DEVELOPMENT AND CHARACTERIZATION OF RISPERIDONE SUBLINGUAL TABLETS BY USING WET GRANULATION TECHNIQUE

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International Journal of Pharmaceutical Biological and Chemical Sciences (IJPBCS)

ISSN: 2278-5191 (Online) IJPBCS | VOLUME 8 | ISSUE 2 | APR-JUN 2019 | 17-25 Original Research Article – Pharmaceutical Sciences

International Journal of Pharmaceutical Biological and Chemical Sciences K. Sandhya Rani* et al

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DEVELOPMENT AND CHARACTERIZATION OF RISPERIDONE

SUBLINGUAL TABLETS BY USING WET GRANULATION TECHNIQUE

K. Sandhya Rani1_{, Shaik Shabbeer}1_{, P. Poli Reddy}1_{, B. Bharathi}2

1_{Swami Ramanandha Tirtha Institute of Pharmaceutical Sciences, Ramanandha nagar, Nalgonda- 508004.}

2_{Syncorp clincare technologies, Hyderabad.}

*Corresponding Author Email:[email protected]

ABSTRACT

Sublingual tablet of oral formulations of these drugs have been developed to improve their acceptability to patients and thus improve compliance. The focus of present investigation was to improve solubility, bioavailability and to achieved rapid onset action. sublingual tablets of risperidone were prepared by direct compression technique. Eight Formulations were formulated using sodium starch glycolate and crosscaramelose as superdisintegrants on Friability, Disintegration time. In addition, the prepared tablets were also evaluated for weight variation, thickness, diameter, friability, content uniformity, wetting time and drug release studies. Formulation reveals fast dissolution and disintegration rate of optimized risperidone sublingual tablet, which is prerequisite for rapid management of schizophrenia.

Key words:

Risperidone, wet granulation technique, FTIR studies, cross caramelose, Sodium starch glycolate, Drug release studies.

1.INTRODUCTION

Oral administration is the most popular route due to ease of ingestion, pain avoidance, versatility (To accommodate various types of drug candidates) and most importantly, patient compliance.1_{Also, solid oral delivery systems do}

not require sterile conditions and are, therefore, less expensive to manufacture. A vast variety of pharmaceutical research is directed at developing new dosage forms for oral administration. 2,3 _{Most of these}

efforts have focused on either formulating novel drug

delivery systems or increasing the patient compliance.4

The sublingual route usually produces a faster onset of action than orally ingested tablets and the portion absorbed through the sublingual blood vessels bypasses the hepatic first-pass metabolic processes.5_{Drug delivery, and quick}

drug delivery into the systemic circulation can be obtained. Sublingual administration can offer an attractive alternative route of administration. 6,7 _{The advantage of the}

sublingual drug delivery is that the drug can be directly absorbed into systemic circulation by pass particularly beneficial to pediatric and geriatric patients.8_{In addition}

sublingual mucosa and abundance of blood supply at the sublingualregion allow excellent drug penetration to achieve high plasma drug concentration with rapid onset of an action.9_{Risperidone, a water-insoluble}

second-generation antipsychotic drug, is widely used in the clinical management of schizophrenia, bipolar disorder, and irritability in children. 9-Hydroxyrisperidone, a major metabolite of risperidone, was pharmacologically as much potent as the parent compound. The serum concentration of the active moiety is thus the sum of serum concentrations of risperidone and 9-hydroxyrisperidone.

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2. MATERIALS AND METHOD 2.1 MATERIALS

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ISSN: 2278-5191(Online)

Int J Pharm Biol Chem.Sci.

2.2 METHODODOLOGY 12,13

Table-1: Formulation table for Risperidone sublingual tablets

S.NO. INGREDIENS F1 F2 F3 F4 F5 F6 F7 F8

1 Risperidone 5 5 5 5 5 5 5 5

2 Cross caramellose 2.5 5 7.5 10 - - - -

3 Sodium starch glycolate - - - - 2.5 5 7.5 10

4 Povidone 10 10 10 10 10 10 10 10

6 Lactose 76.5 74 71.5 69 76.5 74 71.5 69

7 Saccharrine sodium 1 1 1 1 1 1 1 1

8 Magnesium stearate 3 3 3 3 3 3 3 3

9 Talc 2 2 2 2 2 2 2 2

10 Total 100 100 100 100 100 100 100 100

Preparation of tablets by wet granulation method

The sublingual tablets of Risperidone were prepared using different combinations Sodium starch glycolate and croscarmellose sodium (CCS) as superdisintegrants, Lactose as a diluent, sodium saccharin as sweetening agent, alcoholic solution of PVP (10 % w/v) as binder and magnesium stearate with talc as a flow promoters. The API and excipients were mixed together, and a enough amount of alcoholic solution of PVP (10 %w/v) was added and mixed to form a coherent mass. The wet mass was granulated using sieve no. 12 and dried at 60○ C for 30 min. The dried granules were regranulated by passing through sieve no. 16. The dried granules were then blended with talc, magnesium stearate and compressed into tablets using a 6 mm punch rotary tablet machine. During compression the hopper containing granules was covered with black paper to prevent degradation of the drug.

Evaluation studies Bulk Density

Mass thickness is characterized as the mass of powder isolated by mass volume.

It is ascertained utilizing the accompanying condition Mass thickness = weight of test taken/volume noted

Tapped density

A precisely measured amount of the powder (W) was deliberately filled the graduated barrel and the volume (vo) was estimated.

Tapped thickness = weight of test taken/tapped volume Where, Vo = beginning volume; Vf = last volume.

Compressibility index

In view of the obvious mass thickness and the tapped thickness, the rate Compressibility of the mass medication was dictated by the accompanying recipe.

Carr’s index = Tapped thickness - Bulk thickness/Tapped thickness X 100

Hausner's ratio

It shows the flow properties of the powder. The proportion of tapped thickness to the mass thickness of the powder is called Hausner proportion.

Hausner's proportion = Tapped thickness/Bulk thickness

Angle of repose

The stream attributes are estimated by point of rest. Edge of rest is characterized as the most extreme point conceivable between the surface of a heap of the powder and the even plane.

tan = h/r

Where, h= height of the pile; r= radius of the base of the conical pile; θ= angle of repose

Evaluation of tablets14,15

Weight variation

Twenty tablets were Characterized chosen from each group and exclusively weighed. The normal weight and standard deviation of 20 tablets was ascertained. The cluster finishes the test for weight variety test if not more than two of the individual tablet weights digress from the normal weight by more than the rate.

Thickness

Twenty tablets were evaluated chosen from each group and there thickness was estimated by utilizing vernier caliper. Thickness of three tablets from each cluster was estimated and mean was computed.

Hardness

Hardness demonstrates the capacity of a tablet to withstand mechanical stuns while taking care of. The hardness of the tablets was resolved utilizing Monsanto hardness analyzer. It is communicated in kg/cm2_{. Three tablets were}

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Friability

The prepared tablets are under kept for the friability test the friability test is done by the Roche friabilator. First the tablets initial weight has to take after that the weighed tablets are poured in the fraibiltaor which is stating for 100 revolutions. Tablets were dedusted and reweighed, tablets should not lose more than 1% of their initial weight.

Content Uniformity

A quantity equivalent to 25mg of resperidone was transferred to a 100mL volumetric flask. To it, 50mLof Phosphate buffer 6.8was added and shaken for 1hour to dissolve drug. The solution was filtered, and residue was washed with 25mLof Phosphate buffer 6.8. The washing obtained was added to initial filtrate and volume was made upto 100mLwith Phosphate buffer 6.8. From above solution 1mLof stock solution was diluted to 10mL. The drug content was determined spectrophotometrically.

Wetting time

Petri dish (ID= 6.5cm) containing 6mLof simulated saliva pH, a tablet was put on the paper containing amaranth powder on the upper surface of the tablet, and the time required for formation of pink color was measured as wetting time. Three trials for each batch were performed and standard deviation was also determined.

In vitro drug release studies

The In-vitro dissolution studies are done by using USP-II apparatus paddle method. The temperature is maintained 37.5 0_{C. The rpm is 100. The 1ml of the solution is}

withdrawn and again same amount of sample is placed in the bowl for maintain of the sink conditions. The medium is the 6.8 buffer solution. The withdrawal sample is preparing dilutions and kept under for the analysing of the absorbance in U.V Spectroscopy.

Drug release kinetics

Zero order: Zero order: This form of elimination is

referred to as elimination which is independent of time or concentration. it will take a linear approach on a graph.

First order: This first order reaction is a reaction that

proceeds at a rate that depends linearly on only one reactant concentration.

Higuchi equation:

Mathematical model aimed to describe drug release from a matrix system was proposed by Huguchi in 1961. Initially conceived for planar systems, it was then extended to different geometrics and porous systems

ft = Q = A√ where,

Q is the amount of drug released in time t per unit area A,

C is thedrug initial concentration,

Cs is the drug solubility in the matrix media and

D is the diffusivity of the drug molecules (diffusion coefficient) in the matrix substance.

Korsmeyer-Peppas model Korsmeyer: Derived a simple

relationship which described drug release from a polymeric system equation.

Stability studies

The sublingual tablets of Risperidone were set on plastic tubes containing desiccant and put away at surrounding conditions, for example, at room temperature, 40±2oc and icebox 2-8oc for a time of 3 months.

3.RESULTS AND DISCUSSION

Drug and excipient compatability studies

FT-IR Spectra of Risperidone and F3 formulation were recorded. All these peaks have appeared in formulation and physical mixture, indicating no chemical interaction between Risperidone and polymer. It also confirmed that the stability of drug during microencapsulation process.

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Fig-2: FTIR Studies of optimized formulation

Evaluation studies

Pre compression parameters

a) Bulk Density: The bulk density for the formulated

blend was carried out for all formulation and found in the range of 0.431-0.471

b) Tapped density: The tapped density for the

formulated blend was carried out for all formulation and found in the range of 0.515-0.563.

c) Angle of repose: The angle of repose for the formulated

blend was carried out. It concludes that all the formulations blend was found to be in the range of 29 to310

d) Compressibility index: Compressibility index was

carried out, it found between 10% to 14.90% indicating the powder blend have the required flow property for compression.

Characterization of Formulation

Table-2: Pre compression parameters of Risperidone fast dissolving tablets

F. No Bulk

density

Tapped density

Compressibility

index Hausner ratio

Angle of repose (o₎

F1 0.431 0.522 17.43 1.21 29

F2 0.471 0.563 16.34 1.19 29

F3 0.463 0.524 11.64 1.13 30

F4 0.455 0.515 11.65 1.13 30

F5 0.462 0.531 12.99 1.14 31

F6 0.458 0.534 14.23 1.16 29

F7 0.449 0.521 13.81 1.16 31

F8 0.451 0.530 14.90 1.17 30

Post compression parameters Weight variation:

All the formulated (F1 to F8) tablets passed weight variation test as the % weight variation was within the pharmacopoeial limits of 7.5% of the weight. The weights of all the tablets were found to be uniform with low standard deviation values.

Thickness:

Tablets mean thickness (n=3) were uniform in F1 to F8 formulations and were found to be in the range of 2.3 mm to 2.6 mm.

Hardness:

The measured hardness of tablets of each batch ranged between 3.24 to 3.46 kg/cm2_{. This ensures good handling}

characteristics of all batches.

Friability:

The % friability was less than 1% in all the formulations ensuring that the tablets were mechanically stable.

Content Uniformity:

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Disintegration Time:

In the presented studies, three different types of in vitro methods of tablet disintegration were used: those where the only factor leading to the disintegration was water wicking into the matrix of the tablet, the tests with water agitation or stirring, and the methods where direct destructive forces were put on the tested tablet, such as grinding or pressing with additional weight. Therefore, disintegration tests showed great variability in the data measured with

different methods. The shortest registered disintegration time was 2.25 s, while the longest greatly exceeded 2.81 sec.

Wetting Time:

The weight of the tablet before keeping in Petri dish was noted (Wb) using Shimadzu digital balance. The wetted

tablet from the Petri dish was taken and re weighed (Wa)

using the same. The shortest registered wetting time was 1.25 s, while the longest greatly exceeded 1.52 sec.

Table-3: Evaluation parameters of Risperidone sublingual tablets B.

No.

Weight variation (mg)

Thickness (mm)

Hardness

(kg/cm2₎

Friability (%)

Drug Content (%)

Disintegration Time (sec)

Wetting time (sec)

F1 99 2.3 3.24 0.52 96.10 54 125

F2 98 2.4 3.26 0.45 95.20 53 134

F3 100 2.6 3.28 0.54 98.55 51 155

F4 97 2.4 3.46 0.51 97.50 49 152

F5 100 2.5 3.40 0.53 96.58 45 128

F6 100 2.6 3.28 0.54 98.55 51 155

F7 97 2.4 3.46 0.51 97.50 49 152

F8 100 2.5 3.40 0.53 96.58 45 128

Dissolution studies

All the three formulation of Risperidone sublingual tablets were subjected to in vitro release studies these studies were

carried out using dissolution apparatus. The dissolution medium consisted of 900 ml of Standard buffer pH 6.8 for period of time.

Table-4: Dissolution Profile of batch no. F1 to F8 %Drug Release

Time F1 F2 F3 F4 F5 F6 F7 F8

0 0 0 0 0 0 0 0 0

2 25.36 26.39 25.98 24.59 26.79 23.40 24.80 23.85 4 35.26 36.29 37.59 39.65 34.56 32.71 33.10 32.71 6 50.26 49.67 50.26 49.99 48.26 48.56 46.29 47.36 8 62.35 59.66 61.29 64.26 63.54 65.30 59.80 60.55 10 70.26 70.98 71.29 73.29 72.59 72.28 70.60 73.60 15 79.36 81.26 82.29 83.96 83.85 82.10 81.90 82.26 20 86.26 87.26 88.99 90.26 89.56 89.25 90.64 88.25

30 93.26 95.35 94.68 93.48 94.56 98.48 95.51 90.58

Fig-3: Percentage drug release of all formulations

0 20 40 60 80 100 120

0 5 10 15 20 25 30 35

F1 F2 F3 F4 F5 F6 F7

F8

% Dru

g

rel

ease

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Release order kinetics

Table-5: Drug release kinetics of optimized formulation

Time (hrs) % CDR SQARE T LOG T LOG%CDR ARA LOG%ARA

0 0 0 0 0 0 0

2 23.40 1 1 1.298635 76.6 1.903687

4 32.71 1.314215 0.30105 1.359835 67.29 1.887054

6 48.56 1.632051 0.47710 1.511349 51.44 1.829561

8 65.30 2 0.52206 1.762604 34.7 1.624385

10 72.28 2.136070 0.70898 1.800786 27.72 1.56573

15 82.10 2.44949 0.77815 1.898451 17.9 1.319106

20 89.25 2.655750 0.77815 1.942256 10.75 1.095169

30 98.48 2.728427 0.82309 1.979184 1.52 0.670246

Zero order kinetics:

Fig-4: Zero order plot for optimized formula

Fig-5: First order for optimized formula

y = 3.0716x + 24.475 R² = 0.8019

0 20 40 60 80 100 120 140

0 10 20 30 40

%

C

D

R

Time

Zero order kinetics

% CDR

Linear (% CDR)

y = 0.0443x + 1.0387 R² = 0.4762

0 0.5 1 1.5 2 2.5

0 10 20 30 40

%

ARA

Time

First order kinetics

LOG%CDR

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Fig-6: Higuchi plot for optimized formula

Fig-7: Korsmayer peppas plot for optimized formula

The drug release from the tablets was found to follow Zero order release based on the “r” value obtained for Zero order (0.801) and first order (0.476) for F6 formulation. Also, the drug release mechanism was found to be “Diffusion” based

on the “r” value of 0.975 obtained for Higuchi’s plot. Similarly, the drug release mechanism was found to be of Anomalous diffusion mechanism based on the “n” value of 0.552 obtained for Peppa’s equation.

Table-6: Drug release kinetics

S.No Kinetic model R2_value

1 Zero order kinetics 0.801 2 First order kinetics 0.476 3 Higuchi model 0.975 4 Krossmayer peppas 0.552

Stability Study

There was no significant change in physical and chemical properties of the tablets of formulation F-6 after 6 months.

Parameters quantified at various time intervals were shown.

y = 114.82x - 2.4771 R² = 0.9751

-20 0 20 40 60 80 100 120

0 0.5 1

%

C

D

R

Root of Time

Higuchi model

% CDR

Linear (% CDR)

y = 0.3698x + 0.0419 R² = 0.5524

0 0.2 0.4 0.6 0.8 1 1.2

0 0.5 1 1.5 2 2.5

Lo

g %

C

D

R

Log T

Krosmayer peppas

LOG T

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Table-7: Stability studies of all formulations F.

Code Parameters Initial

1st Month 2nd Month 3rd Month 4th Month 5th Month 6th Month

Limits as per Specifications

F-6 25

0_C/60%RH

% Release 98.48 98.46 98.42 98.41 98.38 98.31 98.22

Not less than 85 %

F-6

300_C/75%

RH % Release

98.48 98.45 98.45 98.40 98.35 98.29 98.21 Not less than

85 %

F-6

400_C/75%

RH % Release

98.48 98.46 98.44 98.42 98.32 98.25 98.15 Not less than

85 %

4.CONCLUSION

The design prepare and characterization of the sublingual tablets of the Resperidone by using wet granulation technique. In this formulation development first undergo for the pre formulation studies such as the color, odour, taste and solubility studies are done. The API and polymers compatability studies are done by the FTIR studies. For formulation studies the used excipients are the croscaramellose, sodium starch glycolate and lactose and talc were used. The eight formulations are done in this F6 formulation are release the drug up to the 8 hrs. It is compared to innovator it release the drug. The post compression parameters are also done. Such as the weight variation, friability, thickness, disintegration are done. All parameters are come within range of limits. The stability studies are done for 90days.The kinetic profile data is calculated it is following the zero order and higuchi model.

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*Corresponding author Email address: