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Formulation and Kinetic Drug Release study in Gastrorentive Drug delivery system in Gastroprokinetic Drugs

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Formulation and Kinetic Drug Release study in Gastrorentive Drug delivery system in Gastroprokinetic Drugs .

R.M chandira* ,D.bhowmik,Chiranjib, B.Jayakar

Vinayaka missions college of pharmacy
Vinayaka missions university
Salem-636008,Tamilnadu
debjit_cr@yahoo.com

Abstract

A fair amount of work has been included in pharmaceutical literature on kinetic of drug release. Various models were tested for explaining the kinetics of drug dissolution. Itopride hydrochloride is the drug of first choice in the therapy of upper dyspepsia at this time in Czech Republic. It is a prokinetic drug that activates the gastrointestinal motility through synergism of its dopamine D2 - receptor antagonistic action and its acetylcholine esterase inhibitory action.. Optimized formulation F10 containing 125 mg HPMC K100M, 40 mg HPMC K15M, and 40 mg carbopol 934P was consider as the best product with respect to in vitro drug release for 24 hours release action, total floating time and improved bioavailability and site-specific action. Tablets of batch F10 possessed quick buoyancy lag time of 110 sec. and good total floating time of 24 hrs. The results showed that the drug release rate was decreased as the viscosity of the polymer was increased. In order to examine the release mechanism of Itopride hydrochloride from the prepared floating tablets of the optimized formulation (F10), the results of the dissolution study was examined in accordance to the kinetic models. The regression coefficient R2 value nearer to 1 indicated the model fitting of the release mechanism. Kinetic Release Data of Different Model for Optimized . The optimized formulation of Itopride Hydrochloride floating tablets (F10) was found to fit partially the Higuchi model Higuchi(Slope-24.16 ,R2 value- 0.9947),and completely the Korsemeyer-Peppas model, which justified the non-fickian release of the optimized formulation

Introduction
The hydrodynamic balanced system (HBS) also called Floating drug delivery system (FDDS) is an oral dosage form (capsule or tablet) designed to prolong the residence time of the dosage form within the GIT. It is a formulation of a drug with gel forming hydrocolloids meant to remain buoyant in the stomach contents. Drug dissolution and release from the dosage form retained in the stomach fluids occur at the pH of the stomach under fairly controlled conditions3 As Itopride Hydrochloride is a prokinetic drug and its primary site of action is stomach and also the drug pH range is 3.5 to 5.5 it would be beneficial to formulate a floating drug delivery system of itopride hydrochloride, which would be once a day formulation.Floating Drug Delivery Systems (FDDS) have a bulk density lower than gastric fluids and thus remain buoyant in the stomach for a prolonged period of time, without affecting the gastric emptying rate. While the system is floating on the gastric contents, the drug is released slowly at a desired rate from the system. After the release of the drug, the residual system is emptied from the stomach. This results in an increase in the GRT and a better control of fluctuations in the plasma drug concentrations.

Materials and methods-

Itopride hydrochloride is procured by Micro Labs Ltd., Hosur, HPMC K100M, HPMC K15M is gifted by Colorcon Asia Pvt. Ltd., Goa, Carbopol 934 P is gifted by Corel Pharma, Ahmedabad, Poly Vinyl Pyrrolidine K30, Magnesium Stearate, Talc, Aerosil is procured by Loba Chemie.

Formulation of Hydrodynamically balance Tablets:
Hydrodynamically balance Tablets containing Itopride HCl were prepared by direct compression technique using varying concentrations of different grades of polymers with sodium bicarbonate and citric acid. All the ingredients were accurately weighed and sifted through different mesh sieves accordingly. Then, except magnesium stearate, all other ingredients were blended in glass mortar uniformly. After sufficient mixing of drug as well as other components, magnesium stearate was added, as post lubricant, and further mixed for additional 2-3 minutes. The tablets were compressed with 11mm punch using rotary tablet machine.
.Table No. 1: Composition of All The Formulations (Batch F1 – Batch F10)
Ingredient F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
Itopride HCl 150 150 150 150 150 150 150 150 150 150
HPMC K100M --- 100 --- 50 --- 100 100 100 110 125
HPMC K15M 100 --- --- 100 100 --- 50 50 40 40
Carbopol 934P --- --- 100 --- 50 50 --- 50 50 40
MCCP Ranq 100 100 100 50 50 50 50 --- --- ---
Sodium Bicarbonate 60 60 60 60 60 60 60 60 60 60
Citric Acid 30 30 30 30 30 30 30 30 30 30
Poly vinyl Pyrrolidine K30 10 10 10 10 10 10 10 10 10 10
Magnesium Stearate 10 10 10 10 10 10 10 10 10 5
Talc 5 5 5 5 5 5 5 5 5 5
Aerosil 5 5 5 5 5 5 5 5 5 5
Total weight 470 470 470 470 470 470 470 470 470 470
*All the quantities are in mg

Compatibility study
They provide framework for the drug in combination with the excipients in the fabrication of the dosage forms and establish that active drug has not undergone degradation. This can be confirmed by carrying out infrared light absorption scanning spectroscopy.
I.R. Studies: It is one of the most powerful analytical techniques for chemical identification of drug.
Method: The pure drug and its formulation were subjected to IR studies. In the present study, the potassium bromide disc (pellet) method was employed.

Post-compression Parameters
1) Tablet density:
Tablet density is an important parameter for floating tablets. The tablet will only float when its density is less than that of gastric fluid (1.004). The density was determined using following relationship.
V = r2h
d = m/v
Where, v = volume of tablet (cc)
r = radius of tablet (cm)
h = crown thickness of tablet (cm)
m = mass of tablet (g)

2) Buoyancy/ floating time:
The time between introduction of dosage form and its buoyancy on the simulated gastric fluid and the time during which the dosage form remain buoyant were measured. The time taken for dosage form to emerge on surface of medium called floating lag time (FLT) or buoyancy lag time (BLT) and total duration of time by which dosage form remain buoyant is called total floating time (TFT).
3) Swelling study:
The swelling behavior of a dosage form was measured by studying its weight gain or water uptake. The dimensional changes can be measured in terms of the increase in tablet diameter and/or thickness over time. Water uptake was measured in terms of percent weight gain, as given by the equation.
WU = (Wt – W0) X 100
W0
Where, WU = Swelling Index
Wt = Weight of dosage form at time t.
W0 = Initial weight of dosage form
4)Effect of Hardness on Buoyancy Lag Time or Floating Lag Time
Formulation F10 was selected to study the effect of hardness on buoyancy lag time. The tablets of batch F10 were compressed at three different compression pressures to get the hardness of 4.5kg/cm2, 5.5kg/cm2 and 7kg/cm2. The tablets were evaluated for buoyancy lag time. The method followed was same as that of buoyancy test.
5)Method of Analysis
1)Identification: The retention time of the principle peak related to Itopride HCl in the chromatogram obtained with the sample preparation corresponds to that of the peak related to Itopride HCl peak in the chromatogram obtained with the standard preparation, as obtained in assay of Itopride.
6) Dissolution
Parameter for Dissolution Study
Apparatus Tablet dissolution tester USP
Method USP Type II Apparatus
(Paddle Method)
Dissolution medium 0.1 N Hydrochloric acid (900 ml)
Temperature 37 + 0.5° C
Speed 50 rpm

In vitro release studies were carried out in the dissolution test apparatus (USP Type II). The tests were carried out in 900 ml of 0.1N HCl for 24 hrs at 50 rpm at 37±0.5oC. 10 ml of the aliquot were withdrawn at different predetermined time intervals (0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hr) and filtered. The required dilutions were made with 0.1N HCl and the solution was analyzed for the drug content by High Performance Liquid Chromatography using UV detector detecting at λ max 220 nm using mobile phase as ortho-phosphoric acid and acetonitrile mixture. 10 ml of 0.1N HCl was replaced in the vessel after each withdrawal to maintain sink condition. From this percentage drug release was calculated and this was plotted against function of time to study the pattern of drug release.
Dissolution parameters:
Apparatus : Dissolution apparatus Type II of USP (paddle)
Medium : 900 ml, 0.1M HCl
Speed : 50 rpm
Time : 24 hrs.
Preparation of 0.1 M HCl: 8.5 ml of HCl was added to distilled water and volume made up to 1000ml with distilled water.
Procedure: One tablet was placed to each of the six dissolution vessel containing 900 ml of dissolution medium. The apparatus was run for 24 hours. After each specified interval, 10 ml of sample was withdrawn and the solution was filtered through membrane filters.
Chromatographic condition for HPLC:
Apparatus : High Performance Liquid Chromatography
Column : C8 , 250 x 4.6 mm, 5 μm SS column
Flow rate : 1.0 ml/min
Detector : 220 nm
Mobile phase : Filtered and degassed mixture of Buffer : Acetonitrile in the ratio
750 : 250
Buffer: Added 1.4 ml of ortho-phosphoric acid in 1000 ml of distilled water and adjusted the pH 3.0 by using triethylamine.
Standard preparation: Accurately weighed about 55mg of Itopride HCl (WS) into a 100 ml standard flask, 70 ml of dissolution medium was added, mixed and sonicated to dissolve the content, made up the volume with dissolution medium. 5 ml of the solution was diluted to 50 ml with dissolution medium. The solution was filtered through 0.45 membrane filter paper.
Procedure: Separately injected 20 μl of the filtered portion of the blank, sample preparation and standard preparation into the chromatograph. Recorded the chromatogram and measured the responses for the major peak. The content of Itopride HCl (in percentage) was calculated with respect to the label claim by using the following equation.
AT X WS X 10 X 900 X P X 100 X 1 X 100 = _____ %
AS 100 150 1 100 150

Where, AS : Average area of Itopride HCl peak for standard preparation.
AT : Average area of Itopride HCl peak for sample preparation.
WS : Weight of Itopride HCl taken for standard preparation.
P : Percentage purity of WS on as such basis.

7) Assay (Content of Itopride HCl per tablet):
Standard preparation: Accurately weighed about 0.050 g of Itopride (WS) into a 100 ml volumetric flask, 70 ml of mobile phase was added, mixed and sonicated to dissolve the content, made up the volume with mobile phase. Pipetted out 10 ml of the solution into a 100 ml volumetric flask and made up the volume with mobile phase. The solution was filtered through 0.45 membrane filter paper.
Sample preparation: Weighed 20 tablets, triturated to a fine powder. The powdered tablet equivalent to 50 mg of Itopride was accurately weighed into a 100 ml volumetric flask. 70 ml of mobile phase was added, mixed for 15 minutes and sonicated for 15 minutes, and made up the volume with mobile phase. Pipetted out 10 ml of the solution into a 100 ml volumetric flask and made up the volume with mobile phase. The solution was filtered through 0.45 membrane filter paper.
Chromatographic condition for HPLC :
Apparatus : High Performance Liquid Chromatography
Column : C8 , 250 x 4.6 mm, 5 μm SS column
Flow rate : 1.0 ml/min
Detector : 220 nm
Mobile phase : Filtered and degassed mixture of Buffer : Acetonitrile in the ratio
750 : 250
Buffer : 1.4 ml of ortho-phosphoric acid was added in 1000 ml of distilled water and adjusted the pH 3.0 by using triethylamine.
System suitability: Injected 20 μm of standard solution and recorded the chromatogram. The relative standard deviation of the 5 replicate injections should be less than 2 %. The tailing factor for the Itopride Hcl peak should be not more than 2.0
Procedure: Separately injected 20 μl of the filtered portion of the blank, sample preparation and standard preparation into the chromatograph. Recorded the chromatogram and measured the responses for the major peak. The content of Itopride HCl in percentage was calculated with respect to the label claim by using the following equation.
AT X WS X 10 X 100 X 100 X P X AV X 1000
AS 100 100 WT 10 150
= _____ mg of Itopride HCl per tablet

Where, AS : Average area of Itopride HCl peak for standard preparation.
AT : Average area of Itopride HCl peak for sample preparation.
WS : Weight of Itopride HCl taken for standard preparation (in gram).
WT : Weight of Itopride HCl taken for sample preparation (in gram).
P : Percentage purity of WS on as such basis.
AV : Average weight of tablet (in gram).

8) Mechanism of Drug Release
A fair amount of work has been included in pharmaceutical literature on kinetic of drug release. Various models were tested for explaining the kinetics of drug dissolution.
• Zero-Order Model :
In many of the modified release dosage forms particularly controlled or sustained release dosage forms is zero-order kinetics.
m=k x t
Where, k is zero-order constant, ‘m’ is percentage drug unreleased and t is the time. The plot of percentage drug unreleased (released) versus time is linear.
• First-order Model:
Most conventional dosage forms exhibit this dissolution mechanism. Some modified release preparations, particularly prolonged release formulations, adhere to this type of dissolution pattern.
m= e a x e -bt
Where, ‘a’ is the intercept and b is slope.
It assumes that the drug molecules diffuse out through a gel like layer formed around the drug during the dissolution process. A plot of log percentage drug released versus time is linear.

• Higuchi Model:
A large number of modified release dosage forms contain some sort of matrix system. In such instances, the drug dissolves from this matrix. The dissolution pattern of the drug is dictated by water penetration rate (diffusion controlled) and thus the following relationship applies:
m = (100 – q) x √ t
Where, q is the Higuchi constant (percentage per square root of time)
In Higuchi model, a plot of percentage drug unreleased (or released) versus square root of time is linear.
• Hixon-Crowell Model:
Some specialized dosage forms contain many drug particles of the same size and shape of their agglomerates that dissolve evenly. In such instances the cube-root law can express the dissolution process.
If the dissolution pattern of the drug is dictated by the actual dissolution of drug molecules, then the following relationship applies:
m = [1001/3 – (k x t )]3
Where, k is Hixon-Crowell constant (mass/time) 1/3
In this model, the percentage of drug unreleased versus cube root of time is linear.
• Korsmeyer and Peppas Model:
Mt / Mα = K x t n
Where, Mt / Mα is the fraction of drug release at time‘t’.
n is diffusion exponent, if n=1, the release is zero-order, and if n=0.5, the release is best explained by Fickinian diffusion, and if 0.5 , n , 1 then the release is through anomalous diffusion or case II diffusion.
In this model, a plot of % drug released versus log time is linear.

• Weibull Distribution Model:
When applied to the dissolution data, the Weibull equation expresses the accumulated fraction of material in solution at time t, by:
m = 1 – exp [ (t - t i) b/a ]
Where, a is the scale parameter which defines the time scale of the process, ti is location parameter which represents the lag period before the actual onset of dissolution (in most cases ti =0) and b is the shape parameter.
Result and Discussion
1) Compatibility studies
Compatibility studies were performed using FTIR spectrophotometer. The IR spectrum of pure drug and physical mixture of drug and polymer of optimized formulation were studied. The characteristic absorption peaks of Itopride Hydrochloride were obtained at 1349.93 cm-1, 1590.99 cm-1, 3415.31 cm-1, 3456.78 cm-1, 3502.12 cm-1.
The peaks obtained in the spectrum of each formulation correlates with the peaks of drug spectrum. This indicates that the drug is compatible with the formulation components..

FIG. NO. : Standard Curve Of Itopride HCl By HPLC Method

Retention Time (min) Area (mV-s) Area percent Asymmetry Theoretical plate
6.117 4673808 100.00 0.85 5057.97

2)Tablet Density
To provide good floating behavior in the stomach, the density of the device should be less than that of the gastric contents (1.004g/cm3). All the batches showed density below than that of gastric fluid (1.004). The values were shown in Table 9.
When tablet contacts the test medium, tablet expanded (because of swellable polymers) and there was liberation of CO2 gas (because of effervescent agents, sodium bicarbonate and citric acid). Here, citric acid acts a dual action of effervescent agent as well as it maintains the pH of the environment. The density decreased due to this expansion and upward force of CO2 gas generation. This plays an important role in ensuring the floating capability of the dosage form.
3)Buoyancy Study
On immersion in 0.1N HCl solution pH (1.2) at 370C, the tablets floated, and remained buoyant without disintegration. Table No.9 showed the results of buoyancy study and Fig.18 and 19 showed buoyancy character of prepared tablet of optimized formulation (F10).
From the results it can be concluded that the batch containing HPMC polymers showed good buoyancy lag time (BLT) and total floating time (TFT). Formulation F10 containing HPMC K15M, HPMC K100M and Carbopol 934P showed good BLT of 110 sec and TFT of more than 24 hrs. Carbopol was used as release retardant and it also provided an additional gelatinous layer to the formulation. The tablets floats may be due to the amount of polymer and gas generating agents, which gets partially entrapped in between, the gelatinous layer. The gas generated cannot be entrapped inside the gelatinous layer, and it escapes leading to variation in BLT and TFT.

4) Swelling Study
Swelling ratio describes the amount of water that is contained within the hydrogel at equilibrium and is a function of the network structure, hydrophilicity and ionization of the functional groups.
Swelling study was performed on all the batches for 5 hr. The results of swelling index were given in Table While the plot of swelling index against time (hr) of optimized formulation (F10) is depicted in F
From the results it was concluded that swelling increases as the time passes because the polymer gradually absorb water due to hydrophilicity of polymer. The outermost hydrophilic polymer hydrates and swells and a gel barrier is formed at the outer surface. As the gelatinous layer progressively dissolves and/or is dispersed, the hydration swelling release process is repeated towards new exposed surfaces, thus maintaining the integrity of the dosage form.
In the present study, the higher swelling index was found for tablets of batch F10, containing HPMC K15M, HPMC K100M, and Carbopol 934P having nominal viscosity of 15,000 cps, 100,000cps and 934cps respectively. Thus, the viscosity of the polymer had major influence on swelling process, matrix integrity, as well as floating capability, hence from the above results it can be concluded that linear relationship exists between swelling process and viscosity of polymer.

Table No.2 : Swelling Index of Tablets of Batch F1 to F10

Time Swelling Index (%)
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10
1 hr 80 82 79 76 76 75 82 88 79 89
2 hrs 129 135 130 120 125 131 135 127 130 129
3 hrs 148 162 156 140 142 144 162 168 159 161
4 hrs 168 185 172 161 163 182 185 172 166 187
5 hrs 185 207 189 170 179 197 207 199 186 208

Fig. No: 1Plot of Swelling Index against Time of Optimized Formulation (F10)

5)Drug content uniformity DRUG CONTENT UNIFORMITY:
The percentage of drug content was found to be between 97.01% and 99.82% of Itopride hydrochloride, which was within acceptable limits. Table No. 11 showed the results of drug content uniformity in each batch.
Table No3. : Drug Content Uniformity of Tablets of Batch F1 to F10
Batches Drug content uniformity (%)
F1 97.01
F2 99.51
F3 98.01
F4 97.42
F5 98.41
F6 99.05
F7 99.05
F8 98.46
F9 98.45
F10 99.82

6)Effect of Hardness on Buoyancy Lag Time EFFECT OF HARDNESS ON BUOYANCY LAG TIME:
The effect of hardness on buoyancy lag time for batch F10 was studied. The results of floating lag time of tablet having hardness of 4.5 kg/cm2, 5.5 kg/cm2 and 7 kg/cm2 were 110 sec, 215 sec and 421 sec respectively as tabulated in Table 12. The plot of floating lag time (sec) vs. hardness (kg/cm2) is depicted in Fig. 21. Batch F10 was selected for the study because it showed buoyancy lag time of 110 sec at hardness of 4.5 kg/cm2.
Buoyancy of the tablet was governed by both the swelling of the hydrocolloid particle on surface when it contacts the gastric fluid that in turn results in an increase in the bulk volume and the presence of internal void space in the dry center of the tablet (porosity). On increasing the hardness of the tablets results in increased buoyancy lag time, which might be due to high compression resulting in reduction of porosity of the tablet. Moreover, the compacted hydrocolloid particles on the surface of the tablet cannot hydrate rapidly when the tablet reaches the gastric fluid and as a result of this, the capability of the tablet to float is significantly reduced.
Table No.4 : Effect of Hardness on Buoyancy Lag Time of Batch F10

Hardness in kg/cm2 Buoyancy Lag Time (sec)
4.5kg/cm2 110
5.5kg/cm2 215
7.0kg/cm2 421

Fig. No. 2: Plot of Floating lag time vs. Tablet hardness

7) In-vitro Dissolution study
The in-vitro drug release profiles of tablet from each batch (F1 to F10) were shown in Table No. The plot of cumulative percentage drug release versus time (hr) was plotted and depicted as shown

Fig. No.3 : In-vitro dissolution profile of formulations F 1 to F 9

8)Analysis of Release Mechanism
In order to examine the release mechanism of Itopride hydrochloride from the prepared floating tablets of the optimized formulation (F10), the results of the dissolution study was examined in accordance to the kinetic models. The regression coefficient R2 value nearer to 1 indicated the model fitting of the release mechanism.
Table No.5 : Kinetic Release Data of Different Model for Optimized Batch (F10)
Model Slope R2value
Zero order 4.3156 0.9609
First order -0.0669 0.9279
Hixson-Crowell -0.1436 0.9896
Higuchi 24.16 0.9947
Korsemeyer-Peppas model 0.7014 0.9984

Fig No.4: Plot of cumulative percentage drug released vs. time of optimized formulation (F10) [Zero Order]

Fig No.6: Plot of log cumulative percentage drug retained vs. time of optimized formulation (F10) [First Order]

Fig No. 7: Plot of cumulative percentage drug released vs. root time of optimized Formulation (F10) [Higuchi Matrix]

Fig No.8 : Plot of log cumulative percentage drug released vs. log time of optimized formulation (F10) [Korsmeyer and Peppas Model]

Fig No.9 : Plot of root cube of percentage drug retained vs. time of optimized formulation (F10) [Hixson Crowell]
The optimized formulation of Itopride Hydrochloride floating tablets (F10) was found to fit partially the Higuchi model and completely the Korsemeyer-Peppas model, which justified the non-fickian release of the optimized formulation.

Summary and conclusion
Itopride hydrochloride is gastroprokinetic drug and the site of action is stomach and also the drug pH ranges from 3.5 to 5.5, the present work was aimed to formulate floating tablets of Itopride hydrochloride using an effervescent approach for gastroretentive drug delivery system to improve the local action and ultimately its bioavailability. The tablets were formulated using hydrophilic polymers HPMC K100M, HPMC K15M and hydrophobic polymer carbopol 934P along with effervescing agent sodium bicarconate and citric acid. It was found that carbopol has a negative effect on floating behavior but it was used only for the drug release retardant characteristics. All the formulations were prepared by direct compression method. The prepared tablets of all the formulations were evaluated for physical characters, assay, swelling index, in-vitro drug release, floating lag time, total floating time, tablet density, hardness and friability. The main aim was to optimize the formulation for 24 hours in-vitro release and total floating time to more than 24 hours. Optimized formulation F10 containing 125 mg HPMC K100M, 40 mg HPMC K15M, and 40 mg carbopol 934P was consider as the best product with respect to in vitro drug release for 24 hours release action, total floating time and improved bioavailability and site-specific action. Tablets of batch F10 possessed quick buoyancy lag time of 110 sec. and good total floating time of 24 hrs. The results showed that the drug release rate was decreased as the viscosity of the polymer was increased. Optimized formulation F10 was subjected to curve fitting analysis and the results showed to fit best for Korsemeyer – Peppas equation and followed non-fickian diffusion mechanism with R2 value of 0.9984. The present work can be continued further to prove its stability during shelf life, in-vivo dissolution, in-vivo gastric residence time by using gamma scintigraphy and establishment of in-vitro – in-vivo correlation.

Acknowledgement
We are thankful to DR.B.JAYAKAR, Principal of Vinayaka missions college of Pharmacy, Salem ,Tamilnadu providing excellient Facilities.

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