The document discusses dissolution, which is the process by which a solid substance enters the solvent phase to form a solution. Dissolution is important for drug absorption from oral dosage forms and can be the rate-limiting step. Dissolution testing is used for quality control, formulation development, and correlating in vitro dissolution to in vivo bioavailability. Theories of dissolution include diffusion layer models and surface renewal models. Factors that affect dissolution include drug properties, dosage form factors, particle size, polymorphism, salt formation, and lipid solubility.

1. Dr. Neeraj Mishra
Professor
Department of Pharmaceutics
Email: neerajdops@gmail.com
ISFCP,MOGA
Dissolution: A Tool For
Pharmaceutics

2. Dissolution
 The transfer of molecules or ions from a solid state into solution is
known as dissolution.
 Dissolution and then diffusion is a Pre-requisite for the drug
absorption.
 Physicochemically, ‘‘Dissolution is the process by which a solid
substance enters the solvent phase to yield a solution’’.
 Dissolution (release of the drug from the dosage form) is of primary
importance for all conventionally constructed, solid oral dosage forms in
general, and for modified-release dosage forms in particular, and can be
the rate limiting step for the absorption of drugs administered orally.

4. 9
Solid
dosage
form
Solid
drug
particles
Drug in
solution at
absorption
site
Drug in the
body

5.  Dissolution tests become especially important if dissolution is the rate-
limiting step in drug absorption, e.g., in rapidly disintegrating tablets or
capsules.
 From a Quality Control perspective, dissolution testing is mainly used
to confirm product quality and batch-to-batch consistency and to identify
good and bad formulations.
 Dissolution tests are used to confirm compliance with compendial
(summary of a larger work) specifications and are therefore needed as
part of a marketing authorization.( e.g. Disprin fast dissolving tablet).
 Dissolution testing is widely used in the pharmaceutical industry for
optimization of formulation and quality control.
IMPORTANCE OF DISSOLUTION STUDY

6.  Additionally they are used during product development and stability
testing as part of the development specification for the product. Critically
from an R&D perspective, there is the potential to correlate in vitro
dissolution data with in vivo bioavailability, which would greatly
facilitate product development.
 Most sensitive and reliable predictors of in-vivo availability.
 Such models can be used to screen potential drug and their associated
formulations for dissolution and absorption characteristics.
 Dissolution study also identify potential bioavailability problems.

7.  Dissolution testing as a QC test, to guide formulation development, to
use as a manufacturing/process control tool.
 Dissolution also act as a quality control tool for the uniformity and
reproducibility of the batches.
 Increasingly, in vitro dissolution testing and profile comparison are
relied on to assure product quality and performance and to provide a
biowaiver.( Biowaiver is the official approval for exemption from
conducting a bioequinalence study in the context of an application for
marketing authorization).
 Dissolution studies are used to substitute bioabsorption (in-vivo)
where in-vivo in-vitro corelation are observed.
OBJECTIVES OF DISSOLUTION TESTING

8.  It is research tool to optimize the parameters and ingredients in new
formulations.
 It is also used to assess drug product quality with respect to stability
and shelf life.
 To develop a composition and process for Phase I clinical studies
which are consistent with the intended market composition (qualitative
and quantitative).
 To develop a highly discriminating dissolution test; not as a quality
control tool but as an aid to optimization of a formulation.
 To develop a dosage form with a consistently high performance
throughout its life.
 To develop a dissolution test to serve as a quality control tool.

10. Diffusion layer model/Film Theory
It is a simplest model where dissolution of crystal,
immersed in liquid takes place without involving reactive
or electrical forces. Consist of two consecutive steps:
1. Solution of the solid to form a thin film or layer at
thesolid / liquid interface called as stagnant film
ordiffusion layer which is saturated with the drug this step
is usually rapid (instantaneous).
2. Diffusion of the soluble solute from the stagnant
layer to the bulk of the solution this step is slower and is
therefore the rate determining step in the
drugdissolution.
Theories of Dissolution

12. dc/dt =DAKw/o (Cs- Cb) /Vh
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
Modified Noyes & Whitney equation

13. DANCKWERT’S MODEL (PENETRATION OR SURFACE RENEWALTHEORY)
The model could be visualized as a very thin film having a conc. Ci which is
less than saturation, as it is constantly being exposed to fresh surfaces of
liquid having a conc. much less than Ci. Acc. to model, the agitated fluid
consist of mass of eddies or packets that are continuously being exposed to
new surfaces of solidand then carried back to bulk of liquid.

14. Interfacial barrier model (double barrier or limited salvation
theory)
Based on salvation mechanism & solubility rather than
diffusion.
When considering the dissolution of the crystal will have
a different interfacial barrier given by following equation,
G = ki (Cs – Cb)
Where G = dissolution per unit area
Ki = effective interfacial transport constant
In this theory, the diffusivity D may not be independent
of saturation conc. Cs .
The interfacial barrier model can be extended to both
diffusion layer model and the Dankwert’s model.

15. Factors affecting dissolution and
dissolution rate
 Physicochemical properties of drug : solubility,
particle size, polymorphism, salt formation,
complexation, wettability.
 Dosage form factors: formulation factors and
excipients.
 R= dc/dt=2.24Cs
 Where R= dissolution rate.
 > 1% aq. Solubility avoid B.A. problems.

16. Particle size and S.A. of drug
 Absolute surface area: Total area of solid surface.
 Effective surface area: Area of solid surface exposed.
 Micronisation (<0.1 um) increase energy and increase
interaction, increase surface area and dissolution rate.
 Micronisation of
Non hydrophobic drugs, poorly aq. Soluble drugs increase
dissolution rate. E.g. griseofulvin, chloramphenicol and
tetracyclin.
Physical-Chemical Factors Affecting
Dissolution

17. Polymorphism and Amorphism
Internal structure
Crystalline amorphous
Polymorphs
Enantiotropic
Molecular adducts
Monotropic
Non stoichiometric complex
Stoichiometric complex
Organic solvates
hydrates

18. Polymorphism and Amorphism
 Stable : low energy, high M.P. least aq. Solubility.
 Metastable: high energy, low M.P. and high Aq.
Solubilities, better B.A.
 E.g. chloramphenicol palmitate B ( A,B,C)
 Riboflavin III (I,II,III)
 Metastable to stable ; by dehydrating the molecular
environment, by adding viscosity building agent like
PVP,CMC.
 Amorphous; high Aq. Solubility.
 E.g. amorphous form of novobiosin, chloramphenicol,
cortisone acetate and phenobarbitol.
 Amorphous > metastable > stable.

19. Hydrates/Solvates
 Solvates : molecular adduct where the solvent
molecules are incorporated in crystal lattice .
 Hydrates: solvent water.
 Anhydrous form (high energy state): greater aq.
Solubility.
 E.g. theophylline and ampicilline.
 Organic solvate : more Aq. Solubility than non solvate
 E.g. n-pentanol solvate of fludrocortisone
 Chloroform solvate of griseofulvin.

20. Salt Form of the Drug
 Solubility is pH dependent.
 Weak acidic drug: strong base salt prepared
 Solubility in diffusion layer is greater
 Higher pH favors solubility of weak acid.
 pH of diffusion layer (salt form) > bulk solution (free
acid)
 E.g. Na and K salt of barbiturate and sulfonamide.
 Weak basic drug : strong acid salt
 E.g. HCL salt of alkaloids.
 Solubility in diffusion layer is greater
 Lower pH favors solubility of weak base.
 pH of diffusion layer (salt form) < bulk solution (free
acid)

21. Salt Form of the Drug
 Increased solubility is due to precipitation of drug as very
fine particles in bulk solution.
 Size of the counter ion of the drug also influence solubility,
small size--- high solubility.
 Novobiosine Na > Ca> acid. 50:25:1.
 More soluble salt: poor bioavailability.
 Na phenobarbital < free phenobarbital.
 Due to not disintegration of the tablet.

22. Drug Dissolution (cont.):
Dissolution process of a salt form of a weakly acidic drug
in gastric fluid.

23. Drug stability
 Poor B.A. due to destabilization of drug during its shelf life is
due to
 Degradation of drug in to inactive form
 Interaction with one or more different component

24. pH - Partition Theory:
- According to the pH-partition hypothesis, the
gastrointestinal epithelia acts as a lipid barrier towards
drugs which are absorbed by passive diffusion, and those
that are lipid soluble will pass across the barrier.
- As most drugs are weak electrolytes, the unionized form of
weakly acidic or basic drugs (the lipid-soluble form) will
pass across the gastrointestinal epithelia, whereas the
gastrointestinal epithelia is impermeable to the ionized
(poorly-lipid soluble) form of such drugs.
- Consequently, the absorption of a weak electrolyte will be
determined by the extent to which the drug exists in its
unionized form at the site of absorption.

25.  DRUG pKa AND GI pH:
 Amount of drug that exists in un-ionized form and in ionized form is
a function of pKa of drug and pH of the fluid at the absorption site,
and it can be determined by Handerson-Hasselbach equation:
For weak acids,
 pH = pKa + log [ionized]
 [un-ionized]
 % Drug ionized = 10pH-pKa x 100
 1+10pH-pKa
For weak bases, pH = pKa + log [un-ionized]
 [ionized]
 % Drug ionized = 10pKa-pH x 100
 1+10pKa-pH

26. Lipid solubility of drugs:
- Some drugs are poorly absorbed after oral administration
even though they are non-ionized in small intestine. Low
lipid solubility of them may be the reason.
- The best parameter to correlate between water and lipid
solubility is partition coefficient.
Partition coefficient (p) = [ L] conc / [W] conc
where, [ L] conc is the concentration of the drug in lipid
phase.
[W] conc is the concentration of the drug in aqueous phase.
- The higher p value, the more absorption is observed.

27. DRUG PRODUCT FORMULATION FACTORS
1. DILUENTS:
•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 %.
•Starch particles form a layer on the outer
surface of hydrophobic drug particles
resulting in imparting hydrophilic
character granules & thus increase in
effective surface area & rate of dissolution.
•Dissolution rate is also affected by excipient dilution (drug/excipient
ratio).E.g. in quinazoline comp. dissolution rate increases as the
excipient /drug ratio increases from 3:1 to 7:1 to 11:1.

28. 2. DISINTEGRANTS:
• Added before & after the granulation affects the dissolution rate.
e.g. Na CMC, MCC, Starch, etc.
3. BINDERS AND GRANULATING AGENTS:
• Hydrophilic binder show better dissolution profile with hydrophobic
drug like Phenacetin by implanting hydrophilic properties to granule
surface.
• Large amt. of binder increase hardness & decrease disintegration
/dissolution rate of tablet.
• 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.

29. 4. LUBRICANTS:
• Nature, quality, quantity of lubricant can affect dissolution rate.
Effect of Magnesium Stearate on dissolution of salicylic acid tablet.
•It should be added in small amount (1% or less) and should be tumbled
or mixed gently for only very short time. Prolonged mixing will increase
the dissolution time.

30. 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.
6. COATING POLYMERS:
• Tablets with MC coating were found to exhibit lower dissolution
profiles than those coated with HPMC at 37ºC.

31. THANK YOU…