Formulation and Evaluation of Loperamide Hydrochloride Mouth Dissolving Tablet by Using Super Disintegrants

 

Venkatalakshmi  R*1, Sasikala C1 and SP Silambarasan2

1Shri Vishnu College of Pharmacy, Vishnupur, West Godavari,  Bhimavaram – 534 202, Andhra Pradesh, India.

2Dep. of Pharmaceutical Analysis, Adhiparasakthi College of Pharmacy, Melmaruvathur, (T.N.), India- 603 319.

*Corresponding Author E-mail: rvenkatalakshmi@yahoo.co.in

 

ABSTRACT:

Loperamide hydrochloride 180 mg mouth dissolving tablet was prepared by using super disintegrants such as Sodium starch glycolate, Croscarmellose Sodium, Crospovidone at various concentration and Sucralose, aspartame used as sweetening agent. The excipients were used for this study was based on the compatibility studies. All the formulations were prepared by direct compression method. Among all the formulations Crospovidone at 10 mg/tablet gives 98 % drug release at 12th   minute by UV method. It was considered as optimized batch. The optimized batch was passes all the evaluation parameters and stability studies .The final formulation were packed in blister package.

 

KEYWORDS: Loperamide hydrochloride, Sodium starch glycolate, Croscarmellose sodium, Crospovidone.

 


INTRODUCTION:

The main problem with the common oral dosage forms is that they have to be swallowed along with water and many patients find it difficult to swallow tablets, especially in elderly and pediatrics, because of the physiological changes associated with these groups. Due to this dysphagic condition, they do not comply with prescription, which results in patient non-compliance. Thus MDTs are beneficial to patients who find it difficult to swallow tablets, moreover some of the drugs which are soluble in saliva are absorbed from the mouth, pharynx and oesophagus as the saliva passes down into stomach, which enhances bioavailability by avoiding first pass metabolism. Loperamide hydrochloride used for to control and symptomatic relief of acute nonspecific or chronic diarrhea. The objective of the present study was to formulate and evaluate Loperamide hydrochloride by using superdisintegrants to develop a new dosage form convenient for geriatric and pediatric dysphagic patients1, 2.

 

MATERIALS AND METHODS:

Loperamide hydrochloride, Sodium starch glycolate, Croscarmellose sodium and  Crospovidone were obtained as a gift samples from Medreich RandD, Bangalore, India. All other reagents and solvent used in the study were of analytical grade.

 

methods:

All the ingredients were mixed as per the formulae (table no.1). LH was separately sifted through # 40 mesh. Mannitol, MCC, aspartame, sucralose and starch1500 all these excipients were separately sifted through #30.The LH and above excipients were mixed for 15 minutes using a 1 Kg capacity double cone blender (Bectochem engineers). Then talc, magnesium stearate, aerosil, flavouring agents for each formulation was sifted through # 40 mesh. These blended mixtures were mixed with Strawberry flavour was used for all formulations were mixed with above drug excipient mixture for 10 minutes. All dilutions during mixing were geometrical. The prepared blends for various formulations were evaluated for Angle of repose , Bulk density , Tapped density, Carr’s index ,  Hausner’s ratio.3-6 ( table no. 2). Then the obtained blend was directly compressed in a twenty seven station rotary Cadmach tablet machine using 8mm round; concave punch, keeping the average weight of each tablet as 180 mg. The prepared tablets were evaluated for Thickness (Vernier Caliper), Hardness Test (Monsanto hardness tester), Friability Test (Roche friabilator) (table no.3), Disintegration time (Electrolab), Wetting time and Water absorption ratio, Moisture uptake by the tablets7 and Drug content and release studies such as uniformity of drug content, In vitro dispersion time, In vitro drug release after dispersion, in vitro dissolution studies8, 9.

 

Ir Spectral Analysis:

A compatibility study was carried out for selection of excipients by using an infrared spectrophotometer (FT-IR 8201 PC spectrometer). To find out if there is any possible chemical interaction between Loperamide hydrochloride and super disintegrents. fig.1.


Fig.1  Loperamide Hcl+Cros Povidone IR Spectrum

 

Table.1. Formulation composition of mouth dissolving loperamide hydrochloride tablets with superdisintegrants

S. No

Tablet Ingredients (mg/tab)

Formulation code

F1

F2

F3

F4

F5

F6

F7

F8

F9

1

Loperamide hydrochloride

2.0

2.0

2.0

2.0

2.0

2.0

2.0

2.0

2.0

2

Mannitol

127

124.5

119.5

127

124.5

119.5

127

124.5

119.5

3

Microcrystalline cellulose

25.0

25.0

25.0

25.0

25.0

25.0

25.0

25.0

25.0

4

Aspartame

2.0

2.0

2.0

2.0

2.0

2.0

2.0

2.0

2.0

5

Sucralose

4.5

4.5

4.5

4.5

4.5

4.5

4.5

4.5

4.5

6

Starch-1500

2.0

2.0

2.0

2.0

2.0

2.0

2.0

2.0

2.0

7

Croscarmellose sodium

2.5

5.0

10.0

-

-

-

-

-

-

8

Crsopovidone

-

-

-

2.5

5.0

10.0

-

-

-

9

Sodium starch glycollate

-

-

-

-

-

-

2.5

5.0

10.0

10

Purified Talc

4.0

4.0

4.0

4.0

4.0

4.0

4.0

4.0

4.0

11

Colloidal silicon dioxide (Aerosil)

5.0

5.0

5.0

5.0

5.0

5.0

5.0

5.0

5.0

12

Magnesium stearate

3.0

3.0

3.0

3.0

3.0

3.0

3.0

3.0

3.0

13

Strawberry

1.0

1.0

1.0

1.0

1.0

1.0

1.0

1.0

1.0

 


Table.2 Granules Evaluation

Formulation Code

Bulk density (g/cc)

Tapped density  (g/cc)

Angle of repose (q)

Carr’s index (%)

F1

0.40

0.51

32..15

0.22

F2

0.40

0.50

30.46

20.00

F3

0.43

0.42

27.89

19.57

F4

0.43

0.55

32.005

21.74

F5

0.41

0.52

29.82

20.84

F6

0.38

0.47

27.21

19.24

F7

0.40

0.51

33.69

0.22

F8

0.41

0.52

32.005

20.84

F9

0.40

0.50

28.49

20.00

 

Table.3 Evaluation of thickness, hardness and friability of mouth dissolving Loperamide hydrochloride tablets

Formulation Code

Thickness (mm) ± SD

Hardness (Kg/cm2) ± SD

Friability (%)

F1

3.34±0.02607

2.5±0.14142

0.8

F2

3.38±0.01673

2.4±0.14142

0.9

F3

3.28±0.02280

2.3±0.14142

0.9

F4

3.40±0.02449

2.4±0.14142

0.9

F5

3.35±0.02449

2.2±0.14142

0.9

F6

3.26±0.03033

2.1±0.06324

0.9

F7

3.38±0.00497

2.5±0.14142

0.8

F8

3.29±0.01673

2.4±0.14142

0.9

F9

3.24±0.03521

2.3±0.14142

0.9

 

Wetting time and Water absorption ratio of tablets:

A piece of tissue paper folded twice was placed in a small petridish (internal diameter = 6.5 cm) containing 6 ml of simulated saliva pH (Phosphate buffer pH 6.8). A tablet was placed on the paper, and the time required for complete wetting was measured.

 

Water absorption ratio was determined by using water instead of buffer, R, was calculated using the formula.

R = 100 (Wa - Wb)/Wb

Where Wb and Wa are the weight before and after water absorption.

Six trials for each batch were performed; average time for wetting with standard deviation was recorded10. (Table no.4)

 

Moisture uptake by the tablets:

Ten tablets from each formulation were kept in a desiccator, over calcium chloride at 37ºC for 24 hours. The tablets were then weighed and exposed to 75% RH, at room temperature for two weeks in the dessicator. Required humidity was achieved by keeping saturated sodium chloride solution at the bottom of the desiccator for three days. Tablets were re-weighed and the percentage increase in the weight was recorded in after 10 days. (Table no.4)

 

Uniformity of drug content:

One tablet was crushed and transferred to a 50ml volumetric flask, 20ml of methanol was added, shaken well to dissolve the drug. The volume was made up to 100 ml with water and filtered. Then 5 ml of the filtrate was diluted to 50ml with water again from that 5ml was taken and diluted to 50ml with water. (Table no.5)

 

In-vitro Dispersion Time:

A tablet was put into 10 ml of Phosphate buffer (pH 6.8) in a beaker at 37 ± 0.5ºC. Time required for complete dispersion of a tablet was recorded. This test was performed for six tablets from each batch and average time taken for dispersion with standard deviation was record.11-13 (Table no. 5)

 

In-vitro drug release after dispersion:

To 10 ml of Phosphate buffer solution, pH 6.8 (simulated saliva pH) one tablet was put and time required for complete dispersion was noted. Immediately after complete dispersion of the tablet, 2 ml of the solution was withdrawn and the amount of drug released after dispersion of a tablet was checked Spectrophotometrically at 214 nm after filtration. Six trials for each batch were performed and the average percentage drug released with standard deviation was calculated and recorded14- 16. The results obtained were, shown in (table no 5).

 

In vitro dissolution studies:

In vitro dissolution study was performed by using USP Dissolution Apparatus Type II (Paddle type) [Electro lab (TDT-06T) at 100 rpm. 0.01N HCL 900 ml was used as dissolution medium, and the temperature of which maintained at 37 ± 0.5ºC. 10 ml aliquots of dissolution medium were withdrawn at  different time intervals of 0,3.6,9 and 12 minutes and filtered. The amount of drug dissolved was determined by UV spectrophotometer by measuring the absorbance of the sample at 214 nm. Six trials for each batch were performed and average cumulative percentage drug release with standard deviation was calculated and recorded17-20. (Table no 6), fig-1

 

STABILITY STUDY OF TABLETS FOR FORMULATION F6:

Optimized formulation F6 sealed in blister packaging and various replicates were kept in the humidity chamber maintained at 40°C and 75 % RH for three months. At the end of the study the samples were analyzed for the Drug content and release studies and other Physical parameters21, 22. The results of stability study after three month are given in (table7 and 8).

 

RESULTS AND DISCUSSION:

Pre-compression parameters (all formulation) of the drug –excipients blend has been carried out such as bulk density, tapped density, angle of repose and Carr’s index. For F6 formuation. The obtained value of angle of repose (q) was- 27.21, Hausner’s ratio - 1.3808 and Carr’s index - 19.24 indicating good flow properties. All the parameters were falls within the limits. Than all the formulations have been evaluated for post compression parameters. The thickness of all the tablets was found in range of 3.24 to-3.40 mm for all the formulations within the prescribed limits of IP 1996 (±5%). The tablet hardness was found to be 2.1-2.5 Kg/cm2, the friability of all the formulations were found to be between 0.8-0.9, which was found to be with in the official requirement (i.e. not more than 1%). These values indicated that the tablets were mechanically stable. The drug content estimation data for all the batches were found to be with in the limit (i.e. 95.25 to 99.50). Formulation F6 possess good disintegrating property among all formulations which was observed during in vitro disintegration, wetting time, in vitro dispersion time and in vivo dispersion time.

 

Fig.2 Comparison of maximum % drug released in invitro dissolution studies of loperamide hydrochloride MDT by superdisintegrants (10 mg/tab)

 

F3-Cros carmelose sodium, F6-Cros povidone, F9-Sodium starch glycolate


Table. 4 Water absorption ratio and % moisture uptake studies of mouth dissolving loperamide hydrochloride tablets

Formulation Code

Disintegration Time (Sec) ± SD

Wetting Time (Sec) ± SD

Water absorption ratio(%)± SD

% moisture uptake

F1

25±3.2863

25±3.2863

81.26±0.9832

0.67

F2

19±1.4142

20±2.0000

90.28±3.982

0.50

F3

15±1.4142

17±1.4142

117.40±1.88

0.28

F4

20±2.000

26±2.0000

84.24±6.02

0.50

F5

15±1.4142

17±1.4142

96.66±5.40

0.35

F6

12±1.6733

11±1.4142

125.80±5.10

0.14

F7

30±1.8973

42±1.8973

78.45 ±5.92

0.16

F8

22±1.4142

31±1.4142

84.44±2.96

0.29

F9

18±1.4142

23±2.2803

96.66±1.41

0.40

 

Table.5 % Drug released immediately after in vitro Dispersion and drug content of one tablet of   mouth dissolving loperamide hydrochloride tablets

Formulation Code

% Drug Content w/w (Content uniformity)

In vitro dispersion time (sec)

% Drug released immediately after in vitro Dispersion

F1

98.50

35±1.4142

77.76

F2

98.75

27±2.2803

80.27

F3

98.25

19±2.4494

90.05

F4

97.75

30±1.8973

79.82

F5

98.75

18±1.4142

82.28

F6

99.50

13±1.4142

92.58

F7

95.25

42±3.5213

75.32

F8

98.50

35±2.0000

79.95

F9

97.70

29±2.0000

85.64

 

Table.6 In vitro dissolution profile data for mouth dissolving loperamide hydrochloride tablets for all formulations

Formulation Code

Percentage Drug release* ±SD of  Mouth Dissolving loperamide hydrochloride  Tablets at the following time intervals

3 minutes

6 minutes

9 minutes

12 minutes

F1

75.23±0.9123

79.94±0.9912

87.12±0.9890

90.81±0.4963

2

78.03±1.212

84.09±1.071

89.53±1.491

93.88±1.509

3

80.48±0.9125

84.62±1.511

90.23±1.493

96.32±0.7539

F4

78.73±1.212

80.65±0.9894

88.42±0.6048

91.64±1.208

5

81.29±0.9035

85.27±1.371

90.70±1.221

95.27±0.9331

6

86.08±0.2654

93.73±03.128

96.56±5.759

98.06±5.310

F7

70.39±1.972

78.48±2.106

83.96±0.9910

87.58±0.9744

8

70.68±0.1.972

81.39±1.660

87.29±0.8506

88.18±1.305

9

74.59±1.475

86.65±0.9989

89.52±1.675

92.81±0.9559

 

Table no.7 Uniformity of Content of Mouth Dissolving loperamide hydrochloride

Tablets at initial and after 3 months stability studies at 40°C / 75% RH and 50°C.

Formulation Code

% Drug Content w/w (Initial month)

% Drug Content w/w (After  3rd months)

Complies with the USP limit

At 400C/75%RH

At 500C

F1

98.50

97.50

97.25

Complies

F2

98.75

97.75

97.00

Complies

F3

98.25

96.50

95.75

Complies

F4

97.75

98.00

97.25

Complies

F5

98.75

95.50

95.00

Complies

F6

99.50

97.50

97.25

Complies

F7

95.25

96.25

97.15

Complies

F8

98.50

96.00

96.50

Complies

F9

97.70

95.50

94.75

Complies

 

Table no. 8 In vitro  Dissolution Profile Data for loperamide hydrochloride  MDT at initial and after 3 months stability studies at 40°C / 75% RH and 50°C

Formulation Code

Percentage Drug release* ±SD of  Mouth Dissolving loperamide

hydrochloride Tablets at the end of 12th minutes

Initial

At 400C/75%RH

At 500C

F1

90.81±0.4963

87.88±1.298

88.08±1.862

F2

93.88±1.509

92.26±1.411

91.59±1.368

F3

96.32±0.7539

93.60±2.085

93.00±1.611

F4

91.64±1.208

89.08±1.312

87.40±1.034

F5

95.27±0.9331

93.07±1.611

93.00±1.611

F6

98.06±5.310

95.23±1.571

94.70±2.092

F7

87.58±0.9744

85.08±1.024

84.57±1.206

F8

88.18±1.305

86.72±1.116

85.98±1.046

F9

92.81±0.9559

90.45±1.561

89.84±1.824

 


Formulation containing Crospovidone F6 was showing better drug release in 12th minutes (98.06). All the formulations were subjected to evaluation studies and from these Formulations F6 were selected as best formulations as these formulations showed good matrix integrity and drug release rate. An overall result signifies that crospovidone in the ratio 10 mg per tablet acts as good disintegrant for fast dissolving tablets. In vitro dissolution results proved formulations F6 were better choice among all the formulations.

 

Stability studies were conducted for all the formulation at 450C / 75 % RH and 500C for a period of 3 months as per ICH guidelines. During the study period several parameters like hardness, in vitro disintegration, drug content uniformity and wetting time were evaluated for possible instability problems. No significant changes in parameters were observed throughout the study period.

 

CONCLUSION:

In vitro dispersion, wetting time and in vivo dispersion parameters signified that Crospovidone in ratio 10 mg per tablet act as good disintegrants prepared by direct compression method. Overall formulation F6 were found to be an excellent mouth dissolving tablets with good taste.

 

ACKNOWLEDGEMENT:

We cardially express our sincere thanks to Medreich R and D Ltd, Bangalore, India for providing sample to carryout research work and Sastra University, Tanjavur, India  for carrying out  FTIR spectra’s.

 

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Received on 25.11.2009       Modified on 23.01.2010

Accepted on 26.02.2010      © RJPT All right reserved

Research J. Pharm. and Tech. 3(2): April- June 2010; Page 530-534