Design and Evaluation of Ranitidine Hydrochloride Floating Tablets for oral controlled release.

Choudhury A¹*, Dash SK ², Roy A¹, Bahadur S¹, Saha S¹, Das S¹

¹Department of Pharmaceutics, GRY institute of Pharmacy, Vidhya Vihar, Borawan, M.P.

²Girijanada Chowdhury Institute of Pharmaceutical Science, Azara Hathakhowapara, NH-37, Guwahati 781017, Assam.

ABSTRACT

The purpose of the study was to develop a floating control drug delivery system of ranitidine hydrochloride and investigate the effect of formulation variables on drug release profile and floating property. Ranitidine hydrochloride (RHCl) was used as a model drug because of its short biological half life and site of release at stomach. Tablets were formulated using different concentration hydroxypropyl methyl cellulose K_4M, carbopol 934.where Sodium bicarbonate and Citric acid used as a gas generating agent. The floating behavior and in-vitro dissolution studies are carried out in a USP type II apparatus in 0.1 (N) HCL. It was observed that all the prepared formulation shows good floating capabilities up to 15 to 18 hours and slow steady release profile up to 12 hours. The dissolution profiles were subjected various kinetic release equations and found that drug release from different polymeric matrix follows diffusion controlled process. It has been also observed that combination of HPMC K_4M and carbopol 934 shows better results as compared to their single use.

Keywords: Floating controlled delivery system, Ranitidine Hydrochloride, Hydroxypropyl methylcellulose K4 M, Carbopol-934.

INTRODUCTION

Gastric emptying is a complex process, which is highly variable and makes in-vivo performance of the drug delivery system indecisive. In order to avoid this variability, efforts have been made to increase the retention time of the drug delivery system more than 12hours.When a gel-forming polymer such as semi synthetic derivatives of cellulose used for fabrication of formulation; it was found to be swells in the gastric fluid with a bulk density less than one, which remains buoyant and floats in the gastric fluid for a prolonged period of time. Different approaches have already been developed for the design of floating dosage forms of single and multiple systems. Ranitidine hydrochloride is a H₂ receptor antagonist, widely prescribes in the treatment erosive oesophagitis at a dose of 150mg 4 times a day selected as a model drug for this experimental study. A conventional dose of 150mg can inhibit gastric acid secretion up to 5 hours but not up to 10 hours. Again an alternative dose of 300 mg may lead to plasma fluctuation; thus a sustained release dosage form is desirable^2-3. The biological half-life of drug (about 2.5-3 hours) also in favoure development of sustained release formulation. The combined usage of hydroxypropyl methylcellulose (HPMC) and carbopol in a mucoadhesive delivery has been reported (Khanna et al., 1997; Anlar et al., 1993) to improve the mucoadhesiveness of the combined system. Marcos et al. (Perez Marcos et al., 1994) studied the potential of combining carbopol 974P and HPMC K4M using propranolol hydrochloride as a model drug and found that the amount of water imbibed in carbopol was lower than that of HPMC alone or 1:1mixture of two polymers. Again HPMC and CP934 were added extra granularly without exposing the polymers to granulation fluid for compaction purpose (Durraniet al., 1997)⁴. In consideration of above characters of HPMC K4M and carbopol-934, they were selected as polymer to prepare the formulation.

The aims of present investigation was to develop the floating drug delivery of RHCl for the first time by using the combination of HPMC K4M and carbopol 934 polymers with a view of prolonging gastrointestinal residence time and extended release of drug from its dosages form.

MATERIALS AND METHODS:-

MATERIALS:

Ranitidine hydrochloride was received as a gift sample from Albert David Limited, Kolkata, India. Hydroxypropyl methylcellulose (HPMC K4 M) was purchased from Loba Chemie Pvt. Ltd., Mumbai, India. Carbopol-934, stearic acid, and citric acid anhydrous were purchased from S.D. Fine-Chem. Ltd., Mumbai, India. And sodium bicarbonate was purchased from Titan Biotech Limited, Rajasthan, India. All other ingredients were of laboratory grade.

PREPARATION OF FLOATING TABLETS: ⁵

Ranitidine hydrochloride (153 mg equivalent to 150 mg of ranitidine) was mixed with the required quantities of HPMC K_4M, carbopol-934, sodium bicarbonate, and citric acid by geometric mixing both in single and in combination. RHCL was dispersed in chloroformic solution which content required quantity of stearic acid. The dispersion was stirred and chloroform was evaporated to form a ranitidine hydrochloride-stearic acid mixture. This mixture was then blended with other ingredients as described previously. The powder blend was then lubricated with magnesium stearate (1% wt/wt) and compressed on automatic tablet compression machine (Rimek Mini Press-I; SHAKTI ENGINEERING). The tablets were round and flat with an average diameter of 12 ± 0.1 mm and a thickness of 3.5 ± 0.2 mm.

DRUG RELEASE TESTING: ⁶

Dissolution studies were conducted using standard USP-II dissolution apparatus (VDA-8DR USP standers, VEEGO). In all the dissolution studies, the paddles were rotated at a speed of 50 rpm in 900 ml 0.1(N) at 37±0.5 ^◦C. A series of samples (2 ml) were withdrawn at predetermined time intervals and replaced by an equal volume of dissolution medium. The formulation prepared was subjected to dissolution test for 12 hours. The samples were filtered and then analyzed by UV-Visible spectrophotometer (ModelUV-1700pharmaspec, SHIMADZU) Drug release experiment were conducted in triplicates.

FLOATING PROPERTIES: ⁷

In order to provide quantitative measurements of floating lag time (initial time taken by the formulation to float) and floating duration (time period in which formulation remain floatable condition) continuous manual floating monitoring was perform. For the fulfillment of this study, the formulation was dropped in 1000 ml beaker containing 500 ml of dissolution medium, agitation was provided in optimum speed by means of rotating agitator and there by floating lag time and floating duration were measured under continuous visual supervision .To avoid erroneous result this study were performed three time for each formulation.

DRUG RELEASE KINETIC STUDY: ^7-10

The release data obtained was fitted to zero order, first order, Higuchi equation to determine the corresponding release rate and mechanism of drug release from floating tablet. The formula used for the determination of R² value in each cases are given bellow-

Zero-order = The dissolution data obtained were plotted as cumulative percent drug release verses time.

= %CPR VS T

Higuchi model = In this case the dissolution data obtained were plotted as per percent cumulative drug release verses square root of time.

Equation-

Q_t = Kt^1/2

Where, Q_t = Amount of the released drug in t time.

K = Release rate constant.

Peppas model = this is a simple semi empirical equation can be used to analyze data of controlled release of water soluble drugs from polymer matrices. In this case the dissolution data those obtained were plotted as per log cumulative percent drug release verses log time. The equation predicts the mechanism of diffutional release.

Equation-

M_t/M_α = btⁿ

Where, Mt = Amount of release of drug at t time.

M_α = Over all amount of drug (whole dose).

b = Constant

n = The release exponent, indicate the drug release mechanism.

1^st order = The dissolution data obtained were plotted as percentage amount remaining verses log t.

COMPATIBILITY STUDY:-¹⁵

Drug polymer compatibility studies have been performed by using FT-IR Spectrophotometer (Spectrum RX1) Shimadzu -840 instrument. To investigate the compatibility of formulations, first IR peaks of different functional groups of pure drug and pure polymer has been scan out followed by mixture of drug polymer. The IR peaks of different functional group of pure drug; polymer and drug polymer mixtures thus obtained are analyzes to conclude the result.

RESULTS:

Table-2 shows the result of all the physical parameter of the different batches of prepared floating tablet formulation, which include hardness, floating lag time, floating duration, average percentage deviation. It also content release profile of different formulation batches at 12^th hour. Though the hard ness of all the formulation are found with in the range of (3.2-4.4 kg/cm² ) but it having significant effect on floating capabilities and over all drug release profile. The formulation shows very good response in the point of view of floating capabilities, having the floating lag time with in the range of (1.35-2.25 min) and a floating duration of (12-18 hrs). The cumulative percentage drug release data shows that at 12^th hours all the formulation shows more than 90% of drug release. Although a clear difference between drugs release profile of the formulation prepared by using single polymer and combination of polymer are noticeable. F⁴ formulation shows highest drug release profile among the other formulations.

Table-1. Composition of prepared ranitidine hydrochloride floating tablets

Sl No	Ingredient mg/tablet	Formulation code
		F^1	F^2	F^3	F^4	F^5	F^6	F^7	F^8	F^9
1	Ranitidine HCl	150	150	150	150	150	150	150	150	150
2	HPMC K4M	-	150	75	100	112.5	120	50	37.5	30
3	Carbopol 934	150	-	75	50	37.5	30	100	112.5	120
4	NaHCO3	42	42	42	42	42	42	42	42	42
5	Citric acid	42	42	42	42	42	42	42	42	42
6	Stearic acid	6	6	6	6	6	6	6	6	6
7	Mg stearate	5	5	5	5	5	5	5	5	5
8	Talc	5	5	5	5	5	5	5	5	5

Table-2. Different physical parameters and release profile of prepared formulation.

Formulation code	Hardness (kg/cm^2) N=5	Average percentage deviation N=10	Floating capability		Cumulative drug release at 12^th hr
			Floating lag time (min)	Floating duration (hr)
F^1	4+ 0.83	1.458+1.78	2.05	12	93.87+0.02
F^2	3.2 + 0.98	2.05+1.40	1.44	13	94.88+0.22
F^3	4.4 + 0.88	1.387+ 1.09	1.35	18	95.40+0.14
F^4	3.6 + 0.98	1.482 + 1.23	1.45	17	99.93+0.11
F^5	3.7 + 0.56	2.964 + 0.89	1.48	16	97.98+0.21
F^6	4.0 + 0.74	2.797 + 0.98	2.22	16	98.93+0.06
F^7	4.5 + 0.81	1.043 + 1.29	2.25	17	96.93+0.39
F^8	4.1 + 0.87	1.022 + 1.42	2.05	14	92.49+0.11
F^9	3.8 + 0.93	2.775 + 1.56	1.56	5	98.28+0.08

Table- 3. Release kinetics of different formulation

Formulation	Kinetics of regression coefficient (r^2)
	Higuchi	Peppas	Zero order	First order
F^1	0.9928	0.9933	0.9935	0.9901
F^2	0.9816	0.9841	0.9813	0.9825
F^3	0.9801	0.9806	0.9788	0.9788
F^4	0.9975	0.9566	0.9975	0.9956
F^5	0.9876	0.9226	0.9543	0.9673
F^6	0.9851	0.9838	0.9792	0.9824
F^7	0.9959	0.9856	0.9589	0.9932
F^8	0.9788	0.9794	0.9739	0.9732
F^9	0.9786	0.9796	0.9724	0.9789

Table -4. Time to release of t₅₀, t₇₀, t₉₀ percentage drug release from different formulation.

SL no	Batch code	Time to release (hrs)
		t50%	t70%	t90%
1	F^1	6.30	7.91	10.19
2	F^2	5.60	7.53	9.85
3	F^3	5.06	7.01	9.94
4	F^4	5.50	7.53	9.46
5	F^5	5.32	6.91	8.62
6	F^6	6.50	7.75	9.84
7	F^7	6.59	8.20	9.94
8	F^8	6.39	8.22	10.70
9	F^9	6.22	8.21	10.09

Table-3 shows the kinetic drug release profile of different floating formulation, where different kinetic models like higuchi, zero-order, first-order, and peppas were introduced to identify the proper release kinetics of the prepared formulation. The results obtained based on the (r² ) value, shows that first three formulations (F¹, F², F³ ) follows the peppas model and rest of the formulations follows the higuchi kinetic release model.

Table-4 shows the t_50%, t_70%, t_90% drug release time profile. The resultant data shows a tiny difference in initial drug release of all the formulation followed by a

Fig – [1] comparison of cumulative percentage release of different floating formulation in 0.1 (N) HCl dissolution medium at 50 rpm agitation speed.

relatively higher difference between (F¹, F⁵, F⁸ and F⁹) with rest of the other formulation.

Fig-1 shows the graphical representation of the dissolution data of the prepared formulations, which is plotted by taking time (hrs) in X-axis and cumulative percentage of drug release in Y-axis.

The result of the compatibility study found after peak matching analysis that major peaks of both drug polymer mixture and pure drug was found in the range of 1220,1620,1192,1570,1590,1260 cm-1, which can be consider as a sign of compatibility. IR spectra of pure drug and formulation F⁴ is shown in the Fig-2.

Fig-2. Comparative study IR graph plot of pure Ranitidine hydrochloride and F4 formulation

DISCUSSION:

The study shows that the polymers, HPMC K4M and carbopol-934 having efficiency to produce very good matrix and suitable for design of floating tablet formulation. It also gives a clear view that in a particular formulation, presence of higher amount of HPMC K4M helps the formulation to reduce the floating lag time and on the other hand higher amount of carbopol-934 having negative effect on floating lag time, but it help to increase the floating duration. Carbopol-934 also produces some negative effect on drug release profile, slowdown the release rate. Thus rate of drug release and floating capabilities of a floating tablet is mainly depends on amount and extent of polymer use in time of fabrication. The formulation batches F¹ and F² were prepared by using single polymer and the formulation batches F³, F⁴, F⁵, F⁶, F⁷, F⁸ and F⁹ were prepared by using combined polymers. In consideration to release profile, release kinetics and floating capabilities, the formulation fabricated with 2:1 ratio of HPMC K4 M and carbopol-934 having batch code F4 shows higher cumulative percentage release of 99.93+0.11 as compared to other formulation. It has been also observed that as compared to the single polymer, formulation prepared with combination of polymer shows better results. The study gives an idea that increase of tablet hardness having negative effect on floating lag time as well as dissolution profile of the floating tablet formulation. This phenomenon might be occurred due to extreme integrity of the polymeric mass at higher compression force. Depending upon the r² value of release kinetic profile it can be conclude that the prepared floating tablet formulation follows diffusion controlled release pattern. The reason behind the difference between t⁵⁰ t⁷⁰ and t⁹⁰ values in the latter stages, because of burst release may be occurs due to sudden break down of the loosely aggregated matrix.

On the basis of the dissolution data obtained from the dissolution study, it can be summarize that all the formulation fabricated with combination of polymers shows slow and extended release. Among the several batches of prepared floating formulation, F⁴ formulation contains HPMC: Carbopol -2:1 ratio shows highest cumulative percentage drug release as well as good floating properties.

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Received on 24.08.2009

Accepted on 15.09.2009

© A & V Publication all right reserved

Research Journal of Pharmaceutical Dosage Forms and Technology. 1(2): Sept.-Oct. 2009, 167-170