Formulation And Development of Orodispersible Tablet of Rosuvastatin Using Natural Superdisintegrant

Oral delivery is current standard in the pharmaceutical industry wherever it is regarded as the safest, most suitable and most economical method of drug delivery. ^[1] The oral cavity is an attractive site for the administration of drugs because of ease of administration^{. [2]} Oro-dispersible drug delivery system are novel drug delivery techniques that make the tablets disintegrate in the mouth without chewing and water, and immediate release and enhanced bioavailability, with better patient compliance. ^{[3, 4]} Recently, the European Pharmacopeia adopted new term that is orodispersible tablet that disintegrates/ disperses rapidly in the mouth within a minute or second without need of drinking water or chewing. The United States Food and Drug Administration (USFDA) describe Oro-dispersible tablet as “a solid dosage form that containing active ingredient or medicinal substances which disintegrate /dissolve rapidly within the seconds when tablet placed upon the tongue. ^{[5, 6]} Oro-dispersible tablets have a quick dissolution and rapid absorption which provide rapid onset of action. Furthermore, drug candidates that undergo pregastric absorption when formulated as ODTs may oral bioavailability of drug is improved by avoiding the hepatic first pass metabolism. It provides good stability, accurate dosing, easy of manufacturing. ^{[7, 8]} Recent time of the market studies that indicates the more of the patient population that prefers the orodispersible tablets rather than other dosage forms and most consumers would ask their doctors for orodispersible tablets (70%), purchase ODTs (70%), or prefer ODTs to regular tablets or liquids (> 80%).^[9]

MATERIAL AND METHODS

Materials

Rosuvastatin and Beta-Cyclodextrin were obtained from Yarrow chem. products. (Mumbai). Cassia tora seeds were purchased from local market (Indore). Microcrastalline cellulose, Mannitol, Magnessium Stearate, Talc, Acetonitrile, Ethanol, Methanol, Potassium chloride and Silica gel-G were purchased from Lobachem Pvt. Ltd. And Aspartame, Potassium Dihydrogen phosphate, sodium hydroxide, Hydrochloric acid were purchased from Merck Pvt. Ltd.

METHOD:

Preformulation Study

Drug Characterization:

Determination of wavelength using UV-visible spectroscopy:

10 mg was weighed and dissolved into 10 ml of Phosphate buffer solution (PH 6.8) to prepare a 1000µg/ml stock solution from which a 5µg/ml dilution was prepared. Baseline correction was performed using Phosphate buffer solution (PH 6.8) and sample was scanned between 200-400nm and wavelength of maximum absorbance (λmax) was noted. ^[10]

Preparation of calibration curves:

Calibration curve of rosuvastatin in phosphate buffer pH 6.8:

• Preparation of stock solution

Accurately weighed 100mg of Rosuvastatin was transferred into a 100ml volumetric flask & dissolved. Then sonicated for 15 minute and the volume was made up with phosphate buffer pH 6.8 to obtain a 1000µg/ml stock solution of Rosuvastatin, From the stock solution, 1ml was taken into a 10ml volumetric flask and volume was made up with phosphate buffer pH 6.8 to obtained a 100µg/ml of solution.

• Preparation of dilution

From 100µg/ml solution the appropriate aliquot of 0.2ml, 0.4ml, 0.6ml, 0.8ml, 1.0ml, 1.2ml, 1.4ml, 1.6ml, 1.8ml and 2.0ml were taken into different volumetric flask and diluted up to 10ml with phosphate buffer pH 6.8 to get different concentration range 2-20 µg/ml. The absorbance of each dilution was noted. [11]

Determination of solubility of Rosuvastatin in various mediums:

The solubility of Rosuvastatin in various medium was determined by shake flask method. In this method 5ml of each solvent was taken into a vial and an excess amount of Rosuvastatin was added. The vials were sealed properly and stirred continuously at 37º ± 2 ºC. After solubilization of Rosuvastatin, an extra amount of Rosuvastatin drug was added to the vials containing drug-solvent mixture and stirred for a period of 6 hours (saturation time). The process was repeated until saturation solubility of Rosuvastatin, indicated by presence of undissolved drug. The mixtures were then kept at room temperature for 24 hrs. and the solution were filtered through what man’s filter paper. Then diluted with respective solvents i.e. Acetonitrile, phosphate pH buffer 6.8 and pH 1.2 HCl buffer. The drug concentration was analyzed spectrophotometrically at 241.50nm using UV-visible spectrophotometer (Shimadzu-1800). [12, 13]

Extraction of cassia tora seeds mucilage:

The seeds of Cassia tora were dry milled in a mixer to separate the seed coat.The Cassia tora seeds (100 gm) was soaked in distilled water and shaken for 24 hours. The soaked solution was transferred to hot boiling water and boiled for 2 hours to make the solution more concentrated. The viscous solution obtained was filtered through a muslin cloth. Then transferred to an evaporating dish. The obtained mixture was dried in oven at 40–45?C. It was then powdered and passed through sieve number 60 and stored in an airtight container. [14, 15] Preformulation study

Characterization of Cassia tora seeds mucilage: [16-19]

The prepared Mucilage powder were evaluated in terms of Organoleptic properties, Percentage yield, pH of Mucilage, Solubility of Mucilage, swelling index, Bulk density, Tapped Density , Carr’s Index, Angle of Repose and Hausner’s Ratio.

Drug-excipient interaction study:

The compatibility of the drug was assessed by drug-excipient interaction study. The drug was mixed with various excipients in a 1:1 ratio in glass vials which were properly sealed & labeled and kept undisturbed at 40°C temperature and 75% RH for 15 days. Physical and chemical observations of all the mixtures were done on initial day and 15th day by TLC. [20]

Thin layer chromatography: [21]

The stationary phase was prepared by silica gel-G. The mixture of organic solvent Methanol: water (1:1 v/v) was used as mobile phase.

Calculation of Rf value:

Rf value can be calculated by following formula:

Rf= Distance travelled by solute / Distance travelled by solvent

10mg of Rosuvastatin with β-CD in different ratio was taken. β-cyclodextrin was taken to the mortar-pestle in a small quantity of 50% ethanol was added while triturating to get slurry like consistency. Subsequently drug was incorporated slowly into the slurry and trituration was further continued for one hour. Slurry is then air dried at 25°C for 24 hours, pulverized and passed through sieve no. #60.

Preparation of orodispersible tablet by direct compression:

Orodispersible tablet of Rosuvastatin were prepared by direct compression method. Weighed all the ingredients accurately according to the table no.6.4. All the ingredients were mixed step by step with drug: β-cyclodextrin inclusion complex except formulation (F1, F4 and F7 i.e. only drug was mixed in it) and triturated continued for 15 minutes. Then passed through sieve no. #40. Subsequently talc, magnesium stearate shifted via sieve no. 60# & mixed again ^[25] The powder was compressed using multistation tablet punching machine (Aidmach Pvt. Ltd.) with 8mm flat punch, B-tooling and corresponding dies.

Evaluation Parameter

Precompression Parametres of powder: ^[26-29]

• Bulk Density:

Bulk density is defined as the total mass of the powder divided by the bulk volume and is expressed as gm/ml. This was calculated by using the formula:

Bulk Density = weight of powder(in gm) / Bulk Volume of Powder (in ml)

• Tapped Density:

It is the ratio of total mass of the powder to the tapped volume of powder. Tapped density was calculated by using the following formula:

Tapped Density = weight of powder (in gm) / Tapped Volume of Powder (in ml)

• Carr's index:

The Carr's index of the powder blend was determined by using the formula:

Carr's index (%) I = [(Tapped Density- Bulk Density) / Tapped Density] x 100

• Angle of repose:

It was determined by the funnel method. The Weighed powder were taken in a funnel. A funnel is fitted and is secured with its tip at a height (h) of 2 cm above graph paper which is placed on a horizontal surface. The accurately weighed powder were taken and dropped in funnel. The powder blend was allowed to flow through the funnel freely onto the surface. The angle of repose was calculated by measuring the diameter and height of powder cone and putting the values to the following equation.

θ= tan ^-1 (h/r)

• Hausner's ratio:

If the hausner’s ratio is less than 1.25 that indicates free flowing properties whereas more than 1.25 that indicates the poor flow ability. It was calculated by following formula:

Hausner’s ratio = Tapped density / Bulk density

Post Compression parameter of orodispersible tablet: ^[30-32]

• Weight variation

The twenty tablets were selected randomly from each formulation and the weight of their average weight was determined. Tablets were weighed individually and compared with average weight.

Percentage weight variation= Individual weight- average weight/ average weight×100

• Hardness:

The hardness of the tablet was determined by Monsanto hardness tester. Placed the tablet on the lower plunger and zero reading was taken from Monsanto tester scale. The range of Monsanto hardness tester is “0 to 20” kg. The screw knob was moved forward until the tablet breaks and the force required breaking the tablet was noted. There are three tablets of each formulation batch were tested randomly and the average reading was recorded. It is expressed in kg/cm².

• Thickness:

Thickness of the tablets was calculated by the use of vernier calliper. The scale was set to zero and placed the tablet laterally between the jaws of vernier calliper. Subsequently make certain jaws shall just touch object to be measured. The reading displayed was Record. Take out the sample, clean the jaws and keep the caliper in place. There are three tablet of each formulation batch were checked randomly and standard deviation was measured. It is expressed in mm.

• Friability:

Friability of the tablet was determined using Roche friabilator. Tablets were weighed before placing in friability apparatus. Tablets placed on the friabilator and subjected to 100 revolutions for 4 minute at 25 rpm and dropping the tablet at the height of 6 inches in each revolution. The tablet were reweighed and dedusted.

Percentage friability = Initial weight - Final weight / Initial weight × 100

• Disintegration time:

First suspend the assembly in the beaker containing 6.8 pH phosphate buffer at 37±0.5^°C. The tablet was placed into each of the six tubes of the disintegrating apparatus and one disc was added to each tube. Operated the apparatus until the tablet completely disintegrated. Note down the time taken for the completed disintegration of the tablet without any remitants. Removed the assembly from 6.8 pH phosphate buffer. The tablets were passed the test if all of them have disintegrated.

• Drug content:

The drug content was determined by calibration curve method are as follow:

Ten tablets were taken and amount of drug present in each formulation of tablet was determined. The tablet was crushed in a mortar-pestle and equivalent to 10 mg of drugwas dissolved in phosphate buffer PH 6.8 in a 100ml volumetric flask. Volume was made up to 100ml. The sample was filtered through filter paper. From this solution 1ml were taken in a 10 ml volumetric flask & diluted with phosphate buffer pH 6.8. Further, 1ml were taken were taken and diluted up to 10ml and analyzed for drug content by UV spectrophotometer at 241.5 nm using phosphate buffer (pH 6.8).

• Wetting time & Water absorption ratio:

A piece of tissue paper folded twice was placed in a small petridish containing10 ml of water. A tablet was put on the tissue paper and the time required for the water to diffuse from the wetted absorbent paper throughout the entire tablet was then recorded using a stopwatch.

For water absorption ratio: The wetted tablets were the reweighed. The water absorption ratio and R was determined using following equation

R = 100 × Wa-Wb/Wb×100

Where,

Wa = Weight of the tablet after water absorption Wb = Weight of the tablet before water absorption

• In vitro Drug release study:

In vitro Drug release study was determined by dissolution test apparatus. Maintained the water level in the water bath up to the specific mark and adjusted or maintained temperature from heater knob. 900 ml of phosphate buffer pH 6.8 was poured in dissolution vessel and adjusted temperature between 37±0.5^?C. The shaft was positioned in such a way that its axis is within 2 mm of axis of the vessel and lower edge of blade was 23-27 mm from the inside of bottom of vessel. The paddles were lowered down. The tablet was put in each vessel and paddle was rotated at 50 rpm for 30 min. Withdrawn 5 ml sample at every 5 minutes interval and replaced by equal volume of fresh dissolution medium. Filtered the samples using what man’s filter paper and analyzed for drug release of the samples by UV-visible spectrophotometer at λ max 241.5 nm using phosphate buffer pH 6.8 as blank.

6.5 Stability study:

The stability study of orodispersible tablet was studied at different storage condition. The physical stability of orodispersible tablet was observed by visual appearance and chemical stability was observed by TLC. The TLC values with solvent system methanol: water (1:1) and silica gel-G as stationary phase was determined. ^[33]

RESULT AND DISCUSSION

Preformulation Study Drug Characterization:

Preparation of calibration curve:

Calibration curve of Rosuvastatin in phosphate buffer pH 6.8

The calibration curves of rosuvastatin in phosphate buffer pH 6.8 were prepared and shown below:

Table no.2: Absorbance data of Rosuvastatin in phosphate buffer pH 6.8 for preparation of calibration curve, at 241.5nm

Determination of solubility of Rosuvastatin in various medium:

The solubility of Rosuvastatin in various mediums was studied and the results of study were shown in below table:

Table no.3: Solubility data of Rosuvastatin in different mediums

Determination of solubility of inclusion complex:

The solubility of inclusion complex in phosphate buffer pH 6.8 was studied and the results of study were shown in below table:

Table no.4: Solubility data of inclusion complex:

Characterization of cassia tora mucilage powder: The prepared mucilage powder was evaluated as follows:

The drug (Rosuvastatin) was found to be compatible with various excipients which were selected for formulation of orodispersible tablet. The compatibility was assessed by TLC and the retention factors of all ratios found similar.

The orodispersible tablet of Rosuvastatin were evaluated like weight variation, hardness, thickness, friability, disintegration time, drug content, wetting time and water absorption ratio. The results of the studies were shown in below table:

The percentage cumulative drug release from formulations F1 to F9. The formulation F6 was shows the highest release (96.2%) within 15 minutes

        <a href="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250417160224-1.png" target="_blank">
            <img alt="Percentage cumulative drug release graph from formulation F1-F.png" height="150" src="https://www.ijpsjournal.com/uploads/createUrl/createUrl-20250417160224-1.png" width="150">
        </a>
Figure 3: Percentage cumulative drug release graph from formulation F1-F9

Evaluation of precompression parameters of powder of optimized tablet (F6):

The bulk density, tapped density, Carr's index, angle of repose and Hausner's ratio of optimized formulations ware performed and shown in table no. 10. All the results shown that the optimized formulations possess a good flow property.

The orodispersible tablet of Rosuvastatin were evaluated like weight variation, hardness, thickness, friability, disintegration time, drug content, wetting time and water absorption ratio and in vitro drug release study. The results of the study were shown in below table:

Table no.12: Disintegration Time, Drug Content, Wetting time & water absorption Ratio, and of optimized tablet (F6):

Stability study: Stability studies for three month were performed at different storage condition for optimized orodispersible tablet (F6). The optimized orodispersible tablet were found to be stable with no change in physical appearance and TLC values (Rf) were found similar at different storage condition at different time interval. It was concluded that the formulation is stable at different storage conditions.