1. INTRODUCTION^1-9:

The first sustained release tablets were made by Howard Press in New Jersy in the early 1950's. The first tablets released under his process patent were called 'Nitroglyn' and made under license by Key Corp. in Florida.

Sustained release, prolonged release, modified release, extended release or depot formulations are terms used to identify drug delivery systems that are designed to achieve or extend therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose.

The goal in designing sustained or sustained delivery systems is to reduce the frequency of the dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required or providing uniform drug delivery. So, sustained release dosage form is a dosage form that release one or more drugs continuously in predetermined pattern for a fixed period of time, either systemically or to a specified target organ.^{16, 17.}

Sustained release dosage forms provide a better control of plasma drug levels, less dosage frequency, less side effect, increased efficacy and constant delivery. There are certain considerations for the preparation of extended release formulations:

1. If the active compound has a long half-life, it is sustained on its own,

2. If the pharmacological activity of the active is not directly related to its blood levels,

3. If the absorption of the drug involves an active transport and

4. If the active compound has very short half-life then it would require a large amount of drug to maintain a prolonged effective dose.

Figure 1: Hypothetical plasma concentration-time profile from conventional multiple dosing and single doses of sustained and controlled delivery formulations.

Terminology^14,15:

Modified release delivery systems may be divided conveniently in to four categories.

A) Delayed release

B) Sustained release

· Controlled release

· Extended release

C) Site specific targeting

D) Receptor targeting

Sustained (zero-order) drug release has been attempted to be achieved with various classes of sustained drug delivery system:

A) Diffusion sustained system.

i) Reservoir type.

ii) Matrix type

B) Dissolution sustained system.

i) Reservoir type.

ii) Matrix type

C) Methods using Ion-exchange.

D) Methods using osmotic pressure.

E) pH independent formulations.

F) Altered density formulations.

Fig. 2: Schematic representation of diffusion sustained drug release: reservoir system

Fig. 3: Schematic representation of diffusion sustained drug release: matrix system

2. MATERIALS AND EQUIPMENT’S:

Table 1: List of Materials Used:

Name of the material	Source
Allopurinol	Merck Specialities Pvt Ltd, Mumbai, India
HPMC K 100M	Merck Specialities Pvt Ltd, Mumbai, India
Guar gum	Merck Specialities Pvt Ltd, Mumbai, India
Chitosan	Merck Specialities Pvt Ltd, Mumbai, India
Xanthan gum	Merck Specialities Pvt Ltd, Mumbai, India
β – CD	Merck Specialities Pvt Ltd, Mumbai, India
Pvp k 30	Merck Specialities Pvt Ltd, Mumbai, India
MCC pH 102	Merck Specialities Pvt Ltd, Mumbai, India
Magnesium stearate	Merck Specialities Pvt Ltd, Mumbai, India
Talc	Merck Specialities Pvt Ltd, Mumbai, India

Table 2 : List of Equipment’s used:

Name of the Equipment	Manufacturer
Weighing Balance	Sartourious
Tablet Compression Machine (Multistation)	Lab Press Limited, India.
Hardness tester	Monsanto, Mumbai, India.
Vernier calipers	Mitutoyo, Japan.
Roche Friabilator	Labindia, Mumbai, India
DissolutionApparatus	Labindia, Mumbai, India
UV-Visible Spectrophotometer	Labindia, Mumbai, India
pH meter	Labindia, Mumbai, India
FT-IR Spectrophotometer	Per kin Elmer, United States of America.

3. METHODOLOGY:

3.1. Preformulation Studies:

a) Determination of absorption maxima:

100mg of Allopurinol pure drug was dissolved in 100ml of Methanol (stock solution)10ml of above solution was taken and make up with100ml by using 0.1 N HCl (100μg/ml).From this 10ml was taken and make up with 100 ml of 0.1 N HCl (10μg/ml). and pH 6.8 Phosphate buffer UV spectrums was taken using Double beam UV/VIS spectrophotometer. The solution was scanned in the range of 200 – 400.

b) Preparation calibration curve:

100mg of Allopurinol pure drug was dissolved in 100ml of Methanol (stock solution)10ml of above solution was taken and make up with100ml by using 0.1 N HCl (100μg/ml).From this 10ml was taken and make up with 100 ml of 0.1 N HCl (10μg/ml). The above solution was subsequently diluted with 0.1N HCl to obtain series of dilutions Containing 5,10,15,20 and 25 μg/ml of Allopurinol per ml of solution. The absorbance of the above dilutions was measured at 250 nm by using UV-Spectrophotometer taking 0.1N HCl as blank. Then a graph was plotted by taking Concentration on X-Axis and Absorbance on Y-Axis which gives a straight line Linearity of standard curve was assessed from the square of correlation coefficient (R²) which determined by least-square linear regression analysis. The above procedure was repeated by using pH 6.8 phosphate buffer solutions.

3.2. Drug – Excipient compatibility studies:

Fourier Transform Infrared (FTIR) spectroscopy:

The physical properties of the physical mixture were compared with those of plain drug. Samples was mixed thoroughly with 100mg potassium bromide IR powder and compacted under vacuum at a pressure of about 12 psi for 3 minutes. The resultant disc was mounted in a suitable holder in Perkin Elmer IR spectrophotometer and the IR spectrum was recorded from 3500 cm to 500 cm. The resultant spectrum was compared for any spectrum changes.

3.3. Preformulation parameters:

The quality of tablet, once formulated by rule, is generally dictated by the quality of physicochemical properties of blends. There are many formulations and process variables involved in mixing and all these can affect the characteristics of blends produced. The various characteristics of blends tested as per Pharmacopoeia.

Angle of repose:

The frictional force in a loose powder can be measured by the angle of repose. It is defined as, the maximum angle possible between the surface of the pile of the powder and the horizontal plane. If more powder is added to the pile, it slides down the sides of the pile until the mutual friction of the particles producing a surface angle, is in equilibrium with the gravitational force. The fixed funnel method was employed to measure the angle of repose. A funnel was secured with its tip at a given height (h), above a graph paper that is placed on a flat horizontal surface. The blend was carefully pored through the funnel until the apex of the conical pile just touches the tip of the funnel. The radius (r) of the base of the conical pile was measured. The angle of repose was calculated using the following formula:

Tan θ = h / r Tan θ = Angle of repose

h = Height of the cone , r = Radius of the cone base

Table 3: Angle of Repose values (as per USP)

Angle of Repose	Nature of Flow
<25	Excellent
25-30	Good
30-40	Passable
>40	Very poor

Bulk density:

Density is defined as weight per unit volume. Bulk density, is defined as the mass of the powder divided by the bulk volume and is expressed as gm/cm³. The bulk density of a powder primarily depends on particle size distribution, particle shape and the tendency of particles to adhere together. Bulk density is very important in the size of containers needed for handling, shipping, and storage of raw material and blend. It is also important in size blending equipment. 10 gm powder blend was sieved and introduced into a dry 20 ml cylinder, without compacting. The powder was carefully leveled without compacting and the unsettled apparent volume, Vo, was read.

The bulk density was calculated using the formula:

Bulk Density = M / V_o

Where, M = weight of sample, V_o = apparent volume of powder

Tapped density:

After carrying out the procedure as given in the measurement of bulk density the cylinder containing the sample was tapped using a suitable mechanical tapped density tester that provides 100 drops per minute and this was repeated until difference between succeeding measurement is less than 2 % and then tapped volume, V measured, to the nearest graduated unit. The tapped density was calculated, in gm per L, using the formula:

Tap = M / V

Where,

Tap= Tapped Density

M = Weight of sample

V= Tapped volume of powder

Measures of powder compressibility:

The Compressibility Index (Carr’s Index) is a measure of the propensity of a powder to be compressed. It is determined from the bulk and tapped densities. In theory, the less compressible a material the more flowable it is. As such, it is measures of the relative importance of interparticulate interactions. In a free- flowing powder, such interactions are generally less significant, and the bulk and tapped densities will be closer in value.

For poorer flowing materials, there are frequently greater interparticle interactions, and a greater difference between the bulk and tapped densities will be observed. These differences are reflected in the Compressibility Index which is calculated using the following formulas:

Carr’s Index = [(tap - b) / tap] × 100

Where,

b = Bulk Density

Tap = Tapped Density

Table 4: Carr’s index value (as per USP):

Carr’s index	Properties
5 – 15	Excellent
12 – 16	Good
18 – 21	Fair to Passable
2 – 35	Poor
33 – 38	Very Poor
>40	Very Very Poor

3.4. Formulation development of Tablets:

All the formulations were prepared by direct compression. The compositions of different formulations are given in Table 5. The tablets were prepared as per the procedure given below and aim is to prolong the release of Allopurinol. Total weight of the tablet was considered as 300mg.

Procedure:

1) Allopurinol and all other ingredients were individually passed through sieve no 60.

2) All the ingredients were mixed thoroughly by triturating up to 15 min.

3) The powder mixture was lubricated with talc.

4) The tablets were prepared by using direct compression method. All the quantities were in mg

3.5. Evaluation of post compression parameters for prepared Tablets:

The designed formulation tablets were studied for their physicochemical properties like weight variation, hardness, thickness, friability and drug content.

Weight variation test:

To study the weight variation, twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight. The weight variation test would be a satisfactory method of deter mining the drug content uniformity. Not more than two of the individual weights deviate from the average weight by more than the percentage shown in the following table and none deviate by more than twice the percentage. The mean and deviation were determined. The percent deviation was calculated using the following formula.

% Deviation =

(Individual weight – Average weight )

---------------------------------------------------------------------------------------------------------------------× 100

(Average weight)

Hardness:

Hardness of tablet is defined as the force applied across the diameter of the tablet in order to break the tablet. The resistance of the tablet to chipping, abrasion or breakage under condition of storage transformation and handling before usage depends on its hardness. For each formulation, the hardness of three tablets was determined using Monsanto hardness tester and the average is calculated and presented with deviation.

Thickness:

Tablet thickness is an important characteristic in reproducing appearance. Tablet thickness is an important characteristic in reproducing appearance. Average thickness for core and coated tablets is calculated and presented with deviation.

Friability:

It is measured of mechanical strength of tablets. Roche friabilator was used to determine the friability by following procedure. Preweighed tablets were placed in the friabilator. The tablets were rotated at 25 rpm for 4 minutes (100 rotations). At the end of test, the tablets were re weighed, loss in the weight of tablet is the measure of friability and is expressed in percentage as

% Friability = [ ( W1-W2) / W] × 100

Where,

W1 = Initial weight of three tablets

W2 = Weight of the three tablets after testing

3.6. Determination of drug content:

Tablets were tested for their drug content. Ten tablets were finely powdered quantities of the powder equivalent to one tablet weight of drug were accurately weighed, transferred to a 100 ml volumetric flask containing 50 ml water and were allowed to stand to ensure complete solubility of the drug. The mixture was made up to volume with media. The solution was suitably diluted and the absorption was determined by UV –Visible spectrophotometer. The drug concentration was calculated from the calibration curve.

Table 5: Formulation composition for tablets

Formulation no	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	F11	F12
Allopurinol (mg)	100	100	100	100	100	100	100	100	100	100	100	100
Guar gum (mg)	50	100	150	-	-	-	-	-	-	-	-	-
Xanthan gum (mg)	-	-	-	50	100	150	-	-	-	-	-	-
Chitosan (mg)	-	-	-	-	-	-	50	100	150	-	-	-
HPMC K100M (mg)	-	-	-	-	-	-	-	-	-	50	100	150
β- CD (mg)	50	50	50	50	50	50	50	50	50	50	50	50
PVP K-30 (mg)	20	20	20	20	20	20	20	20	20	20	20	20
Mg. stearate (mg)	4	4	4	4	4	4	4	4	4	4	4	4
Talc(mg)	4	4	4	4	4	4	4	4	4	4	4	4
MCC P^H 102(mg)	172	122	72	172	122	72	172	122	72	172	122	72
Total Wt of Tablet (mg)	400	400	400	400	400	400	400	400	400	400	400	400

Table 6: Pharmacopoeial specifications for tablet weight variation

Average weight of tablet (mg) (I.P)	Average weight of tablet (mg) (U.S.P)	Maximum percentage difference allowed
Less than 80	Less than 130	10
80-250	130-324	7.5
More than	More than 324	5

3.3.1. In vitro drug release studies:

Dissolution parameters:

Apparatus--USP-II, Paddle Method

Dissolution Medium--0.1NHCl, pH 6.8 Phosphate buffer

RPM --50

Sampling intervals (hrs)-0.5,1,2,3,4,5,6,7,8,10,11,12

Temperature--37°c + 0.5°c

Procedure:

900ml 0f 0.1 HCl was placed in vessel and the USP apparatus –II (Paddle Method) was assembled. The medium was allowed to equilibrate to temp of 37°c + 0.5°c. Tablet was placed in the vessel and apparatus was operated for 2 hours and then the media 0.1 N HCl was removed and pH 6.8 phosphate buffer was added process was continued from upto 12 hrs at 50 rpm. At definite time intervals withdrawn 5 ml of sample, filtered and again 5ml media was replaced. Suitable dilutions were done with media and analyzed by spectrophotometrically at 248 and 250nm using UV-spectrophotometer.

3.3.2. Application of Release Rate Kinetics to Dissolution Data:

Various models were tested for explaining the kinetics of drug release. To analyze the mechanism of the drug release rate kinetics of the dosage form, the obtained data were fitted into zero-order, first order, Higuchi, and Korsmeyer-Peppas release model.

Zero order release rate kinetics:

To study the zero–order release kinetics the release rate data ar e fitted to the following equation.

F = K_o

Where,

‘F’ is the drug release at time‘t’, and ‘K_o’ is the zero order release rate constant. The plot of % drug release versus time is linear.

First order release rate kinetics:

The release rate data are fitted to the following equation

Log (100-F) = kt

A plot of log cumulative percent of drug remaining to be released vs. time is plotted then it gives first order release.

Higuchi release model:

To study the Higuchi release kinetics, the release rate data were fitted to the following equation.

F = k t1/2

Where,

‘k’ is the Higuchi constant.

In higuchi model, a plot of % drug release versus square root of time is linear.

Korsmeyer and Peppas release model:

The mechanism of drug release was evaluated by plotting the log percentage of drug released versus log time according to Korsmeyer- Peppas equation. The exponent ‘n’ indicates the mechanism of drug release calculated through the slope of the straight Line.

M_t/ M_∞ = K tⁿ

Where, M_t/ M_∞ is fraction of drug released at time ‘t’, k represents a constant, and ‘n’ is the diffusional exponent, which characterizes the type of release mechanism during the dissolution process. For non-Fickian release, the value of n falls between 0.5 and 1.0; while in case of Fickian diffusion, n = 0.5; for zero-order release (case I I transport), n=1; and for supercase II transport, n > 1. In this model, a plot of log (M_t/ M_∞) versus log (time) is linear.

Hixson-Crowell release model:

(100-Q_t)^1/3= 100^1/3– K_HC.t

Where,

k is the Hixson-Crowell rate constant.

Hixson-Crowell model describes the release of drugs from an insoluble matrix through mainly erosion. (Where there is a change in surface area and diameter of particles or tablets).

4. RESULTS AND DISCUSSION:

The present study was aimed to developing Sustained release tablets of Allopurinol using various polymers. All the formulations were evaluated for physicochemical properties and invitro drug release studies.

4.1. Analytical Method:

Graphs of Allopurinol was taken in Simulated Gastric fluid (pH 1.2) and in p H 6.8 phosphate buffer at 250 nm and 252 nm respectively.

Table 7: Observations for graph of Allopurinol in p H 6.8 phosphate buffer (252nm)

Conc [µg/l]	Abs
0	0
2	0.065
4	0.142
6	0.218
8	0.281
10	0.375

Table 8: Observations for graph of Allopurinol in 0.1N HCl 250nm):

Conc [µg/l]	Abs
0	0
2	0.126
4	0.265
6	0.406
8	0.519
10	0.638

4.4 Pre formulation parameters of powder blend:

Table 11: Pre-Compression parameters of Powder blend

Formulation Code	Angle of Repose	Bulk density (gm/ml)	Tapped density (gm/ml)	Carr’s index (%)	Hausner’s Ratio
F1	23.11±0.1	0.47±0.05	0.53±0.057	11.32±0.58	1.12±0.015
F2	22.67±0.57	0.45±0.057	0.56±0.015	16.07±1	1.24±0.015
F3	22.54±0.57	0.52±0.01	0.60±0.051	13.33±0.057	1.15±0.01
F4	25.43±0.63	0.55±0.015	0.62±0.057	11.29±0.015	1.12±0.01
F5	26.34±0.58	0.47±0.05	0.56±0.015	12.50±0.01	1.19±0.005
F6	25.22±0.51	0.56±0.015	0.63±0.011	11.11±0.05	1.12±0.015
F7	24.18±0.56	0.49±0.02	0.58±0.01	15.51±0.02	1.18±0.01
F8	25.22±0.56	0.57±0.057	0.66±0.017	13.63±0.057	1.15±0.015
F9	23.05±0.54	0.50±0.057	0.59±0.051	15.25±0.046	1.18±0.015
F10	22.06±0.57	0.48±0.05	0.58±0.01	15.51±0.04	1.19±0.005
F11	23.58±056	0.51±0.05	0.59±0.05	13.55±0.017	1.15±0.01
F12	24.03±0.57	0.52±0.01	0.62±0.05	16.12±0.01	1.19±0.01

Table 12: Post-Compression parameters of Tablets:

Formulation codes	Weight variation(mg)	Hardness(kg/cm2)	Friability (%loss)	Thickness (mm)	Drug content (%)
F1	398.95±0.01	4.2±0.1	0.45±0.015	5.1±0.1	98.3±0.1
F2	399.15±0.015	4.7±0.1	0.54±0.015	5.2±0.057	99.3±0.15
F3	400.26±0.01	4.2±0.57	0.55±0.02	5.3±0.057	98.2±0.15
F4	405.36±0.017	4.0±0.1	0.56±0.01	5.5±0.1	99.2±0.1
F5	397.25±0.02	4.2±0.1	0.48±0.05	5.1±0.057	99.3±015
F6	396.26±0.015	4.1±0.57	0.45±0.015	5.2±0.11	97.2±0.1
F7	402.5±0.15	4.3±0.11	0.51±0.01	5.3±0.1	102.3±0.2
F8	403.63±0.015	4.4±0.1	0.52±0.015	5.3±0.1	103.5±0.15
F9	405.85±0.01	4.5±0.1	0.53±0.015	5.4±0.057	10.3±0.2
F10	396.74±0.020	4.1±0.57	0.45±0.1	5.2±0.1	99.5±0.15
F11	401.36±0.015	4.3±0.57	0.49±0.015	5.0±0.15	102.3±0.1
F12	402.58±0.02	4.2±0.1	0.50±0.1	5.1±0.15	99.8±0.2

Note:All the parameters such as weight variation, friability, hardness, thickness and drug content were found to be within limits.

4.6. In-Vitro Drug Release Studies

Table 13: Dissolution Data of Allopurinol Tablets Prepared With Guar gum In Different Concentrations

TIME (hr)	CUMULATIVE percent drug dissolved
TIME (hr)	f1	f2	f3
0	0	0	0
0.5	10.82±1	7.51±0.98	5.46±1.5
1	15.35±1.02	11.72±0.1	8.81±0.1
2	25.81±1.5	19.84±1	13.54±1
3	32.71±0.99	25.55±0.015	20.48±0.015
4	40.09±1	31.08±0.015	26.34±0.2
5	46.78±0.57	39.46±1	33.47±0.99
6	53.01±0.015	46.38±0.057	40.52±0.85
7	59.45±1	51.08±1.5	46.45±1.5
8	65.38±1.05	60.76±0.2	53.30±1.0
9	71.12±1.02	68.45±1.0	60.09±1
10	80.31±0.95	75.32±0.99	67.31±1.5
11	88.15±0.85	81.91±1	74.84±0.015
12	94.62±1.05	89.82±0.88	80.56±0.1

Table 14: Dissolution Data of Allopurinol Tablets Prepared With Xanthan gum In Different Concentrations

TIME (hr)	CUMULATIVE percent drug dissolved
TIME (hr)	f4	f5	f6
0	0	0	0
0.5	15.58±1.02	10.47±1.01	7.35±0.98
1	24.31±0.99	16.31±1	11.41±0.1
2	30.72±1	20.74±0.95	18.09±1
3	36.86±0.015	25.80±1.015	23.24±0.015
4	45.08±1.5	31.43±0.2	30.08±0.99
5	51.72±1	39.52±0.95	36.71±1.05
6	60.81±0.57	45.63±1.02	41.35±1
7	67.56±1.05	52.74±0.99	47.42±0.15
8	76.72±0.95	60.80±1.05	54.58±0.1
9	87.87±1	68.64±1	60.62±1.5
10	98.73±0.2	75.78±0.98	66.71±0.2
11		82.91±1.03	72.88±0.85
12		91.75±1.01	81.09±1

Fig. 15: Dissolution profile of Allopurinol (F1, F2, F3 formulations

Fig 16: Dissolution profile of Allopurinol (F4, F5, F6 formulations)

Table 15: Dissolution Data of Allopurinol Tablets Prepared With Chitosan In Different Concentrations

*TIME* (hr)	CUMULATIVE percent drug dissolved
*TIME* (hr)	f7	f8	f9
0	0	0	0
0.5	16.20±1.01	12.81±0.57	10.74±1.01
1	22.54±1.0	16.74±1	15.51±1
2	30.71±1.10	24.58±0.58	20.84±1.015
3	38.83±1.5	30.25±0.5	26.74±1.015
4	44.94±0.99	37.38±1	30.82±0.2
5	50.09±1.015	45.56±1.02	36.95±0.95
6	56.45±0.2	50.81±0.2	43.84±1.02
7	63.52±0.57	58.72±1.02	50.76±0.99
8	70.61±1.02	62.84±1	58.54±1
9	79.92±0.85	70.72±0.5	63.18±1.05
10	85.83±0.95	79.84±1	70.24±1.01
11	95.93±1.05	85.72±0.57	77.82±0.98
12	95.81±1.01	99.08±0.57	85.91±0.015

Fig. 17: Dissolution profile of Allopurinol (F7, F8, F9 formulations)

Table 16: Dissolution Data of Allopurinol Tablets Prepared With HPMC K100M In Different Concentrations

Time (hr)	CUMULATIVE percent drug dissolved
Time (hr)	f10	f11	f12
0	0	0	0
0.5	11.74±0.58	8.74±0.57	5.32±1.5
1	18.81±0.57	14.65±0.58	10.54±1.01
2	25.75±0.63	20.85±1.015	15.75±1
3	30.68±1.05	27.41±0.57	21.84±0.015
4	37.74±1	34.84±1.01	30.98±0.2
5	45.85±0.015	40.75±0.57	36.84±1.05
6	51.94±1	47.81±1.02	43.73±1.0
7	60.75±0.57	55.75±0.1	50.64±0.99
8	68.85±1.05	61.84±1	56.84±1.5
9	75.75±0.99	70.76±0.5	62.38±1.0
10	81.52±1	78.85±0.98	70.45±0.85
11	88.75±0.2	84.70±1.03	75.54±0.98
12	94.51±1.05	90.83±1.01	84.14±1

Fig.18: Dissolution profile of Allopurinol (F10, F11, F12 formulations)

From the dissolution data it was evident that the formulations prepared with Xanthan gum 100 as polymer were unable to retard the drug release up to desired time period i.e., 12 hours.

Whereas the formulations prepared with Chitosan retarded the drug release in the concentration of 100 mg (F8 Formulation ) showed required release pattern i.e., retarded the drug release up to 12 hours and showed maximum of 99.08% in 12 hours with good retardation.

The formulations prepared with HPMC k 100 showed more retardation even after 12 hours they were not shown total drug release. Hence they were not considered.

Table 17: Release kinetics data for optimised formulation F8

CUMULATIVE (%) RELEASE Q	TIME (T)	ROOT (T)	LOG( %) RELEASE	LOG (T)	LOG (%) REMAIN	RELEASE RATE (CUMULATIVE % RELEASE / t)	1/CUM% RELEASE	PEPPAS log Q/100	% Drug Remain-ing
0	0	0			2.000				100
12.81	0.5	0.707	1.108	-0.301	1.940	25.620	0.0781	-0.892	87.19
16.74	1	1.000	1.224	0.000	1.920	16.740	0.0597	-0.776	83.26
24.58	2	1.414	1.391	0.301	1.877	12.290	0.0407	-0.609	75.42
30.25	3	1.732	1.481	0.477	1.844	10.083	0.0331	-0.519	69.75
37.38	4	2.000	1.573	0.602	1.797	9.345	0.0268	-0.427	62.62
45.56	5	2.236	1.659	0.699	1.736	9.112	0.0219	-0.341	54.44
50.81	6	2.449	1.706	0.778	1.692	8.468	0.0197	-0.294	49.19
58.72	7	2.646	1.769	0.845	1.616	8.389	0.0170	-0.231	41.28
62.84	8	2.828	1.798	0.903	1.570	7.855	0.0159	-0.202	37.16
70.72	9	3.000	1.850	0.954	1.467	7.858	0.0141	-0.150	29.28
79.84	10	3.162	1.902	1.000	1.304	7.984	0.0125	-0.098	20.16
85.72	11	3.317	1.933	1.041	1.155	7.793	0.0117	-0.067	14.28
99.08	12	3.464	1.996	1.079	-0.036	8.257	0.0101	-0.004	0.92

Fig. 19 : Zero order release kinetics graph

Fig. 20 : Higuchi release kinetics graph

Fig. 21: Kors meyer peppas graph

Fig. 22: First order release kinetics graph

4.7. Application of Release Rate Kinetics to Dissolution Data:

From the above graphs it was evident that the formulation F8 was followed Zero order release kinetics.ss

5. CONCLUSION:

The aim of the present study was to develop sustained release formulation of Allopurinol to maintain constant therapeutic levels of the drug for over 12 hrs. Xanthane gum, Guar gum and Chitosan,HPMC K 100 M were employed as polymers. Allopurinol dose was fixed as 100 mg. Total weight of the tablet was considered as 400 mg. Polymers were used in the concentration of 50, 100 and 150 mg concentration. All the formulations were passed various physicochemical evaluation parameters and they were found to be within limits. Whereas from the dissolution studies it was evident that the formulation (F8) showed better and desired drug release pattern i.e., 99.08 % in 12 hours. It contains the natural polymer Chitosan as sustained release material. It followed zero order release kinetics mechanism.

The conclusions drawn from the present investigation are;

1) Allopurinol sustain release tablets containing 100 mg of drug were prepared successfully using HPMC and Xanthan gum, Guargum, Chitosan in different combinations and there were total twele formulation were prepared. Based on observations, one formulations were selected and used for further Evaluation parameters. The evalution parameters exhibited satisfactory characteristics regarding to Friability, Weight variation, Disintegration of drug, and other quality control parameters. Diluent such as MCC and Talc, Mg. stearate (Lubricating agent, Glidant) were included in the formulations.

2) The in vitro release of Allopurinol From the formulations of F1,F2,F3 prepared by using Guargum is polymers and ratio is 50,100,150 the concentration of polymers will increases the drug retardation increases the drug will be stable up to 12 hours at high concentration of polymer.

3) The in vitro release of Allopurinol From the formulations of F4,F5,F6 prepared by using Xathan gum is polymers and ratio is 50,100,150 the concentration of polymers will increases the drug will be stable up to 12 hours at high concentration of polymer but the retardation is less.

4)The in vitro release of Allopurinol From the formulations of F7,F8,F9 prepared by using Chitosan is polymers and ratio is 50,100,150 the concentration of polymers will increases the drug retardation Decreases the drug will be stable up to 10 hours at high concentration of polymer.

5)The in vitro release of Allopurinol From the formulations of F10,F11,F12 prepared by using HPMC K 100M is polymers and ratio is 50,100,150 the concentration of polymers will increases the drug retardation increases the drug will be stable up to 12 hours at high concentration of polymer.

6)Among al those formulations F8 is the best formulation and polymer is Chitosan concentration about 100 mg it shows maximum retardation(96.91%) up to 12 hours so F8 is the optimised formulation

(or)

7)The in vitro release of Allopurinol from the Formulations 1 to 12 was in the range of 96.91% in 12 hours, in phosphate buffer solution, pH 1.2. The release kinetics indicated zero order release from all the Formulations.

8) Zero order diffusion model and Hixon-Crowell cube root law were applied to test the release mechanism. R²values are higher for Zero order model compared to Hixon – Crowell model for all the Formulations. Hence Allopurinol release from the Formulations followed diffusion Zero order rate controlled.

6. REFERENCES:

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Received on 01.07.2016 Accepted on 25.07.2016

Asian J. Pharm. Ana. 2016; 6(3): 155-166.

DOI: 10.5958/2231-5675.2016.00025.9

Wave number in cm^-1	Characteristic bands
2964.624	Alkanes
1063.689	Amines (C-N)
1578.536	Arenes
1157.999	Alcohols

S.No.	Characteristic bands	Standard wave no. range	Pure drug	Guar gum	Xanthangum	Chitosan	HPMCK100m
1	Alkanes	2850-3000	2964.624	2936.118	2962.665	2967.791	2983.726
2	Amines (C-N)	1000-1250	1063.689	1064.795	1057.746	1063.608	1062.784
3	Arenes	1500-1600	1578.536	1578.941	1584.509	1573.113	1560.791
4	Alcohols	970-1250	1157.999	1147.043	1149.746	1157.595	1156.683