FORMULATION AND DEVELOPMENT OF MATRIX TABLET IN DRUG DELIVERY SYSTEM

                   SAYAN PRAMANIK
             Bengal school of technology
                (A college of pharmacy)


INTRODUCTION: -

Oral route is one of the most popular routes of drug delivery due to its ease of administration, patient compliance, least sterility constraints and flexible design of dosage form. Over 90% of the formulations manufactured today are ingested orally. This shows that this class of formulation in the most popular worldwide and the major attention of the researcher in toward this direction. With advanced in technology and increase in awareness, toward modification in standard tablets is done to achieve better acceptability as well as bioavailability because of which newer and more efficient tablet dosage forms are being developed.[1]
These are the type of controlled drug delivery systems, which release the drug in continuous manner by both dissolutions 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. [2-3]
One of the least complicated approaches to the manufacture of sustained release dosage forms involves the direct compression of blend of drug, retardant material and additives to formulate a tablet in which the drug is embedded in a matrix of the retardant. Alternatively, drug and retardant blend may be granulated prior to compression. The materials most widely used in preparing matrix systems include both hydrophilic and hydrophobic polymers. Commonly available hydrophilic polymers include Hydroxypropyl methylcellulose (HPMC), Hydroxypropyl cellulose (HPC), Hydroxyethyl cellulose (HEC), Xanthan gum, Sodium alginate, Poly (ethylene oxide) and cross-linked homopolymers and copolymers of Acrylic acid. It is usually supplied in micronized forms because small particle size is critical to the rapid formation of gelatinous layer on the tablet surface. [4-6]
Tablet ingested orally are meant to be swallowed intact along with sufficient quantity of the potable water. Exceptions are chewable tablet and oral dispersible tablets. Standard compressed tablets this class includes tablets like, multiple compressed tablets, compression coated tablets, layered tablets, modified released tablets etc.
Most conventional oral drug products, such as tablets and capsules, are formulated to release the active drug immediately after oral administration, to obtain rapid and complete systemic drug absorption. Such immediate-release products result in relatively rapid drug absorption and onset of accompanying pharmacodynamic effects. However, after absorption of the drug from the dosage form is complete, plasma drug concentrations decline according to the drug's pharmacokinetic profile. Eventually, plasma drug concentrations fall below the minimum effective plasma concentration (MEC), resulting in loss of therapeutic activity. Before this point is reached, another dose is usually given if a sustained therapeutic effect is desired. An alternative to administering another dose is to use a dosage form that will provide sustained drug release, and therefore maintain plasma drug concentrations, beyond what is typically seen using immediate-release dosage forms. In recent years, various modified-release drug products have been developed to control the release rate of the drug and/or the time for drug release.
Introduction of matrix tablet as sustained release (SR) has given a new breakthrough for novel drug delivery system (NDDS) in the field of Pharmaceutical technology. It excludes complex production procedures such as coating and palletization 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. [7-11]
The purpose of this research was to develop and optimize a sustained release matrix tablet of freely soluble drug, tramadol hydrochloride using natural gums (Gum copal and Gum Dammar) as cost effective, nontoxic easily available matrixing polymers. Sustained release tablet of Tramadol HCl (dose 100mg) were produced by wet granulation method. The prepared batches of tablets were evaluated for hardness, weight variation, friability, drug content, and in-vitro dissolution profile and found satisfactory. A 32 full factorial design was used for optimization by taking the Gum copal (X1) and Gum Dammar (X2) as an independent variable. Tramadol hydrochloride is a centrally acting analgesic available throughout the world. Its dual opioid and non-opioid mechanisms of action, favorable efficacy and safety clinical profiles and non-controlled regulatory status in most markets contribute to its widespread use. A drawback of the immediate-release formulation of tramadol four times-a-day dosing due to its short elimination half-life 5.5 hr. and thus it is necessary for the drug to develop a sustained dosage form with reduced risk of drug administration, side effects and improved patient compliance. The formulations were found to have good preformulation characteristics. FTIR spectroscopy indicated the absence of any significant chemical interaction within drug and excipients. [12]

OBJECTIVES: 

Recently, controlled release drug delivery has become the standards in the modern pharmaceutical design and intensive research has been undertaken in achieving much better drug product effectiveness, reliability and safety. Oral sustain release drug delivery medication will continue to account for the largest share of drug delivery systems. Hence in this work to formulate tablets in order to avoid the first pass metabolism and increase the bioavailability. Hence in this work an attempt was made to formulate sustain release system for in order to achieve even plasma concentration profile up to 24 hrs.
Reason for the selection of -API as a model drug,
i) Being BCS class II drug it is low soluble in water and highly permeable. And it is necessary to sustain the drug release.
ii) Bioavailability after oral administration is 20% Silent features to design formulation in sustain release tablets.
iii) Less risk of dose dumping.
iv) Less inter and intra subject variability.
v) High degree of dispersion in the digestive tract thus minimizing the risk of high local drug concentrations.
vi) Drug may reach the site of optimum absorption in a reproducible fashion so reproducible bioavailability.

vii) Transport of drug is independent of gastric emptying.

ADVANTAGES OF MATRIX TABLET: - [14-15]

i) Easy to manufacture 

ii) Versatile, effective and low cost 

iii) Can be made to release high molecular weight compounds 

iv) The sustained release formulations may maintain therapeutic concentrations over prolonged periods.  

v) The use of sustain release formulations avoids the high blood concentration.  

vi) Sustain release formulations have the potential to improve the patient compliance.  

vii) Reduce the toxicity by slowing drug absorption. 

viii) Increase the stability by protecting the drug from hydrolysis or other derivative changes in gastrointestinal tract.

ix) Minimize the local and systemic side effects. 

x) Improvement in treatment efficacy.

xi) Minimize drug accumulation with chronic dosing.

xii) Usage of less total drug.

xiii) Improvement the bioavailability of some drugs.

DISADVANTAGES OF MATRIX TABLET: [14-15] 

i) The remaining matrix must be removed after the drug has been released.   

ii) High cost of preparation.  

iii) The release rates are affected by various factors such as, food and the rate transit through the gut.  

iv) 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.

Factor affecting the design and performance of controlled drug delivery:[16]

1. Drug properties  

• Partition coefficient
• Drug stability 
• Protein binding 
• Molecular size and 
• Diffusivity. 

2. Biological properties

• Absorption 
• Metabolism
• Elimination and 
• biological half-life
• Dose size 
• Route of administration 
• Target sites 
• Acute or chronic therapy 
• Disease condition 

Oral controlled drug delivery systems:[17]

Oral controlled release drug delivery is a drug delivery system that provides the continuous oral delivery of drugs at predictable and reproducible kinetics for a predetermined period throughout the course of GI transit and also the system that target the delivery of a drug to a specific region within the GI tract for either a local or systemic action. All the pharmaceutical products formulated for systemic delivery via the oral route of administration, irrespective of the mode of delivery (immediate, sustained or controlled release) and the design of dosage form (either solid dispersion or liquid), must be developed within the intrinsic characteristics of GI physiology. Therefore, the scientific framework required for the successful development of oral drug delivery systems consists of basic understanding of 

(i) Physicochemical, pharmacokinetic and pharmacodynamic characteristics of the drug.  

(ii) The anatomic and physiologic characteristics of the gastrointestinal tract and 

(iii) Physicochemical characteristics and the drug delivery mode of the dosage form to be designed.  

The main areas of potential challenge in the development of oral controlled drug delivery systems are: -  

1) Development of a drug delivery system: 

To develop a viable oral controlled release drug delivery system capable of delivering a drug at a therapeutically effective rate to a desirable site for duration required for optimal treatment. 

2) Modulation of gastrointestinal transit time: 

To modulate the GI transit time so that the drug delivery system developed can be transported to a target site or to the vicinity of an absorption site and reside there for a prolonged period of time to maximize the delivery of a drug dose.  

3) Minimization of hepatic first pass elimination: 

If the drug to be delivered is subjected to extensive hepatic first-pass elimination, preventive measures should be devised to either bypass or minimize the extent of hepatic metabolic effect.   

Methods used to achieve controlled release of orally administered drugs [18]

A. Diffusion controlled system: Basically, diffusion process shows the movement of drug molecules from a region of a higher concentration to one of lower concentration.  

This system is of two types 

a) Reservoir type: 

A core of drug surrounded by polymer membrane, which controls the release rate, characterizes reservoir devices.  

b) Matrix type: 

Matrix system is characterized by a homogenous dispersion of solid drug in a polymer mixture.  

B. Dissolution controlled systems 

a) Reservoir type: 

Drug is coated with a given thickness coating, which is slowly dissolved in the contents of gastrointestinal tract. By alternating layers of drug with the rate controlling coats, a pulsed delivery can be achieved. If the outer layer is quickly releasing bolus dose of the drug, initial levels of the drug in the body can be quickly established with pulsed intervals. 

b) Matrix type: 

The more common type of dissolution-controlled dosage form. It can be either a drug impregnated sphere or a drug impregnated tablet, which will be subjected to slow erosion.

C. Bioerodible  and combination of diffusion and dissolution systems:

It is characterized by a homogeneous dispersion of drug in an erodible matrix. (a) bulk-eroding and (b) surface-eroding Bio erodible systems.   

D. Methods using ion exchange:

It is based on the drug resin complex formation when an ionic solution is kept in contact with ionic resins. The drug from these complexes gets exchanged in gastrointestinal tract and released with excess of Na+ and Cl- present in gastrointestinal tract. 

E. Methods using osmotic pressure: It is characterized by drug surrounded by semi permeable membrane and release governed by osmotic pressure.  

F. pH–Independent formulations: 

A buffered controlled release formulation, is prepared by mixing a basic or acidic drug with one or more buffering agents, granulating with appropriate pharmaceutical excipients and coating with GI fluid permeable film forming polymer. When GI fluid permeates through the membrane the buffering agent adjusts the fluid inside to suitable constant pH thereby rendering a constant rate of drug release.  

G. Altered density formulations: Several approaches have been developed to prolong the residence time of drug delivery system in the gastrointestinal tract. High-density approach Low-density approach. 

CLASSIFICATION OF MATRIX TABLETS: [19-21] 

On the Basis of Retardant Material Used: Matrix tablets can be divided in to 5 types.

1. Hydrophobic Matrices (Plastic matrices):[19]

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: [20]

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 formulations.  

3. Hydrophilic Matrices:[21]

Hydrophilic polymer matrix systems are widely used in oral controlled drug delivery because of their flexibility to obtain a desirable drug release profile, cost effectiveness, and broad regulatory acceptance. 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, 

A. Cellulose derivatives: Methylcellulose 400 and 4000cPs, Hydroxyethyl cellulose; Hydroxypropyl methylcellulose (HPMC) 25, 100, 4000 and 15000cPs; and Sodium carboxymethylcellulose.  

B. Non cellulose natural or semi synthetic polymers:Agar-Agar; Carob gum; Alginates; Molasses; Polysaccharides of mannose and galactose, Chitosan and Modified starches.  

Polymers of acrylic acid: Carbopol-934, the most used variety. 

4. Biodegradable Matrices:[21]

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 nonenzymatic process in to oligomers and monomers that can be metabolized 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:[21]

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 (Phaeophycean) by the use of dilute alkali.   

On the Basis of Porosity of Matrix: [22-25] 

Matrix system can also be classified according to their porosity and consequently, Macro porous; Micro porous and Nonporous systems can be identified:  

1. Macro porous 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. Micro porous System: 

Diffusion in this type of system occurs essentially through pores. For micro porous 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. 

POLYMERS USED IN MATRIX TABLET:[26]

Hydrogels 

Polyhydroxyethylemethylacrylate (PHEMA), Cross-linked polyvinyl alcohol (PVA), Cross-linked polyvinyl pyrrolidone (PVP), Polyethylene oxide (PEO), Polyacrylamide (PA)  

Soluble polymers 

Polyethylene glycol (PEG), polyvinyl alcohol (PVA), Polyvinylpyrrolidone (PVP), Hydroxypropyl methyl cellulose (HPMC)  

Biodegradable polymers 

Polylactic acid (PLA), Polyglycolic acid (PGA), Polycaprolactone (PCL), Polyanhydrides, Polyorthoesters 

Non-biodegradable polymers 

Polyethylene vinyl acetate (PVA), Polydimethylsiloxane (PDS), Polyether urethane (PEU), Polyvinyl chloride (PVC), Cellulose acetate (CA), Ethyl cellulose (EC)  

Mucoadhesive polymers 

Polycarbophil, Sodium carboxymethyl cellulose, Polyacrylic acid, Tragacanth, Methyl cellulose, Pectin 

Natural gums 

Xanthan gum, Guar gum, Karaya gum, Locust bean gum

Method of Preparation of Matrix Tablet  

A. Wet Granulation Technique [27]

•  Milling and mixing of drug, polymer and excipients.
•  Preparation of binder solution.
• Wet massing by addition of binder solution or granulating solvent.
•  Screening of wet mass.
• Drying of the wet granules.
• Screening of dry granules. 
• Blending with lubricant and disintegrate to produce “running powder” 
• Compression of tablet. 

B. Dry Granulation Technique [28]

• Milling and mixing of drug, polymer and excipients.
• Compression into slugs or roll compaction.
• Milling and screening of slugs and compacted powder.
• Mixing with lubricant and disintegrate 
• Compression of tablet 

C. Sintering Technique [29]

Sintering is defined as the bonding of adjacent particle surfaces in a mass of powder, or in a compact, by the application of heat. Conventional sintering involves the heating of a compact at a temperature below the melting point of the solid constituents in a controlled. The changes in the hardness and disintegration time of tablets stored at elevated temperatures were described as a result of sintering. The sintering process has been used for the fabrication of sustained release matrix tablets for the stabilization and retardation of the drug release.  

PREPARATION OF MATRIX TABLET OF TRAMADOL HYDROCHLORIDE: -

Materials: Tramadol hydrochloride was obtained as gift sample from Shakti Bioscience (Mumbai, India). Gum Copal and Gum Dammar obtained from AV Overseas (New Delhi, India), HPMC 15cps, Dicalcium Phosphate, Magnesium stearate were collected from CDH lab. All other chemicals and reagents used were of high analytical grade. 

Method: Drug Analysis; Tramadol hydrochloride was analyzed by UV- spectrophotometer (SHIMBADZU Japan model-1800) at 272nm. Calibration curve was prepared in phosphate buffer of pH 7.4 in concentration ranges from10-30 mcg/ml. Correlation coefficients were found to be (r2=0.9980) in all cases and no interference of additives used in formulation was observed. 

Preparation of matrix tablet: 

 The matrix tablet containing Tramadol Hydrochloride 100 mg were prepared by wet granulation method. The composition of tablet is shown in table 2. The powders were blended and granulated with isopropyl alcohol which is used as granulating agent. The wet mass was passed through sieve no.22# and the wet granules were dried at 50 °C for 2 h. The dried granules were lubricated with magnesium stearate. The lubricated granules were compressed with a single station tablet machine.

Table1 : Formulation variable and levels

EVALUATION: -

Micromeritic properties: -

Angle of repose: -

The angle of repose of powder was determined by the funnel method. The accurately weighed powder was taken in a funnel. The height (h) of the funnel was adjusted in such a way that the tip of the funnel just touches the apex of the heap of the powder. The powder was allowed to flow through funnel freely onto the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation.

                     tan θ = h/r (1)

     Therefore, θ = tan h/r

   Where, θ = angle of repose,

  h = height of the pile,

  r = radius of the pile base 

Bulk density: -

Both loose bulk density (LBD) and tapped bulk density (TBD) were determined. Powder from each formulation, previously lightly shaken to break any agglomerates formed was introduced into a 10 ml measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall under its own weight onto a hard surface from the height of 2.5 cm at 2 sec intervals. The tapping was continued until no further change in volume was noted. Bulk density is calculated by using formula:

 Weight of the powder Bulk density (pb) = Bulk volume of the powder

 Weight of the powder Tapped density (p,) = Tapped volume of the powder

Carr’s index: -

It helps in measuring the force required to break the friction between the particles and the hopper. It is expressed in % and given by: -

Carr’s index (%) = [(TBD - LBD) x 100]/TBD 

Where, 

LBD = weight of the powder/volume of the packing 

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

ii) Physicochemical parameters: -

Tablet hardness: -

The resistance of tablet for shipping or breakage, under conditions of storage, transportation and handling, before usage, depends on its hardness. The hardness of tablet of each formulation was measured by using Pfizer hardness tester.

Thickness: -

Thickness of tablets was important for uniformity of tablet size. Thickness was measured by using screw gauze on 3 randomly selected samples.

Friability: -

Friability is the measure of tablet strength. Roche Friabilator was used for testing the friability using the following procedure. Twenty tablets were weighed accurately and placed in the plastic chamber that revolves at 25 rpm for 4 mins dropping the tablets through a distance of six inches with each revolution. After 100 revolutions the tablets were reweighed and the percentage loss in tablet weight was determined.

% loss = (Initial wt. of tablets - Final wt. of tablets)/Initial wt. of tablets*100

Weight variation: -

Twenty tablets were weighed individually and the average weight was determined. Then percentage deviation from the average weight was calculated. According to IP standards, not more than two of the individual weight deviates from the average weight by more than the percentage and none deviates by more than twice that percentage.

Uniformity of drug content: -

Ten tablets were weighed and average weight is calculated. All tablets were crushed and powder equivalent to 8 mg drug was dissolved in 8 ml of 0.1N NaOH and the volume was made up to 100 ml with pH 6.8 phosphate buffer. The solution was shaken for 1 h and kept for 24 h. From the stock solution, 1 ml solution was taken in 10 ml volumetric flask and the volume was made with pH 6.8 phosphate buffer. Solution was filtered and absorbance was measured spectrophotometrically at 379 nm against pH 6.8 phosphate buffer as a blank. Amount of drug present in one tablet was calculated.

Dissolution studies:

The release rate of Lornoxicam from sustained matrix tablets were determined using USP dissolution testing apparatus II (paddle type) at 50 rpm. The dissolution test was performed using 750 ml of 0.1 N HCl (pH 1.2) for 2 h at 37 ± 0.5 °C and then 250 ml of 0.2 M tri sodium phosphate (Na3PO4.12H2O) was added and pH is adjusted to 6.8 as described in the USP 26/NF monograph. Dissolution test was carried out for a period of 12 h using 0.1N HCl (pH 1.2) for first 2 h and then the pH is adjusted to 6.8 for the rest of the period. The temperature of the dissolution medium is maintained at 37±0.5°C. 10 ml of the sample was withdrawn at regular intervals and replaced with the same volume pre-warmed with fresh dissolution medium. After filtration, the amount of drug release was determined from the standard calibration curve of pure drug.

MECHANISM OF DRUG RELEASE FROM MATRIX TABLET: [30-32]

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 behavior for the system can be mathematically described by the following equation: 

                        dM/dh = C_0.dh – C_S/2 ……………… (1) 

Where,  

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 

C_0= Total amount of drug in a unit volume of matrix 

C_S = Saturated concentration of the drug within the matrix.  

Additionally, according to diffusion theory:                  

                        dM   = (D_m. C_S / h) dt........................... (2) 

Where, 

D_m = 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] ½ ……………… (3) 

When the amount of drug is in excess of the saturation concentration then: 

                    M=[2Cs.Dm.Co.t]^(1/2)  ………………... (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)……………. (5)

Where, 

 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 path length 

For pseudo steady state, the equation can be written as:  

                  M = [2D. Ca. Co (p/T) t] ½ ………………………. (6) 

The total porosity of the matrix can be calculated with the following equation:  

                   p = pa + Ca/ ρ + Cex / ρex ……………………… (7) 

Where, 

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) ………………………. (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 

• Porosity  

• Tortuosity  

• Polymer system forming the matrix  

EFFECT OF RELEASE LIMITING FACTOR ON DRUG RELEASE: [33-34]

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 linking with the simultaneous forming of water-polymer linking, 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 hem perfusion, 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,  

Polymer particle size 

Polymer viscosity 

Polymer concentration. 

I. Polymer particle size: 

Malamataris stated that when the content of hydroxyl propyl 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 hydroxyl propyl 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:  

                                          J_D= D dc/dx 

Where, 

J_D is flux of diffusion across a plane surface of unit area 

D is infusibility 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 δ_d. 

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 within 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 within 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 hydro soluble 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.

LITERATURE REVIEW:

Gohel M.C et al.,[5] (2009) fabricated modified release tablet of metoprolol succinate using hydroxypropyl methylcellulose (HPMC) and xanthan gum as a matrixing agent. A 32 full factorial design was employed for the optimization of formulation. The percentage drug released at a given time (Y 60, Y 240 and Y 720) and the time required for a given percentage of drugs to be released (t 50%) were selected as dependent variables. The in vitro drug dissolution study was carried out in pH 6.8 phosphate buffer employing paddle rotated at 50 rpm. The similarity factor (f 2) was calculated for selection of best batch considering mean in vitro dissolution data of Seloken® XL as a reference profile. It is concluded that the desired drug release pattern can be obtained by using a proper combination of HPMC (high gelling ability) and xanthan gum (quick gelling tendency). The economy of xanthan gum and faster hydration rate favors its use in modified release tablets. The matrix integrity during dissolution testing was maintained by using hydroxypropyl methylcellulose.

Shishoo C.J et al.,[6] (2002) evaluated In vitro - in vivo correlation of modified release formulations of theophylline. As part of our ongoing study an experimental modified release capsule formulation, containing theophylline (200 mg) loaded microspheres (Formulation F4), was developed, characterized and it’s in vitro and in vivo performance was then compared with that of the three market modified release formulations of theophylline (200 mg)- two tablets (Formulations F2 and F3) and one capsule (Formulation F1). Formulation F1, F2 and F3 were analyzed to find out the best market sample with acceptable bioavailability. All the four formulations were evaluated for in vitro theophylline release using different dissolution test conditions. In vitro studies indicated that only formulation F1 showed pH-dependent drug release while the other three formulations, including experimental formulation F4, showed almost condition-independent dissolution behavior. The bioavailability studies indicated that amongst the market formulations (F1, F2, and F3), formulation F1 and F2 were bioequivalent but F3 failed to demonstrate acceptable dissolution and bioavailability.

Panchagnula R et al., [7] (2007) studied an in vitro evaluation of modified release formulations, marketed in India was conducted and compare their performance with a novel matrix- based multi particulate system. The results indicate that even though the marketed formulations are found to comply to the definition of modified release formulations and predicted to produce therapeutic blood level for a prolonged period of time, the fluctuations were expected to be found uncontrolled expect in the osmotic systems and matrix based multi particulate system. Thus, it was concluded that novel matrix- based multi particulate systems were found to be superior to any other marketed formulations with respect to the therapeutic advantage as well as manufacturing feasibility.

Farrukh Z et al., [8] (2010) evaluated modified-release multiple-unit tablets of loratadine and pseudoephedrine hydrochloride. The immediate-release pellets containing pseudoephedrine hydrochloride alone or in combination with loratadine were prepared using extrusion– spherization method. The pellets of pseudoephedrine hydrochloride were coated to prolong the drug release up to 12 h. Both immediate- and prolonged-release pellets were filled into hard gelatin capsule and also compressed into tablets using inert tableting granules of microcrystalline cellulose Ceolus KG-801. The in vitro drug dissolution study conducted using high-performance liquid chromatography method showed that both multiple-unit capsules and multiple-unit tablets released loratadine completely within a time period of 2 h, whereas the immediate-release portion of pseudoephedrine hydrochloride was liberated completely within the first 10 min of dissolution study. On the other hand, the release of pseudoephedrine hydrochloride from the prolonged release coated pellets was prolonged up to 12 hr. and followed zero-order release kinetic. The drug dissolution profiles of multiple-unit tablets and multiple-unit capsules were found to be closely similar, indicating that the integrity of pellets remained unaffected during the compression process. Moreover, the friability, hardness, and disintegration time of multiple-unit tablets were found to be within BP specifications. In conclusion, modified release pellet-based tablet system for the delivery of loratadine and pseudoephedrine hydrochloride was successfully developed and evaluated.

Gohel M. C et al., [9] (2008) evaluated to prepare novel modified release press coated tablets of venlafaxine hydrochloride. Hydroxypropyl methylcellulose K4M and hydroxypropyl methylcellulose K100M were used as release modifier in core and coat, respectively. A 32 full factorial design was adopted in the optimization study. The drug to polymer ratio in core and coat were chosen as independent variables. The drug release in the first hour and drug release rate between 1 and 12 h were chosen as dependent variables. The tablets were characterized for dimension analysis, crushing strength, friability and in vitro drug release.

The tablets of check point batch were subjected to in vitro drug release in dissolution media with pH 5, 7.2 and distilled water. The kinetics of drug release was best explained by Korsmeyer and Peppas model (anomalous non-Fickian diffusion). The systematic formulation approach enabled us to develop modified release venlafaxine hydrochloride tablets. 

CONCLUSION:

By the above discussion, it can be easily concluded that sustained-release formulation is helpful in increasing the efficiency of the dose as well as they are also improving the patient’s compatibility. More over all these comes with reasonable cost. The dosage form is easy to optimize and very helpful in case of the antibiotics in which irrational use of the same may result in resistance.

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