Formulation And Development of Oral Fast Dissolving Tablets Using a Model Drug

The oral route of drug administration is the most important method of administering the drug for systemic effect. Nevertheless, it is probable that at least 90% of all drugs used to produce systemic effects are administered by the oral route. Patients self-administration cannot be achieved; the sales of the drug constitute only a small fraction of what the market would be otherwise. Drugs that are administered orally, solid oral dosage forms represent the preferred class of product. The term oral drug delivery is used to describe the administration of a dosage form orally for local effect or systemic absorption along the gastrointestinal (GI) tract. Oral drug delivery has been the most commonly used route of administration for decades because it is noninvasive, convenient, pain avoidance and has high patient compliance. It does not need any special sterile conditions. The conventional drug delivery systems have been marked with immediate release and frequent dosing of the medication, which could result in the risk of fluctuation in doses hence, there arises a need for formulation with controlled release that is having a nearly constant or equal blood level. Hence, in today's world, most pharmaceutical scientists are engaged in designing an ideal DDS. This system of dealings must be benefited from the advantage of a single dose throughout the period of treatment, and it must administer the drug at a single site in a controlled way. Oral passage of medicament administration for illness is measured as the most  conventional route. Tablet is a commonly prescribed dosage form as of its accessibility in terms of self-administration, solidity and simplicity in development. Patients particularly paediatric and geriatric, often experience trouble in swallowing conventional tablets and this problem may prove worst during the traveling conditions due to the non-availability or restricted availability of water. These problems of conventional dosage forms can be encountered by the development of mouth dissolving tablets. These tablets disintegrate in the mouth within a very short span i.e. 20-30 sec and comes in contact with saliva resulting in the therapeutic action of active agent. Mouth dissolving tablets show better patient compliance and acceptance with improved bioavailability, efficacy and biopharmaceutical properties, in contrast to conventional tablets. ^[1]

2.MATERIALS AND METHOD

 2.1 MATERIALS: -

Cinnarizine was obtained from Rakshit Pharmaceuticals Limited, Microcrystalline cellulose was obtained from Crest Cellulose Private Limited, Cross povidone was obtained from Cradel Pharmaceuticals Private Limited, Talc (Luzenac Pharma) was obtained from Imerys. Magnesium Stearate was obtained from Peter Greven and Mannitol was obtained from Simson Pharma Limited.

2.2 METHODS:

Preformulation Study:

Physical characterization of API sample:

The API sample was observed visually and viewed under microscope for the determination of its nature and then the result were compared with the official book. Then sample was evaluated for its colour, taste and odour. Melting point of Cinnarizine sample was determined by using DSCmethod. Solubility study was carried out in various media such as 0.1N HCl, pH 6.8 phosphate buffer, Distilled water. Flow of API was determined with the assistance of Bulk density, Tapped density, Carrs' (Compressibility) index, Hausner's ratio, Angle of repose.

Analytical characterization of API Cinnarizine:

Scanning of Cinnarizine in pH buffer 6.8:

10 ug/ml solution of Cinnarizine in pH buffer 6.8 was taken and scanned in range of 400-200 nm against pH buffer 6.8 as a blank using UV spectrophotometer.

Calibration curve of Cinnarizine pH buffer 6.8:

Accurately weighed 100 mg of Cinnarizine and measured 50ml ethanol and transfer into 100 ml volumetric flask and dissolve in suitable quantity of pH buffer 6.8 and lastly make  the volume up to 100 ml using pH buffer to obtain a 1000 µg/ml concentration  stock solution. About 0.1ml, 0.2 ml,  0.3 ml, 0.4 ml, 0.5 ml of this stock solution (1000 µg/ml) was taken in 100 ml volumetric flask and diluted to 100 ml with pH buffer 6.8 solution to get 1 to 5 µg/ml drug concentration. Then they were analyzed spectrophotometrically by measuring the absorbance at 276 nm. A calibration curve of concentration Vs absorbance was plotted and its intercept and slope value were calculated. ^[2,3]

Formulation:

Cinnarizine, Crosspovidone, Microcrystalline Cellulose, Magnesium Stearate, Talc, Mannitol and Croscarmellose Sodium  were weighed accurately using calibrated weighing balance. Co-shift above ingredient from sieve no. #30. Add above material into blender and blend of 15 minutes. Weight and shift Magnesium Stearate from sieve no. #60. Add shifted material into blender and lubricaed for 5 minutes. Then lubricated blend was compressed into tablet using 8.0 mm, round shape, bevel edge, biconvex punches, embossed with “D64” on upper punch and “H” on lower punch.

Table No 1: Formulation trial of batch F01, F02, F03, F04, F05

Evaluation Studies:

Pre-compression evaluation parameters:

The powder blend of all formulations were evaluated for bulk density, tapped density, carr’s index, hausner’s ratio and angle of repose to determine its flow properties during compression.

Bulk density:

Apparent bulk density was determined by pouring the powder blend into a measuring cylinder and measuring the volume and weight and bulk density was determine by using formula

Db = MVb

Tapped density:

The pre-weighed powder was filled in measuring cylinder. Then it was tapped in automated bulk density test apparatus. Carry out 10, 500, and 1250 taps on the same powder blend and read the corresponding volumes V10, V500, and V1250. If the difference between V500 and V1250 is less than or equal to 2 ml, V1250 is the final tapped volume. Tapped density was determined by

Db = MVt

Carr’s index:

Tapped density (Dt) and bulk density (Db) of powder material was used to measure compressibility of a powder material. It was measure used to describe compression capability of the powder material. Carr’s index was determined using following equation

Carr’s index = Dt-DbDt

Hausner’s ratio:

The Hausner’s ratio is a number that measures the flowability of a  powder material. It is calculated by dividing the tapped density of a material by its bulk density: ^[4]

HR = DtDb

Angle of repose:

The angle of repose was determined by using the funnel method. The accurately weight powder blend were taken in the funnel and tip of funnel was blocked by thumb at initially. The height of the funnel was adjusted in such a way the tip of the funnel just touched the apex of the powder blend (Almost 2 cm was fix from plane to tip of funnel). The powder blend was allowed to flow through the funnel freely on to the surface.. It is a measure used to describe flow ability of the powder material. The equation for determining angle of Repose, θ, is ^[5]

θ = tan^-1 h/r

Post-compression evaluation parameters of finished product:

Weight variation:

The weight of the tablet was measured with the help of digital electronic balance. For determination of weight variation, ten tablets were selected randomly from a batch and average weight was determined^[6].

Thickness:

Ten tablets were selected in a batch for the determination of thickness variation with Vernier Caliper.

Hardness:

Adequate hardness is necessary to withstand the mechanical shock of manufacturing packaging and shipping, and to ensure consumer acceptance. Hardness of tablet was determined using Ewereka hardness tester. The tablet was compressed between a holding ansil and a piston and digital screen showed hardness in kp^[6].

Friability:

Friability of the tablets was determined using an Electrolab friabilator. The tablets should be carefully dedusted before  testing. Accurately weigh the tablet sample and place the tablets in the drum. Rotate the drum at 25 rpm for 4 minutes, and remove the tablets. Remove any loose dust from the surface of tablets as before and accurately weigh. Friability was determined by

% Friability = Initial weight-Final weightInitial Weight

Limit: Not more than 1.0%

Drug content:

Five tablets were weighed individually from optimized formulation (F04), then placed in a mortar and powdered with a pestle. An amount equivalent to 100 mg drug was mixed with 100 ml of buffer pH 6.8. The solution was filtered through a Whatmann filter paper (0.22 µm pore size), then diluted with buffer pH 6.8 and then take absorbance at 276 nm wavelength using UV spectrophotometer and the percentage of drug content was calculated by formula^[7]

Drug Content (%) = Actual Amount of DrugTheoretical Amount of Drug X 100

In-vitro Drug Release Studies:

In-vitro drug release studies of the Cinnarizine finished products were conducted using the USP Apparatus II (rotating paddle method) at a stirring speed of 50 rpm. The dissolution was performed at 37 ± 0.5°C in 900 ml of buffer pH 6.8 solution as the dissolution medium for 24 hours. 2 ml of sample withdrawn at interval of 5,10,15,20,25,30 min with the replacement of equal volume of dissolution media into dissolution flask. Filter the solution through 0.45 µm membrane. Dilute the sample with buffer pH 6.8 up to 30 ml into 100 ml volumetric flask. Then samples were analyzed at 276nm by UV spectrophotometer (UV-1800 SHIMADZU) ^[8,9]

In vitro Disintegration Time :

The disintegration time was performed by apparatus specified in USP at 50 rpm. 900 ml of buffer pH 6.8 was used as disintegration medium and the temperature of 37°C ± 0.5°C and time in seconds was taken for complete disintegration of the tablet.

Stability studies of the optimized formulation: The selected HDPE Bottle packing formulations stored at 40°C/75% RH for 1 months and evaluated for their physical appearance and drug release at specified intervals of one month^[10].

3. RESULTS AND DISCUSSION:

Physical characterization of API sample:

Table No. 2: Physical characterization of API Cinnarizine (USP)

Solubility Study:

The solubility of Desvenlafaxine Succinate (USP) in different media is presented in Table No. 4 and comparision of solubility with in solvent is shown in Figure No. 1.

Table No. 3: Solubility of Cinnarizine ( USP) at 25⁰C in different media

Figure No. 1: Solubility of Cinnarizine in different media

From table no. 4 it is showing that API have similar solubility in all the studied media store at 25^oC.

Derived Properties:

Table No. 4: Bulk density, Tapped density, Carr’s index, Hausner’s ratio, Angle of repose of API Desvenlafaxine Succinate

From Table no. 4, it is shown that API has poor flow.

Analytical characterization of API Cinnarizine:

Scanning of Cinnarizine in buffer pH 6.8:

Figure No. 2:  UV spectra of Cinnarizine in buffer pH 6.8 at 276 nm

From figure no. 2 it is found that  maximum absorbance of Cinnarizine was at the wavelength 276 nm.

Calibration curve of Cinnarizine buffer pH 6.8:

A spectrophotometric method for estimation of Cinnarizine , based on the measurement of absorbance at 276 nm in buffer pH 6.8, gives a straight line with an equation: y = 0.2888x + 0.0157 and r² = 0.9988 (Figure 3).

Figure No. 3: Standard calibration curve of Cinnarizine in buffer pH 6.8 at 276nm

Drug–excipient compatibility study by using FTIR spectroscopy-

Figure No. 4: FTIR spectrum of pure API Cinnarizin

Figure No. 5: FTIR spectrum of API Croscarmellose Sodium

Table No.6: Functional group and principle peaks present in Croscarmellose Sodium

Figure No. 6: FTIR spectrum of API Cinnarizine and Croscarmellose Sodium

Table No. 7: Functional group and principle peaks present in physical mixture of API mixture of Cinnarizine and Croscarmellose Sodium

From table no 5,6 and 7, FTIR spectral analysis of pure Cinnarizine, pure Croscarmellose Sodium and its mixture of drug and polymer(Cinnarizine and Croscarmellose Sodium),no significant peak shifts, new interactions, or degradation products were observed. Thus, Cinnarizine is compatible with the selected excipients based on FTIR analysis, confirming its stability in the proposed formulation.

Evaluation Studies:

Pre-compression evaluation parameters:

From table no. 8 The evaluated powder blends (F01–F05) demonstrated varying flow properties based on their angle of repose, compressibility index, and Hausner’s ratio.

Table No. 8: Pre-compression evaluation parameters of the powder blend

Post-compression evaluation parameters of finished product:

Physical parameters of batch from F01 to F05:

Table No. 9: Physical parameters of batch from F01 to F05

DISCUSSION:

Batches F01, F02, F03 ,F04 and F05were evaluated .The tablets exhibited consistent average weights ranging from 190.6 to 210.5 mg, with uniform thickness between 3.00 mm and 4.75 mm, reflecting controlled compression and uniformity in tablet size. tablet hardness values ranged from 8.0 to 9.2 kp, indicating sufficient mechanical strength for further processing. Friability for all batches remained well within the acceptable pharmacopeial limit of less than 1%, with F03 showing the lowest friability at 0.14%, indicating comparatively better tablet robustness.

In-vitro drug release profile of batch F01, F02,FO3,F04 and F05

Table No. 10: In-vitro drug release profile of batch F01, F02, FO3, F04 and F05 in release media buffer pH 6.8

Time (MIN)	F01	F02	F03	F04	F05
0	0	0	0	0	0
5	20.46± 0.4	20.46± 0.1	20.03± 0.1	25.01± 0.4	30.00± 0.1
10	40.10± 0.4	40.25± 0.2	50.17± 0.2	50.00± 0.2	60.04± 0.2
15	50.07± 0.6	51.08± 0.5	60.71± 0.1	64.10± 0.1	70.09± 0.5
20	65.03± 0.4	69.08± 0.3	71.95± 0.5	74.02± 0.3	80.01± 0.6
25	74.07± 0.2	68.33± 0.6	74.02± 0.2	80.01± 0.4	86.01± 0.4
30	80.14± 0.4	75.05± 0.1	79.01± 0.6	93.01± 0.3	88.01± 0.3

Figure No. 7: In-vitro drug release profile of batch F01, F02,F03,F04 and F05 in release media buffer pH 6.8

DISCUSSION:

In batch F01, poor flow properties of the lubricated blend resulted in weight variation and inconsistent drug release, with a final release of 74.07%. F02 showed slightly improved flow but exhibited a faster drug release, with a final release of 75.05% .F03 achieved better control with 79.01% .Overall, all three batches released the drug too quickly, indicating insufficient polymer concentration to sustain release. These results prompted an increase in polymer content in further formulations to achieve better control profile.All tablet parameters were within acceptable limits, and the flow properties of the lubricated blends were improved due to increased lubricant concentration. Batch F04, formulated with a 1:1.75 drug-to-polymer ratio, showed a drug release of 93.01%. Hence, F04was selected as the optimized batch.

Stability Studies of optimized formulation:

Stability studies was carried out at 40°C/75% RH for optimized formulation (F04) for 1 month. After each month physical changes like colour, drug content and dissolution profile were recorded.

Table No. 11: Stability study data of optimized formulation (F04) at 40°C/75% RH for 1 month

Formulation F04	Initial	1M 40°C/75% RH HDPE Bottle
(1) Physical stability	White, round shaped	Similar to initial
(2) Drug content (%)	99.28 %	98.76 %
(3) Dissolution Parameters	Apparatus type:USP-II, rpm:-50, Media:-buffer pH6.8 in water, Media volume:-900ml, Sampling points:-5,10,15,20,25,30 min.
Time in min	Cumulative percent drug release	Cumulative percent drug release
5	25.01± 0.4	17.64± 0.6
10	50.00± 0.2	25.15± 0.7
15	64.10± 0.1	45.32± 0.9
20	74.02± 0.3	65.09± 0.5
25	80.01± 0.4	81.70± 0.6
30	93.01± 0.3	90.00± 1.2
Conclusion	24 Hrs profile	Similar to initial