Design and Development of Sustained Release Bilayered Tablets of Glipizide

Salma Banu S.K.* and Venkateswara Rao T.

Bapatla College of Pharmacy, Bapatla Educational Society, Bapatla, Guntur district, Andhra Pradesh-522101

ABSTRACT:

Glipizide, a second generation sulfonylurea is effective in controlling the blood glucose in patients with Non-Insulin Dependent Diabetes Mellitus. As Glipizide possess short biological half life (2-4 hrs), the concept of Bi-layered tablet technology was used to formulate Glipizide as Sustained release tablet formulation. In order to overcome the disproportionate release of drug during intial period in case of general sustained release tablet formulations the concept of Bilayered tablets was utilized. Moreover by fabricating drugs in the form of Bilayered tablets, one can improve the Cmax and the speed of appearance of the drug in patient. Bilayered tablets formulated through Direct Compression was comprised of immediate, sustained release layers were formulated and evaluated through %Weight variation, Hardness, Friability, %Drug content, Swelling index and In-vitro drug release studies. 30% of the drug present in the immediate release layer was released within first 20 minutes and the remaining 70% of the drug release was sustained based on the polymer selected. The formulation comprised of HPC and HPMC as the polymers sustained the drug release for 12hrs and was found to be the best formulations.

KEYWORDS: Bilayered tablets, Glipizide, PVP K-30, Spray Dried Lactose, HPC, HPMC

INTRODUCTION:

The concept of Bilayered tablet technology is utilized for stabilization of two incompatable drugs, taste masking of drugs, delivering two drugs having synergistic effects or to deliver a drug for biphasic drug release profile and for the purpose of extension of patents. A Bilayered tablet comprises of two layers among which the first layer is immediate release layer for sudden onset of action and the second layer is Sustained release layer to maintain the steady state concentrations of drug in the blood.

Glipizide, a second generation sulfonylurea is effective in controlling the blood glucose in patients with Non-Insulin Dependent Diabetes Mellitus. Glipizide is a whitish odorless powder with a molecular weight of 445.55. It is insoluble in water and alcohol but the absolute bioavailability is 1. It has short biological half life of 2-4 hrs and the metabolites formed are devoid of hypoglycaemic activity. As Glipizide possess short biological half life (2-4 hrs), patient should go for frequent administration usually twice or thrice a day which might be a risk to the patient. In order to overcome this Glipizide sustained release dosage forms are formulated. Sustained release or Extended release formulations generally lead to a delayed appearance of effective plasma levels and they cannot provide a prompt disposition of the dose immediately after administration. Some times Glipizide is disproportionately released quickly after a patient administered the normal sustained release composition which results in spike in the level of medication present in the patient’s blood stream. To avoid such problems the concept of Bilayered tablets is uitlised to formulate Glipizide.

Materials:

Glipizide, a gift sample from Orchid Pharma Pvt. Ltd., HPC from Dr. Reddy’s laboratories Hyderabad, HEC from Himedia Pharmaceuticals Pvt. Ltd. Mumbai, HPMC(3000-5600cps) and PVP-K30 from S.D fine chemicals Mumbai, Spray Dried Lactose from Dr. Reddy’s Laboratories, Hyderabad.

Method:

Estimation of Glipizide:

Analytical methods involved in the estimation of Glipizide included are;

UV Spectrophotometric method, Capillary Electrophoresis method, HPLC (High Performance Liquid Chromatography), Volumetric method, Liquid chromatography, Mass Spectrometry.

UV Spectrophotometric method³ was used in the present investigation for the estimation of Glipizide.

Construction of Calibration Curve:

Preparation of Stock solution: 25mg of Glipizide was dissolved in methanol in 25ml volumetric flask to form a clear solution and later it was made up to volume with methanol.

Preparation of Required concentrations: 1ml of stock solution was withdrawn and made up to volume with pH 7.4 phoshate buffer in 100ml volumetric flask to obtain 10µg/ml concentration. 2ml, 4ml, 6ml, 8ml, of solution were withdrawn from the 10µg/ml concentration and made up to volume with pH 7.4 phosphate buffer in 10ml volumetric flak to obtain 2µg/ml, 4µg/ml, 6µg/ml, 8µg/ml respectively, then analysed Spectrophotometrically at 223nm and the results were shown in Table:1 and Fig:1.

Table - 1 Calibration Curve Data:

S. No	Conc (µg/ml)	Absorbance
1	2	0.124±0.001
2	4	0.218±0.003
3	6	0.339±0.004
4	8	0.442±0.003
5	10	0.526±0.002

Fig – 1 Calibration Curve:

Preformulation Studies:

Drug-excepient compatability studies were carried out through Fourier Transform Infrared Spectrophotometer. The samples were scanned over the range of 4000 – 400 cm^-1.

Preparation of Bilayer Tablets:

Loading dose and Maintainance dose were calculated as per the reported method^4,5 and the Bilayered tablets of Glipizide were formulated by Direct Compression Technique.

Formulation of Immediate Release layer

The Immediate release layer was formulated by uniformly mixing the required quantity of Glipizide with the required quantities of binder and diluent as specified in the formulation table -2 Then talc and magnesium stearate were added, mixed thoroughly to attain uniformity in the powder blend.

Formulation of Sustained Release layer

The Sustained release layer was formulated by uniformly mixing required amount of Glipizide with measured quantities of polymer and diluent as specified in the formulation tables-3. Then talc and magnesium stearate were added and mixed thoroughly to attain uniformity in the powder blend

Table – 2 Composition for IR layer of Bilayered tablet:

S. No	Ingredients	Quantity per tablet in mg
		F1	F2	F3	F4
1	Glipizide	3	3	3	3
2	Polyvinyl Pyrrolidine	2.5	1.5	1.5	1.5
3	Micro crystalline cellulose	42.5	43.5	-	-
4	Spray Dried Lactose	-	-	43.5	-
5	Dicalcium Phosphate	-	-	-	43.5
6	Magnesium Stearate	1	1	1	1
7	Talc	1	1	1	1
Total Weight		50	50	50	50

Compression of Bilayer Tablets⁶:

The powder blend of Sustained release layer was placed in the die cavity and compressed slightly. The powder blend of immediate release layer was placed over the slightly compressed SR layer and compressed finally to form a bilayered tablet using 16 station rotary tablet machine (Cadmach, India) with 9mm round shaped flat punches.

Precompressional Parameters7:

Bulk Density: The powder blend of all formulations was evaluated separately in order to determine their bulk densities. Powder blend was weighed (M) and later the weighed powder blend was transferred in to the measuring cylinder and volume occupied was noted (V_b).

D_b = Mass of the powder blend (M)

Vol. occupied by powder blend (V_b )

V_b is known as the bulk volume and Bulk density is expressed in terms of g/ml.

Table – 3 Composition for Bilayered Tablets of Glipizide:

S. No	Ingredients	Quantity in milligrams(mg)
		F5	F6	F7	F8	F9	F10	F11	F12	F13
Immediate Release Layer
1	Glipizide	3	3	3	3	3	3	3	3	3
2	Polyvinyl Pyrrolidine	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5
3	Spray Dried Lactose	43.5	43.5	43.5	43.5	43.5	43.5	43.5	43.5	43.5
4	Magnesium Stearate	1	1	1	1	1	1	1	1	1
5	Talc	1	1	1	1	1	1	1	1	1
Sustained Release Layer
1	Glipizide	7	7	7	7	7	7	7	7	7
2	HPC	30	40	50	-	-	-	-	-	-
3	HPMC(3000-5600cps)	-	-	-	30	40	50	-	-	-
4	HEC	-	-	-	-	-	-	30	40	50
5	Spray Dried Lactose	81	71	61	81	71	61	81	71	61
6	Magnesium Stearate	1	1	1	1	1	1	1	1	1
7	Talc	1	1	1	1	1	1	1	1	1
Total Weight		170	170	170	170	170	170	170	170	170

Tapped Density: Powder blend was transferred into the measuring cylinder and subjected for 100 tappings. The obtained volume was noted as the tapped volume. Tapped density is expressed as g/ml and tapped density is given by the formula;

D_t= mass of the powder blend (M)

Tapped volume (V_t)

Angle of Repose: Angle of repose is the maximum angle possible between the surface of the pile of granules and the horizontal plane. This is one of the measure for flow properties. Powder blend was allowed to flow through the funnel attached to a stand and later height and radius of the heap of the powder blend formed was noted. Based on the height and radius obtained Angle of repose was calculated using the formula;

Tan (ɵ) = height of the heap (h)

radius of the heap (r)

Carr’s Index (or) %Compressibility: Carr’s Index is one more measure to know the flow properties. It is indicated by the letter (I) and expressed in terms of percentage

I=tapped density-bulk density × 100

tapped density

Hausner’s Ratio: Hausner’s ratio was calculated by using the formula;

Hausner’s ratio = tapped density

bulk density

Post Compressional Parameters⁷:

Weight Variation: Twenty tablets were weighed collectively and individually. Average weight was calculated and based on the obtained weights % weight variation was calculated using the formula,

% Weight Variation =

Average weight-Individual weight × 100

Average weight

Hardness: Hardness of the tablet was tested by placing the tablet longitudinally in between the two plungers of the Monsanto tablet hardness tester and the obtained hardness was mentioned in terms of kg/sq.cm.

Friability: The friability of the tablets was determined by Roche Friabilator in which the tablets were subjected to the combined effect of abrasions and shock in a plastic chamber revolving at 25rpm and dropping the tablets at a height of 6 inches in each revolution.

Preweighed sample of tablets were placed in the friabilator and allowed to rotate for 100 revolutions. Later the tablets were dedusted and the tablets were reweighed. Percent friability is given by the formula;

%F = (1-W/W₀)×100

Where, W₀ is the weight of the tablets before the test

W is the weight of the tablets after the test

Estimation of Drug Content⁶: Equivalent to 100mg of Glipizide was accurately weighed from powdered bilayered tablets and it was dissolved in methanol to form a clear solution. Later it was made up to volume with methanol in 100ml volumetric flask. One ml of the sample was withdrawn, suitably diluted with pH 7.4 phosphate buffer and analysed spectrophotometrically at 223nm.

In vitro Dissolution Studies^3,8: In vitro release studies was carried out using USP XXIV 8-station dissolution rate test apparatus using 900ml of phosphate buffer p^H 7.4 for a period of 12hrs at 50 rpm and the temperature was maintained at 37˚c ± 1˚c. 5ml samples were withdrawn at predetermined intervals over 12hrs, and analysed spectrophotometrically at 223nm. 5 ml of fresh dissolution medium was replaced after each sampling in order to maintain sink conditions.

EXPERIMENTAL RESULTS:

Preformulation studies:

Fig – 2 IR Spectra of Glipizide:

Fig – 3 IR Spectra of Hydroxy Propyl Cellulose:

Fig – 4 IR Spectra of Best formulation:

Table– 4 Precompressional parameters for IR layer formulations:

S. No	Precompressional Parameters	Formulations
		F1	F2	F3	F4
1.	Angle of repose ( ̊)	21.5	23	22.4	19.5
2.	Bulk density ( gm/ml)	0.469	0.492	0.457	0.476
3.	Tapped density (gm/ml)	0.536	0.564	0.543	0.554
4.	Compressibility index (%)	12.50	12.76	15.9	14.07
5.	Hausner’s ratio	1.14	1.14	1.19	1.16

Fig – 5 Cumulative Percent Drug Release Plots for IR layer formulation

Fig – 5.1 First Order Release Plots for IR layer formulations:

Table – 5 In-vitro Drug Release Kinetics for IR layer formulations:

Formulation	Correlation Coefficient		K(hr^-1)	T50 (min)	T90(min)
	Zero order	First order
F1	0.7487	0.9219	0.0948	7.31	24.29
F2	0.7407	0.9756	0.1166	5.94	19.75
F3	0.7028	0.9783	0.1298	5.33	17.74
F4	0.7442	0.9221	0.2251	3.07	15

Table – 6 Post Compressional Parameters for Bilayered tablets of Glipizide:

S. No	Formulation	% Weight variation	Drug Content(%)	Friability	Hardness (kg/sqcm)
1	F5	7.420	99.78	0.59	4.7
2	F6	7.262	100.00	0.53	4.5
3	F7	7.153	98 .99	0.54	4.8
4	F8	7.445	99.50	0.47	4.6
5	F9	7.501	100.10	0.35	4.5
6	F10	7.326	99.96	0.29	4.7
7	F11	7.045	102.53	0.43	4.4
8	F12	7.249	99.65	0.25	4.7
9	F13	7.563	99.66	0.52	4.3

Fig 7: Cumulative Percent Drug Release Plots for Bilayered

Tablets of Glipizide formulated with HPC:

Fig 7.1:First order plot for Bilayered Tablets of Glipizide

formulated with HPC:

Fig7.2: Higuchi’s plot for Bilayered Tablets of Glipizide formulated with HPC:

Fig 8: Cumulative Percent Drug Release Plots for Bilayered

Tablets of Glipizide formulated with HEC:

Fig 8.1:First order plot for Bilayered Tablets of Glipizide

formulated with HEC:

Tablets of Glipizide formulated with HPMC(3000-5600cps):

Fig 8.2: Peppas’s plot for Bilayered Tablets of Glipizide

Fig 9: Cumulative Percent Drug Release Plots for Bilayered

formulated with HEC:

Fig 9.1:First order plot for Bilayered Tablets of Glipizide

formulated with HPMC(3000-5600cps):

Fig9.2: Higuchi’s plot for Bilayered Tablets of Glipizide

formulated with HPMC(3000-5600cps):

RESULTS AND DISCUSSION:

Preformulation studies:

Preformulation studies were carried out through Drug-Excepient compatibility studies using FTIR spectrophotometry. The observed principle peaks were identical in the IR spectra of drug and in the IR spectra of the best formulation. Hence it was confirmed that there was no chemical or physical interaction between the drug and the excipients.

Precompressional parameters for IR layer of Bilayered tablet:

The angle of repose for the formulations was found to be in the range of 19.5⁰ - 23⁰ . Bulk density and tapped density for the formulations were in the range of 0.457-0.492 gm/ml and 0.536-0.564 gm/ml. Compressibility index and Hausner’s ratio were in the range of 12.50-15.9 % and 1.14-1.19. The results obtained confirm that all the formulations exhibited the good flow properties as per the Pharmacopeial specifications.

Table – 7 In-vitro Drug Release Kinetics for Bilayered Tablets of Glipizide:

Formulation	Correlation Coefficient				K(hr-¹)	T50(hr)	T90(hr)	Exponential coefficient(n)
	Zero order	First order	Higuchi	Peppas
F5	0.8369	0.9230	0.9901	0.9875	0.3541	2.30	7.10	0.3771
F6	0.8156	0.9480	0.9724	0.9654	0.2230	3.80	10.67	0.3202
F7	0.7343	0.9593	0.9651	0.9357	0.1403	5.40	15.71	0.2889
F8	0.1718	0.9019	0.9083	0.9944	1.2661	0.39	1.97	0.2851
F9	0.5598	0.9326	0.9408	0.9866	0.5232	1.41	4.85	0.2911
F10	0.6750	0.9266	0.9531	0.9844	0.3583	1.87	6.76	0.3077
F11	0.7473	0.9312	0.9905	0.9824	0.4825	1.34	5.60	0.3713
F12	0.8366	0.9427	0.9732	0.9686	0.3243	3.35	7.73	0.3356
F13	0.8130	0.9369	0.9741	0.9732	0.2267	3.67	10.15	0.3259

Studies on In-vitro dissolution profile of Immediate release layer formulations:

Based on the results, the cumulative % drug released for F1, F2, F3, and F4 formulations were found to be 98.59, 99.22, 99.89, and 99.96 respectively. The formulations followed first order kinetics with a regression value of 0.9219, 0.9756, 0.9783, and 0.9221.

The results depict that, the time taken for the release of maximum amount of drug from the formulation F4 containing Spray dried lactose as diluent in the immediate release layer was found to be less, when compared to the time taken for the release of maximum amount of drug form the formulations F1, F2, containing Microcrystalline cellulose and F3 containing Dicalcium phosphate as diluents.

Hence, formulation F4 containing Spray dried lactose as diluent was confirmed as an optimized immediate release layer in order to achieve the minimum effective concentration with in less period of time for further development of this investigation.

Studies on Bilayered tablets of Glipizide:

The precompressional parameters i.e.; angle of repose, bulk density, tapped density, compressibility index and Hausner’s ratio were found to be within the Pharmacopeial limits indicating good flow properties. Similarly the postcompressional parameters i.e.; weight variation, hardness, friability, and percent drug content, were found to be in satisfactory limits.

The Cumulative % drug release for F5, F6, F7, F8, F9, F10,F11,F12,and F13 was 99.80, 99.40, 85.59, 99.42, 99.57, 99.10, 99.28, 99.11, and 98.19 at the end of 8.5hrs, 12hrs, 12hrs,3.5hrs, 6.5hrs, 8.5hrs, 7hrs, 9.5hrs, 12hrs respectively. Results reflect that increase in the concentration of the polymer increases the retardation in the release of the drug from the formulation. To ascertain the mechanism of drug release, in-vitro release data were fitted into various release kinetic models such as First order, zero order, Higuchi, and Peppas. The first order plots obtained were linear with higher regression values when compared with the regression values of zero order plots. Hence the order of release for formulations followed first order kinetics. F5- F7 and F11-F13 exhibited Higuchi’s model, while F8-F10 fitted in Peppas model and the Peppas exponential coefficient i.e. ‘n’ < 0.5 for the formulations F5 to F13 which indicates that the release was governed by Fickian diffusion.

CONCLUSION:

The results conclude that, increase in polymer concentration increases the retardation of drug release from the SR layer of a Bilayered tablet and also leads to decrease in first order release rate constant. The desired drug release rate obtained for F6 and F13 was found to be near to that of the theoretical desired drug release rate (K_s).The formulations F6 and F13 were suitable to sustain the drug release for a period of 12hrs, followed first order kinetics, exhibited Higuchi’s model and Krosmeyer-Peppas exponential coefficient ‘n’ < 0.5 indicates that the release was governed by Fickian diffusion. The optimized Bilayered tablet formulations i.e.; F6 and F13 avoids the release of the drug from the SR layer during the first 20 minutes in order to avoid the problems of dose dumping. Hence we can conclude that in this investigation Bilayered tablets of Glipizide were developed successfully with IR layer comprising of PVP-K30 as binder, Spray Dried Lactose as diluent and SR layer comprising of HPC and HPMC(3000-5600cps) as release retarding polymers for desired drug release rate by Direct Compression technique.

ACKNOWLEDGMENTS:

The authors express their gratitude to Orchid Pharma Pvt. Ltd., Chennai for providing gift sample of Glipizide in order to carry out this research work. The authors are also thankful to the Bapatla Educational Society, Bapatla for providing the infrastructure required to carry out this research work.

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Received on 04.08.2011

Accepted on 11.09.2011

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Research Journal of Pharmaceutical Dosage Forms and Technology. 4(1): Jan. - Feb., 2012, 24-31