Research Article

FORMULATION AND EVALUATION OF GLIPIZIDE SUSTAIN RELEASE MATRIX TABLETS

SANTOSH GIRI, SELLAPPAN VELMURUGAN* AND SAHITHYA CHOWDARY

KLR Pharmacy College, Palvoncha, Khammam, Andhra Pradesh, India. Email: willard_cbe@rediffmail.com

Received: 27 Dec 2012, Revised and Accepted: 03 Feb 2013

ABSTRACT

Objective: The Glipizide matrix tablet were prepared using different hydrophilic polymers (HPMC different grades and sodium CMC) in various proportions as release retarding agent to prolong the drug release and to improve the patience compliance.

Methods: The matrix tablets were prepared by direct compression method. The prepared matrix tablets were subjected to thickness, friability, weight variation test, drug content, hardness, swelling index and in vitro release studies. The drug excipients compatability was evaluated by FTIR and DSC studies.

Results: All the formulation showed compliance with pharmacopoeial standards. The in vitro dissolution study shows that F18 formulation was releases the drug in a controlled manner for 12 hours. Among all the formulations, formulation F18 which contains combination of HPMC K100 & E15 releases the drugs which follow Zero order kinetics via, swelling, diffusion. The DSC and FTIR studies revealed that there was no interaction between drug and excipients. Stability studies were carried out for optimized formulation F18 according to ICH guidelines. Stability studies (40±2oC/75±5% RH) for 3 months indicated that Glipizide was stable in matrix tablets.

Conclusion: Hence different hydrophilic polymers (HPMC different grades and sodium CMC) in various proportions can be used to prepare matrix tablets of glipizide having prolonged therapeutic effect with enhanced patience compliance.

Keywords: Glipizide, HPMC, Sodium CMC, Sustained Release, Matrix Tablets

INTRODUCTION

Sustained release system is types of modified drug delivery system that can be used as an alternative to conventional system. Among different dosage forms, matrix tablets are widely accepted for oral sustained release [1].Sustained release system have benefits like patient compliance, avoid multiple dosing, cost effectiveness, flexibility, increase the plasma drug concentration, avoid side effects, broad regulatory acceptance and overcome the problems associated with conventional drug delivery system [2-4].

Hydrophilic polymers are becoming very popular in formulating oral sustain release matrix tablets. As the dissolution medium penetrates the matrix tablets, the polymer material swells and it form hydrogel by the time thus it is able to controlled drug release [5, 6]. However, the matrix tablet by direct technique is a very simple approach in the pharmaceutical field for its ease, compliance, faster production, in comparison with other controlled release systems. Cellulose ethers such as hydroxypropyl methylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) are widely used hydrophilic polymers as release retardants [7, 8].

Glipizide is widely used sulphonyl urea antidiabetic agent, for the treatment of patients with type II diabetes [9].It is a weak acid (pKa = 5.9) practically insoluble in water and acid solution but as per biopharmaceutical Classification System (BCS) it is highly permeable [10]. The oral absorption is uniform, rapid and complete with nearly 100% bioavailability with an elimination half-life of 2- 4 hours. Glipizide having a short biological half-life (3.4±0.7 h) requiring it to be administered in 2 to 3 doses of 2.5 to 10 mg per day [11]. SR formulations that would maintain plasma levels of drug for 8 to 12 hrs might be sufficient for once a day dosing for glipizide. Sustain

release products are needed for glipizide to prolong its duration of action and to improve patient compliance .The objective of this study was to develop a matrix system to completely deliver glipizide, in a zero order manner over an extended time period by using various hydrophilic polymers.

MATERIAL AND METHODS

Materials

Glipizide was a gift sample from Micro labs ltd, Bangalore. HPMC K4M, K15M, K100M, E15, Sodium CMC were received as gift sample from AET lab, Hyderabad, India. MCC was gift sample from Vilin Bio med Ltd. Roorkee, Ind. Talc from S.D. fine chemicals Pvt. Ltd. Magnesium Sterate was from Himedia Pvt. Ltd. Microcrystalline cellulose was procured from Signet Chemicals. All other ingredients used were of analytical grade

Methods

Matrix tablets preparation

Oral sustain release glipizide matrix tablets were prepared by direct compression technology. The investigated formulations are shown in Table 1. All the powders passed through a 60 mesh sieve. The required quantity of drug, various polymers and fillers were mixed thoroughly. Talc and magnesium stearate were finally added as a glidant and lubricant respectively. The blend was directly compressed (6 mm diameter, round flat faced punches) using multiple punch tablet compression machine (Cad mach Machinery Ltd., Ahmedabad, India). Each tablet contained 5 mg of glipizide. All the tablets were stored in airtight containers for further study.

Table 1: Composition of Glipizide matrix tablets

Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 F15 F16 F17 F18 Glipizide 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 HPMC K4M 15 25 35 HPMC K15M 15 25 35 HPMC K100M 15 25 35 20 15 12.5 HPMC E15 15 25 35 5 10 12.5 Sodium CMC 15 25 35 MCC 78 68 58 78 68 58 78 68 58 78 68 58 78 68 58 78 68 58 Mag. Stearate 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Talc 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Total weight 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100

International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491 Vol 5, Suppl 1, 2013

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Evaluation of tablets

Thickness

Ten randomly selected glipizide matrix tablets from each formulation were used for thickness determination. Thickness of each tablet was measured by using digital Vernier Caliper (Mitutoyo Dial Thickness Gauge, Mitutoyo, Japan) and the results were expressed as mean values of 10 determinations, with standard deviations.

Hardness

The hardness of ten randomly selected glipizide matrix tablets from each batch was measured using Pfizer Hardness tester (Secor Scientific Eng Corporation India).. The test was carried out in triplicate for all batches as per USP XXIV monograph for uncoated tablets. Mean and standard deviation were computed and reported.

Friability

Previously weighed 10 tablets from each batch were taken in Roche friabilator (Roche friabilator, Pharma labs, Ahmedabad, India). After100 revolutions of friabilator tablets were recovered. The tablets were then made free from dust and the total remaining weight was recorded .Friability was calculated from the following formula.

Percentage friability = (Initial weight – Final weight) × 100 Initial weight

Weight variation test

All prepared matrix tablets were evaluated for weight variation as per USP monograph. Twenty tablets were weighed collectively and individually using an electronic balance. The average weight was calculated and percent variation of each tablet was calculated. The percent deviation was calculated using the following formula [12].

Percentage weight variation = (Individual weight – Average weight / Average weight) X 100

Drug content

Ten tablets were weighed and grounded in a mortar to get fine powder; powder equivalent to the mass of one tablet extracted with pH7.4 phosphate buffer and filtered through 0.45µ membrane filter paper. The glipizide content was determined spectrophotometrically at 276nm using an UV- spectrophotometer (Elico, Ahemadabad, India) after suitable dilution [13].

In vitro release studies

The release rate of glipizide from sustained release tablets was determined using USP Dissolution apparatus II (Electrolab, Mumbai, India) .The dissolution test was performed using 500 ml of phosphate buffer pH 7.4 for 12 hours, at 37 ± 0.5°C and 50 rpm. Aliquot (5 ml) of the sample solution was withdrawn at predetermined time intervals and replaced with an equal volume of fresh buffer maintained at 37±0.5ºC.The samples were filtered through a 0.45μ membrane filter and diluted to a suitably. Absorbance of these solutions was measured at 276 nm using Elico UV-VISIBLE spectrophotometer. The release studies were conducted in triplicate [14].

Kinetic release profile

The glipizide release data from all the formulation were fitted in various kinetic models like zero order; first order Higuchi’s model and korsemeyer- peppas equations. A criterion for selecting the most appropriate model was based on goodness of fit, high regression coefficient value [15, 16].

Swelling index study

The extent of swelling was measured in terms of percentage weight gain by the tablet. The swelling behavior of all formulation was

studied. One tablet from each formulation was kept in a petridish containing pH 7.4 phosphate buffers. The tablet was removed every three hour interval up to 12 hour and excess water blotted carefully using filter paper. The swollen tablets were re-weighed (W2). The swelling index (SI) of each tablet was calculated according to the following equation [17].

S.I. = {(Wt-W0) / W0} ×100

Where- W0 = initial weight, Wt = final weight

FTIR Studies & DSC Studies

Compatibility study of glipizide with the excipients was determined by I.R. Spectroscopy (FTIR) using Shimadzu FT-IR spectrometer model. The pellets were prepared with KBr using pure drug, polymers and crushed tablet formulations and analyzed in the frequency range between wave numbers 4000 to 400 cm-1 at 4 cm-1

resolution [18].

The DSC analysis of pure drug, drug+ HPMC E15, drug+ Sodium CMC, drug+ HPMC K4drug+ HPMC K15 and drug+ HPMC K100, were carried out using a Shimadzu DSC 60, (Japan) to evaluate any possible drug-polymer interaction. Accurately weighed 5-6 mg samples were hermetically sealed in aluminium crucible and heated at constant rate of 10oC/min over a temperature range of 40 to 300

oC. Inert atmosphere was maintained by purging nitrogen gas at a flow rate of 50ml/min [19].

Stability studies

To assess the drug and formulation stability, stability studies were done according to ICH guidelines. The formulation (F18) was selected for stability study on the basis of in vitro drug dissolution studies .In the present study, stability studies were carried out at 40°C/75% RH in closed high density polyethylene bottles for 3 months. The samples were withdrawn after periods of 1 month, 2 month and 3 month and evaluated for physical changes, hardness, friability, drug content, during the stability studies [20, 21].

RESULTS AND DISCUSSION

The physical attributes of the tablet were found to be satisfactory. Typical tablet defects, such as capping, chipping and picking, were not observed. The physicochemical characterizations of different batches of glipizide matrix tablets are given in (Table 2).The thickness of the tablets were ranged between 2.40± 0.08 to 2.65± 0.09 mm. All the batches showed uniform thickness. Weight variations for different formulations were found to be 98.2±0.36 to 224±1.42 mg. The average percentage deviation of all tablet formulations was found to be within the limit, and hence all formulations passed the test for uniformity of weight as per official requirement .The hardness of all the matrix tablets formulations were ranged from 6.0±0.44 to 7.5 ± 0.55 kg/cm2. The percentage friability of all the formulations was ranged from 0.32% to 0.53%. In the present study, the percentage friability for all for formulations was within the prescribed limits. The percentage of drug content for F1 to F18 was found to be in between 97.26 ± 0.96 to 101.7 ± 1.1 of glipizide which indicates that by direct compression we can get a good quality of Glipizide matrix tablets.

The drug release from the tablets prepared using hydrophilic polymers was slow and spread over 12 h, depending upon the concentration and type of polymer used, whereas drug release from all the tablets prepared employing polymer HPMC E15 were given relatively rapid. Tablets prepared employing HPMC K4M, HPMC K15M, HPMC K100M, Sodium CMC showed drug release over 12 h. The order of increasing release retarding effect observed with various polymers was HPMC E15 < HPMC K4M < HPMC K15M < Sodium CMC < HPMC K100M. It is evident from the in vitro dissolution data that increase in hydrophilic polymer concentration decreases the release rate this might be due to increase in diffusional path length, which the glipizide molecule may have to travel. Comparative dissolution profile is presented in fig. 1.1-1.3.

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Table 2: Physico chemical properties of Glipizide matrix tablets

Formulation code Hardness (kg/cm2)a Thickness (mm)a Friability a Weight variation Drug content a F1 6.5 ± 0.48 2.40 ± 0.08 0.39 98.2 ± 0.36 98.14 ± 1.1 F2 6.0 ± 0.44 2.55 ± 0.09 0.52 98.9 ± 1.36 98.19 ± 0.50 F3 6.5 ± 0.52 2.65 ± 0.09 0.48 99.2 ± 1.37 98.58 ±0.52 F4 6.8 ±0.42 2.46 ± 0.08 0.35 99.2 ± 1.36 97.26 ± 0.96 F5 6.0 ± 0.4 2.53 ± 0.09 0.38 99.8 ± 1.41 100.58 ± 0.99 F6 6.1 ± 0.3 2.56 ± 0.09 0.39 99.5 ± 1.39 98.40± 0.97 F7 6.5 ± 0.44 2.50 ± 0.09 0.32 99.8 ± 1.40 98.42 ± 0.72 F8 7.2 ± 0.53 2.48 ± 0.08 0.36 99.3 ± 1.38 99.26 ± 0.8 F9 6.8 ± 0.5 2.60 ± 0.09 0.38 98.2 ± 1.36 98.17 ± 1.24 F10 6.7 ± 0.52 2.52 ± 0.09 0.36 99.2 ± 1.37 98.26 ± 0.96 F11 6.5 ± 0.48 2.58 ± 0.09 0.38 98.3 ± 1.36 99.58 ± 0.98 F12 7.3 ± 0.54 2.64± 0.08 0.4 102 ± 1.42 101.7 ± 0.9 F13 6.34 ± 0.37 2.50 ± 0.09 0.33 101.2 ± 1.4 99.6 ± 0.98 F14 6.55 ± 0.39 2.45 ± 0.08 0.35 99.6 ± 1.38 100.1 ± 0.9 F15 7.0 ± 0.41 2.42± 0.08 0.38 100.2 ± 1.39 101.7 ± 1.1 F16 6.3 ± 0.47 2.32± 0.08 0.34 101.3 ± 1.3 98.26 ± 0.97 F17 6.5 ± 0.52 2.58 ± 0.09 0.37 98.3± 1.36 99.58 ± 0.98 F18 7.1 ± 0.55 2.65 ± 0.09 0.43 99.2 ± 1.31 100.4 ± 0.83

Mean ± SD; a n = 10

Fig. 1.1: Comparative release profile of formulation F1 to F6

Fig .1.2: Comparative release profile of formulation F7 to F12

Fig .1.3: Comparative release profile of formulation F13 to F18

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The in vitro dissolution data were fitted in different kinetic models viz. zero order, first order, Higuchi and Korsemeyer- Peppas equation (Table.3). The zero-order plots were found to be fairly linear as indicated by their high regression values for

F18 formulation. The release exponent n was between 0.387 to 0.771 (0.5 < n < 0.89), which appears to indicate a coupling of the diffusion and erosion mechanism so-called anomalous diffusion.

Table 3: Kinetic parameters of matrix tablets

Formulation code F1 F2 F3 F4 F5 F6 F7 F8 F9 Zero order 0.946 0.962 0.981 0.962 0.954 0.941 0.981 0.968 0.98 First order 0.784 0.732 0.803 0.868 0.851 0.743 0.708 0.64 0.599 Higuchi 0.99 0.986 0.977 0.988 0.994 0.995 0.976 0.98 0.949 Peppas 0.988 0.989 0.99 0.987 0.993 0.987 0.982 0.982 0.959 n 0.532 0.579 0.66 0.536 0.587 0.582 0.678 0.638 0.615 Formulation code F10 F11 F12 F13 F14 F15 F16 F17 F18 Zero order 0.97 0.971 0.993 0.891 0.912 0.91 0.967 0.97 0.972 First order 0.762 0.676 0.641 0.845 0.747 0.706 0.65 0.68 0.704 Higuchi 0.98 0.985 0.955 0.989 0.988 0.995 0.965 0.963 0.964 Peppas 0.971 0.988 0.991 0.969 0.963 0.984 0.95 0.943 n 0.544 0.592 0.771 0.387 0.401 0.429 0.518 0.526 0.532

Swelling study was performed on all the batches (F1 to F18) for 12 hours. The result of swelling index was shown in table 4. Formulation containing sodium CMC showed higher swelling indices as compared with other formulation containing HPMC K4, HPMC

K15, HPMC K100 and HPMC E15. The direct relationship was observed between swelling index and polymer concentration and type, and as polymer concentration increases in matrix tablets, swelling index was found to increase.

Table 4: Swelling index study

Time (hrs) F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 F15 F16 F17 F18 1 118 134 158 218 226 247 74 82 139 42 46 58 190 225 242 116 122 125 3 122 159 197 232 247 258 88 102 146 54 59 62 218 238 263 127 139 149 6 113 172 261 249 258 272 102 114 163 68 72 79 229 252 278 135 148 174 9 106 186 253 198 206 242 93 98 132 57 63 66 212 240 253 112 136 `161 12 98 202 245 176 183 204 77 86 126 42 51 59 207 216 228 103 119 143

* Formulation F17 to F20 disintegrated with few hours (Data not shown)

FT-IR studies were carried out to know the compatibility. FT-IR results revealed that there was no significant difference in the peaks of glipizide and HPMC K100 in matrix tablets compared to pure glipizide as shown in figure 2.1-2.3. It was found that there was no interference to the drug with excipients and polymer used in the formulations.

Fig .2.1: FTIR spectra of Glipizide pure drug

Fig. 2.2: FTIR spectra of formulation F7

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Fig. 2.3: FTIR spectra of formulation F18

Pure powdered glipizide showed a melting endotherm at 216.4 C, and optimized formulation F18 showed melting endotherm at 208 C. Optimized formulation showed their identical peaks at defined temperature range. Presence of all peaks indicates that all

ingredients are compatible with drug and there is no incompatibility between the selected ingredients. Thermogram of different formulations and drug are shown in figure 3.1-3.6.

Fig .3.1: DSC thermogram of Glipizide pure drug

Fig. 3.2: DSC thermogram of formulation F1

Fig .3.3: DSC Thermogram of formulation F4

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Fig. 3.4: DSC thermogram of formulation F13

Fig .3.5: DSC Thermogram of formulation F18

F-18 formulation was selected for the stability studies. The results of stability study were shown in Table 5. The glipizide matrix tablets did not show any significant change in physicochemical parameters

and other tests (Table 5). Thus, it was found that the matrix tablets of glipizide (F18) were stable under short term storage conditions for at least 3 months.

Table 5: Stability study results of formulation F18

Formulation code Stability period Hardness (Kg/cm2) Friability % Drug content % F18 0 7.1 ± 0.55 0.43 100.4 ± 0.83

30 Days 6.9 ± 0.4 0.57 99.34 ± 0.84 60 Days 6.5 ± 0.7 0.62 98.26 ± 0.81 90 Days 6.2 ± 0.5 0.69 97.13 ± 0.74

Mean ± SD; n = 3

CONCLUSION

The present work was to study the effect of various hydrophilic polymers on in vitro release rate from sustained release tablet of Glipizide. The sustained release drug delivery was a promising approach to achieve a prolonged therapeutic action of drug. Different types of matrix forming polymers HPMC K4M, HPMC K15M, HPMC K100M, HPMC E15 and sodium CMC alone & combination were studied. Formulation F18 containing HPMC K100 & E15 in combination showed controlled drug release for 12h, emerging as best formulation. The cumulative percentage drug was decreased by increase in polymer concentration. Mechanism of drug release of optimized formulation F-18 found to be zero order non-Fickian diffusion. FTIR & DSC studies proved the no chemical interaction in drug and polymer of the developed matrix tablets. The stability studies were carried out according to ICH guideline and selected F18 formulation were stable at 40°C/75% RH up to 3 months .The controlled and efficient drug delivery system developed in the present study will maintain plasma Glipizide levels better, which will overcome the drawbacks associated with the conventional therapy.

ACKNOWLEDGMENT

The authors are thankful to Aurobindo Pharma Ltd.,Hyderabad for providing gift samples. Authors are also thankful to the chairman

K.L.R Pharmacy College, Paloncha, Andhra Pradesh for permitting to carry out research work.

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