OBJECTIVE:

Formulation developments of taste masked fast disintegrate tablets of Racecadotril by solid dispersion technique and with polymeric granulation. The study was carried out with an objective to develop an Analytical method of Racecadotril by using UV method followed by carrying out various techniques to mask the intensely bitter taste of the drug.

INTRODUCTION:

Racecadotril is an antidiarrheal drug which acts as a peripherally acting enkephalinase inhibitor. racecadotril has an antisecretory effect—it reduces the secretion of water and electrolytes into the intestine. It is an effective and safe drug for acute diarrhea in adults and children. Chemically racecadotril is N-[(R,S)-3-acetylmercapto-2-benzylpropanoyl]-glycine benzyl ester. The Drug Controller General of India approved it as an antidiarrheal in October 2001. Racecadotril is rapidly converted to thiorphan which interacts specifically with the active site of enkephalinase to produce potent blockade of the enzyme preventing inactivation of endogenous opioid peptides (enkephalines) released by sub mucosal and myenteric neurons. The enkephalines in turn mediate their effect through delta receptor activation that induces a selective increase in chloride absorption by inhibiting adenylate cyclase.

It is needed to taste masking and rapidly disintegrating tablets formulation (i) To mask the bitter taste of Racecadotril, (ii) To enhance the patient compliance especially the pediatric and geriatric groups of patients who have difficulty in swallowing the tablets and capsules due to bitter taste of the drug and under developed muscular, nervous system and dysphasia^1-4.

The aim of this study was to prepare, using taste masked granules, rapidly disintegrating tablets of Racecadotril, a bitter drug. The taste masked granules were prepared by solid dispersion technique and with polymeric granulation.

Methodology:

i) UV spectroscopy analytical method development for analysis of Racecadotril:

The analytical method was carried out by using 70:30 ratio of water: Acetonitrile as solvent system. The λ_maxwas found to be 232 nm and the linearity range was between 15µg/ml - 85 µg/ml with regression coefficient as 0.999⁵. (Fig-1)

Fig:1 Calibration curve

(ii) Taste masking of bitter taste of Racecadotril:

The taste masking of Racecadotril was done by two methods viz. (table-1)

(1) Solid dispersion technique using fusion method by using

Drug: Stearic acid (1:1, 1:2, 1:5),

Drug: PEG 4000 (1:2, 1:5),

Drug: PEG 6000 (1:2, 1:5)

(2) By simple blending the drug with Microcrystalline cellulose (MCC), sucrose and granulated with polymer Hydroxy Propyl Cellulose (HPC) in Isopropyl alcohol^6-8.

Table 1: Taste Masking Trials

Composition	Ratio	Inference
Plain drug (R)	-	Intensely bitter
R: PEG -4000	1:1	Bitter
	1:2	Bitter
	1:5	Bitter
	1:10	Bitter
R: PEG-6000	1:1	Bitter
	1:2	Bitter
	1:5	Bitter
	1:10	Bitter
R: Stearic acid	1:1	Slightly bitter
	1:2 (selected)	Taste masked
	1:5	Taste masked
	1:10	Taste masked
R:HPC	Wet Granulation	Slightly bitter

(iii) Formulation of fast disintegrate tablet dosage form:

Preformulation and compatibility study was carried out for prototype formulation. Tablets containing 10mg of Racecadotril were prepared by dry granulation method and the various development trials were taken with compatible super-disintegrante. The most important parameter that needs to be optimized in the development of fast dispersible tablets is the disintegration time of tablets. (Table-2,3and 4)

These taste masked granules were directly compressed into tablets using sodium starch glycolate as a super-disintegrant^9-12.

Table 2: Formulation Development trial: Formulation-1 (T-1)

T-1: Formulation with Solid Dispersion Granules
Sr. no.	Ingredients	Rational	Qty per unit
1	Solid dispersion mixture (R: Mg stearate=1:2) (equiv. to 10 mg of Racecadotril)	Active taste mask granules	30 mg
2	Mannitol	Sweetener	25 mg
3	Sucrose	Sweetener	35 mg
4	MCC	Diluent	30 mg
5	SSG(sodium starch glycolate)	Super disintegrant	15 mg
6	Peppermint flavor	Flavoring agent	2 mg
7	Sodium bicarbonate	disintegrant	10 mg
8	Aerosil	Glidant	5 mg
9	Magnesium stearate	Lubricant	3 mg
Tablet weight			150 mg

Table 3: Effect of Different Disintegrating Agents

Disintegrating Agents	Disintegration time (min)
MCC	6
Aerosil	7
SSG	1
Cross Carmellose	3

Table 4: Formulation Development trial: Formulation-2 (T-2)

T-2: Formulation by wet granulation with polymer HPC
Sr. no	Ingredients	Qty per unit
1	Racecadotril)	10 mg
2	Sucrose	30 mg
3	MCC	30 mg
4	HPC (IPA solution)	10 mg
5	Mannitol	28 mg
6	SSG(sodium starch glycolate)	20 mg
7	Peppermint flavor	2 mg
8	Sodium bicarbonate	10 mg
9	Aerosil	5mg
10	Magnesium stearate	5mg
Tablet weight		150 mg

(iv) Evaluation of developed formulations:

Tablets were evaluated for weight variation, hardness, friability, thickness, disintegration time and in-vitro drug release characteristics^12-15. (Table-5)

Table 5: Evaluation of Formulations

Sr. no.	Evaluation Parameters	Observations
Sr. no.	Evaluation Parameters	T-1	T-2
1	Weight (mg) ( n= 20)	150 .00± 1.53	150 .00± 1.20
2	Diameter(cm) (n= 6)	0.6±0.02	0.6±0.02
3	Thickness (cm) (n= 6)	0.30±0.1	0.35±0.1
4	Hardness ( Kg/sq m) (n= 6)	2.50±0.21	3.0±0.21
5	Friability ( n= 6)	0.50%	0.38%
6	Wetting time (sec) (n= 3)	20.00±0.52	15.00±0.25
7	In Vitro Disintegration time (sec) (n=6)	30.26±1.50	20.26±1.50
8	Disintegration time in oral cavity (sec) (n=3)	40.00±1.37	28.00±1.50
9	Drug content (mg) (n=3)	9.89±0.13	9.95±0.20

Dissolution Parameters:

Apparatus: USP type –II, RPM: 50, Temperature: 37°C ± 0.5°C, Volume: 900 ml

Media: 4.5-pH Acetate buffer

Analytical detection

Instrument: Shimadzu UV 2450

Detection by UV at 232 nm

Blank Preparation: - Use dissolution medium as blank

Sample Preparation: - Place one tablet in each of six bowls and operate the apparatus for 90 minutes at the end of 5, 10, 15, 30, 45, 60 and 90 minutes, collect the sample and filter through 0.45 micron filter. Use the clear solution for UV reading.

Drug Release Profile: Media 4.5pH acetate buffer (T = trial formulation % release) (Fig.-2)

Table 6: Dissolution Profile

Time (minutes)	% Drug release
Time (minutes)	T-1	T-2
5	20.56	30.00
10	35.28	42.35
15	40.95	50.25
30	55.32	65.89
45	68.92	70.54
60	76.21	78.25
90	76.61	80.00

Fig.-2 Dissolution Profile

RESULTS AND DISCUSSION:

Tablets were evaluated for weight variation, hardness, friability, disintegration time, in-vitro drug release characteristics and stability. It was found that PEG 4000 and 6000 were unable to mask the bitter taste of the drug. But on the other hand, Stearic acid and Hydroxy Propyl Cellulose both were successful in masking the bitter taste of Racecadotril. Out of these Stearic acid and granulation with HPC both gave good release profiles. Developed tablets provide rapid disintegration and release in dissolution. Evaluation parameters for developed tablet were found within acceptance limit specified in pharmacopoeia.

REFERENCES:

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Received on 28.01.2010 Modified on 28.02.2010

Research J. Pharm. and Tech.3 (4): Oct.-Dec.2010; Page 1050-1052

Design and Evaluation of Taste Masked Fast Disintegrating Tablet of Racecadotril

OBJECTIVE: