High Density Gastro Retentive Microspheres Of Famotidine Biology Essay


The main aim of the present work was to fabrication of gastro retentive high density microspheres with both synthetic and natural polymers for the sustained release of Famotidine to treat gastric ulcers. The microspheres were prepared by the coacervation phase separation technique. Famotidine was checked for its compatibility with polymers used by Fourier Transform Infrared spectroscopy (FTIR). The surface morphology 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 and the dissolution data was treated with mathematical kinetic models. Accelerated stability studies were also carried out to the optimized formulation (F-6). The FTIR spectrum of pure drug and drug-polymer blend showed the stable character of Famotidine in the micro capsules. The microspheres were found to be spherical. The microspheres had good entrapment efficiency and percentage yield. The release of drug from the microspheres extended up to 12 h. The release kinetics data and characterization studies indicate that drug release from microspheres was diffusion sustained and that the microspheres were stable. The study revealed that Gellan gum and Karaya gum in combinations found to be effective combination for microspheres.

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Key words: Famotidine, Microspheres, Gellan gum, Karaya gum, Titanium dioxide.


Microspheres drug delivery systems made from the natural, biodegradable polymers have been attracted by several researchers for last decade in sustaining the drug delivery1. Microspheres have varied applications and are prepared using various polymers. However, the success of microspheres is limited due to their short residence time at the site of absorption/action2. High density microspheres provide an increase 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 fluid3. High density systems have advantages like increased gastric residence time and specific targeting of drugs in the absorption site, efficient absorption and enhanced bioavailability4, 5. Titanium dioxide was selected as high density material in formulating microspheres6. Gellan gum was obtained from Pseudomonas elodea, which is chemically D-glucose, D-glucuronic acid and rhamnose in ß-1, 4 linkages whereas Karaya gum was obtained from the plant Sterculia urens, which is chemically Mixture of D-galactose, L- rhamnose and D-galacturonic acid7.

Famotidine is a histamine H2-receptor antagonist. It is widely prescribed in gastric ulcers, duodenal ulcers, Zollinger- Ellison syndrome and gastro esophageal reflux disease. In the management of benign gastric and duodenal ulceration the dose is 40 mg daily by mouth at bedtime, for 4 to 8 weeks. In gastro esophageal reflux disease the recommended dose is 20 mg by mouth twice daily for 6 to 12 weeks; where gastroesophageal reflux disease is associated with esophageal ulceration, the recommended dosage is 40 mg twice daily for a similar period. For the short term symptomatic relief of heartburn or non-ulcer dyspepsia a dose of 10 mg up to twice daily is suggested. In the Zollinger-Ellision syndrome the initial dose by mouth is 20 mg every 6 h, increased as necessary; dose up to 80 mg daily have been employed. The low bioavailability (40-45%) and short biological half-life (2.5-4.0 h) of famotidine favors development of a sustained release formulation8. In contest of the above principle, a strong need was recognized for the development of a dosage form to deliver sustained release gastro retentive delivery system of Famotidine.



Famotidine was obtained as a gift sample from Waksman Selman Pharmaceuticals, Anantapur, India (Batch # F 01697), Gellan gum, Karaya gum; Formaldehyde and Titanium oxide were procured from SD Fine Chemicals, Mumbai, India. Sunflower oil was procured from MORE super market, Anantapur, India. All the reagents were of analytical reagent grade and double distilled water was used throughout the experiment.

Preformulation Studies

Solubility analysis

Preformulation solubility analysis was done to select a suitable solvent system to dissolve the drug and also to test its solubility in the dissolution medium which was to be used.

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.

Compatibility Studies

Fourier Transform Infrared Spectroscopy

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Fourier Transform Infrared (FTIR) spectrums of Famotidine with gums used were obtained individually and in combinations on a Fourier Transform Infrared (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. This spectral analysis was employed to check the compatibility of drugs with the polymers used.

Preparation of microspheres

Gellan gum, Karaya gum and Titanium dioxide mixture containing Famotidine microspheres were prepared by coacervation phase separation technique utilizing temperature change9, 10. Gellan gum, Karaya gum and Titanium dioxide were dissolved in 10 ml of water which was previously heated to 500 C, to this Famotidine was added and stirred at 300 rpm with the help of magnetic stirrer for 15 m to get a stable dispersion. The dispersion was poured drop wise into the 10 ml of sunflower oil which was also previously heated to 500 C on a water bath. The mixture was stirred with a help of magnetic stirrer for 2 h at 300 rpm at room temperature. At the end of 2nd h crosslinking agent formaldehyde 0.5 ml 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 microspheres. This Procedure was followed to prepare 6 batches of Famotidine microspheres with different ratios of Gellan gum and Karaya gum mixtures. The core: coat ratio, amount of drug and polymers used were given in Table 1.

Flow Properties11

Angle of repose

This was determined by using funnel method. Powder was poured from a funnel that can be raised vertically until a maximum cone height (h), was obtained. Diameter of heap, (D), was measured. The angle of repose (Ó¨) was calculated by the following equations.

tan Ó¨ = h / r

Ó¨ = tan-1 (h / r)

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

Loose Bulk density

The sample under test was screened through sieve # 18, the sample equivalent to 25 g was accurately weighed and filled in a 100 ml graduated cylinder, the powder was leveled, and the unsettled volume, V0 was noted. The bulk density was calculated in g/cm3 by the following equation.

Db = M / V0

Where, M= Mass of powder, V0= Bulk volume of the powder

Tapped Bulk Density

The sample under test was screened through sieve # 18 and the weight of sample equivalent to 25 g was filled in 100 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 500 times initially and the tapped volume V0 was noted. Tapping was proceeding further for an additional tapping 750 times and tapped volume Vb was noted. The difference between two tapping volume was less than 2%, so Vb was considered as a tapped volume Vf. The tapped density was calculated in g/ cm3 by the following equation.

Dt = M / Vt

Where, M = Mass of powder, Vt = Tapped volume of the powder.

Compressibility Index

The bulk density and tapped density was measured and compressibility index was calculated by the following equation.

IC = Dt - Db / Dt

Where, Dt = Tapped density of the powder, Db = Bulk density of the powder

Hausner ratio

The ratio of Tapped density and bulk density gives the Hausner ratio and it was calculated using the following equation.

HR= Dt / Db

Where, Dt = Tapped density of the powder, Db = Bulk density of the powder

Particle Size Analysis

Particle size distribution was analyzed by placing 5 g of the formulated microspheres in a set of standard test sieves and shaken for a particular time interval using Indian Standard Sieves # 16, #20, #30, #40, #60 and #80. The particles collected in each sieve were weighed and the percentage particles retained was calculated 12.

Percentage yield

The percent yield12 of each batch of formulation was calculated using the following equation.

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

Surface associated drug content

The Famotidine encapsulated microspheres prepared were evaluated for surface associated drug content on the surface of microspheres. From each batch, 100 mg of microspheres were 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. All the experiments were conducted in triplicate (n=3).

Estimation of drug loading/incorporation efficiency

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Drug loaded microspheres equivalent to 40 mg were powdered and suspended in water and then sonicated (Power sonic 505, Hwashin technology co, Korea) for about 20 m. It was shaken for another (Orbitex, Scigenics biotech, India) 20 min for the complete extraction of drug from the microspheres. The mixture was filtered through a 0.45 μm membrane filter (Millipore, Bangalore, India). Drug content was determined by UV- visible double beam spectrophotometer (Ellico SL210, India) at 288 nm. The percent entrapment was calculated using the following equation12.

Total incorporation efficiency =surface associated drug + entrapped drug

Determination of wall thickness

Wall thickness of microspheres was determined by the following equation12.

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

Where, h= wall thickness, r = arithmetic mean radius of microspheres,

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

P = proportion of medicament in microspheres.

Estimation of Famotidine

The content of Famotidine in the microspheres was estimated by a double beam UV spectrophotometer based on the measurement of absorbance at 288 nm in phosphate buffer (pH 7.4). 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.

In vitro 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 microspheres 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 ± 0.50C. A 5 ml sample was withdrawn at specific time intervals and replaced with an equivalent volume of dissolution fluid. Drug content was determined by UV - visible double beam spectrophotometer at 288 nm. The release studies were conducted in triplicate.

In vitro drug release kinetic studies

Kinetic model had described drug dissolution from solid dosage form where the dissolved amount of drug is a function of test time. The exact mechanism of Famotidine release from the microsphere was further studied by kinetic models. The drug release data was analyzed by zero order, first order, Higuchi13, Korsmeyer Peppa's14 and Hixson Crowell15 models. The criteria for selecting the most appropriate model were chosen on the basis of goodness of fit test.

Scanning Electron Microscopy studies

The surface morphology of selected microspheres (F-6) was studied by scanning electron microscopy (SEM) (FE-SEM, Carl Zeiss, Germany). The samples were coated to 200A0 thickness with gold palladium using prior to microscopy.

Accelerated Stability studies

The promising formulation (F-6) was tested for a period of 3 months at different temperature of 400C with 75% RH, for their drug content16.


The Famotidine 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 1320C which is within the reported limit 133.50C. It complies with IP standards thus indicating the purity of the drug sample. The FTIR spectrum of the pure drug was found to be similar to the standard spectrum of Famotidine. It was observed that all the characteristic peaks of Famotidine were present in the pure drug spectrum were present in combination spectra which indicates the compatibility of the drug with the polymers used. The FTIR spectrums were shown in Fig. 1 and 2. The angle of repose of formulated microspheres was ranged from 22.26±0.18 to 28.12±0.250 which indicates the microspheres have excellent flow properties. 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 Loose Bulk density and the tapped Bulk density values were utilized for determining the compressibility Index which was raged from 15.55±0.12 to 28.34±1.15% and the Hausner ratio which was ranged from 0.010±0.001 to 1.176±0.001. These studies revealed the granules have good flow properties. All these values were represented in table 2. The average particle sizes of F-1 to F-6 formulations were Particle size was 615.00, 494.00, 362.00, 562.00, 704.00 and 630.00 μm respectively. The sieve analysis details of Famotidine microspheres were shown in Table 3. The percentage yields of among formulated micro capsules, 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 microspheres was ranged from 15.54±0.02 to 24.16±0.54 μm. The wall thickness of formulated microspheres was found to be increased from F-1 to F-6. All these values were shown in Table 4. In vitro drug release kinetics data studies indicate that the formulations either followed zero order release or the Higuchi release model. Famotidine release from microspheres was diffusion sustained. The in vitro kinetic data (Zero order, First order, Higuchi, Korsmeyer Peppas and Hixson Crowell) was tabulated in Table 5, 6 and represented in Fig. 3, 4, 5, 6 and 7. The accelerated stability revealed that the formulated Famotidine microspheres were stable even at accelerated environmental conditions. The SEM results shows that the microspheres were spherical and with a smooth surface. The SEM photographs were shown in Fig. 8. The results indicate that F-6 formulation showed the slowest release rate while FTIR indicated that there was no drug polymer interaction. The results of accelerated stability study showed the stable nature of the drug. Good entrapment efficiency was observed with formulation F-6. SEM demonstrated the spherical nature of the microspheres and the presence of drug particles on their surface.


The Famotidine microspheres prolonged drug release for 12 h or longer. The formulated Famotidine microspheres reduced the frequency of administration and the dose-dependent side effects associated with the repeated administration of conventional Famotidine tablets. No drug polymer interaction was found and Famotidine was remained stable over a long period of time.


The authors greatly acknowledged the Waksman Selman Pharmaceuticals, Anantapur, India, for the gift sample of Famotidine. The authors are grateful to Indian Institute of Sciences, Bangalore, India for help in performing the characterization studies.