INTRODUCTION:

Oral drug delivery system has been regarded as the most convenient and economical method of drug administration with good patient compliance. In the recent years enormous development in taste masking technologies has given rise to novel strategies such as child-friendly fast dissolving dosage form, chewable tablets and taste-masked suspension.

Difficulty in swallowing conventional tablets and capsule is especially in pediatric, geriatric and dysphasic patients. Dysphagia is observed in about 35% of the general population, as well as up to 60% of the elderly population.

When introduced into mouth, orodispersible tablets disintegrate rapidly on contact with saliva and enable oral administration without water or chewing. They are also called as rapid disintegrating tablets, mouth dissolving tablet, rapid melt, porous tablet, quick dissolving tablet, fast dissolving tablet, oro-dispersible tablet.

United State Food and Drug Administration (USFDA) defined orodispersible tablet as, “A solid dosage form containing medicinal substances which disintegrates rapidly usually within a matter of seconds, when placed upon the tongue”.

According to CDER- ODTs are considered solid oral preparations that disintegrate rapidly in the oral cavity, with an in-vitro disintegration time of approximately 30 sec or less.

Levocetrizine Dihydrochloride is the active R (-) enantiomer of cetrizine and is a third generation non-sedating selective peripheral H1-receptor antagonist used in seasonal allergic rhinitis, perennial allergic and chronic urticaria. It has been approved and widely prescribed for alleviating symptoms of allergic rhinitis in many countries. It is absorbed rapidly after oral administration and half-life is 6-10 hr. which is appropriate for once a day formulation and provide onset of action for fast relief. Levocetrizine dihydrochloride has a bitter taste that hinders the suitable development of suitable orodispersible dosage forms. To overcome this problem, the objective of the present research was to formulate pharmaceutically acceptable oro-dispersible tablets of levocetrizine dihydrochloride using Kyron T-134 ion exchange resin by direct compression method that become a useful and economic choice of a taste masked composition for patients.

MATERIALS AND METHODS:

Levocetrizine Dihydrochloride was obtained from Medley Pharmaceutical Ltd. Andheri Croscarmellose sodium, Sodium starch glycolate, Crospovidone and MCC were obtained from Jinendra Scientific Jalgaon. Other excipients were used of AR grade.

METHOD:

The orodispersible tablets of levocetrizine dihydrochloride were prepared by direct compression method. Weighed the entire ingredient properly. Drug resin complex (levocetrizine dihydrochloride and Kyron T- 134) was passed through the sieve 60#. MCC (PH-102), pearlitol SD-200 were passed through sieve 22#. Croscarmellose sodium, aspartame, flavor, citric acid, Mg. stearate, talc were passed through sieve 40#. After sifting geometrical mixing of MCC (PH-102), pearlitol SD-200 with levocetrizine dihydrochloride. Then mixed all remaining ingredients. The blend was compressed onto 250mg weight of tablet using 9mm S/C punch on CIP Lab Press tablet punching machine. The compression force and mass of all tablets were kept stable and each tablet containing levocetrizine dihydrochloride equivalent to 5mg levocetrizine dihydrochloride.

Design of Experiment:^8-11

Current investigation aims at developing orodispersible tablet of taste masked levocetrizine dihydrochloride by using optimization technique. CCD is most efficient in estimating the influence of individual variables and their interactions using minimum experimentation. Based on preliminary trials, levels of CCS were selected as 3, 5, and 7% whereas levels of drug resin complex were 35, 40, 45%. Thirteen formulations were generated by taking nine possible combinations among which center point was repeated 4 times and mean values were taken for further study. Two factor, three level CCD was used and response surface methodology was applied to investigate the relative significant of the two independent variables, concentration of croscarmellose sodium (X₁), concentration of drug -resin complex (X₂) and their interaction on the dependent variables or responses i.e. Disintegration time (Y₁), Drug release (Y₂), Hardness (Y₃). The statistical experimental design was generated and evaluated for the quality of fit of the model and the constant and regression coefficients were calculated. To graphically show the influence of each factor on the responses, the countour plots were generated using the Design Expert*Software (Version 7.1.5 stat-Eanse Inc. Minneapolis, USA).

Purification of Ion Exchange Resin:^13,14

Accurately weighed resin kyron T-134 washed with distilled water, methanol and several times with distilled water to eliminate organic and color impurities until elute neutral. The wet resin were activated by 0.1M HCl: 0.1 M NaOH (50:50) and washed with distilled water. Then resin were dried overnight in hot air oven at 50⁰C and kept in amber glass vials.

Preparation of drug resin complex:^15,16,17

100mg of resin placed in beaker containing 25ml of distilled water and allowed to swell for 90 min. The pH of the resin solution was adjusted to 6.5 to 7.0 by using 1M KOH solution. Then accurately weighed 100mg of levocetrizine dihydrochloride was added to the resin solution and stirred for 4 to 5hr. During stirring, pH of the sample checked frequently and adjusted to 6.5 to 7.0 by using 1M KOH solution. The mixture was filtered through whatman filter paper no. 41 and residue was washed with 75ml of distilled water and put it for drying at 60⁰C for 2 hours in oven.

Table 1: Composition of batches generated by central composite design

Ingredients	Batches
Ingredients	LH1	LH2	LH3	LH4	LH5	LH6	LH7	LH8	LH9
Levocetrizine Dihydrochloride: Kyron T-134 equivalent to 5mg	10	10	10	10	10	10	10	10	10
MCC PH 102	120	118	115	120	127.5	122	122.47	97.5	97.5
Crosscarmellose Sodium	2.5	7.5	7.5	12.5	2.5	12.5	2.5	12.5	15
Pearlitol SD 200	100	97	100	90	92.5	87.5	97.53	112.5	110
Aspartame	5	5	5	5	5	5	5	5	5
Citric Acid	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5
Orange Flavour	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Mg. Stearate	1.25	1.25	1.25	1.25	1.25	1.25	1.25	1.25	1.25
Talc	1.25	1.25	1.25	1.25	1.25	1.25	1.25	1.25	1.25
Average wt. (mg)	250	250	250	250	250	250	250	250	250

Evaluation of Pre-compression parameters of granules:^17,18

1. Bulk density (BD):

Bulk density was determined by pouring a weighed quantity of tablet blend into graduated cylinder and measured the height. Bulk density is the ratio of total mass of the powder to the untapped volume of the powder.

2. Tapped density (TD):

Tapped density is the ratio of mass of tablet blend to tapped volume of tablet blend. Accurately weighed amount of tablet blend poured in graduated cylinder and height is measured. The cylinder was allowed to 100 tap under its own weight onto a hard surface. It is the ratio of total mass of the powder to the tapped volume of the powder. It’s unit g/ml.

3. Compressibility index and Hausner’s ratio:

The compressibility index (CI) and Hausner’s ratio (HR) is measure of the propensity of the powder to be compressed. As such they are the measures of inter particulate interaction. In a free flowing powder, such interactions are generally less significant and the bulk and tapped densities will be closer in values. For poorly flowing powder there are greater inter- particulate interactions and therefore a greater difference in bulk density and tapped density. These differences are also reflected in Carr's index and Hauser ratio.

4. Angle of Repose:

The angle of repose has long been used to characterize bulk solids. The friction forces in a loose powder can be measured by the angle of repose. It is an indicative of the flow properties of the powder. It is defined as maximum angle possible between the surface of the pile of powder and the horizontal plane.

Evaluation of Pre-Compression parameters of granules:^18,19

Evaluation of pre-compression parameters of granules was done by using Tap Density Tester (Electrolab ETD-1020). Weighed sifted 20gm of granules accurately. Filled it into 100ml of graduated measuring cylinder and mounted on a holder. Carefully leveled the granules without compacting and noted the unsettled apparent volume. Vo. mechanically tapped the cylinder containing the granules by raising the cylinder and allowing it to drop under its own weight using a suitable mechanical tap density tester that provides a fixed drop of 3mm (±10%) at a nominal rate of 250 drops per minute is used. Tapped the cylinder 100 times initially and measured the tapped volume, Vb. Then by passing the ARROW button of the tester B.D, T.D, C.I, H.R (bulk density, tapped density, compressibility index, Hausner’s ratio) values were displayed on tester screen and also recorded it. Compared the values of these parameters with the standard values for detection of flow properties of granules.

Evaluation of post-compression parameters of ODT: ^{17,18,19,20,21}

1. Weight variation:

Weigh individually 20 units selected at random or, for single dose preparation in individual containers the contents of 20 units, and calculate the average weight. Not more than two of the individual weights deviate from the average weight by more than the percentage shown in the table and none deviates by more than twice the percentage.

2. Thickness:

The uniformity of the diameter and thickness was measured using Vernier caliper. The average diameter and thickness of the tablet was calculated. The test passed if none of the individual diameter and thickness value deviated by ±5% of the average.

3. Hardness:

Monsanto hardness tester was used to check the hardness of the tablet. The tablet was placed vertically between the jaws of the tester. The two jaws placed under tension by spring and screw gauge. By turning the screw, the load was increased and at collapse the applied pressure from the spring was measured in kg/cm.

4. Friability:

The laboratory friability tester is known as the Roche friabilator. Friability is a measure of the resistance of the tablet to abrasion. Friability subjects the tablets to the combined effects of abrasion and shock by utilizing a plastic chamber that rotates at 25rpm, dropping the tablets form a height of 6 inches with each revolution. Twenty tablets were weighed accurately and placed in the friabilator and was operated for 100 revolutions or 4 minutes. The percentage weight loss usually should not exceed 0.5-1%.

5. Wetting time:

A piece of tissue folded twice was placed in a small petridish having diameter of 10cm containing 10 milliliters of distilled water and water- soluble dye methylene blue. A tablet was carefully placed on the paper at the time required for complete tablet wetting were measured. The appearance of dye on the surface of tablet was taken as a sign for complete wetting.

6. Drug content:

Three tablets of each batch of formulations were weighed and crushed in mortar. Tablets were triturated using mortar and pestle and tablet powder equivalent to 5mg of levocetrizine dihydrochloride was taken and first dissolved in 15 ml distilled water and volume was made up to 50ml using distilled water. Then 1 ml of this solution was diluted up to 10 ml using distilled water. This solution was measured using double beam UV-visible spectrophotometer at 231.20 nm. Drug content was calculated using formula.

7. Disintegration time:

The disintegration test is a significant characteristic required for orodispersible tablets. The disintegration time limit of 30 sec or less for ODT is described in center for drug evaluation and research. Typically disintegration time for orodispersible tablet is 5-30 sec. The test was carried out on 6 tablets using the disintegration test apparatus. Distilled water at 37±2⁰C was used as a disintegration media and the time in second taken for complete disintegration of the ODTs tablet with no palatable mass remaining in the apparatus was measured in seconds.

8. In-vitro dissolution study:

Dissolution profile of ODT of levocetrizine dihydrochloride was determined using the USP type- II apparatus with a paddle speed at 50 RPM. Dissolution was performed in 900ml phosphate buffer pH 6.8 maintained at 37±0.5⁰C. 5 ml of the samples were withdrawn with 5 ml phosphate buffer pH 6.8 as a dissolution medium. Withdrawn Samples were filtered through a whatman filter paper. Suitably diluted with phosphate buffer pH 6.8 and analyzed at 231.20 nm using a UV-Visible spectrophotometer1800.

RESULT AND DISCUSSION:

Table 2: Pre-compression parameters of CCD batches

Precompression Parameters

Batches

LH1

LH2

LH3

LH4

LH5

LH6

LH7

LH8

LH9

Bulk Density (gm/ml)

0.60±

0.025

0.55±

0.020

0.71±

0.026

0.64±

0.020

0.67±

0.028

0.68±

0.024

0.64±

0.015

0.63±

0.025

0.64±

0.018

Tapped Density (gm/ml)

0.80±

0.021

0.82±

0.018

0.86±

0.08

0.84±

0.014

0.80±

0.012

0.78±

0.012

0.82±

0.014

0.81±

0.012

0.81±

0.014

Compressibility Index (%)

14.12±0.50

15.0±

0.55

11.55±

0.82

14.0±

1.32

13.32±

0.41

11.89±

0.57

12.40±

0.34

14.8±0.50

13.31±

1.00

Hausner’s Ratio

1.12±

0.05

1.14±

0.07

1.13±

0.05

1.13±

0.05

1.18±

0.05

1.09±

0.06

1.19±

0.05

1.10±

0.06

1.20±

0.05

Angle of Repose (°C)

27.8

30.8

26.0

30.3

34.0

33.72

31.1

32.5

32.7

Table 3: Post-compression parameters of CCD batches

Post Compression Parameters	Batches
Post Compression Parameters	LH1	LH2	LH3	LH4	LH5	LH6	LH7	LH8	LH9
Weight Variation (mg)	249± 2.1	248± 1.24	250± 1.24	247± 1.69	249± 0.81	248± 1.63	249± 0.47	248± 2.49	249± 1.63
Thickness (mm)	4.82± 0.01	4.81± 0.01	4.80± 0.008	4.82± 0.02	4.84± 0.02	4.85± 0.02	4.84± 0.01	4.83± 0.01	4.85± 0.012
Hardness (Kg/cm²)	1.2± 0.08	1.1± 0.12	1.1± 0.12	1.2± 0.08	1.4± 0.04	1.4± 0.12	1.3± 0.16	1.2± 0.04	1.1± 0.08
Friability (%)	0.68± 0.04	0.74± 0.04	0.80± 0.02	0.78± 0.06	0.65± 0.02	0.67± 0.10	0.65± 0.08	0.72± 0.06	0.75± 0.06
Wetting Time (Sec)	22	30	38	34	29	27	24	39	27
DT (Sec)	27	22	26	24	22	23	25	24	22
Drug Released (%)	99.83	99.80	98.26	97.34	97.67	98.10	97.57	98.25	97.05

Fig 1: In-vitro drug released study of optimized batches of levoctrizine dihydrochloride oro-dispersible tablet generated by CCD (LH1-LH9)

Characterization of powder flow properties:

The prepared blend for all batches granules shows very good free-flowing properties. Compressibility index and Hausner’s ratio was found to be in the range of 11.55% to 15% and range of 1.09 to 1.20 respectively. The results show in table 2.

All the compressed tablets were evaluated for weight variation, thickness, hardness and friability which were found in official limit as per USP. The formulated tablets were disintegrated within 22 to 27 seconds. The wetting time for tablets was observed within a 28 to 45 seconds. The percentage drug released for optimized formulation LH3 was found to be 98.26%. All the results were shown in table 3.

Uniformity of dispersion:

The tablets from preliminary and optimized batches were tested for uniformity of dispersion. The tablets were considered as passable as there was no residue remained on the screen.

Statistical analysis and optimization:²⁶

The 2-factor Central Composite Design was applied to optimize the mouth dissolving tablets of levocetrizine dihydrochloride and to evaluate the effects of formulation variables. The response surface methodology was used to illustrate the quantitative effect of variables on response. Statistically analysed data clearly indicate that the DT, %DR and hardness values were mainly depending upon the select independent. The regression equations for the responses fitted in quadratic model were generated. ANOVA was used to identify the significant effect. Obtained value of F is larger than critical F-value, the result was found to be significant at that level of probability (p<0.05). Only statistically significant (p<0.05) coefficient were included in regression equation.

Regression Equations of Quadratic Model:

Disintegration Time:

Final equation in terms of coded form

DT = 26.92 - 0.30X₁ + 0.91X₂ + 1.25X₁X₂ – 0.56X₁² + 1.44X₂²

Concerning disintegration time, the results of multiple linear regression analysis showed that coefficient X1 bear negative sign. It revealed the disintegration time decreased with increase in croscarmellose sodium and while disintegration time increased with increase in drug-resin complex. Croscarmellose sodium 5% w/w and drug-resin complex 40% w/w were selected as the optimum concentration that showed the minimum disintegration time of 25 seconds. It observed that further increase in concentration of superdisintegrants led to the fall in disintegration time. ANOVA was used to identify the significant effect. Obtained value of F is larger than critical F-value, the result was found to be significant at that level of probability (p<0.05).

% Drug Released:

Final equation in term of coded form

%DR = 98.26 + 2.34X₁ + 1.30X₂ +2.09X₁X₂ – 2.46X₁²-1.59X₂²

Concerning dissolution, the results of multiple linear regression analysis showed that the coefficient X1 and X2 bear positive sign. More amount of CCS was expected to increase the % drug release due to faster disintegration of tablet. ANOVA was used to identify the significant effect. The result was found to be significant at that level of probability (p<0.05).

Hardness:

Final equation in term of coded form

HR = 2.63 + 0.17X₁ + 0.090X₂-0.30X₁X₂ – 0.70 X₁² -2.00X₂²

From the results of multiple linear regression analysis, the coefficients X1and X2 bear positive sign bear sign for hardness of tablet. Addition of more amount of CCS increase the hardness and concentration DRC also increases hardness. ANOVA was used to identify the significant effect. The result was found to be significant at that level of probability (p<0.05).

Table 4: Result of analysis of variance

Y1 = Disintegration Time

Model

Residual

Total

DF*

SS*

MS*

P value probe> F

174.44

147.68

336.92

87.22

24.61

5.37

0.0089-Significant

Y2 = % Drug Released

Model

Residual

Total

129.31

41.95

171.27

25.86

5.99

4.32

0.0424– Significant

Y3 = Hardness

Model

Residual

Total

0.67

0.39

1.09

0.22

0.079

9.82

0.0230–Significant


Fig 2: 3D response surface graph showing the influence of CCS (X1) and drug- resin complex (X2) on disintegration time (Y1)	Fig 3: 3D response surface graph showing the influence of CCS (X1) and drug-resin complex (X2) on the % drug released (Y2)

Fig 4: 3D response surface graph showing the influence of CCS (X1) and drug-resin complex (X2) on the hardness (Y3)	Fig 5: Overlay plot showing composition for optimized batch

CONCLUSION:

It was concluded that ODTs of levocetrizine dihydrochloride were successfully prepared by taste- masking method using weak cation exchange resin polymer Kyron T-134 and croscarmellose sodium as superdisintegrant using central composite design. As per design guideline it shows disintegration time within 5-30 seconds. The data observed showed that experimental design was successfully applied to optimize the concentration of superdisintegrant to formulate ODTs with desirable properties of less disintegration time 26Sec,% drug released 98.26% and hardness 2.6 Kg/cm². Central composite design could be successfully applied for the development of levocetrizine dihydrochloride oro-dispersible tablets. In near future ODT's market will expand very surely.

CONFLICT OF INTEREST:

The authors no conflicts of interest.

ACKNOWLEDGEMENT:

The authors are greatly thankful to the Department of Pharmaceutics, Shree Sureshdada Jain Institute of Pharmaceutical Education and Research, Jamner Dist. Jalgaon, Maharashtra for providing the laboratory facilities for the completion of this research work.

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Received on 25.01.2022 Modified on 26.04.2022

Res. J. Pharma. Dosage Forms and Tech.2022; 14(4):276-282.

DOI: 10.52711/0975-4377.2022.00045