Formulation and Evaluation of Metformin HCL Gastroretentive Floating Sustained Released Tablet

The oral route of drug administration is widely preferred due to its higher patient acceptance and convenience. The Metformin HCl sustained-release floating tablet was formulated using the wet granulation method. These tablets are designed to float on the surface of a liquid medium, achieving a density of less than 1. The formulation incorporates both effervescent and non-effervescent systems. In the non-effervescent system, swellable polymers such as Hydroxypropyl Methylcellulose (HPMC) K 100 and Xanthum Gum are responsible for the tablet’s buoyancy. In the effervescent system, the presence of Sodium Bicarbonate (acting as a base) reacts with gastrointestinal fluids, generating effervescence, which further decreases the tablet’s bulk and enhances its floating property. This formulation is designed for sustained and prolonged drug release over an extended period. Metformin HCl, an antihyperglycemic agent, is primarily utilized for the management of Type 2 Diabetes Mellitus by reducing blood glucose levels.

Metformin Hydrochloride Profile

1. 1. Chemical Name:
   • IUPAC Name: 1,1-Dimethylbiguanide hydrochloride
   • Molecular Formula: C4H11N5•HCl
   • Molecular Weight: 165.63 g/mol

• Chemical Structure:

2. Physical Appearance:
   • White or almost white, crystalline powder.
   • Odorless or slightly bitter taste.
3. Solubility:
   • Soluble in water, practically insoluble in organic solvents like ethanol and    chloroform.
4. Pharmacological Classification:
   • Antidiabetic drug (Biguanide class).
5. Mechanism of Action:
   • Reduces hepatic glucose production.
   • Increases insulin sensitivity by enhancing peripheral glucose uptake.
   • Decreases intestinal glucose absorption.
6. Therapeutic Indications:
   • Type 2 Diabetes Mellitus, especially in overweight or obese patients, as part of a broader treatment plan (lifestyle modification, diet, and exercise).
7. Dosage:
   • Typical initial dose: 500 mg to 850 mg once or twice a day, with or after meals.
   • Maintenance dose: Can go up to 2,000–2,500 mg daily, divided into 2–3 doses.

Medicinal Uses of Metformin HCL:

1. Treatment of Type 2 Diabetes Mellitus

Metformin is most commonly used for the management of Type 2 Diabetes, a condition where the body becomes resistant to insulin, leading to high blood glucose levels. Metformin helps by:

• Reducing hepatic glucose production (liver’s production of glucose).
• Increasing insulin sensitivity in peripheral tissues, such as muscle and fat, allowing the body to use glucose more effectively.
• Decreasing intestinal glucose absorption, which helps in reducing postprandial (after-meal) blood glucose spikes.

2. Polycystic Ovary Syndrome

Metformin is sometimes used off-label to treat Polycystic Ovary Syndrome (PCOS), a condition characterized by insulin resistance, irregular periods, and elevated androgen levels. In PCOS, Metformin can help:

• Improve insulin sensitivity.
• Regulate menstrual cycles.
• Lower testosterone levels, which can reduce symptoms such as acne and excess hair growth.
• Improve fertility in women with PCOS.

3. Gestational Diabetes

Metformin is occasionally used to manage gestational diabetes, a condition of high blood sugar during pregnancy. It is usually prescribed when lifestyle changes such as diet and exercise are insufficient to control blood glucose levels.

4. Prevention of Type 2 Diabetes

Metformin may be prescribed to individuals with pre-diabetes (a condition where blood glucose levels are higher than normal but not yet in the diabetic range). Metformin can help delay or prevent the onset of Type 2 Diabetes, especially in people who are overweight or obese.

5. Weight Management

In some cases, Metformin is used off-label to assist with weight loss in patients who are obese or overweight. Although it is not approved solely as a weight loss medication, it may help reduce appetite and lower body weight, particularly in individuals with insulin resistance or metabolic syndrome.

6. Cardiovascular Benefits

There is emerging evidence suggesting that Metformin may have cardiovascular benefits, particularly in people with diabetes. Some studies indicate that Metformin may:

• Reduce the risk of cardiovascular events (heart attacks, strokes) in diabetic patients.
• Improve lipid profiles, such as lowering LDL cholesterol and triglycerides.

7. Cancer Prevention

Early research suggests that Metformin may have potential anti-cancer effects. Some studies indicate that Metformin may slow the growth of certain types of cancer cells, particularly in individuals with Type 2 Diabetes. However, more clinical research is needed before it can be recommended as a cancer treatment.

Authentication Parameters

Melting Point Determination

The determination of the melting point is an essential preformulation parameter that indicates the temperature at which a solid transition into a liquid under atmospheric pressure. At the melting point, the solid and liquid phases exist in equilibrium. The melting point of Metformin HCl was determined using two different methods: the conventional method and the digital method. Melting point is Melting Point (?c) 223 - 225?c and standard is 223 - 226?c.

Log P Value Determination

The Log P value, which reflects the partitioning of a drug between an organic solvent and water, is determined using the partition coefficient method. In this procedure, 1 g of the drug is added to a separating funnel containing 25 ml of octanol and 25 ml of water in equal volumes. The funnel is shaken for 20-25 minutes, and the mixture is allowed to stabilize. After stabilization, the aqueous phase is separated and filtered. The absorbance of the filtrate is measured, and the Log P value is calculated as the ratio of the drug's concentration in the water phase to its concentration in the organic (octanol) phase. Log p Value is 0.4 and standard is 0.5

Solubility Studies

Solubility is defined as the maximum amount of solute that can be dissolved in a given volume of solvent to form a homogeneous solution at a specific temperature and pressure, resulting in a saturated solution. Solubility of drug in Water 16.99.

Procedure:

• Various solutions are prepared using the following solvents: water, pH 1.2 acidic buffer, pH 6.8 phosphate buffer, and pH 7.4 phosphate buffer.
• The drug is added to each of these solutions until a supersaturated solution is formed.
• The mixtures are placed on an orbital shaker for 24 hours. After this period, the mixture is filtered, and the filtrate is collected for absorbance measurements.
• The concentration of the drug solubilized in each solution is then determined.

MATERIAL AND METHODS

Table of Ingredients:

Table 1: Table of Ingredients

Trial 1:  Formulation Table

Table 2: Formulation Table

METHODOLOGY:

1. Selection of Ingredients and Weighing

• The following ingredients are selected and weighed accurately:
  • Metformin HCl (the active pharmaceutical ingredient).
  • HPMC K100 (Hydroxypropyl Methylcellulose K100, a polymer for sustained release and floating property).
  • Xanthan Gum (a natural polysaccharide used as a binder and stabilizer).
  • Sodium Bicarbonate (used in the effervescent system for the floating mechanism).
• The weighed components are transferred to a mortar and pestle for proper mixing and uniform distribution of all ingredients.

2. Preparation of Binder Solution

• A binder solution is prepared using PVP K30 (Polyvinyl Pyrrolidone K30) as the binder, which helps in the cohesion of granules.
  • Preparation of Binder Solution:
    • 0.11 gm of PVP K30 is dissolved in 1.5 ml of Isopropyl Alcohol (IPA).
    • The solution is thoroughly mixed until a homogeneous binder solution is obtained.
• This binder solution is gradually added to the mixed dry powders (Metformin HCl, HPMC K100, Xanthan Gum, Sodium Bicarbonate) to form a dough-like mass.

3. Formation of Granules

• The dough mass, once formed, is passed through a 12-mesh sieve to break the mass into smaller granules.
• The granules are then dried in an oven at a temperature of 40-50°C for about 10–15 minutes to remove excess moisture and ensure uniformity in size.
• After drying, the granules should be checked for uniform size and moisture content.

4. Addition of Lubricant and Sieving

• After drying, Talc (a common lubricating agent) is added to the granules. This helps reduce friction during tablet compression and ensures smooth ejection from the die.
• The mixture containing the lubricant is passed through a 40-mesh sieve to obtain fine, uniform granules.
• The sieved granules are then ready for compression.

5. Compression of Tablets

• The granules are compressed into tablets using a tablet punching machine. The compression is carried out using an 8-station single or multi-rotary tablet punching machine.
  • Tablet Weight and Compression Force: The formulation is compressed into tablets of the required weight, with a hardness appropriate for the intended use.
  • The machine settings (e.g., compression force, punch size) should be optimized to ensure proper tablet hardness, shape, and appearance.

Observation: The First Trial is failed due to Cracking of tablets, so decided addition of Xanthum Gum