INTRODUCTION:

It is evident from the recent scientific and patient literature, that there is an increased interest in novel dosage forms that are retained for a prolonged and predictable period of time^1-5. Poor absorption of many drugs in the lower GI tract makes it necessary for controlled release dosage forms to be maintained in the upper GIT, particularly in the stomach and upper small intestine^6-8.

One of the approaches for achieving a prolonged and predictable drug delivery in the GI tract is to control the gastric residence time (GRT). Dosage forms with prolonged gastric residence and controlled drug delivery are called gastro retentive drug delivery systems (GRDDS), these are also known as gastro retentive dosage form (GRDF or GRDS)^9-11. GRDFs extend significantly the period of time over which the drugs may be released. The various pharmaceutical approaches for gastro retention are classified as follows: Mucoadhesive systems, Modified shape systems, Altered density systems. Mucoadhesives enhances the efficacy of drug delivery, through an intimate and prolonged contact between the drug delivery device and the site of absorption^12-15. Direct compression tablets are compressed directly from powder blend of the active ingredients and suitableexcipients. No pretreatment of the powder blends by wet or dry granulation procedure is necessary. Directcompression vehicles or carriers must possess good flow and compressible characteristics. The advantage of directcompression was made possible by the commercial availability of direct compression tablet vehicles that possessboth fluidity and compressibility^16-19. Direct compression for tablets containing 25% or less of drug substances frequently can be used by formulating with a suitable diluent that acts as a carrier or vehicle for the drug^20-23.The aim of the present study was to develop floating tablets of Ziprasidone HCl by direct compression method. Ziprasidone HCl whose physicochemical properties and short life makes it suitable candidate for floating drugdelivery system and to achieve efficacious blood levels over long periods of time.

MATERIALS AND METHOD:

Materials:

Hydroxy propyl methyl cellulose (K4,K15,K100), Microcrystalline cellulose, NaHCO₃, Magnesium stearate, were purchased from Loba, Chemie Pvt. Ltd., India. Ziprasidone HCLwas received as a gift sample from Hetero Drugs, Hydrabad India. All chemicals were used without further purification.

Method:

Estimation of Ziprasidone HCL:

Preparation of standard stock solution:

The estimation ofZiprasidone HCLis carried out by preparing stock solution in 0.1 N HCl and further made up dilutions and measures the absorbance at 318nm by using an UV Spectrophotometric method^24-25. The method obeyed Beer’s law in the concentration range of 10-30 μg/ml.

Drug-polymer compatibility by FT-IR spectroscopy:

A drug-polymer compatibility was analyzed using FourierTransform Infrared spectrophotometer (Varian 640-IR, USA). The spectra were taken in the wave number region 4000-400 cm⁻¹ as KBr pellets of drug (Ziprasidone HCL), polymer and tablet.

Preparation of ziprasidone hydrochloride floating tablets

Accurately weighed quantities of polymer and MCC were taken in a mortar and mixed thoroughly, to this mixture required quantity of Ziprasidone HCL was added and mixed slightly with pestle. Accurately weighed quantity of Sodium bicarbonate was taken separately in a mortar and powdered with pestle^26-28. The powder is passed through sieve #40 and mixed with the drug blend which is also passed through sieve #40. The whole mixture was collected in a plastic bag and mixed for 3 minutes. To this Magnesium stearate was added and mixed for 5 minutes, later Talc was added and mixed for 2 minutes. This mixture was compressed into tablets using a 16-station punching machine with 8 mm round flat faced punches^29-31. The drug and polymer ratio was varied to get floating tablets of varying polymer concentrations as shown in Tables No. 2 to 4.

Characterization of ziprasidone HCl floating tablets:

The thickness, diameter of the tablets was determined using Verniercalipers. The hardness of thetablets (n=6) was determined by using Monsanto hardness tester^25-26. The friability (%) of the tablets was determined using Roche friabilitor. Weight variation est of the tablets was carried out as per the official method^30,31.

Weight Variation:

Tentablets were selected at a random and average weight was calculated. Then individual ltabletswere weighed and the individual weight was compared with an average weight³².

Average Weight – Intial Weight

% weight variation = --------------------------------- × 100

Average Weight

Thickness and diameter:

Five tablets were picked from each formulation randomly and thickness and diameter was measured individually. And tablet thickness and diameter was measured by using verniercalliper and it is expressed in mm³³.

Hardness:

Hardness indicates the ability to resistance to shipping and breakage under condition of storage, transportation and handling before usage depends on its hardness³⁴. The hardness of each batch of tablet was checked by using Monsanto hardness tester. The hardness was measured in terms of kg/cm². 5 tablets of each formulation were chosen randomly and tested for hardness.

Friability:

Friability refers to loss in weight of tablets in the containers due to removal of fines from the tablet surface. Friability generally reflects poor cohesion of tablet ingredients³⁵. Roche Friabilatorwas used for the purpose. The % friability was then calculated by the following formula:

Intial Weight- Final Weight

Percentage friability = ------------------------------X 100

Intial Weight

Content uniformity:

Twenty tablets were weighed and the power equivalent to 30mg of Ziprasidone HCl was taken in 100ml volumetric flask containing 80ml of methanol. The content was shaken well for 30 minutes and made up to the volume with saline buffer pH 7.4 solutions and determined the Ziprasidone HCl content by measuring the absorbance at 318nm.

In vitro buoyancy studies:

The in-vitro buoyancy was determined by floating lag time and floating time. The tablets were placed in dissolution vessel containing 900 ml of 0.1 N HCl. The time required for the tablets to rise to the surface and a float was determined as floating lag time³⁶. The duration for which the tablet remains afloat on surface of solution is known as floating time.

In vitro dissolution studies:

The release rate of Ziprasidone HCl floating matrix tablet was determined using USP Dissolution testing apparatus (basket type)³⁷. The dissolution test was performed using 900 ml of 0.1 N HCl and 2% SLS, at 37±0.5°C and speed of 50 rpm. Aliquots of 10 ml samples were withdrawn from a zone midway between the surface of dissolution medium and the top of rotating basket not less than 1 cm apart from the vessel wall at one hour interval and were replaced with fresh dissolution medium for 12 hours. Absorbance of these solutions was recorded at 318 nm using UV spectrophotometer. Results weregiven in the Table no. 5 and 6.

Floating properties of tablets:

The tablets were placed in a 100 ml glass beaker containing 0.1 N HCl.

1 Floating Lag Time: The time required for the tablet to rise to the surface of the medium and float was determined as floating lag time

2 Floating Duration Time: The time for which the tablet remained floating on the surface of medium was determined as floating duration time.

Stability Studies:

Selected formulation were subjected to stability studies as per ICH guidelines at 30°C/ 65 % RH and 40°C / 75% RH for 6 month. Sample were taken and analyzed at 1^st, 3^rd and 6^thmonth as per the ICH guidline³⁸.

Table1: Calibration curve data f Ziprasidone HCl.

Concentration (μg)	Absorbance
10	0.061
15	0.085
20	0.111
25	0.138
30	0.165

RESULTS:

Fig. 1.Calibration curve data of Ziprasidone HCl.

Table 2: Composition of tablets formulated with HPMCK4M. Weight ( mg)

Ingredients	F1	F2	F3	F4
Ziprasidone HCL	30	30	30	30
HPMC K4M	15	30	45	60
M.C.C.	116.1	101.1	86.1	71.1
NaHCO₃	16.2	16.2	16.2	16.2
Mg. Sterate	0.9	0.9	0.9	0.9
Talc	1.8	1.8	1.8	1.8
Total	180	180	180	180

Table 3: Composition of tablets formulated with HPMCK15M. Weight ( mg)

Ingredients	F5	F6	F7
Ziprasidone HCL	30	30	30
HPMC K15M	30	45	60
M.C.C.	101.1	86.1	101.1
NaHCO₃	16.2	16.2	16.2
Mg. Sterate	0.9	0.9	0.9
Talc	1.8	1.8	1.8
Total	180	180	180

Table 4: Composition of tablets formulated with HPMCK100M. Weight ( mg)

Ingredients	F8	F9	F10
Ziprasidone HCL	30	30	30
HPMC K100M	30	45	60
M.C.C.	101.1	86.1	71.1
NaHCO₃	16.2	16.2	16.2
Mg. Sterate	0.9	0.9	0.9
Talc	1.8	1.8	1.8
Total	180	180	180

Table No. 5. Cumulative percentage drug release of the formulations prepared with HPMC K4M (F1 to F4)

Time(hrs)	F1(25%)	F2(35%)	F3(45%)	F4(60%)
0	0	0	0	0
0.5	57.56	34.68	25.80	10.08
1	78.30	40.89	36.57	23.81
2	88.56	60.08	60.00	30.47
4	91.02	95.01	81.46	60.22
8	100	100	93.50	95.30

Table No.6. Cumulative percentage drug release of the formulations prepared with HPMC K15M (F5 to F7) and with HPMCK100 (F8 to F10)

Time (hrs)	F5 (40%)	F6 (35%)	F7 (25%)	F8 (60%)	F9 (45%)	F10 (45%)
0	0	0	0	0	0	0
0.5	3.2	2.23	23.25	10.08	5.32	5.62
1	8.16	19.07	43.62	23.81	15.2	30.80
2	16.23	2903	65.33	30.47	30.2	55.50
4	35.50	95.01	76.26	60.22	65.20	66.30
8	64.29	100	90.60	95.30	100	95.02

Fig. 2.Absorption spectrum of ZiprasidoneHCl.

Fig 3: FT-IR spectrum of a) HPMC, b) ZiprasidoneHCl, c) Tablet

Table No. 8.Floating properties of prepared formulations

FormulationCode	Floating lagtime	Total floating time
F1	60 sec	>4
F2	55 sec	>6
F3	47 sec	>8
F4	61 sec	>12
F5	69 sec	>12
F6	67 sec	>12
F7	49 sec	>12
F8	71 sec	>12
F9	55 sec	>12
F10	59 sec	>12

Fig.4. Floating study of tablet at different time interval

DISCUSSION:

All the tablets of different formulations were subjected to various evaluation tests such as thickness, hardness, weight variation and drug content in prepared tablets. The results of the tests were shown in Table No.7. The drug content of all the formulations was determined and was found to be within the permissible limit. This study indicated that all the prepared formulations were good. The Drug polymer compatibility of tablet was assessed by FT-IR spectroscopy and result reveled that characteristics peaks of drug was also present in same wave number in physical mixture and also tablet formulation. This conforms the chemical stability of ZiprasidoneHCl in formulated tablets (Fig. 3).All the formulations were tested for floating properties like floating lag time and total floating time. The results of are shown in Table No. 8. All the formulations floated within 71 sec and total floating time was greater than 12 hrs except for formulations F1-F3. The floating of tablet at different time interval are shown in Fig.4. Stability study data showed selected formulation (F6) showed no significant variation in the disintegration, friability, hardness and in-vitro drug release.

CONCLUSION:

The hydro dynamically balanced dosage form of ZiprasidoneHClwas targeted to be developed using direct compression technique. ZiprasidoneHClwas formulated as a floating tablet. This was enrobed in a coating matrix containing HPMC of different viscosity grades mixed with a gas generating system. The purpose of fabricating the formulation in this manner was to ensure that the content uniformity of the potent drug was dependent on mixing of the drug with the polymeric layer. The product was designed as tablet of 180 mg floating tablet containing 30 mg drug. It was observed that formulation (F6) containing HPMC K15M 60% alone gave the acceptable release profile.

In the present study gastro relative floating matrix tablet of ziprasidoneHClwere successfully prepared by direct compression method. The study showed that ratio of polymer agent can be used as matrix forming agent to sustain release of the drug to the concentration of polymers increased drug release rate decreased among all there formulation F6 was found to be the best formulation. Stability study data showed selected formulation (F6) showed no significant variation in the disintegration, friability, hardness and in-vitro drug release.Thus, it is well understoodthat ZiprasidoneHClloaded floating tablet was stable and shows better drug release proﬁle.

ACKNOWLEDGMENT:

Authors want to acknowledge the facilities provided by the Rungta College of Pharmaceutical Sciences and Research, Kohka, Kurud Road, Bhilai, Chhattisgarh, India. The authors also wants to acknowledge Chhattisgarh Council of Science and Technology (CGCOST) for providing financial assistance under mini research project (MRP) vide letter no. 1124/CCOST/MRP/2015; Dated: September 4, 2015 and 1115/CCOST/MRP/2015; Dated: September 4, 2015.

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Received on 16.08.2017 Modified on 20.09.2017

Research J. Pharm. and Tech 2018; 11(5):2080-2085.

DOI: 10.5958/0974-360X.2018.00386.4

Formulation	Hardness (kg/cm2)	Thickness (mm)	Weight Variation (mg)	Friability (%)	Drug Content (%)
F1	5.50±0.24	3.384±0.05	180.60±2.12	0.1	97.20
F2	5.65±0.18	3.276±0.06	199.33±1.45	0.25	100.02
F3	5.40±0.37	3.186±0.03	182.80±1.63	0.19	99.32
F4	5.80±0.26	3.186±0.04	178.09±2.43	0.22	98.58
F5	5.55±0.56	3.234±0.06	180.05±4.51	0.18	99.48
F6	5.45 ±0.35	3.45 ±0.06	179.37±3.89	0.22	99.85
F7	5.50±0.40	3.38±0.05	180.09±4.12	0.16	96.96
F8	5.50±0.25	3.45±0.25	178.65±4.20	0.16	99.28
F9	5.50±0.54	3.50±0.04	185.15±4.61	0.15	99.73
F10	5.48±0.71	3.50±0.07	181.50±4.39	0.1	98.12