Formulation Optimization & Evaluation of Co-Processed Excipients for Orally Disintegrating Tablet of Bilastine

Co-processed excipients (CPEs) have gained significant attention in pharmaceutical formulation due to their ability to overcome the limitations of individual excipients. Unlike simple physical mixtures, co-processed excipients are engineered combinations of two or more existing excipients, designed to provide synergistic improvements in flowability, compressibility, and functional performance without compromising the stability or efficacy of the active pharmaceutical ingredient (API). This approach is particularly valuable in the development of orally disintegrating tablets (ODTs), where rapid disintegration, mechanical strength, and patient acceptability are critical. In the present study, co-processed excipients were developed using banana powder a natural, biodegradable excipient with good swelling properties and microcrystalline cellulose (MCC), a well-established binder and filler with excellent compressibility. The co-processing was carried out using the solvent evaporation method to enhance compatibility and improve powder characteristics. The main objective was to formulate and optimize a novel ODT of Bilastine, an antihistaminic agent, by utilizing these co-processed excipients. To achieve this, a Central Composite Design (CCD) under Response Surface Methodology (RSM) was employed to evaluate the effect of varying concentrations of banana powder and MCC on critical formulation parameters such as angle of repose, Carr’s index, Hausner’s ratio, and disintegration time. By optimizing the CPE composition, the study aims to improve not only the manufacturing efficiency but also the functional performance of the ODT, ensuring rapid disintegration and effective drug release for enhanced patient compliance and therapeutic outcomes.

MATERIALS & METHODS:

MATERIALS:

Bilastine (Medley Pharma Ltd ; Andheri) , Banana Powder (Nutribud Foods Pvt.Ltd.) , MCC (Jinendra Scientifics ;Jalgaon), Orange Flavor( Marc Flavors ,Greater Noida), Aspartame( Jinendra Scientifics ;Jalgaon), Aerosil (Medley Pharma Ltd ; Andheri),Magnesium Steareate (Loba Chemie;Mumbai).

Preformulation study: ⁽⁴⁾

Determination of UV Spectrum of Bilastine:

Bilastine solution (10 ug/ml) was prepared in phosphate buffer pH 6.8. This solution scanned under double beam UV visible spectrophotometer (Shimadzu-1800) and spectrum was recorded in the wavelength ranges between 200 - 400 nm. Spectrum was shown in Fig. No. 2.

Standard Calibration Curve of Bilastine:

Weigh accurately 10 mg of Bilastine, transfer it into 100 ml volumetric flask add phosphate buffer pH 6.8 to obtained concentration 100 ug/ml. From this solution, pipette out 0.5, 1, 1.5, 2 & 2.5ml, transfer each to 10 ml volumetric flask and make up the volume up to 10 ml with phosphate buffer pH 6.8 to get 5, 10, 15, 20 & 25 ug/ml concentration of Bilastine respectively. Absorbance of each solution was measured at 282 nm using UV visible spectrophotometer (Shimadzu 1800) and phosphate buffer pH 6.8 as reference standard and the standard curve was generated. The standard calibration curve shown in Fig.No.3

Drug Excipient Compatibility Study: ^(7,9,12)

• Fourier Transform Infrared Spectroscopy:

Fourier transformed infrared technique was one of the most powerful techniques was identify functional groups. The FTIR analysis method uses infrared light to scan test samples and observe chemical properties. The FTIR studies were carried out using FTIR 1-5 Affinity. The Potassium bromide disc method used for preparation of the sample. The infrared spectrum of pure Bilastine, CPE, Bilastine+ CPE were showed in fig no. 4,5&6

• DSC Analysis:

DSC is one of the most common analytical techniques used to characterize pharmaceutical solids. This technique is used to study what happens to polymers/ samples upon heating Drug and excipients in the ratio 1:1 was analyzed for DSC. The DSC spectrum of pure Bilastine were showed in fig no. 7 and the DSC spectrum of CPE were shown in fig no. 8  and the DSC spectrum of mixture of Bilastine with CPE were shown in fig no.9 respectively

Method of Preparation:

Preparation of Co-Processed Excipients Using Solvent Evaporation method: ⁽¹²⁾

Firstly, weigh all ingredients properly. Dissolve the banana powder in water to form a slurry.  Gradually add the weighed MCC to the banana slurry while stirring continuously to ensure uniform mixing. Heat the slurry gently to allow the solvent (water) to evaporate.  Once most of the solvent has evaporated transfer the mixture to a hot air oven maintained at 40°C-60°C for drying. When the mixture becomes semi-dry ,pass it through a 22#mesh to obtain granules. Finally, dry the granules again until the desired moisture content is achieved.

Fig. CPE of Banana Powder +MCC

Preparation of Tablet^{: (5)}

Weigh all ingredients properly. Pass the drug (Bilastine) #60 mesh and CPE through a #22 mesh sieve. Pass aspartame orange flavour through #60 mesh sieve. Add the magnesium stearate and aerosil into a above blend and mixed them properly in a polybag. Weigh 200 mg of the prepared tablet blend and compress it using a KBr Press fitted with an 8mm punch.

Optimization: ^(6,7)

Optimization of the formulation was carried out using a statistical approach to identify the most suitable composition of co-processed excipients (CPE) for Bilastine orally disintegrating tablets (ODT). The Central Composite Design (CCD), a response surface methodology under the Design of Experiments (DOE) software, was employed for this purpose .Two independent formulation variables—concentration of banana powder (X?) and concentration of microcrystalline cellulose (MCC,X?)—were selected for optimization. Their effects were studied on four dependent response variables: angle of repose (Y?), Carr’s index (Y?), Hausner’s ratio (Y?), and disintegration time (Y?). These responses were chosen as indicators of powder flow properties and tablet performance.

Table 1: Independent Variables & There Levels in CCD

Table 2: Dependent Variables with There Actual Coded Values

Table 3: Composition of Co-Processed Excipients Batches Generated by CCD

All Ingredients are in gm.

Table 4: Composition of Bilastine ODT Using Co-Processed Excipients Generated by CCD

All Ingredients are in mg.

Evaluation Parameter of Co-Processed Excipients & Tablets:

Pre-Compression Parameter of Co-Processed Excipients: ⁽¹⁷⁾

1. Bulk Density:

 It is the ratio of total mass of powder to the bulk volume of powder. It was measured by pouring the weighed powder (passed through standard sieve #20) into a measuring cylinder and initial weight was noted. This initial volume is called the bulk volume. From this the bulk density is calculated according to the formula mentioned below. It is expressed in g/ml and is given by:

2. Tapped Density

 It is the ratio of total mass of the powder to the tapped volume of the powder. Volume was   measured by tapping the powder for 750 times and the tapped volume was noted if the difference between these two volumes is less than 2%. If it is more than 2%, tapping is continued for 1250 times and tapped volume was noted. Tapping was continued until the difference between successive volumes is less than 2% (in a bulk density apparatus).

3. Carr’s Index:

Compressibility index (Cl) was determined by measuring the initial volume (VO) and final volume (V) after hundred tapings of a sample in a measuring cylinder. Cl was calculated using equation:

4. Hausner’s Ratio:

A similar index to indicate the flow properties can be defined by Hausner's ratio. Hausner's ratio can be calculated by using following formula:

5. Angle of Repose:

Angle of repose was determined by using funnel method. The accurately weighed blend was taken in a funnel. The height of the funnel was adjusted in such a way that the tipof the funnel just touches the apex of the heap of blend. The drug las solid dispersion) excipients blend was allowed to flow through the funnel frely on to the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation:

Post-Compression Parameter of Tablets: ^(15,17)

1. Hardness:

The tablet crushing strength was determined using a Monsanto hardness tester. Three tablets were randomly sampled from each formulation batch ,and the average reading was recorded .  

2. Weight variation:

To determine variation 20 tablets of each formulation were individually weighed using an electronic balance. The average weight was calculated and the individual tablet weight was then compared to the average value.

3. Friability:

A total of 10 tablets were accurately weighed and placed in the drum of the friabilator. The instrument was operated at 25 revolutions per minute (rpm) for 4 minutes, making a total of 100 revolutions. After the test, the tablets were dedusted using a soft brush, and the final weight was recorded.

4. Thickness:

Tablet thickness is a crucial element in both duplicating appearance and counting with filling machinery the uniform thickness of the tablets is used as a counting mechanism by some filling equipment micrometer was used to measure thickness.

5. Disintegration Test:

The disintegration time is the release rate of the active ingredients from the tablets. The disintegration times can be recorded utilizing USP tablet disintegration apparatus during this test. The time taken for the suppository to melt or disperse is when immersed in a water bath maintained at constant temp (37±20 C). The time required for the tablet to melt or dispersed in the surrounding water was noted. Unless intended for modified release or for prolonged local action. They comply the test for disintegration of tablets.

6. Drug Content:

ODT containing 20mg of the drug was made to dissolve in 100ml of the buffer pH6.8 and then absorbance were measured at 282 nm using UV spectrophotometer and the amount of the drug present was calculated using the calibration curve.

7. Wetting Time:

Take a double folded tissue paper was placed in a petri dish containing 6 ml of methylene blue solution. Then the tablet was placed on tissue paper containing methylene blue and the time required for complete wetness of tablet was recorded as wetting time the randomly three tablets were chosen from each formulation and the average wetting time was recorded.

8. In-Vitro Dissolution Study: ⁽⁶⁾

The in-vitro dissolution study of Bilastine orodispersible tablets (ODT) was conducted using a dissolution tester (USP TDL-08L) equipped with a USP Type II paddle apparatus. The study utilized phosphate buffer (pH 6.8) as the dissolution medium, with a volume of 900 ml maintained at a temperature of 37 ± 0.5 °C to simulate physiological conditions. The paddle rotation speed was set at 50 rpm to ensure consistent mixing. Drug concentration was determined spectrophotometrically at a wavelength of 282 nm. At specified time intervals, 5 ml aliquots were withdrawn from the dissolution vessel and immediately replaced with fresh buffer to maintain sink conditions. The amount of drug dissolved at each time point was calculated and expressed as a percentage of the total drug content. These values were then plotted against time to generate a dissolution profile, allowing for analysis of the release kinetics of Bilastine from the orodispersible tablets.

9. Stability Study:

Stability studies were conducted over a period of 30 days under accelerated conditions of 40°C±2°C and 75%±5% RH. During this period, the oro-dispersible tablet (ODT) were evaluated for any alterations in various parameters such as average weight, hardness, thickness, friability disintegration time, drug content, drug release percentage, and other relevant characteristics. The Bilastine ODT remained both physically and chemically stable, exhibiting no signifiant changes in their physical attributes. Among the formulations, B5 maintained its integrity and original properties, with only slight variations observed in above parameters, all of which remained within acceptable limits.

RESULT & DISCUSSION:

Preformulation Study:

 Determination of UV Spectrum of Bilastine:

Standard Calibration Curve of Bilastine:

Table No. 5: Observation Table for Calibration Curve of Bilastine

Drug Excipient Compatibility Study:

• Fourier Transform Infrared Spectroscopy:

DSC Analysis:

Fig. No.7 DSC Analysis of Bilastine

Pre-Compression Parameter :

Bulk Density:

Bulk Density of  optimized batches of CPE was found  in the range of 0.2941g/ml to 0.4545 g/ml. Results are shown in table no.6

Tapped Density:

Tapped Density of optimized batches of CPE was found in the range of 0.3263g/ml to 0.51g/ml. Results are shown in table no.6

Carr’s Index :

Carr’s Index of Optimized batches of CPE was found in the range of 9.870%  to 20.184%. Results are shown in table no.6

Hausners Ratio:

Hausners Ratio of Optimized batches of CPE was found in the range of 1.09 to 1.201. Results are shown in table no.6

Angle of Repose:

Angle of Repose of optimized batches of CPE was found in the range of 13.82° to 29.68°. Results are Shown in table no.6

Table No.6 Pre-compression Parameter of CPE Generated by CCD:

Post-Compression Parameter of Tablets:

Hardness:

Hardness of Bilastine ODT was found in the range of 1.6±1.5 to 1.9±0.5. Results are shown in table no.7

Weight variation:

Weight Variation of Bilastine ODT was found in the range of 194±2 to 200±3. Results are shown in table no.7

Friability:

Friability of Bilastine ODT was found in the range of 0.4±0.06 to 0.60±0.035. Results are shown in table no.7

Thickness:

Thickness of Bilastine ODT was found in the range of 3.66 to 4.80. Results are shown in table no.7

Disintegration Test :

Disintegration Time  of Bilastine ODT was found in the range of 9.05 to 15.20 . Results are shown in table no.7

Drug Content:

Drug Content in Bilastine ODT was found in the range of 93.23 to 102.32 . Results are shown in table no. 7

Wetting Time:

Wetting Time of Bilastine ODT was found in the range of 10 to 28.06 . Results are shown in table no.7

In Vitro Dissolution Test:

Drug Release of Bilastine ODT within 10 min was found in the range of 88.84 to 108.50. results are shown in table no. 8

Table No.7 post-compression parameter of Bilastine ODT using Optimized CPE generated by CCD

All the values were in mean ±SD, n=3

Table No. 8 Percentage Drug Release of Bilastine ODT:

Fig No. In-Vitro Drug Release Profile of Optimized Batches Bilastine ODT(B1-B10)

Data Analysis: ⁽⁷⁾

Angle of Repose:

Following regression equation could describe the Angle of Repose response,

Angle of Repose (Y1) = + 33.2 – 2.1X1 – 1.4X2

Concerning Disintegration, the results of multiple linear regression analysis showed that the coefficients X1 and X2 bear a negative sign. The negative sign of X1 and X2 indicate an inverse relationship with response Y1 (Angle of repose). It reveals that the concentration of Banana Powder and MCC shows a reducing effect on Angle of repose. As the concentration of both X1 and X2 increases, the response Y1 (Angle of Repose) decreases, which is desirable for Good Flowability. ANOVA was used to identify the significant effect. The result was found to be significant at that level of probability.

Carr’s Index:

Following regression equation could describe the Carr’s Index response,

Carr’s Index (Y2) = + 15.45– 2.28X1 – 0.8445X2

Concerning Disintegration, the results of multiple linear regression analysis showed that the coefficients X1 and X2 bear a negative sign. The negative sign of X1 and X2 indicate an inverse relationship with response Y1 (Carr’s Index). It reveals that the concentration of Banana Powder and MCC shows a reducing effect on Angle of repose. As the concentration of both X1 and X2 increases, the response Y2 (Carr’s Index) decreases, which is desirable for better powder flow properties. ANOVA was used to identify the significant effect. The result was found to be significant at that level of probability.

Hausner’s Ratio:

Following regression equation could describe the Hausner’s ratio response,

Hausner’s Ratio (Y3) = + 1.14– 0.0237X1 – 0.0095X2

Concerning Disintegration, the results of multiple linear regression analysis showed that the coefficients X1 and X2 bear a negative sign. The negative sign of X1 and X2 indicate an inverse relationship with response Y3 (Hausner’s Ratio). It reveals that the concentration of Banana Powder and MCC shows a reducing effect on Angle of repose. As the concentration of both X1 and X2 increases, the response Y3 (Hausners Ratio) decreases, which is desirable for better powder flow properties. ANOVA was used to identify the significant effect. The result was found to be significant at that level of probability.

Disintegration Time:

Following regression equation could describe the Disintegration Time response,

Disintegration Time (Y4) = + 20.4– 2.2X1 – 1.6X2

Concerning Disintegration, the results of multiple linear regression analysis showed that the coefficients X1 and X2 bear a negative sign. The negative sign of X1 and X2 indicate an inverse relationship with response Y4 (Disintegration Time). It reveals that the concentration of Banana Powder and MCC shows a reducing effect on angle of repose. As the concentration of both X1 and X2 increases, the response Y4 (Disintegration Time) decreases, which reduces Disintegration Time. ANOVA was used to identify the significant effect. The result was found to be significant at that level of probability.

Graphical Representation:

Fig No. Effect of Independent Factors X1& X2 On four dependent factors Y1, Y2, Y3 & Y4

(a), (b), (c)&(d) indicates Response Surface Contour Graph Showing the Influence of Banana Powder(X1) and MCC (X2) on Angle of Repose (Y1), Carr’s Index (Y2) & Hausner’s ratio (Y3) & Disintegration Time (Y4). (e), (f), (g)&(h) indicates Response Surface 3D Graph Showing the Influence of Banana Powder(X1) and MCC (X2) on Angle of Repose (Y1), Carr’s Index (Y2) & Hausner’s ratio (Y3) & Disintegration Time(Y4)

Stability Study: