Overview Of Dissolution

Testing As Per USFDA

SUBMITTED TO : Dr. JAMSHED HANEEF

SUBMITTED BY : SHAIK ABDHUL RAHEEM
M PHARM 2nd SEM PHARMACEUTICAL ANALYSIS
Content

1. Introduction
2. Mechanism of dissolution
3. Factors affecting dissolution
4. Dissolution test apparatus as per USP
5. Case study
 ?
[Link] is dissolution

 Dissolution is defined as the process by which solid substances enters in solvent to yield a
solution. Stated simply, dissolution is the process by which a solid substance dissolves.
 Fundamentally, it is controlled by the affinity between the solid substance and the
solvent.
2. Why we need to perform dissolution test ?
 Measures the extent and rate of solution from a dosage form.
 Dissolution of drug is important for prediction of bioavailability and therapeutic
effectiveness.
 It is used to assure batch-to-batch quality, to provide process control.
[Link] is dissolution rate ?
 Dissolution Rate: is the amount of drug substance that goes in solution per unit time
under standardized conditions of liquid/solid interface, temperature and solvent
composition.
 MECHANISM OF DISSOLUTION
1. Diffusion Layer Model (Film Theory)
2. Danckwert’s Model (Penetration or Surface Renewal Theory)
3. Interfacial Barrier Model (Double Barrier Mechanism OR Limited Solvation Theory)
[Link] Layer Model (Film Theory)
 Also called 'film theory'.
 Formation of a thin film at the interface, called as stagnant layer.
 2 steps are involved:
Step 1: Solution of the solid to form a thin film or layer at the solid/liquid interface called
as stagnant film or diffusion layer which is saturated with the drug this step is usually
rapid (instantaneous).
Step 2: Diffusion of the soluble solute is from the stagnant layer to the bulk of the
solution. This step is slower . dc/dt=k( Cs-Cb)
Or
 This step is rate determining step in this dC/dt =DAKw/o (Cs-Cb)/Vh
where,
film theory. dc/dt=rate of drug dissolution
K=dissolution rate constant
Cs=concentration of drug in stagnant layer
Cb= concentration of drug in bulk of solution at
time t
Cs-Cb=concentration gradient for diffusion of
drug
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
  Danckwert’s Model (Penetration or Surface Renewal Theory)

He ruled out the existence of stagnant layer. During digestion, stomach is in motion. In
that motion there is turbulence of dissolution medium.
In such turbulence there is no chance of formation of stagnant layer.
According to this model, constantly renewed macroscopic packets of solvent (eddies)
reach the solid surface and absorb the molecule of solute delivering them to the bulk
solution.
Where
m = mass of solid dissolution
r = rate of surface renewal (or the interfacial tension)
v= volume of dissolution medium
dc/dt =rate of drug dissolution
A=surface area of the dissolving solid
Cs=concentration of drug in stagnant layer(film)
Cb = concentration of drug in bulk of solution at time “t”
Cs-Cb= concentration gradient for diffusion of drug
D= diffusion coefficient
 [Link] Barrier Model (Double Barrier or Limited
Solvation Theory)

The Interfacial Barrier Model (limited solvation theory) proposed by Wilderman (1909)
considered that interfacial transport, rather than diffusion through the film, is the
limiting step due to a high activation energy level for the former. According to this model,
an intermediate concentration can exist at the interface as a result of solvation
mechanism and is a function of solubility rather than diffusion.
G = K (Cs – Cb)
Where
G=Dissolution per unit area
K= is the effective interfacial transport constant
 FACTORS AFFECTING DISSOLUTION

Factors related to drug Factors related to the

Factors related to the product formulation dissolution test parameters
physicochemical properties
of the drug

1. Granulating agent 1. Tilt

and binders 2. Vibration
1. Solubility 2. Disintegrants and 3. agitation intensity
2. Particle size diluents 4. Temperature
3. Polymorphism 3. Lubricants 5. Dissolution medium
4. Salt formation 4. Salt formation 6. Viscosity of the
dissolution medium
 Particle size on dissolution
According to Nernst –Brunner theory , the dissolution rate is directly proportional to the surface area of the
drug.
Particle size decreases surface area will increase
Superior dissolution rate observed after micronization of certain sparingly soluble drugs
Ex:
1. Griseofulvin
2. Chloramphenicol
3. Tetracycline
4. Salfadiazine
5. Norethisterone acetate
 Polymorphism
Many drugs are able to crystallize in several forms. having a different energy, and there
by differing physicochemical properties.
Melting point
Solubility
Density
Stable polymorph having least aqueous solubility of the drug.
Ex: Riboflavin
The polymorphic form III of riboflavin is 20 times more soluble than form I.
 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.
E.g. sodium and potassium salts of Penicillin G, phenytoin, barbiturates, tolbutamide etc.

 hydrochlorides and sulphates of weak bases are commonly used due to high solubility.
E.g. epinephrine, tetracycline.
  factors related to Drug product formulation

 Granulating and binders

Solvang and Finholt have shown that Phenobarbital tablets, granulated with gelatin
solution, provide faster dissolution rate in gastric fluid than those prepared using sodium
carboxymethylcellulose or polyethylene glycol 6000 as a binder.
This observation was attributed to the fact that gelatin improve hydrophilic
characteristics to the hydrophobic drug surface.
 Disintegrants and Diluents
manufacturing of Phenobarbital tablets Copagel (low viscosity grade of sodium carboxy
methylcellulose).
The effect on the dissolution rate of tablets by the addition of disintegrants, before and
after granulation, was assessed.
When added before granulation, Copagel gave tablets with a remarkably slow dissolution
rate. However, when added after granulation, Copagel did not result in lowering the
dissolution rate.
 Lubricants
The nature, quality, and quantity of lubricants added can affect the dissolution rate.
magnesium stearate, a hydrophobic lubricant, tends to retard the dissolution rate of
salicylic acid tablets, whereas sodium lauryl sulfate enhances dissolution.
due to its hydrophilic character.
factors related to the Dissolution test parameters

 Tilt
USP states that the axis of the stirring element shall not deviate more than 0.2 cm from
the axis of the dissolution vessel, which defines centering of the stirring shaft to within ±2
mm.
excess of 1.5 (degrees) may increase dissolution rates using Method 2 from 2% to 25%
 Agitation intensity
The degree of agitation, or the stirring conditions, is one of the most important variables
to consider in dissolution.
thickness of the diffusion layer is inversely proportional to agitation speed
 Temperature
Because drug solubility is temperature-dependent, careful temperature control during
the dissolution process is very important and should be maintained within 0.5°C.
Generally, a temperature of 37°C is always maintained during dissolution determinations.
 VIBRATION
The excessive vibration of dissolution apparatus increases dissolution rates.
 pH OF DISSOLUTION MEDIUM
Weak acids, dissolution rate increases with increase in PH where as for weak bases,
increase with decrease in pH.
 COMPRESSION FORCE
The compression process influence density, porosity, hardness, disintegration time &
dissolution of tablet.
The curve obtained by plotting compression force versus rate of dissolution can take one
of the 4 possible shapes
 Classification of dissolution apparatus
Type of USP I.P B.P E.P
apparatus

Type 1 Basket apparatus Paddle Basket apparatus Paddle apparatus

apparatus

Type 2 Paddle apparatus Basket Paddle apparatus Basket apparatus

apparatus

Type 3 Reciprocating cylinder Flow through cell Flow through cell

Type 4 Flow through cell
Type 5 Paddle over disk

type 6 Rotating cylinder

Type 7 Reciprocating holder
 Dissolution apparatus USP
Apparatus Design Used
TYPE 1 Vessel: -Made of borosilicate glass. 1. Tablets
Rotating basket Semi hemispherical bottom 2. capsules,
Capacity 1000mI 3. delayed release suppositories,
shaft: Stainless steel
Rotates smoothly without and floating dosage forms
significance wobble(100 rpm)
Speed regulator
Water bath:-Maintained at 37±0.50°C
Dosage form is kept in basket

TYPE 2 Vessel: -Same as basket apparatus orally disintegrated

Rotating paddle Shaft: -The blade passes through the shaft chewable tablets. capsules.
so that the bottom of the blade fuses with , controlled release product,
bottom of the shaft. suspension
Stirring elements: -coated with Teflon
For laboratory purpose
-Stainless steel
Rotation speed 25-50 rpm
Water-bath: -Maintains at 37±0.50°C
Sinkers : -Platinum wire used to prevent
tablet/capsule from floating
Dosage form placed in sinkers
Apparatus Design Used
TYPE 3 Vessel: cylindrical flat bottom glass vessel Tablets, beads, controlled and
Reciprocating set of reciprocating cylinders extended release formulations
cylinder stainless steel fittings(SS316) and
screens made of nonsorbing or non-
reactive materials.
Agitation type: -Reciprocating -5-35 rpm
Volume of dissolution medium:-
200-250ml
Water bath:- Maintain at 37±0.50°C
Dosage form is placed in cylinder

TYPE 4 DESIGN: Reservoir : -For dissolution Low solubility drugs ,micro

FLOW THROUGH CELL medium Pump : -Forces dissolution particulates ,implants, suppositories
medium through cell controlled release formulations
-Holding a sample
-Flow rate 10-100ml/min or 240-960ml/h
-Laminar flow is maintained
-Peristaltic/centrifugal pumps are not
recommended
37±0.50°C
Apparatus Design Used
TYPE 5 Vessel&Shaft: same as paddle Transdermal patches ,
Paddle apparatus ointments,emulsions
over Starring element, rpm 25-50 Modification: disk design and volume
disk Vol: 900ml
Temp: 32 Sample holder:-disk
assembly that hold a product in such
a way that release surface is parallel
with paddle
-Paddle is directly attached over disk
assembly

TYPE 6 Vessel:- In place of basket, cylinder is Transdermal Patches

Rotating used.
cylinder Shaft :-Stainless steel 316
Sample :- Mounted to cuprophan
(inner porous cellulosic material)
an entire system adheres to cylinder.
- Dosage unit is placed in cylinder
and release from side out.
Water-bath: maintained at
32±0.50°C
Apparatus Design Used
Type 7 Vessel:-Flat bottomed cylindrical Controlled-release formulations
Reciprocating disk vessel (non-disintegrating oral
-Volume of dissolution medium 50- formulations
200ml and transdermal formulations
Shaft :spring holder /acrylic rod
Sample : -Placed on disk shaped
holders
Agitation :-Reciprocation
-Reciprocating frequency 30
cycle/minute
Water-bath:-Maintain at 32±0.50°C

1. Purified water
2. Dilute acid( 0.001N-0.1N HCL)
3. Stimulated gastric fluid
4. Stimulated intestinal fluid Dissolution
5. Surfactants (SLS, polysorbate )
6. Aqueous buffers pH5-7 medium
Case study
Title: Comparison Of Different Methods For Enhancing The Dissolution Rate Of Pooly Soluble
Drugs : Case Of Griseofulvin.
AIM : The dissolution enhancement of the poorly soluble drug griseofulvin by micronization by
milling and by precipitation from supercritical fluidsand adsorption on a carrier (silica aerogel).
Materials and methods:
1. griseofulvin from zhonghua pharmaceuticals factory shanghai.
2. Silica aerogels
3. BET surface area analyzer
4. Micronization by milling particle size of 10-12 µm
5. Micronization by RESS
[Link] aerogels loaded with griseofulvin..
 Physical properties of griseofulvin

Particle size µm BET surface area Form

1. Crystalline 177 0.6 Crystalline

griseofulvin
[Link] griseofulvin 5.3 4.4 Crystalline

[Link] griseofulvin 0.43 8.8 Crystalline

[Link]-aerogel 0.7-10 577 Noncrystalline

formulation
Result

Dissolution profiles of griseofulvin in

phosphate buffer (artificial gut fluid pH
7.4)
Conclusion : Three different methods for the dissolution release enhancement of
griseofulvin. Micronization by milling ,micronization by RESS and adsorption on
hydrophilic silica aerogels. Grisiofulvin nanoparticles obtained by RESS dissolve faster
than microparticles obtained by conventional milling. However the dissolution rate of
grisiofulvin adsorbed onn hydrophilic silica aerogels is by far higher than the dissolution
rate of grisiofulvin nanoparticles.
Rapid collapse of the aerogel structure in aqueous solution. thus adsorption of poorly
soluble drugs on silica aerogels provides a powerful tool to generate a very fast
dissolving formulation of drugs in case the decrease of particle size by micronizetion
methods is not sufficient.
Reference
 Smirnova, I., Türk, M., Wischumerski, R., & Wahl, M. A. (2005, June). Comparison of
Different Methods for Enhancing the Dissolution Rate of Poorly Soluble Drugs: Case of
Griseofulvin. Engineering in Life Sciences, 5(3), 277–280.
[Link]
 Lachman, L. (2016). The Theory and Practice of Industrial Pharmacy. New Delhi: CBS
Publisher & Distributers Pvt Ltd.
 Linda A, F. (2013). Remington essential of pharmaceutics. London:
Pharmaceutical press
Acceptance criteria for immediate release oral solid dosage forms

Basket Method (USP apparatus 1)

1. Stirring rate = 100 RPM
2. 500 mL of 0.1N HCl in aqueous medium
3. No surfactant in medium
4. 37±0.5°C B. Paddle Method
(USP apparatus 2)
5. Stirring rate = 50 RPM
6. 500 mL of 0.1N HCl in aqueous medium
7. No surfactant in medium
8. 37±0.5°C