Formulation Development and Evaluation of Floating Drug Delivery System for H₂-Blocker Drug (Roxatidine Acetate)

Rajesh Mujoriya*, Dharmendra Mundhada, Sangram Pawar

Department of Pharmaceutics, Agnihotri College of Pharmacy, Wardha, Maharashtra

*Corresponding Author E-mail: raj_mujoriya@live.com

ABSTRACT:

The present study has been a satisfactory attempt, to formulate and evaluate floating tablet of Roxatidine Acetate with a view of improving bioavailability and giving a controlled release of a drug. Floating tablet of Roxatidine Acetate will reduce the frequency of administration of drug and helps to minimize dose of drug and side effects associated with the drug. Roxatidine Acetate Floating Drug Delivery systems can be prepared by wet granulation method using HPMCK₄M: Eudragit-RL100 polymer ratio and PVPK-30 as a binder, Sodium-bi-Carbonate: Citric acid as gas generating agent. The given floating tablet of Roxatidine Acetate was made to prepare with different polymer combination such as Eudragit-RL100: HPMCK4M and varying concentration of HPMCK₄M, PVPK30. Comparing the all formulations, Floating drug delivery system formulation of F5 was considered as an ideal formulation which exhibited 99.26% of drug release in 8 hours, and floating lag time of 11seconds with a total floating time of 12 hours.

KEYWORDS: Floating tablet, bioavailability, controlled release, wet granulation method, floating lag time, total floating time.

INTRODUCTION:

Oral delivery of drugs is by far the most preferable route of drug delivery due to the ease of administration, patient compliance and flexibility in formulation, etc. from immediate release to site-specific delivery, oral dosage forms have really progressed¹. However, it is a well accepted fact that it is difficult to predict the real in vivo time of release with solid, oral controlled release dosage form. Thus, drug absorption in the GI tract may be very short and highly variable in certain circumstances². One of the most feasible approaches for achieving a prolonged and predictable drug delivery profile in the GI tract is to control the gastric residence time (GRT) is floating drug delivery system³.

Certain types of drugs can benefit from using gastric retentive devices. These includes (a) drugs locally acting in the stomach (b) drugs having a narrow absorption window in the stomach (c) that are unstable in the intestinal or colonic environments, (d) have low solubility at high pH values⁴.

Suitable Drugs for Gastroretention⁵:-

1. Narrow absorption window in GI tract, e.g., riboflavin and Levodopa

2. Basically absorbed from stomach and upper part of GIT, e.g., chlordiazepoxide

And cinnarazine.

3. Drugs that disturb normal colonic bacteria, e.g., amoxicillin trihydrate.

4. Locally active in the stomach, e.g., antacids and misoprostol.

5. Drugs that degrade in the colon, e.g., ranitidine HCl and Metronidazole.

Types Of Floating Drug Delivery Systems⁶

Various approaches have been pursued to increase the retention of an oral dosage form in the stomach. These systems include:

A. Floating systems

B. Bioadhesive systems

C. Swelling and expanding systems

D. High density systems and

E. Modified systems

MATERIALS AND METHOD:

Roxatidine Acetate was obtained as gift sample from Anazeal Reasearch Lab, Mumbai. Eudragit-RL100, PVP K-30 & HPMC K₄M was obtained from Mahalakshmi chemicals, Hyderabad. Sodium-Bi-Carbonate, Citric acid, Magnesium stearate, Talc & Lactose was obtained from Samar Chemicals, Nagpur.

Experimental Details^7-10

Characterization of Pure Drug

Pure Drug has been characterize by various parameters like Solubility, Identification by FT-IR, Melting range, Sulphated ash, Loss on drying, Heavy Metals and Assay.

Preformulation Study

Preformulation testing was done to investigate of physical and chemical Properties of a drug substance alone and when combined with excipients. It is the first step in the rational development of dosage forms.

Compatibility Study

To analyze the compatibility between Roxatidine Acetate and excipients proposed to incorporate into the formulation. Roxatidine Acetate is mixed with excipients in different ratio. These mixtures were kept in a 6ml glass white colour vials and packed properly. These vials are exposed to Room temperature, 30°c / 65% relative humidity and 40˚c / 75%RH.16 gm of blend is prepared which is filled in 3 vials.

Method of Preapration of Floating Tablet by Wet Granulation Method:

Floating Matrix Tablet of Antihypertensive Roxatidine Acetate was prepared by Wet granulation method using Eudragit-RL100 and HPMCK₄M as polymer. All the ingredients (except glidents and lubricant) and drug were accurately weighed and individually passed through Sieve No.60. Granulation was done with a solution of calculated quantity of PVP K-30 in sufficient Isopropyl alcohol. The wet mass was passed through Sieve No.12/16 and dried at 45-55°C for 2 hours. Dried granules were passed through Sieve No.18/22 and mixed with magnesium stearate and talc and the blend thus obtained was compressed using a single station compression machine.

Table No. 1: Formulation of Floating tablets

Sr. No.	Ingredients	HPMCK4M				Eudragit-RL100
		F1	F2	F3	F4	F5	F6	F7	F8
1	Roxatidine Acetate	150	150	150	150	150	150	150	150
2	HPMCK4M	100	100	100	120	80	80	80	80
3	Eudragit-RL100	--	--	--	--	50	40	30	20
4	PVP K-30	10	20	30	20	10	10	10	10
5	Sodium-Bi-Carbonate	50	50	50	50	50	50	50	50
6	Citric Acid	15	15	15	15	15	15	15	15
7	Lactose	65	55	45	35	35	45	55	65
8	Magnesium-stearate	5	5	5	5	5	5	5	5
9	Talc	5	5	5	5	5	5	5	5
	Total (mg)	400	400	400	400	400	400	400	400

Fig. No. 1:- IR Spectra of Roxatidine Acetate Powder

RESULT:

Identification by FT-IR

IR spectrum of Roxatidine Acetate showed the characteristic absorption peaks at 3236, 3062, 1581 and 1265 cm-1denoting stretching vibrations of –NH, aromatic –CH, –NH bending and aromatic C-O groups respectively.

Development of calibration curve of Roxatidine Acetate

Preparation of 0.01 M Phosphate Buffer Preparation of 0.01M phosphate buffer:

7g of Potassium dihydrogen orthophosphaste was weighed accurately and dissolved in about 500 ml of distilled water and diluted with distilled water upto 1000 ml, and the pH was adjusted upto 6.8 with the sodium hydroxide solution and filtered through 0.45µ Whatmann filter paper .This buffer solution was used as diluent.

Preparation of standard stock solution and calibration curve:

100 mg of Roxatidine acetate was accurately weighed into 100 ml volumetric flask, dissolved in 0.1N HCl and volume was made up with 0.1N HCl. Pipette 1ml of above solution into 10ml volumetric flask and the volume was made with 0.1N HCl. Aliquots of 2ml, 4ml, 6ml, 8ml, 10ml, 20ml, 30ml. from standard solution were diluted to 10 ml with 0.1N HCl. The absorbance of these solutions was measured at 313nm with UV-VIS spectrometer.

Fig. No. 2. calibration curve of Roxatidine Acetate

Characterization of Pure Drug

Table No. 2: Characterization of Pure Drug

Sr. No	Characterization	Specification	Result
1.	Description	white powder	almost white powder
2.	Solubility	Freely soluble in water	Complies
3.	Identification by FT-IR	To match with working standard	Matches with the working standard
4.	Melting range	146^0C	Complies
5.	Sulphated ash	Not more than 0.1%	Complies
6.	Loss on drying	Not more than 0.5%	Complies
7.	Heavy Metals	20 ppm max	Complies
8.	Assay	Not less than 99.0% w/w and not more than 101.0% w/w on anhydrous basis	Complies

Preformulation Study

Table no. 3: Preformulation Study

Sr. No	Characterization	Specification	Result
1	Description	White powder	A almost white powder
2	Solubility	Freely soluble in water	Complies
3.	Melting range	146°C	Complies
4.	Identification by FT-IR	To match with working standard	Matches with the working standard
5.	Loss on drying	Not more than 0.5%	Complies
6.	Assay	Not less than 99.0% w/w and not more than 101.0% w/w on anhydrous basis	Complies

Compatibility Study at Room temperature, 30°c / 65% relative humidity and 40˚c / 75%RH

Table no. 4: Compatibility Study

Sr. No	Drug + Excipients	Proportion	Initial Observation of color	Final observation		Conclusion
				2nd week	4th week
1.	Drug	NA	White	White	White	Compatible
2.	Drug+ Eudragit RL 100	1:10	White	White	White	Compatible
3.	Drug+ HPMCK4M	1:10	Creamy White	Creamy White	Creamy White	Compatible
4.	Drug+ PVP K30	1:10	Pale-Yellowish Brown	Pale-Yellowish Brown	Pale-Yellowish Brown	Compatible
5.	Drug + Sodium bicarbonate	1:10	White	White	White	Compatible

Evaluation of Floating tablets⁴

Table No. 5: Evaluation of Floating tablets

Batch	F1	F2	F3	F4	F5	F6	F7	F8
TEST	MICROMERETIC PROPERTIES
Angle of repose(θ)	29.12	27.75	27.30	26.67	24.44	25.11	25.90	26.59
Bulk density (g/ml)	0.222	0.200	0.190	0.181	0.210	0.166	0.166	0.173
Tapped density (g/ml)	0.266	0.235	0.222	0.210	0.235	0.190	0.190	0.200
Compressibility Index (%)	16.76	14.89	14.41	13.42	10.60	12.63	12.63	13.50
Hausener’s ratio	1.19	1.17	1.16	1.15	1.11	1.14	1.14	1.15
Flow properties	Fair	Good	Good	Good	Excellent	Good	Good	Good
PHYSICAL EVALUATION OF FORMULATED TABLET BATCHES
Thickness (mm)	4.32±0.04	4.35±0.01	4.50±0.06	4.35±0.04	4.35±0.01	4.32±0.02	4.32±0.03	4.50±0.02
Hardness (kg/cm^2) ±SD	5.25±0.08	4.35±0.14	4.50±0.09	4.50±0.11	4.35±0.03	4.50±0.12	5.25±0.40	5.25±0.17
Friability (%) ±SD	0.83±0.05	0.53±0.06	0.36±0.09	0.53±0.04	0.46±0.01	0.76±0.02	298 ±2.0	98.74±0.17
Weight Variation (mg) ±SD	298±1.15	300±2.08	305 ±1.52	300±1.52	300±0.57	0.73±0.04	298±3.05	98.71±0.20
Drug Content Uniformity (%)	98.36±0.25	98.40±0.30	98.42±0.25	98.50±0.25	98.96±0.30	0.39±0.09	305 ±0.57	98.70±0.17
FLOATING PROPERTIES
Buoyancy Lag Time (Sec)	13sec	14sec	15sec	12sec	11sec	13sec	12sec	13sec
Total Floating Time (Hr)	>12	>12	>12	>12	>12	>12	>12	>12
SWELLING INDEX (%)
1 hrs	18.10	17.06	19.21	22.2	28.68	24.39	26.03	21.09
2 hrs	41.25	36.06	28.46	43.24	30.78	27.47	44.05	36.06
3 hrs	40.66	41.49	36.06	38.21	36.73	42.03	45.73	49.55
4 hrs	38.22	53.23	49.55	61.22	46.05	36.07	38.22	53.51
5 hrs	31.32	51.70	52.55	59.19	65.07	40.22	34.30	39.12
6 hrs	27.12	37.38	39.9	49.13	73.66	46.19	41.23	42.12
7 hrs	22.21	31.14	37.38	41.23	53.61	36.22	38.24	36.22
8 hrs	24.11	25.49	25.74	31.56	50.22	33.01	30.25	30.24

a) Initial stage of floating of tablet b) After 11 sec floating of tablet c) After 11 sec floating of tablet

Fig. 3: Buoyancy studies of batch F5 tablet

Fig.No.4: Relationship between Swelling Index & Time of batches F1-F4.

Fig.No.5: Relationship between Swelling Index & Time of batches F5-F8

Dissolution study (In-vitro Drug Release Study)

Table no. 6: Dissolution study

% OF DRUG RELEASE IN 0.1N HCL AT 1.2 Ph
	HPMCK4M				Eudragit-RL100:HPMCK4M
TIME(hr)	F1±S.D	F2±S.D	F3±S.D	F4±S.D	F5±S.D	F6±S.D	F7±S.D	F8±S.D
0h	00	00	00	00	00	00	00	00
1h	12.16±1.0	12.34±0.13	12.40±0.12	12.44±0.23	13.54±0.16	13.08±0.63	12.81±0.43	12.81±0.76
2h	30.46±0.84	31.56±0.35	31.47±0.64	30.46±0.89	31.11±0.53	31.47±0.45	30.10±0.45	28.44±0.98
3h	41.30±1.14	40.39±0.57	37.08±0.47	41.31±0.43	44.45±0.78	41.13±0.24	40.66±0.65	38.44±0.65
4h	51.11±1.13	51.02±0.79	51.09±0.88	54.79±0.75	55.46±0.34	48.72±0.54	51.11±0.32	48.78±0.76
5h	54.70±0.43	57.74±0.57	65.73±0.78	64.94±0.39	69.12±0.58	68.51±0.62	67.50±0.32	63.87±0.85
6h	67.25±1.33	69.29±0.95	77.33±0.56	78.10±0.48	79.68±0.62	77.00±0.75	75.51±0.23	77.85±0.41
7h	77.83±0.85	79.61±1.05	84.28±0.71	86.78±0.52	91.55±0.95	90.19±0.56	89.35±0.24	87.65±0.45
8h	91.79±1.03	93.67±0.13	95.83±0.60	96.89±0.33	99.26±0.32	98.75±0.76	97.44±0.43	97.38±0.56

Fig.No.6: In-vitro Drug release study of Batches F1-F4

Fig.No.7: In-vitro Drug release study of Batches F5-F8

Drug Release Kinetic Model Fitting Study

Fig.No.8: Zero order Kinetics for Formulations F1 to F8

Fig.No.9: First order Kinetics for Formulations F1 to F8.

Fig.No.10: Higuchi Matrix drug release for formulation F1-F8

Fig.No.11: Peppas drug release for formulation F1-F8

4.9 Stability Study:

Table 7: Evaluation of formulation (F4) kept for stability at 40⁰C / 75%RH

Parameter	0 week	1 week	2 weeks	3 weeks	4 weeks
Appearance	White	White	White	White	White
Thickness (mm)	4.16±0.04	4.16±0.04	4.16±0.04	4.16±0.04	4.16±0.04
Hardness (Kg/cm2)	5.21±0.03	5.17±0.028	5.10±0.021	5.07±0.02	5.00±0.015
Buoyancy Lag time (sec)	20	20	20	18	17
Duration of Floating	>12	>12	>12	>12	>12
Drug content (%)	99.9±0.57	99.8±0.99	98.7±0.98	98.2±0.95	98.2±0.95

Table 8: In-vitro drug release study of formulation (F5) kept for stability at 40⁰C / 75%RH:

Time (Hrs)	Cumulative % Drug Released
	0 week	1 week	2 week	3 week	4 week
1	46.00±0.294	46.81±1.07	45.98±0.23	45.73±0.95	45.02±0.12
2	50.36±0.100	50.39±2.62	49.78±0.39	49.11±0.44	48.96±0.16
4	60.94±0.203	60.90±0.34	59.65±0.24	59.11±0.32	60.94±0.43
6	66.47±0.100	65.89±0.25	65.48±0.75	65.08±0.68	64.29±0.20
8	79.10±0.192	79.19±0.53	78.55±0.79	78.23±0.42	77.26±0.40
10	91.10±0.109	91.10±0.77	90.78±1.19	90.45±0.31	90.05±0.39
12	99.47±0.402	99.36±0.38	98.84±0.73	98.57±0.41	98.00±0.17

Figure 12: Comparative dissolution profile of formulation F5 before and after stability study.

DISCUSSION:

Roxatidine Acetate Floating Drug Delivery systems can be prepared by wet granulation method using HPMCK4M: Eudragit-RL100 polymer ratio and PVPK-30 as a binder, Sodium-bi-Carbonate: Citric acid as gas generating agent. The In-vitro dissolution profiles of all the prepared Roxatidine Acetate floating drug delivery system formulations were found to extend the drug release over a period of 8 hours and the drug release rate decreased with increase in polymer concentration, it is concluded that formulation F5 (HPMCK4M: Eudragit-RL100) is the best formulation among all other formulations because it is showing very controlled release of drug from tablet formulation. Comparing the all formulations, Floating drug delivery system formulation of F5 was considered as an ideal formulation which exhibited 99.26% of drug release in 8 hours, and floating lag time of 11seconds with a total floating time of 12 hours. The given floating tablet of Roxatidine Acetate was made to prepare with different polymer combination such as Eudragit-RL100: HPMCK4M and varying concentration of HPMCK4M, PVPK30. The study reveals that the drug release from formulations is depend upon the swelling, nature of gel matrix, release and diffusion ability of polymers. From the observation it is concluded that the drug release from F5 (HPMCK4M: Eudragit-RL100) shows that, as HPMCK4M used in combination with Eudragit-RL100, the drug release of formulation is increases as compare to F1-F4 (HPMCK4M) & F6-F8 (Eudragit-RL100: HPMCK4M). This is because of the swelling properties of polymers. Formulation F5 batch indicate the best swelling index i.e. 50.22% than other formulations. Developed floating tablets possessed the required physicochemical parameter such as like hardness, friability, weight variation, drug content, swelling index and floating properties. All the developed floating tablets floated up to 12 hour. Stability study of F5 batch has a good stability property. From the above observation it is concluded that formulation F5 (HPMCK4M: EudragitRL-100) is the best formulation among all other formulations because F5 batch gives the good controlled release of drug from tablet formulations.

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Received on 07.04.2016 Modified on 23.04.2016

Accepted on 10.05.2016 ©A&V Publications All right reserved

Res. J. Pharm. Dosage Form. & Tech. 2016; 8(3): 190-198.

DOI: 10.5958/0975-4377.2016.00026.4