High Density Gastric Retentive Ranitidine Hydrochloride Micro Spheres Biology Essay

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The main aim of the present work was to prepare and evaluate gastro retentive micro spheres for the controlled release of Ranitidine Hydrochloride using synthetic (Ethyl Cellulose) and natural polymers (Gellan and Karaya gums) and high density material (Titanium dioxide). The micro spheres were prepared by the coacervation phase separation technique. The drug was checked for its compatibility with polymers used by Fourier Transform Infrared spectroscopic (FTIR) studies. The surface morphology of micro spheres was studied by scanning electron microscopic (SEM) studies. The percentage of yield, surface associated drug content, drug entrapment efficiency and in vitro dissolution studies were performed. Accelerated stability studies were also carried out to the optimized formulations (F-5 and F-6). The FTIR spectrum of pure drug and drug-polymer blend showed that there were no incompatibilities of Ranitidine Hydrochloride with the polymers used. SEM studies showed that the micro spheres were in spherical shape. The micro spheres found to have good entrapment efficiency and percentage yield. The release of drug from the micro spheres extended up to 12 h. The release kinetics data and characterization studies indicated that drug release from micro spheres was diffusion controlled and the accelerated stability studies proved that the prepared micro spheres were stable. The study revealed that Ethyl cellulose with Gellan gum, Karaya gum and Titanium dioxide in combinations yields good quality micro spheres with promising characteristics.

Key words: Ranitidine Hydrochloride, Micro spheres, Ethyl cellulose, Gellan gum, Karaya gum, Titanium dioxide.


Micro spheres drug delivery systems made from the natural, biodegradable polymers have been attracted by several researchers for last decade in sustaining the drug delivery (Baken, 1987). However micro spheres prepared with synthetic polymers have good physical and mechanical characteristics. Micro spheres prepared with both synthetic and natural polymers will have all the advantages what an ideal micro spheres should have. However, the success of micro spheres is limited due to their short residence time at the site of absorption/action (Chien, 1982). High density micro spheres provide an increase in gastric residence time by making them to sink in gastric fluid. This can be achieved by coupling high density materials which has higher density then gastric fluid (Kondo, 1979). High density systems have advantages like increased gastric residence time and specific targeting of drugs in stomach, efficient absorption and enhanced bioavailability (Gutcho, 1976 and Vyas, 2002). Titanium dioxide was used as high density material in the present study (Ansel, 2000). Gellan gum was obtained from Pseudomonas elodea, which is chemically D-glucose, D-glucuronic acid and rhamnose in β-1, 4 linkage whereas Karaya gum was obtained from the plant Sterculia urens, which is chemically mixture of D-galactose, L- rhamnose and D-galacturonic acid (Rakesh et al., 2010).

Ranitidine Hydrochloride is a histamine H2-receptor antagonist. It is widely prescribed in active duodenal ulcers, gastric ulcers, Zollinger-Ellison syndrome, gastro esophageal reflux disease and erosive esophagitis. The recommended adult oral dosage of Ranitidine Hydrochloride is 150 mg twice daily or 300 mg once daily. The effective treatment of erosive esophagitis requires administration of 150 mg of Ranitidine Hydrochloride 4 times a day. A conventional dose of 150 mg can inhibit gastric acid secretion up to 5 h but not up to 10 h. An alternative dose of 300 mg leads to plasma fluctuations; thus a controlled release dosage form of Ranitidine Hydrochloride is desirable. The short biological half-life of drug (~2.5-3 h) also favors development of a controlled release formulation (Reynolds, 1996). In contest of the above principle, a strong need was recognized for the development of a dosage form to deliver controlled release gastro retentive delivery system of Ranitidine Hydrochloride.



Ranitidine Hydrochloride was obtained as a gift sample from Waksman Selman Pharmaceuticals, Anantapur, India (Batch # R 005289), Ethyl cellulose, Gellan gum, Karaya gum, Glyceraldehyde and Titanium oxide were procured from SD Fine Chemicals, Mumbai, India. Sunflower oil was procured from MORE super market, Anantapur, India. All the regents used were of analytical reagent grade and double distilled water was used throughout the experiment.

Preformulation Studies

Solubility analysis

Solubility analysis was performed for Ranitidine Hydrochloride pure drug to estimate the purity and to select a suitable solvent system and dissolution medium to dissolve the drug. Melting Point determination

Melting point determination of the obtained sample was done because it is a good first indication of purity of the sample since the presence of relatively small amount of impurity can be detected by a lowering as well as widening in the melting point range. Melting point of obtained sample was determined by using ………………….

Determination of λ max using UV spectrophotometer:

100 mg of Ranitidine Hydrochloride was accurately weighed and dissolved in 100 ml of 0.1 M Hydrochloric acid. 1 ml of above solution was further diluted to 100 ml with 0.1 M Hydrochloric acid. The so obtained solution was scanned on a UV Scanner between 200 to 400nm using double beam UV/visible spectrophotometer (Elico SL210, Hyderabad, India).. The maximum peak obtained in the graph was considered as λ max for the pure drug.

Fourier Transform Infrared Spectroscopic (FTIR) studies

FTIR spectrums of pure sample of Ranitidine Hydrochloride was procured by FTIR spectrophotometer (Perkin Elmer, spectrum-100, Japan) using the KBr disk method (5.2510 mg sample in 300.2502 mg KBr). The scanning range was 500 to 4000 cm-1 and the resolution was 1 cm-1. The spectrum was studied for characteristic peaks of Ranitidine Hydrochloride.

Compatibility Studies

FTIR studies

FTIR spectrums of Ranitidine Hydrochloride with polymers used were obtained individually and in combinations by FTIR spectrophotometer using the KBr disk method (5.1346 mg sample in 300.1679 mg KBr). The scanning range was 500 to 4000 cm-1 and the resolution was 1 cm-1. This spectral analysis was employed to check the compatibility of drugs with the polymers used.

Preparation of micro spheres

Ranitidine Hydrochloride micro spheres were prepared by coacervation phase separation technique utilizing temperature chance (Hwang et al., 1998 and Deshpande et al., 1996). Ethyl cellulose, Gellan gum, Karaya gum and Titanium dioxide were dissolved in 10ml of methanol. To this Ranitidine Hydrochloride was added and stirred at 300 rpm with the help of magnetic stirrer for 10 min to get a stable dispersion. The dispersion was poured drop wise into the 100ml of sunflower oil at room temperature. At the end of 2 h crosslinking agent Glyceraldehyde (0.5ml) was added to the dispersion medium and stirring was continued for next 30 min. Finally it was kept in refrigerator for 24 h to ensure the rigidness of micro spheres. This Procedure was followed to prepare 6 batches of Ranitidine Hydrochloride micro spheres with different ratios of Ethyl cellulose, Gellan gum and Karaya gum. The core: coat ratio, amount of drug and polymers used were given in Table 1.

Flow Properties

Angle of repose

This was determined by using funnel method. The formulated micro spheres were poured from a funnel that can be raised vertically until a cone formed. The height (h) and radius (r) of heap was measured. The angle of repose (Ó¨) was calculated by the eq.1 and 2 (Banker, 1987).

tan Ó¨ = h / r 1

Ó¨ = tan-1 (h / r) 2

Where, Ó¨ = Angle of repose, h = height of the pile (cm) and r = radius (cm) of the pile.

Loose Bulk density (LBD)

The sample under test was screened through sieve # 18 and the weight of sample equivalent to 25 g was filled in 50 ml graduated cylinder. The volume was noted and the loose bulk density was calculated in g/ cm3 by the eq. 3.

LBD = Weight of the Powder/ Volume of the packing 3

Tapped Bulk Density (TBD)

The sample under test was screened through sieve # 18 and the weight of sample equivalent to 25 g was filled in 50 ml graduated cylinder. The mechanical tapping of the cylinder was carried out using tapped density tester (………………) at a nominal rate of 300 drops per min for 2 min. The tapped density was calculated in g/ cm3 by the eq. 4.

TBD = Weight of the powder/ Tapped volume of the packing 4

Compressibility Index

The compressibility index of the micro spheres was determined by Carr's compressibility index and it has shown in eq. 5.

Carr's Index (%) = (TBD - LBD)/ TBD x 100 5

Where, TBD = Tapped density, LBD = Loose Bulk density

Hausner ratio (HR)

The ratio of TBD to LBD was related to inter particle friction and could be used to predict micro spheres flow properties. Hausner ratio can be calculated using the eq. 6.


Where, TBD = Tapped Bulk Density, LBD = Loose Bulk density

Particle Size Analysis

Particle size distribution was analyzed by placing 15 g of the formulated micro spheres in a set of standard test sieves and shaken for a 30 min using Indian Standard Sieves # 16, #20, #30, #40, #60 and #80 in a sieve shaker (…………………………). The particles collected in each sieve were weighed, the percentage particles retained was calculated and rom this average particle size was calculated.

Percentage yield

The percent yield of each batch of formulation was calculated using the eq. 7.

% yield = (weight of microspheres)/weight of solid starting material -100 (7)

Surface associated drug content

The Ranitidine Hydrochloride encapsulated micro spheres were evaluated for surface associated drug content on the surface of micro spheres. From each batch, 100 mg of micro spheres was shaken in 20 ml of 0.1N HCl for 5 min and then filtered through what man filter paper 41. The amount of drug present in filtrate was determined spectroscopically and calculated as a percentage of total drug content (Gohel and Amin, 1998). All the experiments were conducted in triplicate (n=3).

Estimation of drug loading/incorporation efficiency

Drug loaded micro spheres equivalent to 100 mg of Ranitidine Hydrochloride was suspended in water and then sonicated (Power sonic 505, Hwashin technology co, Korea) for about 20 min. It was shaken for 20 min in mechanical shaker (Orbitex, Scigenics biotech, India) for the complete extraction of drug from the micro spheres. The mixture was filtered through a 0.45 μm membrane filter (Millipore, Bangalore, India). Drug content was determined by double beam UV/visible spectrophotometer (Elico SL210, Hyderabad, India) at 313 nm. The percentage of drug entrapped was calculated using the eq. 8.

Total incorporation efficiency =surface associated drug + entrapped drug (8)

Determination of wall thickness

Wall thickness of micro spheres was determined by the eq. 9. (Dubey and Parikh 2004) All the experiments units were studied in triplicate (n=3).

h = [r (1-P) d1/3{Pd2+ (1-P) d1}] - 100 (9)

Where, h= wall thickness, r = arithmetic mean radius of micro spheres,

d1 and d2 = densities of core and coat material respectively,

P = proportion of medicament in micro spheres.

Estimation of Ranitidine Hydrochloride

The content of Ranitidine Hydrochloride in the micro spheres was estimated by a double beam UV/visible spectrophotometer based on the measurement of absorbance at 313 nm in 0.1 M Hydrochloric acid. The method obeyed Beer's law (at 1 to 10 mg/ml). The mean error and precision were found to be 0.9% and 1.0% respectively. These experiments were conducted for six times.

Drug Release Study

In vitro drug dissolution studies were performed using USP type I dissolution apparatus (DR-3, Campbell Electronics, Mumbai, India) at 75 rpm. The micro spheres were weighed and filled in the empty capsule shells and placed in the basket. The dissolution medium (900ml) consisted of 0.1M HCl for first 2 h and then changed to phosphate buffer pH 7.4 from 3rd to 12th h; Temperature was maintained at 37 ± 0.5oC. A 5 ml sample was withdrawn at specific time intervals and replaced with an equivalent volume of dissolution fluid. Drug content was determined by double beam UV/visible spectrophotometer at 313 nm. The release studies were conducted in triplicate (Ibrahim, 2002).

In vitro drug release kinetic studies

The exact mechanism of Ranitidine Hydrochloride release from the microsphere was further studied by kinetic models. The drug release data was analyzed by zero order, first order, Higuchi (Higuchi, 1963), Korsmeyer Peppas (Peppas, 1989) and Hixson Crowell models (Hixson, 1931). The criteria for selecting the most appropriate model were chosen on the basis of goodness of fit test.

Scanning Electron Microscopic (SEM) studies

The surface morphology of selected micro spheres (F-6) was studied by SEM analysis using scanning electron microscope (FE-SEM, Carl Zeiss, Germany). The samples were coated with 200Ao thickness gold prior to microscopy. The SEM photographs were shown in Figure 10.

Accelerated Stability studies

The promising formulations (F-5 and F-6) were tested for stability at stressed storage conditions of temperature (40±2oC) and Relative humidity (75±5% RH). The percent drug content after accelerated stability studies was determined (Remunan, 1992).


The Ranitidine Hydrochloride sample was found to be freely soluble in water and in methanol, sparingly soluble in ethanol and very slightly soluble in methylene chloride. The melting point of the obtained drug sample was found to be 132oC which is within the reported limit 133.5oC. The pure drug showed λ max at 303 nm in UV spectral study and the drug showed characteristic peaks of Ranitidine Hydrochloride indicating the purity of the drug sample.

The FTIR spectrum of Ranitidine Hydrochloride showed characteristic peaks at wave numbers 3431.82 (3300-3500) (N-H), 2991.84 (2850-3000) (C-H), 3238.31, 3174.70, 3090.42, 2904.20, 2789.18, 2668.68, 2599.76 (3300-2500 (O-H), 1249.44 (1350-1550) (N=O), 1063.86 (1220-1020) (C-N) and 1002.71 (1000-1300) (C-O) (Figure 3). Infrared absorption spectrum of placebo tablet blend spectrum showed prominent peaks at wave numbers 2920.0 (2850-3000) (C-H), 3435.16 (3300-3500) (N-H), 3002.79, 2887.74, 2816.03 (3300-2500) (O-H), 1299.38, 1173.24 (1000-1300) (C-O) (Figure 4). The major FTIR peaks observed in formulated tablet blend (F-5) were 3441.60 (3300-3500) (N-H), 2925.73, (2850-3000) (C-H), 2860.38 (3300 - 2500 (O-H), 1453.69, 1381.54 (1350-1550) (N=O), 1242.45, (1220 -1020) (C-N) and 1151.14 (1000-1300) (C-O). (All these values were represented in cm-1). This indicates that there were no chemical incompatibility between Ranitidine Hydrochloride with polymers and excipient used (Ethyl cellulose, Gellan gum, Karaya gum and Titanium dioxide).

The angle of repose of formulated micro spheres was ranged from 22.26±0.18 to 28.12±0.25o which indicates the micro spheres have excellent flow properties (25-30o). The Loose Bulk density of formulations was ranged from to 0.419±0.02 to 0.741±0.05 g/cm3 and the tapped Bulk density of formulations were ranged from 0.584±0.08 to 0.875±0.05 g/cm3. The compressibility Index was 15.55±0.12 for the formulation F-6 indicating good compressibility properties (12-16%). The Hausner ratio was ranged from 0.010±0.001 to 1.176±0.001. All these values were represented in table 2.

The average particle sizes of F-1 to F-6 formulations were Particle size 515.45±5.5, 494.78±2.6, 512.62±5.9, 502.23±7.8, 504.91±6.2 and 498.52±2.5 μm respectively, indicating the uniformity in particle size. The percentage yields of among formulated micro spheres, F-6 showed highest percentage yield of 86.75±0.24%. The surface associated drug content was least for F-6 (10.41±0.09). High drug entrapment efficiency was observed to the formulation F-6 and it was 92.58±2.39%. The wall thickness of formulated micro spheres was ranged from 15.54±0.02 to 19.25±0.35μm. The wall thickness of formulated micro spheres was found to be increased as increase in ratio of polymer. All these values were shown in Table 3.

In vitro drug release kinetics data studies indicate that the formulations either followed zero order release or the Higuchi release model. Ranitidine Hydrochloride release from micro spheres was diffusion controlled. The kinetic values of in vitro dissolution data was tabulated in Table 4, 5 and represented in Figures 5, 6, 7, 8 and 9. The accelerated stability revealed that the optimized micro spheres (F-5 and F-6) were stable even at accelerated storage conditions. The drug content in the formulation after stability studies were tabulated in Table 6. The SEM results shows that the micro spheres were spherical and with a smooth surface. The SEM photographs were shown in Figure 10.


The Ranitidine Hydrochloride micro spheres prolonged drug release for 12 h or longer. The study concluded that combination of synthetic (Ethyl Cellulose) and natural polymers (Gellan and Karaya gums) with high density material (Titanium dioxide) as gastro retentive drug delivery systems stays as good combination for preparing gastro retentive drug delivery systems.