Dissolution apparatus, invivo-invitro corelation, factor affecting,BCS classification ..
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6. Dissolution Rate
Dissolution Rate→dissolution rate is the transfer rate of individual
drug molecules from the solid particles into solution as individual
free drug molecules. Dissolution rate is determined by the crystal
forces.
The rate is dissolution is given by noyes and whitney.
(Noyes - whitney’s equation)
Dc/dt = k (cs-cb) –———– (A)
Dc/dt = Ds/h . (Cs-C)
Where
Dc/dt= dissolution 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
7. Principle of dissolution
The principle function of the dissolution test may be
summarised as follows:
Optimisation of therapeutic effectiveness during product
development and stability assessment.
Routine assessment of production quality to ensure
uniformity between production lots.
Prediction of in-vivo availability, i.e. bioavailability (where
applicable).
8. Dissolution Testing
Dissolution and drug release tests are in-vitrDissolution and drug release tests are in-
vitro tests that measure the rate and extent of dissolution or release of the drug
substance from a drug product, usually aq.medium under specified conditions.
It is an important QC procedure for the drug product and linked to product
performance in-vivo.
Need for dissolution testing=⟩
Evaluation of bioavailability.
Batch to batch drug release uniformity.
Development of more efficacious and therapeutically optical dosage forms.
Ensures quality and stability of the product
9. Applications of dissolution
Dissolution test is an official quality control test used to
monitor the uniformity of release of drug from the dosage
form.
Using dissolution test it is possible to correlate in-vivo and
in-vitro tests.
11. 1. Diffusion layer model
Also called film theory.
Broad of a thin at the interface, called as stagnant layer.
2 steps are involved:
1. Interaction of solvent with drug surface to form a
saturated drug layer, called stagnant layer.
2. Diffusion of drug molecules from stagnant layer into bulk of
the system.
12. Diagram representing diffusion
through the stagnant layer
Noyes- Whitney’s equation
dC/dt = dissolution rate of the drug
K = dissolution rate constant
Cs = concentration of drug in the stagnant layer, and
Cb = concentration of drug in the bulk of the solution at time t
13. Modified Noyes- Whitney’s equation:
Where,
D = diffusion coefficient (diffusivity) of the drug
A = surface area of the dissolving solid
Kw/o = water/oil partition coefficient of the drug
V = volume of dissolution medium
h = thickness of the stagnant layer
(Cs-Cb) = concentration gradient for diffusion of drug.
14.
15. 2. Danckwert’s model
Also called “penetration or Surface Renewal Theory”.
m = Mass of solid disslved, and
y = rate of surface renewal (or the
interfacial tension).
16. 3. Interfacial barrier model
Drug dissolution is a function of solubility rather than diffusion.
Intermediate concentration exist at the interface as a result of
salvation.
Dissolution rate per unit area, G is given by,
where Ki = effective interfacial transport constant.
17. Factors affecting dissolution are :
Surface area
Porosity
Temperature
Agitation
Viscosity
Polymorphism
Surface active agents
Salt form of the drug
Dissolution medium and ph
Solvents
Factors Affecting dissolution
18. 1.Surface area
Rate of dissolution is directly proportional to surface area.
The increase in surface area offers more contact with
solvents hence faster dissolution. The surface area can be
increased by reducing the particle size.
Micronization of drugs like griseofulvin, chloramphenicol
and salts of tetracycline gives superior dissolution.
19. 2.Porosity
Increase in porosity results in increase in surface area.
Through the pores, the solvent enters and brings about easy
dissolution.
3.Temperature
• For most of the drugs solubility increases with increase in
temperature and usually dissolution is carried out at 37°C, the
body temperature
20. 4. Agitation
The dissolution of a solid in a solvent is a mass transfer
phenomenon from the solid to the bulk of the liquid
through the diffusion layer. Thus agitation and stirring
enhances dissolution. Usually agitation condition
ranging from 25 to 100 rpm are used.
5.Viscosity
• Increase in vicosity of solvent decrease the
dissolution rate of solutes. The drug release is
delayed into the bulk
21. 6.Polymorphism
Different polymorphism forms of a substance show
different dissolution rates. Amorphous forms dissolve
faster than crystalline forms.
Example:
Aspirin shows two polymorphism form with different
dissolution rates. Novobiocin amorphous form has a
greater solubility.
22. 7.Surface active agents
They increase dissolution rate by increasing the
wettability of solutes by solvents and by increasing the
penetration of solvent into solutes
Example: Tween 80.
8. Salt form
Most drugs are either weak acids or bases. The
dissolution can be enhanced by converting them to their
salt forms.
Example
Barbiturates and sulphonamides are converted to their
Na or K salt. Similarly alkaloids are converted into
23. 9.Dissolution MEDIUM and pH
The dissolution rate depends on the solubility of
the drug. Hence different media for different
products are used at a particular pH.
Exampl: 7.4 pH phosphate buffer.
10.Solvates
Anhydrous form has greater solubility than hydrates.
Organic solvates have better dissolution.
Example
Anhydrous ampicillin is more soluble than its
trihydrate. Succinyl sulphatiazole solvate of n-pentanol
is more soluble than non-solvate drug.
24. Dissolution apparatus
There are seven different types of dissolution apparatus defined
in the United States Pharmacopeia (USP)
1. Basket type
2. Paddle type
3. Reciprocating cylinder
4. Flow through cell
5. Paddle over disc
6. Rotating cylinder
7. Reciprocating disc
25. 1. Basket type
1. It comprises borosilicate glass and holds a capacity
of upto 1000 ml.
2. The shape is semihemispherical at the bottom
while its shaft is made out stainless steel.
3. The shafts holds the cylinder basket. it is usually
referred to as a rotating basket because it rotates
smoothly and it’s rotating speed must be in form
with the recommended USP.
4. The common speed limit is 100 rpm.
5. It is used for capsules or tablets, Suppositories
floating dosage Form and a Delayed release
26. 2. Paddle type
1. This apparatus is specially made and its come with a
coated paddle that reduces the disturbance from the
stirring.
2. Apparently,it has a blade that comes in contact with the
bottom of the Shaft.
3. It also has a platinum wire that protects the capsules
from floating.
4. The paddles motor speed is usually at 40 and The
paddle is kept at 37 C.
5. The paddle is kept in the position that specified in the
current USP.
6. It has a motor speed of 50 rpm For capsules while it is
25 rpm for suspensions
27. cylinder
1. This dissolution apparatus is usually considered
In product development for Controlled release
preparations.
2. The reason for this is to aid The release a product
in GI tracts By exposing them to various
physicochemical Condition and mechanical
conditions.
3. It is an easy method for drug testing and it is does
not pose any problem with the pH values of its
solutions.
4. It is used for extended release chewable tablets.
28. 4. Flow through cell
1. It is made by two types Which are the Open system and close system.
2. The open system Has fresh dissolution medium pumped through the cell and
then the fraction received.
3. The fractions are usually drawn every 30 minutes.
4. The Dissolution test conducted with this apparatus should be conducted in the
best Sink condition available.
5. The closed system on the other hand is where The dissolution medium is
pumped into the circle but not replaced by a fresh medium.
6. It is normally used for drug with a low dosage and The test is conducted in small
volume.
7. The flow throughout the cell operators is designed like a reservoir and is
commonly used for implants
30. 5. Paddle over the disc
1. It has a shaft and also has a disk assembly that
can hold the product in a way that the surface
will be leveled with the paddle.
2. The paddle is joint with the disc assembly.
3. The paddle height is Positions 2.5 cm above the
surface off the screen
4. Its volume capacity is 900ml.
5. Medium temperatures Are generally kept at
32°C +/- 0.5°C (Skin temperature) for patches
31. cylinder
1. It uses a vessel instead of a basket cylinder and it
is also has a cylinder made out of stainless steel.
2. The apparatus is placed on cuprophan to follow the
cylinder.
3. The dosage quality is placed inside the cylinder
and it would be extracted from outside into the
water bath.
4. The problem with this drug testing dissolution in
Pharma is that the transdermal patches cannot be
cut a smaller size.
32. 7. Reciprocating Disk
1. This apparatus has a flat bottom cylinder shaped Vessels with a
volume capacity of 50-200ml.
2. It is usually placed on a disk shape holder.
3. It also produce transdermal patches and the dosage quantity extracted
in the water bath.
4. It is used the controlled release formation and only applies to small
dosages.
34. In vitro – in vivo correlation (ivivc):-
The in vitro – in vivo correlation (IVIVC) is a scientific
approach to describe the relationship between an In vitro
property of a dosage from [e.g, the rate (or) extent of durg
release] and a relevant in vivo response [e.g, plasma drug
concentration (or) amount of drug absorbed].
The IVIVC is needed
to establish dissolution specifications and to support and/or
validate the use of dissolution methods.
35. Correlation levels:-
The concept of correlation have been divided based on their
ability to reflect the plasma concentration time profile upon
the administration of the drug.
They are:-
1. Level A
2. Level B
3. Level C
36. Level A correlation:-
This level of correlation is the highest category of correlation.
An In vitro dissolution curve can serve as a surrogate for in Vivo
performance.
Therefore a change in manufacturing site, minor formulation
modifications.
This is excellent quality control procedure.
37. Level B correlation:-
Level B IVIVC utilizer the principles of statistical moment
analysis. In this level of correlation. The mean in vitro dissolution
time [MDT Vitro] (or) the mean in vivo dissolution time [MDT
Vivo]. This is not considered a point to point correlation.
Level B correlation does not uniquely reflect the actual in vivo
plasma level curves.
Therefore, one cannot rely upon a level B correlation alone to
justify formulation modifications, manufacturing site, etc.
38. Level c correlation:-
In this level of correlation, one dissolution time point is
compared to one mean pharmacokinetic parameter such as
AVC, Tmax. (Or) Cmax.
Therefore, it represents a single point correlation.
This is the lowest level of correlation as partial relationship
between the absorption and dissolution is established.
40. Introduction:
◇The biopharmaceutis classification system is guidance for predicting
the intestinal drug absorption provide by the U.S food and drug
administration.
DEFINITION:
• The biopharmaceutical classification system is a scientific
fremework.
• for classifying a drug substance.
• Its based on aqueous solubility and intestinal permeability &
dissolution rate.
41. Drug development tool thag allow estimqtion of the contribution
of 3 major factors, that affect oral drug absoraption from
immediate release solid oral daosage forms.
◇ Solubility
◇ Dissolution
◇ Intestinal permeability
Bcs classification is mainly four classes:
1. Class 1
2. Class 2
3. Class 3
4. Class 4
42. Class 1
High solubility
High permeability
Class 2
Low solubility
High permeability
Class 3
High solubility
Low permeability
Class 4
Low solubility
Low permeability
Low solubility
High solubility
Low
permeability
High
permeability
■BCS classification
43. Class Solubility Permeability
Rate limiting
factor
1 High High
Drug dissolution
it dissoltution is
very fast than
gastric emptying
time
2 Low High Dissolution
3 High Low Perrmeability
4 Low Low Case dependent
drug modification,
site condition
According to the BCS, drug substances
are Classified as follow:
44. Trick
Class
Class- 1
Class- 2
Class- 3
Class- 4
S.
Hi
Lo
Hi
Lo
P.
Hi
Hi
Lo
Lo
Lo
Hi
Lo
H
i
Hi
Hi
Lo
Lo
Where
S. = SOLUBILITY
P. = PERMEABILITY
S. = Hi,Lo,Hi,Lo
P.= Hi,Hi,Lo,Lo
45. CLASS – 1 [5-10% Drug in market]
Ideal for oral route.
Drug dissolution and absorption rapidly.
Rapid therapeutic action
Exp. Metoprolol
46. Class – 2 (60-65%)
Oral route for administration.
Drug absorbed rapidly.
Drug dissolve slowly.
Bioavailability is controlled
Exp.carbamapazine
Dosage form
Rate of release of
the drug substances
47. Class – 3 (5-10%)
Oral route for administration.
Drug is limited.
Drug dissolve rapidly.
Exp. Atenenol
48. Class – 4 (10-20%)
Poorly absorbed by oral administration.
Solubility and permeability both limited.
Slow dissolution rate.
An alternate rout of administration.
Exp. Furosemide
49. ◇some dimensionless numbers
are used in BCS classification:
☆AN~ Absorption number
☆DO~ Dose number
☆ DN~ Dissolution number
50. O1. Absorption number(an)-
Defined as ratio of mean residence time to the mean absorption time.
AN = mean residence time
it drug rapidly absorb then absorption time will very less, and
absorption number will higher.
mean absorption time
02. Dissolution number(dn)-
Defined as ratio of mean residence time to the mean
dissolution time.
DN = mean residence time
It drug rapidaly then dissolution time will very
less and dissolution number will higher.
mean dissolution time
51. 03. Dose number (Do)-
This is mass divided by the product of uptake valume (250)
ml and solubility of drug
Do = mass of drug
Cs = saturation salubility.
Uptake volume Vo×Cs
52. ■Application:
1. Predict in-vivo performance of drug based on soluble and
permeability.
2. Aid in earliest stage of drug development reasearch
3. Help in deciding drug delevery .
4. To use biowaiver consideration.
5. Application in both the Priclinical and clinical drug development
process.
