Formulation and Invitro - Evaluation of Gastroretentive Floating Tablets of Metformin Hydrochloride

The primary goal of this research is to develop floating tablets containing Metformin Hydrochloride. This will be achieved by utilizing both synthetic and natural polymers and employing the direct compression method. The study involves a structured work plan: first, conducting pre-formulation studies (including organoleptic properties and solubility); second, formulating the floating tablets via direct compression; and finally, evaluating the formulated tablets against several pharmaceutical parameters (Tablet thickness, hardness, friability, weight variation, in vitro buoyancy, swelling index, assay and in vitro dissolution).

Oral delivery is the most user-friendly and favored method for getting medications into the general blood flow. Lately, oral controlled-release drug administration has captured attention in the pharmaceutical sector because of its therapeutic advantages, such as simpler dosing regimens, better patient adherence and versatility in formulation. Nonetheless, drugs that are quickly taken up by the gastrointestinal system and possess short elimination half-lives are rapidly cleared from the systemic circulation.

?Gastro-retentive drug delivery systems (GRDDS) prolong the swelling time of dosage forms in the stomach, thereby boosting oral bioavailability. These systems ensure ongoing drug liberation before the absorption site, which supports maximum bioavailability. The main benefit of GRDDS is sustaining steady drug concentrations over an extended duration, making them well-suited for prolonged drug release. Since drug absorption in the GI tract is highly inconsistent, extending gastric residency increases the period available for absorption. Floating drug delivery systems (FDDS) present a potential method for achieving gastric retention.

MATERIALS AND METHODS

MATERIALS

The chief material Metformin hydrochloride was provided by Strides Pharma Science Ltd, Bengaluru. HPMC K 100, HPMC K15 was purchased from Micro – labs Ltd, Hosur. Guar Gum was purchased from Sha Narendra and Sons, Chennai. Carbomer, Magnesium stearate and Lactose was purchased from Isochem Laboratories, Kochi.  Polyvinylpyrrolidone was purchased from Sisco Research Laboratories Pvt. Ltd, Taloja. Sodium bicarbonate was purchased from SRL Pvt. Ltd, Chennai and Citric acid and Talc was purchased from Spectrum Reagents and Chemicals, Kochi.

METHODOLOGY

CALIBRATION CURVE OF METFORMIN HYDROCHLORIDE

Preparation of Standard Curve of Metformin Hydrochloride:

10 mg of metformin hydrochloride pure drug was dissolved in water. From this stock solution 10 ml of solution was taken and made up with 100 ml of water. From here 10 ml was taken and composed with 100 ml of water (10μg/ml).

Aliquoted the portion of above solution containing 0.1,0.2,0.3,0.4,0.5μg/ml by using water. The absorbance of resultant solution was measured at 232 nm by using UV Spectrophotometer taking water as blank.

Then plotted graph of concentration on x-axis and absorbance on 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.

Table 1:  Standard Calibration Curve Data of Metformin Hydrochloride

Standard Calibration Curve of Metformin Hydrochloride

Figure 1:  Standard Curve of Metformin Hydrochloride

PREFORMULATION STUDIES

Pre-formulation studies involve the investigation of physical and chemical properties of the drug substance, both alone and in combination with excipients. It is the first and most essential step in the rational design of dosage forms.

The data obtained from Pre-formulation studies assist the formulator in developing a stable, safe and bio available product. Proper understanding of these parameters enhances the chances of formulating an acceptable and effective dosage form.

Pre-formulation is therefore considered a prerequisite for the development of any drug delivery system. The studies carried out on the drug included:

• Solubility
• Melting point
• Flow properties
• Compatibility studies

ORGANOLEPTIC PROPERTIES

The organoleptic properties such as colour, odour and taste of the Active Pharmaceutical Ingredient (API) were evaluated.

A) Colour: A small quantity of Metformin Hydrochloride was placed on a butter paper and observed under a well-illuminated area to determine its colour.

B) Odour: A very small quantity of Metformin Hydrochloride was smelled carefully to identify its characteristic odour.

C) Taste: A small quantity of Metformin Hydrochloride was tasted cautiously with the help of the tongue to determine its taste characteristics.

SOLUBILITY TEST

The solubility of a drug is defined as the amount of drug that dissolves in a given quantity of solvent to produce a saturated solution at a constant temperature and pressure. Solubility is an important physicochemical property influencing drug absorption and bioavailability.

EVALUATION OF PRECOMPRESSION PARAMETERS

MICROMERITIC PROPERTIES

ANGLE OF REPOSE

The angle of repose is a measure of the internal frictional forces between particles in a powder or granule. It represents the maximum angle possible between the surface of a pile of powder and the horizontal plane.

In this method, the powder blend was allowed to flow freely through a funnel fixed to a stand such that the lower tip of the funnel was positioned 6 cm above a flat surface. A sheet of graph paper was placed on the surface to facilitate measurement. The powder was allowed to fall until the tip of the heap formed just touched the funnel.

The height (h) and radius (r) of the heap were measured and the angle of repose (θ) was calculated using the following formula:

tan θ = (h/r)

θ = tan^-1 (h/r)

Where:

θ = Angle of repose

h = Height of the pile (cm)

r = Radius of the pile (cm)

BULK DENSITY

Bulk density is defined as the mass of powder per unit bulk volume, including the spaces between particles. It is an important parameter indicating the packaging and flow properties of powders.

To determine bulk density, a pre-weighed measuring cylinder was used. A specific quantity (e.g., 4 g) of pre-sieved powder was carefully transferred into the cylinder using a funnel and the volume occupied by the powder was recorded.

The bulk density was then calculated using the formula:

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

TAPPED DENSITY

Tapped density was determined by placing a known mass of powder into a graduated cylinder. The cylinder was then mechanically tapped using a tapper apparatus (approximately 100 taps) until a constant volume was obtained.

The final volume after tapping represents the tapped volume, which is used to calculate the tapped density.

Tapped density =Weight of the powder Tapped volume of the powder

COMPRESSIBILITY INDEX

The compressibility of a powder can be defined as its ability to decrease in volume under pressure. It also indicates the capability of the powdered material to be compressed into a tablet of specified tensile strength. The compressibility index is a useful parameter for predicting the flow properties of powders based on their bulk and tapped densities.

The compressibility index (Carr’s Index) is calculated using the following formula:

Compressibility Index = Tapped density - Bulk density  Tapped density  X 100

HAUSNER’S RATIO

The Hausner’s ratio is another important parameter used to evaluate the flow ability and porosity of powder materials. It is derived from the ratio of tapped density to bulk density. Lower Hausner’s ratio values indicate better flow properties, while higher values suggest poor flow characteristics.

Hausner’s Ratio = Tapped Density / Bulk Density

Table 2: Scale of Flowability

FOURIER TRANSFORM INFRARED SPECTROSCOPY (FTIR)

FTIR spectra of the pure drug, physical mixture and optimized formulations were recorded using a Fourier Transform Infrared (FTIR) spectrophotometer (Shimadzu IR Affinity Spectrophotometer). The analysis was performed by dispersing the samples in KBr and compressing them into pellets under pressure. These pellets were placed in the light path for recording the IR spectra. The scanning range was from 4000 cm?¹ to 400 cm?¹, with a resolution of 1 cm?¹.

FORMULATION OF METFORMIN HYDROCHLORIDE FLOATING TABLETS BY DIRECT COMPRESSION METHOD

Floating tablets of Metformin Hydrochloride were prepared using the direct compression method as described below.

PROCEDURE

1. SIEVING

The active pharmaceutical ingredient (API) was passed through sieve no. 40. All other excipients mentioned in the formulation table were also passed through the same sieve. The sieved materials were then dry-mixed in a poly bag for 10 minutes to obtain a uniform mixture.

2. LUBRICATION

Magnesium stearate was passed through sieve no. 60 and then added to the pre-mixed powder blend. The mixture was further blended in a polybag for 5 minutes to ensure proper lubrication and uniformity.

3. COMPRESSION

The final blend was compressed into tablets using a 16-station rotary tablet press equipped with 11 mm flat-faced punches. The resulting tablets were collected and stored in airtight containers for further evaluation.

COMPOSITION OF METFORMIN HYDROCHLORIDE TABLET

Table 3: Composition Of Metformin Hydrochloride Tablets

POST-COMPRESSION PARAMETERS

The prepared tablets were evaluated for the following post-compression parameters to ensure their physical quality and mechanical integrity.

GENERAL APPEARANCE

The tablets were visually inspected for any physical defects such as cracks, depressions or pinholes. The colour, shape and surface finish of the tablets were observed to ensure uniformity and smoothness. A good-quality tablet should be free from visible defects and its surface should be uniform, polished and smooth. Examination was carried out externally under a biconvex lens to detect any surface irregularities such as cracks, depressions or pinholes.

HARDNESS TEST

The hardness of a tablet indicates its ability to withstand mechanical shocks during handling, packaging and transportation. It is also referred to as the crushing strength of the tablet. For this test, 5 to 10 tablets were randomly selected from each batch and tested using a Monsanto Hardness Tester. The hardness was expressed in kg/cm² and the mean value along with the standard deviation was calculated.

THICKNESS

The thickness of tablets ensures uniformity in tablet size, which is essential for dose uniformity and packaging compatibility. A sample of 20 tablets was randomly selected and the thickness of each tablet was measured using a digital Vernier caliper. The average thickness and standard deviation were calculated and the results were expressed in millimeters (mm).

FRIABILITY

Friability testing evaluates the ability of tablets to resist mechanical stress such as abrasion or breakage during processes like handling, packaging and transportation. A sample of 6 tablets was randomly selected and tested using a Roche Friabilator operated at 25 rpm for 4 minutes. The percentage weight loss was calculated by measuring the total weight of the tablets before and after the test. The % Friability was calculated using the formula below.

% Friability =  Initial weight - Final weight   Initial weight X 100

Note: A friability value of less than 1% was considered acceptable for compressed tablets.

WEIGHT VARIATION TEST

To determine weight uniformity, 20 tablets from each formulation batch were individually weighed using an electronic balance. The average tablet weight was calculated and the individual weights were compared with this average value. According to pharmacopeial standards, not more than two individual tablets should deviate from the average weight by more than the percentage deviation specified and none should deviate by more than twice that limit.

% Deviation=Average Weight – Individual Tablet WeightAverage Weight X 100

Table 4: Weight Variation of Tablets and Percentage Deviation

DRUG CONTENT OF METFORMIN HYDROCHLORIDE:

The drug content uniformity for each formulation was evaluated to ensure accurate dosage in every tablet. A quantity of tablets equivalent to 10 mg of Metformin Hydrochloride was accurately weighed, finely powdered and transferred into a 100 ml volumetric flask containing 100 ml of water. The mixture was stirred magnetically until complete dissolution and then the volume was made up to 100 ml with water. The resulting solution was filtered. From this 1 ml of filtrate was further diluted to 100 ml with water in a separate volumetric flask. The absorbance of the final solution was measured using a UV–Visible Spectrophotometer at 232 nm, employing distilled water as the blank.

IN-VITRO BUOYANCY STUDIES

The in-vitro buoyancy behavior of the floating tablets was characterized by measuring two parameters:

• Floating Lag Time (FLT) – the time taken for a tablet to rise to the surface of the medium.
• Total Floating Time (TFT) – the duration for which the tablet continuously remains afloat.

The study was carried out as per the method described by Rosa et al. The tablets were placed in a 100 ml beaker containing 0.1 N HCl maintained at 37 ± 0.5 °C. The floating lag time was recorded as the time required for the tablet to emerge on the surface and the total floating time was noted as the period the tablet remained buoyant on the surface of the dissolution medium.

SWELLING INDEX

The swelling behavior of the floating tablets was evaluated by measuring their weight gain over time. Tablets were individually placed in a beaker containing 250 ml of 0.1 N HCl maintained at 37 ± 0.5°C to simulate gastric conditions. At predetermined time intervals (every 1 hour), the tablets were carefully removed from the medium, gently blotted with tissue paper to remove excess surface water and then weighed. The increase in tablet weight indicated the extent of swelling.

The Swelling Index (SI) was calculated using the following formula:

SI= Weight of Tablet at Time - Weight of Tablet Before Immersion Weight of Tablet Before Immersion X 100

IN-VITRO DISSOLUTION STUDIES

The in-vitro dissolution study was conducted to evaluate the drug release profile of Metformin Hydrochloride floating tablets. The test was performed using a USP Type II (Basket) apparatus containing 900 ml of 0.1 N HCl maintained at 37 ± 0.5°C, with the basket rotated at 50 rpm.

The total duration of the dissolution test was 6 hours. Samples (1 ml each) were withdrawn at predetermined time intervals - initially at 0 hour and subsequently at 1-hour intervals. Each time, the withdrawn volume was replaced with an equal amount of fresh dissolution medium to maintain sink conditions.

The collected samples were filtered and appropriately diluted with 0.1 N HCl and the absorbance of each sample was measured at 232 nm using a UV-Visible Spectrophotometer. The cumulative percentage drug release was then calculated based on the absorbance values.

ORGANOLEPTIC PROPERTIES

The Organoleptic Properties of Metformin Hydrochloride was given in the below table

Table 5:  Organoleptic properties

SOLUBILITY TEST

Table 6:  Solubility profile of Metformin Hydrochloride

FTIR SPECTRAL STUDIES

The FT-IR studies were carried out for pure Metformin Hydrochloride raw material, a natural polymer (Guar gum) and a synthetic polymer (HPMC K100, HPMC K 15, Carbomer). The spectra of the drug, polymers and their combinations were evaluated to determine any possible interactions between the drug and the excipients used in the formulation. The analysis was performed using IR Spectroscopy (SHIMADZU). Results are given below,

Figure 2:  FT-IR Spectrum of Pure Metformin Hydrochloride

Figure 3: FT- IR Spectrum of HPMC K100

Figure 4:  FT- IR Spectrum of HPMC K15

Figure 5:  FT- IR Spectrum of Guar gum

Figure 6:  FT- IR Spectrum of Carbomer

Figure 7: FT- IR Spectrum of Pure Metformin Hydrochloride + HPMC K100

Figure 8: FT- IR Spectrum of Pure Metformin Hydrochloride + HPMC K15

Figure 9: FT- IR Spectrum of Pure Metformin Hydrochloride + Guar gum

Figure 10: FT- IR Spectrum of Pure Metformin Hydrochloride + Carbomer

DISCUSSION

The FT-IR analysis indicates that the drug is compatible with all the excipients. The FT-IR spectrum of the physical mixture displays all the characteristic peaks of Metformin Hydrochloride confirming that no interaction has taken place between the drug and the formulation components.

PRE COMPRESSION PARAMETERS

MICROMETRIC PROPERTIES

The powder mixtures were assessed for various micromeritic parameters, including angle of repose, bulk density, tapped density, compressibility index and Hausner’s ratio. The findings are presented in the table below.

Table 7:  Pre-compression parameters

DISCUSSION

The angle of repose for Formulations I and III was measured as 24°13' and 27°40' respectively indicating excellent flow characteristics. Formulations II and IV showed angles of 33°69' and 30°93’ demonstrating good flow behavior.

The bulk density values ranged from 0.555 to 0.666 g/cm³, while the tapped density varied between 0.666 and 0.769 g/cm³. The compressibility index was observed within 11.6–16.6% and the Hausner ratio fell between 1.132 and 1.200.

Overall, these micromeritic evaluations confirm that Formulations I, II, III and IV exhibit good to excellent flow properties.

POST COMPRESSION PARAMETERS

GENERAL APPEARANCE

The general appearance of all formulations was examined and found as follows

Table 8:  General Appearance of the Formulations

OTHER PARAMETERS

Table 9:  POST COMPRESSION PARAMETERS

Table 10: Swelling Index of Metformin Hydrochloride

.Figure 11: INVITRO BUOYANCY TEST

DISCUSSION

The hardness of the Metformin Hydrochloride floating tablets was evaluated and found to be in the range of 6.2 to 6.4 kg/cm² indicating that the tablets possess adequate mechanical strength and sufficient hardness to withstand handling and transportation. All the formulations of the Metformin Hydrochloride floating tablets successfully passed the weight variation test and the obtained values remained within the acceptable pharmacopeial limits.

The friability results of the Metformin Hydrochloride floating tablets showed less than 1% weight loss confirming that all the formulations complied with the friability requirements and exhibited good resistance to abrasion.

The thickness of the tablets was measured and found to be in the range of 5.14 mm to 5.16 mm indicating uniformity across all formulations.

The swelling index of the Metformin Hydrochloride floating tablets was observed to be in the range of 90% to 95%, which ensures adequate matrix expansion required for maintaining buoyancy and controlled drug release.

ASSAY OF METFORMIN HYDROCHLORIDE BY UV SPECTROSCOPY METHOD

The assay of Metformin Hydrochloride floating tablets was done by UV Spectroscopy method as per the procedure given in the methodology.

The assay values of the Metformin Hydrochloride floating tablets are given in the below table.

Table 11: Assay of Metformin Hydrochloride by UV method

DISCUSSION

The assay values of the Metformin Hydrochloride floating tablets were observed to range from 92.18% to 95.86%. According to the I.P., the permissible limit for Metformin Hydrochloride floating tablets is 90–110%. These findings indicate that the assay results of Metformin Hydrochloride fall within the acceptable range.

IN-VITRO DISSOLUTION STUDIES

The In-Vitro drug release of the Metformin Hydrochloride floating tablets.

Table 12:  In-Vitro dissolution release of Metformin Hydrochloride floating tablets

Percentage Drug Release of Metformin Hydrochloride Floating Tablet

Figure 12:  In-Vitro Drug Release of Metformin Hydrochloride Floating Tablet