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ORIGINAL ARTICLE
Year : 2013  |  Volume : 2  |  Issue : 1  |  Page : 42-46

Formulation and dissolution kinetics of fast-release glibenclamide tablets


Department of Pharmaceutics, Faculty of Pharmacy, Taif University, Taif, Saudi Arabia

Date of Web Publication29-May-2013

Correspondence Address:
Amani Mirghani Elsayed
Department of Pharmaceutics, Faculty of Pharmacy, Taif University, Taif
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-0521.112630

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  Abstract 

Background: Glibenclamide is oral antidiabetic drug that belongs to a class of medications known as sulfonylureas. It is indicated for the treatment of Type II non-insulin-dependent diabetes. Aim: The purpose of this work was to improve the dissolution of glibenclamide by utilizing solid dispersion technology. Materials and Methods: Glibenclamide was dispersed in water-soluble polymers; polyethylene glycol (PEG) 6000, and polyvinylpyrrolidone (PVP) using fusion and solvent method, respectively. The solubility and dissolution kinetics of solid dispersions were studied. Results: The effect of various drug:polymer ratios on the equilibrium solubility of glibenclamide was evaluated. The solubility increased as the amount of polymers was increased. Glibenclamide-PVP solid dispersion showed a threefoldincrease in the solubility of glibenclamide as compared to glibenclamide-PEG solid dispersion. The dissolution of dispersed glibenclamide was diffusion-controlled. The hydrodynamic layer thickness is influenced by the stirring rate. The data indicated that increasing the stirring rate decreased the thickness of the hydrodynamic layer. Tablets with an improved dissolution profile as compared to commercial product Euglucon® tablets were prepared. Conclusions: The solubility and dissolution profiles of glibenclamide were improved by solid dispersion technology. This may lead to enhancement of the bioavailability and efficiency of the drug.

Keywords: Glibenclamide, polyethylene glycol, polyvinylpyrrolidone, solid dispersion


How to cite this article:
Elsayed AM. Formulation and dissolution kinetics of fast-release glibenclamide tablets. Saudi J Health Sci 2013;2:42-6

How to cite this URL:
Elsayed AM. Formulation and dissolution kinetics of fast-release glibenclamide tablets. Saudi J Health Sci [serial online] 2013 [cited 2022 May 23];2:42-6. Available from: https://www.saudijhealthsci.org/text.asp?2013/2/1/42/112630


  Introduction Top


The bioavailability of many poorly water-soluble drugs is limited by their dissolution rates, which are in turn controlled by the surface area that they present for dissolution. Conventional methods of decreasing particle size include milling, grinding, fluid energy micronization, and application of ultrasonic waves. The resultant fine particles may not produce the expected fast dissolution and absorption. This is mainly due to possible aggregation and agglomeration of the fine particles and their poor wettability in water. In addition, drugs with plastic properties are difficult to subdivide by the above methods. [1] Recently, solid dispersion approach was utilized to reduce the particle size of drugs to improve their solubility. [2],[3] Dispersing water-insoluble drugs in a hydrophilic carrier was found to enhance the rate of dissolution and hence biologic availability of several drugs. These include nabilone, sulfisoxazole, and mefenamic acid. [4],[5],[6]

Glibenclamide (GLC) is an oral hypoglycemic agent indicated for the treatment of Type II non-insulin-dependent diabetes. Glibenclamide is a poorly water-soluble drug and can be classified as a class II drug according to the Biopharmaceutical Classification Scheme. For class II drugs, the rate of drug dissolution is almost the principal barrier to its oral absorption. The dissolution rate of glibenclamide was enhanced by micronization in some countries. This improved its bioavailability and led to the reduction of initial dose to 1.5-3 mg. [7]

The purpose of the present work was to prepare solid dispersions of glibenclamide by fusion and solvent methods and to determine the parameters which affect the dissolution rate of glibenclamide when dispersed in polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP).


  Materials and Methods Top


Materials

Glibenclamide powder was a gift from Wafra Pharma Laboratories (Sudan). PEG 6000 was obtained from Breakland Scientific Supplies (U.K.). PVP was a gift from Amipharma laboratories (Sudan). Avicel PH 101, sodium starch glycolate and lactose were a gift from General Medicine Company (Sudan). Chloroform was obtained from Loba Chemie (India). Euglucon ® tablets, manufactured by Roche, had a manufacturing date 12/2007 and an expiration date 12/2012.

Methods

Different ratios of glibenclamide-PEG were prepared (1:0.5, 1:1, 1:2, 1:3, 1:5, and 1:7) by fusion method. The calculated amount of PEG (corresponding to each ratio) was placed in a beaker and heated in a water-bath to 70°C (just above its melting point) until melted, then glibenclamide was incorporated into the molten PEG with constant stirring for 5 min. The mixture was transferred to an ice-bath and cooled with constant stirring to homogenously disperse the drug throughout the matrix. Particle size was reduced by grinding.

Different ratios of glibenclamide-PVP were prepared (1:0.5, 1:1, 1:2, 1:3, 1:5 and 1:7) by solvent method. PVP and glibenclamide (corresponding to each ratio) were dissolved in chloroform. The volume of chloroform was determined from the solubility of the drug and the polymer in the solvent (7.14 mg/ml and 35.7 mg/ml, respectively). Chloroform was allowed to evaporate at 70°C under vacuum using the rotary evaporator. The evaporator was allowed to work at 210 rpm for a time sufficient for complete removal of chloroform (165 ml/30 min.). The solid dispersion was scraped off using a spatula and comminuted by a mortar and pestle.

Excess solid of glibenclamide free or dispersed in PEG or PVP was shaken in screw-capped vials with 20 ml of distilled water for 24 hrs. at 37°C. The samples were then filtered through 0.45 μm filter unit (Ultipore ® , India). The concentration of glibenclamide was determined using 6405 a UV/Vis spectrophotometer (Jenway, England) at a wavelength of 300 nm. Samples were run in triplicate and the average values were taken.

Different ratios of glibenclamide-PEG and glibenclamide-PVP solid dispersion powders were manufactured as tablets by direct compression of the powder using the hydraulic press and applying a pressure of about 40 MPa for 20 seconds. Another lot of glibenclamide tablets were also prepared from the solid dispersion (1:1 and 1:3 ratio) and other excipients. Each 160 mg tablet contained 5 mg glibenclamide (or an amount of solid dispersion containing 5 mg glibenclamide), 5% sodium starch glycolate and a filler (consisting of 50% lactose and 50% Avicel PH 101). The components of each tablet were geometrically mixed using porcelain mortar and pestle for about 10 minutes. Tablets were manufactured by compression of powder mixture by applying a pressure of about 40 MPa for 20 seconds using hydraulic press. Tablets were sealed properly with aluminium foil.

The dissolution rates of tablets made from different ratios of glibenclamide-PEG and glibenclamide-PVP solid dispersions were determined at 37°C at different stirring rates (50, 100, 150, and 200 rpm) using USP (United Stated Pharmacopoeia) dissolution test apparatus 1 (Veego Scientific, DA-6D USP Standards, India). The dissolution medium was 500 ml distilled water. The disc in its mould was attached centrally on the surface of the upper part of the USP dissolution basket apparatus leaving a lower surface of 1.33 cm 2 available for dissolution. At a pre-determined time intervals, 5 ml aliquots were withdrawn and immediately filtered through a 0.45 μm Millipore filter. The same volume of fresh medium was added to the test medium. The concentration of glibenclamide was determined spectrophotometrically at 300 nm. Three replicates were performed on each batch and the average values were taken. The same procedure was followed to measure the release of glibenclamide from Euglucon tablets and tablets made from solid dispersions and other excipients except here the USP dissolution test apparatus II was used at 100 rpm. Two tablets from each batch were placed in the dissolution medium.


  Results and Discussion Top


Bioavailability of drugs depends on several factors; the most important ones are drug solubility in an aqueous environment and drug permeability through lipophilic membranes. For orally administered drugs, a fair solubility in gastric medium is a prerequisite for absorption. Glibenclamide is practically insoluble in water; hence, its absorption is dissolution limited. In this study, the equilibrium solubility of glibenclamide and dissolution kinetics were assessed after dispersion of the drug in two water soluble polymers, polyethylene glycol, and polyvinyl pyrrolidone.

To study the influence of the water soluble carriers on equilibrium solubility of glibenclamide, studies were performed to evaluate this parameter. [Table 1] lists the values of the equilibrium solubility of glibenclamide-PEG and glibenclamide-PVP solid dispersions. [Table 1] clearly shows that increasing the amount of PEG or PVP incorporated resulted in an increase in the aqueous solubility of glibenclamide. In case of glibenclamide-PEG, the increase in the aqueous solubility may be due to improved wetting or decreased hydrophobicity or crystallization of the drug in a metastable form or conversion of the drug to an amorphous form. It was found that glibenclamide is mainly present in a non-crystalline form state when dispersed on PEG 4000. [8] The enhancement of solubility in case of PVP was attributed to the inhibition of crystallization of drugs by PVP giving dispersions containing amorphous drugs. Sulfisoxazole-PVP of 1:3 ratio was amorphous, but a 10:1 ratio contained crystalline drug. [9]
Table 1: Equilibrium solubility of free and dispersed glibenclamide1

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From [Table 1] it is obvious that PVP enhanced the aqueous solubility of glibenclamide approximately three times that of PEG of the same ratio. The moderate increase in solubility in case of glibenclamide-PEG solid dispersion may be due to limited solubility of the drug in the carrier. The melting point of glibenclamide is 171-174°C while that of PEG is 58-65°C. Therefore, glibenclamide and PEG do not form solid solution. Solid solutions have high solubility due to the molecular dispersion of the drug in the matrix. [1] Certain drug-carriers, e.g., tolbutamide-mannitol, were found to display miscibility gap within their phase diagram, and consequent irregular crystallization may lead to only moderate increases in solubility. [10]

Dissolution may be defined as the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent. Dissolution behavior of drugs has a significant effect on their pharmacological activity. In fact, a direct relationship between in vitro dissolution rate of many drugs and their bioavailability has been demonstrated and is generally referred to as in vitro-in vivo correlation.

According to the film theory of Nernst-Brunner [11] the dissolution rate can be calculated from equation1



where dc is the dissolution rate, D is the diffusion coefficient of the solute, v is the volume of the dissolution medium, Cs is the solubility of the solute, and Cb is the concentration at any time, t.

This model didn't introduce the concept of changing surface area during dissolution; therefore, one surface of the tablets was exposed to the dissolution medium. The curves of the amount of drug released from a constant surface at different stirring rates versus time were drawn. Linearity was demonstrated both by correlation coefficients (r ≥ 0.90) and by visual inspection of the curves as illustrated in [Figure 1].
Figure 1: Release of glibenclamide in distilled water from glibenclamide-PVP solid dispersion (1:5) tablets at different stirring rates

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The linearity of the curves suggested that the dissolution adhered to the above model and the rate of dissolution was governed by the rate of diffusion from the hydrodynamic layer to the bulk of the solution. In order to calculate both D and h, Levich [12] developed the following two equations



where J is the flux (dissolution rate per unit surface area), υ is the kinematic viscosity of the dissolution medium, and ω is the angular speed of rotation. The slopes of [Figure 1] were divided by the exposed surface area of the tablets (1.33 cm 2 ) to calculate fluxes at different stirring rates.

[Figure 2] and [Figure 3] show fluxes of glibenclamide dispersed in various concentrations of PEG or PVP as a function of angular speed of velocity, respectively. The slopes of these curves are equivalent to:
Figure 2: Flux (J) of glibenclamide dispersed in various concentrations of PEG as a fuction of angular speed of rotation (ε½)

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Figure 3: Flux J of glibenclamide dispersed in various concentrations of PVP as a function of angular speed of rotation (ε½)

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The calculated D values were shown in [Table 2]. There was a slight increase in the diffusion coefficient with increasing proportions of the polymers. Najib and Suleiman [13] also noticed an increase in the diffusivity of diflunisal with increasing percentage of PEG 4000.
Table 2: Values of diffusion coefficient of dispersed glibenclamide

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[Table 3] lists the hydrodynamic layer thickness values. The thickness of this layer decreased with increasing stirring rates. This may be attributed to the increase of flow of the fluid moving adjacent to the particle surface. The change of the flow from laminar to turbulence results in reduction of the amount of liquid adhering to the solid surface and the thickness of the hydrodynamic layer. [13]
Table 3: Values of hydrodynamic layer thickness at different stirring rates

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The dissolution profiles of tablets having the same weight as Euglucon ® and contain 5 mg glibenclamide dispersed on PEG or PVP and other excipients were also plotted and compared with Euglucon ® tablets [Figure 4]. The percentage released after 45 minutes had the sequence of Euglucon ® being the lowest (63.75%) followed by glibenclamide (67%), glibenclamide-PEG 1:1 (67.5%), glibenclamide-PEG 1:3 (69.75%), glibenclamide-PVP 1:1 (76.5%), and finally the highest glibenclamide-PVP 1:3 (84%). These values were subjected to t-test, and it was found that Euglucon had significantly lower in vitro release than tablets made from glibenclamide-PVP 1:1 and 1:3 dispersions at a probability level of 95%.
Figure 4: Release of Glibenclamide in distilled water from various forumlations at 37°C and 100 rpm

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Although glibenclamide-PEG dispersions had higher solubility than the free drug, the dissolution profiles of the tablets made from these dispersions showed no significant difference between them and Euglucon ® . The compression pressure used during the manufacturing of tablets may alter the crystalline state of the dispersed glibenclamide.

 
  References Top

1.Habib MJ. Pharmaceutical solid dispersion technology. Lancester (USA): Technomic Publishing Company Inc; 2001.  Back to cited text no. 1
    
2.Upadhyay P, Pandit J. Formulation of fast-release gastroretentive solid dispersion of glibenclamide with gelucire 50/13. Trop J Pharm Res 2012;11:361-9.  Back to cited text no. 2
    
3.Ahire B, Rane B, Bakliwal S. Pawar S. Solubility enhancement of poorly water soluble drug by solid dispersion techniques. Int J Pharm Tech Res 2010;2:2007-15.  Back to cited text no. 3
    
4.Kassem MA, El-Ridy MS, Khairy LM. Pharmacokinetics of sulfisoxazole solid dispersions in rabbits. Drug Dev Ind Pharm 1987;13:1171-96.  Back to cited text no. 4
    
5.Ramadan EM, Abd El-Gawad H, Nouh AT. Bioavailability and erosive activity of solid dispersions of some non-steroidal anti-inflammatory drugs. Pharm Ind 1987;49:503-13.  Back to cited text no. 5
    
6.Rao KR, Nagabhushanam MV, Chowdary KP. In vitro dissolution studies on solid dispersions of mefenamic acid. Indian J Pharm Sci 2011;73:243-7.  Back to cited text no. 6
    
7.Martindale: The Extra Pharmacopoeia. 32 nd ed. London: Pharmaceutical Press; 1999. p. 319-20.  Back to cited text no. 7
    
8.Bartsch SE, Griesser UJ. Physicochemical properties of the binary system glibenclamide and polyethylene glycol 4000. J Therm Anal Calorim 2004;77:555-69.  Back to cited text no. 8
    
9.Seikawa H, Nakanoa M, Arita T. Inhibitory effect of polyvinylpyrrolidone on the crystallization of drugs. Chem Pharm Bull (Tokyo) 1978;26:118-26.  Back to cited text no. 9
    
10.El-Banna HM, Daabis NA, Mortada LM, Abd-Elfattah S. Physicochemical study of drug binary systems. Part 3: Tolbutamide-urea and tolbutamide-mannitol systems. Pharmazie 1975;30:788-92.  Back to cited text no. 10
    
11.Okazaki A, Mano T, Sugano K. Theoretical dissolution model of poly-disperse drug particles in biorelevant media. J Pharm Sci 2008;97:1843-52.  Back to cited text no. 11
    
12.Levich VG. Physico-chemical hydrodynamics. New Jersey (USA): Prentice-Hall; 1962.  Back to cited text no. 12
    
13.Najib MN, Suleiman S. The kinetics of dissolution of diflunisal and diflunisal-polyethylene glycol solid dispersion. Int J Pharm 1989;57:197-203.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]


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