Samarth Institute of Pharmacy, Belhe, Maharashtra, India
Metformin hydrochloride (MET) is an oral hypoglycemic agent which improves glucose tolerance in patients with type 2 diabetes and diminishes basal plasma levels of glucose. The aim of this study was to develop and optimize MET matrix tablets for SR application. The SR matrix tablet of MET was prepared by wet granulation technique using Polyvinyl pyrrolidone K30 and hydroxyl propyl methylcellulose of different viscosity grades (HPMC K4M, HPMC K15M, and HPMC K100M). The influence of varying the polymer ratios was evaluated. The excipients used in this study did not modify physicochemical properties of the drug. Sustained release (SR) formulations of metformin address the drug's short half-life, allowing for once-daily dosing and potentially better patient compliance compared to immediate-release (IR) forms. This review highlights the current trends in the formulation of matrix-based SR systems for Metformin HCl, focusing on the role of polymers, formulation strategies, and comprehensive evaluation techniques.
Diabetes is one of the major causes of death and disability in the world. Diabetes is a long-lasting health condition that affects how our body turns food into energy. If you have diabetes your body does not make enough insulin that cause serious health problems, like heart disease, vision loss and kidney disease. Diabetes mellitus are be classified into two main types. First is type I or juvenile diabetes which is also called as insulin dependent diabetes and second type is type I or non-insulin dependent diabetes mellitus, this Type II diabetes is most common type of diabetes. Oral drug delivery is the most widely utilized route of administration among all the routes [nasal, ophthalmic, rectal, transdermal and parenteral routes] that have been explored for systemic delivery of drugs via pharmaceutical products of different dosage form. Oral route is considered most natural, uncomplicated, convenient and safe, due to its cease of administration, patient acceptance, and cost-effective manufacturing process. Presently pharmaceutical industries are focusing on development of sustained release formulations due to its inherent boons. There are several advantages of sustained release drug delivery over conventional dosage forma like improved patient compliance due to less frequent drug administration, reduction of fluctuation in steady-state drug levels, maximum utilization of the drug, increased safety margin of potent drug, reduction in healthcare costs through improved therapy and shorter treatment period. Sustained releases products are designed to bring the blood level of a drug immediately to therapeutic concentrations by means of an initial dose portion called loading dose and then sustain this level for a certain prolong time with the maintenance portion. The basic goal of sustained release is to provide promising way to decrease the side effect of drug by preventing the fluctuation of the therapeutic concentration of the drug in the body and increase patient compliance by reducing frequency of dose. Sustained release tablets and capsules commonly taken only once or twice daily, compared with counterpart conventional forms that may have to take three or four times daily to achieve the same therapeutic effect Novel drug delivery systems are designed to achieve a continuous delivery of drugs at predictable and reproducible kinetics over an extended period of time in the circulation. The potential advantages of this concept include minimization of drug related side effects due to controlled therapeutic blood levels instead of oscillating blood levels, improved patient compliance due to reduced frequency of dosing and the reduction of the total dose of drug administered. Hence, the combination of both sustained release and control release properties in a delivery system would further enhance therapeutic efficacy Controlled and Sustained Release has both been used in inconsistent and confusing manner. Both represent separate delivery process. Sustained release constitutes any dosage form that provides medication over an extended time or denotes that the system is able to provide some actual therapeutic control whether this is of a temporal nature, spatial nature or both. Sustained release systems generally do not attain zero order type release and usually try to mimic zero order release by providing drug in a slow first order Sustained release usually tries to mimic zero order release by providing drug in slow first order fashion.
Benefits of Sustained Release Matrix Tablet
Sustain-release matrix tablets offer numerous advantages:
Drawbacks of Sustained Release Matrix Tablet
II. Matrix-Based Drug Delivery Systems
These are the type of controlled drug delivery systems, which release the drug in continuous manner by both dissolution controlled as well as diffusion controlled mechanisms. To control the release of the drugs, which are having different solubility properties, the drug is dispersed in swellable hydrophilic substances, an insoluble matrix of rigid non swellable hydrophobic materials or plastic materials. Introduction of matrix tablet as sustained release (SR) has given a new innovation for novel drug delivery system in the field of Pharmaceutical technology. It excludes complex production procedures such as coating and pelletization during manufacturing and drug release rate from the dosage form is controlled mainly by the type and proportion of polymer used in the preparations. Hydrophilic polymer matrix is widely used for formulating an SR dosage form. Matrix systems are broadly used for the purpose of sustained release. It is the release system which prolongs and controls the release of the drug that is dissolved or dispersed. In fact, a matrix is defined as a well-mixed composite of one or more drugs with gelling agent i.e. hydrophilic polymers. By the sustained release method therapeutically effective concentration can be achieved in the systemic circulation over an extended period of time, thus achieving better compliance of patients. Initially, drug particles located at the surface of the release unit will be dissolved and the drug released rapidly. Thereafter, drug particles at sequentially increasing distances from the surface of the release unit will be dissolved and released by diffusion in the pores to the exterior of the release unit. In this system the drug reservoir is prepared by homogeneously dispersing drug particles in a rate controlling polymer matrix fabricated from either a lipophilic or a hydrophilic polymer. The drug is dispersed in the polymer matrix either by blending a therapeutic dose of finely ground drug particles with a liquid polymer or a highly viscous base polymer, followed by cross-linking of the polymer chain, mixing drug and polymer at an elevated temperature. It can also be fabricated by dissolving the drug and the polymer in a common solvent, followed by solvent evaporation at an elevated temperature and/or under a vacuum. In this sense, the term “matrix” indicates the three dimensional network containing the drug and other substances such as solvents and excipients required for the specific preparation.
Classifications of Matrix Tablets
A. On the basis of Retardent material used:
1. Hydrophobic matrices (Plastic matrices)
2. Lipid matrices
3. Hydrophilic matrices
4. Biodegradable matrices
5. Mineral matrices
B. On the basis of porosity of matrix
1. Macro porous system
2. Micro porous system
3. Non-porous system
A. On the basis of Retardent material used
1. Hydrophobic matrices (Plastic matrices)
It was first proposed in 1959 to use hydrophobic or inert materials as matrix materials. This technique compresses the medication into a tablet after combining it with an inert or hydrophobic polymer to provide prolonged release from an oral dose form. The dissolving medication diffuses through a network of channels that are present between compressed polymer particles, resulting in sustained release. Various materials such as polyethylene, polyvinyl chloride, ethyl cellulose, and acrylate polymers and their copolymers have been employed as inert or hydrophobic matrices. In these formulations, liquid penetration into the matrix is the rate-controlling step. Diffusion is one potential medication release mechanism in these kinds of tablets. When water and gastrointestinal fluid are present, certain kinds of matrix tablets become inert.
2. Lipid matrices:
These matrices were created using lipid waxes and associated substances. Such matrices allow for both pore diffusion and erosion-mediated drug release. Therefore, release properties are more responsive to the makeup of the digestive fluid than they are to the completely insoluble polymer matrix. For several prolonged release formulations, carnauba wax has been used as a retardant base in conjunction with stearyl alcohol or stearic acid.
3. Hydrophilic matrices:
Hydrophilic polymer matrix systems are extensively employed in oral controlled drug delivery due to their cost-effectiveness, wide regulatory acceptability, and flexibility in achieving a desired drug release profile. In the field of controlled release, hydrophilic polymers with high gelling capabilities are used as base excipients in the formulation of the pharmaceuticals into gelatinous capsules or, more frequently, tablets. Spread an well-mixed mixture of one or more medications and a gelling agent (hydrophilic polymer) is referred to as a matrix. We refer to these systems as scalable controlled release ystems. Three broad classes of polymers are utilized in the creation of hydrophilic matrices.
a) Cellulose Derivatives
b) Non-Cellulose/Natural/Synthetic Polymers
4. Biodegradable matrices:
These are composed of polymers with an unstable backbone made up of monomers connected to one another by functional groups. Enzymes produced by nearby live cells or by nonenzymatic processes biologically break them down or erode them, converting them into oligomers and monomers that can be digested or eliminated. Examples include modified natural polymers, such proteins and polysaccharides, and synthetic polymers, like polyanhydrides and aliphatic poly(esters).
5. Mineral matrices:
These are made of polymers that come from different kinds of seaweed. Alginic acid, for instance, is ahydrophilic carbohydrate that is produced by diluting alkali and is derived from some types of brown seaweed (Phaephyceae).
B. On the basis of porosity of matrix:
1. Macro porous system
Within these systems, the medication diffuses through matrix holes with a size range of 0.1 to 1 μm. The size of the diffusant molecule is smaller than this pore size.
2. Micro porous system
In this kind of system, diffusion primarily takes place through pores. The size of pores in micro porous systems is between 50 and 200 A°, which is marginally bigger than the size of diffusant molecules.
3. Non-porous system
Molecules in non-porous systems diffuse over network meshes because they lack pores. In this instance, there is no pore phase present only the polymeric phase.
III. Formulation Strategies for Metformin SR Matrix Tablets
Table1.Selection of Matrix Forming Polymer
Commonly Used Polymer
Manufacturing Techniques of Tablet
Tablets are Commonly Manufactured by:
Wet Granulation
Wet granulation is a size-enlargement technique in which fine powder particles are crystallized or brought together into bigger, stronger and more permanent structures called granules which using a non-toxic granulating fluid such as water, isopropanol or ethanol or mixtures of these fluids.
Figure2. Wet Granulation Technique of Tablet Manufacturing
Dry Granulation
While the dry granulation technique removes a number of unit operations, it still requires milling or micronization of medications, measuring, mixing, slugging, dry screening, lubrication and tablet compression
Figure2. Dry Granulation Technique of Tablet Manufacturing
Direct Compression
The term "direct compression" (or direct compaction) refers to the method of compressing powdered active drug materials and appropriate excipients into a firm compact without using the granulation process.
Figure3. Direct Granulation Technique of Tablet Manufacturing
IV. Evaluation Techniques
Evaluation of Powder Blends of Metformin hydrochloride
The powder blends of metformin hydrochloride formulations were evaluated before compression to assess the flow properties of the powder.
Bulk density
Required amount of powder m was transferred into the measuring cylinder, and apparent volume V, was measured, bulk density in g per ml is calculated by the formula.
Bulk density m/V
Where m-mass of powder, V apparent volume.
Tapped density
After determination of bulk density, the measuring cylinder Va volume in ml was measured initially, later the same cylinder was set for 100 tappings on tapped density apparatus and measure the tapped volume finally Vb. Calculate tapped density in g per ml by the formula [9].
Tapped density = Va/Vb.
Where Va initial volume, Vbfinal tapped volume.
Carr's index
It is an indirect method of measuring powder flow from bulk densities to measure bridge strength and stability. Carr's index of each formulation was calculated according to the equation. Carr’s index (Tapped density bulk density)/tapped density "100.
Hausner ratio
It is essential to determine the compressibility strength of powder. It was calculated according to equation.
Hausner ratio = Tapped density/bulk density.
Lower Hausner's ratio (<1.25) indicates better flow properties than higher ones (>1.25).
Angle of repose
Accurately weighed quantity of powder was transferred into a funnel which was adjusted to a height of 2 cm in such a way that the tip of funnel touches apex of a pile of powder heap [11]). Finally, the height and radius of powder cone were measured using the following equation.
tan 0 = h/r.
Where 8 angle of repose, h = height of pile, r radius of pile base.
Evaluation of Metformin Hydrochloride Sustained-Release Matrix Tablets
Weight variation
Ten tablets from each batch were selected randomly and weighed on a digital balance (Shimadzu, Japan) individual weights were compared with average weight. The percentage difference in the weight variation should be within the permissible limits
Thickness
The thickness of all formulations was determined on screw gauge (Pharma Labs, Ahmedabad, India). Standard deviation values indicate all formulations were within the range [13].
Tablet hardness
Hardness of the tablets for shipping or breakage under conditions of storage, transportation, handling depends on hardness which was determined using Monsanto hardness tester [14] (E 30, Dwaraka Mai, Hyderabad).
Friability
The Friability of five tablets was determined using Roche friabilator (Electrolab, Mumbai). This device subjects’ tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25 rpm and dropping the tablets at the height of 6 inches in each revolution. Pre-weighed sample of tablets was placed in the friabilator and was subjected to 100 revolutions dedusted and reweighed [15]. The friability (F) is given by the formula:
F=(1-W/W) *100
Where, W, is the weight of the tablets before the test. W is the weight of the tablet after the test.
Drug content
Five tablets were weighed accurately and powdered, powder equivalent to 10 mg of drug was dissolved in phosphate buffer pH 7.4, filtered using 0.2 um membrane filter [16]. The drug content was measured by ultraviolet (UV)-spectrophotometer (Shimadzu, Japan) at 233 nm.
In vitro drug release.
In vitro, drug release studies for the prepared tablets were conducted using USP Type II paddle dissolution apparatus (Electrolab, Mumbai, India) at 100 rpm. One matrix tablet was placed in each flask of dissolution apparatus the study was conducted in 900 ml 0.1 N Hcl 37±0.5°C in first 2 h and later 900 ml of phosphate buffer pH 7.4 for remaining 12 h. 5 ml samples were withdrawn at regular intervals and same volume was replaced to maintain sink conditions [17]. The samples were analyzed after suitable dilutions with UV-spectrophotometer (Shimadzu, Japan) at 233 nm. All the experimental units were carried in triplicates.
Kinetic analysis of dissolution data
The in vitro drug release data were fitted into zero-order, first-order, and Higuchi by employing the method of least squares the mechanism of drug release was compared for all the formulations.
Mt/M∞ = Ktn
Mt/M∞ = b+k2t1/2
Mt/M∞ = a+k3t
In Peppas equation, Mt/M∞ is the fraction of drug released up to time t, K kinetic constant and n is the release exponent indicative of the release mechanism. In Higuchi and zero-order release equations, k1, k2, and k3 are constants. On the other hand, Higuchi equation expresses a diffuse release mechanism.
CONCLUSION
Matrix-based sustained release formulations of Metformin HCI offer significant benefits in terms of patient compliance and therapeutic efficiency. Future trends focus on personalization and advanced fabrication techniques. Selection of the right polymer and evaluation strategy is key to successful formulation.
ACKNOWLEDGMENT
We would like to acknowledge and express our profound thanks to Ms Khaladkar S.M. for enabling our endeavor. Her guidance and instruction enabled me to finish every stage of writing my paper. We thank our institute for giving us the opportunity to carry out this review.
REFERENCES
Dhage Shubhangi*, Lonkar Sagar, Naik Pranav, Khaladkar Shraddha, Matrix-Based Sustained Release Formulations of Metformin Hydrochloride: Current Trends and Evaluation Techniques, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 5, 4439-4448. https://doi.org/10.5281/zenodo.15522076
10.5281/zenodo.15522076
