Optimization Of Drug Is Of Paramount Importance Biology Essay

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Drugs were there since ancient times and they will be there till there is life on this planet. However over the years we have learnt that optimization of drug is of paramount importance and in the process; patient safety, convenience, compliance, economic and industrial feasibility are also to be overlooked (Edith M1994).

Oral route has been one of the most popular routes of drug delivery due to its ease of administration, patient compliance, least sterility and flexible design of dosage forms. Conventional drug therapy involves the intermittent dosing of a therapeutic agent that has been formulated to ensure stability, activity and bioavailability of the active pharmaceutical ingredient (API). However, many drugs present difficulties when administered by conventional methods due to toxicity and low therapeutic index problems.

Novel drug delivery systems, are being employed both experimentally and therapeutically to alter the body distribution of drugs with a view to reduce the toxicity of existing drugs and delivering them more efficiently. Controlled-release systems have been designed to maintain plasma drug levels in the therapeutic range and thus minimize the effects of such problems. (Agis K 1992; Stephen BD 2002).The aim and objective in designing a controlled release system is to deliver drugs at a rate necessary to achieve and maintain a constant drug slowly over several hours, to protect the stomach from irritating effects of the drug (Aulton ME 1995).

Basically there are three basic modes of drug delivery (Remington 2000)

Targeted delivery

Controlled delivery

Modulated release

Targeted delivery refers to the systemic administration of drug carrier with the goal of delivering the drug to specific cell types, tissues, organs.

Controlled release refers to the use of delivery device with the objective of releasing the drug in to the patient body at a predetermined rate, or at a specific time or worth specific release profiles.

Modulated release implies of a drug delivery device that release the drug at a variable rate controlled by environmental conditions, biofeedback, sensor input or an external control device.

Definition

Controlled drug delivery system can be defined as the one, which releases the drug at a predetermined rate locally or systematically for a period of time i.e. it shows a predictability and reproducibility in the drug release kinetics which shows that the discharge of drug ingredients from a controlled release drug delivery system proceed at a rate profile which are predictable kinetically and also reproducible from one unit to other.

Fig.1: A hypothetical plasma concentration-time profile from conventional multiple dosing and single doses of sustained and controlled delivery formulations

2.1DESIGN OF CONTROLLED-RELEASE SYSTEMS

The proportion of drug input into the body or dosing rate is determined by the rate of drug release from the delivery device. Multiple kinetic models and equations can be used to describe the drug release kinetics from controlled-release systems, but formulations that give zero-order drug release in-vivo are widely accepted as ideal form many drug therapies. However, controlled-release products have been studied to produce many different release profiles. Systems exhibiting first-order drug release kinetics are also frequently employed to achieve the goals of controlled drug release therapies. Hence, a zero- or first-order release model is frequently considered while calculating the desired drug release kinetics (Aulton ME,1995 and Gwen MJ,1996).

2.1.1 Single unit dosage forms Single unit dosage forms are the oral delivery systems that consist of one unit that contains a single dose of the drug and is intended to be administered singularly. The most widely investigated example is the monolithic matrix-based tablet (Katznendler 1997, Nellore 1998, Pickler 1998). The advantages of this dosage form include high drug loading and the availability of well-characterized and cost-effective production methods. Drug release from these systems is controlled by a variety of mechanisms, including drug diffusion, tablet erosion, matrix swelling or a combination of these mechanisms. Film-coated and osmogen controlled single unit dosage forms have also been studied for modified release applications (Cao 2004, Zang 2003).

2.1.2 Multiple unit dosage forms These are the solid oral dosage forms which consist of a multiple tiny and discrete particulates, which include mini-tablets, pellets and granules. These systems provide flexibility during formulation development and therapeutic benefits to patients. A significant advantage of multiparticulates is that they can be divided into desired doses without formulation or process changes. They can also be blended to deliver concurrently incompatible bioactive agents or particles with different drug release properties.

Controlled delivery attempts to (Objective)

Sustaining drug delivery at a determined rate by maintaining a relatively steady and stable effective drug levels in the body with minimization of unwanted side effects related with a solution kinetic pattern.

Localize drug action by spatial of controlled release systems into the diseased tissue or organ or adjacent to the organs.

Target drug action to particular target cell type with the help of carriers or chemical derivatization to deliver drugs.

2.2 DRUGS SUITABLE FOR EXTENDED RELEASE FORMULATIONS

Not all drugs lend themselves to the formulation of extended release product. The important factor that are to be considered in the choices of a drug as a candidate of CR preparations are as follows (The Remington pharmaceutical sciences 2000 ; Sansom NL 1999).

Biological half life

Only drugs with short half biological half lives (2-4hours) make good candidates for CR systems, but larger dose may be required to maintain high release rate. Conversely, drugs which are having long half lives may be administered at fewer recurrent intervals and hence there won't be any benefit in formulating these drugs as prolonged release formulations.

Binding of drugs to tissues

eg: Tissue-bound ACE inhibitors, requires less frequent dosing is desirable, although in -spite of their shorter biological half-lives.

Drugs with irreversible effects

eg: platelet cyclo-oxygenase inhibition by aspirin.

The correlation stuck between response and plasma/blood concentration is comparatively flat or if the dose administered results in concentrations which are in the plasma region of the dose response relationship

eg: Thiazides that are used in treatment of hypertension

The drugs were metabolized pharmacologically to active metabolite(s) which are eliminated slowly than the parent drug

Eg: Quinapril, Trandolapril, Venalafaxine

Therapeutic range

Drugs that are highly potent such as cardiac glycosides should not be considered for CR preparations due to loss in flexibility in dosage regimen and potential sudden dose dumping.

GI absorption

Most CR formulations are dissolution controlled, in which release rate from the dosage form is the rate limiting step. Once the drug is released, it is transferred to blood through the lumen of intestine. Therefore efficient drug absorption from gastrointestinal tract is a prerequisite for oral controlled release dosage forms.

Stability to wide range of GI enzymes, flora and PH

For an orally administered drug, stability in the GI contents is necessary to ensure absolute and reproducible drug input into the body, since drug will be exposed to luminal contents. Unlike conventional dosage forms, a CR formulation is exposed to the entire PH range and enzymes.

c. First pass metabolism

Hepatic metabolism may render a drug unsuitable for oral CR release. This is because systemic availability for such a drug is highly reduced when input rate is small. The desired biopharmaceutic characteristics of drugs to be used in the development of oral CR dosage forms are:

Molecular weight : < 1000

Solubility : > 0.1μg/ml at PH 1 to 7.8

Non ionized moiety : > 0.1% to 11% at PH 1 to 7.8

Apparent partition

Coefficient : 0.5 to 2.0

General absorbability : From all GI segments

Release should not be influenced by PH and enzymes

Stability : stable in GI environment

Less protein binding

2.2.3 Drugs which are not ideal candidates for CR formulations

Extensive first pass metabolism (except prodrugs)

Extremely short elimination half life (low therapeutic index)

Extremely long elimination half life (narrow therapeutic range)

Bioavailability problems and instability in GI environment (Yie Chien 2009)

Potential Advantages of controlled drug therapy (Paulaitis 1983)

Avoid patient compliance problems

Employ less total drug

Minimize or eliminate local side effects.

Minimize or eliminate systemic side effects.

Chronic use leads to reduction in drug activity

Drug accumulation can be minimized during chronic dosing.

Improves efficiency in treatment

The condition can be cured or controlled more promptly and reduces fluctuation of drug levels in blood.

Bioavailability of some drugs can be increased

Limitations of Oral CRDDS

On the other hand oral CRDDS suffer from a number of potential disadvantages:

Relatively poor in-vitro in-vivo correlation and possible dose dumping.

Reduced potential for dose change or withdrawal in event of toxicity and loss of effect due to diarrhea (too fast transit time).

Reasons for Oral CRDDS

There is a clinical need to develop the CR formulations to improve drug therapy over that achieved with their conventional counterparts, especially in the following cases: (Palakodaty 1983)

Short elimination half-life(t1/2) and minimum effective concentration(MEC) required for the therapy. Shorter the half life of a drug, larger will be the fluctuations between the maximum steady state concentration (Cssmax) and the minimum steady state concentration (Cssmin) upon multiple dosing. If MEC is therapeutically required, either frequent dosing of a conventional drug product or development of a CR product is necessary.

Similarly the drugs having reasonably long elimination half life and either wide or narrow therapeutic range may also need to be formulated as CR products mainly for :

Two to three day extension and

Minimize the fluctuations between Cssmax and Cssmin with narrow therapeutic range drugs.

DESIGN OF ORAL CONTROLLED RELEASE DRUG DELIVERY SYSTEMS BASED ON MECHANISM OF RELEASE

2.3.1 Classification of controlled drug delivery systems

Continuous release drug delivery systems

Dissolution controlled drug systems

Matrix type b) Reservoir type

Diffusion controlled release systems

Matrix type b) Reservoir type

Dissolution and diffusion controlled release drug delivery systems

Ion exchange resin drug complexes

Slow dissolving salts and complexes

PH reliant formulations

Osmotic pressure controlled systems

Hydro-dynamic pressure controlled drug delivery systems

Deferred transit and constant/continuous release drug delivery systems

Altered density systems

High density

Low density

Floating

II Mucoadhesive systems

III Size dependent systems

Deferred release systems

Intestinal release drug delivery systems

Colonic release drug delivery systems

2.3.2 Mechanism of drug release

Sustained release tablets are often classified according to the mechanism of drug release. The following are the most common means used to achieve a slow controlled release of the drug from tablets (Aulton ME 2002; Robinson JR 1987 and Gwen MJ 1996).

Dissolution control

Drug transport control by diffusion

Dissolution and diffusion controlled

Erosion control

Drug transport control by convective flow

Ion-Exchange control

A) Dissolution controlled release system

Dissolution controlled extended release system can also be obtained by covering drug particles with a slowly dissolving coating. The release of the drug from such units occurs in two steps, (Lachman L 1996).

The liquid that surrounded the release unit dissolves the coating (rate liming dissolution step )

The solid drug is exposed to the liquid and subsequently dissolves.

The basic principle of dissolution control is as follows. If the dissolution process is diffusion layer controlled, where the rate of diffusion from the solid surface through an unstirred liquid film to the bulk solution is rate limiting, the flux J is given by:

J= -D (dc/dx)

Where D is the diffusion coefficient and dc/dx is the concentration gradient from the solid surface to the bulk solution. The flow rate of material is given by

Dm/dt = - (DA/h) (Cb-Cs) = KA (Cs-Cb)

Where K is the intrinsic dissolution rate constant.

Fig.2: Dissolution controlled release system (a) reservoir and (b) matrix swelling-controlled release systems

Diffusion controlled release systems

Drug release from a diffusion controlled unit mainly comprises of two steps:

The liquid that surrounds the dosage form penetrates the release unit and dissolves the drug, a concentration gradient of dissolved drug is thus established between the interior and the exterior of the release unit

The dissolved drug will diffuse in the pores of the release unit or the surrounding membrane and thus be released, or alternatively, the dissolved drug will partition into the membrane surrounding the dose unit and diffuse in the membrane.

A dissolution step is thus normally involved in the release process but the diffusion step is the rate controlling step (fig.3)

C) Bioerodible and combination of diffusion and dissolution systems

A simple expression describing release from all three of the erodible matrices can be given by

= 1- ( 1- )n

Where n=3 for a sphere, n=2 for a cylinder

Fig 3: Drug release form matrix diffusion controlled-release drug delivery systems with the drug homogenously dispersed in: (a) an erodible polymer matrix; and (b) a hydrophilic, swellable polymer matrix.

Erosion controlled release system

Drug release from an erosion system can thus be described in two steps:

Matrix material, in which the drug is dissolved or dispersed, is liberated from the  surface of the tablet.

The drug is subsequently exposed to the gastrointestinal fluids and mixed with (if the drug is dissolved in the matrix) or dissolved in (if the drug is suspending in the matrix) the fluid.

Fig.4: Schematic illustration of the mechanism of drug release from an erosion based matrix tablet

E) Osmotically controlled release systems

Controlled delivery of active agents occurs by with the utilization of osmotic pressure. This system is mainly independent of the physiological factors of gastrointestinal tract and hence can be used for systemic as well as targeted drug delivery of drugs. (Bhosle VA 2002).

Fig.5: Schematic illustration of the mechanism of drug release from an Osmotically controlled release system

F) Ion-exchange systems

Ion-exchange systems generally use resins composed of water-insoluble cross-linked polymers. The drug diffusing rate from the resin is controlled by the rigidity of the resin, diffusional path length and area of diffusion. This system is advantageous for drugs that are highly susceptible to degradation by enzymatic processes.

2.4 POLYMERS USED IN SR OR CR FORMULATIONS

Now-a-days compressed hydrophilic matrices have become most popular as modified release dosage forms for oral administration. Mainly the hydrophilic swellable polymers used to prolong the drug release, cellulose ethers in particular hydroxypropylmethyl cellulose (HPMC), sodium carboxymethyl cellulose provoked considerable interest because of its good compression characteristics, including when directly compressed, and have adequate swelling properties that allow rapid formation of an external gel layer controlling drug release. The polymers that have been used widely used for matrix tablets are xanthan gum, guar gum, ethyl cellulose(semi inert), polyethylene oxide(PEO), polyvinyl alcohol(PVA), eudragit RS 100, eudragit RL 100. Rarely used materials are polystyrene, polyvinyl acetate, cellulose acetate, fat compounds like carnuba wax, hydrogenated castor oil etc (Carmen FR 2008).

2.4.1 Functions of polymers in Oral controlled release

For the most part, oral controlled release system utilizes principle such as diffusion, dissolution, and permeation for achieving a constant rate of drug delivery. Polymers are uniquely suited as materials of construction for oral delivery systems.

2.4.2 Polymer properties that affect the release of active substances

A good understanding of polymer properties such as diffusion, solubility and structural considerations is important is important in the selection of materials to be used as system components to regulate the fluxes of active ingredients (Berner B 1991).

The flux of a species migrating through a polymeric given in the following equation.

Flux = Ã- permeability Ã- concentration difference

Diffusivity

Diffusivity is the component of permeability that accounts for the geometrical constraints encountered by the diffusing species in weaving across the polymeric film. (Jacobs 1993).

Solubility parameters

In reservoir- type systems, for both monolithic and reservoir-type systems, the addition of a second component, such as a drug solvent, to a polymer can change the strength of polymer intermolecular forces and therefore the physical properties of the polymer. The strength of the intermolecular forces of a polymer is measured by its cohesive energy density (CED). The solubility parameter of a polymer also describes intermolecular forces (Burell H 1975).The relationship between the solubility parameter δ and CED is shown in equation:

δ = (CED)0.5

2.5 TECHNIQUES USED IN THE PRODUCTION OF SUSTAINED RELEASE TABLET

Compressed tablets can be prepared mainly by using following methods (The Remington 2000)

Wet granulation method

Dry granulation method

Direct compression

2.5.1 Wet granulation

The active ingredients, diluents and disintegrant are blended well sifted through a screen of suitable fines to remove or break up lumps. The prepared binding agent solution was added with slow stirring, to the powder till the mass gets the dampness or wet mass consistency and is allowed to pass through a 6 or 8 mesh screen.

Moist materials from the wet milling step is placed on large sheets of paper on shallow wire trays and placed in drying cabinets with a circulating air current and thermostat heat control. The dried granules size is further reduced by passing them through a smaller mesh screen (no: 22/44) which gives more uniform granules. The lubricants are added as fine powders after dry granulation. It is usually screened through 60 or 100 mesh nylon cloth to eliminate lumps as well as to increase the covering power of the lubricants. The lubricants are blended with granules very gently, preferably in a blender and weighed quantities were compressed into tablets with the help of a tableting machine or tablet press.

2.5.2 Dry granulation

The active ingredients, diluents (if required) and part of lubricants are blended. One of the constituents must have cohesive property. The powdered material is then "slugged" or compressed into large flat tablets or pellets of about 1 inch diameter. The slugs are then comminuted through suitable mesh screen with the help of hand and by mills for larger quantities. The lubricants remaining is added to the granulation and blended gently and the material is compressed into tablets.

2.5.3 Direct compression

Direct compression involves compression of the tablets directly from powdered material without altering the physical nature of the material itself. It involves only two operations, in sequence, powder mixing and tableting. (James ; Swabick 1994; Wardnop J 1998)

2.6 EVALUATION OF GRANULES

( Mathew 2007, Raghuram Reddy K 2003)

2.6.1 Angle of Repose

It can be done by using funnel method. A funnel is attached to a stand and tip of the funnel is adjusted to a height of 2cm from the ground. Weighed amount of granules were taken and made to pass through the funnel slowly until the heap of granules touches the tip of the funnel. A powdered cone is formed whose diameter is measured and angle of repose is calculated by using the following formula:

Where h = height and r= radius of the powder cone.

2.6.2 Bulk Density

In this both loose bulk density (LBD) and tapped bulk density (TBD) were determined. A specified quantity of granules were taken from each formula and shaken slightly to break the agglomerates if present. Then the granules are transferred into a 10ml measuring cylinder and initial volume is noted. Then the cylinder is tapped for atleast 50times from a height of 2.5 cm with 2 seconds interval and it was continued until no further change in the volume was noted.

LBD =

TBD =

2.6.3 Compressibility Index

It can be determined by Carr's Compressibility index.

Carr's index (%) =

2.6.4 Hausner's ratio

It is the ratio of tapped density to bulk density.

Hausner's ratio =

2.7 EVALUATION OF SUSTAINED RELEASE TABLETS

In the evaluation of tablets the physical, chemical and bioavailability properties of tablets should be evaluated. The following are the different properties, which are to be evaluated. (As per USP-2000, IP and BP)

2.7.1 Weight variation

The weight variation test would be satisfactory method for determining drug content uniformity of drug distribution. In practice this test is performed by taking 20tablets, from a batch, weighed at a time and the average weight is calculated. Then the tablet is weighed individually. The percentage deviation can be determined by using the following formula.

% deviation =

2.7.2 Hardness test/ crushing strength

The hardness of tablets from each batch can be tested by using monsanto hardness tester. The tester consists of barrel containing a compressible spring held between two plungers. The upper plunger was then forced against a spring by tuning the thread bolt until the tablet fractures. The force (or) load of fracture was recorded the zero force reading was deducted from it. Oral tablets have a hardness of 4 to 10 kg/cm2 and sustained release tablets have about 10-20 kg/cm2.

Friability

It is a measure of tablet strength. The friability is determined by using Roche friabilator. The normal revolution of this friabilator is 25rpm. The friability is determined by:

F = 100Ã- (1-w/w0)

Where w0 = weight of tablets before friability

w = weight of tablets after friability

For conventionally compressed tablets, the limit is 0.5% to 1% of their weight.

2.7.4 Swelling Studies

The drug release mechanism from hydrophilic polymeric matrices involves solvent penetration, hydration and swelling of the polymer, diffusion of the dissolved drug in the matrix and erosion of the gel layer. The diffusion coefficient of drug in the dehydrated polymer matrix is low initially but increases considerably as the polymer matrix imbibes more and more water and forms a gel, as time progresses. The hydration rate of the polymer matrix, and thereby the gel formation depends considerably on viscosity, polymer proportion and to a lesser degree on polymer particle size. (Goyal A, 2009)

2.7.5 Dissolution

In-vitro tablet dissolution is found to be a standardized technique for measuring the drug release rate from a dosage form. The main role of the dissolution test could be summarized as follows

Therapeutic effectiveness is optimized at the time of product development and stability measurement.

To maintain the uniformity among the production lots, regular assessment of production quality is performed.

2.7.6 Dissolution kinetics

Three categories of dissolution test specifications for drug products are described in the guidance. Single point specifications are recommended as a routine quality control test for highly soluble and rapidly dissolving drug products. This comparison method can be employed in evaluating scale-up and post-approval changes such as manufacturing site changes, component and composition changes, equipment changes and process changes. Two-point specifications are suggested for characterizing the quality of drug product and for accepting product sameness under SUPAC-related changes.

Method used to compare dissolution data is :

Model dependent methods (zero order, first order, Higuchi's, Korsmeyer's)

2.8 FACTORS AFFECTING THE ORAL SUSTAINED-RELEASE DOSAGE FORM DESIGN (Gwen JM 1996; Vincent 1996)

2.8.1 Biological Factors

Biological half life and duration of Action

These play a vital role in the consideration of drug for controlled release. The half life (t1/2) of a drug quantitatively describes the elimination rate. Each drug has its own distinctive elimination rate, which is the sum of all elimintion processes, including metabolsm, urinary excrtion, and all other that removes drug permanently from the bloodstream. Compounds with short half lives and shows good activity are excellent candidates for sustained-release preparations, there by the dosing frequency of the drug can be reduced. But, this is limited, in that drugs which have very short half lives and may require excessively large amounts of drug in each dosage unit to maintain sustained effects, forcing the dosage form itself to becom limitingly large.

Absorption

The absorption characteristics of a drug can significantly affect its suitability as a sustained release product. The compounds that have low absorption rate constants will probably be poor candidates for sustaining systems.

Distribution

An important factor in the overall drug elimination kinetics is the distribution of drugs into tissues, because it not only lowers the concentration of circulating drug but it also can be rate limiting in its equilibration with blood and extracellular fluid.

Metabolism

Side effects

Margin of safety

Role of Diseased state

Role of circadian Rhythm

2.8.2 Physicochemical Factors

a. Dose size

For orally administered systems, there is an upper limit to the bulk size of the dose to be administered. In general a single dose of 0.5-1.0g is considered maximal for a conventional and sustained release dosage forms.

b. Ionization, PKa and aqueous Solubility

Most drugs are weak acids or bases. Since the unchanged form of a drug preferentially permeates across lipid membranes, it is important to note that the relationship between the PKa of the compound and the absorptive environment. Drugs with uncharged form are advantageous for drug permeation. For many compounds, the site of maximum absorption will also be the area in which the drug is the least soluble.

c. Partition Coefficient

Partition coefficient is generally defined as the ratio of the fraction of drug in an oil phase to that of an adjacent aqueous phase. The partition coefficient of oil-soluble drugs becomes important in determining the effectiveness of membrane barrier penetration.

2.8.3 Factors influencing drug release from matrix systems

The feasibility of formulating a drug into a controlled release drug delivery is dictated by the biopharmaceutical and pharmacokinetic aspects of drug absorption and disposition, which is a composite processes, described by the LADMER (Liberation, Absorption, Distribution, Metabolism, Elimination, and Response) system (Mathena 2004).

Fig.6: Variables influencing the kinetics and mechanism of drug release from matrix tablets

Drug Related Factors

Drug solubility

A drug with high solubility shows faster release, while poorly water soluble (< 0.01 mg/ml) often result in incomplete release because of their poor solubility and dissolution rate in the matrix. Drugs which exhibiting PH-dependent solubility, particularly in the gastrointestinal PH range are poor candidates for matrix-based oral controlled release drug delivery.

Dose/Drug content

Drug with a large dose size (>500mg) are difficult to design into a matrix-based controlled release drug delivery system because of the requirement of high amount of polymers or other matrix formers, along with general excipients.

Molecular weight and size

According to classical Higuchi's model the release rate from a matrix- based controlled release drug delivery is proportional to the square root of the diffusion coefficient, which, in turn, depends on molecular weight and diameter of the solute molecule and the viscosity of the diffusion medium. Drugs with a M.W. >500Da are thought to have poor diffusivity in hydrophilic matrices due to the constrain imposed by the aqueous gel structure.

Particle size and shape

Particle size and shape of the soluble drugs, also influences drug release, mainly because of the difference in effective surface area and thus, the intrinsic dissolution rate.

Polymer related factors

Drug release from the matrix-based controlled release drug delivery depends on drug diffusion through polymers and/or erosion of polymers.

Polymer type

Primarily silicon derivatives have been used for preparation of CR matrix systems, but now the trend has been shifted to use water-soluble or bio-erodible polymers. Drug will be released from a hydrophobic matrix through aqueous pores formed in the drug depletion zone, while drug diffuses across the hydrated gel layer in the case of hydrophilic matrix.

Formulation variables Major variables include are

Formulation Geometry

Geometric factors play an important role in regulating the drug dissolution from matrices for a fixed formulation composition. An eluting medium penetrates at the same rate to a certain depth of tablet, regardless of tablet size, where hydration, polymer relaxation, and molecular rearrangement occur, allowing the formation of gel.

From fig.10 below it can be observed that modulation of the effective surface area gives a scope to achieve the desired rates.

Fig.10: Schematic diagram showing the effect of tablet size on drug release from a hydrophilic matrix; h and H are thickness of small and large tablets, h1 and H1 are thickness after hydration, r and R are radius of small and large tablets.

Processing technique

Binding solvents can significantly influence the drug release from hydrophilic matrices. The degree of swelling and gel forming ability of a polymer changes in the presence of a solvent, however the changes in characteristics of a polymer depend on the type of solvent used during wet granulation process.

Formulation Excipients

Studies of possible interaction between excipients in the solid dosage forms are necessary because these interactions can affect the drug release and bioavailability. The presence of hydrophobic diluents can result in a more resistant gel layer, which reduces the infiltration of aqueous mediums an drug diffusion. The addition of soluble fillers enhances the dissolution of soluble drugs by decreasing the tortusity and, thus, the diffusional path length, while insoluble fillers affect the diffusion rate by blocking the surface pores of the tablet. Incorporating a surfactant may result in an increase in drug release rate through improved wetting or solubilization. Binding agents used during the granulation process coat drug particles and also changes the rheology of the gel layer, leading to retardation in release rates; however the degree of retardation is determined by the swelling and hydrating capacities of the binding agent, amount of binder added and the method of addition

Other excipients such as plasticizers may enhance drug-release rates, which may be due to increased dissolution rate of the plasticized polymer, while generally used lubricants will retard drug release rates because of their hydrophobic nature.

2.9 MATRIX TABLET

One of the least complicated approaches to the manufacture of sustained release dosage forms involves the direct compression or granulation of blends of drug, retardant material, and additives to form a tablet in which drug is embedded in a matrix core of retardant. (Lachman L 1996; Robinson JR 1996)

Materials used as retardants in matrix tablets

Insoluble inert polymers

Tablets prepared from these materials are designed to be ingested intact and not break a part in GI tract. Eg: polyethylene, poly vinyl chloride, ethyl cellulose, methyl acrylate - methacrylate copolymer.

b) Insoluble, erodable polymers

These form matrices that control release through both pore diffusion and erosion. Release characteristics are therefore more sensitive to digestive fluid composition than to the totally insoluble polymer matrix. Total release of drug from wax-lipid matrices is not possible , since a certain fraction of the dose is coated with impermeable wax films. Eg: carnuba wax in combination with stearic acid, stearyl alcohol, castor wax and triglycerides.

c) Hydrophilic polymers

This group represents non-digestible materials that form gels in situ. Drug release is controlled by penetration of water through a gel layer produced by hydration of the polymer and diffusion of drug through the swollen, hydrated matrix, in addition to erosion of the gelled layer. Eg: methyl cellulose, hydroxyl ethyl cellulose, HPMC, sodium alginate, xanthan gum, guar gum etc.

2.9.1 Types of matrix tablet

Hydrophilic Matrix Tablet

For example sodium carboxymethyl cellulose, methylcellulose, HPMC, hydroxyethylcellulose, polyethylene oxide, polyvinyl pyrrolidine, poly vinyl acetate, gelatin, natural gums etc. several commercial patented hydrophilic matrix systems are currently in use, such as synchron technology and hydro dynamically balanced system. Main advantages of hydrophilic matrix systems are ease of manufacture and excellent uniformity of matrix tablet.

Fat wax matrix tablet

The drug can be incorporated into fat wax granulations by spray congealing in air, blend congealing in an aqueous media with or without the aid of surfactants and spray drying techniques. Eg: polyethylene, ethyl cellulose, glyceryl esters of hydrogenated resins has been added to modify the drug release pattern.

c) Plastic matrix tablets

For example polyvinyl chloride, polyethylene, polyvinyl acetate, vinyl chloride copolymer, vinyllidine chloride, acrylate or methyl methacrylate polymer, ethyl cellulose, cellulose acetate, polystyrene.With plastic material(s) tablets can be easily prepared by direct compression of drug provided the plastic material can be comminuted or granulated to desired particle size to facilitate mixing with drug particles.

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