Design and Development of Floating Tablet of Glipizide

Nirav Patel¹, Nagesh C. ¹*, Jinal Patel², Chandrashekhar S¹, Jani Devdatt¹.

¹Maratha Mandal’s College of Pharmacy, Belgaum-590016, Karanataka.

²A.P.M.C. college of Pharmaceutical Education and Research, Motipura, Himatnagar-383001, Gujarat.

ABSTRACT:

The purpose of this investigation was to prepare a gastro retentive drug delivery system of Glipizide. Floating tablets of Glipizide were prepared employing different polymers like HPMC K15M, HPMC K100M, sodium alginate, Carbopol 940, and PVP K30 by effervescent technique. Sodium bicarbonate and citric acid were incorporated as a gas generating agent. The Floating tablets were evaluated for uniformity of weight, hardness, friability, drug content, in vitro buoyancy, swelling study, dissolution studies and stability studies. The drug release profile and floating properties was investigated. The prepared tablets exhibited satisfactory physico-chemical characteristics. All the prepared batches showed good in vitro buoyancy. The tablet swelled radially and axially during in vitro buoyancy studies. It was observed that the tablet remained buoyant for 16-24 hours. Stability studies were performed on the promising formulations at 40±2º C with 75±2 RH for 3 months.

KEYWORDS: Glipizide, gatroretentive, intragastric floating tablets, buoyancy studies, swelling studies

INTRODUCTION:

Oral route of administration is the most important and convenient route for drug delivery. The benefits of long-term delivery technology have not been fully realized for dosage forms designed for oral administration. This is mainly due to the fact that the extent of drug absorption from gastrointestinal tract is determined by gastrointestinal physiology; irrespective of the control release properties of the device prolonged gastric retention improves bioavailability.¹

Gastric retentive dosage forms are designed to be retained in the stomach and prolong the gastric residence time of the drugs. Prolonged gastric retention improves bioavailability, reduces drug waste and improves solubility for drugs that are less soluble in a high pH environment.²

Based on the mechanism of flotation, delivery systems can be classified in two types. Effervescent floating drug delivery system and non-effervescent floating drug delivery system it release the drug from floating drug delivery system. These systems when reached to stomach, carbon dioxide is liberated by the acidity of gastric contents and is entrapped in the jellified Hydrocolloid. This is prepared by swellable polymers such as HPMC, sodium alginate, carbopol 940 and PVP K30 and various effervescent components like sodium bicarbonate and citric acid mixtures may be used.³

Glipizide is a second generation sulfonylurea used in the treatment of hyperglycemia. It’s poorly soluble in acidic acid it absorbs rapidly and completely. However its absorption is erratic in diabetic patients due to the impaired gastric motility or gastric emptying to overcome the presence study gastric retentive controlled release dosage form of the drug in the form tablet was formulated with different polymers. The object of the present work is preparing floating tablets in controlled fashion. The gas generating agent sodium bicarbonate and citric acid were added in different concentrations with varying amount of retardation and investigated the release profile following USP type-II in vitro dissolution model.⁴

MATERIALS AND METHODS:

Materials:

Glipizide was received as gift sample from supra chemicals Mumbai. HPMC K15M and HPMC K100M as a gift sample from Wallace pharmaceutical goa. All other chemicals were of analytical grade.

Methods:

Preparation of oral Floating tablet:

Floating tablets containing glipizide were prepared by direct compression technique using varying concentrations of different grades of polymers with sodium bicarbonate and citric aci

All the powders were accurately weighed and passed though an 80 mesh sieve (180 micrometer size). Then, except Magnesium stearate all other ingredients were blended uniformly in glass mortar. 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 blend was compressed into tablets having average weight of 250mg using a single punch tablet machine (Proton, India) fitted with an 8mm round flat punches. The compositions of all formulations are given in (table1).^{5, 6, 7}

Evaluation of tablet properties:

Determination of pre-compression parameters:

As per standard procedures, the preformulation studies including Bulk density, Tapped density, Compatibility study, Hausner’s ratio and Angle of repose was performed of the powder.⁸

Determination of post-compression parameters:

1. Hardness test

Pfizer hardness tester was used for the determination of hardness of tablets.⁸

2. Friability

Twenty tablets were accurately weighed and placed in the friabilator (Roche’s Friabilator) and operated for 100 revolutions. The tablets were dedusted and reweighed. The tablets that loose less than 1% weight were considered to be compliant⁹.

The % friability was then calculated by,

3. Weight variation

20 tablets were selected randomly from the lot and weighed individually to check for weight variation¹⁰.

4. Content uniformity test:

The Glipizide floating tablets were tested for their drug content. Five tablets were finely powdered; quantities of the powder equivalent to 15mg of Glipizide were accurately weighed and transferred to a 100 ml of volumetric flask. The flask was filled with 0.1N HCl (pH 1.2 buffers) solution and mixed thoroughly. The solution was made up to volume 100ml and filtered. Dilute 1 ml of the resulting solution to 10 ml with 0.1N HCl. The absorbance of the resulting solution was measured at 276 nm using a Shimadzu UV-visible spectrophotometer. The linearity equation obtained from calibration curve was used for estimation of Glipizide in the tablet formulations¹¹

Table 1: Composition of Gastroretentive Floating Tablets of Glipizide (F1 to F8)

Ingredients* (mg)	Formulation Code
	F1	F2	F3	F4	F5	F6	F7	F8
Glipizide	15	15	15	15	15	15	15	15
HPMC K100M	80	70	60	50	-	-	-	-
HPMC K15M	40	50	60	70	-	-	-	-
Sodium Alginate	-	-	-	-	40	60	80	100
Carbopol 940	30	30	30	30	40	40	40	25
PVP K30	10	10	10	10	10	10	10	10
Sodium Bicarbonate	60	60	60	60	90	90	70	70
Citric Acid	10	10	10	10	20	20	20	20
Aerosil	-	-	-	-	25	5	5	5
Talc	-	-	-	-	5	5	5	-
Mg. Stearate	5	5	5	5	5	5	5	5
Total	250	250	250	250	250	250	250	250

*All the ingredients are in mg. per tablet

Table 2: Pre-Compression Parameters of Designed Formulations (F1 to F8)

Formulation code	Pre-compression Evaluation Parameters
	Bulkdensity(gm/ml) (n=3)Mean±SD	Tapped density(gm/ml) (n=3)Mean±SD	Carr’s Index (%)	Angle of repose (n=3) Mean±SD	Hausner Ratio
F1	0.5143±0.005	0.6042±0.013	14.87	22º75’±2.243	1.1748
F2	0.4839±0.007	0.5806±0.006	16.65	25º93’±1.327	1.1998
F3	0.5028±0.004	0.5806±0.006	13.40	24º53’±1.102	1.1548
F4	0.5113±0.005	0.6124±0.012	16.49	25º92’±1.944	1.1975
F5	0.4865±0.009	0.5806±0.006	16.20	19º43’±1.281	1.1934
F6	0.5264±0.009	0.6209±0.015	15.22	22º91’±2.188	1.1795
F7	0.5029±0.009	0.5963±0.017	15.67	22º58’±2.448	1.1858
F8	0.5028±0.004	0.5921±0.006	15.08	23º89’±1.102	1.1776

Table 3: Post-Compression Parameters of Designed Formulations (F1 to F8)

Formulation code	Post-compression Evaluation Parameters
	Thickness (mm) (n=3) Mean±SD	Hardness Kg/cm^2 (n=3) Mean±SD	Weight Variation (mg) (n=20) Mean±SD	Friability (%) (n=10)	Drug Content (%) (n=3) Mean±SD
F1	4.38±0.030	5±0.100	249.7±0.948	0.284	98.47±0.899
F2	4.39±0.052	4.7±0.200	250.8±1.032	0.325	96.67±0.907
F3	4.39±0.035	5.3±0.200	248.7±0.823	0.245	97.33±0.759
F4	4.37±0.040	4.6±0.208	249.1±0.737	0.287	96.86±0.969
F5	3.2±0.162	4.9±0.208	249.8±0.918	0.325	96.00±0.921
F6	3.1±0.125	4.9±0.200	249.2±0.788	0.288	97.80±0.659
F7	3.2±0.165	4.7±0.152	249.7±0.948	0.367	97.33±0.529
F8	3.2±0.145	4.7±0.100	249.6±0.843	0.326	95.13±0.901

5. In vitro Buoyancy Studies:

The in vitro buoyancy was determined by floating lag time, as per the method described by Rosa et al. The tablets were placed in a 250 ml beaker, containing 200 ml of 0.1 N HCl. The time required for the tablet to rise to the surface and float was determined as Floating Lag Time (FLT) and the time period up to which the tablet remained buoyant is determined as Total Floating Time (TFT) ^{12, 13}.

6. Swelling Study:

The floating tablets were weighed individually (designated as W₀) and placed separately in glass beaker containing 200 ml of 0.1 N HCl and incubated at 37°C±1°C. At regular 1-h time intervals until 24 h, the floating tablets were removed from beaker, and the excess surface liquid was removed carefully using the tissue paper. The swollen floating tablets were then re-weighed (Wt), and % swelling index (SI) was calculated using the following formula^14,

SI (%) = (Wt – W₀/ W₀) x 100

7. In vitro Dissolution Studies:

The In vitro dissolution study was performed by using a United States Pharmacopeia (USP) type II (paddle) apparatus at a rotational speed of 100 rpm. Exactly 900 ml of 0.1 N HCl was used as the dissolution medium and the temperature was maintained at 37^oC ± 0.5^oC. A sample (5ml) of the solution was withdrawn from the dissolution apparatus at specified time interval for 24 h and the same volume was replaced with pre -warmed fresh dissolution media. The samples were diluted to suitable concentration with 0.1 N HCl. Absorbance of these solutions was measured at 276nm using a UV spectrophotometer^{16, 17}.

Table 4: Floating Lag Time and Total Floating Time of Designed Formulations (F1 to F8)

Formulation Code	Floating lag time (sec.) (n=3) Mean±SD	Total Floating Time (hrs.)
F1	99±1.525	> 24 hrs.
F2	103±1.498	> 24 hrs.
F3	109±1.823	> 24 hrs.
F4	112±1.765	> 24 hrs.
F5	57±1.230	> 24 hrs.
F6	62±1.189	> 20 hrs.
F7	69±1.852	> 20 hrs.
F8	79±1.497	> 16 hrs.

8. Curve fitting analysi

The mechanism of Glipizide release from the floating tablets was studied by fitting the dissolution data of optimized formulation in following models

1. Zero order

2. First order

3. Higuchi model

4. Korsemeyer and Peppas equation Based on the slope and the R² values obtained from the above models the mechanism of drug release was decided¹⁸.

9. Stability studies:

The optimized formulation of Glipizide were packed in amber color bottle and aluminum foil laminated on the upper part of the bottle and these packed formulation was stored in ICH certified stability chambers maintained at 40^οC and 75% RH (zone III conditions as per ICH Q₁ guidelines) for 3 months.

Table 5: Swelling Index of Gastroretentive Floating Tablets of Glipizide

Formulation	Swelling Index (%) Time (hrs) (n=3) Mean±SD
	1 hrs	2 hrs	3 hrs	4 hrs	5 hrs
F1	83±1.234	128±0.921	163±1.101	191±0.793	210±1.212
F2	81±0.949	134±0.859	161±0.669	185±1.189	204±0.993
F3	77±1.209	131±0.791	147±1.059	183±0.929	198±0.989
F4	73±0.991	127±1.009	143±0.853	179±0.947	191±0.881
F5	83±1.151	124±0.861	147±0.907	186±1.071	202±1.119
F6	77±0.981	129±0.754	147±1.107	179±1.003	198±0.982
F7	79±0.893	127±0.723	143±0.894	181±0.751	196±0.925
F8	75±0.984	117±0.833	147±1.038	161±1.069	179±1.211

Figure 1: Swelling Index of Gastroretentive Floating Tablets of Glipizide

The samples were withdrawn periodically and evaluated for their content uniformity, in vitro buoyancy studies and for in vitro drug release¹⁹.

RESULT AND DISCUSSION:

Pre-compression parameters:

Results of the pre-compression parameters performed on the blend for batch F1 to F8 are tabulated in Table 2.

The bulk density and the tapped density for all the formulations varied from 0.4839±0.007 to 0.5264±0.009 g/ml and 0.5806±0.006 to 0.6209±0.015 g/ml respectively.

The percentage compressibility of powder was determined using carr’s compressibility index. Carr’s index lies within the range of 13.40 to 16.65 %. All formulations show good compressibility. Angle of repose of all the formulations was found to be less than 30^o, which indicates a good flow property of the powders. The values were found to be in the range of 19^o43’±1.281 to 25º93’±1.327. Hausner ratio was found to be in the range of 1.1548 to 1.1998.

Post-compression parameters:

The formulated tablets were subjected for post- compressional evaluation such as thickness, hardness, weight variation, friability, drug content, in vitro buoyancy studies, swelling studies, in vitro dissolution studies, and stability studies.

Tablet thickness (n=3) were almost uniform in all the formulations and values for tablets ranged from 3.1±0.125 to 4.39±0.052 mm. The hardness of all formulations was in the range of 4.6±0.208 to 5.3±0.200 kg/cm², indicating satisfactory mechanical strength.

The weight variation values of tablets ranged from 248.7±0.823 to 250.8±1.032 mg. All the tablets passed weight variation test as the % weight variation was within the Pharmacopoeias limits of ±7.5% of the weight. The friability values ranged from 0.245 to 0.367 %. All the values are below 1% indicating that the tablets of all formulations are having good compactness and showing enough resistance to the mechanical shock and abrasion. The percent drug content of tablets was found to be in between 95.13±0.901 to 98.47±0.899 % of glipizide, which was within the acceptable limits. Table 3 shows the results of physicochemical characters of glipizide tablets.

Table 6: In vitro Dissolution Data for Formulation F1 to F8

Time (hrs.)	Cumulative % Drug Release of Formulation F1 to F8(n=3) Mean±SD
	F1	F2	F3	F4	F5	F6	F7	F8
0.5	6.53±0.231	5.07±0.611	6.67±0.611	7.73±0.611	8.53±0.611	13.20±0.800	14.67±0.611	16.13±0.462
1	9.10±0.610	8.43±0.803	9.37±0.614	10.58±1.010	11.78±0.614	17.27±0.402	17.81±0.613	22.36±1.224
2	14.98±0.614	11.78±0.615	12.45±0.803	13.79±1.012	15.00±0.614	21.70±1.746	23.83±0.614	29.32±0.807
3	19.82±0.614	14.87±1.203	15.80±1.011	19.01±1.012	20.48±0.803	25.59±2.581	28.93±0.402	36.03±1.226
4	24.64±0.234	19.68±0.807	20.49±0.806	23.84±1.410	25.45±1.011	31.34±3.830	36.56±0.802	41.80±1.064
6	31.60±0.612	25.44±1.011	25.71±1.204	29.33±1.608	32.41±1.012	39.51±4.427	45.27±0.615	52.63±0.801
8	40.44±1.408	32.41±1.012	31.61±1.013	36.70±1.015	41.51±1.012	47.82±3.512	52.65±0.803	68.69±0.796
12	54.89±2.211	41.38±1.606	38.97±1.606	43.94±1.410	56.76±1.410	62.93±1.634	65.49±0.804	79.45±0.235
16	67.77±1.816	56.50±1.414	52.75±1.813	59.04±1.608	71.91±1.608	76.21±0.455	77.03±1.011	93.11±1.006
20	81.44±2.213	73.78±1.812	68.69±1.610	73.66±1.813	83.06±1.813	91.75±0.611	92.96±0.616	-
24	95.52±2.215	89.34±1.415	86.65±1.813	90.01±1.210	93.13±2.213	-	-	-

Figure 2: In vitro Drug Released Profile of Formulations F1 to F4

Figure 3: In vitro Drug Released Profile of Formulations F5 to F8

Table 7: Release Kinetics Data of All the Formulations

Formulation code	% CDR	Zero order	First order	Higuchi	Korsmeyer-peppas
		R^2	R^2	R^2	n	R^2
F1	95.52	0.991	0.881	0.969	0.735	0.999
F2	89.34	0.994	0.897	0.934	0.750	0.985
F3	86.65	0.988	0.893	0.931	0.694	0.979
F4	90.01	0.988	0.900	0.952	0.673	0.986
F5	93.13	0.986	0.947	0.972	0.690	0.990
F6	91.75	0.977	0.935	0.978	0.575	0.981
F7	92.96	0.957	0.933	0.991	0.554	0.995
F8	93.11	0.936	0.970	0.992	0.535	0.990

Table 8: Stability Study of Formulation F1

Time (month)	Drug content (%)	Floating behaviour		In vitro Drug Release at 24hr (%)
		FLT (sec)	Total Floating Time (hrs)
Zero	98.47	99	> 24 hrs.	95.52
First	98.23	100	> 24 hrs.	95.23
Second	97.93	99	> 24 hrs.	95.01
Third	97.89	101	> 24 hrs.	94.93

Table 9: Stability Study of Formulation F5

Time (month)	Drug content (%)	Floating behaviour		In vitro Drug Release at 24hr (%)
		FLT (sec)	Total Floating Time (hrs)
Zero	96	57	> 24 hrs.	93.13
First	95.81	56	> 24 hrs.	93.01
Second	95.69	57	> 24 hrs.	92.93
Third	95.72	58	> 24 hrs.	92.98

In vitro Buoyancy Studies

In vitro buoyancy of the tablets from each formulation (F1 to F8) was evaluated and the results are mentioned in Table 4. Where, the highest and lowest floating lag time (FLT) was observed with the formulation F4 and F5 respectively. The concentration of the natural polymers increases the floating lag time also increases and total floating time (TFT) decreases.

Swelling index:

The swelling index of the tablets from each formulation (F1 to F8) was evaluated and the results are mentioned in Table 5 and plot of % swelling index vs. time (hrs) is depicted in Figure 1. Where, the highest and lowest swelling was observed with the formulation F1 and F8 after 5 hrs respectively. The swelling index increases by increasing the contact time with pH 1.2 buffers as the polymer gradually absorbs buffer due to hydrophilic nature the polymer with resultant swelling.

In vitro Dissolution Studies

In vitro dissolution studies of all the formulations of IGF tablets of glipizide were carried out in 0.1 N HCl. The study was performed for 24 hrs, and cumulative drug release was calculated at different time intervals. The in‐vitro drug release profiles for the formulations (F1-F8) were tabulated in Table 6. The plot of cumulative percentage drug release V/s time (hr) for formulations (F1-F4) and (F5-F8) were plotted and depicted in Figure 2 and Figure 3 respectively. Effects of various ingredients and their concentration on drug release were studied. It was observed that the type of polymer influences the drug release pattern. The in vitro drug release was observed that as the concentration of polymer is increased in formulations (F5 to F8) the time of drug release was decreased.

Curve fitting analysis:

The data obtained from in vitro dissolution studies were fitted to zero-order, first-order, higuchi and Korsemeyer–Peppas equations. The dissolution data obtained were plotted as Time versus cumulative percent drug released as zero order, Time versus log cumulative percent drug remaining as First order release kinetics, Square root of time versus cumulative percent drug released as Higuchi equation and Log time versus log cumulative percent drug released as per Korsemeyer-Peppas equation. The best fit with the highest determination R² coefficients was shown by both peppas and zero order models followed by Higuchi model which indicate the drug release via diffusion mechanism. Zero-order rate equation, which describe the system where release rate is independent of the concentration of the dissolved species. The Korsemeyer-peppas equation is used to analyze the release of pharmaceutical polymeric dosage forms, when the release mechanism is not well known or when more than one type of release phenomena could be involved. The values of n with regression coefficient of all the formulations are shown in Table 7. The value of n was in the range of 0.535 to 0.750, indicating non- Fickian diffusion. From the results it was confirmed that all the formulations are following zero order models followed by higuchi model which indicate the drug release via diffusion mechanism. The slope value from korsemeyer plots confirmed that the formulations are following non-fickian diffusion. The reason for showing zero order kinetics may be the presence of alkalizing agents in the formulation. The regression co-efficients for different drug release kinetics models were shown in Table 7.

Stability studies:

The accelerated stability studies were carried out according to ICH guidelines. Optimized formulations F1 and F5 were packed in amber color bottle and aluminum foil laminated on the upper part of the bottle and these packed formulation was stored in ICH certified stability chambers maintained at 40^οC and 75% RH (zone III conditions as per ICH Q₁ guidelines) for 3 months. The samples were tested for any changes in physical appearance, drug content, in vitro buoyancy studies and in vitro drug release studies at monthly intervals. The results of stability studies did not show any significant change in the physical appearance, drug content, in vitro buoyancy studies and in-vitro dissolution studies of above four formulations as shown in the Table 8 and Table 9.

CONCLUSION:

Gastroretentive floating drug delivery Systems offers a simple and practical approach to achieve increased gastric residence and to modify drug release profiles essential for controlled, site specific and localized drug action. Lower values of angle of repose below 30 indicate good flow properties of blends. All the prepared tablets were found to be of circular shape with no cracks. Friability and hardness were within the standard limits thus showing good mechanical strength of tablets. The drug content was well within the Pharmacopoeial limits indicating uniform distribution of drug within the controlled release gastro-retentive dosage form. The drug release data were explored for the type of release mechanism followed. The best fit with the highest determination R² coefficients was shown by both of the models (Zero and Peppas) followed by Higuchi model which indicate the drug release via non-fickian diffusion mechanism. Short-term stability studies of optimized formulations F1 and F5 indicate, that there are no significant changes in drug content and dissolution parameter values after 3 months storage at 40±2ºC.

ACKNOWLEDGEMENT:

The authors are thankful to the Management, Maratha Mandal’s College of Pharmacy to providing necessary facilities to carry out this work.

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Received on 30.08.2012

Modified on 17.09.2012

Accepted on 29.09.2012

© A&V Publication all right reserved

Research Journal of Pharmaceutical Dosage Forms and Technology. 4(5): September –October, 2012, 260-26