RESEARCH ARTICLE Soumya et.al / IJIPSR / 2 (11), 2014, 2850-2861
Department of Industrial Pharmacy ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2850
FORMULATION AND EVALUATION OF CARISOPRODOL
EXTENDED RELEASE MATRIX TABLET
1Kesi Reddy Soumya*,
2Rajesh Kumar Kumpati,
3Dr N. Srinivas
1,3Department of Industrial Pharmacy, Malla reddy institute of pharmaceutical sciences,
Maisammaguda, Dhulapally, (Post Via Hakimpet, secunderabad-500014) Telangana, INDIA
2Department of Pharmaceutics, Samskruti College of Pharmacy, Hyderabad, Telangana, INDIA
Corresponding Author:
Kesi Reddy Soumya
Deparment of Industrial Pharmacy
Malla reddy institute of pharmaceutical sciences
Secunderabad-500014, Telangana, INDIA
Email: [email protected]
Mobile: +91 8897456783
International Journal of Innovative
Pharmaceutical Sciences and Research www.ijipsr.com
Abstract
The Present study was undertaken with an aim to formulate and evaluate Carisoprodol Extended release tablets,
A centrally acting skeletal muscle relaxant whose mechanism of action is not completely understood but may be
related to its sedative actions. It is used as an adjunct in the symptomatic treatment of musculoskeletal
conditions associated with painful muscle spasm. Preformulation studies were carried and results were found to
be satisfactory. The compatible excipients were selected for the formulation development.Experiment was
performed by using both dry and wet granulation techniques based on the flow properties of API. In order to
increase the flow property of the tablets, wet granulation was chosen for further formulation and found to be
satisfactory. During development of formula, in-process tests such as bulk density, tapped density, Carr’s index,
Hausner’s ratio and angle of repose were evaluated for granules and hardness, friability, weight variation,
thickness and disintegration were evaluated for the core tablets. Core tablets were coated with coating
suspension.Finished products were evaluated for hardness, friability, weight variation, thickness, disintegration,
dissolution and drug content.The developed trials were tested for in-vitro dissolution profile and compared with
the reference product Carisoma. The in-vitro dissolution of E3 was nearest to the reference product (f2 = 85.17).
The coated tablets of E3 formulations were packed in HDPE containers and stability studies performed at 45°C
/75% RH, 25oC /60% RH for 2 months. Stability samples were evaluated initially and after 2 months. The
results were compared with the pre-determined specifications. All the results were found to be satisfactory.
Keywords: Carisoprodol, Extended Release Tablet.
RESEARCH ARTICLE Soumya et.al / IJIPSR / 2 (11), 2014, 2850-2861
Department of Industrial Pharmacy ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2851
INTRODUCTION
Dosage forms are also referred to as “Drug Delivery Systems” or “Finished Drug Products”. A
drug delivery system (DDS) is defined as a formulation or a device that enables the introduction
of a therapeutic substance into the body and improves its efficacy and safety by controlling the
rate, time, and site of release of drugs in the body. It should minimize exposure of the drug
substance to other receptors of the patient that might result in adverse effects. This process
includes the administration of the therapeutic product, the release of the active ingredients by the
product and then subsequent transport of the active ingredients across the biological membranes
to the site of action.1Oral drug delivery is the most desirable and preferred method of
administering therapeutic agents to attain systemic effects mainly because of patient acceptance,
convenience in administration and cost-effective manufacturing process.For many drug
substances, conventional immediate-release formulations provide clinically effective therapy, by
maintaining the required balance of pharmacokinetic and pharmacodynamic profiles with an
acceptable level of safety to the patient. Conventional drug therapy requires administration of
periodic doses of therapeutic agents. These agents are formulated to produce maximum stability,
activity and bioavailability. For most drugs, conventional methods of drug administration are
effective, but some drugs which are unstable or toxic and have narrow therapeutic window.
Conventional dosage forms are also associated with many side effects and in some cases the
initial dose may not be adequate enough to reach the therapeutic range to elicit pharmacological
response. In such cases, a method of continuous administration of therapeutic agent is desirable to
maintain fixed plasma levels. Beside this, the repeated drug administration at the regular intervals
may result in severe side effect. These problems of conventional dosage forms have been
overcome by controlled drug delivery system. Controlled Drug Delivery Systems have a number
of advantages over traditional systems such as improved efficiency, reduced toxicity and
improved patient convenience. The main goal of controlled drug delivery systems is to improve
the effectiveness of drug therapies [1-10].
MATERIALS AND METHODS
MATERIALS
Carisoprodol was obtained as gift sample from Divis Drugs Ltd. Eudragit L100-55, Hydroxy
propyl cellulose were obtained as gift sample from M.B Sugars & pharmaceuticals. Sodium starch
glycolate was obtained as gift sample from Dow chemicals. Sodium hydroxide, Talc and Stearic
RESEARCH ARTICLE Soumya et.al / IJIPSR / 2 (11), 2014, 2850-2861
Department of Industrial Pharmacy ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2852
acid were obtained as gift sample from Shin- Etsu. Tri ethyl citrate was obtained as gift sample
from Roquettte.All other chemicals/Solvents were procured from market are of analytical grade.
METHOD
PREPARATION OF CARISOPRODOL CORE TABLETS
DIRECT COMPRESSION METHOD
All the ingredients-Carisoprodol and Sodium Starch Glycolate (SSG), L-HPC have been weighed
individually into separate poly bags.These ingredients are then sifted though sieve no. 40 and
Lubrication-Weighed amount Stearic Acid sieved though mesh sieve no. 60 are added to the
above blend and blending is carried out for 5 more min.Compression-The lubricated blend is
compressed using 16×8 mm Oblong deep concave punch toolings.Description of core tablets.
Table 1: Formula for the preparation of core tablets by Direct Compression method
WET GRANULATION METHOD
Weighing and sifting: Carisoprodol and Sodium Starch Glycolate (SSG) were weighed and sieved
though sieve number 40 and collected and mixed in a poly bag. Binder was prepared by
dissolving L-HPC in the purified water under stirring and it was continued until clear solution was
obtained.Dry mix Carisoprodol, SSG in rapid mixing granulator for 10 min. Binder was added at
slow speed to granulate the mixture.The wet mass was milled though multi mill though sieve
number 12.The wet granules were dried in fluid bed drier at a temperature of 60°C and the dried
granules were sieved though sieve number 18.SSG was sieved though sieve number 40, blended
with the above dried granules for 3 min.Stearic acid was added to pre-lubricated granules and
lubricated for 2 min.The lubricated granules were compressed with 16 mm concave punches with
a tablet weight of 500 mg, respectively on a 12 stationary compression machine. White and
Oblong biconvex tablet plain on both sides.
S No INGREDIENTS F1 (mg / tab)
1. Carisoprodol 500
2. L-HPC LH-11 10
3. Crospovidone 20
4. Stearic acid 5
Total weight of core tablet (mg) 535
RESEARCH ARTICLE Soumya et.al / IJIPSR / 2 (11), 2014, 2850-2861
Department of Industrial Pharmacy ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2853
Table 2: Optimization of core tablets by Aqueous Wet Granulation
* Purified water was evaporated during drying of granules.
ENTERIC COATING OF THE SELECTED CORE TABLETS
Procedure for enteric coating of core tablets:
The Optimized core tablets were loaded into coating pan and the tablet bed was warmed till the
temperature reaches to 50oC-55
oC. The enteric coating dispersion should be kept under
continuous stirring during the coating process. The coating was continued till target weight build
has been achieved. More than 2% build up of enteric coating has been given to the core tablets.
After target build up has been achieved, the pan speed was reduced and spray gun was turned off.
Then the tablets were warmed at the temperature of 38C-40C for 10 minutes. The enteric coated
tablets were then collected into a container.
Table 3: Different enteric coating percentages applied to the selected formulation
Parameters E2 E3 E4 E5
Weight of tablets (gm) 134.94 107.54 80.04 51.64
Initial weight (gm) 131.2 104.32 76.82 48.82
Weight after coating (gm) 137.02 110.01 76.82 48.82
% Coating (%) 4 6 8 10
Weight of 50 tablets (gm) 27.40 27.5 28.2 28.65
Average weight (mg) 548 555 564 573
Among the various trial batches of core tablet formulations prepared by Wet granulation method,
one formulation was optimized and different percentages of enteric coating have been applied.
These coated formulations were labeled as E1, E2, E3, E4 and E5.
S No INGREDIENTS Trial Batches (mg/Tablet)
F2 F3 F4 F5 F6 F7 F8 F9 F10
1. Carisoprodol 500 500 500 500 500 500 500 500 500
2. L – HPC 0.5 1 4 8 12 16 20 16 16
3. Crospovidone 15 - - - - - - - -
4. SSG - 14 14 14 14 14 14 14 14
4. Purified water* q.s q.s q.s q.s q.s q.s q.s q.s q.s
Pre-Lubrication
5. SSG - 2.5 2.5 2.5 2.5 2.5 2.5 5 5
Lubrication
6. Stearic Acid 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 5
Total weight of the core 518 520 523 527 531 535 539 537.5 535
RESEARCH ARTICLE Soumya et.al / IJIPSR / 2 (11), 2014, 2850-2861
Department of Industrial Pharmacy ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2854
RESULT & DISCUSSION
PREFORMULATION STUDIES
Particle Size Distribution (PSD)
Table 4: PSD of Carisoprodol
DRUG-EXCIPIENT COMPATIBILITY STUDY
Table 5: Results for Compatibility Study
Coating material – Eudragit + Tri ethyl citrate + talc , C- Complies
Standard Calibration Curves
The λmax was obtained at 280 nm in methanol, at 280 nm in phosphate buffer (pH 6.8). The
standard calibration curve for Carisoprodol with regression value of 0.9994 and 0.999 was shown
in figures 7.1 and 7.2 respectively. The relation between drug concentration and absorbance is
linear and the curve obeys Beer – Lambert’s law within the concentration range of 5 to 40 µg/mL
of Carisoprodol. The calculation of in-vitro drug release and assay was based on this calibration
curve.
Sieve No Aperture Size Weight of the
drug + Sieve
Weight
Retained (g)
% Weight
Retained %CDR
18 1000 381.4 0.3 1.5 1.5
50 297 374.0 19.1 95.5 97.0
70 210 335.0 0.6 0.3 100
120 125 329.0 0 0
140 105 323.0 0 0
170 88 321.0 0 0
S. No Composition
Details
Observation at various storage conditions and durations
Initial 40 / 75% RH 602°C 2-8°C
2W 4W 1W 2W 3M
1. Carisoprodol (API) Off white C C C C C
2. API + SSG Off white C C C C C
3. API + L-HPC Off white C C C C C
4. API + Stearic Acid Off white C C C C C
5. API + Eudragit L 100-55 Off white C C C C C
6. API + Coating material Off white C C C C C
RESEARCH ARTICLE Soumya et.al / IJIPSR / 2 (11), 2014, 2850-2861
Department of Industrial Pharmacy ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2855
Table 6: Calibration of Carisoprodol in Fig. 1: Standard Curve of Carisoprodol in
pH 6.8 Buffer pH 6.8 Buffer
S No Concentration
(µg/mL)
Absorbance at
332 nm
1. 5 0.131
2. 10 0.24
3. 15 0.352
4. 20 0.455
5. 25 0.557
6. 30 0.647
7. 35 0.75
8. 40 0.86
Table 7: Calibration of Carisoprodol in Fig. 2: Standard Curve of Carisoprodol in
Methanol Methanol
S. No Concentration
(µg/mL)
Absorbance at
280 nm
1. 5 0.045
2. 10 0.086
3. 15 0.13
4. 20 0.181
5. 25 0.231
6. 30 0.275
7. 35 0.32
8. 40 0.385
EVALUATION OF CARISOPRODOL BLEND
Carisoprodol Blends were formulated by using dry granulation method in F1 and wet granulation
method for F2-F10. After the preparation of the Carisoprodol blends in each formulation, all the
Preformulation studies were performed and the results were tabulated in the Table 7.8.
Table 8: Evaluation of flow properties of blends of various trial batches were mean ± SD,
n=3
Formulation
Code
Angle of
Repose
Bulk
Density
Tapped
Density Carr’s Index
Hausner’s
Ratio
F1 44.91±2.05 0.49±0.013 0.62±0.061 20.97±2.445 1.26±0.028
F2 26.52±1.32 0.78±0.008 0.78±0.025 10.28±0.009 1.01±0.009
F3 29.56±1.64 0.66±0.003 0.75±0.165 9.56±0.009 1.18±0.165
F4 27.46±1.52 0.78±0.012 0.86±0.231 9.36±0.156 1.14±0.156
F5 28.41±1.69 0.72±0.011 0.79±0.013 9.24±1.447 1.10±0.018
F6 29.25±1.39 0.62±0.028 0.69±0.009 7.91±0.124 1.08±0.015
F7 28.54±0.42 0.68±0.009 0.74±0.011 8.20±0.098 1.89±0.001
F8 29.96±2.18 0.70±0.089 0.77±0.011 8.29±0.089 1.09±0.021
F9 29.93±1.70 0.62±0.015 0.67± 0.006 7.60±0.075 1.08±0.005
F10 28.47±0.70 0.66±0.008 0.71± 0.026 7.75±0.689 1.08±0.008
RESEARCH ARTICLE Soumya et.al / IJIPSR / 2 (11), 2014, 2850-2861
Department of Industrial Pharmacy ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2856
EVALUATION OF CARISOPRODOL UNCOATED TABLETS
The tablets of different formulations of Carisoprodol were subjected to evaluation tests such as
tablet weight, thickness, and hardness and disintegration time.
Table 9: Evaluation of Carisoprodol Uncoated Tablets (F2- F6) were mean ± SD
Table 10: Evaluation of Carisoprodol Uncoated Tablets (F7- F10) were mean ± SD
S.
No Tests Specification F2 F3 F4 F5 F6
1. Description
white coloured
oblong shaped
uncoated tablet
Complies Complies Complies Complies Complies
2. Average
weight (g)
Varies(0.515-
0.535) 0.5203 0.5244 0.5256 0.5281 0.5297
3.
Weight
variation
(n=20)
±5% from the
average weight +2.1 to -2.3 +2.3 to -2.5
+2.8 to -
2.7 +3.7 to -2.9 +2.4to-2.5
4. Thickness
(mm) 6–6.5 6.25±0.24 6.19±0.39 6.18±0.28 6.11±0.25 6.22±0.34
5. Hardness
(kp) 8-12 6.8±0.01 4.5±0.02 7.8±0.03 10±0.02 10.58±0.08
6. Friability
(%w/w) NMT 1%
Failed due
to capping 1.16±0.01 0.21±0.01 0.19±0.01 0.23±0.04
7.
Disintegrati
on Time
(min)
0-15 18 10 10.5 11 12
S No Tests Specification F7 F8 F9 F10
1. Description
white coloured
oblong shaped
uncoated tablet
Complies Complies Complies Complies
2. Average
weight (g)
Varies(0.515-
0.535) 0.530 0.5312 0.532 0.536
3.
Weight
variation
(n=20)
±5% from the
average weight +2.4 to -2.8 +3.3 to -2.5 +1.8 to- 2.7 +3.7 to -2.9
4. Thickness
(mm) 6–6.5 6.18±0.16 6.22±0.29 6.38±0.58 6.22±0.25
5. Hardness (kp) 8-12 10.5±0.05 10.8±0.03 10.3±0.05 10.5±0.02
6. Friability
(%w/w) NMT 1% 0.4±0.01 0.36±0.01 0.22±0.03 0.23±0.06
7. Disintegration
Time (min) 0-15 12 10 8.5 8.2
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Department of Industrial Pharmacy ISSN (online) 2347-2154
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Table 11: Dissolution profile of Uncoated tablets of the Trial batches in pH 6.8 buffer
Time (min) F5 F6 F7 F8 F9 F10
0 0 0 0 0 0 0
10 14.85 15.59 20.33 24.23 21.52 26.25
20 29.85 32.7 58.96 52.54 59.64 68.39
30 61.22 59.03 82.31 78.14 70.24 82.04
45 85.46 88.12 90.4 83.70 89.74 96.23
60 97.56 98.89 98.89 98.20 98.36 99.79
Fig. 3: Dissolution profile of Un-coated tablets Fig. 4: Dissolution profile of Un-coated tablets
of the Trial batches F5, F6, F7 in pH 6.8 buffer of the Trial batches F8, F9, F10 in pH 6.8 buffer
DISCUSSION
The first trial was performed using direct compression and it was observed that the flow of the
blend was poor, weight variation of tablets was observed and the disintegration time of the
product was observed on higher side. In order to overcome this problem, next trials were planned
using wet granulation process. In the sond trial, disintegration was on higher side. In order to
avoid it, changing the disintegrant, crospovidone to SSG to reduce the disintegration time. In the
third trial, the physical parameters were not found to be satisfactory. Sticking and capping was
observed during the compression stage. In order to overcome this problem, the next trial was
planned by increasing the concentration of HPC and by distributing SSG both in intra and extra
granular portions to improve the flow of the blend. In the fourth trial, the compression parameters
were found to be satisfactory and no manufacturing issues were observed. Dissolution of the test
product was observed to be on higher side when compared to the innovator. In order to decrease
the dissolution rate, the next trials were planned by increasing the binder concentration from 4-16
mg until the dissolution values were similar compared to the innovator product. In the eight trial,
the dissolution of the test product was on lower side compared to that of innovator. In order to
combat this, to the F7 formulation optimize the concentrations of extragranular disintegrant and
RESEARCH ARTICLE Soumya et.al / IJIPSR / 2 (11), 2014, 2850-2861
Department of Industrial Pharmacy ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2858
lubricant. From these trials, formulation F10 was selected as optimized formulation for enteric
coating.
EVALUATION OF CARISOPRODOL ENTERIC COATED TABLETS
Table 12: Evaluation of Carisoprodol Uncoated Tablets (E1 to E5)
DISSOLUTION TEST OF ENTERIC COATED TABLETS
The following results were compared with Innovator product.
Table 13: Dissolution profile of Enteric coated tablets of the Innovator and Trial batches in
pH 6.8 buffer, after 2 h in 0.1N HCL
S.
No Tests Specification E1 E2 E3 E4 E5
1. Description
white coloured
oblong shaped
enteric coated
tablet
Complies Complies Complies Complies Complies
2. Average weight
(g)
Varies (0.540-
0.585) 0.5433 0.5528 0.5682 0.5746 0.5863
3.
Weight
variation
(n=20)
±5% from the
average
weight
+2.6 to -3.2 +2.8 to -
2.5
+2.1 to –
2.7
+3.3 to -
3.1 +2.5 to-3.6
4. Thickness
(mm) 6–8 7.25±0.36 7.19±0.52 7.18±0.28 7.11±0.25 7.23±0.33
5. Hardness (kp) 10-15 11.8±0.01 12.5±0.03 13.6±0.2 14.2±0.02 14.5 ±0.06
6. Friability
(%w/w) NMT 1% 0.24±0.01 0.23±0.01 0.22±0.06 0.45±0.01 0.32±0.04
7. Disintegration
Time (min) 0-15 8 10 10.5 11 12
8. Coating
uniformity (%) -- 3.25 3.37 3.52 3.41 3.64
9.
Coating
process
uniformity (%)
-- 87.16 82.36 76.88 70.58 68.91
10. % LOD -- 2.37 3.12 4.65 2.05 5.22
Time Intervals
(min) Innovator
E1 E2 E3 E4 E5
2% 4% 6% 8% 10%
0 0 0 0 0 0 0
10 22.65 32.45 27.85 22.16 21.05 18.28
20 77.18 82.13 73.54 75.47 72.16 66.04
30 84.32 92.01 86.74 88.22 81.21 75.61
45 92.65 96.65 93.63 96.25 88.26 89.38
60 98.64 99.03 96.21 99.48 94.36 92.28
RESEARCH ARTICLE Soumya et.al / IJIPSR / 2 (11), 2014, 2850-2861
Department of Industrial Pharmacy ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2859
Fig. 5 & 6: Dissolution profile of Enteric coated tablets of the Innovator and Trial batches in
pH 6.8 buffer, after 2 hr in 0.1N HCl
STABILITY DATA OF THE SELECETED FORMULATION (E3)
Accelerated Stability Studies
Stability studies were conducted at 40ºC / 75% RH for about 2 months in stability chamber
(thermo lab). Samples were collected and analyzed after 2nd
month.
Table 14: Stability Test Data of E3 batch Fig. 7: Stability data of E3 after 2 months
Tests E3
Initial 2M
Assay (%) 99.92 97.56
Time (min) % CDR
10 22.16 16.32
20 75.47 69.15
30 88.22 88.92
45 96.25 92.48
60 99.48 96.54
By comparing the initial values of Assay, and %CDR of E3 batch with their respective values
analyzed after 2 months of stability studies, a very minute difference have been found between
those values. Hence it was concluded that E3 was stable formulation.
CONCLUSION
The Present study was undertaken with an aim to formulate and evaluate Carisoprodol Extended
release tablets, mainly used for the treatment a centrally acting skeletal muscle relaxant whose
mechanism of action is not completely understood but may be related to its sedative actions. It is
used as an adjunct in the symptomatic treatment of musculoskeletal conditions associated with
painful muscle spasm. Preformulation studies were carried and results were found to be
satisfactory. Experiment was started with physical parameters such as bulk density, tapped
RESEARCH ARTICLE Soumya et.al / IJIPSR / 2 (11), 2014, 2850-2861
Department of Industrial Pharmacy ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2860
density, Carr’s index, Hausner’s ratio and angle of repose of the Active Pharmaceutical
Ingredient. The compatible excipients were selected for the formulation development. Experiment
was performed by using both dry and wet granulation techniques based on the flow properties of
API. In order to increase the flow property of the tablets, wet granulation was chosen for further
formulation and found to be satisfactory. During development of formula, in-process tests such as
bulk density, tapped density, Carr’s index, Hausner’s ratio and angle of repose were evaluated for
granules and hardness, friability, weight variation, thickness and disintegration were evaluated for
the core tablets. Core tablets were coated with coating suspension. Materials used for coating
were shown in the Table 6.6. Finished products were evaluated for hardness, friability, weight
variation, thickness, disintegration, dissolution and drug content. The developed trials were tested
for in-vitro dissolution profile and compared with the reference product Carisoma. The in-vitro
dissolution of E3 was nearest to the reference product (f2 = 85.17). The coated tablets of E3
formulations were packed in HDPE containers and stability studies performed at 45°C /75% RH,
25oC /60% RH for 2 months. Stability samples were evaluated initially and after 2 months. The
results were compared with the pre-determined specifications. All the results were found to be
satisfactory. It may be concluded from the present study that Carisoprodol Extended release
tablets showed acid resistance and the release was comparable with that the innovator. It was
evident from the results that 6% Eudragit L 100-55 coated tablets followed first order release and
formulation E3 was found to be an optimized formulation.
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1. Thomas N. Tozer, Malcolm Rowland’s. Introduction to Pharmacokinetics and
Pharmacodynamics, 4th
edition: p 106.
2. Remington’s, The Science and Practice of Pharmacy. 21th
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3. Loyd V. Allen, Nicholas G. Popovich., Ansel’s Pharmaceutical Dosage Forms and Drug
Delivery Systems, 8th
edition: p 261-276.
4. Michael E. Aulton. Pharmaceutics The design and manufacture of medicines. 3rd
edition,
2007: 109-168, 223, 304, 616.
5. Martin, A., Bustamante, P., Lippincott. Text book of Physical Pharmacy. 4th
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2007:313 – 316.
6. Indian Pharmacopoeia, Vol. Ι, 323, 1996.
RESEARCH ARTICLE Soumya et.al / IJIPSR / 2 (11), 2014, 2850-2861
Department of Industrial Pharmacy ISSN (online) 2347-2154
Available online: www.ijipsr.com November Issue 2861
7. Jens.T.Cartensen. Drug Stability principles and practices. 2nd
edition revised and
expanded, 360- 379.
8. Subrahmanyam, C.V.S. Text Book of Physical Pharmaceutics. 2nd
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10. S. Yoshioka, Stability of drugs and dosage forms. 2006: 205-216.
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