Evaluation and Development
of Osmotic drug delivery of venlafaxine Hydrochloride
Tablet
Jyotir
Patel*
Department
of Pharmacy, Shri Jagdish Prasad
Jhabarmal
Tibrewala
University, Vidyanagari, Jhunjhunu,
Rajasthan, India
*Corresponding Author E-mail:
ABSTRACT:
Osmotic systems utilizes the principle of osmosis for delivery of
drug. It is advantageous that drug release from the osmotic devices independent
of physiological environment and pH. Drug release can
be optimized to zero order release rate by modifying formulation properties. Venlafaxine Hydrochloride(VH), an antidepressant agent structurally unrelated
to other antidepressants, is used to treat melancholia, generalized anxiety
disorder (GAD), panic disorder, post-traumatic stress disorder, and hot flashes
in breast cancer survivors. Absolute bioavailability is 45% and a single oral
dose is well absorbed (at least 92%). Depressive illness generally requires
long duration of drug therapy and plasma concentration substantially need to
remain constant for better tolerability. Compared to Venlafaxine
immediate release (IR) dosage form extended release dosage forms(ER) are well
tolerated. Venlafaxine hydrochloride is highly water
soluble drug(570mg/ml), so incorporation of release
retardant polymers may modify release pattern for longer duration of release.
Hence, it was decided to formulate CPOP of venlafaxine
hydrochloride using release retardant hydrophilic polymers.
KEYWORDS: Venlafaxine Hydrochloride (VH), Osmotic drug delivery
1. INTRODUCTION:
Venlafaxine Hydrochloride(VH), an antidepressant agent structurally unrelated
to other antidepressants, is used to treat melancholia, generalized anxiety
disorder (GAD), panic disorder, post-traumatic stress disorder, and hot flashes
in breast cancer survivors. Absolute bioavailability is 45% and a single oral
dose is well absorbed (at least 92%). It exhibits linear kinetics over dose
range of 75 to 450 mg/day. For ER, C max is 150 ng/mL (260 ng/mL for ODV) and T max is 5.5 h (9 h for ODV). It
is extensively metabolized in the liver. The only major metabolite is O-Desmethyl venlafaxine (ODV),
which is active. Elimination half-life
of VH is 5 h (11 h for ODV).
Depressive illness generally requires long
duration of drug therapy and plasma concentration substantially need to remain
constant for better tolerability.
Compared to venlafaxine
immediate release (IR) dosage form extended release dosage forms(ER) are well
tolerated. Venlafaxine IR shows probability of
sustained elevation in supine diastolic blood pressure (SDBP), vomiting,
headache, nausea and diarrhoea. Whereas
in case of Venlafaxine ER these all adverse effects
probability significantly reduced. CPOP formulations provide zero order
constant release of drug throughout whole day, so patient compliance and
quality of life improves.
2. MATERIAL AND EQUIPMENT USED:
Venlafaxine Hydrochloride (Gifted by Zydus cadila health care, Ahmadabad),
Cellulose acetate, Pearlitol 25C (Mannitol),
Pearlitol 25C (Mannitol), Hydroxy propyl methyl cellulose
50 cps, Carbopol 934P, Stearic
acid, Aerosil,
PVP-K30, Magnesium stearate, Glacial acetic
acid, Disodium hydrogen phosphate, Potassium dihydrogen
phosphate, Sodium acetate, Hydrochloric acid AR.
UV/VIS Double beam
spectrophotometer (Shimadzu UV 2450 corporation.), Tablet dissolution test
apparatus USP, Rotary tablet machine,
Hardness tester, Friability tester, pH meter, FTIR, Digital Balance,
Spray pan coater
3. EXPERIMENTAL WORK
3.1 Preparation of Tablets of Venlafaxine Hydrochloride by Direct Compression Method
Venlafaxine Hydrochloride and all the excipients were accurately weighed and were transferred to
glass mortar and triturated well for size reduction. Then the powder blend was
passed through 60# screen. Then the powder blend was uniformly mixed in polybag. The resulting powder mixture was directly
compressed using 6 mm punch on rotary tablet press. The weight of each tablet
was maintained to 150 mg throughout study.
3.2 Coating of Tablets
The coating was carried out by spray pan coating
machine. The components of coating solution are given in Table 4.11. Pan was
made up of stainless steel, having diameter of 22 cm and was rotating at a
speed of 30 rpm. The spray rate was fixed at
4-6mL/min. Coated tablets were dried at 50˚C for 12 h and the
average weight gain after drying was controlled up to 20±1% w/w(n=20).
3.3 Evaluation
Parameters
1. Hardness and
Friability of uncoated tablets:
The tablets were tested for determination of crushing
strength by using Pfizer hardness tester. The friability of tablets were checked by using Roche Friabilator,
at 25 rpm for 4 minutes.
2. Uniformity of
coating:
The tablet coat thickness was measured by using
micrometer screw gauge. The weight gain after coating was measured using
digital balance. Weight of uncoated and coated tablets measured following
increase in weight gain was determined.
3. In Vitro Drug
Release study:
In vitro drug release of the formulations was carried
out by using USP paddle-type apparatus (rotating speed of 50 rpm, at 37±1°C).
The dissolution medium was SGF (pH 1.2, 900 mL) for
first 2 h, acetate buffer(pH 4.5) for next 2 hours and
SIF (phosphate buffer, pH 6.8, 900 mL) for subsequent
hours. Samples were withdrawn at specified intervals, suitably diluted and
analyzed by UV spectroscopic method at 224 nm.
4. Drug Release
as function of Agitation Intensity:
To study the effect of agitation intensity, drug
release studies were performed at a relatively high (150 rpm), medium (100) and
low (50 rpm) agitation intensity and using the USP dissolution apparatus,
similarly as described above.
5. Effect of pH of the Dissolution Medium
on Release Rate:
Release rates of Venlafaxine
hydrochloride from CPOPs in SGF pH 1.2, Acetate buffer pH 4.5 and SIF pH 6.8
were compared using USP dissolution apparatus at 50 rpm, similarly as described
above.
3.4 Optimization of
parameter
A) Core Tablet
Formulation:
Venlafaxine Hydrochloride and all the excipients were accurately weighed and were transferred to
glass mortar and triturated well for size reduction. Then the powder blend was
passed through 60# screen. Then the powder blend was uniformly mixed in polybag. The resulting powder mixture was directly
compressed using 6 mm punch on rotary tablet press. The weight of each tablet
was maintained to 150 mg throughout study.
To achieve optimal flow property Aerosil
was used in concentration of 2%w/w of total tablet weight.
Table A: Optimization of Core
Tablet Formulation
|
Ingredients |
Batch 1 |
Batch 2 |
Batch 3 |
|
Venlafaxine Hydrochloride |
42.43 |
42.43 |
42.43 |
|
PVP K30 |
7.5 (5%) |
11.25 (7.5%) |
15 (10%) |
|
Pearlitol
25C |
94.07 |
90.32 |
86.57 |
|
Aerosil |
3 |
3 |
3 |
|
Magnesium stearate |
3 |
3 |
3 |
|
Hardness(Kg/cm2) |
6.1 |
6.5 |
7.0 |
|
Friability |
0.1% |
0.1% |
0.1% |
# Amount given in mg, Total tablet weight is 150 mg.
B) Coating Composition (Solvent System)
1 General coating composition:
Cellulose Acetate 3%w/v and PEG 400 30%
w/w of dry powder weight of cellulose acetate dissolved in appropriate solvent
system.
2 Preparation of coating solution:
The cellulose acetate (CA) powder was
accurately weighed and added to required amount of solvent. In case of mixed
solvent system, cellulose acetate was first dissolved in solvent in which it is
more soluble than other solvent. Next solvent which having
less capacity to dissolve CA is added to the preformed CA solution. This
whole mixing is done using stirrer for proper mixing to avoid lump formation.
After formation of clear CA solution, accurately weighed amount of PEG 400 was
added to the solution and mixed. Required quantity of FDC yellow color was
added to coating solution and mixed properly to get uniform blend.
3 Film casting method:
The coating solution was casted in petry plate to get coating thickness similar to tablet coat
thickness. It was dried in hot air oven at 50˚C temperature for 12 Hrs.
Films were removed from petry plate and subjected to
tensile strength measurement.
4. RESULT AND DISCUSSION:
Coating
Composition
The optimum solvent composition was
determined to be acetone: Isopropyl alcohol (60:40). All batches show no
significant difference in tensile strength made by solvent casting method.
Batches M1-M6 do not contain IPA as solvent, when
these coating solution sprayed the rough tablet surface was generated. This is
due to rapid evaporation of solvent from coating solution droplet before
reaching to tablet surface. Moreover, In batches M7
and M8 the increasing amount of IPA was used. IPA has boiling point higher than
other solvents used. In batch M8 the tablet surface was found to be smooth.
This is because IPA (Boiling point 80˚C to 85˚C) does not evaporate
as rapid as DCM and methanol, so coating solution droplets do not dry in
between spray nozzle and tablet surface path.
Coating thickness:
1. Coating membrane Integrity study:
The tablets were coated for 5%, 10%, 15%
and 20% weight gain. Then the tablets were dried for 50˚C in hot air oven
for 12 Hrs. Coated tablets then subjected to 500 ml of distilled water under
stirred condition. At different time intervals the coat of tablets was examined
manually for any cracks in coating surface. The tablets which remain intact up
to 24 Hrs. is observed and relevant coating thickness should be kept constant
throughout study.
D) IN VITRO
RELEASE PROFILE OF PURE DRUG
In vitro release
study of drug was carried out using USP basket type apparatus. Accurately
weighed amount of venlafaxine hydrochloride was kept
in basket wrapped in muslin cloth. The release profile was generated in SGF (pH
1.2).
Venlafaxine
hydrochloride pure drug showed more than 90% drug release within 10 min. The
drug is freely soluble (Solubility 572 mg/ml). So, to control release of drug
incorporation of release retardant polymer required in core tablet formulation.
Table C.1:
Optimization Of Coating Thickness
|
Ingredients |
Batch T1 |
BatchT2 |
Batch T3 |
Batch T4 |
|
Venlafaxine Hydrochloride |
42.43 |
42.43 |
42.43 |
42.43 |
|
HPMC 50 cps |
4.24(10%) |
12.72(30%) |
- |
- |
|
Carbopol
934P |
- |
- |
2.12(5%) |
6.36(15%) |
|
Pearlitol® |
89.83 |
81.35 |
91.95 |
87.71 |
|
PVP K30 |
7.5 |
7.5 |
7.5 |
7.5 |
|
Aerosil |
3 |
3 |
3 |
3 |
|
Magnesium stearate |
3 |
3 |
3 |
3 |
|
Percent weight
gain of tables after coating |
Tablet coat
rupturing after following time period in Hrs. |
|||
|
5% |
1.5 |
1 |
1 |
1 |
|
10% |
2.0 |
2.0 |
1.0 |
1.5 |
|
15% |
3.5 |
5.5 |
3.0 |
4.0 |
|
20% |
Remains Intact
for 24 Hrs |
Remains Intact
for 24 Hrs |
Remains Intact
for 24 Hrs |
Remains Intact
for 24 Hrs |
# Polymer
percentage with respect to dose of drug
Table 4.1:
Effect of solvent composition on tensile strength of film and tablet coat
surface appearance
|
Batch |
Acetone |
DCM |
Methanol |
Isopropyl Alcohol |
Tensile Strength (N/cm2) |
Tablet coat
Surface |
|
M1 |
100 |
- |
- |
- |
1.564 |
Rough |
|
M2 |
80 |
- |
20 |
- |
1.547 |
Rough |
|
M3 |
60 |
- |
40 |
- |
1.374 |
Rough |
|
M4 |
- |
100 |
- |
- |
1.433 |
Rough |
|
M5 |
- |
80 |
20 |
- |
1.382 |
Rough |
|
M6 |
- |
60 |
40 |
- |
1.349 |
Rough |
|
M7 |
80 |
- |
- |
20 |
1.572 |
Better compare
to above batches |
|
M8 |
60 |
- |
- |
40 |
1.591 |
Smooth |
# Tensile
strength in N/cm2
Table D.1: In
Vitro Release study of pure drug
|
Time (Min) |
Abs. |
DF |
Conc. (µg/ml) |
Conc. (mg/7ml) |
Error |
mg/900 ml |
Cumulative (mg/900ml) |
CPR |
|
0 |
0.000 |
0 |
0.000 |
0.000 |
0.000 |
0 |
0.000 |
00.00 |
|
10 |
0.758 |
2 |
41.027 |
0.205 |
0.000 |
36.924 |
36.924 |
98.46 |
|
20 |
0.761 |
2 |
41.189 |
0.205 |
0.411 |
37.070 |
37.481 |
99.95 |
|
40 |
0.761 |
2 |
41.189 |
0.206 |
0.411 |
37.070 |
37.482 |
99.95 |
|
60 |
0.76 |
2 |
41.135 |
0.205 |
0.411 |
37.022 |
37.433 |
99.82 |
|
120 |
0.759 |
2 |
41.081 |
0.205 |
0.411 |
36.972 |
37.384 |
99.69 |
Figure .D.1: In
vitro release profile of pure drug
E) OPTIMIZATION OF RELEASE RETARDANT POLYMERS
AND PORE FORMING AGENT
1. Batches
formulated using HPMC 50 cps as release retardant in tablet core composition
Table E:
Optimization of Release Retardant Polymers and Pore Forming Agent
|
Ingredients |
VNL1 C6 |
VNL2 C6 |
VNL3 C6 |
|
|
Venlafaxine Hydrochloride |
42.43 |
42.43 |
42.43 |
|
|
HPMC 50
cps |
4.24
(10%) |
8.48
(20%) |
12.72
(30%) |
|
|
Pearlitol®
25C |
89.83 |
85.59 |
81.35 |
|
|
PVP K30 |
7.5 |
7.5 |
7.5 |
|
|
Aerosil |
3 |
3 |
3 |
|
|
Magnesium
stearate |
3 |
3 |
3 |
|
|
Core
tablet evaluation |
||||
|
Hardness |
5-6 kg/cm2 |
|||
|
Friability |
0.1 % |
|||
|
Coating
composition |
||||
|
Cellulose
acetate |
3% w/v in Acetone : Isopropyl alcohol (60:40) |
|||
|
PEG 400 |
30% w/w
of dry cellulose acetate powder |
|||
|
Coating
level |
20±0.5 % |
|||
# Polymer percentage with respect to dose of drug
#C6 indicates
30% w/w of PEG 400 in coating composition
Table 4.E1:
IN VITRO RELEASE STUDY OF BATCH VNL1 C6, VNL2 C6 & VNL3 C6
|
Time (Hrs.) |
VNL1 C6. |
VNL2 C6 |
VNL3 C6 |
|
0 |
0.000 |
0.000 |
0.000 |
|
1 |
12.065 |
6.876 |
1.427 |
|
2 |
21.787 |
16.475 |
10.118 |
|
3 |
35.146 |
28.008 |
19.819 |
|
4 |
53.939 |
28.462 |
26.982 |
|
5 |
60.564 |
39.488 |
34.457 |
|
6 |
72.276 |
44.702 |
42.847 |
|
7 |
76.384 |
54.905 |
52.546 |
|
8 |
81.625 |
65.593 |
54.687 |
|
12 |
91.698 |
81.828 |
80.201 |
|
16 |
96.972 |
92.092 |
91.300 |
|
20 |
97.261 |
99.715 |
99.887 |
|
24 |
97.393 |
99.887 |
99.970 |
Figure E: Comparison of Batches formulated using HPMC 50 cps
F) Batches formulated using Carbopol 934P as release retardant in tablet core
composition
Table F:
Batches formulated using Carbopol 934P as release retardant in tablet
core composition
|
Ingredients |
VNL4 C6 |
VNL5 C6 |
VNL6 C6 |
|
Venlafaxine Hydrochloride |
42.43 |
42.43 |
42.43 |
|
Carbopol
934P |
2.12(5%) |
4.24(10%) |
6.36(15%) |
|
Pearlitol®
25C |
91.95 |
89.83 |
87.71 |
|
PVP K30 |
7.5 |
7.5 |
7.5 |
|
Aerosil |
3 |
3 |
3 |
|
Magnesium
stearate |
3 |
3 |
3 |
|
Core
tablet evaluation |
|||
|
Hardness |
5-6 kg/cm2 |
||
|
Friability |
0.1 % |
||
|
Coating
composition |
|||
|
Cellulose
acetate |
3% w/v in Acetone : Isopropyl alcohol (60:40) |
||
|
PEG 400 |
30% w/w
of dry cellulose acetate powder |
||
|
Coating
level |
20±1.0 % |
||
# Polymer
percentage with respect to dose of drugG Batches
formulated using Stearic acid as release retardant in
tablet core composition
Table F1: IN
VITRO RELEASE STUDY OF BATCH VNL4 C6
|
Time (Hrs.) |
VNL4 C6 |
VNL5 C6 |
VNL6 C6 |
|
0 |
0.000 |
0.000 |
0.000 |
|
1 |
6.746 |
6.032 |
2.984 |
|
2 |
19.670 |
14.514 |
11.757 |
|
3 |
34.025 |
26.953 |
21.329 |
|
4 |
47.345 |
34.261 |
27.186 |
|
5 |
59.027 |
49.955 |
35.305 |
|
6 |
67.049 |
54.281 |
40.438 |
|
7 |
75.442 |
60.566 |
54.228 |
|
8 |
85.793 |
65.167 |
59.848 |
|
12 |
94.721 |
90.825 |
78.925 |
|
16 |
99.597 |
98.794 |
86.988 |
|
20 |
99.884 |
99.229 |
91.206 |
|
24 |
100.01 |
99.361 |
99.708 |
Figure F: Comparison of Batches formulated using Carbopol
934P
Table G:
Batches formulated using Stearic acid as release
retardant in tablet core composition
|
Ingredients |
VNL7 C6 |
VNL8 C6 |
VNL9 C6 |
|
Venlafaxine Hydrochloride |
42.43 |
42.43 |
42.43 |
|
Stearic
acid |
6.36(15%) |
8.48(20%) |
10.60(25%) |
|
Pearlitol®
25C |
87.71 |
85.59 |
83.48 |
|
PVP K30 |
7.5 |
7.5 |
7.5 |
|
Aerosil |
3 |
3 |
3 |
|
Magnesium
stearate |
3 |
3 |
3 |
|
Core
tablet evaluation |
|||
|
Hardness |
5-6 kg/cm2 |
||
|
Friability |
0.1 % |
||
|
Coating
composition |
|||
|
Cellulose
acetate |
3% w/v in Acetone : Isopropyl alcohol (60:40) |
||
|
PEG 400 |
30% w/w
of dry cellulose acetate powder |
||
|
Coating
level |
20±1.0 % |
||
# Polymer
percentage with respect to dose of drug
Table G: IN
VITRO RELEASE STUDY OF BATCH VNL7 C6, VNL8 C6, VNL9 C6
|
Time (Hrs.) |
VNL7 C6. |
VNL8 C6 |
VNL9 C6 |
|
0 |
0.000 |
0.000 |
0.000 |
|
1 |
6.357 |
5.643 |
3.957 |
|
2 |
19.538 |
14.968 |
12.219 |
|
3 |
33.503 |
28.129 |
23.287 |
|
4 |
48.255 |
35.115 |
27.001 |
|
5 |
59.164 |
51.133 |
28.130 |
|
6 |
68.877 |
55.330 |
47.377 |
|
7 |
77.019 |
62.854 |
54.006 |
|
8 |
89.847 |
78.941 |
59.195 |
|
12 |
99.050 |
91.944 |
83.879 |
|
16 |
99.752 |
99.060 |
90.668 |
|
20 |
99.886 |
99.751 |
98.271 |
|
24 |
100.01 |
100.14 |
98.704 |
Figure G: Comparison of Batches formulated using Stearic
Acid
I.
Batches formulated using Carbopol 934P and Stearic acid in combination as release retardant in tablet
core composition
Table I:
Batches formulated using Carbopol 934P and Stearic acid in combination as release retardant in tablet
core composition
|
Ingredients |
VNL10 C6 |
VNL11 C6 |
VNL12 C6 |
|
Venlafaxine Hydrochloride |
42.43 |
42.43 |
42.43 |
|
Stearic
acid |
10.60(25%) |
10.60(25%) |
10.60(25%) |
|
Carbopol
934P |
2.12(5%) |
4.24(10%) |
6.36(15%) |
|
Pearlitol®
25C |
81.35 |
79.23 |
77.11 |
|
PVP K30 |
7.5 |
7.5 |
7.5 |
|
Aerosil |
3 |
3 |
3 |
|
Magnesium
stearate |
3 |
3 |
3 |
|
Core
tablet evaluation |
|||
|
Hardness |
5-6 kg/cm2 |
||
|
Friability |
0.1 % |
||
|
Coating
composition |
|||
|
Cellulose
acetate |
3% w/v in Acetone : Isopropyl alcohol (60:40) |
||
|
PEG 400 |
30% w/w
of dry cellulose acetate powder |
||
|
Coating
level |
20±0.5 % |
||
# Polymer
percentage with respect to dose of drug
Table I : IN VITRO RELEASE STUDY OF BATCH VNL10 C6, VNL11 C6 &
VNL12 C6
|
Time (Hrs.) |
VNL10 C6 |
VNL11 C6 |
VNL12 C6 |
|
0 |
0.000 |
0.000 |
0.000 |
|
1 |
5.124 |
4.605 |
2.984 |
|
2 |
11.508 |
10.788 |
10.126 |
|
3 |
21.327 |
20.409 |
19.493 |
|
4 |
25.686 |
24.897 |
23.849 |
|
5 |
30.146 |
29.422 |
27.396 |
|
6 |
46.672 |
45.623 |
44.113 |
|
7 |
52.503 |
51.583 |
48.119 |
|
8 |
57.036 |
56.181 |
54.010 |
|
12 |
94.434 |
83.660 |
69.045 |
|
16 |
96.989 |
96.461 |
77.737 |
|
20 |
99.350 |
99.346 |
85.155 |
|
24 |
99.885 |
99.622 |
98.893 |
Figure I: Comparison of Batches formulated using
J)
Batches formulated using Carbopol 934P and HPMC 50
cps in combination as release retardant in tablet core composition
Table J:
Batches formulated using Carbopol 934P and HPMC 50
cps in combination as release retardant in tablet core composition
|
Ingredients |
VNL13 C6 |
VNL14 C6 |
|
Venlafaxine Hydrochloride |
42.43 |
42.43 |
|
HPMC 50
cps |
8.48(20%) |
8.48(20%) |
|
Carbopol
934P |
4.24(10%) |
6.36(15%) |
|
Pearlitol®
25C |
81.35 |
79.23 |
|
PVP K30 |
7.5 |
7.5 |
|
Aerosil |
3 |
3 |
|
Magnesium
stearate |
3 |
3 |
|
Core
tablet evaluation |
||
|
Hardness |
5-6 kg/cm2 |
|
|
Friability |
0.1 % |
|
|
Coating
composition (C6) |
||
|
Cellulose
acetate |
3% w/v in Acetone : Isopropyl alcohol (60:40) |
|
|
PEG 400 |
30% w/w
of dry cellulose acetate powder |
|
|
Coating
level |
20±1.0 % |
|
# Polymer
percentage with respect to dose of drug
Table J.:
IN VITRO RELEASE STUDY OF BATCH VNL13 C6, VNL14 C6
|
Time (Hrs.) |
VNL13 C6 |
VNL14 C6 |
|
0 |
0.000 |
0.000 |
|
1 |
14.530 |
12.389 |
|
2 |
23.236 |
21.332 |
|
3 |
32.024 |
26.991 |
|
4 |
38.334 |
33.544 |
|
5 |
45.021 |
37.624 |
|
6 |
54.972 |
44.887 |
|
7 |
61.223 |
52.688 |
|
8 |
66.541 |
60.558 |
|
12 |
87.964 |
76.908 |
|
16 |
95.387 |
89.391 |
|
20 |
99.276 |
97.612 |
|
24 |
99.101 |
99.092 |
Figure J: Comparison of Batches formulated using HPMC 50cps and Carbopol
934P
K. In vitro
release study of batches coated by coating solution(C3)
containing 15% w/w PEG 400 as pore former.
For these study
take a batch of VNL3C3, VNL6C3,VNL12C3,,VNL14C3.
Table K.:
IN VITRO RELEASE STUDY OF BATCH VNL3 C3, VNL6 C3& VNL9 C3, VNL12 C3 &
VNL14 C3
|
Time (Hrs.) |
VNL3 C3 |
VNL6 C3 |
VNL9 C3 |
VNL12 C3 |
VNL14 C3 |
|
0 |
0.000 |
0.000 |
0.000 |
0.000 |
0.000 |
|
1 |
5.124 |
4.086 |
3.697 |
2.270 |
1.038 |
|
2 |
10.399 |
9.285 |
10.065 |
9.666 |
8.028 |
|
3 |
19.950 |
18.119 |
21.384 |
15.186 |
12.632 |
|
4 |
29.656 |
24.755 |
27.512 |
22.391 |
18.919 |
|
5 |
36.950 |
32.096 |
33.741 |
27.387 |
23.909 |
|
6 |
39.990 |
38.333 |
46.560 |
35.176 |
28.176 |
|
7 |
49.986 |
50.629 |
52.240 |
40.893 |
31.526 |
|
8 |
56.955 |
56.567 |
61.076 |
49.991 |
36.958 |
|
12 |
75.778 |
70.819 |
74.105 |
67.522 |
57.469 |
|
16 |
89.057 |
82.768 |
82.003 |
86.403 |
76.302 |
|
20 |
98.784 |
92.879 |
94.700 |
96.421 |
93.494 |
|
24 |
99.880 |
98.935 |
99.597 |
99.215 |
99.981 |
Figure K: Comparison of bacthes coated by coating composition(C3) containing 15% w/w PEG 400
L. EFFECT OF
LEVEL OF PORE FORMING AGENT CONCENTRATION (PEG 400) ON IN VITRO RELEASE PROFILE
Table L.:
Batch Coding of coating Composition
|
Batch |
PEG 400 (%w/w
of dry weight of cellulose acetate) |
|
C1 |
5 |
|
C2 |
10 |
|
C3 |
15 |
|
C4 |
20 |
|
C5 |
25 |
|
C6 |
30 |
# Coating
solution contains 3% w/v CA; Solvent system composed of acetone :
IPA (60:40)
Table L.:
IN VITRO RELEASE STUDY OF BATCH VNL14 C1, VNL14 C2, VNL14 C3, VNL14 C4, VNL14
C5 & VNL14 C6
|
Time (Hrs.) |
VNL14 C1 |
VNL14 C2 |
VNL14 C3 |
VNL14 C4 |
VNL14 C5 |
VNL14 C6 |
|
0 |
0.000 |
0.000 |
0.000 |
0.000 |
0.000 |
0.000 |
|
1 |
0.389 |
1.038 |
1.038 |
3.114 |
4.022 |
12.389 |
|
2 |
0.850 |
6.006 |
8.028 |
10.779 |
12.937 |
21.332 |
|
3 |
5.287 |
9.555 |
12.632 |
15.582 |
19.051 |
26.991 |
|
4 |
7.594 |
14.140 |
18.919 |
21.870 |
24.955 |
33.544 |
|
5 |
9.695 |
18.795 |
23.909 |
26.210 |
31.706 |
37.624 |
|
6 |
11.533 |
22.604 |
28.176 |
31.909 |
37.678 |
44.887 |
|
7 |
15.521 |
26.473 |
31.526 |
37.484 |
45.473 |
52.688 |
|
8 |
18.609 |
28.517 |
36.958 |
42.211 |
52.495 |
60.558 |
|
12 |
35.976 |
48.291 |
57.469 |
65.327 |
74.058 |
76.908 |
|
16 |
48.725 |
58.249 |
76.302 |
82.804 |
86.765 |
89.391 |
|
20 |
56.361 |
65.283 |
93.494 |
98.032 |
93.553 |
97.612 |
|
24 |
64.100 |
77.910 |
99.981 |
100.00 |
99.982 |
99.092 |
Figure L: Effect of conc. of pore forming agent (PEG 400) on In vitro release
M. EFFECT OF
pH OF DISSOLUTION MEDIUM ON IN VITRO RELEASE PROFILE :
For these study take batch according to VNL14C3. And dissolution done
by using different media. First media
having pH 1.2, second media having pH4.5 and third media having pH 6.8 and
compared the release profile.
Table M.: IN
VITRO RELEASE STUDY OF BATCH VNL14 C3 IN DISSOLUTION MEDIA HAVING pH 1.2, pH
4.5. & pH 6.8..
|
Time (Hrs.) |
pH 1.2. |
pH 4.5. |
pH 6.8.) |
Conc.(mg/7ml) |
Error |
mg/900ml |
Cumulative
(mg/900ml) |
CPR |
|
0 |
0.000 |
0.000 |
0.000 |
0.000 |
0.000 |
0.000 |
0.000 |
0.000 |
|
1 |
0.778 |
1.038 |
1.686 |
0.002 |
0.000 |
0.292 |
0.292 |
0.778 |
|
2 |
6.396 |
8.028 |
9.271 |
0.013 |
0.015 |
2.384 |
2.399 |
6.396 |
|
3 |
10.016 |
12.632 |
16.554 |
0.021 |
0.034 |
3.722 |
3.756 |
10.016 |
|
4 |
15.514 |
18.919 |
24.877 |
0.032 |
0.053 |
5.765 |
5.818 |
15.514 |
|
5 |
18.937 |
23.909 |
29.488 |
0.039 |
0.071 |
7.030 |
7.101 |
18.937 |
|
6 |
25.152 |
28.176 |
37.601 |
0.052 |
0.091 |
9.341 |
9.432 |
25.152 |
|
7 |
29.752 |
32.635 |
41.755 |
0.061 |
0.113 |
11.044 |
11.157 |
29.752 |
|
8 |
35.713 |
36.965 |
46.604 |
0.074 |
0.135 |
13.257 |
13.392 |
35.713 |
|
12 |
55.248 |
62.622 |
70.764 |
0.114 |
0.188 |
20.530 |
20.718 |
55.248 |
|
16 |
73.880 |
78.548 |
83.682 |
0.152 |
0.266 |
27.438 |
27.705 |
73.880 |
|
20 |
82.396 |
93.507 |
93.927 |
0.170 |
0.322 |
30.576 |
30.899 |
82.396 |
|
24 |
98.553 |
99.981 |
100.04 |
0.203 |
0.373 |
36.584 |
36.957 |
98.553 |
Figure M: Effect of pH on In
vitro release
N. EFFECT OF AGITATION INTENSITY ON IN VITRO
RELEASE PROFILE
In these study we have done release profile of
drug in same media with different rpm(50,100,150) and
compared its release profile. Which is shown in figure N.
Table N.: IN
VITRO RELEASE STUDY OF BATCH VNL14 C3 AT 50 RPM, 100RPM.
|
Time (Hrs.) |
50 RPM |
100 RPM |
150 RPM |
|
0 |
0.000 |
0.000 |
0.000 |
|
1 |
1.168 |
4.022 |
6.746 |
|
2 |
3.398 |
10.132 |
16.474 |
|
3 |
7.127 |
14.144 |
19.918 |
|
4 |
13.866 |
19.841 |
27.112 |
|
5 |
19.642 |
27.047 |
30.868 |
|
6 |
21.239 |
30.804 |
32.259 |
|
7 |
28.488 |
34.021 |
38.463 |
|
8 |
34.007 |
38.930 |
46.193 |
|
12 |
51.387 |
56.764 |
65.412 |
|
16 |
74.703 |
75.973 |
83.259 |
|
20 |
89.116 |
93.951 |
93.924 |
|
24 |
99.826 |
99.789 |
100.04 |
Figure N: Effect of agitation
intensity on In Vitro Release
O. EFFECT OF
COATING THICKNESS ON IN VITRO RELEASE :
In these study
we have used 20%,22.5% & 25% weight gain &
compared its release profile, which is shown in figure O.
Table O: IN
VITRO RELEASE PROFILE OF BATCH HAVING COATING WEIGHT GAIN 20 %,22.5 % & 25
%
|
Time (Hrs.) |
20 % |
22.5 % |
25 % |
|
0 |
0.000 |
0.000 |
0.000 |
|
1 |
1.038 |
0.843 |
0.519 |
|
2 |
8.028 |
7.506 |
6.069 |
|
3 |
12.632 |
10.086 |
8.710 |
|
4 |
18.919 |
12.448 |
12.964 |
|
5 |
23.909 |
22.962 |
18.597 |
|
6 |
28.176 |
27.912 |
22.215 |
|
7 |
31.526 |
28.918 |
24.975 |
|
8 |
36.958 |
35.967 |
29.751 |
|
12 |
57.469 |
55.639 |
48.040 |
|
16 |
76.302 |
74.010 |
65.948 |
|
20 |
93.494 |
94.331 |
86.136 |
|
24 |
99.981 |
101.74 |
93.487 |
Figure O: Effect of coating thickness on In Vitro release
5. CONCLUSION:
After seeing the
above result of the all the batches the best batch which having the best
release profile during 24hr study in invitro drug
release profile was batch No. VNL14
C3.
6. REFERENCES:
1) D. Prabakaran, Paramjit Singh, Parijat Kanaujia, Vivek Mishra, Controlled Porosity
Osmotic Pumps of Highly Aqueous Soluble Drug Containing Hydrophilic Polymers as
Release Retardants, PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY Vol. 9, No. 4, pp.
435–442, 2004
2) Drug comparisions and facts, 2006.F. Theeuwes, Elementary osmotic pump, J.
Pharm. Sci. 64 (1975) 1987–1991.
3) R.L. Jerzewski, Y.W. Chien, Osmotic drug delivery, in: A. Kydonieus
(Ed.), Treatise On Controlled Drug Delivery:
Fundamentals, Optimization, Application, Marcel Dekker, New York, 1992, pp.
225–253.
4) P.S.L.Wong, B. Barclay, J.C. Deters, F. Theeuwes,
Osmotic device with dual thermodynamic activity, US patent 4,612,008, Sept. 16,
1986.
5) D.R. Swanson, B.L. Barclay, P.S.L. Wong, F. Theeuwes, Nifedipine
gastrointestinal therapeutic system, Am. J. Med. 83 (Suppl. 6B) (1987) 3–9.
6) F. Theeuwes, P.S.L.Wong, T.L. Burkoth, D.A.
Fox, Osmotic systems for colon-targeted drug delivery, in: P.R. Bieck (Ed.), Colonic Drug Absorption and Metabolism, Marcel
Dekker, New York, 1993, pp. 137–158.
7) L. Dong, K. Shafi, J. Wan,
P. Wong, A novel osmotic delivery system: L-OROS Softcap,
in: Proceedings of the International Symposium on Controlled Release of
Bioactive Materials, Paris (July), 2000
8) L. Dong, P. Wong, S. Espinal,
L-OROS HARDCAP: A new osmotic delivery system for controlled release of liquid
formulation, in: Proceedings of the International Symposium on Controlled
Release of Bioactive Materials, San Diego (June), 2001
9) G.M. Zentner, G.S. Rork, K.J. Himmelstein, The
controlled porosity osmotic pump, J. Control. Release 1 (1985) 269–282.
10) G.M. Zentner, G.S. Rork, K.J. Himmelstein,
Controlled porosity osmotic pump, US patent 4,968,507, Nov. 6, 1990.
11) G.M. Zentner, G.S. Rork, K.J. Himmelstein, Controlled
porosity osmotic pump,Journal of controlled release 1 (1985) 269–282.
12) P. Schultz, P. Kleinebudde,
A new multiparticulate delayed release system. Part
I. Dissolution properties and release mechanism, J. Control. Release 47 (1997)
181–189.
13) J.R. Cardinal, S.M. Herbig,
R.W. Korsmeyer, J. Lo, K.L. Smith, A.G. Thombre, Asymmetric membranes in delivery devices, US
patent 5,698,220, Dec. 16, 1997.
14) S.M. Herbig, J.R. Cardinal,
R.W. Korsmeyer, K.L. Smith, Asymmetric-membrane
tablet coatings for osmotic drug delivery, J. Control. Release 35 (1995)
127–136.
15) A.G. Thombre, J.R. Cardinal,
A.R. DeNoto, S.M. Herbig,
K.L. Smith, Asymmetric membrane capsules for osmotic drug delivery I.
Development of a manufacturing process, J. Control. Release 57 (1999) 55–64.
16) L. Liu, J. Ku, G. Khang, B.
Lee, J.M. Rhee, H.B. Lee, Nifedipine controlled
delivery by sandwiched osmotic tablet system, J. Control. Release 68 (2000)
145–156.
17) www.drugbank.com
18)
Raymond C Rowe,
Paul J Sheskey and Siân C
Owen, Handbook of pharmaceutical excipients.
Received on 15.04.2013 Accepted on 15.05.2013
© Asian Pharma
Press All Right Reserved
Asian J. Pharm.
Res. 3(2): April- June
2013; Page 86-97