International Journal of Innovative Pharmaceutical …...Malla reddy institute of pharmaceutical sciences Secunderabad-500014, Telangana, INDIA Email: [email protected] Mobile:

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.

mailto:[email protected]




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




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




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




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




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




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




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




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




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




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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4. Michael E. Aulton. Pharmaceutics The design and manufacture of medicines. 3rd

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5. Martin, A., Bustamante, P., Lippincott. Text book of Physical Pharmacy. 4th

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International Journal of Innovative Pharmaceutical …...Malla reddy institute of pharmaceutical sciences Secunderabad-500014, Telangana, INDIA Email: [email protected] Mobile: