Formulation, Development and Evaluation of Clarithromycin Floating Tablets by Using Synthetic and Natural Polymer for Eradication of Helicobacter Pylori Infection

Oral administration is the most convenient and preferred method for delivering drugs to systemic circulation. Recently, oral controlled release drug delivery has gained interest in the pharmaceutical field due to its therapeutic benefits, including simplified dosing, improved patient compliance, and formulation flexibility. However, drugs that are rapidly absorbed from the gastrointestinal tract and have short half-lives are quickly eliminated from systemic circulation.

Gastro retentive drug delivery systems (GRDDS) extend the retention time of dosage forms in the stomach, enhancing oral bioavailability. These systems provide continuous drug release before the absorption window, supporting optimal bioavailability. The primary advantage of GRDDS is maintaining consistent drug levels over an extended period, making it suitable for sustained drug delivery. Because drug absorption in the gastrointestinal tract is highly variable, prolonging gastric retention increases the time available for absorption. Floating drug delivery systems (FDDS) offer a promising approach for gastric retention.

This approach is particularly advantageous for drugs such as clarithromycin, which is frequently employed in the treatment of infections caused by Helicobacter pylori (H. pylori). Effective therapy for these infections requires prolonged drug contact with the stomach lining. H. pylori, a spiral-shaped, gram-negative bacterium, are a primary cause of chronic gastritis, peptic ulcers, and more severe conditions including gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma.

MATERIALS AND METHODS

MATERIALS

The chief material Clarithromycin and HPMC K100M were provided by Micro-labs limited, Hosur. Locust Bean Gum was purchased from Sha Narendra and Sons, Chennai. Sodium bicarbonate was purchased from SRL private limited Chennai.  Microcrystalline Cellulose was purchased from Yarrow chem product, Mumbai. Magnesium stearate was purchased from Isochem Laboratories, Kochi and Talc was purchased from Spectrum Reagents and Chemicals,

METHODOLOGY

Calibration Curve Of Clarithromycin

Preparation of 0.1 N HCL Solutions:

8.4 ml of concentrated HCL solution was taken in volumetric flask and made up with 1000 ml of distilled water.

Preparation of Standard curve of Clarithromycin:

10 mg of clarithromycin pure drug was dissolved in 10ml of methanol. From this stock solution, 1ml of solution was taken and made up with 10 ml of 0.1N HCL .From here 1 ml was taken and composed with 10 ml of 0.1 N HCL (10µg / ml ).

Aliquoted  the portion of the above solution containing 2, 4, 6, 8, 10µg/ml by using 0.1N HCL. The absorbance of resultant solution was measured at 210 nm by using UV Spectrophotometer taking 0.1 N HCL as blank.

Then plotted a graph of concentration on the x-axis and absorbance on the y-axis, which gives a straight line. Linearity of standard curve was evaluated from the square of correlation coefficient (R²) which determined by least square y= mx + c method of analysis.

Pre-formulation can be defined as an investigation of physical and chemical properties of drug substance alone and when combined with excipients. It is the first step in the rational information useful to the formulator in developing stable and bioavailable dosage forms. The use of pre-formulation parameter maximizes the chances in formulating acceptable, safe, efficacious and stable product. It is one of the important prerequisite in development of any drug delivery system. Pre formulation studies were performed on the drug, which included solubility, melting point, flow properties, compatibility studies.

Organoleptic Properties

The organoleptic properties like color, odor and taste of API were evaluated.

1. Color: A small quantity of clarithromycin was taken in a butter paper and viewed in well illuminated place
2. Odor: Very small quantity of clarithromycin was smelled with the help of nose to get odor
3. Taste: A small quantity of clarithromycin was used to taste with the help of tongue 

Solubility Test:

Assessing the solubility of clarithromycin in ethanol, methanol, acetone and methylene chloride in a test tube and in water. When 10 mg of the medication is taken with 2ml of water ethanol, methanol, acetone, and methylene chloride, the drug's solubility is indicated as being Soluble, slightly soluble.

Evaluation Of Precompression Parameters

Micrometric Properties

Angle Of Repose

The frictional forces in a loose powder or granules can be measured by angle of repose. This is the maximum angle possible between the surface of a pile of powder or granules and the horizontal plane. The powders were allowed to flow through the funnel fixed to a stand so that the lower tip of the funnel was 2.5cm above the surface; a graph paper was placed on a flat surface. The blend was allowed to fall freely on the graph paper through the funnel till the tip of the heap formed just touches the funnel. The height and radius of the heap was noted and from this angle of repose was determined by using following formula,

tan θ = h/r

θ= tan-?(h/r)

where       θ= angle of repose.

 h= height of the pile in cm

 r= radius of the pile in cm.

Bulk Density

The term bulk density refers to a measure used to describe a packaging of particles. It was determined by using a balance and measuring cylinder. Initially the weight of the measuring cylinder was tarred. Then 4g pre-sieved bulk drug were poured into the measuring cylinder using a funnel. Then volume of the powder was taken. Bulk density of the powder was calculated using following formula.

Bulk density = Weight of the powder  Volume occupied by the powder

tapped density

Tapped density was determined by placing a graduated cylinder containing same mass of powder used for bulk density on a mechanical tapper apparatus which is operated for a fixed number of taps (approx100) until powder bed volume has reached a minimum.

Bulk density = Weight of the powder Tapped Volume of powder  

Compressibility Index

Compressibility of a powder can be defined as the ability to decrease in volume under pressure and compatibility as the ability of the powdered material to be compressed into a tablet of specified tensile strength. It can be used to predict the floe properties based on density measurement.

Bulk density = Tapped density-Bulk density Tapped density  ×100

Hausner’s Ratio:

Hausner’s ratio is also used the measure the porosity and the flow ability of the powder. It can be calculated from the bulk and tapped density. Hausner’s ratio is calculated by using the formula

Hausner's ratio = Tapped density Bulk density

Scale Of Flowability:

FTIR spectra for pure drug, physical mixture and optimized formulations were recorded using a Fourier transform Infrared spectrophotometer. The analysis was carried out in Shimadzu-IR Affinity spectrophotometer. The samples were dispersed in KBr and compressed into disc / pellet by application of pressure. The pellets were placed in the light path for recording the IR spectra. The scanning range was 4000 cm^-1 the resolution was 1cm ^-1.

Formulation Of Clarithromycin Floating Tablets By Direct Compression Method

Floating tablets of clarithromycin were prepared by direct compression method.

Direct Compression Method:

Sieving: The active ingredient was passed through the sieve # 40. The other ingredients given in the formulation table were passed separately through the same sieve. Dry mixing all the materials (including the active ingredient) were taken in poly bag and mixed for 10 minutes.

Lubrication: The magnesium stearate was passed through the sieve #60 and mixed together with the powder in a poly bag for 5 minutes to get a uniform blend.

Compression: Finally, the tablet blend was compressed into tablets by using 16 station rotary tablet press which contains punch size of 11 mm in diameter.

Composition Of Clarithromycin Floating Tablets

The compressed tablets were evaluated for the following parameters.

General Appearance

The tablet should be free from cracks, depressions, pinholes etc. The color and polish of the tablets should be uniform on whole surface. The surface of the tablets should be smooth. The tablets were examined externally under a biconvex lens for surface cracks depression and pinholes.

Hardness Test

The strength of a tablet to stand against applied load /pressure is known as hardness. It is also known as crushing strength. Randomly take 5-10 tablets from prepared batch and hardness should be determined by crushing the tablet by hardness tester and then find out the average and standard deviation. Hardness is determined by using hardness tester (Monsanto). The value of hardness was calculated in kg/cm².

Thickness

Twenty tablets from the sample were randomly taken and individual tablet thickness was measured using digital Vernier caliper. Average thickness and standard deviation values were calculated. The thickness was denoted in mm.

Friability

Friability is to measure the extent of tablet breakage during physical stress conditions like packaging, transportation etc. A sample of randomly selected 6 tablets was evaluated for friability using Roche friabilator at 25 rpm for minutes. The % weight loss is calculated by measuring the total weight of 6 tablets before and after operation. Formula for calculating the % weight loss is given below.

%Friability = Initial Weight - Final weight    Initial Weight  ×100  

Weight Variation Test

To study weight variation 20 tablets of each formulation were weighed using an electronic balance, average weights was calculated, individual tablet weights were compared with the average weight. Not more than two individual weights deviate from the average weight by more than the percentage deviation and none should deviate by more than twice that percentage.

%Deviation= Average  Weight -tablet weight Average Weight  ×100

Table 5: Weight Variation of Tablet and Percentage Deviation

The drug content in each formulation was determined by weighing randomly selected tablets pulverizing to a fine powder and powder equivalent to 10 mg of clarithromycin was weighed and dissolved in 10 ml of methanol in volumetric flask using magnetic stirrer, the volume was adjusted to 100ml with 0.1 N HCL. The solution was filtered through a 0.45 µ membrane filter, An aliquot of 1ml solution were diluted to 10 ml of 0.1 N HCL in separate volumetric flask. The absorbance of resultant solution was measured by using UV Visible Spectrophotometer at 210 nm using 0.1N HCL as blank.

In-Vitro Buoyancy Studies:

The In-vitro buoyancy was characterized by floating lag time and total floating time. As per the method described by Rosa et al, the tablets were placed in a 100 ml beaker containing 0.1 N HCL, which was determined at 37°C. The time required for the tablet to rise to the surface of the medium was determined as the buoyancy lag time or floating lag time. The duration of which the dosage form constantly remained on the surface of medium was determined as the total buoyancy time or total floating time.

Swelling Index:

The swelling behavior of a dosage unit was measured by studying its weight gain. The swelling index of tablet was determined by placing the tablets in a beaker containing 250 ml of 0.1 N HCL at 37±0.5°C. The tablets were removed from every one hour from the medium. After draining free water by blotting with tissue paper, these were weighed for weight gain on the analysis balance. Swelling index (SI) was calculated by using following formula;

SI=    Weight of tablet at time-Weight of tablet before immersion  Weight of Tablet before immersion   ×100

In-Vitro Dissolution Studies:

USP 32 (Apparatus 2) paddle method. The dissolution test was performed with 900 ml of 0.1 N HCL, at 37°C and rotated speed at 50 rpm. The test duration was 12 hours. Sampling was carried out after 0.5 hour and then at hourly intervals. A 5ml sample of the solution was withdrawn and replaced with fresh dissolution medium to maintain sink conditions. The filtered samples were diluted with suitable volume of 0.1 N HCL and absorbance of 210nm using UV-Visible spectrophotometer.

RESULTS AND DISCUSSION

Preformulation Studies

Organoleptic Properties:

The Organoleptic properties of Clarithromycin was given in the below table

Table 6: Organoleptic Properties

Solubility Test

Table 7:  Solubility Profile of Clarithromycin

FTIR Spectral Studies:

The FT-IR studies are carried out for pure clarithromycin raw material, Natural polymer (Locust bean gum) and Synthetic polymer ( HPMC K100) and combination of drug and natural polymer and synthetic polymer were carried out to find any interaction between drug and excipients used in the formulation. This study was carried out by IR Spectroscopy (SHIMADZU). The results are given below,

Table 8:  FT-IR Spectral Data of Pure Clarithromycin

Table 9:  FT-IR Spectral Data of HPMC K100

Table 10:  FT-IR Spectrum of Locust Bean Gum

Table 11: FT-IR Spectrum Data of Clarithromycin + HPMC K100

Table 12: FT-IR Spectral Data of Clarithromycin + Locust Bean Gum

Table 13:  FT-IR Spectral Data of Clarithromycin+ HPMC K100 + Locust Bean Gum

DISCUSSION: The FT-IR spectral studies show that the drug is compatible with all the excipients. The FT-IR spectrum of physical mixture shows all the characteristic peaks of Clarithromycin, thus confirming that no interaction of drug occurred with the components of the formulation.

Pre Compression Parameters

Micrometric Properties

The powder blends are evaluated for the micrometric properties such as angle of repose, bulk density, tapped density, compressibility index and hausner’s ratio. The results are given in the below table.

The angle of repose of Formulation ? &? was found to be 24°39’ and 24°19’ which indicates excellent flow property and angle of repose of Formulation ? was found to be 25°66’ which indicates good flow property. The bulk density was found to be between 0.465 to 0.471 g/cm ?, tapped density was found to be between 0.518 to 0.528 g/cm ?, the compressibility index was found in the range of 9.2 to 9.9 % and the Hausner’s ratio lies between 1.100 to 1.105.The above results in the term of micrometric properties reveals that the flow property of Formulation ?, ?, ? was excellent and good.

Post Compression Parameters

General Appearance

Table 15: General Appearance of the Formulations

Other Parameters

Table 17: Swelling Index of Clarithromycin

The Swelling Percentage of clarithromycin tablets was found in the range between 90 to 95%.

Invitro Buoyancy

Test

Assay Of Clarithromycin by UV Spectroscopy Method

The assay of clarithromycin floating tablets was done by UV spectroscopy method as per the procedure given in the methodology. The assay values of the clarithromycin floating tablets are given in the below table.

Table 19: Assay of Clarithromycin by UV method

DISCUSSION

The assay of clarithromycin floating tablets was found in the range between 90.28% and 103%. As per I.P. the acceptable limit of the clarithromycin floating tablets is90 to110%. The above results revealed that the assay of Clarithromycin was within the acceptable limit(90-110%)s.

In Vitro Dissolution Studies

The In Vitro drug release of the clarithromycin floating tablets were given in the table

Table 20:  In-vitro dissolution release of clarithromycin floating tablets

Percentage Drug Release of Clarithromycin Floating Tablet