Dissolution studies Factor affecting dissolution and Invitro- Invivo Correlation

1. Dissolution
1
Dissolution studies Factor affecting
dissolution and Invitro- Invivo
Correlation

2. *What is dissolution?
- Dissolution is a process in which a solid substance
solubilizes in a given solvent to yield a solution i.e. mass
transfer from the solid surface to the liquid phase.
- It depends on the affinity between the
solid substance and solvent.
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3. - It quantifies the speed
of the dissolution process.
- It depends on
 chemical natures of the solvent and solute,
 temperature (and possibly to a small degree, the
pressure),
 degree of undersaturation,
 presence of a means of mixing,
 interfacial surface area, and
 the presence of "inhibitors" (e.g., substances adsorbed on
the surface).
 It is defined as the amount of drug substance that goes in
solution per unit time under standardized conditions of
temperature, pH and solvent composition and constant
surface area.
* Rate of dissolution
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4. * Need of dissolution
Drug in the blood
and the body
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5. - Initial mechanical lag.
- Wetting of dosage form.
- Penetration of dissolution
medium.
- Disintegration.
- De-aggregation.
- Dissolution.
- Occlusion of some particles.
* Mechanism of dissolution
The S-Shaped dissolution curve of solid dosage form
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6. - For optimization of formulation and quality control.
- To identify the manufacturing variable, like the binding
agent effect, mixing effects, granulation procedure,
coating parameters and comparative profile studies.
- To show that the release of drug from the tablet is close to
100%.
- To show that the rate of drug release is uniform batch to
batch.
- And to show that release is equivalent to those batches
proven to be bioavailable and clinically effective.
* Application of dissolution
studies
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7. *Theories of dissolution
1. Diffusion layer model
2. Danckwert’s model
3. Interfacial barrier model
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8. - Also called ‘film theory’.
- 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.
* 1. Diffusion layer model
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9. Noyes- Whitney’s equation:
where,
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.
Diffusion layer Model
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10. 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.
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11. - Noyes- Whitney’s equation represents first order kinetics, for
which the driving force is concentration gradient.
- This is true for in- vitro dissolution which is characterized by
non sink condition.
- The in- vivo dissolution is rapid as sink conditions are
maintained by absorption of drug in systemic circulation I.e.
Cb = 0 .
- Under sink condition,
dissolution rate follows
zero order kinetics.
Dissolution rate under sink and non- sink conditions
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12. *The Hixson-Crowell Cube Root
Law
- Major assumptions in Noyes-Whitney relationship is that the
surface area remains constant throughout dissolution process.
- However, size of drug particles will decrease as drug dissolves.
and thus changes the effective surface area.
- Thus, Hixson & Crowell modified the equation to represent rate of
appearance of solute by weight in solution.
where,
M0 = initial mass of powder
M = mass of powder dissolved in time, t
k = cube root dissolution rate constant
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13. *2. Danckwert’s Model
-Also called “Penetration or Surface Renewal Theory”.
-Danckwert’s 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.
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14. Where,
m = mass of solid dissolved,
and
γ = rate of surface renewal
(or the interfacial tension)
Danckwert’s Model
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15. *3. Interfacial Barrier Model
-Drug dissolution is a function of solubility rather
than diffusion.
-Intermediate concentration exist at the interface
as a result of solvation.
-Dissolution rate per unit area, G is given by,
where,
Ki = effective interfacial transport
constant.
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16. *Factors affecting dissolution
rate
1. Factors related to Physicochemical
Properties of Drug
2. Factors related to Drug Product
Formulation
3. Processing Factor
4. Factors Relating Dissolution Apparatus
5. Factors Relating Dissolution Test
Parameters
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17. *Factor related to
physicochemical properties
of drug
1. Particle size of drug
- 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.
- E.g. Micronisation of non-hydrophobic drug like griseofulvin leads to
increase in dissolution rate.
- Micronisation of hydrophobic powders can lead to aggregation and
floatation, when powder is dispersed into dissolution medium.
- E.g. hydrophobic drugs like aspirin, phenacetin and phenobarbital
shows decrease in dissolution rate, as they tend to adsorb air at the
surface and inhibit their wettability.
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18. 2. 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.
- E.g. Poorly soluble drug :griseofulvin,
spironolactone
Hydrophilic drug :neomycin
Solubility
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19. 3. 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. E.g.
Ampicillin anhydrate faster dissolution rate than trihydrate.
- Amorphous forms of drug tend to dissolve faster than
crystalline materials. E.g. Novobiocin suspension, Griseofulvin.
- Metastable(high activation energy)
polymorphic form have better
dissolution than stable form.
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20. 4. Salt formation
- It is one of the common approaches used to increase drug
solubility and dissolution rate. E.g. sodium and potassium salts of
Penicillin G, phenytoin, barbiturates etc.
- While in case of Phenobarbital, dissolution of sodium salt was
slower than that of weak acid.
Dissolution and absorption of an acidic drug administered in salt form
Dissolution
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21. *Factors related to drug
product formulation
1. Binders and granulating agents:
- In general, the hydrophilic ( aqueous) binders show
better dissolution profile with poorly wettable drugs
like phenacetin by imparting hydrophilic properties
to the granule surface.
- Large amounts of such binders increase hardness
and decrease disintegration / dissolution rates of
tablets.
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22. .
Rate of dissolution of phenacetin from ▲powder, ●
granules, and ○ tablet in diluted gastric juice.
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23. 2. Disintegrants
- Disintegrating agent added before & after the granulation
affects the dissolution rate.
- E.g. 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.
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24. Effect of starch content on dissolution rate of salicylic
acid tablet, ○ 5 %, ● 10 % and × 20 % starch in granules.
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25. 3. Effect of lubricants / anti-frictional agents
- The nature, quantity, and quality of lubricants added can
affect the dissolution rate.
- 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 promote
drug dissolution.
- E.g. Magnesium stearate, a hydrophobic lubricant, tend to
retard the dissolution rate of salicylic acid tablet, whereas
sodium lauryl sulfate enhances its dissolution, due to its
hydrophobic but surface activity, which increases wetting and
better solvent penetration into tablet.
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26. (A) Effect of magnesium stearate on
dissolution rate of salicylic acid from
rotating disc made from fine salicylic
acid powder, ○ 3 % Mg. Stearate, ● no
lubricant added.
(B) Effect of lubricant on dissolution
rate of salicylic acid contained in
compressed tablet, × 3 % Mg. Stearate
, ● no lubricant, and ○ 3 % Sodium
lauryl sulphate.
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27. 4. Coatings
- In general, the deleterious effect of various coatings on drug
dissolution from a tablet dosage form is in the following order:
Enteric coat > Sugar coat > Non- enteric film coat.
5. Buffers
- Buffers are sometimes useful in creating the right atmosphere for
drug dissolution, e.g. buffered aspirin tablets.
6. Complexing agents
- A complexed drug may have altered stability, solubility, molecular
size, partition coefficient and diffusion coefficient.
- E.g. Enhanced dissolution through formation of a soluble complex of
ergotamine tartarate-caffeine complex and hydroquinone-digoxin
complex.
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28. *Processing factors
1. Method of granulation
- Wet granulation has been shown to improve the
dissolution rate of poorly soluble drugs by
imparting hydrophilic properties to the surface of
granules.
- 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.
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29. 2. 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
1. tighter bonding increases hardness
2 . higher compression force cause
deformation crushing or fracture of
drug particle or convert a
spherical granules into disc Shaped
particle
3.& 4. both condition
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1 2
3 4

30. *Factors related to
dissolution apparatus
1. AGITATION
-Rate of dissolution depends on type of agitation used, the
degree of laminar and turbulent flow in system, the shape and
design of stirrer.
- Speed of agitation should be such that it prevent turbulence
and sustain a reproducible laminar flow, which is essential for
obtaining reliable results.
- So, agitation should be maintained at a relatively low rate.
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31. 2. SAMPLING PROBE POSITION & FILTER
- Sampling probe can affect the hydrodynamic of the system.
- USP states that sample should be removed at approximately
half the distance from the upper surface of basket or paddle
and surface of dissolution medium and not closer than 1 cm to
the side of the flask.
3. STIRRING ELEMENT ALIGNMENT
- The USP / NF states that the axis of the stirring element
must not deviate more than 0.2 mm from the axis of the
dissolution vessel.
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32. *Factors related to
dissolution test parameters
1. Vibration
- The excessive vibration of dissolution apparatus
increases dissolution rates.
2. Vessel design and construction
- Plastic vessels provide more perfect hemisphere
than glass vessels.
3. Temperature control
- Should be maintained at 37 ± 0.5 º C
4. Dissolution medium parameters
- Surface tension, pH, Viscosity, De-aeration
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33. *Dissolution apparatus
Based on the absence or presence of sink conditions, there
are two principal types of apparatus:
1 . Closed- compartment apparatus:
It is basically a limited volume apparatus operating under non-
sink conditions. e.g. beaker type apparatuses such as the rotating basket
and the rotating paddle apparatus.
2 . Open- compartment ( continuous flow- through ) apparatus:
It is the one in which the dosage form is contained in a column
which is brought in continuous contact with fresh, flowing dissolution
medium ( perfect sink condition ).
3 . A third type called as dialysis systems are used for very poorly
aqueous soluble drugs for which maintenance of sink conditions would
otherwise require large volume of dissolution fluid.
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34. *USP compendial apparatus
1. Basket type (USP apparatus 1)
2. Paddle type (USP apparatus 2)
3. Reciprocating cylinder type (USP
apparatus 3)
4. Flow - through cell type (USP apparatus 4)
5. Paddle over disc type (USP apparatus 5)
6. Cylinder type (USP apparatus 6)
7. Reciprocating holder type (USP apparatus
7)
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35. *Basket type (USP apparatus 1)
Design:
Vessel:- Made up of transparent, inert material
(borosilicate glass)
Semi hemispherical bottom
Capacity: 1000ml
Shaft:- Stainless steel 316
Rotates smoothly without significance wobble
Basket:- Stainless steel 316
Gold coatings up to 0.0001 inch (2.5 µm)
Water bath:- Maintained at 37± 0.5˚c
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36. - Dosage form contained within
basket
- Dissolution should occur within
Basket
- pH change by media exchange
Uses:- Capsules, tablets,
delayed release dosage form,
suppositories, floating dosage
forms.
Agitation:- Rotating stirrer
Usual speed: 50 to 100 rpm
Disadvantage:- Formulation
may clog to 40 mesh screen
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Fig. Basket stirring element

37. *Paddle type (USP apparatus 2)
Design:
Vessel:- Made up of transparent, inert material
(borosilicate glass)
Semi hemispherical bottom
Capacity: 1000ml
Shaft:- The blade passes through shaft so that
bottom of blade fuses with bottom of shaft.
Stirring elements:- Made of Teflon for laboratory purpose
Stainless steel 316
Water bath:- Maintain at 37± 0.5˚c.
Sinkers:- Small loose wire helix used to prevent
capsule/tablet from floating.
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38. - Dosage form should remain at the bottom
center of the vessel.
- pH change by media change.
Useful for:- Tablets
Capsules
Agitation:- Rotating stirrer
Usual speed: 25 to 100 rpm
Advantages:- Easy to use and robust
pH change possible
Can be easily adapted to apparatus 5
Disadvantages:- Floating dosage forms require sinker
Positioning of tablet.
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Fig. Paddle stirring element

39. Dissolution 39

40. *Reciprocating cylinder type
(USP apparatus 3)
Design:
Vessel:- Cylindrical flat bottom glass vessel.
Agitation:- Reciprocating
Generally 6-35 cycles/min
Volume of dissolution fluids:- 200-250 ml
Water bath:- Maintain at 37 ± 0.5˚C
Use:- Extended release
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41. - The apparatus consist of a set of cylindrical flat– bottomed glass
vessel equipped with reciprocating cylinders.
- The vessels are partially immersed in a suitable water
bath of any convenient size that permits holding the
temperature at 37 º C ± 0.5 º C during the test.
- The dosage unit is placed in reciprocating cylinder
& the cylinder is allowed to move in upward and
downward direction constantly.
Total distance it travels during stroke is 9.9- 10.1 cm.
Useful for:- Tablets, Beads, controlled release
Formulations.
Advantages:- Easy to change the pH-profiles
Hydrodynamics can be directly influenced by
varying the dip rate.
Disadvantages:- Small volume (max. 250 ml)
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41
Fig. Reciprocating cylinder

42. *Flow-through cell type
(USP apparatus 4)
The apparatus consist of a reservoir for the dissolution medium
and a pump that forces medium through the cell holding the test
sample.
Dissolution fluid is collected in separate reservoir.
Temperature is maintained at 37 º C ± 0.5 º C.
Useful for:- Low solubility drugs, powders and granules,
micro particles, implants.
Advantages:- Easy to maintain sink
condition.
Easy to change media pH
Disadvantages:-De-aeration necessary
High volumes of media
Labor intensiveDissolution 42
Fig. Flow through cell

43. Tablets 12mm Tablets 22.6mm Powder/ Implants Suppository/
Granule soft gelatin capsule
Cell types
Dissolution 43

44. *Paddle over disc type
(USP apparatus 5)
This uses the paddle apparatus 2 with a
stainless steel disk designed for holding
transdermal system at the bottom of the
vessel.
The disk holds the system flat and is
positioned such that the release surface
is parallel with the bottom of the paddle
blade.
Media volume used is 900 ml which is
maintained at 37 º C ± 0.5 º C.
Useful for transdermal patches.
Disadvantages:- Disk assembly restrict
the size of patch.
Transdermal patch retainer ( Hanson style)
Dissolution 44
Fig. Paddle over disc

45. * Cylinder type
(USP apparatus 6)
 This is a modification of Basket
apparatus 1, in which the basket is replaced
with a stainless steel cylinder as a stirring
element.
 Sample is mounted to cuprophan (inner porous
cellulosic material) and entire system is adhere to
cylinder.
 The dosage unit is placed on the cylinder with
release side out.
 Useful for testing of transdermal patches.
Dissolution 45
Fig. Cylinder type
Cylinder stirring element

46. *Reciprocating holder type
(USP apparatus 7)
 The assembly consist of a set of calibrated solution containers,
a motor and drive assembly to reciprocate the system vertically.
 The sample holder may take the form of disc,
cylinder or a spring or acrylic rod,
or it may simply be the rod alone.
 Capacity is 50– 200 ml.
 Reciprocating frequency is 30 cycles/ min.
 Useful for transdermal patches and
solid dosage forms.
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46

47. Holder types
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48. *IVIVC
(In vitro- in vivo correlation)
IVIVC is an approach to describe the relationship
between an in-vitro property of dosage form ( rate and
extent of drug release) and a relevant in- vivo response
( plasma drug conc. or amount of drug absorbed )
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49. *Purpose of IVIVC
- Serves as a surrogate for in- vivo bioavailability and to
support biowaiver.
- Used in optimization of formulation.
- To reduce the number of human studies during
formulation development.
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50. *Levels of correlation
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51. *Level A correlation
- The % of drug dissolved at a given time is correlated to %
absorbed.
- Highest category of correlation.
- Represents point to point correlation between in vitro
dissolution time course and in vivo response time course.
- Utilizes all the dissolution and plasma level data available to
develop correlation.
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52. *Level B correlation
- The mean in vitro dissolution time (MDT) is compared either
to the mean residence time (MRT) or to the mean in vivo
dissolution time.
- Is not a point-to-point correlation.
- Does not reflects the actual shape of in- vivo plasma level
curve.
- Level B correlations are rarely seen in NDAs.
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53. *Level C correlation
- One dissolution time point (t50% t90% etc.) is compared to
one mean pharmacokinetic parameter such as AUC, Tmax ,
Cmax .
- A single point estimation and does not reflect the entire
shape of plasma drug concentration curve.
- Weakest level of correlation.
- Can be useful in early stages of formulation development
when pilot formulations are being selected.
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54. *References
* D.M. Brahmankar, Sunil B. Jaiswal. pg. no. 29- 59 and 328- 335.
* The science and practice of of pharmacy by Remington 21st edition Pg. no. 673- 688.
* United states of pharmacopoeia, 2009. pg. no. 263- 276
* Principles and Application of Biopharmaceutics and Pharmacokinetics by H.P. Tipnis and Amrita
Bajaj. Pg. no. 332- 350.
* The theory and the practice of Industrial pharmacy by Lachman L, Liberman HA, Indian edition
2009. Pg. no. 302- 303.
* Article on Dissolution testing of various dosage forms by TK Indira.
(http://www.pharmainfo.net/Dissolution/dissolution-testing-various-dosage-forms)
* http://apps.who.int/phint/en/p/docf/
* www.wikipedia.com
* www.ei-instrument.com for images
* https://www.google.co.in/search?q=theory+of+dissolution&espv=2&biw=1600&bih=799&site=we
bhp&source=lnms&tbm=isch&sa=X&sqi=2&ved=0CAgQ_AUoA2oVChMIjf-
ckKuXyAIVUEiOCh2mUQ5i#imgrc=_
* http://www.pharmainfo.net/dissolution-test
* https://www.youtube.com/watch?v=CTxc9CCXurk
* https://www.youtube.com/watch?v=cG2IHw7S3nw
* https://www.youtube.com/watch?v=vmohYJn89NA
* https://www.youtube.com/watch?v=b40PbkbLP_M
* https://www.youtube.com/watch?v=nFShFBlzT5k
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55. Dissolution
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