Formulation and Evaluation of Taste Masking Lercanidipine Hydrochloride Oral Disintegrating Tablets

Lercanidipine is an antihypertensive drug. It is a dihydropyridine class of calcium channel blockers. It is extremely bitter. The reason for this exploration was to build up a non-bitter orally breaking down the tablet of inadequately solvent medication viz Lercanidipine. The bitterness of drug, masked through complexing Tulsion 339 in various ratios. Sodium starch glycolate, crospovidone, low substituted hydroxypropyl cellulose selected as super disintegrants in the formulation. The formulated tablets were assessed for various properties like Drug content, crushing strength, friability, wetting time, water retention proportion, breaking downtime and in-vitro disintegration time and dissolution studies. The disintegration time obtained in the range between 38.46-51.40 seconds. Release studies observed between 5 to 30minutes. From the prepared formulations, formulation using Low substituted hydroxypropyl cellulose with 5% concentration showed 98.89% drug release within 30minutes. Thus F9 was considered as best among the other formulations With effective dissolution and improves patient intake. Drug release Kinetic analysis (r) based on best curve itting method for optimized lercandipine formulation showed irst order kinetics proves that the drug release depends upon its concentration.

Lercanidipine, Tulsion 339, super disintegrants, oral disintegrating tablets, disintegration time A Lercanidipine is an antihypertensive drug. It is a dihydropyridine class of calcium channel blockers. It is extremely bitter. The reason for this exploration was to build up a non-bitter orally breaking down the tablet of inadequately solvent medication viz Lercanidipine. The bitterness of drug, masked through complexing Tulsion 339 in various ratios. Sodium starch glycolate, crospovidone, low substituted hydroxypropyl cellulose selected as super disintegrants in the formulation. The formulated tablets were assessed for various properties like Drug content, crushing strength, friability, wetting time, water retention proportion, breaking downtime and in-vitro disintegration time and dissolution studies. The disintegration time obtained in the range between 38.46-51.40 seconds. Release studies observed between 5 to 30 minutes. From the prepared formulations, formulation using Low substituted hydroxypropyl cellulose with 5% concentration showed 98.89% drug release within 30minutes. Thus F9 was considered as best among the other formulations With effective dissolution and improves patient intake. Drug release Kinetic analysis (r 2 ) based on best curve itting method for optimized lercandipine formulation showed irst order kinetics proves that the drug release depends upon its concentration.

INTRODUCTION
The oral route of drug administration has been generally accepted and up to 50-60% of total dosage forms are administered orally. Solid dosage forms viz tablets and capsules are worldwide accepted dosage forms due to its precise dose, self medication, a non-invasive route which makes the solid dosage forms as patient user-friendly. However, the substantial drawbacks of these traditional dosage formulations include dysphagia for pediatric and geriatrics patients. This problem mainly encounters 35% of the general population. These traditional tablets need water for administration. This issue causes dif iculty in swallowing when water is not available. Hence Dispersible tablets plays a dominant role for these purposes, which can quickly dissolve or disintegrate in the oral cavity and have drawn a good interest to the patients (Saini and Garg, 2019).
The word "orodispersible tablet" was adapted by European Pharmacopoeia as a tablet to be inserted in the mouth where it easily disappears before swallowing, suggesting maximum DT of 3 min as calculated in a conventional disintegration test apparatus. Other synonyms of ODT includes quick melts, rapid melts, fast dissolving, fast disintegrating, rapid dissolve or mouth dissolving tablets (Mohanachan-dran et al., 2011).
The bitter taste of orally administered medicinal products often results in patient non-compliance with the use of medicinal products, especially for children and the elderly. Sadly, most medicines have a natural, bitter taste that can cause a burning sensation in the throat or mouth. In particular, a bitter taste can reduce patient compliance and thus reduce the ef iciency of pharmacotherapy (Suryadevara et al., 2017).
The Drug Lercanidipine HCl used in the present study is a type-II biopharmaceutical classi ication system since it has low solubility and high permeability. Its recommended for relief of seasonal allergic rhinitis related symptoms in adults and children 2 years of age and is intended for chronic idiopathic urticaria therapy in adults and children 6 months of age and older (Suresh et al., 2007). Lercanidipine HCl shows low bioavailability so its aqueous solubility should be targeted by a Bioavailability Improvement strategy.
It is used in the treatment of Hypertension, due to its selectivity and speci icity on the smooth vascular cells.

MATERIALS
Lercanidipine and Polacrallin potassium (Tulsion 339) was obtained from Spectrum pharma research solutions, Mumbai, Sodium starch glycolate, Crosspovidone, Low substituted hydroxypropyl cellulose, Sodium hydroxide and Sucralose were obtained from SD ine chemicals, Mumbai, Microcrystalline cellulose, Magnesium stearate, Talc were obtained from Central drug house (p) Ltd, New Delhi, potassium dihydrogen phosphate and sodium hydroxide were obtained from Finar chemicals ltd, Ahmedabad.

Drug and Excipient Compatibility by using FTIR
The interaction study between the drug and Tulsion 339 and other excipients were performed using FTIR. The pellets were prepared on KBR press. The spectra were recorded over the wavenumber range of 3500 cm −1 .The pictorial optimized formulation shown in Figure 2.
Standard calibration curve of pureLercanidipine using U.V. spectroscopy

Preparation of standard stock solution
Standard stock solution of Lercanidipine was prepared by dissolving accurately weighed 100mg of Lercanidipine in the little quantity of phosphate buffer pH-6.8 in 100ml volumetric lask. The Volume was made up to the mark using the same buffer. From this 10ml was pipette out and Volume was made up to 100 ml with phosphate buffer pH-6.8 to get standard stock solution containing drug 100µg/ml.

Spectrophotometric scanning of Lercanidipine
From the stock solution, the ultraviolet scan was taken between the wavelength 200-400nm. Which gave the highest peak at 240nm and the same was selected for Lercanidipine estimation.

Preparation of standard plot of Lercanidipine
From the standard stock solution series of dilution were made to 5, 10, 15, 20, 25, 30 µg/ml solution using phosphate buffer pH-6.8 and corresponding absorbance was measured at 240 nm in a U.V spectrophotometer. Results are depicted in Figure 1.

Formulation development
As the drug is highly bitter irst attempt was made to mask the bitterness of the drug by using ion exchange resin such as Tulsion 339. Several trails were carried out with different ratios such as 1:1, 1:2, and 1:3, respectively.

Preparation of drug resinate complex
Lercanidipine was complexed with ion exchange resin using polacrillin potassium (Tulsion 339) to masks the taste with the following procedure.
Step-II Drug resin complexation was prepared by a simple aqueous binding process. The ion-exchange resin particles were uniformly dispersed in a drug ethanolic solution with a mass ratio under magnetic stirring to achieve an equilibrium state.

Step-III
The complexes were subjected to iltration and cured with deionized water to decant the unbound drug and other ions. The complexes further dried in a hot air oven for 4 h at 40 • C to get powdered mass and stored in a tight glass vial.
Step-IV From the above complexes, the best complex is selected based on Drug loading ef iciency.

Characterization of the complex for drug content
From the prepared Drug resonated-complex, equivalent to 8mg of drug was stirred through magnetic stirrer until the entire drug was leached out from the complex using 100ml of 6.8-phosphate buffer for 60min. The inal solution was iltered through Whatman's ilter paper after serial dilutions using pH-6.8 phosphate buffer and the drug content was assayed spectrophotometrically at 240 nm.
From the observations Drug & Tulsion 339 complex ratio, as shown in Table 1, 1:2 used for study due to the high percentage of drug content in the complex.

Interpretation of drug-resinated complex palatability
Palatability was determined by time intensity method. Here ive human volunteers were selected and suf icient quantity of sample was placed in the mouth for 10 sec. to determine any bitter levels from the given resin complex based on 0-3 scale. A higher value is the sign of strong bitter taste.

Angle of repose
A glass funnel was selected with a stem of 15-30 mm and ixed to the funnel stand; Below which a graph paper was placed to determine the lowability of granules. Prepared Granules were assessed to form a heap. Heap circumference was marked and the pile height was measured using two rulers. The height was measured and noted it as (h). The area (πr 2 ) was determined, radius(r) was calculated and substituted in the formula (θ =tan −1 h/r), to obtain the angle of repose. Repeated the experiment twice more and calculate the average angle of repose (Kaur et al., 2020).

Bul k density
Lubricated blend sieved through #20 was correctly weighed to 25 g and transferred to a graduated cylinder of 100ml. Level the Powder carefully and read the unsettled apparent Volume (V0) without compacting. The apparent bulk density in gm/ml can be depicted as follows, Bulk density = W eight of powder Bulk volume Tapped densit y It is determined using the standard procedures and calculated as follows,

Carr's Index
It is an essential parameter to determine the powder compressibility and packing characterstics before the compression process. It can be determined as follows,

Hausner's Ratio
Hausner's Ratio is a number of co-related to a powder's lowability. The Hausner Ratio formula is as shown in the equation below,

Preparation of tablet
Using the lubricated blend as shown in Table 2, Lercanidipine Orally disintegrating tablets were compressed on 16 stations cadmach rotary compression machine equipped with 9mm biconcave punches and constant hardness is maintained for all the tablets. Five tablets were randomly selected, checked for color, odor and shape and the data was noted

Thickness
Thickness and diameter was measured for ive tablets from all the batches using vernier calipers.

Hardnes s test
It was tested using 'Monsanto' Hardness tester. Five tablets were randomly selected and placed between the two plungers using a compressible spring on a stainless steel barrel. The initial reading was noted when the lower plunger was in tablet contact and subjected forcilbly to move the upper plunger until the tablet breaks by appling compressional force. Barell containing Pointer on the guage indicates the force, which is a measure of the hardness of tablet strength.

Weight variation test
20 tablets were randomly selected and determine the individual weights and their average Weight. Calculate the percentage deviation of IP standards.

Friability test
For this test, Roche friabilator was used to assess the friction and shock to overcome chipping and breaking of tablets during compression and handling. It has a plastic chamber spins at 25rpm y lowering the tablets from a distance of six inches for each revolution. Usually, preweighed tablets are placed in the friabilator subjected to 100 revolutions. The tablets are then de-dusted and reweighed (Panigrahi et al., 2010).
Compressed tablets weigh less than 1.0% of their initial Weight are acceptable for consideration.

In-Vitro Dispersion Time
It is the time takenfor the tablet to fully disintegrate into ine particles. Three tablets were randomly chosen from each batch and In-vitro dispersion time was performed using 6.8 phosphate buffer (Liberman et al., 1987).

In-Vitro D isintegratio n Test
It is one of the most important criteria for the prepared tablets to meet out the needs. It can be performed using disintegration Test apparatus IP. Each tablet is placed into one tube of the glass assembly. The entire assembly is suspended in the beaker containing distilled water and subjected for running until the tablet disintegrates, time was noted.

Standard
The tablets must disintegrate within 30seconds when subjected to a disintegration test examination.

Taste evaluation
Taste assessment using time intensity process conducted in 6 volunteers. A tablet was placed in the oral cavity for 10 seconds and the recorded bitterness levels and continued the test for different time intervals and repeated the test for comparison (Yunxia et al., 1996).

Water absorption ratio
A tissue paper of the desired size is taken, folded twice and kept on the surface of a small Petri dish illed with 6 ml of distilled water. The single tablet was taken and placed on the Petri dish containing paper. Complete wetting time was observed and recorded. The last tablet was then reweighed (Kuchekar et al., 2003).
Water absorption ratio= f inal weight − initial weight initial weight × 100

Wetting time
Tissue papers cut down to a circular shape of 10cm diameter in size and dipped in 6ml(w/v)of Methylene blue dye solution in a Petri dish. A tablet was carefully placed on the surface. The time at which colour development on the upper tablet surface is observed (Yunxia et al., 1999).

Drug content uniformity test
From each formulation, 5 tablets were randomly selected weighed and powdered. Equivalent quantity of 100mg drug was transferred to 100 ml volumetric lasks. The powder substance is solubilised with small pH-6.8 phosphate buffer volume and subjected for sonication for half an hour. Later solution was iltered and the desired Volume was made using pH-6.8 phosphate buffer. The inal concentration was diluted to 10µg/ml and absorbance was observed at 240nm (Seager, 1998).

Invitro drug release
Drug release studies carried out using USP type-(paddle) apparatus at a speed of 50 rpm for a speci ied time period of 30mins at temperature (37±0.5 0 c) (Mallet, 1996). The samples were iltered and the amount of drug measured at 240 nm using UV Visible Spectrophotometer (Pahwa and Gupta, 2011).
All the post compression parameters were tabulated in table Tables 4, 5 and 6 respectively.

Kinetic study
The dissolution data was subjected to various kinetic models such as zero order, irst order, Higuchi, Korsmeyer Peppas etc. to know the drug release kinetics of the optimized formulation (Figures 3 and 4).
From the above observations, Kinetic analysis (r 2 ) for the optimized formulation of Lercanidipine shows First order kinetics (R 2 =0.94) indicated that the drug release depends upon its concentration (Tables 7, 8 and 9).

CONCLUSIONS
In the present research investigation, an attempt was made to explore by use of cation exchange resins i,e: Tulsion-339 as a taste masking agent in the formulation of oral disintegrating tablets of Lercanidipine Hcl.
Drug resin complex was prepared in the ratio of 1:1,1:2, 1:3 among them maximum drug content was observed for1:2 ratio i,e.. 96.88% which was further inalized for formulations using super disintegrants sodium starch glycolate, cross povidone and L-HPC. From the above results, F9 with L-HPC showed maximum drug release 98.89% in 30 min and showed less disintegration of 38.46 seconds. There is no signi icant change in stability studies. Lercandipine tastes masked ODT are successfully prepared using minimum excipients and a simple method of manufacture.