FORMULATION AND IN VITRO EVALUATION OF

Dumpeti Janardhan et al: Formulation and in vitro Evaluation of Gastroretentive Drug Delivery System…

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Formulation and in vitro Evaluation of Gastroretentive Drug Delivery System for Ranitidine Hydrochloride Dumpeti Janardhan, Meka Lingam, Chinnala Krishna Mohan, and Vobalaboina Venkateswarlu* Novel Drug Delivery Systems Laboratory, University College of Pharmaceutical Sciences, Kakatiya University, Warangal - 506 009, Andhra Pradesh, India. ABSTRACT: The purpose of this investigation was to prepare a gastroretentive drug delivery system of ranitidine hydrochloride. Currently, floating tablets are one of the important categories of drug delivery systems with gastric retentive behavior. Ranitidine is a H2 blocker and absorbed from the upper part of GIT and hence there is need to develop a dosage form that releases the drug in stomach so that it can be absorbed from upper part of GIT leading to improved bioavailability. Six different gastroretentive tablets of ranitidine HCl were prepared by direct compression using different concentrations of Hydroxy propyl methyl cellulose (HPMC K4M), Carbopol, Sodium carboxy methyl cellulose, sodium bicarbonate and citric acid. The formulations were coded as HE1, HE2, HC1, HC2, HEC1 and HEC2. The formulations were evaluated for pharmacopoeial quality control tests and all the physical parameters evaluated for quality control were within the acceptable limits of Pharmacopoeia. All the formulations were subjected to in vitro drug release study and compared with that of marketed formulation. The floating lag time of the prepared formulations is good except for one formulation (HC1) and the floating time for all the formulations was >12 hours except HC1 which does not float at all. In conclusion, effervescent is essential for the formulation to have good floating property and carbopol retards the drug release in floating formulations. The statistical analysis of the parameters dissolution efficiency of dissolution data, floating behavior and drug content after storage at 40°C and 75% RH for three months showed no significant change by Student’s t-test indicating that formulation (HEC1) could provide a minimum shelf life of 2 years. KEYWORDS: Ranitidine HCl, floating tablets, controlled release, bioavailability.

Introduction

Moreover, colonic metabolism of ranitidine is partly responsible for the poor bioavailability of ranitidine from the colon (Basit A and Lacey L 2001). These properties of RHCl do not favor the traditional approach to sustained release delivery. Hence, clinically acceptable sustained release dosage forms of RHCl prepared with conventional technology may not be successful. The gastroretentive drug delivery systems can be retained in the stomach and assist in improving the oral sustained delivery of drugs that have an absorption window in a particular region of the gastrointestinal tract. These systems help in continuously releasing the drug before it reaches the absorption window, thus ensuring optimal bioavailability. It is also reported that oral treatment of gastric disorders with an H2-receptor antagonist like ranitidine or famotidine used in combination with antacids promotes local delivery of these drugs to the receptor of the parietal cell wall. Local delivery also increases the stomach wall receptor site bioavailability and increases the efficacy of drugs to reduce acid secretion (Coffin M and Parr 1995). This principle may be applied for improving systemic as well as local delivery of RHCl, which would efficiently reduce gastric acid secretion. Several approaches are currently used to prolong gastric retention time. These include floating drug delivery systems, also known as

Ranitidine hydrochloride (RHCl) is a histamine H2receptor antagonist. It is widely prescribed in active duodenal ulcers, gastric ulcers, Zollinger-Ellison syndrome, gastroesophageal reflux disease, and erosive esophagitis. The recommended adult oral dosage of ranitidine is 150 mg twice daily or 300 mg once daily. The effective treatment of erosive esophagitis requires administration of 150 mg of ranitidine 4 times a day (St Louis MO 1996). A conventional dose of 150 mg can inhibit gastric acid secretion up to 5 hours but not up to 10 hours. An alternative dose of 300 mg leads to plasma fluctuations; thus a sustained release dosage form of RHCl is desirable (Somade S, Singh K 2002). The short biological half-life of drug (~2.5-3 hrs) also favors development of a sustained release formulation. A traditional oral sustained release formulation releases most of the drug at the colon, thus the drug should have absorption window either in the colon or throughout the gastrointestinal tract. Ranitidine is absorbed only in the initial part of the small intestine and has 50% absolute bioavailability(Lauritsen K 1990, Grant S 1989). *Corresponding author: Vobalaboina Venkateswarlu Novel Drug Delivery Systems Laboratory University College of Pharmaceutical Sciences, Kakatiya University, Warangal - 506 009, Andhra Pradesh, India. Phone: +91-870-2439299 Fax: +91-870-2438844. E-mail: [email protected]

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International Journal of Pharmaceutical Sciences and Nanotechnology

Volume 1 • Issue 3 • October - December 2008

hydrodynamically balanced systems, swelling and expanding systems, polymeric bioadhesive systems, modified-shape systems, high-density systems, and other delayed gastric emptying devices (Singh B and Kim 2000, Chawla G and Bansal A 2003). In context of the above principles, a strong need was recognized for the development of a dosage form to deliver RHCl in the stomach and to increase the efficiency of the drug, providing sustained action. The present investigation applied a systematic approach to the development of gastroretentive RHCl dosage forms.

The dissolution test was performed using 900 ml of 0.1N HCl, at 37 ± 0.5°C and 50 rpm. A sample (5 ml) of the solution was withdrawn from the dissolution apparatus hourly for 12 hrs, and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45-μ membrane filter and diluted to a suitable concentration with 0.1N HCl. Absorbance of these solutions was measured at 317 nm using a UV/Vis doublebeam spectrophotometer (Elico ltd SL 164, India). Cumulative percentage drug release was calculated using an equation obtained from a standard curve.

Materials and Methods

Stability

Materials Ranitidine hydrochloride (RHCl) was received as a gift sample from Dr. Reddys Lab Ltd, Hyderabad, India. Hydroxy propyl methylcellulose (HPMC K4 M), Carbopol 934 were received as gift samples from Cadila Pharmaceuticals Ltd, Ahmedabad, India. Sodium bicarbonate, sodium carboxy methyl cellulose and citric acid anhydrous, magnesium stearate were purchased from S.D.Fine-Chem Ltd, Ahmedabad, India. All other chemicals were of analytical grade.

Methods Preparation of Ranitidine Hydrochloride Floating Tablets RHCl (168 mg equivalent to 150 mg of ranitidine) was mixed with the required quantities of HPMC K4 M/Carbopol 934/Sodium carboxy methyl cellulose, sodium bicarbonate, and citric acid by geometric mixing then passed through #40 mesh (ASTM). Magnesium stearate was weighed and passed through #60 mesh (1% w/w) then mixed with above blend and final blend was compressed into tablets using 11 ± 0.1 mm round concave punches and corresponding dies on rotary tablet compression machine (16 stationary, Riddhi, India). The composition of different formulations were shown in Table 1. in vitro Buoyancy Studies The in vitro buoyancy was determined by floating lag time, as per the method described by (Rosa M, Zia H, Rhodes T 1994). The tablets were placed in a 100-mL beaker containing 0.1N HCl. The time required for the tablet to rise to the surface and float was determined as floating lag time. in vitro Dissolution Studies The release rate of RHCl from floating tablets (n = 3) was determined using United States Pharmacopoeia (USP) 24 XXIV Dissolution Testing Apparatus 2 (paddle method).

To assess the drug and formulation stability, stability studies were done according to ICH and WHO guidelines (B.R.Mathews 1999). Optimized formulation (HEC1), sealed in aluminum packaging and various replicates were kept in the humidity chamber (LabTop, India) maintained at 40°C and 75% RH for 3 months. At the end of studies, samples were analyzed for the drug content, in vitro dissolution, floating behavior and other physicochemical parameters.

Results and Discussion The results of quality control tests reveal that all the tablets are meeting the official pharmacopoeia requirements (Table 2). The content uniformity is in the range of 95 – 98%. The floating lag time of the prepared formulations HE1, HE2, HC2, HEC1 and HEC2 are good except HC1(Fig. 1) and the floating time for all the formulations was more than 12 hrs except HC1(Fig. 2), which does not float at all. Formulations prepared with effervescent have shown good floating lag time and good floating characters, whereas the formulations prepared with carbopol have longer floating lag times. Carbopol slowly swells and attains the density < 1 for floating. Increased floating time was observed with formulations containing carbopol. The presence of effervescent reduced floating lag time, which may be because of entrapment of gas in the tablets. Dissolution profiles revealed that total drug was released from the marketed tablets in 30 min. The average percentage drug release from formulations HE1, HE2, HC1, HC2, HEC1 and HEC2 were shown in Fig. 3. A retarded drug release is seen in formulation HEC1 and containing effervescent and carbopol because of the reduced surface area of contact and retardation of hydration. Higuchi and zero order equation were applied for dissolution profiles and values were shown in Table 3. These results confirm the significance of amount of polymer and effervescent required optimizing the floating formulations for control release.


Table 1. Composition of different floating formulations. Effervescent

Carboxymethyl

NaHCO3 +

cellulose sodium

citric acid (mg)

(mg)

-

40

12

420

168

-

40

12

470

200

168

20

-

12

400

HC2

250

168

20

-

12

450

HEC1

200

168

20

40

12

440

HEC2

250

168

20

40

12

490

Formulation

HPMC

Ranitidine

Carbopol

code

K4M (mg)

HCl (mg)

(mg)

HE1

200

168

HE2

250

HC2

Total tablet weight (mg)

Table 2 : Formulations and their quality control tests. Formulation code

Weight Variations (mg)

Friability (%)

Hardness (Kg/Cm2)

Thickness (mm)

HE1

420 ± 3.2

0.68

4.56 ± 0.19

5.91 ± 0.02

HE2

470 ± 3.9

0.62

4.57 ± 0.20

6.92 ± 0.01

HC2

400 ± 3.6

0.77

4.66 ± 0.24

6.23 ± 0.01

HC2

450 ± 3.7

0.64

4.78 ± 0.13

7.12 ± 0.01

HEC1

440 ± 3.3

0.59

4.79 ± 0.17

6.76 ± 0.01

HEC2

490 ± 3.9

0.67

4.65 ± 0.20

7.32 ± 0.01

Floating lag time(min)

16

HC2

14 12 10 8 6 4 2

HE1

HE2 HC1 not floated

HEC1

HEC2

0 Formulations

Fig 1. Floating lag time of different formulations.

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After 30 min

6hr

12 hr

Fig 2. Photograph showing in vitro floating and swelling of tablets in the dissolution medium.

110 100 90 80 70 60 50 40 30 20 10 0

Cumulative % drug released

230

0

100

200

300

400

500

600

700

800

Time (min)

Zinetac HC2

HE1 HEC1

HE2 HEC2

HC1

Fig 3. Cumulative percentage of Ranitidine released from formulations versus time (n = 3). Table 3. Higuchi and zero order equation has been applied to all the formulations and the results shown below. R2

Formulations Higuchi

zero order

HE1

0.9859

0.9260

HE2

0.9688

0.8796

HC1

0.9833

0.9043

HC2

0.9742

0.8962

HEC1

0.9883

0.9869

HEC2

0.9702

0.9973


In view of the potential utility of the formulation, stability studies were carried out at 40°C and 75% RH for three months (climatic zone IV condition for accelerated testing) to assess their long-term (2 years) stability. The protocols of stability studies were in compliance with the guidelines in the WHO document (B.R.Mathews 1999) for stability testing of products intended for the global market. After storage, the formulation was subjected to a drug

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assay, floating behavior and in vitro dissolution studies. The statistical analysis of the parameters dissolution efficiency of dissolution data (Table 4), floating behavior and drug content (Table 5) after storage at 45°C and 75% RH for three months showed no significant change by Student’s t-test indicating that formulation (HEC1) could provide a minimum shelf life of 2 years.

Table 4. Ranitidine released from formulation (HEC1). %Ranitidine released

Time (h)

% Ranitidine released (Initial)

30

17 ± 0.4

15 ± 1.5

60

23 ± 1.8

24 ± 2.9

90

29 ± 2.3

31 ± 4.7

120

35 ± 0.8

36 ± 4.3

240

49 ± 1.2

48 ± 3.4

360

61 ± 4.3

60 ± 0.8

480

73 ± 3.3

71 ± 1.6

600

87 ± 4.3

89 ± 2.4

720

98 ± 2.2

95 ± 3.9

(3 Months )*

*Storage at 40 °C/75% RH for three months.

Table 5. Characteristics of HEC1 formulation.

Drug (%)

Hardness 2 (Kg/Cm )

Before storage

98.4 ± 1.1

3 Months at 40°C/75% RH

97.5 ± 1.2

Floating behavior Floating lag time (min)

Floating Duration(hr)

Matrix integrity

4.79 ± 0.17

0.25 ± 0.08

13 ± 1.5

Very good

4.82 ± 0.51

0.32 ± 0.11

13 ± 0.5

Very good

Conclusions Effervescent is essential for the formulations to have good floating property and Carbopol retards the drug release in the floating formulations

References B. R. Mathews, Regulatory aspects of stability testing in Europe, Drug Dev. Ind. Pharm. 25: 831-856 (1999). Basit A, Lacey L. Colonic metabolism of ranitidine: implications for its delivery and absorption.IntJPharm. 227(1-2):157-165 2001.

Chawla G, Bansal A. A means to address regional variability in intestinal drug absorption.PharmTech. 27: 50-68 (2003). Coffin M, Parr A. Ranitidine solid dosage form. US Patent 5: 407-687. April 18, (1995). Grant S. Ranitidine: an updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in peptic ulcer and other allied diseases. Drugs. 37: 801-870 (1989). Lauritsen K. Clinical pharmacokinetics of drugs used in the treatment of gastrointestinal diseases. Clin Pharmacokinet. 19: 11-31, 94-125 (1990).

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