Matrix Tablets : An Important Tool for Oral Controlled-Release Dosage Forms Submitted by sunilkamboj | 12 / Nov / 2009
An appropriately designed controlled-release drug delivery system can be a major advance towards solving problems concerning the targeting of a drug to a specific organ or tissue and controlling the rate of drug delivery to the target tissue. Matrix tablets are an interesting option when developing an oral controlled release formulation. The present study focuses on oral controlled-release dosage forms and types of various polymers used to formulate matrix tablets. The use of polymers in controlling the release of drugs has become important in the formulation of pharmaceuticals. Watersoluble polymers such as polyethylene glycol and polyvinylpyrrolidone may be used to increase the dissolution rates of poorly soluble drugs. Hydrogels provide the basis for implantation, transdermal and oral controlled release systems. Hydroxypropyl methylcellulose (HPMC) is cellulose ether which may be used as the basis for hydrophilic matrices for controlled release oral delivery.
Keywords: Control-release, Matrix tablets, Polymers, Hydrogels, HPMC.
The term modified-release dosage form is used to describe products that alter the timing and rate of release of drug substance. A modified-release dosage form is defined “as one for which the drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions, ointments, or promptly dissolving dosages forms. The USP/NF presently recognizes several type of modified-release dosage forms as:
1. Oral Dosage Forms
·Modified release dosage forms
·Extended release e.g. controlled release, sustained release and prolonged release
·Delayed release e.g. enteric-coated tablets.
2. Intramuscular Dosage Forms
·Water-immiscible injections e.g. oils
3. Subcutaneous Dosage Forms
4. Transdermal Delivery Systems
·Patches, creams, etc.
5. Targeted Delivery Systems
Controlled release drug delivery system is capable of achieving the benefits over the conventional dosage forms as:
Drawbacks Associated with Conventional Dosage Forms:
1.Poor patient compliance, increased chances of missing the dose of a drug with short half-life for which frequent administration is necessary.
2.The unavoidable fluctuations of drug concentration may lead to under medication or over medication.
3.A typical peak-valley plasma concentration-time profile is obtained which makes attainment of steady-state condition difficult.
4.The fluctuations in drug levels may lead to precipitation of adverse effects especially of a drug with small Therapeutic Index (TI) whenever over medication occur.
Advantages of Controlled Release Drug Delivery Systems
Therapeutic advantage: Reduction in drug plasma level fluctuation; maintenance of a steady plasma level of the drug over a prolonged time period, ideally simulating an intravenous infusion of a drug.
Reduction in adverse side effects and improvement in tolerability: Drug plasma levels are maintained with in a narrow window with no sharp peaks and with AUC of plasma concentration versus time curve comparable with total AUC from multiple dosing with immediate release dosage forms.
Patient comfort and compliance: Oral drug delivery is the most common and convenient for patients, and a reduction in dosing frequency enhances compliance.
Reduction in healthcare cost: The total cost of therapy of the controlled release product could be comparable or lower than the immediate release product. With reduction in side effects, the overall expense in disease management also would be reduced. This greatly reduces the possibility of side effects, as the scale of side effects increase as we approach the maximum safe concentration.
Avoid night time dosing: It is also good for patients to avoid the dosing at night time.
These are the type of controlled drug delivery systems, which release the drug in continuous manner. These release the drug 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 nonswellable hydrophobic materials or plastic materials.
Classification Of Matrix Tablets
A. On the Basis of Retardant Material Used: Matrix tablets can be divided in to 5 types.
1. Hydrophobic Matrices (Plastic matrices):
The concept of using hydrophobic or inert materials as matrix materials was first introduced in 1959. In this method of obtaining sustained release from an oral dosage form, drug is mixed with an inert or hydrophobic polymer and then compressed in to a tablet. Sustained release is produced due to the fact that the dissolving drug has diffused through a network of channels that exist between compacted polymer particles.
Examples of materials that have been used as inert or hydrophobic matrices include polyethylene, polyvinyl chloride, ethyl cellulose and acrylate polymers and their copolymers.
The rate-controlling step in these formulations is liquid penetration into the matrix. The possible mechanism of release of drug in such type of tablets is diffusion. Such types of matrix tablets become inert in the presence of water and gastrointestinal fluid.
2. Lipid Matrices:
These matrices prepared by the lipid waxes and related materials. Drug release from such matrices occurs through both pore diffusion and erosion. Release characteristics are therefore more sensitive to digestive fluid composition than to totally insoluble polymer matrix. Carnauba wax in combination with stearyl alcohol or stearic acid has been utilized for retardant base for many sustained release formulation.
3. Hydrophilic Matrices:
The formulation of the drugs in gelatinous capsules or more frequently, in tablets, using hydrophilic polymers with high gelling capacities as base excipients, is of particular interest in the field of controlled release. Infect a matrix is defined as well mixed composite of one or more drugs with a gelling agent (hydrophilic polymer). These systems are called swellable controlled release systems.
The polymers used in the preparation of hydrophilic matrices are divided in to three broad groups
1.Cellulose derivatives: methylcellulose 400 and 4000 cPs; hydroxyethylcellulose; hydroxypropylmethylcellulose (HPMC) 25, 100, 4000 and 15000 cPs; and sodium carboxymethylcellulose.
2.Noncellulose natural or semisynthetic polymers: agar-agar; carob gum; alginates; molasses; polysaccharides of mannose and galactose; chitosan and modified starches.
3.Polymers of acrylic acid; corbopol 934, the most used variety.
4. Biodegradable Matrices:
These consist of the polymers which comprised of monomers linked to one another through functional groups and have unstable linkage in the backbone. They are biologically degraded or eroded by enzymes generated by surrounding living cells or by nonenzymetic process in to olegomers and monomers that can be metabolised or excreted.
Examples are natural polymers such as proteins and polysaccharides; modified natural polymers; synthetic polymers such as aliphatic poly (esters) and poly anhydrides.
5. Mineral Matrices:
These consist of polymers which are obtained from various species of seaweeds. Example is Alginic acid which is a hydrophilic carbohydrate obtained from species of brown seaweeds (Phaephyceae) by the use of dilute alkali.
B. On the Basis of Porosity of Matrix
Matrix system can also be classified according to their porosity and consequently, macroporous; microporous and non-porous systems can be identified:
1. Macroporous Systems:
In such systems the diffusion of drug occurs through pores of matrix, which are of size range 0.1 to 1 μm. This pore size is larger than diffusant molecule size.
2. Microporous System:
Diffusion in this type of system occurs essentially through pores. For microporous systems, pore size ranges between 50 – 200 A°, which is slightly larger than diffusant molecules size.
3. Non-porous System:
Non-porous systems have no pores and the molecules diffuse through the network meshes. In this case, only the polymeric phase exists and no pore phase is present.
Advantages of Matrix Tablets
·Easy to manufacture
·Versatile, effective and low cost
·Can be made to release high molecular weight compounds
Disadvantages of the matrix systems:
·The remaining matrix must be removed after the drug has been released.
·The drug release rates vary with the square root of time. Release rate continuously diminishes due to an increase in diffusional resistance and/or a decrease in effective area at the diffusion front. However, a substantial sustained effect can be produced through the use of very slow release rates, which in many applications are indistinguishable from zero-order.
Polymers used in Matrix Tablets
Polyhydroxyethyle methylacrylate (PHEMA)
Cross-linked polyvinyl alcohol (PVA)
Cross-linked polyvinyl pyrrolidone (PVP)
Polyethylene oxide (PEO)
Polyethylene glycol (PEG)
Polyvinyl alcohol (PVA)
Polyvinyl pyrrolidone (PVP)
Hydroxypropyl methyl cellulose (HPMC)
Polylactic acid (PLA)
Polyglycolic acid (PGA)
Polyethylene vinyl acetate (PVA)
Polydimethyl siloxane (PDS)
Polyether urethane (PEU)
Polyvinyl chloride (PVC)
Cellulose acetate (CA)
Ethyl cellulose (EC)
Sodium carboxymethyl cellulose
Drug Release from Matrix systems
Drug in the outside layer exposed to the bathing solution is dissolved first and then diffuses out of the matrix. This process continues with the interface between the bathing solution and the solid drug moving toward the interior. It follows that for this system to be diffusion controlled, the rate of dissolution of drug particles within the matrix must be much faster than the diffusion rate of dissolved drug leaving the matrix.
Derivation of the mathematical model to describe this system involves the following assumptions:
a) A pseudo-steady state is maintained during drug release;
b) The diameter of the drug particles is less than the average distance of drug diffusion through the matrix;
d) The bathing solution provides sink conditions at all times.
The release behaviour for the system can be mathematically described by the following equation:
dM/dh = Co . dh - Cs/2 Equation 1
dM = Change in the amount of drug released per unit area
dh = Change in the thickness of the zone of matrix that has been depleted of drug
Co = Total amount of drug in a unit volume of matrix
Cs = Saturated concentration of the drug within the matrix.
Additionally, according to diffusion theory:
dM = ( Dm . Cs / h) . dt Equation 2
Dm = Diffusion coefficient in the matrix.
h = Thickness of the drug-depleted matrix
dt = Change in time
By combining equation 1 and equation 2 and integrating:
M = [Cs . Dm . (2Co −Cs) . t] 1/2 Equation 3
When the amount of drug is in excess of the saturation concentration, then:
M = [2Cs . Dm . Co . t] 1/2 Equation 4
Equation 3 and equation 4 relate the amount of drug release to the square-root of time. Therefore, if a system is predominantly diffusion controlled, then it is expected that a plot of the drug release vs. square root of time will result in a straight line. Drug release from a porous monolithic matrix involves the simultaneous penetration of surrounding liquid, dissolution of drug and leaching out of the drug through tortuous interstitial channels and pores. The volume and length of the openings must be accounted for in the drug release from a porous or granular matrix:
M = [Ds.Ca.p/T. (2Co – p.Ca) t]1/2 Equation 5
p = Porosity of the matrix
t = Tortuosity
Ca = solubility of the drug in the release medium
Ds = Diffusion coefficient in the release medium.
T = Diffusional pathlength
For pseudo steady state, the equation can be written as:
M = [2D.Ca .Co( p/T)t] 1/2 Equation 6
The total porosity of the matrix can be calculated with the following equation:
p = pa + Ca/ ρ + Cex/ ρex Equation 7
p = Porosity
ρ = Drug density
pa = Porosity due to air pockets in the matrix
ρex = Density of the water soluble excipients
Cex = Concentration of water soluble excipients
For the purpose of data treatment, equation 7 can be reduced to:
M = k. t 1/2 Equation 8
Where k is a constant, so that the amount of drug released versus the square root of time will be linear, if the release of drug from matrix is diffusion-controlled. If this is the case, the release of drug from a homogeneous matrix system can be controlled by varying the following parameters:
• Initial concentration of drug in the matrix
• Polymer system forming the matrix
• Solubility of the drug.
In certain systems there is a bimodal or anomalous release of the active ingredient. In these systems there is diffusion; additionally, the extended release polymer may become hydrated and begin to dissolve leading to release upon erosion. These systems are complex and difficult to mathematically model since the diffusional path length undergoes change due to the polymer dissolution.
A series of transport phenomena are involved in the release of a drug from a swellable, diffusion/erodable matrix:
a.) Initially, there are steep water concentration gradients at the polymer/water interface, resulting in absorption of water into the matrix.
b.) Due to the absorption of water, the polymer swells, resulting in dramatic changes of drug and polymer concentration, increasing the dimensions of the system and increasing macromolecular mobility.
c.) Upon contact with water the drug dissolves and diffuses out of the device.
d.) With increasing water content, the diffusion coefficient of the drug increase substantially.
e.) In the case of a poorly water-soluble drug, dissolved and undissolved drug coexist within the polymer-matrix
f.) Finally, the polymer itself dissolves.
These systems are described in terms of fronts. The following fronts have been defined, with regard to anomalous release systems:
• The “swelling front”, the erosion front, and the diffusion front. The swelling front separates the rubbery region (swelling polymer area) which has enough water absorbed within the polymer to lower the Tg of the polymer below the respective environmental temperature allowing for macromolecular mobility and swelling, from the non-swelling polymer region (where the polymer exhibits a Tg that is above the respective environmental temperature).
• The “erosion front” separates the matrix from the bulk solution and is the interface between the unstirred layer with polymer concentration gradient and the well stirred medium.
• The “diffusion front” is between the swelling and erosion front and separated the areas of non dissolved drug from the area of dissolved drug.
With regard to swelling matrix systems, alternate models have been proposed to describe the diffusion, swelling, and dissolution processes occurring with into the system and these phenomena lead to drug release.
The gel strength is important in the matrix performance and is controlled by the concentration, viscosity and chemical structure of the rubbery polymer. This restricts the suitability of the hydrophilic polymers for preparation of swellable matrices. Polymers such as carboxymethylcellulose, hydroxypropylcellulose or tragacanth gums do not form the gel layer quickly. Consequently, they are not recommended as excipients to be used alone in swellable matrices.
In 1985 Peppas introduced a semi-empirical equation describing the drug release behaviour from anomalous-release, hydrophilic matrix systems:
Q = k . t n Equation 9
Q = Fraction of drug release in time (t)
t = Time
k = Rate constant (incorporates characteristics of polymer system and drug)
n = Diffusional exponent
The value of n is indicative of the drug release mechanism.
In order to describe relaxational transport, then modified equation 9 in order to account for relaxational transport:
Q = k1 . tn + k2 . t 2 n Equation 10
k1 = Fickian diffusion constant
k2 = Relaxational mechanism constant
If the surface area of the system is fixed, which is unlikely, the value of n should be 0.5 and equation 10 is transformed to:
Q = k1 . t0.5 + k2 . t Equation 11
The first term of this equation accounts for diffusional phenomena, while the second term of this equation accounts for polymer erosion.
Effect of Release Limiting Parameter on Drug Release
The mechanistic analysis of controlled release of drug reveals that partition coefficient; diffusivity; diffusional path thickness and other system parameters play various rate determining roles in the controlled release of drugs from either capsules, matrix or sandwich type drug delivery systems.
A. Polymer hydration: It is important to study polymer hydration/swelling process for the maximum number of polymers and polymeric combinations. The more important step in polymer dissolution include absorption/adsorption of water in more accessible places, rupture of polymer-polymer linkings with the simultaneous forming of water-polymer linkings, separation of polymeric chains, swelling and finally dispersion of polymeric chain in dissolution medium.
B. Drug solubility: Molecular size and water solubility of drug are important determinants in the release of drug from swelling and erosion controlled polymeric matrices. For drugs with reasonable aqueous solubility, release of drugs occurs by dissolution in infiltrating medium and for drugs with poor solubility release occurs by both dissolution of drug and dissolution of drug particles through erosion of the matrix tablet.
C. Solution solubility: In view of in vivo (biological) sink condition maintained actively by hemoperfusion; it is logical that all the in vitro drug release studies should also be conducted under perfect sink condition. In this way a better simulation and correlation of in vitro drug release profile with in vivo drug administration can be achieved. It is necessary to maintain a sink condition so that the release of drug is controlled solely by the delivery system and is not affected or complicated by solubility factor.
D. Polymer diffusivity: The diffusion of small molecules in polymer structure is energy activated process in which the diffusant molecules moves to a successive series of equilibrium position when a sufficient amount of energy of activation for diffusion Ed has been acquired by the diffusant is dependent on length of polymer chain segment, cross linking and crystallinity of polymer. The release of drug may be attributed to the three factors viz,
i.Polymer particle size
i. Polymer particle size: Malamataris stated that when the content of hydroxypropyl methylcellulose is higher, the effect of particle size is less important on the release rate of propranolol hydrochloride, the effect of this variable more important when the content of polymer is low. He also justified these results by considering that in certain areas of matrix containing low levels of hydroxypropyl methylcellulose led to the burst release.
ii. Polymer viscosity: With cellulose ether polymers, viscosity is used as an indication of matrix weight. Increasing the molecular weight or viscosity of the polymer in the matrix formulation increases the gel layer viscosity and thus slows drug dissolution. Also, the greater viscosity of the gel, the more resistant the gel is to dilution and erosion, thus controlling the drug dissolution.
iii. Polymer concentration: An increase in polymer concentration causes an increase in the viscosity of gel as well as formulation of gel layer with a longer diffusional path. This could cause a decrease in the effective diffusion coefficient of the drug and therefore reduction in drug release. The mechanism of drug release from matrix also changes from erosion to diffusion as the polymer concentration increases.
E. Thickness of polymer diffusional path: the controlled release of a drug from both capsule and matrix type polymeric drug delivery system is essentially governed by Fick’s law of diffusion:
JD = D dc/dx Equation 12
JD flux of diffusion across a plane surface of unit area where D is diffusibility of drug molecule, dc/dx is concentration gradient of drug molecule across a diffusion path with thickness dx.
F. Thickness of hydrodynamic diffusion layer: It was observed that the drug release profile is a function of the variation in thickness of hydrodynamic diffusion layer on the surface of matrix type delivery devices. The magnitude of drug release value decreases on increasing the thickness of hydrodynamic diffusion layer δd.
G. Drug loading dose: The loading dose of drug has a significant effect on resulting release kinetics along with drug solubility. The effect of initial drug loading of the tablets on the resulting release kinetics is more complex in case of poorly water soluble drugs, with increasing initial drug loading the relative release rate first decreases and then increases, whereas, absolute release rate monotonically increases.
In case of freely water soluble drugs, the porosity of matrix upon drug depletion increases with increasing initial drug loading. This effect leads to increased absolute drug transfer rate. But in case of poorly water soluble drugs another phenomenon also has to be taken in to account. When the amount of drug present at certain position with in the matrix, exceeds the amount of drug soluble under given conditions, the excess of drug has to be considered as non dissolved and thus not available for diffusion. The solid drug remains with in tablet, on increasing the initial drug loading of poorly water soluble drugs, the excess of drug remaining with in matrix increases.
H. Surface area and volume: The dependence of the rate of drug release on the surface area of drug delivery device is well known theoretically and experimentally. Both the in vitro and in vivo rate of the drug release, are observed to be dependent upon surface area of dosage form. Siepman et al. found that release from small tablet is faster than large cylindrical tablets.
I. Diluent’s effect: The effect of diluent or filler depends upon the nature of diluent. Water soluble diluents like lactose cause marked increase in drug release rate and release mechanism is also shifted towards Fickian diffusion; while insoluble diluents like dicalcium phosphate reduce the Fickian diffusion and increase the relaxation (erosion) rate of matrix. The reason behind this is that water soluble filler in matrices stimulate the water penetration in to inner part of matrix, due to increase in hydrophilicity of the system, causing rapid diffusion of drug, leads to increased drug release rate.
J. Additives: The effect of adding non-polymeric excipients to a polymeric matrix has been claimed to produce increase in release rate of hydrosoluble active principles. These increases in release rate would be marked if the excipients are soluble like lactose and less important if the excipients are insoluble like tricalcium phosphate.
This review has elaborated various matrices, polymers and release mechanism from the matrix tablets. Various rate limiting parameters have been described which can affect the drug release from matrix tablets. By studding various polymers, it is concluded that ether cellulose polymers (especially HPMC), on account of its specific characteristics, have been used largely in hydrophilic matrices for oral controlled-release systems that can be developed for tablets or capsules dosage forms
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Sunil kamboj , G. D. Gupta, and Jagmohan oberoy
Sunil kamboj is working as a lecturer in Ganpati Institute of Pharmacy. He has completed his M. Pharm from College of Pharmacy,. Bela, Ropar. He has completed his M. Pharm project from Ranbaxy Research Lab, Gurgaon. He has completed his Graduation from GGS college of Pharmacy, Yamuna Nagar (HR). He has very good academic and extra circular record.
Dr.G. D. Gupta is a Director and Principal in ASBASJSM College of Pharmacy, Bela, Ropar, India. Dr. Gupta has author of number of books and published more than 100 Research Paper / Abstract in National and International conferences.
Dr. Jagmohan oberoy is a Director and Principal in Ganpati Institute of Technology and Management. He has published ample no of research papers at national and international level.