the three
water soluble carriers tested (HPMC, PVP and HPC-L), PVP solid dispersions
gave higher dissolution rates than the other two solid dispersions. At 9:1 ratio of
drug:carrier, PVP, HPC-L and HPMC solid dispersions gave 9.93, 6.03 and 2.75
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156
fold increases in the dissolution rate of ritonavir respectively. With all the three
soluble carriers the dissolution rate was increased as the carrier concentration was
increased from 5% to 10%. At 20% carrier concentration the rate was decreased
due to the aggregation of solid dispersion particles resulting in a decrease in
dissolution rate with all the three carriers. Hence a concentration of 10% carrier
(corresponding to a drug: carrier ratio of 9 : 1) is considered optimum for
enhancing the dissolution rate with the water soluble carriers PVP, HPC-L and
HPMC. The order of increasing dissolution rate observed with various polymers
was PVP > HPC-L >HPMC.
Water dispersible superdisintegrants gave much higher enhancement in the
dissolution rate of ritonavir. All the superdisintegrants tested gave rapid and
higher dissolution of ritonavir when compared to pure drug. The dissolution of
ritonavir from these solid dispersions also followed first order kinetics. Among the
superdisintegrants tested croscarmellose sodium and crospovidone gave much
higher enhancement in the dissolution rate of ritonavir (Table 6.7). A 47.24 and
28.15 fold increase in the dissolution rate of ritonavir was observed with the solid
dispersions in croscarmellose sodium and crospovidone at 1: 1 ratio of drug:
carrier respectively. At 1:1 ratio of drug: carrier, the order of increasing
dissolution rate observed with various superdisintegrants was croscarmellose
sodium > crospovidone > Primogel> Prosolve. In each case the dissolution rate
was increased as the concentration of carrier was increased from 25% to 50%. At
66% carrier concentration (a drug: carrier ratio of 1:2), there was no further
increase in the dissolution rate in majority of the dispersions. Hence a drug: carrier
ratio of 1:1 is considered optimum for enhancing the dissolution rate in the case of
water dispersible superdisintegrants. Overall, all the superdisintegrants tested were
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157
found to be good carriers for solid dispersions and for enhancing the dissolution
rate of ritonavir.
Among all the carriers used in preparing solid dispersions the order of their
efficiency in enhancing the dissolution rate of ritonavir was croscarmellose
sodium > crospovidone > PVP > HPC-L > Primogel > Prosolve > HPMC. These
carriers gave an enhancement of 47.24, 28.15, 9.93, 6.03, 5.08, 4.65 and 2.75
folds respectively.
Thus the dissolution rate and dissolution efficiency of ritonavir were
markedly enhanced by solid dispersion of ritonavir in water soluble and water
dispersible carriers.
Mechanisms of Increased Dissolution Rate of Solid Dispersions
The observed increase in the dissolution rate of ritonavir from its solid
dispersions is due to the following possible mechanisms.
1. Due to the possible reduction in particle size and deposition of the drug in
'miniscular' form on the surface of the water dispersible superdisintegrants
used as carriers during the process of preparation by solvent evaporation.
2. Increased wettability of drug particles when they are dispersed in the
hydrophilic water soluble polymers.
3. The easy and rapid dispersibility of superdisintegrants might have also
contributed to the increased dissolution rate. As the superdisintegrants
used as carriers remain suspended in the dissolution medium the drug
particles deposited on them are continuously exposed to the solvent action
and undergo rapid dissolution.
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4. The absence of aggregation and agglomeration between drug particles due
to the presence of carrier will also contribute to the increased dissolution
rate.
Evaluation by X-Ray Diffraction
The changes in the physical state of the drug in the solid dispersions were
evaluated by XRD. X-ray diffractograms of ritonavir and its solid dispersions,
which gave highest enhancement in the dissolution rate of ritonavir i.e. ritonavir -
PVP (9:1) in the case of soluble carriers and ritonavir - croscarmellose sodium
(1:1) in the case of superdisintegrants, were taken. The X-ray diffractograms of
ritonavir and its solid dispersions are shown in Figs. 6.15-6.17.
The X-ray diffractogram of ritonavir exhibited characteristic diffraction
pattern indicating its crystalline nature. Several diffraction peaks were observed
with varying intensity counts. The poor dissolution rate of ritonavir is due to its
crystalline nature. In the X-ray diffractograms of solid dispersions (Figs. 6.16 and
6.17) the diffraction peaks of ritonavir were disappeared or much reduced
indicating that the drug is present in amorphous form in the solid dispersions.The
rapid dissolution of ritonavir from the solid dispersions is due to the conversion of
crystalline drug into amorphous form in the preparation of solid dispersions.
Evaluation by FTIR Spectra
Drug and carrier interactions in the solid dispersions prepared were
evaluated by FTIR spectral study. The FTIR spectra of ritonavir and its solid
dispersions, which gave highest enhancement in the dissolution rate of ritonavir
i.e. ritonavir - PVP (9:1) in the case of soluble carriers and ritonavir -
croscarmellose sodium (1:1) in the case of superdisintegrants, are shown in Figs.
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6.18 - 6.19. The FTIR spectra of ritonavir (Fig 6.18-6.19) indicated characteristic
peaks at 3,480 cm−1 (N–H stretching amide group), 2,964 cm−1 (hydrogen-
bonded acid within the molecule), 1,716 cm−1 (ester linkage), 1,645, 1,622, and
1,522 cm−1 (–C═C– stretching aromatic carbons). The spectra of ritonavir solid
dispersions tested also showed the above characteristic peaks.These spectral
observations indicated no interaction between ritonavir and the carriers used in the
solid dispersions.
Evaluation by Differential Scanning Calorimetry
DSC was used to evaluate drug - excipient interactions in the solid dispersions,
which gave highest enhancement in the dissolution rate of ritonavir i.e. ritonavir -
PVP (9:1) in the case of soluble carriers and ritonavir - croscarmellose sodium
(1:1) in the case of superdisintegrants.The DSC thermograms of ritonavir,
ritonavir - PVP (9:1) and ritonavir -croscarmellose sodium (1:1) are shown in
Figs. 6.20 - 6.22. All the thermograms exhibited sharp endothermic melting peaks.
The melting peaks observed in DSC thermograms are as follows.
S. No. Sample Melting
point C
1 Ritonavir 124.28
2 Ritonavir- PVP (9:1) SD 123.37
3 Ritonavir- croscarmellose sodium (1:1) SD 123.74
The melting peaks observed were in good agreement with the literature
value of ritonavir. The melting peaks were observed at the same temperature for
pure drug as well as its solid dispersions.
The FTIR and DSC studies, thus, indicated no interaction between ritonavir and
the two carriers, PVP and croscarmellose sodium, which gave highest
enhancement in the dissolution rate of ritonavir.
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CONCLUSIONS
1. The dissolution of ritonavir from all the solid dispersions prepared was
rapid and several times higher than the dissolution of ritonavir as such.
2. Among the three water soluble carriers PVP solid dispersions gave highest
enhancement (9.93 fold) in the dissolution rate of ritonavir. The order of
increasing dissolution rate observed with various water soluble carriers
was PVP > HPC-L > HPMC.
3. Water dispersible superdisintegrants gave much higher enhancement in the
dissolution rate of ritonavir.
4. Among the superdisintegrants tested, croscarmellose sodium and
crospovidone gave markedly higher enhancement in the dissolution rate of
ritonavir, 47.24 and 28.15 fold respectively. The order of increasing
dissolution rate observed with various superdisintegrants was
croscarmellose sodium > crospovidone > primogel >Prosolve.
5. The dissolution rate and dissolution efficiency of ritonavir were markedly
enhanced by solid dispersion of ritonavir in water soluble polymers and
superdisintegrants.
6. The FTIR and DSC studies indicated no interaction between ritonavir and
the two carriers, PVP and croscarmellose sodium, which gave highest
enhancement in the dissolution rate of ritonavir.
7. Ritonavir is present is an amorphous form in the solid dispersions which
contributed to the rapid dissolution of ritonavir from the solid dispersions.
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6.2 FORMULATION AND EVALUATION OF RITONAVIR TABLETS
EMPLOYING SELECTED SOLID DISPERSIONS
Solid dispersions in PVP (9:1) SD F5, crospovidone (1:1) SD F17 and
croscarmellose sodium (1:1) SD F20 exhibited a marked enhancement in the
dissolution rate and efficiency of ritonavir. The feasibility of formulating these
solid dispersions into compressed tablets with enhanced dissolution rate was
evaluated. These solid dispersions were formulated into tablets with usual tablet
additives as per the formulae given in Tables 6.8 and 6.13. The tablets were
prepared by wet granulation and direct compression methods. A total of 8
ritonavir tablet formulations were made and all the tablets were evaluated for
content of active ingredient, hardness, friability, and disintegration time and
dissolution rate characteristics. The results are given in Tables 6.9, 6.10, 6.14, and
6.15.
Preparation of Ritonavir Tablets
Compressed tablets each containing 100 mg of ritonavir were prepared
employing selected solid dispersions by wet granulation and direct compression
methods.
Wet granulation method
The required quantity of solid dispersion containing the medicament and
other ingredients were taken in a mortar. The aqueous mucilage of binder was
added and mixed thoroughly to form dough mass. The mass was passed through
mesh No. 12 to obtain wet granules. The wet granules were dried at 60°C for 4 hr.
The dried granules were passed through mesh No. 16 to break the aggregates. Talc
(2%) and magnesium stearate (2%) were passed through mesh No. 100 onto dry
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granules and blended in a polyethylene bag. The tablet granules were then
compressed into tablets on a rotary multi-station tablet punching machine (M/s.
Cadmach Machinery Co. Pvt. Ltd., Mumbai) to a hardness of 6-7 kg/sq.cm using
9 mm round and flat punches.
Direct compression method
For direct compression Prosolve was used as directly compressible
vehicle. Solid dispersion containing the medicament, Prosolve and other
excipients were blended thoroughly in a closed polyethene bag and were directly
compressed into tablets on a rotary multi-station tablet punching machine (M/s.
Cadmach Machinery Co. Pvt. Ltd., Mumbai) to a hardness of 6-7 kg/sq.cm using
9 mm round and flat punches.
Evaluation of Tablets
All the tablets prepared are evaluated for content of active ingredient, hardness,
friability, disintegration time, dissolution rate and dissolution efficiency.
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Table 6.8
Formulae of Ritonavir Tablets Prepared with Selected Solid Dispersions by Wet Granulation Method
Ingredient mg / tab Formulation
TF29 TF30 TF31 TF32
Ritonavir 100 - - -
SDF 5 - 111 - -
SDF 17 - - 200 -
SDF 20 - - - 200
Potato starch 45 45 45 45
Talc 6 6 6 6
Magnesium stearate 6 6 6 6
Acacia 6 6 6 6
Lactose up to
(Total tablet weight (mg))
300 300 300 300
TF 29 - Control: Ritonavir
TF30:SDF5 - Ritonavir: PVP (900:100)
TF31: SDF 17 - Ritonavir: Crospovidone (500:500)
TF 32: SDF 20 - Ritonavir: Croscarmellose sodium (500:500)
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Table 6.9
Drug Content, Hardness, Friability and Disintegration Time of Ritonavir Tablets Formulated with Selected Solid Dispersions by Wet Granulation
Method
Tablet Formulation
Ritonavir content
(mg/Tab)
Hardness (kg /Cm2)
Friability
(%)
Disintegration Time (min.)
TF29 99.80 5.5 0.90 4.2
TF30 100.89 5.3 0.75 7.0
TF31 99.30 5.4 0.95 0.5
TF32 99.40 5.5 0.90 5.3
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Table 6.10
Dissolution Profiles of Ritonavir Tablets Prepared with Selected Solid
Dispersions
Time
(min)
Percent RitonavirDissolved (⎯x ± s.d.) (n=3)
TF29 TF30 TF31 TF32
5 15.44
±1.02
22.72
±1.23
43.24
±1.11
69.04
± 1.42
10 20.27
±1.04
30.16
±1.02
79.95
±1.23
83.69
±1.47
20 29.34
±1.23
45.01
±1.64
91.48
±1.09
94.26
±1.19
30 38.68
±1.02
60.32
±1.44
94.66
±1.55
100.05
±1.87
TF 29- Control- Ritonavir
TF30:SDF5 - Ritonavir: PVP (900:100)
TF 31: SDF 17 - Ritonavir: Crospovidone (500:500)
TF 32: SDF 20 - Ritonavir: Croscarmellose sodium (500:500)
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Fig. 6.23: Dissolution Profiles of Ritonavir Tablets Prepared with Selected Solid Dispersions by Wet Granulation Method
TF 29- Control-Ritonavir
TF 30: SDF5 - Ritonavir: PVP (900:100)
TF 31: SDF 17 - Ritonavir: Crospovidone (500:500)
TF 32: SDF 20 - Ritonavir: Croscarmellose sodium (500:500)
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35
Percent Ritonavir Dissolved
Time (min)
TF37
TF38
TF39
TF40
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Fig. 6.24: First Order Dissolution Profiles of Ritonavir Tablets Prepared with Selected Solid Dispersions by Wet Granulation Method
TF 29 - Control: Ritonavir
TF 30: SDF5 - Ritonavir: PVP (900:100)
TF 31: SDF 17 - Ritonavir: Crospovidone (500:500)
TF 32: SDF 20 - Ritonavir: Croscarmellose sodium (500:500)
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Table 6.11
Correlation Coefficient (r) Values in the Analysis of Dissolution Data as per Zero order and First order Models
Formulation Correlation Coefficient (r) Value
Zero order First order
TF29 0.998 0.999
TF30 0.990 0.999
TF31 0.704 0.916
TF32 0.897 0.979
Table 6.12
Dissolution Parameters of Ritonavir Tablets Formulated with Selected Solid Dispersions by Wet Granulation Method
Formulation T50 (min) K1 (min-1) DE30 (%) Percent drug dissolved in 10 min.
TF29 >30 0.0128 23.86 20.27±1.04
TF30 22 0.0266 36.38 30.16±1.02
TF31 6.0 0.0898 73.46 79.95±1.23
TF32 3.5 0.1812 80.53 83.69±1.47
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Table 6.13
Formulae of Ritonavir Tablets Prepared with Selected Solid Dispersions
by Direct Compression Method
Ingredient (mg/tab)
Formulation
TF33 TF34 TF35 TF36
Ritonavir 100 - - -
SDF5 - 111 - -
SDF17 - - 200 -
SDF20 - - - 200
Acacia 6 6 6 6
Potato starch 45 45 45 45
Talc 6 6 6 6
Magnesium stearate 6 6 6 6
Prosolve qs to
Total weight of the Tablet (mg)
300 300 300 300
TF 33 – Control- Ritonavir
TF 34: SDF 5 - Ritonavir: PVP (900:100)
TF 35: SDF 17 - Ritonavir: Crospovidone (500:500)
TF 36: SDF 20 - Ritonavir: Croscarmellose sodium (500:500)
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Table 6.14
Drug Content, Hardness, Friability and Disintegration Time of Ritonavir Tablets Formulated with Selected Solid Dispersions
by Direct Compression Method
Tablet Formulation
Ritonavir Content (mg/tab)
Hardness
(kg /Cm2)
Friability
(%)
Disintegration Time (sec.)
TF33 100.50 5.0 0.95 13
TF34 99.47 4.8 0.85 50
TF35 99.18 5.1 0.90 27
TF36 100.21 5.0 0.79 119
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Table 6.15
Dissolution Profiles of Ritonavir Tablets Prepared with Selected
Solid Dispersions by Direct Compression Method
Time (min)
Percent Ritonavir Dissolved ( x ± s.d.) (n=3)
TF33 TF34 TF35 TF36
5 28.57
±1.02
72.13
±1.32
77.05
±1.47
71.0
±1.12
10 40.38
±1.11
73.62
±1.66
94.55
±1.97
96.44
±1.74
20 48.83
±1.47
92.02
±1.22
97.99
±1.33
99.58
±1.01
30 56.22
±1.21
92.02
±1.54
99.11
±1.74
99.99
± 1.47
TF 33: Control - Ritonavir
TF34: SDF5 - Ritonavir : PVP (900:100)
TF 35: SDF 17 - Ritonavir: Crospovidone (500:500)
TF 36: SDF 20 - Ritonavir: Croscarmellose sodium (500:500)
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Fig. 6.25: Dissolution Profiles of Ritonavir Tablets Prepared with Selected Solid Dispersions by Direct Compression Method
TF 33: Control: Ritonavir
TF 34: SDF 5 - Ritonavir: PVP (900:100)
TF 35: SDF 17 - Ritonavir: Crospovidone (500:500)
TF 36: SDF 20 - Ritonavir: Croscarmellose sodium (500:500)
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35
Percent Ritonavir Dissolved
Time (min)
TF37
TF38
TF39
TF40
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Fig. 6.26: First Order Dissolution Profiles of Ritonavir Tablets Prepared
with Selected Solid Dispersions by Direct Compression Method
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Table 6.16
Correlation Coefficient (r) Values in the Analysis of Dissolution Data as per Zero order and First order Model
Formulation
Correlation Coefficient (r) Value
Zero Order First Order
TF33 0.937 0.967
TF34 0.840 0.846
TF35 0.636 0.927
TF36 0.560 0.986
Table 6.17
Dissolution Parameters of Ritonavir Tablets Formulated with Selected Solid Dispersions by Direct Compression Method
Formulation T50 (min.) K1 (min-1) DE30(%) Percent drug dissolved in 10 min.
TF33 22 0.0185 40.50 40.38±1.11
TF34 3.0 0.0584 76.43 73.62±1.66
TF35 3.0 0.1215 85.63 94.55±1.97
TF36 3.0 0.3048 85.80 96.44±1.74
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RESULTS AND DISCUSSION
All the tablets prepared contained ritonavir within 100±5% of the labeled
content. Hardness of the tablets was in the range 5-6 kg / sq.cm and was
satisfactory. The percentage weight loss in the friability test was less than 0.95 in
all the tablet formulations prepared. All the tablets formulated disintegrated
rapidly within 7 min. (Tables 6.9 and 6.14). Overall tablets formulated employing
direct compression method, disintegrated more rapidly when compared to those
tablets formulated with wet granulation method. However, all tablets fulfilled the
official (I.P) disintegration time specification for uncoated tablets. Thus all the
tablets formulated employing solid dispersions were found to be of good quality,
fulfilling all official (I.P) and other requirements of compressed tablets.
Dissolution Characteristics
The dissolution profiles of ritonavir tablets prepared employing ritonavir
and its selected solid dispersions are given in Table 6.10 and 6.15 and shown in
Figs. 6.23 and 6.24.
All the tablets formulated employing solid dispersions gave rapid and
higher dissolution of ritonavir when compared to that of ritonavir plain tablets (i.e.
TF 29 and TF 33).
Ritonavir dissolution from all the tablets prepared by wet granulation as
well as direct compression method followed first order kinetics with correlation
coefficient ‘r’ above 0.846 (Table 6.11 and 6.16). The first order dissolution plots
of various tablets are shown in Figs. 6.25 and 6.26. The dissolution parameters
estimated from the dissolution data of various tablets are summarized in Tables
6.12 and 6.17. All dissolution parameters (K1, DE 30, T50 and percent dissolved in
10 min.) indicated rapid and higher dissolution of ritonavir from tablets
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formulated employing its solid dispersions when compared to plain ritonavir
tablets prepared by wet granulation (TF 29) and direct compression (TF 33)
methods.
Ritonavir tablets formulated employing its solid dispersions and prepared
by direct compression method gave rapid and higher dissolution of ritonavir when
compared to the corresponding tablets prepared by wet granulation method. K1
(min -1) and DE30 values were higher in the case of tablets prepared by direct
compression method when compared to those prepared by wet granulation
method.
In the wet granulation method, a 2.07, 7.01 and 14.85 fold increase in the
dissolution rate (K1) of ritonavir was observed with the tablets formulated
employing solid dispersions in PVP (9 : 1), crospovidone (1:1) and
croscarmellose sodium (1:1) respectively. Whereas in the direct compression
method a 3.15, 6.56, and 16.47 fold, increase in the dissolution rate (K1) of
ritonavir was obtained with the tablets formulated employing solid dispersions in
PVP (9:1), crospovidone (1:1) and croscarmellose sodium (1:1) respectively.
In both the wet granulation and direct compression methods tablets
formulated employing solid dispersions in croscarmellose sodium (1:1) gave
highest enhancement in the dissolution rate and dissolution efficiency of ritonavir.
The order of increasing dissolution rate observed with tablets formulated
employing various solid dispersions was croscarmellose sodium > crospovidone >
PVP.
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CONCLUSIONS
1. Solid dispersions of ritonavir in PVP, crospovidone and croscarmellose
sodium could be formulated into tablets by both wet granulation and direct
compression methods.
2. Ritonavir tablets formulated employing solid dispersions gave much
higher dissolution rates and DE30 values when compared to plain tablets.
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Drug Inven. Today, 2010; 2(7): 349.
3. Chiou WL, and Riegelman S. J. Pharm. Sci., 1971; 60 (9), 1281-1302.
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