EFFECT OF SUPERDISINTEGRATING AGENT ON THE RELEASE OF METFORMIN HCl FROM IMMEDIATE RELEASE TABLETS
Department of Pharmacy, University of Chittagong, Bangladesh. Department of Pharmacy, Jagannath University, Dhaka, Bangladesh. Department of Pharmacy, University of Science and Technology Chittagong, Bangladesh
Keywords: Super disintegration, Metformin, Immediate release tablet
Abstract

Immediate release tablet of Metformin HCl needs to formulate for emergency treatment of type-II diabetes. The prime objective of the present research was to formulate immediate release tablet of Metformin HCL for rapid action by using Sodium starch glycolate, Collidon CL and Crosscarmellose Na as super disintegrants.Wet granulationmethod was adapted for the tablet preparation, maize starch used as a diluent, Povidone k-30 as a binder, sodium starch glycolate, collidon CL and crosscarmellose Na as super disintegrants in different concentration (2-5%). Aerosol -200 to provide proper flow characteristics and magnesium stearate as a lubricant. Total nine formations were prepared and evaluated for hardness, thickness, diameter, friability, weight variation, disintegration time and in-vitro drug release. All the formulations were compared for disintegration time and % drug release. All formulations are evaluated for pre-compression and post-compression parameters. The result obtained showed that the selected batch of tablet formulations containing sodium starch glycolate provides a short DT between 40 to 22 seconds, with sufficient crushing strength and acceptable friability.

Article Information

Identifiers and Pagination:
Year:2014
Volume:6
First Page:344
Last Page:350
Publisher Id:19204159.6:4.2014
Article History:
Received:June 4, 2014
Accepted:July 17, 2014
Collection year:2014
First Published:October 1, 2014

INTRODUCTION:

 Most common tablets are those intended to be swallowed whole and to disintegrate and release their medicaments rapidly in the gastrointestinal tract (GIT). The proper choice of disintegrant and its consistency of performance are of critical importance to the formulation development of such tablets [1].  The bioavailability of a drug is dependent on in vivo disintegration, dissolution, and various physiological factors [2]. Superdisintegrants provide quick disintegration due to the combined effect of swelling and water absorption of the formulation. Due to swelling of superdisintegrants, the wetted surface of the carrier increases, this promotes the wettability and dispersibility of the system, thus enhancing the disintegration, dissolution and bioavailability [3].

Metformin hydrochloride is an orally administered antihyperglycemic agent, used in the management of type II diabetes (NIDDM) and type I diabetes (IDDM). It is a very bitter drug and highly soluble in water [4]. This work aims at the design a formulation with the immediate release of Metformin HCl. Different types of disintigrating agents (Sodium starch glycolate, Collidon CL, and Crosscarmellose Na) were investigated and evaluated for their efficacy in formulating such kind of dosage form. Metformin HCI (500mg) was used as a model drug.

MATERIAL AND METHOD:

Materials:

Metformin Hydrochloride, Starch, Povidon k -30, Na-Starch glycolate, Collidon CL, Crosscarmallose-na, Aerosil -200 and Mg-stearate from ACI pharmaceuticals limited, Bangladesh. Potassium Di-hydrogen orthophosphate and Di-Sodium hydrogen orthophasphate collected from UAP laboratories.

Formulations:

In this research work, nine (09) probable formulations were designed to take Metformin Hydrochloride as a model drug and containing three super disintegrants such asNa-starch glyccolate,Collidon CL, Crosscarmalose sodium formulation design summarized as table 1.

Table 1: Formulations of Metformin HCL immediate release tablets.

Preparation of granules: [5]

Granules preparation is done in a series of steps in the laboratory. At first the active drug (Metformin HCl), diluent (Starch) and ¾of stated amount of superdisintegrants are passed through a 40 mesh sieve to obtain fine particles. Then, the active drug, superdisintegrants and the diluent under current investigation are appropriately weighed and mixed together for 10 minutes in a mortar. Then the binder solution is prepared by dissolving the above stated amount of povidone k-30 in sufficient amount of water.This solution is then added drop by drop to the dry mixture in the mortar. During this addition the mixture is continuously mixed in a clockwise direction, an action. This mixing process is continued for a further 10 minutes until all the binding solution has been added. At the end of this mixing, a uniform mixture of wet mass is obtained.Then the wet mass is then passed through a 16 mesh sieve to obtain granules. The granules were dried in an oven to get dry granules at 600 C. Finally, these granules are mixed with the above declared quantities of aerosil-200, 1/4 superdisintegrant and magnesium stearate to obtain granules with the pre-requisite flow properties. The active drug and all the other excipients were taken in such amounts that at least 40 tablets of each formulation could be prepared.

Pre-compression Study/ Evaluation of Prepared Granules: [5]

After preparation of granules pre-compression study like the angle of repose, bulk and tapped densities, Hausner ratio, compressibility index were performed.

Post-compression Study/ Mesurement of some Physical Parameters: [5, 7]

Post compression evaluation like hardness, thickness, diameter measurement, friability test, weight variation test and in-vitro dissolution study was performed.

In-vitro Dissolution: [5, 6, 7]

Dissolution studies were conducted according to the USP method (USP XXII) using apparatus 2. In all cases the conditions were maintained to be exactly the same, i.e. the RPM was maintained at 100 while the temperature maintained always at 370±0.5C. Dissolution medium 900 ml of the prepared buffer was poured. The dissolution was then set up with paddles and the tablets directly placed in the dissolution vessel. The example, 5 min, 10 min, 15 min, etc, 10ml of sample was then withdrawn, at each withdrawal, 10ml of fresh dissolution medium was immediately added to maintain the sink condition. The dissolution was carried out for one hour. This was done to get a simulated picture of drug release in the in-vivo condition. The sample that was collected was first filtered, and then diluted, being assayed at 233 nm using a UV spectrophotometer. The amount of drug released was calculated with the help of a straight line equation obtained from the standard curve of Metformin HCL at the same?max the percentage of drug released in thus calculated and plotted against time. This drug release profile was fitted into several mathematical models to get an idea of the release mechanism of the drug from the dosage form.

Model Dependent Analysis of the Dissolution data of the different formolations: [6]

Several kinetic models have been proposed to describe the release characteristics of a drug from a dosageform.The dissolution data of all the formulations are treated in these various pharmacikinetic models to identify the probable mechanism of release of the drug from the dosage form.The dissolution data,s were fitted in the following four models like zero order kinetics, first order kinetics, higuchi plotting, korsmeyer poling etc.

RESULT AND DISCUSSION:

Evaluation of granules: Granules are prepared by wet granules method and all the granules of 09 formulations were evaluated on different parameters and results are summarized as table 2. It is evident from the table 2, that all the above formulations quite readily meet prerequisite crieteria for showing good flowability. Formulation F 04 and F 06 showed higher angle of repose, and lower compressibility index and Hausner ratio.The lowest value of bulk and tapped densities was given by F 06, the lowest value of compressibility index and Hausner ratio was given by F 05 and the lowest value of angle of repose was given by F 07.

Table 2: Evaluation of granules (during pre-formulation study).

Evaluation of tablets: All the granules were compressed into tablets and tables are evaluated for different acceptable parameters and all the results are summarized as table 3.

Table 3: Post Compression Study/Evaluation of tablets.

578 mg. Average weight and weight variation analysis follows the standard of pharmacopoeia. The  average diameter was also found to be pretty much consistent varying insignificantly between the ranges of (13.04-13.27)mm.The average thickness of the tablets also ranged between (3.22-3.69)mm; however the variations were not alarming, result remained within the acceptable range. On the contrary, friability of the tablets of different formulations varied greatly range from (0.14-0.32) % but in pharmacopoeial range.The friability was found to be the greatest for formulations F 09.This indicates maximum loss of tablets upon attrition. According to some authentic references the maximum friability range should be in between (0.5-1)%. As the friability values for none of the formulations exceed 1%, it does not pose any serious problems. Hardness of the tablets of the different formulations varied widely ranging from (8.42-8.93)kg.Since hardness greater than 5.10 kg is considered acceptable, all the formulations are therefore thought to show the desired requisite hardness.

Disintegration test: After the above study tablet of all formulations were tested for disintegration and mean dissolution time. Results are summarized as table 4.

Table 4: Disintegration and Successive Mean Disintegration Time

From the table 4, it was seen that the lowest disintegration time (1.90) was found when sodium starch glycolate was used as a disintegrant and the highest  disintegration time (2.60) was found when Crosscarmellose sodium was used as a disintegrant. All disintegrating agents enhanced disintegration time. With respect to disintegration time, the following trend is observed amongst the disintegrants, Sodium starch Glycolate > Collidon CL > Crosscarmellose sodium.

Dissolution and Drug release Profile: Dissolution and total drug release profile summerized in figure 1 and table 5.

Figure 1: Drug release pattern of all formulations.

From the figure 1 and table 5, it was seen that the highest % of drug release (93.81) was found when sodium starch glycolate was used as a disintegrant and the lowest % of drug release (79.91) was found when Crosscarmellose sodium was used as a disintegrant. With respect to % of drug release, same trend like disintegration is observed amongst thedisintegrants, Sodium starch Glycolate > Collidon CL > Crosscarmellose sodium.

Model dependent drug release kinetics analysis was performed and results are summarized as table 6. The dissolution data,swere fitted in the following four models like zero order kinetics, first order kinetics, higuchi plotting, korsmeyer poling etc.

Table 5: Summery of Drug Release Model kinetics

Formulation F 01, F02, F03, F04, F05, F06 and F09  best fits with Higuchi (R2 ) and First order (R2) kinetic models near to same extent and then with Korsmeyer (R2) model. The value of release exponent obtained from Korsmeyer model, which indicates that the release pattern of Metformin HCL from F 01, F02, F03, F04, F05, F06 and F09 was followed Fickian transport mechanism, which appears to indicate a Class 01 diffusion mechanism (Higuchi).

F 07 best fits with Higuchi (R2 = 0.954) and First order (R2 = 0.907) kinetic models to same extent and then with Korsmeyer (R2 = 0.887) model. The value of release exponent obtained from Korsmeyer model is 0.481 which indicates that the release pattern of Metformin HCL from F 07 was followed Anomalous/non-Fickian transport mechanism. Whereas F 08 follows Higuchi model (R2 = 0.952). The value of n for Korsmeyer release is 0.431. This value indicates that the drug was released by Anomalous/non-Fickian transport mechanism.

CONCLUSION

The in-vitro drug relese profile of all formulations was evaluated and this in-vitro release studies demonastrated that, the release of Metformin HCL from all tablet formulations was generally immediate. The tablets conforming to good quality,displayed various drug release mechanisms. High concentration of super disintegrants used in the formulations caused high percent release of drug, while lower concentration caused low release.Thus, the release characteristics were significantly influenced by the characteristics and concentration of super disintegrants used. The release characteristics were also influenced by changing the type of disintegrants. Most release mechanism could be well depicted by the Higuchi model with the release from tablets being class1 diffusion. Disintegration time, % of drug release and dissolution time was also observed for all formulations.Again, the various mechanical and physical parameters of granules and tablets such as the flow properties, hardness, friability etc. were seen to comply with the standards set by the different international organizations e.g. pharmacopeias. Thus the granules and tablets were found satisfactory in terms of its physical parameters as well as the drug release profile from the immediate release tablets.

REFERENCE:

1.       P. S. Mohanachandran, P. G. Sindhumol& T. S.Kiran. Superdisintegrants: An Overview. International Journal of Pharmaceutical Sciences Review and Research. Volume 6, (2011) 105-109.

2.       Mukesh C. Gohel, Rajesh K. Parikh, Bansari K. Brahmbhatt& A. R. Shah. Preparation and Assessment of Novel CoprocessedSuperdisintegrant Consisting of Crospovidone and Sodium Starch Glycolate: A Technical Note. AAPS PharmSciTech. 8 (1) (2007) E1-E6.D.

3.       T. Kaur, B. Gill, S. Kumar & G. D. Gupta. Mouth Dissolving Tablets: A Novel Approach to Drug Delivery. International Journal of Current Pharmaceutical Research. Vol 3 (2010) 1-7.

4.       Hermann LS, Melender A. Biguanides: basic aspects and clinical use. New York: Wiley; 1992. p. 292-7.

5.       Lachman, L.M Lieberman, H.A, and Kanig, J.L. The Theory and Practiec of Industrial Pharmacy.Varghese publishing House, Dadear Bombay.2rd Edition, 1970.

6.    Shargel L, susanna Wu. Applied Biopharmaceutics& Pharmacokinetics. 5 th ed. MacGraw-Hill; 2005:439, 542-543.

7. United state pharmacopoeia, 2001.


© 2016 The Author(s). This open access article is distributed under a Creative Commons Attribution (CC-BY) 4.0 license. You are free to: Share — copy and redistribute the material in any medium or format Adapt — remix, transform, and build upon the material for any purpose, even commercially. The licensor cannot revoke these freedoms as long as you follow the license terms. Under the following terms: Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. No additional restrictions You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits
Editor in Chief
Prof. Dr. Cornelia M. Keck (Philipps-Universität Marburg)
Marburg, Germany

Bibliography

Welcome to the research group of Prof. Dr. Cornelia M. Keck in Marburg. Cornelia M. Keck is a pharmacist and obtained her PhD in 2006 from the Freie Universität (FU) in Berlin. In 2009 she was appointed as Adjunct Professor for Pharmaceutical and Nutritional Nanotechnology at the University Putra Malaysia (UPM) and in 2011 she obtained her Venia legendi (Habilitation) at the Freie Universität Berlin and was appointed as a Professor for Pharmacology and Pharmaceutics at the University of Applied Sciences Kaiserslautern. Since 2016 she is Professor of Pharmaceutics and Biopharmaceutics at the Philipps-Universität Marburg. Her field of research is the development and characterization of innovative nanocarriers for improved delivery of poorly soluble actives for healthcare and cosmetics. Prof. Keck is executive board member of the German Association of Nanotechnology (Deutscher Verband Nanotechnologie), Vize-chairman of the unit „Dermocosmetics“ at the German Society of Dermopharmacy, active member in many pharmaceutical societies and member of the BfR Committee for Cosmetics at the Federal Institute for Risk Assessment (BfR).

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doi: http://dx.doi.org/10.21065/19204159
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