DRUG DISSOLUTION

Definition-• 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.

• 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.

2

Drug Dissolution ProcessDrug Dissolution Process

• Initial mechanical lag

• Wetting of dosage form

• Penetration of dissolution medium

• Disintegration• Deaggregation • Dissolution• Occlusion of some

particles4

Intrinsic dissolution rate (IDR), which is the rate of mass transfer per area of dissolving surface and typically has the units of mg cm-2

min-1.

IDR should be independent of boundary layer thickness and volume of solvent. Thus IDR measures the intrinsic properties of the drug only as a function of the dissolution medium, e.g. its pH, ionic strength, counters ions etc.

5

Where: m - Amount of dissolved material, kg t - Time, seconds A - Surface area of the interface between the dissolving

substance and the solvent,m2

D - Diffusion coefficient, m2/s d - Thickness of the boundary layer of the solvent at the

surface of the dissolving substance, m Cs - concentration of the substance on the surface,

kg/m3 Cb - concentration of the substance in the bulk of the

solvent, kg/m36

Application:2

7

Theories of Drug Dissolution

I. Diffusion layer model/Film Theory

II. Danckwert’s model/Penetration or surface renewal Theory

III. Interfacial barrier model/Double barrier or Limited solvation theory.

I. Diffusion layer model/Film Theory :-

• It involves two steps :-

a. Solution of the solid to form stagnant film or diffusive layer which is saturated with the drug

b. Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this is r.d.s in drug dissolution.

• The rate of dissolution is given by Noyes and Whitney:

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

= k (Cs- Cb) dc dt

Modified Noyes-Whitney’s Equation -

dC dt

Where, 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.

DAKw/o (Cs – Cb ) Vh

=

Sink conditionA Sink conditions describe a dissolution system that is sufficiently dilute so that the dissolution process is not impeded by approach to saturation of the compound of interest.

Sink conditions affect the production of the sample but not the condition of the solution upon sampling.

In vivo condition, there is no conc. 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 maintain.

13

• Dissolution rate under sink condition follow zero order dissolution rate.

Co

nc

of d

issl

ove

dru

g

Time

First order under non sink condition

Zero order dissolution

Under sink condition

14

For obtaining IVIVC sink condition can be achieved by:

1) Bathing the dissolving solid in fresh solvent from time to time.

2) Increasing the volume of dissolution fluid.3) Removing the dissolved drug by partitioning it

from the aqueous phase of dissolution fluid into the organic phase placed either above or below the dissolution fluid for e.g. hexane or chloroform.

4) Adding a water miscible solvent such as alcohol to the dissolution fluid.

5) By adding selected adsorbents to remove the dissolution drug.

• In vitro sink condition is so maintain that Cb always less than 10% of Cs.

15

HIXON-CROWELL CUBE ROOT RELATIONSHIP• Major assumptions in Noyes-Whitney relationship is that the

S.A.(A) term remains constant throughout dissolution process. This is true for some formulations, such as transdermal patches.

• However, size of drug particles from tablets, capsules and suspensions will decrease as drug dissolves.

• This decrease in size of particles changes the effective S.A.• Thus, Hixon & Crowell modified the eq to represent rate of

appearance of solute by weight in solution by multiplying both sides of volume term.

W01/3– W1/3 = kt W0 = original mass of drug W = mass of drug remaining to dissolve at time t K = dissolution rate constant

16

• This is first order dissolution rate process, for which the driving force is concentration gradient.

• This is true for in-vitro dissolution which is characterized by 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.

• Under sink conditions, if the volume and surface area of the solid are kept constant, then

dC

dt

• This represents that the dissolution rate is constant under sink conditions and follows zero order kinetics.

= K

II. Danckwert’s model/Penetration or surface renewal Theory :-

• Dankwert takes into account the eddies or packets that are present in the agitated fluid which reach the solid-liquid interface, absorb the solute by diffusion and carry it into the bulk of solution.

• These packets get continuously replaced by new ones and expose to new solid surface each time, thus the theory is called as surface renewal theory.

• The Danckwert’s model is expressed by equation

Where,

m = mass of solid dissolved

Gamma (γ) = rate of surface renewal

dCdt

=dmdt

= A (Cs-Cb). DγV

III. Interfacial barrier model/Double barrier or Limited solvation theory :-

• The concept of this theory is explained by following equation-

G = Ki (Cs - Cb)

Where,

G = dissolution rate per unit area,

Ki = effective interfacial transport constant.

S

Film boundary

Bulk solution

Cs

C

Stagnant layer

In this model it is assumed that the reaction at solid surface is not instantaneous i.e. the reaction at solid surface and its diffusion across the interface is slower than diffusion across liquid film.

therefore the rate of solubility of solid in liquid film becomes the rate limiting than the diffusion of dissolved molecules

equation : dm/dt = Ki (Cs – C ) K = effective interfacial transport rate

constant

3) Interfacial layer model

Biopharmaceutical Classification System 

  High Solubility (Dose Vol. NMT 250 mL)

Low Solubility (Dose Vol. >250 mL)

High Permeability(Fract. Abs. NLT 90%)

CLASS І

e.g. Propranolol metoprolol

CLASS II

e.g. piroxicam, naproxen

Low Permeability(Fract. Abs. <90%)

CLASS III

e.g. ranitidine cimetidine

CLASS IV

e.g. furosemide hydrochlorothiazide

 

Drug release mechanism in CDDS

Slow zero order releaseSlow first order releaseInitial rapid release followed by slow zero order releaseInitial rapid release followed by slow first order release

• Zero order kinetics

• First order kinetics

• Hixoncrowell cube-root model

• Higuchi model

• Korsmeyer peppas model

• The equation for zero order kinetics is

Qt=Qo+Kot

Qo=initial amount of drug

Qt=cumulative drug released at t

Ko=zero order release constant

t= time in hours

• It describes the system where the drug release rate is

independent of its concentration of the dissolved substance.

• A graph is plotted between the time taken on x axis and cumulative percentage of drug release on y axis and it gives straight line

Time(hours)

Cum

mula

tive %

of

dru

g r

ele

ase

• First order release equation is

logQt=logQo + Kt/2.303

Qt=cumulative amount of drug released at time t

Qo= initial amount of drug

K= first order rate constant

t= time in hours

• Here the drug release rate depends on concentration

( unimolecular reaction)

• A graph is plotted between time taken on x- axis and log cumulative percentage of drug release on y- axis will give a straight line

Time(hours)

Log %

of

dru

g r

ele

ase

• THE HIXSON-CROWELL RELEASE EQUATION IS

∛Qo- Q∛ t=KHCt

Qo=initial amount of drug

Qt= cumulative amount of drug released at time t

KHC= hixson crowell release constant

t= time in hours

• It describes the drug releases by dissolution and with

the change in surface area and diameter of particle.

• A linear plot of cube root initial concentration minus cube root of percent remaining vs time gives straight line .

• And release is dissolution rate controlled. • slope gives K value

Time (hours)

∛Q

o-∛

Qt

• Higuchi equation is

Q=[Dt/Ƭ (2A-tCs)Cst]1/2

or Q=Kt1/2

Q=cumulative drug release at time t

D= diffusion coefficient of drug in in matrix

Cs=solubility of drug in polymeric matrix

Ƭ= tortuosity of capillary system

A=total amount of drug in unit volume matrix

K= higuchi release constant

• Higuchi equation suggest s that the drug release is by diffusion

• A graph is plotted with square root of time taken on x- axis and cumulative % of drug release on y- axis

• It gives a straight line, slope gives K value

√Time ( hours)

cum

ula

tive %

of

dru

g r

ele

ase

• Korsmeyer –peppas equation is

F=Mt/M∞ = Ktn

F= fraction of drug released at time t

Mt=amount of drug released at time t

M∞=amount of drug released at infinite time

K= kinetic constant

t= time in hours

n= diffusion or release exponent

• n is estimated from linear regression of (Mt/M∞) vs time(t)

• If n= 0.45 then indicate fickian diffusion• If o.45<n<0.89 then indicates anomalous diffusion or non-fickian

diffusion• If n= 0.89 then indicates case-2relaxtaion or super case transport-2

• A graph is plotted between log time taken on x-axis and log of cumulative percentage of drug release at y-axis it gives a straight line.

Log time

cum

ula

tive %

of

dru

g r

ele

ase

• There are basically three general categories of dissolution apparatus :

1. Beaker methods

2. Open flow-through compartment system

3. Dialysis concept

Classification

1. BEAKER METHODS

to accessing therapeutic efficacy.Monitoring batch to batch consistency.High cost of in vitro dissolution test.Assessment of bioequivalence.Requirement for regulatory approval for

product marketing and is a vital component of the quality control program.

40

I.P. I.P. USPUSP B.P.B.P. E.P. E.P.

Type 1Type 1Paddle Paddle

apparatusapparatus Basket Basket apparatusapparatus

Basket Basket apparatusapparatus

Paddle Paddle apparatusapparatus

Type 2Type 2Basket Basket apparatusapparatus

Paddle Paddle apparatusapparatus

Paddle Paddle apparatusapparatus

Basket Basket apparatusapparatus

Type 3Type 3Reciprocating Reciprocating cylindercylinder

Flow through cell Flow through cell apparatusapparatus

Flow through Flow through cell apparatuscell apparatus

Type 4Type 4Flow through Flow through cell apparatuscell apparatus

Type 5Type 5Paddle over Paddle over diskdisk

Type 6Type 6 cylindercylinder

Type 7Type 7Reciprocating Reciprocating holderholder

41

Design:Vessel:- Made up of borosilicate glass semi hemispherical bottom Capacity: 1000mlShaft:- Stainless steel 316 Rotates smoothly without significance woobleBasket:- Stainless steel 316 Gold coatings up to 0.0001 inchWater bath:- Maintained at 37± 0.5˚c

42

• Dosage form contained within basket

• Dissolution should occur within Basket

• pH change by media exchange

• Uses: Capsules, tablets, delayed release, suppositories, floating dosage forms.

43

• • Drug product – Solids (mostly floating) • Monodisperse (tablets) • Polydisperse (encapsulated beads)• Agitation – Rotating stirrer – Usual speed: 50 to 100 rpm• Disadvantage– Formulation may clog to 40 mesh screen

44

45

• Dosage form should remain at the bottom centre of the vessel

• Sinkers used for floaters

• Useful for :• – Tablets• – Capsules • pH change by media

addition46

• • Drug product – Solids (mostly non floating) • Monodisperse (tablets) • Polydisperse (encapsulated beads)

• • Agitation – Rotating stirrer – Usual speed: 25 to 100 rpm

• Standard volume: 900/1000 ml

• Advantages:1. Easy to use and robust2. Ph change possible 3. Can be easily adapted to apparatus 5

• Disadvantages – Floating dosage forms require sinker – Positioning of tablet

47

48

Design:

1.vessel: cylindrical flat bottom glass vessel.

2.Agitation type: -reciprocating

-generally 5-35 rpm

3. Volume of dissolution fluids: 200-250 ml

4. Water bath: maintain at 37±0.5˚c

5. Use: extended release

49

The assembly consists of a set of cylindrical, flat-

bottomed glass vessels; a set of glass reciprocating cylinders; )stainless steel fittings (type 316 or equivalent) and screens that are made of suitable nonsorbing and nonreactive aterial(polypropelene) and that are designed to fit the tops and bottoms of the reciprocating cylinders; and a motor and drive assembly to reciprocate the cylinders vertically inside the vessels

50

• The vessels are partially immersed in a suitable water bath of any convenient size that permits holding the temperature at 37 ± 0.5 during the test.

• The dosage unit is placed in reciprocating cylinder & the cylinder is allowed to move in upward and downward direction constantly. Release of drug into solvent within the cylinder measured.

• Useful for: Tablets, Beads, controlled release formulations

• Standard volume: 200-250 ml/station

• Advantages: 1) Easy to change the pH-profiles 2) Hydrodynamics can be directly influenced by varying

the dip rate.

• Disadvantages: 1) small volume (max. 250 ml) 2) Little experience 3) Limited data

51

Apparatus 3 – Reciprocating cylinder

52

53

USP APPARATUS 4 - FLOW THROUGH CELL

54

• The assembly consists of a reservoir and a pump for the Dissolution Medium; a flow-through cell; a water bath that maintains the Dissolution Medium at 37 ± 0.5

• The pump forces the Dissolution Medium upwards through the flow-through cell.

• 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 to obtain the flow rate specified in the individual monograph.

• Collect the elute by fractions at each of the times stated.• Perform the analysis as directed in the individual

monograph

55

• Useful for: Low solubility drugs, Micro particulates, Implants, Suppositories, Controlledrelease formulations

• Variations: (A) Open system & (B) Closed system• Advantages:• 1. Easy to change media pH2. PH-profile possible• 3. Sink conditions• Disadvantages:• 1. Deaeration necessary• 2. High volumes of media• 3. Labor intensive

Tablets 12 mm Tablets 22,6 mm Powders / Granules Implants Suppositories / Soft gelatine capsules

56

APPARATUS 4 – FLOW-THROUGH CELL

57

Design1. Vessel:2. Shaft:3. Stirring elements4. Sample holder: - Disk assembly that hold the

product in such a way that release surface is parallel with paddle.

5. Paddle is directly attached over disk assembly.6. Samples are drawn away b/w the surface of

medium and top of paddle blade.7. Volume; 900ml8. Temperature; 32˚c

58

USP APPARATUS 5 - PADDLE OVER DISK

59

• Use the paddle and vessel assembly from Apparatus 2 with the addition of a stainless steel disk assembly designed for holding the transdermal system at the bottom of the vessel.

• The disk assembly holds the system flat and is positioned such that the release surface is parallel with the bottom of the paddle blade

• The vessel may be covered during the test to minimize evaporation. Useful for: Transdermal patches

• Standard volume: 900 ml• Disadvantages: Disk assembly restricts the patch size. Borosilicate Glass 17 mesh is standard (others available) Accommodates patches of up to 90mm 60

Design;1. Vessel: in place of basket cylinder is used.2. Cylinder : stainless steel 316.3.Sample: - mounted to cuprophan(inner porous

cellulosic material) an entire system is adhere to cylinder.-Dosage unit is place in cylinder and

released from outside.4. Water bath : maintain at 32±.0.5˚c Use : transdermal patches can not be cut into small

size.

61

USP APPARATUS 6 - CYLINDER

62

• Use the vessel assembly from Apparatus 1 except to replace the basket and shaft with a stainless steel cylinder stirring element

• The temperature is maintained at 32°C ± 0.5°C

• The dosage unit is placed on the cylinder with release side out

• The dosage unit is placed on the cylinder at the beginning of each test, to the exterior of the cylinder such that the long axis of the system fits around the circumference of the cylinder & removes trapped air bubbles.

• Place the cylinder in the apparatus, and immediately rotate at the rate specified in the individual monograph.

63

64

USP APPARATUS 7 – RECIPROCATING HOLDER

65

• The assembly consists of a set of volumetrically calibrated solution containers made of glass or other suitable inert material, a motor and drive assembly to reciprocate the system vertically

• The temperature is maintained at 32°C ± 0.5°C• • The dosage unit is placed on the cylinder with release side out The

solution containers are partially immersed in a suitable water bath of any convenient size that permits maintaining the temperature, inside the containers at 32 ± 0.5 For Coated tablet drug delivery system attach each system to be tested to a suitable Sample holder 66

•For Transdermal drug delivery system attach the system to a suitable sized sample holder with a suitable O-ring such that the back of the system is adjacent to and centered on the bottom of the disk-shaped sample holder or centered around the circumference of the cylindrical-shaped sample holder. Trim the excess substrate with a sharp blade.

67

Advantages of the Beaker Methods

The basket method is the most widely used procedure which confines the solid dosage form to a limited area which is essential for better reproducibility.

It is 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.

2. OPEN FLOW-THROUGH COMPARTMENT SYSTEM

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 eccentricity, vibration,

stirrer position don’t 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.

3. DIALYSIS SYSTEM

Here, dialysis membrane used as a selective barrier between fresh solvent compartment and the cell compartment containing dosage form.

It can be used in case of very poorly soluble rugs and dosage form such as ointments, creams and suspensions.

THE ROTATING FILTER METHOD

It consists of a magnetically driven rotating filter assembly and a 12 mesh wire cloth basket.

The sample is withdrawn through the spinning filter for analysis.

ROTATING FLASK DISSOLUTION METHOD

This consists of a spherical flask made of glass and supported by a horizontal glass shaft that is fused to its sides.

The shaft is connected to a constant speed driving motor.

The flask is placed in a constant temperature water bath and rotates about its horizontal axis.

ROTATING AND STATIC DISK METHODS

The compound is compressed into non disintegrating disc

Mounted – One surface is exposed to medium

Assumption – Surface area remains constant

Used to determine the intrinsic dissolution rate

Types of dosage form Release method

Solid oral dosage forms(conventional) Basket,paddle,reciprocating cylinder, or flow through cell

Oral suspension Paddle

Orally disintegrating tablets Paddle

Chewable tablets Basket,paddle,reciprocating cylinder

Transdermal-patches Paddle over disk

Suppositories Paddle, modified basket, or dual chamber flow through cell

80

FACTORS AFFECTING DISSOLUTION RATE4

Factors related to Physicochemical Properties of Drug

Factors related to Drug Product Formulation Processing Factor Factors Relating Dissolution Apparatus

Factors Relating Dissolution Test Parameters Miscellaneous factors

81

FACTORS RELATED TO PHYSICOCHEMICAL PROPERTIES OF DRUG

1) DRUG SOLUBILITY• Solubility of drug plays a prime role in controlling its

dissolution from dosage form. Aqueous solubility of drug is a major factor that determines its dissolution rate. Minimum aqueous solubility of 1% is required to avoid potential solubility limited absorption problems.

• Studies of 45 compound of different chemical classes and a wide range of solubility revealed that initial dissolution rate of these substances is directly proportional to their respective solubility.

• Ex. Poorly soluble drug :griseofulvin, spironolactone

hydrophilic drug :neomycin82

2 ) SALT FORMATION• It is one of the common approaches used to increase

drug solubility and dissolution rate. It has always been assumed that sodium salts dissolve faster than their corresponding insoluble acids. Eg.sodium and potassium salts of Peniciilin G, sulfa drugs, phenytoin, barbiturates etc.

• While in case of Phenobarbital dissolution of sodium salt was slower than that of weak acid. Same is the case for weak base drug, strong acid salts, such as hydrochlorides and sulphates of weak bases such as epinephrine, tetracycline are commonly used due to high solubility. However, free bases of chlortetracycline, methacycline were more soluble than corresponding hydrochloride salt at gastric pH values, due to common ion suppression.

83

3) PARTICLE SIZE

There is a direct relationship between surface area of drug and its dissolution rate. Since, surface area increases with decrease in particle size, higher dissolution rates may be achieved through reduction of particle size.

• Micronization of sparingly soluble drug to reduce particle size is by no means a guarantee of better dissolution and bioavailability.

• Micronization of hydrophobic powders can lead to aggregation and floatation. when powder is dispersed into dissolution medium. So, mere increase in S.A. of drug does not always guarantee an equivalent increase in dissolution rate. Rather, it is increase in the “effective” S.A., or area exposed to dissolution medium and not the absolute S.A. that is directly proportional to dissolution rate.

84

• Hydrophobic drugs like phenacetin, aspirin shows decrease in dissoln. rate as they tend to adsorb air at the surface and inhibit their wettability. Problem eliminated by evacuating surface from adsorbed air or by use of surfactants. So these drugs in-vivo exhibit excellent wetting due to presence of natural surfactants such as bile salts

• Eg. therapeutic conc. of griseofulvin was reduced to half by micronization

85

• 4) SOLID STATE CHARACTERISTICS

• Solid phase characteristics of drug, such as amorphicity, crystallinity, state of hydration and polymorphic structures have significant influence on dissolution rate.

• Anhydrous forms dissolve faster than hydrated form because they are thermodynamically more active than hydrates. Eg. Ampicillin anhydrate faster dissolution rate than trihydrate.

• Amorphous forms of drug tend to dissolve faster than crystalline materials. E.g.Novobiocin suspension, Griseofulvin.

86

• Where in the dissolution rate of amorphous erythromycin estolate is markedly lower than the crystalline form of erythromycin estolate.

• Metastable(high activation energy)polymorphic form have better dissolution than stable form

87

5) Co precipitation or Complexation

Co precipitation as well as complexation are use for enhancing the dissolution rate of drug due to,

Formation energetic amorphous drug phase or Drug being molecularly dispersed orFormation of co accervates

e.g.1) Hydroflumethiazide – PVP co precipitate has four times more solubility than crystalline drug.

2) Dissolution rate of sulfathiazole could be significantly increased by co precipitating the drug with povidone

88

FACTORS RELATED TO DRUG PRODUCT FORMULATION

1)DILUENTS• Studies of starch on dissolution rate of salicylic acid

tablet by dry double compression process shows three times increase in dissolution rate when the starch content increase from the 5 – 20 %.

• Here starch particles form a layer on the outer surface of hydrophobic drug particles resulting in imparting hydrophilic character to granules & thus increase in effective surface area & rate of dissolution

89

FACTORS RELATED TO DRUG PRODUCT FORMULATION

1)DILUENTS• Studies of starch on dissolution rate of salicylic acid

tablet by dry double compression process shows three times increase in dissolution rate when the starch content increase from the 5 – 20 %.

• Here starch particles form a layer on the outer surface of hydrophobic drug particles resulting in imparting hydrophilic character to granules & thus increase in effective surface area & rate of dissolution

Time in min.

10 20 30 40 50

100

80

60

40

20Am

t of

dis

solv

ed m

g

10% starch

5% starch

The dissolution rate is not only affected by nature of the diluent but also affected by excipient dilution (drug/excipient ratio).

90

2)DISINTEGRANTS

• Disintegrating agent added before & after the granulation affects the dissolution rate.

• Studies of various disintegrating agents on Phenobarbital tablet showed that when copagel (low viscosity grade of Na CMC) added before granulation decreased dissolution rate but if added after did not had any effect on dissolution rate.

• Microcrystalline cellulose is a very good disintegrating agent but at high compression force, it may retard drug dissolution.

• Starch is not only an excellent diluent but also superior disintegrant due to its hydrophilicity and swelling property.

91

3)BINDERS AND GRANULATING AGENTS

• The hydrophilic binder increase dissolution rate of poorly wettable drug.

• Large amt. of binder increase hardness & decrease disintegration /dissolution rate of tablet.

• Non aqueous binders such as ethyl cellulose also retard the drug dissolution.

92

• Phenobarbital tablet granulated with gelatin solution provide a faster dissolution rate in human gastric juice than those prepared using Na –carboxymethyl cellulose or polyethylene glycol 6000 as binder.

• In Phenobarbital tablet, faster dissolution rate was observed with 10% gelatin whereas decrease in dissolution rate with 20% gelatin. This was due to higher concentration which formed a thick film around tablet.

• Water soluble granulating agent Plasdone gives faster dissolution rate compared to gelatin.

93

4) Lubricants

• Lubricants are hydrophobic in nature (several metallic stearate & waxes) which inhibit wettability, penetration of water into tablet so decrease in disintegration and dissolution.

• The use of soluble lubricants like SLS and Carbowaxes which promote drug dissolution.

94

5)SURFACTANTS

• They enhance the dissolution rate of poorly soluble drug. This is due to lowering of interfacial tension, increasing effective surface area, which in turn results in faster dissolution rate.

• E.g. Non-ionic surfactant Polysorbate 80 increase dissolution rate of phenacetin granules.

95

6)WATER-SOLUBLE DYES

• Dissolution rate of single crystal of sulphathiazole was found to decrease significantly in presence of FD&C Blue No.1.

• The inhibiting effect was related to preferential adsorption of dye molecules on primary dissolution sources of crystal surfaces. They inhibit the micellar solubilization effect of bile salts on drug.

• Riboflavin tablet decrease when used FD & C Red no.3 dye in film coat

96

7)Effect of coating component on tablet dissolution

• Coating ingredient especially shellac & CAP etc. Also have significant effect on the dissolution rate of coated tablet. Tablets with MC coating were found to exhibit lower dissolution profiles than those coated with HPMC at 37ºC.

97

PROCESSING FACTORS1) METHOD OF GRANULATION

• Granulation process in general enhances dissolution rate of poorly soluble drug.

• Wet granulation is traditionally considered superior. But exception is the dissolution profile of sodium salicylate tablets prepared by both wet granulation and direct compression where the dissolution was found more complete and rapid in latter case.

• A newer technology called as APOC “Agglomerative Phase of Comminution” was found to produce mechanically stronger tablets with higher dissolution rates than those made by wet granulation. A possible mechanism is increased internal surface area of granules produced by APOC method.

98

2)COMPRESSION FORCE• The compression process influence density, porosity, hardness,

disintegration time & dissolution of tablet.

1. tighter bonding

2 . higher compression force cause deformation crushing or fracture of drug particle or convert a spherical granules into disc Shaped particle

3.& 4. both condition99

3) DRUG EXCIPIENT INTERACTION

• These interactions occur during any unit operation such as mixing, milling ,blending, drying, and/or granulating result change in dissolution.

• The dissolution of prednisolone found to depend on the length of mixing time with Mg-stearate

• Similarly as increase in mixing time of formulation containing 97 to 99% microcrystalline cellulose or another slightly swelling disintegrant result in enhance dissolution rate.

100

4) STORAGE CONDITIONS

• Dissolution rate of hydrochlorothiazide tablets granulated with acacia exhibited decrease in dissolution rate during 1 yr of aging at R.T

• For tablets granulated with PVP there was no change at elevated temperature but slight decrease at R.T.

• Tablets with starch gave no change in dissoln. rate either at R.T. or at elevated temperature.

101

1) AGITATION• Relationship between intensity of agitation and rate of

dissolution varies considerably acc. to type of agitation used, the degree of laminar and turbulent flow in system, the shape and design of stirrer and physicochemical properties of solid.

• Speed of agitation generates a flow that continuously changes the liq/solid interface between solvent and drug. In order to prevent turbulence and sustain a reproducible laminar flow, which is essential for obtaining reliable results, agitation should be maintained at a relatively low rate.

• Thus, in general relatively low agitation should be applied.

102

2) STIRRING ELEMENT ALIGNMENT

• The USP / NF XV states that the axis of the stirring element must not deviate more than 0.2 mm from the axis of the dissolution vessel which defines centering of stirring shaft to within ±2 mm.

• Studies indicant that significant increase in dissolution rate up to 13% occurs if shaft is offset 2-6 mm from the center axis of the flask.

• Tilt in excess of 1.5 0 may increase dissolution rate from 2 to 25%.

103

3) SAMPLING PROBE POSITION & FILTER• Sampling probe can affect the hydrodynamic of the

system & so that change in dissolution rate.

• For position of sampling, USP states that sample should be removed at approximately half the distance from the basket or paddle to the dissolution medium and not closer than 1 cm to the side of the flask.

• Accumulation of the particulate matter on the surface may cause significant error in the dissolution testing.

104

FACTORS RELATING DISSOLUTION TEST PARAMETERS

1)TEMPERATURE

• Drug solubility is temperature dependent, therefore careful temperature control during dissolution process is extremely important.

• Generally, a temp of 37º ± 0.5 is maintained during dissolution of oral dosage forms and suppositories. However, for topical preparations temp as low as 30º and 25º have been used

105

2) DISSOLUTION MEDIUM• Effect of dissolution air on dissolution medium Altering PH Dissolved air tends to release slowly in form of tiny air bubble that

circulate randomly and affect hydrodynamic flow pattern Specific gravity decrease leads to floating of powder which leads to

wetting and penetration problem.

• Dissolution media composition & PH Addition of Na – sulfate decrease the dissolution rate. Addition of urea increase dissolution rate.

106

• Volume of dissolution medium and sink conditions

 Volume generally 500, 900 or 1,000 ml. Simulated gastric fluid(SGF) - pH 1.2. Simulated intestinal fluid (SIF)- pH 6.8 (not exceed pH 8.0).• The need for enzymes should be evaluated case-by-case

like…. (Pepsin with SGF and pancreatin with SIF• If drug is poorly soluble, a relatively large amount of fluid

should be used if complete dissolution is to be expected.

107

• In order to minimize the effect of conc. gradient and maintain sink conditions, the conc. of drug should not exceed 10-15% of its maximum Solubility in dissolution medium selected.

• However, some insoluble drug a huge volume of dissoln. medium that would be required to maintain the sink conditions. For these, different approaches have been tried like…. 

continous flow method where fresh solvent is pumped continuously into dissolution flask at a fixed flow rate while maintaining a constant volume.

Use of non-ionic surfactant in conc. above CMC. Use of alcoholic solution (10-30%).

108

DISSOLUTION MEDIUM EXAMPLE

Water Ampicillin caps., butabarbital sodium tabs.

Buffers Azithromycin caps., paracetamol tabs.

HCL solution Cemetidine tabs.

Simulated gastric fluid Astemizole tabs., piroxicam caps.

Simulated intestinal fluid Valproic caps., Glipizide tabs.

Surfactant solution Clofibrate caps, danazol caps

DISSOLUTION ACCEPTANCE CRITRIA

• Q –Value –

• Define as a percentage of drug conten dissolved in a given time period.

DISSOLUTION ACCEPTANCE CRITRIA

STAGE No. of Dosage units tested

Acceptance criteria

S1 6 No Dosage unit is less then Q+5%

S2 6 Average of 12 dosage units (S1+S2) and no dosage unit is less then Q-15%

S3 12(6+6+12=24) Average of 24 dosage units >- And not more than two dosage units are less than Q-15% and No dosage unit is less than Q-25%

Method for comparison of dissolution profile

• Difference factor (F1 Value)-

• Define as calculate the % Difference between 2 curves at each time point and is a measurement of the relative error between 2 curves.

• f1= {[Σ t=1n |Rt-Tt|] / [Σ t=1n Rt]} ×100.

• Values range from 0 to 15

• Similarity Factor (F 2 value)-define as

measurement of similarity in % Dissolution

between two curve.

• Where Rt and Tt = cumulative % dissolved

for reference and test

• Values range from 50 to 100 113

USP SGF (simulated gastric fluid)NaCl 2.0 gPurified pepsin 3.2 gHCl 7.0 mLPurified water qs. 1000 mLMedia has a pH of about 1.2USP SIF (simulated intestinal fluid)Monobasic potassium phosphate 6.8 g in Purified

water 250 mLNaOH (0.2 N) 77 mL and Purified water 500 mLPancreatin 10.0 gAdjust with either 0.2 N NaOH or 0.2 N HCl to a

pH of 6.8 ± 0.1.Purified water qs. 1000 mL

Oral Drug Absorption

Gastric Emptying

Transit PermeationDissolution

Metabolism

In Vivo and In Vitro Relationship: Scientific Issues

• Limits to oral drug absorption

– Dissolution-limited

– Solubility-limited

– Permeability-limited

• Limits to oral drug absorption

– Dissolution-limited

– Solubility-limited

– Permeability-limited

Gastric Emptying

Transit PermeationDissolution

Metabolism

SolubilitySolubility

Dissolution Permeation

Conc Solubility

IN VITRO IN VIVO CORRELATION

In vitro-in vivo correlation

• A predictive mathematical model that describes the relationship between an in-vitro property of a dosage form and an in-vivo response.

• Key goal in development of dosage form and good understanding of in vitro and in vivo performance of dosage form

• Formulation optimization requires altering some parameters – bioavailability studies

• Regulatory guidance developed to minimize the additional bioavailability studies

120

Purpose of IVIVC• The optimization of formulations

– may require changes in the composition, manufacturing process, equipment, and batch sizes.

– In order to prove the validity of a new formulation,

which is bioequivalent with a target formulation, a considerable amount of efforts is required to study bioequivalence (BE)/bioavailability(BA).

• The main purpose of an IVIVC model– to utilize in vitro dissolution profiles as a surrogate for

in vivo bioequivalence and to support biowaivers

– Data analysis of IVIVC attracts attention from the pharmaceutical industry.

Basic approaches

• By establishing a relationship usually linear, between the in vitro dissolution and in vivo bioavailability parameters.

• By using data from previous bioavailability studies to modify the dissolution methodology.

• In vitro – in vivo correlation can be achieved using

Pharmacological correlation Semi quantitative correlation Quantitative correlation

In vitro-in vivo correlations

• Correlations based on the plasma level data

• Correlations based on the urinary excretion data

• Correlations based on the pharmacological response

DEFINITION

• USP definition “The establishment of rational relationship b/w a biological

property or a parameter derived from a biological property produced by a dosage form and physicochemical property of same dosage form”

• FDA definition

“It is predictive mathematical model describing the relationship b/w in vitro property of dosage form and a relevant in vivo response”

IMPORTANCE • Serves as a surrogate of in vivo and assist in

supporting biowaivers

• Validates the use of dissolution methods and specification

• Assist in QC during mfg and selecting the appropriate formulation

IVIVC levels

• Level A:– Point to point correlation is developed between in vitro

dissolution rate and the in vivo rate of absorption

• Level B:– Utilises statistical moment analysis and the mean in vitro

dissolution time is compared to either the mean residence time or the mean in vivo dissolution time

• Level C:– single point correlation that relates one dissolution time point to

one pharmacokinetic parameter

Multiple level C

Level A correlation

• Highest category correlation

• Represents point to point relationship

• Developed by two stage procedure

DeconvulationComparison • Purpose – define

direct relationship

0

20

40

60

80

100

120

0 20 40 60 80 100 120

% Drug Dissolved

% Drug Absorbed

Level B correlation

• Utilizes the principle of statistical moment analysis

MDT vitro is compared with MRT vivo

• No point to point correlation

• Does not reflect the actual in vivo plasma level curves

Level C correlation

• Dissolution time point (t 50%,t 90% ) is compared to one mean pharmacokinetic parameter ( Cmax ,tmax ,AUC)

• Single point correlation

• Weakest level of correlation as partial relationship b/w absorption and dissolution is established

• Useful in the early stages of formulation development

Multiple level C correlation

• It reflects the relationship b/w one or several

pharmacokinetic parameter of interest and

amount of drug dissolved at several time point of

dissolution profile

• Base on Early

Middle

Late stage

Applications

• Ensure batch to batch consistency

• Serve as a tool in the development of a new dosage form with desired in-vivo performance

• Assist in validating or setting dissolution specifications