Formulation and Evaluation of Fast Disintegrating Tablet of Atenolol Using Modified Okra Gum as Natural Super Disintegrant

Fast dissolving drug delivery systems

(FDDDS) are formulations designed to disintegrate or dissolve rapidly in the oral cavity, allowing for quick drug release and absorption. These systems are particularly beneficial for patients who may have difficulty swallowing tablets or capsules, such as paediatric and geriatric populations, as well as those with certain medical conditions. (Jadhav SD et al., 2012) These were first came into existence in 1970 as an alternative to tablets, syrups and capsules, for pediatric and geriatric patients which rapidly disintegrate and dissolve in saliva and then easily swallowed without need of water which is a major benefit over conventional dosage form The FDTs dissolve or disintegrate within 60 seconds when placed in the mouth without drinking or chewing. The active ingredients are absorbed through mucous membranes in the mouth and GIT and enter the blood stream. But due to certain disadvantages of fast dissolving tablets like: their physical solid form, sometimes difficult to carry, store and handle, leave unpleasant taste/grittiness in mouth if not formulated properly. Psychological fear of swallowing, chewing or choking, low pressure moulded tablets fabricated by different manufacturing methods and their expensive packaging cost.

• 1. Advantages of fast dissolving drug delivery systems
• Ease of Administration: FDDDS typically eliminates the need for water or other liquids for administration. This is particularly advantageous for patients who may have difficulty swallowing tablets or capsules, such as pediatric, geriatric, or bedridden patients. Suitable for patients with swallowing disorders, dysphagia, or those who experience difficulty in ingesting traditional oral dosage forms.
• Improved Patient Compliance: The convenience of fast dissolving formulations enhances patient compliance. Patients are more likely to adhere to their medication regimens when the dosage form is easy to use and doesn't require additional steps like swallowing with water. Particularly beneficial for individuals who have an aversion to swallowing pills.
• Rapid Onset of Action: FDDDS allows for quick drug release and absorption due to the rapid dissolution or disintegration of the dosage form in the oral cavity. Suitable for drugs where rapid onset of action is crucial, such as analgesics or anti-allergic medications.
• Improved Bioavailability: The rapid dissolution of drugs in FDDDS can enhance their bioavailability. This is important for drugs with low solubility or those that undergo significant first-pass metabolism. Enhanced absorption can lead to improved therapeutic outcomes.
• Convenience for Caregivers: Caregivers, including healthcare professionals or family members, find FDDDS convenient to administer to patients who may have difficulty taking conventional tablets or capsules. Reduces the need for assistance in administering medications, especially in non-hospital settings.
• Discreet and Portable: FDDDS often comes in discreet packaging and is easily portable. This is beneficial for patients who need to take medications outside their homes or in public places. Convenient for patients with busy lifestyles or those who may need to carry medications with them.
• Taste Masking: Many FDDDS formulations are designed with taste-masking technologies, making them more palatable and improving patient acceptance. Especially important for pediatric patients who may resist medication due to unpleasant taste.
• Reduced Risk of Choking: Since FDDDS dissolves or disintegrates rapidly in the mouth, there is a lower risk of choking compared to traditional solid dosage forms. It's important to note that while FDDDS provides these advantages, the choice of the appropriate formulation depends on the specific drug, patient population, and therapeutic requirements. Additionally, considerations such as stability, manufacturing processes, and cost-effectiveness play a role in the development and adoption of fast dissolving drug delivery systems.

MATERIALS AND METHOD

MATERIALS

Atenolol was procured as a gift sample from Medrich Ltd. Bangalore. Okra, Sodium starch glycolate, Magnesium stearate, mannitol, talc, meglumine and MCC used were of analytical grade. All the ingredients and their uses in formulation of tablet were shown in Table no. 1.

Table no. 1: Ingredients used in formulation of tablet

METHODS

Preformulation studies

UV spectrophotometric analysis

Lambda max is the wavelength of light in the ultraviolet region at which maximum absorbance is exhibited by the compound. Sample was dissolved in water to prepare stock solution and scan in UV spectrophotometer. Atenolol was estimated by UV visible spectroscopy. Spectrophotometric estimation of atenolol was carried out in pH 6.8. The study was carried out in triplicates. 100mg of drug was placed in volumetric flask and dissolved in pH 6.8 buffer. From this solution, 10 ml solution was withdrawn and further diluted to 100 ml with buffer to yield the standard stock solution of atenolol (100 µg/ml).

Melting point

Melting point is one of the identification tests for organic compounds. The melting point of the drug was determined by capillary melting point method using melting point apparatus (Tempo, India). The drug was filled in a thin-walled capillary tube, with sealed one end. The capillary was then placed in melting point apparatus and the temperature of the apparatus was gradually increased. The temperature range over which the drug melts was observed.

Solubility

The solubility studies of drug in aqueous and non-aqueous phases are the important properties during formulation consideration and behaviour and transport of drugs in the body. Equilibrium solubility was determined at room temperature, for this, systems of each solvent (DW, Ether, Chloroform, Methanol, Ethanol & PBS pH 6.8) were taken individually in volumetric flask and drug was added gradually in each solvent and vigorously shaken on shaker. As the saturation point was reached a pinch of drug was added to it and the flask was shaken for 15min and placed in the flask shaker for 24 hrs. After 24 hrs it was removed and observed. Since un-dissolved drug was found it was kept for 24hrs undisturbed. After 24 hrs, the solution was filtered and diluted suitably with reagent blank and absorbance was taken against reagent blank and recorded.

Preparation of standard calibration curves

10 mg of atenolol was weighed accurately and transferred to 100 ml volumetric flask and dissolved in small amount of water, after that volume was made up to 100 ml with water so as to obtain stock solution of 100 µg/ml. Stock solution was taken in aliquots of 0.1 ml, 0.2 ml, up to 0.5 ml in to a series of 10 ml volumetric flasks and volume was made up to the mark with water. The solutions were filtered through Whatman filter paper no. 1 and filtrate was analyzed at λmax 225nm using UV visible spectrophotometer. water was used as blank solution. The standard curve was plotted between absorbance and concentration.

Drug- excipients compatibility studies

Drug excipients compatibility study was done by using I.R. spectroscopy different mixtures of drug and carrier were prepared and analysed by I.R. in the range of 400- 4000 cm-1. Small amount of sample was taken and analysed by placing it in powder sample compartment and it was check for any interaction between drug and excipients. (Badola et al., 2015)

Extraction and isolation of okra mucilage Method of extraction:

Okra was obtained from local market. Collected okra was carefully washed and dried under shade for 24 h, further dried at 30– 40°C until constant weight was obtained. Size was reduced through grinder. Powdered fruit passed through sieve no. #22 and stored it in air tight container for further use. Extraction of mucilage includes two steps

Step 1: Extraction of mucilage: powdered fruit kept in 500ml of distilled water. Heated with stirred continuous at 60°C for approximately 4h. Concentrated solution has filtrated through muslin. Cloth and cool at 4°C-6°C

Step 2: Isolation of Mucilage: Extracted gum has isolated in acetone. This allows filtration through muslin cloth. Washed with acetone and the mucilage filtrated through muslin cloth. Pressed mucilage was further dried to constant weight at 35–45°C in hot air oven. Hard mucilage cake was grinded and sieved through sieve # 22, stored in desiccators for further used. (Farooq U et al., 2013) and X2) represent the average result of changing 1 factor at a time from its low to high value. The interaction terms (X1X2) show how the response changes when 2 factors are simultaneously changed. The polynomial terms (X1X1 and X2X2) are included to investigate nonlinearity. The results were shown in Table no. 2 (Hardenia S et al., 2016)

Table no. 2: Formulation of different formulation of atenolol fast disintegrating tablet

Precompression parameters

Angle of Repose: Angle of repose was determined using funnel method. The blend was poured through funnel that can be raised vertically until a maximum cone height (h) was obtained. Radius of the heap (r) was measured and angle of repose was calculated using the formula

Tan ? = h/r ? = tan-1 h/r

Where, θ is the angle of repose, h is height of pile; r is radius of the base of pile.

Bulk Density: Apparent bulk density (Db) was determined by pouring the blend into a graduated cylinder. The bulk volume (Vb) and weight of powder (M) was determined. The bulk density was calculated using the formula

Db = M/Vb

Tapped Density: The measuring cylinder containing known mass of blend was tapped for a fixed time. The minimum volume (Vt) occupied in the cylinder and weight (M) of the blend was measured. The tapped density (Dt) was calculated using the following formula

Dt= M/Vt

Carr’s Compressibility Index: The simplest way of measurement of free flow of powder is compressibility, an indication of the ease with which a material can be induced to flow is given by compressibility. The compressibility index of the granules was determined by Carr’s compressibility index, which is calculated by using the following formula

I = Dt-Db/Dt×100

Hausner Ratio: Hausner ratio is an indirect index of ease of powder flow. It is calculated by the following formula

Hausner ratio= Dt/Db

Where Dt is tapped density and Dd is bulk density. (Lachman, Lieberman'S 1987)

Evaluation of tablets

Hardness

Hardness of tablet is defined as the force applied across the diameter of the tablet in the order to break the tablet. It is done by using hardness tester like Pfizer hardness tester or Monsanto tablet hardness tester.

Thickness

Thickness of tablets is determined using Vernier caliper. An average value is calculated by using tablets in triplicate and then the mean ± standard deviation values of thickness are notified.

Friability

Friability is measured of mechanical strength of tablets. Roche friabilator is used to determine the friability by following procedure. A reweighed tablet is placed in the friabilator. Friabilator consist of a plastic chamber that revolves at 25 rpm, dropping the tablets at a distance of 6 inches with each revolution. The tablets are rotated in the friabilator for 4 minutes for 100 revolutions. At the end of test, tablets are reweighed; the loss in the weight of tablet is the measure of friability and is expressed in percentage as;

% Friability= initial weight- final weight/ initial weight* 100

Weight variation:

The tablets were selected randomly from each formulation and weighed individually to check for weight variation. The U.S Pharmacopoeia allows a little variation in the weight of a tablet. The following percentage deviation in weight variation is allowed (Table no. 3).

Table no. 3: Percentage deviation in weight variation

Disintegration time

The test is carried out using the disintegration apparatus. Distilled water is used as a disintegration media and the time taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus is measured. The process of breakdown of a tablet into smaller particles is called as disintegration. The invitro disintegration time of a tablet was determined using disintegration test apparatus as per I.P. specifications. I.P. Specifications: Place one tablet in each of the 6 tubes of the basket and run the apparatus using simulated gastric pH 6.8 maintained at 37°C ± 2°C as the immersion liquid. The assembly should be raised and lowered between 30 cycles per minute in the distilled maintained at 37°C ± 2°C. The time in seconds taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured and recorded.

In-vitro drug release studies: The in vitro drug release is studied using USP dissolution apparatus II (paddle type) at 50 rpm in 900 ml of phosphate buffer (pH 6.8) at37±0.5ºC. Six tablets of each formulation were used in the dissolution test. An equal volume of the medium is introduced into the container after each withdrawal to maintain a constant volume. The absorbance of the samples is determined by UV Spectrophotometer at given max. The mean values of drug released are plotted as cumulative % drug release vs. time. (Sharma A et al., 2019)

Stability studies

Storing tablets at Stability studies were carried out at 6 months at 40?/75% RH relative humidity conducted stability study for two months. The drug content and dissolution behaviours from FDTs were tested in six-month intervals. Each tablet was individually wrapped in a aluminium foil and packed in PVC bottle and put at above specified conditions in a heating humidity chamber. After six months of interval, tablet sample was analysed for drug content and dissolution. (Swain RP et al., 2015, Patel B et al., 2009)

RESULTS AND DISCUSSION

Preformulation Study

Identification of drug

The colour, odour, and taste of the drug were characterized and recorded. The results were shown in table no. 4.

Table no. 4: Organoleptic identification of atenolol.

Identification of Drug by UV spectroscopy (lambda max determination)

Atenolol exhibited its maximum absorption at 225 nm and was shown in Figure no. .

Figure no. 3: Determination of lambda max of Atenolol

Melting Point

Melting point of Atenolol was determined by capillary method. Fine powder of Atenolol was filled in capillary tube (previously sealed at one end). The capillary tube inserted in sample holder of melting point apparatus and a thermometer is also placed in the apparatus. The temperature at which powder melted was noticed and was found in the range of 152-155?.

Solubility

Solubility studies of atenolol was carried out using different solvents. The results were shown in table no. 5

Table no. 5:  Results of Solubility determination of atenolol

Preparation of standard calibration curves of Atenolol in pH 6.8

It obeyed Beer’s law in the range of 5-30 μg/ml. Linear regression of absorbance on concentration gave equation y = 0.01438x + 0.0073 with a correlation coefficient of 0.998. So, calibration curve of atenolol in Buffer pH 6.8 showed in figure 3 was linear in concentration range of 5-30 μg/ml. Results were shown in table no. 6.

Table no. 6: Values of concentration and absorbance of atenolol using UV spectrophotometer.

Figure no. 4: Calibration curve of Atenolol in pH 6.8

Preparation of standard calibration curves in water

It obeyed Beer’s law in the range of 5-30 μg/ml. Linear regression of absorbance on concentration gave equation y = 0.0253x + 0.1389 with a correlation coefficient of 0.997. So, calibration curve of atenolol in Buffer pH 6.8 showed in figure 4 was linear in concentration range of 5-30 μg/ml. Results were shown in table no. 6.

Table no. 7: Values of concentration and absorbance of atenolol using UV spectrophotometer.

Figure no. 5: Calibration curve of Atenolol in distilled water

Drug- excipients compatibility studies: The pure drugs (Atenolol) along with formulation excipients and studies were carried out by mixing definite proportions of drug and excipients (ratio 1:1) and kept on glass vials.

Figure no. 6: FTIR spectra of Atenolol

Figure no. 7: FTIR spectra of Okra gum mucilage

Figure no. 8: FTIR spectra of Sodium starch glycolate

Figure no. 9: FTIR spectra of Magnesium stearate

Figure no. 10: FTIR spectra of Mannitol

Figure no. 11: FTIR spectra of meglumine

Figure no. 12: FTIR spectra of MCC

Figure no. 13: FTIR spectra of Oleic acid

Figure no. 14: FTIR spectra of Blend

• Precompression characterization

All ingredients were weighed accurately and blended. The powder blends were studied for precompression parameters such as angle of repose, bulk density, tapped density, Carr’s index and Hausner Ratio. Angle of repose of all the blends comes in the range of 19-22, that means they were showing an excellent nature of flow. Carr’s index shows compressibility property of blend, and the blends show excellent to good compressibility properties, results shows that all the prepared blend comes under the range of 11- 27 The Hausner ratio is an indirect measure of the property of a bulk material to reduce its volume under mechanical influence. It is also a measure of the ability to compress and of the interaction between the particles. Results of Hausner’s ratio comes in the range of 1.13-1.38 which shows good to passable flow characteristics. Results of the precompression parameters i.e. angle of repose, bulk density, tapped density, Carr’s index and Hausner Ratio shows in table no. 15

Table no. 15: Precompression parameters

Evaluation of tablet

Prepared formulations were evaluated using various parameters. Hardness of tablets were found in the range of 11.2-21.1. Results of thickness of tablets shows 2.44-2.56 mm, which shows an acceptable range that can be swallowed easily. Friability test were performed on the formulations, and all the formulations shows friability under 1%, that shows all the formulations passed the friability test. Average weight of the formulations comes in the range of 297.9mg to 301.05mg. Formulations were passed the weight variation test, as they come under the variation less than 5%. Drug content of all the formulations were found to be above 98%. Formulation blends containing different concentration of natural and synthetic super disintegrant. The concentration of okra gum at 8mg in combination with 1 mg sodium starch glycolate in Formulation F4, shows maximum drug release of 97.7% with least disintegration time of 74 seconds. All the results of post compression studied were shown in Table no. 8.

Table no. 8: Evaluation of tablet formulations

Figure no. 15: In-vitro disintegration time of Atenolol tablets

  Stability studies

Selected formulation i.e., F4, has been taken for stability studies. Formulation F4 was kept in stability chamber for 6 months at 40?/75% RH. Results of stability studies were shown in table no. 9.

Table no. 9: Stability studies of selected formulation (F4)