Formulation and Evaluation of sustained release Sodium Alginate beads of Indomethacin

 

Sajan Maharjan*, Neha Prajapati, Amit Shrestha

Department of Pharmacy, Central Institute of Science and Technology (CiST College)

(Affiliated to Pokhara University), Sangam Chowk, New Baneshwor, Kahmandu, Nepal

*Corresponding Author E-mail: maharjansajan02@gmail.com

 

ABSTRACT:

The present investigation was to design pellets loaded with Indomethacin for extended release.Indomethacin pellets were prepared using sodium alginate as gelling agent (bead forming agent), HPMCK100 as release retardant and Lactose as a diluent in different concentration. Pellets were evaluated for physico-chemical properties such as compatibility, yield value, swelling index, loss on drying, loose surface crystal study, drug content, dissolution and kinetic study. In vitro drug release studies were carried out using USP rotating basket type I method and the samples were analyzed at 318nm by UV spectrophotometer. FT-IR studies revealed that there was no interaction between drug and polymers used in the study. The drug release was found linear in Higuchi plot which confirms that diffusion is one of the mechanisms of drug release. With the help of minitab software optimized formulation was designed whose concentration was sodium alginate 5.31 gm and HPMC K 100 0.64 gm for 100 gm of solution. The optimized formulation has shown the sustained drug release up to 12hrs.

 

KEYWORDS: indomethacin, sodium alginate beads, sustained release.

 

 


INTRODUCTION:

Microencapsulation is well known method to delay and modify drug release characteristics. For oral use, it has been employed to sustain the drug release and to reduce or eliminate gastrointestinal tract irritation. It is a process of enclosing micron size particles of solid or liquid or gases in an inert shell resulting in the formation of microparticles or microcapsules or microspheres. [1]

 

Multiple unit dosage forms such as microspheres or beads have gained popularity as oral drug delivery systems because of more uniform distribution of drug in the gastrointestinal tract, more uniform drug absorption,

 

reduced local irritation and elimination of unwanted intestinal retention of polymeric material, when compared to non-disintegrating single unit dosage form. [2]

 

The beads are small, solid and free flowing particulate carriers containing dispersed drug particles either in solution or crystalline form that allow a sustained release or multiple release profiles of treatment with various active agents without major side effects.

 

Sustained/controlled release dosage forms are designed to achieve a prolonged therapeutic action by releasing the medication over an extended period of time by administration of single dose.

 

Indomethacin is a non-steroidal anti-inflammatory drug with analgesic and antipyretic properties. It is commonly used drug as a prescription medication to reduce fever, pain, swelling from inflammation. It has shorter elimination half-life (4.5hour) makes it a suitable candidate for prolongation of its release from dosage forms.  Oral dose for adults was 25-50 mg, 2-3 times a day. To reduce the dosage frequency, controlled release formulations of Indomethacin can be designed in the form of microcapsules for patient compliance and reduce adverse effects.[3]

 

Formulation of sodium alginate beads is economic compared with other sustain release dosage form as compression machine is not required. It also improves patient compliance due to less frequent drug administration. It results in decreased side effect profile and reduction of fluctuation in steady state drug levels. Maximum utilization of drug is also seen in such formulation of sodium alginate beads.

 

MATERIAL AND METHODOLOGY:

Material

Active Drug:

Indomethacin – Gifted by Hukam Pharmaceuticals Pvt. Ltd.

 

Excipients:

S.

N.

Name of Raw Materials

Manufacturer

1

Sodium Alginate

A gift from Simca Laboratories Pvt. Ltd.

2

HPMC K 100

HiMedia Laboratories Pvt. Ltd, Mumbai, India

3

Lactose

HiMedia Laboratories Pvt. Ltd, Mumbai, India

4

Calcium Chloride

HiMedia Laboratories Pvt. Ltd, Mumbai, India

 

Methods:

Preliminary study:

Sodium alginate industrial grade of concentration 1%-7% and HMPC K100 of concentration 0.1%-0.8% was chosen for the preliminary study. But beads weren’t formed at concentration 1% and 2% of sodium alginate in combination with 0.1%-0.8% HPMC K 100. Beads were formed at 3% and 4% of sodium alginate in combination with 0.1%-0.8% HPMC K 100 but of low strength. Finally, at concentration of 5%-7% sodium alginate in combination with 0.1%-0.8% HPMC K 100 desired beads were formed. At concentration above 7% sodium alginate and 0.7% HPMC K100, viscous solutionwas formed which caused difficulty in mixing and also restricted in passing through syringe. Hence, suitable concentration for sodium alginate and HPMC K100 was chosen to be 5%-7% and 0.1%-0.8% respectively for the formation of better beads.

 

Selection of Concentration of Sodium alginate and HPMC K100:

Sodium Alginate (%)

HPMC K 100(%)

Result

1

0.1

No

1

0.8

No

2

0.1

No

2

0.8

No

3

0.1

No

3

0.8

Yes, but of low strength

4

0.1

No

4

0.8

Yes, but of low strength

5

0.1

Yes

5

0.8

Yes

5

0.8

Beads formed but very viscous

6

0.1

Yes

6

0.7

Yes

6

0.8

Beads formed but very viscous

7

0.1

Yes

7

0.7

Yes

7

0.8

Beads formed but very viscous

7

0.1

Yes

7

0.7

Yes

7

0.8

Beads formed but very viscous

 

Design of experiment (DOE):

Central Composite Design (CCD) was used to design the formulation which can fit a full quadratic model. A rotatable experimental plan was carried out by a central composite design (CCD) with α=1.414 consisting of 13 experiments. Minitab 16 software was used to design this experment.For two variables (n = 2) and three levels (low (-1), mid (0) and high (+1)), the total number of experiments were 13, determined by 4 cube points, 4 axial points and 5 Centre points.

 

The concentration range of polymers were selected according to the preliminary study:

For Sodium alginate- Low: 5.0%, High: 7.0%

For HPMC K 100- Low: 0.1%, High: 0.8%


 

Details about concentration of drug and other excipients used in formulation are shown below:

FN

Indomethacin

Sodium alginate

HPMC K 100

Lactose

Total

Water(ml)

1

2.44

7.00

0.20

0.80

8.00

100.00

2

2.44

4.59

0.45

2.96

8.00

100.00

3

2.44

6.00

0.10

1.90

8.00

100.00

4

2.44

6.00

0.45

1.55

8.00

100.00

5

2.44

6.00

0.45

1.55

8.00

100.00

6

2.44

7.00

0.70

0.30

8.00

100.00

7

2.44

6.00

0.45

1.55

8.00

100.00

8

2.44

5.00

0.20

2.80

8.00

100.00

9

2.44

7.41

0.45

0.14

8.00

100.00

10

2.44

6.00

0.45

1.55

8.00

100.00

11

2.44

6.00

0.80

1.20

8.00

100.00

12

2.44

5.00

0.70

2.30

8.00

100.00

13

2.44

6.00

0.45

1.55

8.00

100.00

optimized

2.44

5.32

0.65

2.04

8.00

100.00


METHODOLOGY:

i.         all materials required for the experiment including the drug used (Indomethacin), sodium alginate and calcium chloride were weighed accurately

ii.       Distilled water was then added to the weighed quantity of sodium alginate to make aqueous mucilage in a beaker and allowed to heat for 5-10 minutes in a hot plate.

iii.     Distilled water was also added to the weighed quantity of calcium chloride to make a clear solution.

iv.     The aqueous mucilage of sodium alginate was then stirred in a magnetic stirrer at a suitable speed (rpm) for about 30 minutes.

v.       The drug was dispersed in the aqueous mucilage of sodium alginate subsequently and stirred at suitable speed in the magnetic stirrer.

vi.      The beads were formed by dropping the bubble free dispersions through a syringe with the help of a needle into the gently agitated calcium chloride solution.

vii.    Beads were cured for 30 mins and then filtered & washed thoroughly with distilled water.

viii.  The pellets were then oven dried for 2-4 hrs at about 50°C and air dried at room temperature subsequently for few hours.

ix.     Dried pellets were then filled in hard gelatin capsule.[4]

 

EVALUATION:

Drug excipient compatibility study:

Compatibility of the drug with excipients was determined by FT-IR spectral analysis to determine possible drug-polymer interactions. IR spectra of pure drug Indomethacin and its mixture with polymers, Sodium alginate, HPMC K 100and Lactose in the ratio of 1:1 (Drug: Polymer) were observed.[5]

 

Drug content:

A quantity of the mixed content of 20 capsules containing 50 mg of indomethacin was weighed, then 10 ml of water was added and allowed to stand for 10 min, with occasionally swirling. 75ml of methanol was added to produce 100ml and filtered. To 5 ml of filtrate was added sufficient of a mixture of equal volumes of methanol and phosphate buffer pH 7.2 to produce 100ml. Standard was prepared in similar manner and absorbance of both sample and standardwere measured at 320 nm in UV Spectrometer.

 

Yield Value:

The yield value of sodium alginate beads was determined by comparing the whole weight of beads formed against thecombined weight of the excipients and drug.[6]

                                      Mass of beads obtained

% yield value =––––––––––––––––––––––––––––––– X 100

                          Total weight of drug and polymer used

Loose Surface Crystal Study:

This study shows immediate release of drug present on the surface of the beads in dissolution media. 100mg of beads were suspended in 100ml of phosphate buffer (pH 7.4), simulating the dissolution media. The samples were shaken vigorously for 15min in a mechanical shaker. The amount of drug leached out from the surface was analyzed spectrophotometrically at 320 nm. Percentage of drug released with respect to entrapped drug in the sample was recorded.[7]

 

Invitro Dissolution Study:

Dissolution studies of indomethacin beads was performed as per USP (for extended release indomethacin capsules) using Type-I apparatus in phosphate buffer of pH 7.4 maintaining temperature at 37±0.5°C and 100 rpm. The 5 ml of sample was withdrawn at various time intervals and replenished with an equal volume of fresh dissolution media. The drug content in the sample was analyzed spectrophotometrically at 318nm.

 

Swelling Index Study[8]:

The extent of swelling was measured in terms of % weight gain by the beads. The swelling behaviors of all the formulations were studied.20 mg of beads from each formulation was kept in Petri dish containing distilled water. At the end of 1 hour, the beads were withdrawn, soaked with tissue paper and weighed. Then for every 1 hour, weight of beads was noted and the process was continued till the end of 8 hours. The % weight gain by the beads was calculated by the following formula:

Swelling Index (SI) = [(Wt – W0)/ W0)] x 100

Where, Wt= Mass of swollen beads at time t

W0= Mass of dry beads at t=0

 

Loss on Drying:

1 gm of beads was weighed in petridish and then kept in pre heated oven at 60c for 6 hours.

% loss on drying at 60C = Wstart-Wdry× 100%

Wstart–Wtare

 

RESULT AND DISCUSSION:

Physical Parameter:

Colour:

Sodium alginate beads of all the formulations (F1 to F13) were white in color before drying and creamy white color after drying.

 

Shape:

Before drying beads was circular shape. After drying beads was irregular shape.


 

Beads before drying                                                                             Beads after drying

 


FT-IR:

IR spectroscopic studies were conducted to determine possible drug-polymer interactions. IR spectra of pure drug Indomethacin and its mixture with polymers

Sodium alginate, HPMC K 100and Lactose in the ratio of 1:1 (Drug: Polymer), were observed and interpreted as below:


 

IR spectra of Indomethacin:

 

IR spectra of Indomethacin + HPMC K 100:

IR spectra of Indomethacin + Lactose:

 

IR spectra of Indomethacin + Sodium alginate:

 


From the results obtained, it was observed that there was no effect of excipients upon the drug, as the major peaks of the drug were seen in the mixture in the similar frequencies as that of pure drug.

 

Yield, LOD, Drug Content, Loose crystal study and swelling index:

The yield value of all the formulations (F1 to F13) and optimized formulation were within a range of 92.40% to 97.1%.The loss on drying of all the formulations and optimized was found within a range of 0.02% to 0.05%.The drug content in all the formulations and optimized were found within a range of 96.88% to 100.34% which was in range 90%-110% as per IP 2014.The loose surface crystal study in all the formulations and optimized were found within a range of 28.24% to 35.6%.The swelling index of all the formulations and optimized were found within a range of 1.44% to 3.12%.


 

FN

Yield (%)

LOD (%)

Drug Content (%)

Loose Crystal Study (%)

Swelling Index (%)

1

97.10

0.02

98.89

34.35

1.74

2

94.17

0.03

99.05

32.34

2.12

3

95.77

0.03

96.88

34.68

1.98

4

93.75

0.04

97.60

35.67

2.22

5

92.65

0.05

100.02

34.87

1.44

6

97.50

0.04

99.77

33.79

1.53

7

92.40

0.03

97.86

33.45

2.65

8

93.37

0.04

99.77

31.38

1.97

9

96.56

0.03

99.54

33.76

2.45

10

94.60

0.03

98.80

29.94

2.76

11

95.00

0.02

98.77

28.24

1.48

12

95.07

0.03

100.34

32.84

2.84

13

95.50

0.02

99.09

30.34

3.12

Optimized

96.55

0.02

99.05

31.14

2.13

 


In vitro Dissolution Study:

The in vitro release studies of formulations were carried out with dissolution apparatus-1 (as per USP) for a period of 12 hours. The in vitro release behavior was

carried out with using phosphate buffer pH 6.8 as a dissolution medium. The drug release study was observed at every 1-hour interval.


 

FN

1sthr

2ndhr

3rdhr

4thhr

5thhr

6thhr

7thhr

8thhr

9thhr

10thhr

11thhr

12thhr

1

42.11

52.44

65.03

94.64

62.43

63.73

69.55

85.78

71.89

71.37

75.62

73.71

2

46.19

86.48

90.56

88.56

86.33

86.22

87.43

89.00

87.69

87.78

86.22

90.99

3

60.95

70.24

81.35

69.02

80.34

96.81

97.16

89.26

87.52

97.68

103.41

99.68

4

16.06

40.54

54.09

59.99

68.85

74.58

77.45

82.14

84.92

87.78

90.04

96.34

5

16.16

41.01

53.99

60.42

67.77

75.43

78.79

83.12

83.42

88.1

91,24

97.23

6

15.28

32.82

60.26

63.02

66.7

72.06

74.76

93.68

70.67

80.49

94.99

99.06

7

15.57

39.98

53.68

60.43

69.98

75.55

76.78

83.24

85.88

88.02

91.45

97.68

8

15.80

50.18

83.18

75.97

88.16

90.73

90.99

70.67

95.94

97.16

88.21

99.85

9

9.63

18.58

34.73

44.63

54.78

78.75

85.78

89.87

95.76

93.76

90.87

90.0

10

17.36

41,33

55.67

60.66

69.89

75.67

78.89

81.99

85.55

88.00

91.1

95.99

11

13.97

24.92

35.42

47.84

55.65

62.08

66.25

69.20

76.84

88.88

89.95

94.90

12

29.60

41.15

53.66

67.55

73.54

76.06

84.91

88.13

90.91

92.03

95.25

100.89

13

16.67

40.84

55.56

60.67

67.89

75.00

77.99

83.55

85.89

88.78

90.76

97.66

Optimized

23.34

43.97

57.04

63.86

68.07

73.9

75.24

79.31

86.82

91.69

95.1

98.78

 

The graphical representation of cumulative percentage release of drug release vs time is shown below:

 

Contour plot

The contour plot of 1st,2nd, 4th, 6th,12thhr Vs Conc of HPMC k100 and Sodium alginate are given below:

 


Analysis of response surface design:

The results of in vitro drug release were analyzed at 1st, 4th, 6th and 12th hour.

 

Equation derived from the regression coefficients at different time points are shown below:

 

1st hr = 128-35.0 X+77 Y +4.03 X2+140.8 Y2- 40.6 X.Y

 

2nd hr = 275 - 61.0 X - 11 Y + 4.42 X2 + 31.1 Y2 - 10.6 X.Y

 

4th hr = 283 - 70.9 X + 73 Y + 6.28 X2+ 35.1 Y2 - 23.2 X.Y

 

6th hr = 266 - 43.0 X - 176.8 Y + 2.29 X2 + 12.3 Y2 + 23.0 X.Y

 

12th hr = 58.9 + 25.8 X - 136.4 Y - 3.37 X2 + 0.4 Y2+ 24.3 X.Y

 

Where

X represents Sodium alginate

Y represents HPMC K 100

 

Negative coefficients of Sodium alginate suggest that it has significant effect in retarding the drug release whereas positive coefficients of HPMC K 100 confirms that HPMC K 100 alone does not have any significant effect in retarding the drug release.

 

The interaction between sodium alginate and HPMC K100 has shown negative coefficient in all time periods which suggests significant synergistic influence in retarding the drug release. The interaction of sodium alginate with sodium alginate andHPMC K100 with HPMC K100 has shown synergistic effect in initial time periods.

 

Optimization of the formulation:

Based on the in vitro release profile of all the formulations, optimization was done at four different time points and as per the limits of USP.

 

Limits of Dissolution as per USP:

(for indomethacin extended release capsules)

Time (h)

Amount Dissolved

1

15%-40%

2

35%-55%

4

55%-75%

6

65%-85%

12

NLT 75%

 

Drug release at 1st hour, 4th hour, 6thhour and 12th hour was considered to optimize the formulation.

 

For all the four responses, the optimized plot was obtained by using response optimizer in Minitabas shown in figure below:

 

 

As per the optimized plot, the optimized formulation of the sustained release pellets should contain concentrations of 5.3172% of sodium alginate and 0.6464% of HPMC K100. The predicted responses were 24.7082% drug release at 1st hour with desirability 0.80902, 45.0257% drug release at 2ndhour with desirability 0.99743, 65.0477% drug release at 4thhour with desirability 0.99523, 71.8051% drug release at 6th hour with desirability 0.68051 and 96.5986% drug release at 12th hour with desirability 0.72993. The composite desirability of the targeted response was 0.8321.

 

Optimized formulation was then prepared by the above-mentionedprocedure using 5.3172% of sodium alginate and 0.6464% of HPMC K100 and other required excipients. It was then evaluated in similar manner as that of other formulations(F1-F13)

 

Comparison with marketed formulation:

The optimized formulation was also compared with the marketed formulation whose graphical representation of cumulative percentage release of drug release vs time is shown below

 

CONCLUSION:

Sodium alginate beads of indomethacin was successfully formulated by using sodium alginate as gelling agent (bead forming agent), HPMCK100 as release retardant and Lactose as a diluent. All the formulations were creamy white beads with irregular shape. Response surface design, regression analysis, contour plots, and desirability function obtained from response optimizer have been proven to be a useful approach for the optimization of formulations. The optimized formulation has shown sustained drug release over the period of 12 hours and also all the drug release was within the specified range of USP.Thus, the optimized formulation can be used as a sustained release formulation. Ease of administration and reduced frequency of administration is it’s another importance which results in better patient compliance

 

REFERENCES:

1.   Nagpal, M., et al., Formulation development and evaluation of alginate microspheres of ibuprofen. Journal of Young Pharmacists, 2012. 4(1): p. 13-16.

2.   Menon, T.V. and C. Sajeeth, Formulation and evaluation of sustained release sodium alginate microbeads of Carvedilol. International Journal of Pharm Tech Research, 2013. 5(2): p. 746-753.

3.   Kumari, K. and U. Rani, Controlled release of metformin hydrochloride through crosslinked blends of chitosan-starch. Adv Appl Sci Res, 2011. 2(2): p. 48-54.

4.   Chakraverty, R., Preparation and evaluation of sustained release microsphere of norfloxacin using sodium alginate. International Journal of Pharmaceutical Sciences and Research, 2012. 3(1): p. 293.

5.   Chidambaram, M. and K. Krishnasamy, Drug-drug/drug-excipient compatibility studies on curcumin using non-thermal methods. Advanced pharmaceutical bulletin, 2014. 4(3): p. 309.

6.   Menon, T.V. and C. Sajeeth, Formulation and evaluation of sustained release sodium alginate microbeads of carvedilol. International Journal Pharm Tech, Research, 2013. 5(2): p. 746-753.

7.   Sherina, V., K. Santhi, and C. Sajeeth, Formulation and evaluation of sodium alginate microbeads as a carrier for the controlled release of nifedipine. Int J Pharm Chem Sci, 2012. 1: p. 699-710.

8.   Patel, N., et al., Development and evaluation of a calcium alginate based oral ceftriaxone sodium formulation. Progress in biomaterials, 2016. 5(2): p. 117-133.

 

 

 

 

Received on 31.05.2019            Accepted on 25.06.2019           

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2019; 9(3):165-172.

DOI: 10.5958/2231-5713.2019.00028.X