ISSN: 2373-6367PPIJ

Pharmacy & Pharmacology International Journal
Research Article
Volume 2 Issue 3 - 2015
Formulation Development and Evaluation of Gabapentin Controlled Release Tablets
Neha M Dembla1*, Arun Pandian Maniyam2 and Surendra Agarwal3
1Department of Pharmaceutics, Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, India 2Department of Pharmaceutics, Vinayaka Missions University, India 3Department of Quality Assurance, Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, India
Received: January 25, 2014 | Published: May 27, 2015
*Corresponding author: Neha M Dembla, Department of Pharmaceutics, Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, India, Email: @
Citation: Dembla NM, Maniyam AP, Agarwal S (2015) Formulation Development and Evaluation of Gabapentin Controlled Release Tablets. Pharm Pharmacol Int J 2(3): 00021. DOI: 10.15406/ppij.2015.02.00021

Abstract

The objective of the present study was to develop a pharmaceutically equivalent, stable, robust, cost effective and quality improved formulation of Gabapentin controlled release tablets by using different grades of controlled release polymer. The design of dosage form was performed by choosing Hydroxypropyl Methyl Cellulose (HPMC K100MCR), Hydroxypropyl Methyl Cellulose (HPMC K15MCR), Microcrystalline Cellulose (MCC) and Di-calcium phosphate polymers as matrix builders. The drug-polymer compatibility studies were performed. Blend Uniformity was studied and accordingly the flowability was optimized for the powder blend. Tablets were prepared by direct compression with free flowing powder. The network formed by HPMC, MCC and DCP had been coupled satisfactorily with the controlled resistance, in vitro release and FT-IR. Mean dissolution time was also reported to compare various dissolution profiles. The formula was finalized by comparing the in vitro dissolution with that of the innovator SR and IR tablets. Optimized formulation of Gabapentin was formulated using 23% HPMC K100MCR and 10% of DCP. In vitro drug release profile was examined 98.69% within 12h. The releases of the formulation were fitting to Hixson Crowell model suggesting controlled zero order release from the formulation. The results suggested that direct compression is a suitable method to formulate controlled release Gabapentin tablets and it can perform therapeutically better than conventional immediate release dosage form.
Keywords: Gabapentin; Controlled release; In vitro release

Abbreviations

API: Active Pharmaceutical Ingredient; MEC: Minimum Effective Concentration; CRDDS: Controlled Release Drug Delivery System; MSC: Maximum Safe Concentration; PHN: Post Herpetic Neuralgia; RH: Relative Humidity; HPMC: Hydroxy Propyl Methyl Cellulose; mg: Milli Gram; gm: Grams; ICH: The International Conference on Harmonization; USP: United States Pharmacopeia; NA: Not Applicable; SR: Sustained Release; IR: Immediate Release

Introduction

Immediate release/Conventional release tablets achieve a rapid onset of action, once they reach the Maximum Effective Concentration; they start to get eliminated from the body. Controlled release tablets of Gabapentin are often prescribed for chronic, severe neuronal pain caused as a result of certain long standing diseases. Controlled release tablets are used for a prolonged duration of action with minimal therapeutic effect. They are formulated with natural high intense polymer to achieve sustained release of the API [1]. Controlled release tablets are formulated with a loading dose and a maintenance dose [2]. The loading dose gives an immediate plasma concentration of the API to have immediate effect and the maintenance dose maintains the level of the drug in the plasma for the MEC [1]. Gabapentin is generally used as an anti-convulsant and an analgesic. Neuropathic pain is caused due to diseases affecting the somatosensory system. A common cause for such pain is Varicella. The disease is often localized to a single sensory dermatologic distribution and the pain is perpetuated by the resulting break down and the subsequent healing of the affected skin [3].
Gabapentin is classified as a class II drug which is readily soluble in water and partially absorbed in the gut. Current studies on Gabapentin do not show the specific receptor for binding [4]. Hence, to treat the neuropathic pain, Gabapentin course is started with a dose of 300 mg, 600 mg or 1800 mg/day [5]. Due to this high dose treatment, physicians often treat with lower doses further to avoid suicidal symptoms. Gabapentin has a biological half life of 5-7 hours which gives the scope for the development of Controlled release tablets. Controlled release tablets will help to reduce the dose dependency and improve patient compliance [6]. Due to its crystalline properties, Gabapentin forms an intact matrix with the high viscous polymers.

Materials and Methods-List of Instruments Used

Single Pan Electronic Weighing Balance - Sartorious BT 223S ; Hot air oven - Unilab, India; Blender- Rimek Kalweka HD- 400Ac, India, Rotary Compression Machine- GMI, Friability Test Apparatus- ElectroLab, EF-2, India, Monsanto Hardness Tester- Dr. Schleuniger Pharmatron, Dissolution Test Apparatus- Electrolab, Model-TDT-08L, USP, U.V-Spectrophotometer- Shimadzu Corporation, Japan, Perk Elimer, Sonicator- Spincotech Pvt. Ltd, Italy, pH-meter- Mettler, Toledo, Tap Density Apparatus- Electro Lab ETD - 1020, India, Moisture Balance (Halogen Moisture Analyzer)- Mettler Toledo, US, Vernier Caliper- Mitutoyo Corps, Japan.
Pre formulation study

The detailed physical and chemical properties of a drug substance, alone and in combination with excipient were evaluated in preformulation studies. The particle size distributions of the polymer powders were measured. Particle shape was analyzed microscopically. Flow properties were assessed by utilizing a tap densiometer (Electro Lab ETD - 1020, India) and calculating the Hausner ratio.

Procedure for drug and excipient incompatibility study
Gabapentin drug was mixed with excipients in various ratios. Aliquots of these mixtures and the drug alone were kept in open 5mL glass vials, exposed to 40°C and 75% relative humidity for one month and, at intervals of 2 weeks and 4 weeks, the samples were withdrawn to make physical observations and analyzed after the exposure of the drug and excipient. Physical observation no significant color changes were observed after exposure of drug and excipient to 25°C/60% relative humidity (RH) and 40°C/75% RH for 4 weeks. FTIR Spectra of the drug-excipient study revealed no interaction.
Method of preparation of tablets

The API (Gabapentin), Polymers and diluent were passed through sieve no 60. The API, polymers and diluent were mixed in a V- blender, and then the other excipients sifted through sieve no 60. Were added and mixed in geometric proportions, except the lubricant. The mixture was blended well for 10 minutes. Then the lubricant which was previously sifted through sieve no.60 was added and mixed thoroughly for 5 minutes. Compaction behavior was evaluated by compressing the blends into 9 mm capsular tablets with an instrumented single punch tabletting machine (Compression Machine- GMI) at a compression speed of 10 rpm. Compression force and upper and lower punch displacement were recorded during the compaction process (MGC plus, catman, HBM, Darmstadt, Germany). The blend formula as given in Table 1 was then directly compressed to produce tablets with 9 mm capsular punch.

Ingredients

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

Gabapentin API

600

600

600

600

600

600

600

600

600

600

MCC PH 101

100

100

100

-

-

-

-

-

-

-

HPMC K15MCR

75

90

110

-

-

-

-

-

20

-

Eudragit RSPO

75

60

40

-

-

-

-

-

-

-

SLS

50

50

50

50

50

50

50

50

50

50

Talc

50

50

50

50

50

50

50

50

20

10

Magnesium Stearate

50

50

50

50

50

50

50

50

10

10

Dibasic Calcium Phosphate

-

-

-

200

150

100

40

50

130

100

HPMC K100 MCR

-

-

-

50

100

150

210

175

150

230

Aerosil

-

-

-

-

-

-

-

25

20

20

Table 1: Table 1: Composition (mg) of Gabapentin 600 mg tablet formulations.
Each quantity mentioned in mg
Total weight of the tablet = 1000mg
Each tablet contains = 600 mg of the API.
Characteristics of tablet formulations
isintegration, friability, content uniformity of dose and dissolution profile (Table 2). The average weight was measured over 20 units, as recommended by the United State Pharmacopoeia (U.S.P), 2006. The hardness was determined in a Schleuniger Hardness Tester over 10 tablets. For each formulation, the friability was tested in a Roche Friabilator over a sample of 20 tablets and the acceptance criterion was a maximum loss of 2% of initial weight (U.S.P. 2006). Dissolution profile was determined by analyzing samples by UV Spectrophotometer, Shimadzu Corporation, Japan. Gabapentin controlled release tablets were evaluated as per the specified limit of USP to meet the quality of formulation [2]. Tablets were evaluated for individual and average weight variations, thickness, hardness, assay and in vitro drug release. Individual and average weight variations were measured in the Single Pan electronic balance- Sartorius BT 223S. The friability was tested using 6.0 gm of tablets for 100 RPM in Roche Friabilator and the limit was kept NMT 2% as per USP. Dissolution was performed by using Dissolution Apparatus by Electrolab.
Dissolution
Tablet dissolution was assessed in a standard USP 24 apparatus II in 900 mL of Deionised water. The stirring speed was 100 rpm. A total of 6 tablets were used in the test. Temperature was maintained at 37°C ± 0.5°C throughout the experiment. Dissolution was monitored for 12 h, samples being taken at 1, 2, 4, 6, 8, 10, 12 h. After the collection of each sample, the dissolution medium was replenished with the same volume of fresh medium. The samples were diluted to 100mL with dilution medium and analyzed for drug content by 198.1 nm. A calibration curve was generated from a Shimadzu Corporation, Japan at 198.1 nm [3,4].
Kinetics of the in vitro drug release

To study the release kinetics, data obtained from in vitro drug release studies were plotted Hixon Crowell kinetic models. The kinetic parameters for the in vitro release of gabapentin were determined and then analyzed in order to find the drug release.

Batch Number

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

Bulk Density (g/ml)

0.46

0.48

0.4

0.65

0.5

0.72

0.54

0.55

0.53

0.48

Tapped Density (g/ml)

0.59

0.61

0.52

0.81

0.62

0.89

0.67

0.64

0.62

0.57

Hausner’s Ratio

1.28

1.27

1.28

1.25

1.24

1.23

1.23

1.15

1.16

1.17

Compressibility Index (%)

22.0

21.31

23.07

20.02

19.35

19.1

21.31

14.06

13.92

14.71

Angle of Repose (°)

44

42

41

41

40

41

40

38

35

35

Table 2: Evaluation of blend batches.
Stability studies

The SPSS 19 (IBM, NY, USA) software was used to compute the outcome measures. The initial measured variable was quality of life. One way ANOVA, analysis of variance was performed on the FMF patients before and after education. As a posttest Tukey analysis was applied. Additionally, in order to compare two groups each other, student t-test was performed, p<0.05 was considered statistically significant and confidence intervals were set to 0.95.

Results & Discussion

Direct compression into tablets requires good flowability and compatibility of the excipients to guarantee reproducibility of the process and product quality. The flowability of a powder depends on material properties like the particle surface, size and shape. Particles were found with average particle size of 28.8 µm for almost all the excipients after Sieving. All the excipients and API were found stable. Study revealed that drug has compatibility with all the selected excipients (Figure 1-7).

Figure 1: FTIR Spectrum Curve of Gabapentin + HPMCK100mcr.
Figure 2: FTIR Spectrum Curve of Gabapentin + Micro Crystalline Cellulose.
Figure 3: FTIR Spectrum Curve of Gabapentin + Dibasic Calcium Phosphate.
Figure 4: FTIR Spectrum Curve of Gabapentin + Aerosil 200M.
Figure 5: FTIR Spectrum Curve of Gabapentin + HPMCK100mcr.
Figure 6: FTIR Spectrum Curve of Gabapentin + Sodium Lauryl Sulphate.
Figure 7: FTIR Spectrum Curve of Gabapentin + Magnesium Stearate.
Blend evaluation

According to the USP specifications, the flow properties of the powder blend is ‘‘good’’ if the angle of repose is between 31 and 35. Values between 25 and 30 indicate excellent flow characteristics and values of 36 or above indicate fair to poor flow properties. Accordingly, a formulation was adopted for modifications in the trials. Blend uniformity studies suggested poor flowability with the batches F1- F8 so increased quantity of Lubricant and glidant were used in the formulation. This improved flowability significantly while the flow was good for the formulation F9-F10 as shown in Table 3.

Evaluation of tablet formulations

The early indication showed that the Formulation F1-F4 had low hardness and other parameters meet the USP Specified limit. Table 4 summarizes the results obtained from the tests conducted on all batches. All batches met the requirement for weight variation test according to USP 32. The disintegration time for the tablets correlated well with their hardness (the greater the hardness of the tablet the longer was the time needed to achieve disintegration) F4, F6, F7 and F10 batches passed the test for Drug Content in Tablets which should not be less than 98.0 percent and not more than 102.0 percent.

For formulations F1-F4 it was found that the release was retarded compared to the marketed formulation. In formulation F5, it was found faster in earlier time points. Formulation F6-F9 found that release was satisfactory in early time points and faster in the later time points. Adequate results were obtained only for F10, while its difference factor was well within the specified limit of reference limit Pharmacopeia forum, 2006 (Table 4) (Figure 8).

Kinetics of the in vitro drug release

The kinetic parameters for the in vitro release of gabapentin CR tablets were analyzed in order to find the drug release. Hixson Crowell Kinetic model were investigated and found F 10 follow the Hixson Crowell model of kinetics. The value of intercept for Hixson Crowell Kinetic model was 0.932 (Figure 9). Zero-order release from swellable hydrophilic matrices occurs as an outcome of continuous diffusional path lengths. When the thickness of the gelled layer and diffusional path lengths are constant, zero-order release can be expected, as seen for formulations F10. In contrast, the majority of formulations that showed non-Fickian release must have had an increasingly thickening gel layer due to slower erosion. This led to a decrease in the drug release rate with time as previously reported. At higher concentrations, the viscosity enhancing polymers contributed by keeping the hydrated layers intact, thus maintaining the integrity of the matrix and slowing the erosion process.

Batch Number

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

Thickness (mm)

7.88

7.85

7.91

7.79

7.78

7.71

7.77

7.89

7.83

7.7

Weight Variation (%)

±2.0

±2.55

±3

±4

±3.6

±3

±2.4

±3.5

±4.2

±2

Hardness (kg/cm2 ) Kp

2-4

2-4

2-4

2-4

3-5

2-4

2-4

2-3

2-5

4-5

Friability (%)

1

0.98

0.96

0.78

0.56

0.67

0.37

0.41

0.29

0.15

Drug Content (%)

97

97.26

96.2

98.93

97

99.89

98.53

97

96

99

Table 3:Characteristics of Tablet formulations.

Time (hrs)

MKTD SR Tablet

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

0

0

0

0

0

0

0

0

0

0

0

0

1

18.83

2.33

3.33

8.33

12.50

47.17

21.67

19.83

18.67

19.50

19.17

2

28.35

13.46

15.17

43.51

49.01

53.05

36.36

24.86

23.35

28.36

30.02

4

45.22

20.21

20.52

48.22

57.57

59.44

59.40

55.05

35.05

42.72

45.22

6

66.44

41.55

43.88

78.28

66.30

64.68

64.63

84.78

47.25

67.93

66.60

8

78.18

45.45

54.59

82.53

79.21

82.08

82.04

82.54

53.64

76.01

78.18

10

85.10

57.12

66.65

89.29

93.96

97.34

97.29

99.46

68.86

87.59

83.43

12

100.52

69.53

71.56

100.22

99.40

98.78

98.73

100.91

99.27

100.69

98.69

Table 4:Dissolution Profile of various Formulations.

Temperature and Humidity Condition

Tested after Time (days)

Hardness (Kp)

Friability (%)

Drug Content (%)

Cum % Drug  Released

25oC ± 2°c  & 60% RH

15

4-5

0.14

99

98.67

30

4-5

0.13

99.22

98.65

40oC ± 2°c  & 75% RH

15

4-5

0.12

99.36

98.76

30

4-5

0.14

99.23

98.66

60°c

15

4-5

0.15

99.26

98.06

30

4-5

0.13

99.19

98.18

Table 5:Stability Study results for F10.

Figure 8: Comparative Dissolution profile of various formulations.
Figure 9: Hixon Crowell Plot for the optimized Formulation.

Conclusion

Controlled release tablets of Gabapentin were studied using the different ratios and grades of rate controlling polymers. The Formula using 23% HPMC K100MCR and 10% of DCP fulfilled all the specified requirements of the USP. Stability studies were conducted on tablets of F10 stored at 250C & 60% RH, 400C & 75% RH and 600C for one month. Tablets were evaluated for hardness, friability, in vitro release profile and drug content. After one month, no significant changes were observed in any of the studied parameters during the study period. Thus, it could be concluded that the formulation was stable. Percentage drug release in 12 h was 98.69%. It was observed that tablets of F10 followed the Hixson Crowell model under Non-Fickian diffusion. From the above results, it was concluded that formulation of controlled release tablets of Gabapentin containing F10 ratios of excipients with the direct blending method was taken as an ideal or optimized formulation.

Acknowledgement

Authors are thankful to Glenmark Pharmaceuticals for providing necessary facilities for carrying out this work, authors are also thankful to Dean, SPPSPTM, SVKM’S NMIMS and Research Director, SPPSPTM for their support and motivation.

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