SIPS Pharmacy collage sagar (MP)

What is dissolution
Dissolution is a process in which a solid substance solubilizes in a given solvent i.e. mass transfer from the solid surface to the liquid phase. Dissolution is RDS for hydrophilic, poorly aqueous soluble drugs like griseofulvin and spirinolactones; absorption of such drugs is often said to be dissolution rate-limited Dissolution refers to the process by which a solid phase (e.g., a tablet or powder) goes into a solution phase such as water. In essence, when a drug dissolves, solid particles separate and mix molecule by molecule with the liquid and appear to become part of that liquid. Therefore, drug dissolution is the process by which drug molecules are liberated from a solid phase and enter into a solution phase

Dissolution Rate
Rate of dissolution is the amount of drug substance that goes in solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition.

HISTORY
1855-Fick conducted studies of diffusion & proposed the first & second law of diffusion. 1855-Noyes &Whitney proposed the fundamental equation of dissolution, based on Ficks second law of diffusion. 1950- Focus of investigation carried out in pharmaceutical research field, based on dissolution.

1960-Dissolution was awarded the compendial

status, dissolution became mandatory U.S.pharmacopial requirement foe several dosage forms.

Importance of & need for dissolution testing:-

Fig.-Disintegration,deaggregation,and dissolution stages as a drug leaves a tablet or granular matrix.

Factors affecting Drug Dissolution

A. Factors relating to the physicochemical properties of drug-

1. Solubility
Solubility plays important role in controlling dissolution from dosage form. Aqueous solubility of drug is a major factor for determines dissolution rates.

2.Particle size and effective surface area of the drug

Particle size and surface area are inversely related to each
other. Two types of surface area Absolute surface area which is the total surface area of any particle. Effective surface area which is the area of solid surface exposed to the dissolution medium. Effective surface area is directly related to the dissolution rate. Greater the effective surface area, more intimate the contact between the solid surface and the aqueous solvent and faster

the dissolution.

3.Polymorphism and amorphism

When a substance exists in more than one crystalline form, the different forms are designated as polymorphs and the phenomenon as Polymorphism. Stable polymorphs has lower energy state, higher M.P. and least aqueous solubility. Metastable polymorphs has higher energy state, lower M.P. and higher aqueous solubility. Amorphous form of drug which has no internal crystal structure represents higher energy state and greater aqueous solubility than crystalline forms.

E.g.- amorphous form of novobiocin is 10 times more soluble than

the crystalline form. Thus, the order for dissolution of different solid forms of drug is

amorphous > metastable > stable

4. Salt form of the drug Dissolution rate of weak acids and weak bases can be enhance by converting them into their salt form. With weakly acidic drugs, a strong base salt is prepared like sodium and potassium salts of barbiturates and sulfonamides. With weakly basic drugs, a strong acid salt is prepared like the hydrochloride or sulfate salts of alkaloidal drugs.

B. Factors relating to the dosage forms (a)Pharmaceutical excipients 1. Diluents

Hydrophilic diluents are vary useful in promoting the dissolution of poorly water soluble hydrophobic drugs by forming a coat onto the hydrophobic surface of drug particles and rendering them hydrophilic. Diluents are either organic or inorganic. Example: Starch, lactose MCC Among the inorganic diluents, dicalcium phospahte is most common One classic example of drug- diluent intercation resulting in poor bioavailability is that of tetracycline and DCP The cause is formation of divalent calcium complex which is poorly soluble and thus unabsorbable

2.Binders or granulating agent

These materials are used to hold the powder together to form granules or promote cohesive compact for directly compressed material and to ensure that the tablet remains intact after compression Examples: Starch, cellulose derivatives, acacia, PVP Hydrophilic binder show better dissolution profile with poorly water soluble drugs by imparting the hydrophilic properties to the granule surface. Proportion of the binder is very critical.

Large amount of such binders increases the hardness and

decreases the disintegration/ dissolution rates of formulation Non-aqueous binders like ethyl cellulose also retarded drug

dissolution rate

3. Disintegrating Agents
These agents overcomes the cohesive strength of tablet
and breakup them up on contact with water which is an important prerequisite to tablet dissolution. Almost all the disintegrating agents are hydrophilic in nature . A decrease MCC is a in the amount of disintegrant can very good disintegrant but at high significantly lower bioavailability.

compression forces, it may retard the dissolution

4. Lubricants
These agents are improve the flow properties of granules or
powder and also reduce the adhesion of tablet granules or tablet material on to the die wall and punches.

The commonly used lubricants are hydrophobic in nature

and known to inhibit wettability, penetration of water into the tablet and their disintegration and dissolution.

This is because the disintegrant gets coated with the

lubricant if blended simultaneously which however prevented by adding the lubricants in the final stage.

The best alternative is use of soluble lubricants like SLS and

carbowax which promote drug dissolution.

5. Colorants
Even a very low concentration of water-soluble dye can have an inhibitory effect on dissolution rate of several crystalline drugs. The dye molecules get adsorbed onto the crystal faces and inhibits drug dissolution

Ex: Brilliant blue retards dissolution of sulfathiazole.

6. Crystal Growth inhibitors

In addition to maintain the initial physical properties of

drug in suspension, crystal growth inhibitors like PVP and

PEG inhibits the conversion of high energy metastable polymorph into stable, less soluble polymorphs

7. Coating
In general, the deleterious effect of various coating on drug dissolution from a tablet dosage form is in the

following order
Enteric coating> sugar coat> non-enteric film coat. The dissolution profile of certain coating material

change om aging e.g. shellac coated tablet, on prolong

storage, dissolve more slowly in the intestine. This can be prevented by incorporating little PVO in the coating.

8. Buffers
Buffer are sometime useful in creating the right atmosphere for drug dissolution as we observed for

buffered aspirin tablet

However certain buffer systems containing potassium cations inhibits the drug absorption as we seen with Vit.

B12 and sulfonamides.

(b)Manufacturing variables
1. Method of granulation
The wet granulation process is the most conventional

technique in the manufacture of tablets and yield tablet

dissolve faster than those made by other granulation. The method of direct compression has been utilized to yield tablets that dissolve faster rate.

2. Compression Force
Higher compression force increase the density and
hardness of tablet, decreases porosity and hence penetrability of the solvent into the tablet, retard wettability by forming a firmer and more effective sealing layer by the lubricant, and in many case, promotes tighter bonding

between the particles.

On the other hand higher compression forces cause deformation, crushing or fracture of drug particles into smaller ones or convert a spherical granules into disc shaped particle with a large increase in the effective surface area.

This results in an increase in the dissolution rate of the tablet. A combination of both conditions may be possible.

In short, the influence of compression force on the

dissolution rate is difficult .

3. Intensity of packing of capsule content

Like the compression force for the tablet, packing density is case of capsule dosage form can either inhibit or promote dissolution. Diffusion of GI fluids into the tightly filled capsules

creates a high pressure within the capsule resulting in

rapid bursting and dissolution of contents. When the capsules filled with finer particles and intense packing have poor drug release and dissolution rate due to dcrease in pore size of the compact and poor penetrabilty of GI fluids

C. Factors relating to apparatus and test parameters

1. Temperature
When the temperature is increases also improve the

drug dissolution
At the same the diffusion coefficient increase due to thermal diffusion From the equation dc/dt= DS/h (Cs-C) we can say the dissolution rate is directly proportional to the dissolution constant IP prescribed the body temperature 370C +for the dissolution study

2. Agitation
If the rate of agitation increases, Cs increases and the thickness of the diffusion layer decrease. The net result is the enhanced dissolution. IP prescribed a motor with agitation condition ranging from 25 to 150 RPM (normally 100)

2. Dissolution medium, pH
The nature of dissolution medium influence the dissolution
rate. IP prescribed different media for different product.

Example: Tetarcyclin tab-0.1 N HCL (1000 ml)

Lithium carbonate tab.-Water (900 ml) Surface Tension,Viscosity of dissolution medium of Deaeration

of dissolution medium affect the dissolution rate

Factors contributing to the faster dissolution rate of a drug dispersed in eutectic are :Reduction of particle size. An increase in drug solubility Absence of aggregation and agglomeration between the fine crystallites of pure drug.

Excellent wettability and dispersibility of a drug as the

encircling soluble carrier readily dissolves and causes the water to contact and wet the particles.

Crystallization of the drug in metastable form after

solidification from the fused solution which has high solubility

It provides:
Data, good and bad formulations. Changes in production process.

Acts as device for pharmaceutical scientist in product

development, Q.C. & research application. Essential preformulation tool, step towards IVIVC . Assessment of the batch-to-batch quality of a drug product

Assessment
formulation

of

the

physical

stability

of

the

Theories of Drug Dissolution.

1.Diffusion layer model/Film Theory.

2.Danckwerts model/Penetration or surface

renewal Theory. 3. Interfacial barrier model/Double barrier or Limited solvation theory.

1. Diffusion layer model/Film Theory :In this two steps are usually involved 1. Solution of the solid to form a thin film or layer at the solid/liquid interface called as the stagnant film or diffusion layer which is saturated with the drug. This step is usually rapid 2. Diffusion of the soluble from the stagnant layer to the bulk of the solution; this step is slower and is therefore the rate limiting step in drug dissolution

 The rate of dissolution is given by Noyes and Whitney:- This

explain the rate of drug dissolution and based on Ficks second law dc/dt=K(Cs-Cb) Where, dc/dt= dissolution rate of the drug, K= dissolution rate constant, Cs= concentration of drug in stagnant layer, Cb= concentration of drug in the bulk of the solution at time t.

Modified Noyes-Whitneys Equation Based on Ficks first law

Where, dC/dt = rate of drug dissolution. D= diffusion coefficient of drug. A= surface area of dissolving solid. Kw/o= water/oil partition coefficient of drug. V= volume of dissolution medium. h= thickness of stagnant layer. (Cs Cb )= conc. gradient for diffusion of drug.

This is first order dissolution rate process, for which the driving force is concentration gradient (Cs-Cb). Under such a situation dissolution said to be non sink conditions. The in-vivo dissolution is rapid as sink conditions are maintained by absorption of drug in systemic circulation i.e. Cb=0 and rate of dissolution is maximum. Thus under in vivo conditions, there is no concentration build up in the bulk of the solution and hence no retarding effect on the dissolution rate of the drug i.e. Cs>> Cb and sink condition are maintained. Under sink conditions, if the volume and surface area of the solid are kept constant, then

Represents that the dissolution rate is constant under sink conditions and follows zero order kinetics.

To obtain good in vitro- in vivo dissolution rate correlation, the

in vitro dissolution must always be carried under sink

condition. This can be achieved by: Bathing the dissolving solid in fresh solvent from time to

time.
To increasing the volume of dissolution fluid. Removing the dissolved drug by partitioning it from the aqueous phase of the dissolution fluid into an organic phase placed either above or below the dissolution fluid for example, hexane or chloroform. Adding a water miscible solvent such as alcohol to the dissolution fluid or By adding selected adsorbent to remove the dissolved drug.

Dissolution rate under non-sink and sink conditions.

Hixson-Crowells cubic root law of dissolution takes into account the particle size decrease and change in surface area, W01/3 W1/3 = Kt
Where, W0=original mass of the drug, W=mass of drug remaining to dissolve at time t, Kt=dissolution rate constant.

2.Danckwerts model/Penetration or surface renewal Theory

Danckwert did not approve of the existence of a stagnant layer and suggested that turbulence in the dissolution medium exist at the solid \ liquid interface. As a result, the agitated fluid consisting of macroscopic mass of eddies or packets reach the solid \ liquid interface in a random fashion due to eddy currents, absorb the solute by diffusion and carry it to bulk. Such solute containing packets are continuously replaced with new packets of fresh solvent due to which the drug concentration at the solid \ liquid interface never reaches Cs and has a lower limiting value of Ci. Since the solvent packets are exposed to new solid surface each time, the theory is called surface renewal theory.

 The Danckwerts model is expressed by equation :

Where, m = mass of solid dissolved, = rate of surface renewal.

3.Interfacial barrier model/Double barrier or Limited salvation theory :The diffusion layer model and the Danckwerts model were based on two assumptions: 1. The rate determining step that control dissolution is the mass transport. 2. Solid solution equilibrium achieved at the solid \ liquid interface. According to the interfacial barrier model, an intermediate concentration can exist at the interface as a result of salvation mechanism and is a function of solubility rather than diffusion. When considering the dissolution of a crystal, each of the crystal will have a different interfacial barrier. Such concept is give by the following equation: G = Ki (Cs - Cb) Where, G = dissolution rate per unit area, Ki = effective interfacial transport constant.

In-vitro dissolution testing models.

Alternative determination . to in vivo bioavailability

Dissolution testing Official in pharmacopeias.

Quantify the extent of release of drug.

Routinely used by Q.C. and R&D. Q.C. Evaluate batch consistency.

R&D

Prediction of drug release.

Factors to be considered while designing of a dissolution test

1.Factors relating to the dissolution apparatus:Design of the container. Size of the container. Shape of the container.

Nature of agitation.
Speed of agitation.

2.Factors relating to the dissolution fluid:Composition. Viscosity.

Volume.
Temperature. Sink condition.

3.Process parameters:Method of introduction of dosage form.

Sampling techniques.
Changing the dissolution fluid.

Classification of dissolution apparatus

There are basically three general categories of dissolution apparatus : 1. Beaker methods (closed-compartment apparatus).

It is a limited volume apparatus operating under non sink

condition. The dissolution fluid is restrained to the size of the container, e.g. rotating basket and rotating paddle apparatus.

2.Open-compartment apparatus.

(continuous

flow-through)

In this dosage form is contained in a column which is

brought in continuous contact with fresh dissolution

medium .It operates under sink condition, e.g. flow through cell apparatus. 3.Dialysis system. For very poorly aqueous soluble drugs sink condition would be difficult to maintain and it require large volume of dissolution fluid.

Various Official Dissolution Test apparatus

Type Type I Type II Type III Type IV Type V I.P. paddle apparatus basket apparatus USP basket apparatus paddle apparatus Reciprocating cylinder flow through cell apparatus Paddle over disk cylinder reciprocating holder B.P. basket apparatus paddle apparatus flow through cell apparatus E.P. paddle apparatus basket apparatus flow through cell apparatus

Type VI
Type VII

Dissolution apparatus & type of dosage form

DOSAGE FORM APPARATUS (USA) Solid dosage form (IR,MR Products) Type 1-basket Type 2-paddle Bead type MR dosage form Type3-Reciprocating cylinder

MR release dosage form that contain Type4-flow through cell apparatus active ingredients with limited solubility Soft gelatin capsules, suppositories, Type 3 & 4 poorly soluble drugs Transdermal dosage form Type5-Paddle over disk Type6-cylinder Non disintegrating oral modified Type7-reciprocating holder dosage form as will as traditional dosage form

1.BEAKER METHODS
Rotating Basket Apparatus (Apparatus 1)-

1.

Closed-compartment. Beaker type apparatus.

Consist of cylindrical transparent covered borosilicate glass vessel with hemispherical bottom. Capacity 1 lit, an inside diameter of 98-106 mm A water-bath set to maintain the dissolution medium at 36.5 to 37.5

2.
3. 4. 5.

A cylindrical Basket made of #22 mesh to hold dosage form .

A motor with a speed regulator capable of maintaining the speed of rotation of the basket within 4 per cent The motor is fitted with a stirring element which consists of a drive shaft and blade forming a basket.

1.BEAKER METHODS
Rotating Basket Apparatus (Apparatus 1) The shaft is positioned so that its axis is within 2 mm of the axis of the vessel and the lower edge of the blade is 23 to 27 mm from the inside bottom of the vessel. Metal parts like basket & shaft are made up of S.S. 316 . The basket may be plated with a 2.5mm (0.0001 inch )layer of gold for use with acidic media

6.

7.

Rotating Paddle Apparatus (Apparatus 2)-

1. 2. 3.

Basket is replaced with a stirrer. Small, loose, wire helix attached to dosage form, to prevent floating.

Distance: Axis is NMT 2mm from vertical axis of vessel. The paddle, blade and shaft may be coated with a suitably inert coating.

PROCEDURES

Place the stated volume of the dissolution medium in the vessel. Equilibrate the dissolution medium to 37o.5 c Place 1 tablet or 1 capsule in the apparatus. Operate the apparatus
Within the time interval, withdraw a specimen from zone midway between the surface of the dissolution medium and the top of the rotating basket or blade , not less than 1cm from vessel wall.

Replace the aliquots withdrawn for analysis with equal

volume of dissolution medium at 37 c.

Rotating Paddle Apparatus (Apparatus 2)INTERPRETATION Stage S1 S2 Number Tested 6 6 Acceptance Criteria each unit is not less than D+5% average of 12 units (s+s) is equal to or greater

than D, and no unit is less than D-15%.

S3 12 average of 24 units (s+s+s) is equal to or greater than D, and no unit is more than 2 unit are less than D-15%, and no unit is less than D25%.

Dissolution testing limit

Level No. Acceptance criteria tested

L1

No individual value lies outside each of the stated ranges and no

individual value is less than the stated amount at the final test time.

L2

The average value of the 12 units (L1 + L2) lies within each of the

stated ranges and is NLT the stated amount at the final test time;
none is more than 10 % of labelled content outside each of t.he stated ranges

L3

12

The average value of the 24 units (L1 +L2 + L3) lies within each of
the stated ranges, and is NLT the stated amount at the final test time; NMT 2 of the 24 units are more than 10 % of labelled content below the stated amount at the final test time; and or more than 20 % of labelled content below the stated amount at the final test time

Both The USP Apparatus 1 And 2 Share Some Common Advantages And Disadvantages.
Advantages

include:

Widely Accepted Apparatus For Dissolution Test, Apparatus Of First Choice For Solid Oral Dosage Forms, Standardized, Easy To Operate, Robust And Broad Experience. Disadvantages include: Limited Volume Of The Dissolution Media, Simulation Of The Gastrointestinal Transit Is Not Possible And Hydrodynamic Conditions Are Not Known. Dissolution Results Obtained With Usp Apparatuses 1 And 2 May Be Significantly Affected By Shaft Wobble, Location Centering, And Coning

Basket and paddle type dissolution apparatus

Sinkers
a small loose piece of nonreactive material can be used. not more than a few turns of wire helix may be

attached to dosage units that would otherwise float.

other validated sinker devices may be used

The Reciprocating Cylinder Apparatus (Apparatus 3)The assembly consists of A set of cylindrical, flat-bottomed glass vessels;

A set of glass reciprocating cylinders;

An inert fittings (stainless steel type 316 or other suitable material),

Screens that are made of suitable nonsorbing and nonreactive

material and that are designed to fit the tops and bottoms of the reciprocating cylinders.

A motor and drive assembly to reciprocate the cylinders

vertically inside the vessels. The reciprocation rate to be selected and maintained at the

specified dip rate given in the individual monograph within 5%.

Useful for Tablets Beads Controlled release formulations USP Apparatus 3 offers advantages like Programmed for dissolution in various media for various time, Prevents the cone formation May start at pH 1 and then pH 4.5 and then at pH6.8 and Attempts to mirror pH changes and transit times in the GI tract. But it has got some disadvantages too, i.e. Disintegrating dosage forms show too low results, Surfactants cause foaming and Volume of dissolution media is too small

PROCEDURE:
Place the stated volume of the dissolution medium in each vessel . Equilibrate the dissolution medium to 37 + 0.5 Place 1 dosage-form unit in each of the six reciprocating cylinders. Operate the apparatus During the upward and downward stroke, the reciprocating cylinder moves through a total distance of 9.9 to 10.1 cm Within the time interval specified withdraw a portion of the solution under test from a zone midway between the surface of the dissolution medium and the bottom of each vessel. Perform The analysis as directed in the individual monograph.

Apparatus 4 Flow through cell

The assembly consists of A reservoir A pump for the pumping of Dissolution Medium; A flow-through cell; A water bath that maintains the Dissolution Medium at 37 0.5C The pump has delivery range between 240 and 960 mL per hour, with standard flow rates of 4, 8, and 16 mL per minute. It must deliver a constant flow (5% of the nominal flow rate); the flow profile is sinusoidal with a pulsation of 120 10 pulses per minute. Useful for: Low solubility drugs Rapid degradation Implants

Advantages: No limitation regarding the volume of media used for the dissolution test, Suitable for low soluble drugs, Gentle hydrodynamic conditions, Simulation of the gastrointestinal transit,Suitable for special dosage forms such as powder and granules, implants. Disadvantages includes: Pump precision may influence the results and

Tablets 12mm Tablets 22 mm Powders/Granules

Implants

Suppositories /soft gel cap

Procedure

Place the glass beads into the cell specified in the

monograph. Place 1 dosage form unit on top of the beads. Assemble the filter head and fix the parts together by means of a suitable clamping device.

Introduce by the pump the dissolution medium

warmed to 37 + 0.5 through the bottom of the cell. Collect the eluate by fractions at each of the times stated. Perform the analysis as directed in the individual monograph.

5) Paddle-over-Disk Apparatus (USP Apparatus 5)

Modification of Apparatus 2. The paddle and vessel assembly from apparatus 2 with the addition of stainless steel disk assembly. Here, stainless steel disk designed for holding transdermal system at the bottom of the vessel.
The disk/device should not , react with, or interfere with the specimen being tested. The disk holds the system flat and is positioned such that the release surface is parallel with the bottom of the paddle blade. Useful for: Transdermal patch Ointments Floaters Emulsions Bolus

Advantages Standard equipment (paddle) can be used, only add a stainless steel disk assembly. Disadvantages Disk assembly restricts patch size.

PROCEDURE
Place the stated volume of dissolution medium in the vessel assemble the apparatus without the disk assembly and equilibrate the medium to 32 + 0.5C Apply the transdermal system disk assembly. The system may be attached to the disk by a suitable adhesive. Place the disk assembly flat at the bottom of the vessel with the release surface facing up and parallel to of the paddle blade and surface of the dissolution medium. Operate the apparatus At each sampling time interval, withdraw a sample from a zone midway between the surface of the dissolution medium and the top of the blade, not less than 1 cm from the vessel wall. Perform the analysis on each sampled aliquot as directed in the monograph.

Cylinder method (Apparatus 6)

The vessel assembly from apparatus 1 except to replace the basket and shaft with a stainless steel cylinder stirring element and to maintain the temperature at 32 + 0.05C The dosage unit is placed on the cylinder at the beginning of each test. The distance between the inside bottom of the vessel and the cylinder is maintained at 25 + 2 mm during the test. Useful for: Transdermal patches

PROCEDURES Place the stated volume of the dissolution medium in the vessel. Equilibrate the dissolution medium to 32 + 0.5C Prepare the test system prior to test as follows. Remove the protective liner from the system and place the adhesive side on a piece of cuprophan. Cuprophan covered side down, on a clean surface, and apply a suitable adhesive to the exposed cuprophan borders. Dry for 1 minutes. Press the cuprophan covering to remove trapped air bubbles. Place the cylinder in the apparatus and immediately rotate at the rate specified Within the time interval specified, withdraw a quantity of dissolution medium for analysis from a zone midway between the surface of the dissolution medium and the top of the rotating cylinder, not less than 1 cm from the vessel wall. Perform the analysis as directed in the individual monograph.

Reciprocating Disc Apparatus(Apparatus7)The assembly consists of a set of calibrated solution containers, a motor and drive assembly to reciprocate the system vertically. Various type of sample holder are used. Useful for: Transdermal patches Solid dosage forms Small volumes.

Advantages of the Beaker Methods.

Most widely used procedure.
Which confines the solid dosage form to a limited area which is essential for better reproducibility. Advantageous for capsules as they tend to float at the surface thus minimizing the area exposed to the dissolution fluid.

Limitation of the Beaker Methods:Clogging of the basket screen by gummy particles. Tendency of the light particles to float. Sensitivity of the apparatus to variables such as vibration, eccentricity, etc. Rapid corrosion of the SS mesh in presence of HCl. Sensitivity of the apparatus to any slight changes in the paddle orientation.

Non-reproducible position of the tablets at the bottom of the flask.

OPEN-COMPARTMENT(continuous flow-through) APPARATUS The dosage form is contained in a small vertical glass column with built in filter through which a continuous flow of the dissolution medium is circulated upward at a specific rate from an outside reservoir using a peristaltic or centrifugal pump. Dissolution fluid is collected in a separate reservoir. E.g. lipid filled soft Gelatin capsule

Advantages.
No stirring and drug particles are exposed to homogeneous, laminar flow that can be precisely controlled. All the problems of wobbling, shaft centricity, vibration, stirrer position dont exist.

There is no physical abrasion of solids.

Perfect sink conditions can be maintained.

Disadvantages.
Tendency of the filter to clog because of the unidirectional flow. Different types of pumps, such as peristaltic and centrifugal, have been shown to give different dissolution results. Temperature control is also much more difficult to achieve in column type flow through system than in the conventional stirred vessel type.

In vitro - In vivo Correlation (IVIVC)

In recent years, the concept and application of the in vitro-in vivo correlation industry, (IVIVC) for pharmaceutical and regulatory dosage forms have been a main focus of attention of pharmaceutical sectors. academia,

The main objective of an IVIVC is to serve as a

surrogate for in vivo bioavailability and to support biowaivers. IVIVCs could also be employed to establish dissolution specifications and to support and/or validate the use of dissolution methods

DEFINITIONS
United State Pharmacopoeia (USP) definition The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.

Food and Drug Administration (FDA) definition IVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.

1. Quality control procedures 2. Tablet or Capsule disintegration 3. Instrumental methods of analysis 4. Dissolution Rate Test The rate of drug absorption Dissolution Profile Parameters In Vivo Performance Proper In-Vitro Dissolution Rate - Correlate the data with the bioavailability

INVITRO DISSOLUTION TESTING

1.Apparatus, 2. Speed of Rotation, 3.Temperature, 4.pH, 5.Samples, 6.Dissolution Media, 7.Sampling time 8. Percent coefficient

CORRELATION LEVELS
Five correlation levels have been defined in the IVIVC FDA guidance . The concept of correlation level is based upon the ability of the correlation to reflect the complete plasma drug level-time profile which will result from administration of the given dosage form .

Level A Correlation
This level of correlation is the highest category of correlation and represents a point-to-point relationship between in vitro dissolution rate and in vivo input rate of the drug from the dosage form. Generally, percent of drug absorbed may be calculated by means of model dependent techniques such as Wagner-Nelson procedure or Loo-Riegelman method or by model-independent numerical deconvolution. These techniques represent a major advance over the singlepoint approach in that these methodologies utilize all of the dissolution and plasma level data available to develop the correlations

Level B Correlation
A level B IVIVC utilizes the principles of statistical moment analysis. In this level of correlation, the mean in vitro dissolution time (MDTvitro) of the product is compared to either mean in vivo residence time (MRT) or the mean in vivo dissolution time (MDTvivo).

Level C Correlation
In this level of correlation, one dissolution time point (t50%, t90%, etc.) is compared to one mean pharmacokinetic parameter such as AUC, tmax or Cmax This is the weakest level of correlation as partial relationship between absorption and dissolution is established. Level C correlations can be useful in the early stages of formulation development when pilot formulations are being selected.

Multiple Level C Correlation

A multiple level C correlation relates one or several pharmacokinetic parameters of interest (Cmax, AUC, or any other suitable parameters) to the amount of drug dissolved at several time points of the dissolution profile. A multiple Level C correlation should be based on at least three dissolution time points covering the early, middle, and late stages of the dissolution profile.

Level D Correlation
Level D correlation is a rank order and qualitative analysis and is not considered useful for regulatory purposes. It is not a formal correlation but serves as an aid in the development of a formulation or processing procedure