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Year : 2015  |  Volume : 6  |  Issue : 1  |  Page : 5-10

Formulation and evaluation of sustained release matrix tablets of pioglitazone hydrochloride using processed Aloe vera mucilage as release modifier

1 Pharmaceutics Research Laboratory, Shri Ram Institute of Technology-Pharmacy, Jabalpur, Madhya Pradesh, India
2 Drug Discovery Laboratory, Shri Ram Institute of Technology-Pharmacy, Jabalpur, Madhya Pradesh, India

Date of Web Publication8-Jan-2015

Correspondence Address:
Divya Bansal
Pharmaceutics Research Laboratory, Shri Ram Institute of Technology-Pharmacy, Jabalpur, Madhya Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2394-2002.148881

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Background: Natural gums and mucilage which hydrates and swells on contact with aqueous media are used as additives in the formulation of hydrophilic drug delivery system. Aim: The purpose of this study was to develop a new monolithic matrix system for complete delivery of Pioglitazone hydrochloride (HCl), in a zero-order manner over an extended time period using processed Aloe vera gel mucilage (PAG) as a release modifier. Materials and Methods: The matrices were prepared by dry blending of selected ratios of polymer and ingredients using direct compression technique. Physicochemical properties of dried powdered mucilage of A. vera were studied. Various formulations of pioglitazone HCl and A. vera mucilage were prepared using different drug: Polymer ratios viz., 1:1, 1:2, 1:3, 1:4, 1:5 for PAG by direct compression technique. Results: The formulated matrix tablets were found to have better uniformity of weight and drug content with low statistical deviation. The swelling behavior and in vitro release rate characteristics were also studied. Conclusion: The study proved that the dried A. vera mucilage can be used as a matrix forming material for controlled release of Pioglitazone HCl matrix tablets.

Keywords: matrix tablet, pioglitazone hydrochloride, processed Aloe vera gel mucilage

How to cite this article:
Choudhary M, Salukhe T, Ganeshpurkar A, Pandey V, Dubey N, Bansal D. Formulation and evaluation of sustained release matrix tablets of pioglitazone hydrochloride using processed Aloe vera mucilage as release modifier. Drug Dev Ther 2015;6:5-10

How to cite this URL:
Choudhary M, Salukhe T, Ganeshpurkar A, Pandey V, Dubey N, Bansal D. Formulation and evaluation of sustained release matrix tablets of pioglitazone hydrochloride using processed Aloe vera mucilage as release modifier. Drug Dev Ther [serial online] 2015 [cited 2017 Mar 25];6:5-10. Available from: http://www.ddtjournal.org/text.asp?2015/6/1/5/148881

  Introduction Top

During the past few decades, research is going on for the use of natural occurring biocompatible polymeric material for designing of dosage form for oral controlled release administration. Natural polymers are biodegradable, biocompatible and nontoxic, local availability with low cost, better patient tolerance as well as public acceptance. Gums and mucilage contain hydrophilic molecule, which can combine with water to form viscous solution or gels. [1] Natural gums and mucilage, which hydrates and swells on contact with aqueous media [2] are used as additives in formulation of hydrophilic drug delivery system. High patient compliance and flexibility in developing dosage forms has made the oral drug delivery systems the most convenient mode of drug administration compared to other dosage forms. Among these, matrix drug delivery systems are achieving more popularity. In the present study, matrix tablet of Pioglitazone hydrochloride (HCl) were prepared using processed Aloe vera gel (PAG). The basic idea behind the development of such a system was to make use of A. vera gel as a release retardant material to control the rate of drug release by the tablets. Pioglitazone HCl is a basic drug with elimination half-life of 3-5 h. It is used in the treatment of type II diabetes mellitus.

The present investigation was carried out with an aim to formulate and characterize sustained release matrix tablets using PAG mucilage.

  Materials and Methods Top


Pioglitazone HCl was obtained as a gift sample from Unichem Laboratory, Mumbai, India. A. vera leaves were collected from plants growing in local areas of Jabalpur, Madhya Pradesh, India. The plant was authenticated from Department of Crop and Herbal Physiology, J.N.K.V.V. Jabalpur, India. Microcrystalline cellulose and magnesium stearate were procured from SD fine chemicals (Mumbai, India). All other chemicals used were of analytical reagent grade.


Extraction of mucilage

vera mucilage was extracted by reported method [3] with slight modifications. Fresh plant leaves were collected and washed with water to remove dirt and debris. Then, incisions were made on leaves and soaked in water for 5-6 h, boiled for 30 min, and allowed to stand for 1 h, for release of mucilage in water. The material was then squeezed from the cloth to remove marc from the solution. Following this, three volumes of acetone was added to the filtrate to precipitate the mucilage. The mucilage was separated, dried in an oven at a temperature <50°C. Dried powder was passed through a No. 80 sieve and stored in a desiccator for further use. Before tablet compression the mucilage was evaluated for flow properties (Carr, 1965) [Table 1].
Table 1: Flow properties of Aloe vera mucilage

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Preparation of matrix tablets

Different tablet formulations were prepared by using different drug: Polymer ratios viz., 1:1, 1:2, 1:3, 1:4, 1:5 for various batches PAG1, PAG2, PAG3, PAG4, PAG5 respectively by direct compression technique [Table 2]. PAG mucilage was used as matrix forming material, while microcrystalline cellulose was used a diluent. All ingredients were passed through a number 80 sieve, weighed, and blends were compressed by direct compression technique, with the help of 9 mm flat faced punches (Cadmach, Machinery Co., Ahmedabad, Gujarat, India). Prior to compression, the powder blend was evaluated for several tests.
Table 2: Composition of matrix tablets of pioglitazone HCl containing varying ratios of PAG

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Evaluation of powder blend

Angle of repose

Funnel method was used for the determination of the angle of repose. The granules were allowed to flow freely from the funnel onto the surface. The diameter of the powder cone was measured, and angle of repose was calculated using the following equation: [4]

tan θ = h/r (Equation 1)

Where, h = height of the powder cone and,

r = radius of the powder cone.

Bulk density

Both loose bulk density (LBD) and tapped bulk density (TBD) were determined. Two gram of powder from each formulation was placed in the measuring cylinder and tapped for certain time period until no change in volume was noted. LBD and TBD were calculated using the following formula:

LBD = Weight of the powder/volume of the packing

(Equation 2)

TBD = Weight of the powder/tapped volume of the packing

(Equation 3)

Compressibility index

The compressibility index of the powder was determined by Carr's compressibility index [5] using the formula:

Carr's Index (%) = (TBD−LBD) × 100/TBD (Equation 4)

Evaluation of tablets


Digital Caliper (Mitutoyo, Digimatic Caliper, New Delhi, India) was used for determination of thickness of the tablets. Twenty tablets from each batch were used, and average values were calculated. [6]

Weight variation test

A total of twenty tablets of each formulation were randomly selected, and their average weight was determined. [7] Not >2 of the individual tablet weights must deviate from the average weight by more than the % deviation and none should deviate by more than twice that percentage (limit for tablet weighing between 130 and 324 mg is 7.5%).

Hardness and friability

The hardness and friability of 20 tablets of each formulation was determined using the Monsanto Hardness Tester and Roche Friabilator (Cadmach, Machinery Co., Ahmedabad, Gujarat, India).

Drug content

Five tablets from each formulation were powdered individually, and a quantity equivalent to 100 mg of pioglitazone HCl was weighed accurately and extracted with a minimum quantity of 0.1 N HCl. Each extract was suitably diluted and analyzed spectrophotometrically at 267 nm using UV-visible spectrophotometer (Shimadzu UV-1700, Japan). [7]

Swelling characteristics

The extent of swelling was measured in terms of % weight gain by the tablet. The swelling behavior of all formulation was studied. One tablet from each formulation was kept in a petri dish containing 0.1 N HCl. At the 1 h interval, the tablet was withdrawn, soaked with tissue paper, and weighed. This process was continued till the end of 12 h. Percentage weight gain by the tablet was calculated by Equation 5.

SI = {(Mt−Mo)/Mo} × 100 (Equation 5)

Where, SI = swelling index,

Mt = Weight of tablet at time t (h) and

Mo = Weight of tablet at 0 time.

In vitro release studies

The in vitro dissolution studies were performed using USP-22 type I dissolution (Veego, Mumbai, India) apparatus at 37 ± 1°C, for 12 h at 50 rpm using 900 ml of 0.1 N HCl for first 2 h, and phosphate buffer of pH 6.8 from 2 to 12 h. 5 ml of sample solution was withdrawn at predetermined time interval, filtered through a 0.45 μm membrane filter, diluted suitably and analyzed spectrophotometrically at 267 nm (Shimadzu Model 1700). An equal amount of fresh dissolution medium was replaced immediately after withdrawal of the sample. Similar studies were performed for marketed preparation (PATH, 15 mg tablet, Lupin). The release studies were conducted in triplicate.

Kinetic release profile

To the release kinetics, data were obtained from in vitro drug release studies were plotted in various kinetic models, zero order (Equation 6) as the cumulative amount of drug released versus time, the first order (Equation 7) as log cumulative percentage of drug remaining versus time, and Higuchi's model (Equation 8) as cumulative percentage of drug released versus square root of time.

Q = K o × t (Equation 6)

Where, K o = Zero order rate constant expressed in units of concentration/time,

t = Time in h.

A graph of concentration versus time would yield a straight line with a slope equal to K o and intercept the origin of the axes. [8],[9]

Log C = log C okt/2.303 (Equation 7)

Where, C o = Initial concentration of drug,

k = First order constant,

t = Time. [10]

Q = k et (Equation 8)

Where, k =

constant, reflecting the design variables of the system,

t = time in h.

The three models discussed above failed to explain drug release mechanism due to swelling (upon hydration) along with a gradual erosion of the matrix. Therefore, the dissolution data were fitted to Koresmeyer equation (Equation 9) which describes the drug release behavior from polymer systems.

Log (Mt/Mα) = log K + n log t (Equation 8)

Where, Mt = amount of the drug release at time "t",

Mα = amount of drug release after infinite time,

K = release rate constant signifying structural and geometric characteristic of the n = diffusion exponent indicating the mechanism of drug release.

To determine the release exponent for different batches of matrix tablet the log value of the percentage of drug dissolved was plotted against log time for each batch according to the equation. A value of (a) n = 0.45 indicates Fickian (Case I) release (b) n > 0.45 but < 0.89 for non-Fickian (Anomalous) release and (c) n > 0.89 indicates super Case II type of release. Case II generally refers to the erosion of the polymeric chain and anomalous transport (non-Fickian) which is a combination of both erosion and diffusion controlled drug release (Bourne, 2002).

Accelerated stability studies

Optimized formulation PAG5 was packed in an air tight high-density polythene bottles and kept at 45°C with 75 ± 5% RH for 3 months as per ICH guidelines for stability. Samples were withdrawn at 0, 30, 60 and 90 days of storage and evaluated for appearance, hardness and drug content.

  Results Top

During the development of a formulation, the flow of the blend can affect the selection of an excipient and gives information whether direct compression is required, or other granulating techniques have to be used. Therefore, dry powdered mucilage extracted from A. vera leaves was evaluated for angle of repose, LBD, TBD, Carr's index, and Hausner's ratio [Table 1]. The results of angle of repose and Carr's index (%) were 22.27 ± 0.32, 12.41 ± 0.11 respectively. The results of LBD and TBD were 0.54 ± 0.02, 0.88 ± 0.06 respectively. The Hausner's ratio was found to be 1.196 ± 0.04. The flow properties of the powder blend was also determined. The angle of repose and Carr's index (%) ranged from 20.46 ± 0.022 to 24.43 ± 0.021 and 12.30 ± 0.88 to 15.897 ± 1.56, respectively. The results of angle of repose (<30) indicate good flow properties of the granules. [11] This was further supported by lower Carr's index values [Table 3]. Generally, compressibility index values up to 15% result in excellent flow properties. The results of LBD and TBD ranged from 0.42 ± 0.04 to 0.45 ± 0.04 and 0.54 ± 0.01 to 0.59 ± 0.02, respectively.

Tablets with different formulation codes were subjected to various evaluation tests, such as thickness, hardness, friability, and uniformity of drug content. The results of these parameters are given in [Table 2]. All the formulations showed uniform thickness (CV <0.5%), uniform weight with little significance difference (P > 0.1) were observed with varying formulation code. In the weight variation test, the pharmacopoeial limit for the percentage deviation for tablets of more than 130 mg to 324 mg is 7.5% difference. The average percentage deviation of all the formulations was found to be within the limit, and hence all formulations passed the test for uniformity of weight as per official requirements. [12] The hardness of the tablets (n = 10) ranged from 5.9 ± 0.2 to 6.5 ± 0.1 kg/cm 2 . The percentage friability of the tablets (n = 10) ranged from 0.079 ± 0.310 to 0.085 ± 0.13%. The percentage friability for all the tablet formulations were below 1%. [13] Drug content was found to be uniform among different batches of the tablets (n = 20) and ranged from 98.01 ± 0.3 to 99.23 ± 0.2 [Table 4]. The swelling index of the prepared tablets was determined [Table 5]. It was observed that swelling index increased with time but later on it decreased. The percentage of swelling was greater in formulation PAG5 which possessed greater concentration of A. vera mucilage.{Table 2}
Table 3: Precompressive parameters of blend (n = 3)

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Table 4: Postcompressive parameters of matrix tablets

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Table 5: Correlation coefficients according to different kinetic equations

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[Figure 1] shows the in vitro drug release profile of sustained release matrix tablets containing Pioglitazone hydrochloride. The rate of drug release from the tablet formulations PAG1 was highest. About 12-22% of the drug was released within 2 h which might be attributed due to surface erosion of the matrix of the tablet before gel layer formation around the tablet core. Tablets are containing a high concentration of A. vera mucilage (formulation PAG5) exhibited slow release of pioglitazone HCl as compared to commercially available SR tablet [Figure 1]. Formulation PAG5 showed 58% of the drug release in 8 h whereas commercially available SR tablet showed the release of 84% in 8 h [Figure 1]. Formulation PAG1, PAG2, PAG3 and PAG4, showed 80%, 78%, 71% and 64% of the drug release respectively in 8 h. When compared with other formulations like PAG1, PAG2, PAG3, and PAG4, formulation PAG5 contained more amount of A. vera mucilage which acted as a release retardant.
Figure 1: Percentage of drug release from the marketed tablet and formulated tablets (n = 3; mean ± standard deviation)

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The drug release kinetic data were for all the formulation is shown in [Table 5]. The kinetics data obtained from the studies reveals that formulations follow zero-order release kinetics and the rate of drug release is independent of concentration. Drug release of the formulation PAG1, PAG2, PAG3, PAG4 and PAG5 had the regression data were of 0.9857, 0.9754, 0.9863, 0.9881 and 0.9942, respectively, exhibiting zero-order kinetics. According to Koresmeyer equation, the formulation PAG1, PAG2, PAG3, PAG4 and PAG5 exhibited the regression values of 0.9894, 0.9845, 0.9812, 0.9783 and 0.9684, respectively. The plot for (log cumulative percentage drug release vs. time) Koresmeyer-Peppas equation correspondingly indicated good linearity for the commercially available SR tablet and formulation PAG5 with regression values of 0.9684 and 0.9943, respectively. The release component n was found to be 0.5148 and 0.6582 respectively. Optimized formulation was subjected to accelerated stability studies [Table 6]. Various parameters like hardness and drug content were retained by the optimized formulation on storing it at varying temperature conditions.
Table 6: Physical and chemical parameters of formulated tablets stored at 45°C (n = 10)

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  Discussion Top

For the preparation of matrix tablets A. vera mucilage was extracted from Aloe barbadensis and found to be yellowish in color. The angle of repose of the obtained mucilage was found to be <30°C, which was indicative of good flow properties. The flow properties of the powder blend were also determined. Obtained values indicated good flow properties of the powder blend. Tablets were compressed using direct compression technique. The prepared tablets were evaluated according to pharmacopoeial standards. The formulated tablets passed weight variation as per the pharmacopoeial standards. The tablets were found to possess uniform thickness. The hardness of all the tablets was found to be >5 kg/cm 2 and loss on the friability was <1% which indicated that tablets can withstand mechanical shock during transportation. The amount of pioglitazone HCl in the prepared tablets was found to be within the limits. All the tablet formulations exhibited acceptable pharmacopoeial properties and complied with specifications for weight variation, drug content, hardness, and friability.

The swelling index of all the tablet formulations was calculated with respect to time. As time increases, the swelling index increased, because weight gained by the tablet increased proportionally as rate of hydration increases up to a certain limit. Later on, it decreases gradually due to dissolution of the outermost gelled layer of the tablet into the dissolution medium. Direct relationship was observed between swelling index and polymer concentration, and as polymer concentration increases, swelling index increased. Similar results were reported by Sujja-areevath et al., and Abrahamsson et al. [14],[15]

A sustained release tablet should release the desired quantity of drug with predetermined kinetics to maintain effective plasma concentration which can be done by formulating a tablet that releases the drug in a predetermined and reproducible manner. By studying the biopharmaceutical and pharmacokinetic profile the release rate of the drug from the tablet can be determined. [16] Drug release from the prepared tablets was found to be >20% after 2 h, and it followed zero-order release kinetics. The rate of drug release from marketed preparation was greater as compared to tablets prepared using A. vera gel mucilage which confirmed its release retardant properties. The value of release component indicates that drug release was governed by more than one process, namely diffusion and erosion. Drug release from a matrix tablet containing hydrophilic polymers generally involves the process of diffusion. Similar results with matrix tablet are reported by Fassihi and Ritschel [17] and Reddy et al. [10] The stability studies indicate that there was no significant change in physical appearance, hardness and drug content of the formulation PAG5. Thus, formulation was stable at different storage conditions.

The results clearly indicate the possible use of PAG for modulating the drug release by using in varying ratios. From the above studies, we can finally conclude that the prepared matrix tablets using PAG as mucilage can be used as a release retardant in the formulation of sustained release matrix tablets.

  Acknowledgments Top

The authors are thankful for Rewa Shiksha Samiti for providing grant for research purpose. Authors are thankful to Unichem Laboratory, Mumbai, India for providing gift sample of pioglitazone HCl.

  References Top

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Carr RL. Evaluating flow properties of solids. Chem Eng 1965;72:163-8.  Back to cited text no. 4
Chowdary KP, Rao YS. Design and in vitro and in vivo evaluation of mucoadhesive microcapsules of glipizide for oral controlled release: A technical note. AAPS PharmSciTech 2003;4:E39.  Back to cited text no. 5
Cooper J, Gunn C. Powder flow and compaction. In: Carter SJ, editor. Tutorial Pharmacy. New Delhi: CBS Publishers and distributors; 1986. p. 211-33.  Back to cited text no. 6
Ministry of Health and Family Welfare (India). Indian Pharmacopoeia. The Pharmacopoeia of India. New Delhi: Controller of Publication, Delhi; 1996. p. 736.  Back to cited text no. 7
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Bourne DW. Pharmacokinetics. In: Banker GS, Rhoides CT, editors. Modern Pharmaceutics. 4 th ed. New York: Marcel Dekker Inc.; 2002. p. 67-92.  Back to cited text no. 9
Reddy KR, Mutalik S, Reddy S. Once-daily sustained-release matrix tablets of nicorandil: Formulation and in vitro evaluation. AAPS PharmSciTech 2003;4:E61.  Back to cited text no. 10
Aulton ME, Wells TL. Pharmaceutics, The Science of Dosage Form Design. London: Churchill Livingstone; 1988.  Back to cited text no. 11
Lachman L, Lieberman HA, Kanig JL. The Theory and Practice of Industrial Pharmacy. Mumbai: Varghese Publishing House; 1987.  Back to cited text no. 12
Saravanan M, Natraj KS, Ganesh KS. Hydroxypropyl methyl cellulose based cephalexin extended release tablets: Influence of tablet formulation, hardness and storage on in vivo release kinetics. Chem Pharm Bull 2003;51:978-83.  Back to cited text no. 13
Sujja-areevath J, Munday DL, Cox PJ, Khan KA. Relationship between swelling, erosion and drug release in hydrophillic natural gum mini-matrix formulations. Eur J Pharm Sci 1998;6:207-17.  Back to cited text no. 14
Abrahamsson B, Alpsten M, Bake B, Larsson A, Sjögren J. In vitro and in vivo erosion of two different hydrophilic gel matrix tablets. Eur J Pharm Biopharm 1998;46:69-75.  Back to cited text no. 15
Defang O, Shufang N, Wei L, Hong G, Hui L, Weisan P. In vitro and in vivo evaluation of two extended release preparations of combination metformin and glipizide. Drug Dev Ind Pharm 2005;31:677-85.  Back to cited text no. 16
Fassihi RA, Ritschel WA. Multiple-layer, direct-compression, controlled-release system: In vitro and in vivo evaluation. J Pharm Sci 1993;82:750-4.  Back to cited text no. 17


  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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