A COMPLETE OVERVIEW OF ALL THE FACTORS THAT AFFECT DISSOLUTION

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FACTORS AFFECTING DISSOLUTION
TESTING
BY: DIKSHA TAPSALE

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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.

3. 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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4. 1. PHYSICOCHEMICAL PROPERTIES OF DRUG
1. PARTICLE SIZE OF DRUG
•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.
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5. 2. DRUG SOLUBILITY
*Minimum aqueous solubility of 1% is required to avoid
potential solubility limited absorption problems.
•Studies on several 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.
E.g. Poorly soluble drug : griseofulvin, spironolactone
Hydrophilic drug :neomycin
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6. 3. SOLID STATE CHARACTERISTICS
•Anhydrous forms dissolve faster than hydrated form because
they are thermodynamically more active than hydrates.
• E.g. Ampicillin anhydrate dissolution rate is faster than
ampicillin trihydrate
•- Amorphous forms of drug tend to dissolve faster than
crystalline materials. E.g. Novobiocin , Griseofulvin.
•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. Eg. Methyl prednisone
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7. 4. 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.
*While in case of Phenobarbital dissolution of sodium salt was
slower than that of weak acid. Due to decreased disintegration
of sodium salt.
*hydrochlorides and sulphates of weak bases are commonly
used due to high solubility.
*E.g. epinephrine, tetracycline
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8. 2. FACTORS RELATED TO DRUG PRODUCT
FORMULATION
1. BINDERS
* The hydrophilic binders like gelatin increase dissolution rate of
poorly wettable drug.
*Non aqueous binders such as ethyl cellulose retard the drug
dissolution.
* 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
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9. Large amount of binder increase hardness & decrease
disintegration /dissolution rate of tablet.
• 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 the tablet.
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10. 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.
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11. 3. EFFECT OF LUBRICANTS
•Lubricants are hydrophobic in nature (metallic stearates)
and prolong the tablet disintegration time by forming water
repellent coat around individual granules.
• This retards the rate of dissolution of solid dosage forms.
•Both amount and method of addition affects the property.
•It should be added in small amount (1% or less) and should
be tumbled or mixed gently for only very short time.
Prolonged mixing affect the dissolution time.
• However, if an enhancing effect in dissolution of
hydrophobic granules is desired, water soluble lubricant
such as SLS or CARBOWAXES may be used.
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12. 4. 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.
•The increase was more pronounced when the surfactant
was sprayed on granules than when it was dissolved in
granulating agent
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13. 5. COATING POLYMERS
•Tablets with MC coating were found to exhibit lower
dissolution profiles than those coated with HPMC at 37ºC.
The differences are attributed to thermal gelation of MC at
temp near 37º, which creates a barrier to dissolution process &
essentially changes the dissolution medium.
*This mechanism is substantiated by the fact that at temp
below the gel point & at increased agitation, the effect
disappears.
*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. 13

14. 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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15. 3. 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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16. 2. COMPRESSION FORCE:
*- The compression process influences 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
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17. 3) DRUG EXCIPIENT INTERACTION
•These interactions occur during any unit operation such
as mixing, milling, blending, drying, and/or granulating
result change in dissolution.
*Increase in mixing time of formulation containing 97 to
99% microcrystalline cellulose (slightly swelling
disintegrant) result in enhance dissolution rate of
prednisolone.
* Polysorbate-80 used as excipient in capsules causes
formation of formaldehyde by autoxidation which causes
film formation by denaturing the inner surface of
capsule. This causes decrease in dissolution rate of
capsules.
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18. 4) STORAGE CONDITIONS
•Dissolution rate of Hydrochlorthiazide tablets granulated
with acacia exhibited decrease in dissolution rate during 1 yr
of aging at room temperature .
•A similar decrease was observed in tablets stored for 14 days
at 50-80ºC or for 4 weeks at 37ºC.
• Tablets with starch gave no change in dissolution rate
either at R.T. or at elevated temperature.
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19. 4)FACTORS AFFECTING DISSOLUTION APPARATUS
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21. 1)ECCENTRICITY OF AGITATING(STIRRING)ELEMENT
 The current official compendium specifies that the stirring shaft
must rotate smoothly without wobble.
 The wobble must not affect the disso rate.
 The axis of rotation of the stirring shaft must not deviate >2mm
from the axis of the stirring vessel.
 The permitted eccentricity limit is upto ±2mm.
 Studies suggest that the degree of eccentricity may be more
significant with the paddle method than the basket method and
should be limited to 1mm.
 Eccentricity is more prevalent at the junction of the shaft .
 To overcome this problem use guide bushing or straighten the
shafts
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22. 2)VIBRATION
 Speed selected by official compendium is 100 rpm.
 Precise speed can be obtained with the use of synchronous
motor.
 Variations in vibration may lead to disturbance in rotational
acceleration.
 This phenomenon is called is torsional vibration.
 Avg. velocity must be upto ±4% of the specified limit.
 Due to influence of vibration the disso rate can increase .
 No device is free of vibration so the objective of conducting
disso testing should be to reduce the vibration from external
sources .
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23. 3)AGITATION INTENSITY
 Degree of agitation is one of the most important factor that can
affect the disso rate.
 Agitation can affect diffusion controlled dissolution because the
thickness of the diffusion layer is inversely proportional to the
agitation speed.
 Agitation intensity mainly depends on dimension and geometry of
the the disso vessel,vol of disso medium and degree of agitation and
shaking.
 The rotation speed of a stirring device in either USP apparatus 1 or 2
produces a flow rate resulting in a changing liquid-solid interface
between the disso medium and the dosage form.
 It thus corresponds to the flow rate in the flow through disso
apparatus for which flow rate is suggested to fall in range of 10 to
100ml/min.
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24. 4)STIRRING ELEMENT ALIGNMENT
 The misalignment of the rotating shaft axis to the axis of the
disso vessel disturbs flow pattern so much that disso rate data
may vary ±25% from test to test.
 The axis of stirring element must not deviate more than
0.2mm from the axis of the stirring shaft.It also constrains tilt.
 Tilt more than 1.5deg may increase disso rate in method 1 and
2 from 2 to 25%.
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25. 5)FLOW PATTERN DISTURBANCES
 For reproducible results the flow pattern should be consistent from
test to test
 The geometry and alignment of the stirring device,vibration and
rotational speed are factors that affect flow pattern.
 The smoothness of the round bottomed flask can make significant
differences in the flow pattern.
 Permanent intrusion of sampling probes and thermometer can
interfere with the flow pattern.
 Automated systems can minimize this problem by introducing the
sampling probe only while withdrawing the sample and while
replacement of the media.
 In order to overcome this problem the vertical distance between the
paddle or basket and round bottomed flask must be maintained to
2.5cm(±2mm) .
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26. 6)SAMPLING PROBES,POSITION AND
FILTERS
 Now a days in automated disso apparatus large filter tipped
probes are immersed.
 Large probes can affect the hydrodynamics of the system
therefore results vary when sampling is done manually.
 Size and location of the probe affect the disso rate.
 Mainly two types of various sized probes are available such
as large and capillary. Large sized probes shows significant
effect while capillary probes do not show any major effect
on disso rate.
 USP states that sample must be removed at approx half the
distance from the bottom of basket or paddle.
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27. 7)DOSAGE FORM POSITION
 Changes or modifications in the design of disso apparatus
can alter the position of dosage form in the disso media.
 With this changes there will be significant change in the
fluid flow pattern and this can affect the disso rate.
 This mainly affects dissolution rate of the multilayered
tablets.
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28. 7)TYPE OF DEVICE
 Parameters such as type and level of agitation, adequacy of
mixing and type of disso media differs from apparatus to
apparatus.
 Also the drawbacks of the disso apparatus varies from one
apparatus to apparatus
 Hence the effect of various factors on the disso rate will vary
from apparatus to apparatus .
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29. 5)FACTORS AFFECTING DISSOLUTION TEST PARAMETERS
1) Temperature:
 USP specifies the disso medium must be held at temp 37°C
±0.5 for oral dosage forms and suppositories, while as for
topical formulations the temp ranges from 25°C to 30°C
 It is important to cover the flasks at least during dissolution
testing .
 Since the drug solubility is temp dependent the careful
monitoring of temp must be done.
 There can be a significant effect of temp on the dissolution
rate because increase in the temperature can increase the
disso rate.
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30. 2)DISSOLUTION MEDIUM
 The constituents,nature and overall characteristics of the disso
medium have a significant effect on the disso performance .
 Selection of disso medium depends on the solubility of the
drugas well as on economics and practicality.
 The three main factors affecting dissolution media are :
1)dissolved gases:
 At any given temp some portion of gas is dissolved in the liquid
and such occurrence can interfere with the reproducibility of
the results.
 The dissolved gas can alter the pH of the medium.
 With the change in temp the dissolved gases can be released in
the form of bubbles and this bubbles can effect the flow rate
and disturb the boundary layer at the solid liquid interface.
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31. 2)Medium pH and composition:
 The pH as well as composition of disso media both can have a
significant effect on disso rate.
 The disso rate can increase or decrease upon addition or
deletion of any component to the disso media.
 Faster disintegration and enhanced disso rates were observed
due to higher acidity of the dissolution medium
3)Viscosity :
 Disso rate decreases with increase in the viscosity of the disso
media, especially in the diffusion controlled processes.
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References:
•Subrahmanyam CVS. Text book of physical pharmaceutics.
2nd edition. Vallabh prakashan.Delhi.2000.
•Brahmankar DM, Sunil BJ. Biopharmaceutics and
pharmacokinetics. 3rd edition. Vallabh prakashan.
Delhi.2015.
•Umesh V Bankar,pharmaceutical dissolution
testing,volume 49,pg no.133 to 179.

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