FACTORS AFFECTING DISSOLUTION RATE

1. Physicochemical Properties of Drug

2. Drug Product Formulation Factors
3. Processing Factors
4. Factors Relating Dissolution Apparatus
5. Factors Relating Dissolution Test Parameters

1. PHYSICOCHEMICAL PROPERTIES OF DRUG

1.1) 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. Minimum aqueous
solubility of 1% is required to avoid potential solubility limited absorption problems.
 Studies of 45 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.
 Fig shows a log-log plot of solubility of several drug Vs their corresponding intrinsic rates of
dissolution at infinite rotation speed. Evident from graph that compounds with high solubility
exhibit significantly higher dissolution rates.
1.2) 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.
Eg. sodium and potassium salts of Peniciilin G, sulfa drugs, phenytoin, barbiturates etc.
 While in case of Phenobarbital dissolution of sodium salt was slower than that of weak acid.
Same is the case for weak base drug, strong acid salts, such as hydrochlorides and sulphates of
weak bases such as epinephrine, tetracycline are
 commonly used due to high solubility. However, free bases of chlortetracycline, methacycline
were more soluble than corresponding hydrochloride salt at gastric pH values, due to common
ion suppression.
1.3) PARTICLE SIZE
 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.
 Micronization of sparingly soluble drug to reduce particle size is by no means a guarantee of
better dissolution and bioavailability.
 Micronization of hydrophobic powders can lead to aggregation and floatation when powder is
dispersed into dissolution medium. So, mere increase in S.A. of drug does not always guarantee
an equivalent increase in dissolution rate. Rather, it is increase in the “effective” S.A., or area
exposed to dissolution medium and not the absolute S.A. that is directly proportional to
dissolution rate.
 Hydrophobic drugs like phenacetin, aspirin shows decrease in dissolution rate as they tend to
adsorb air at the surface and inhibit their wettability. Problem eliminated by evacuating surface
from adsorbed air or by use of surfactants. So these drugs in-vivo exhibit excellent wetting due
to presence of natural surfactants such as bile salts.
1.4) 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 bcz they are thermodynamically more
active than hydrates. Eg. Ampicillin anhydrate faster dissolution rate than trihydrate.

 Amorphous forms of drug tend to

dissolve faster than crystalline materials.
E.g. Novobiocin suspension, 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 forms have better
dissolution than stable forms.

1.5) CO-PRECIPITATION
 Dissolution rate of sulfathiazole could be significantly increased by co-precipitating the drug
with povidone.

2. DRUG PRODUCT FORMULATION FACTORS

 Dissolution rate of pure drug can be altered significantly when mixed with various adjuncts
during manufacturing process such as diluents, dyes, binders, granulating agents, disintegrants
and lubricants.
 Generically identical tablet or capsules exhibited differences in their dissolution rates of their
active ingredients.
2.1) DILUENTS
 Diluents in capsule & tablet influence the dissolution rate of drug.
 Studies of starch on 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
%.
 Here starch particles form a layer on the outer surface of hydrophobic drug particles resulting in
imparting hydrophilic character to granules & thus increase in effective surface area & rate of
dissolution.
 Different types of dissolution apparatus
utilized affect ranking of different
varieties of starch. With stirring type of
agitation, order was potato
starch>cornstarch>arrowroot starch>rice
starch. With oscillating type, a different
order observed.
Corn>rice>arrowroot>potato.
 The dissolution rate is not only affected
by nature of the diluent but 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.
2.2) 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.
 Disintegration and dissolution rate of disintegrants with moderate swelling capacity depend to
a large extent on mixing time of drug/excipient preblende.
 With lubricant. On other hand, disintegrants with strong swelling capacity such as sodium starch
glycolate were hardly affected by mixing time with lubricant.
2.3) BINDERS AND GRANULATING AGENTS
 The hydrophilic binder increase dissolution rate of poorly wettable drug.
 Large amt. of binder increase hardness & decrease disintegration /dissolution rate of tablet.
 Non aqueous binders such as ethyl cellulose also 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.

 Gelatin imparted hydrophilic character

to hydrophobic drug surface whereas
PEG 6000 formed a poorly soluble
complex while NA-CMC was converted
to its less soluble acid form at the low pH
of gastric fluid.
 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 tablet.
 Water soluble granulating agent Plasdone gives faster dissolution rate compared to gelatin.
2.4) LUBRICANTS
 Lubricants are hydrophobic in nature (metallic stearates) and prolong tablet disintegration time
by forming water repellant coat around individual granules. This retarding effect is most imp
factor in influencing rate of dissolution of solid dosage forms.
 Both amount and method of addition affect 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
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.
2.5) 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. The
increase was more pronounced when the surfactant was sprayed on granules than when it was
dissolved in granulating agent.
2.6) WATER-SOLUBLE DYES-
 Dissolution rate of single crystal of sulphathiazole was found to decrease significantly in
presence of FD&C Blue No.1. The inhibiting effect was related to preferential adsorption of dye
molecules on primary dissolution sources of crystal surfaces. They inhibit the micellar
solubilization effect of bile salts on drug.
 Cationic dyes are more reactive in lower conc. than are anionic dyes.
2.7) COATING POLYMERS-
 Tablets with MC coating were found to exhibit lower dissoln 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 dissoln process & essentially changes the dissoln medium. This
mechanism is substantiated by the fact that at temp below the gel point & at increased
agitation, the effect disappears.

3. PROCESSING FACTORS
3.1) METHOD OF GRANULATION-
 Granulation process in general enhances dissolution rate of poorly soluble drug. Wet
granulation is traditionally considered superior. But exception is the dissolution profile of
sodium salicylate tablets prepared by both wet granulation and direct compression where the
dissolution was found more complete and rapid in latter case.
 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.
3.2) COMPRESSION FORCE
 The compression process influence density, porosity, hardness, disintegration time &
dissolution of tablet.
  First condition, higher compression force
increase the density & hardness of tablet,
decrease porosity & hence penetrability of
solvent into the tablet retard the
wettability by forming a firmer & more
effective sealing layer by the lubricant and
in many case tighter bonding between the
particle so decrease dissolution rate of
tablet.

 Second condition, higher compression

force cause deformation, crushing or
fracture of drug particles into smaller ones
or convert spherical granules into disc
shaped particles with a large increase in
the effective surface area so increase in
dissolution rate.

 Combination of both conditions can occur

 In short dissolution decrease at lower pressure (better bonding), then increase at higher
pressure (crushing effect) and decrease again with further increase in pressure bcz of extra
rebonding and formation of denser tablets with poorer dissolution characteristics.
3.3) DRUG EXCIPIENT INTERACTION
 These interactions occur during any unit operation such as mixing, milling, blending, drying,
and/or granulating result change in dissolution.
 The dissolution of prednisolone found to depend on the length of mixing time with Mg-stearate
 Similar as increase in mixing time of formulation containing 97 to 99% microcrystalline cellulose
or another slightly swelling disintegrant result in enhance dissolution rate.
 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
dissoln rate of capsules.
3.4) STORAGE CONDITIONS
 Dissolution rate of Hydrochlorthiazide tablets granulated with acacia exhibited decrease in
dissolution rate during 1 yr of aging at R.T. A similar decrease was observed in tablets stored for
14 days at 50-80ºC or for 4 weeks at 37ºC.
 For tablets granulated with PVP there was no change at elevated temperature but slight
decrease at R.T.
 Tablets with starch gave no change in dissoln. rate either at R.T. or at elevated temperature.
4. FACTORS RELATING DISSOLUTION APPARATUS
4.1) AGITATION
 Relationship between intensity of agitation and rate of dissolution varies considerably acc. to
type of agitation used, the degree of laminar and turbulent flow in system, the shape and
design of stirrer and physicochemical properties of solid.
 Speed of agitation generates a flow that continuously changes the liq/solid interface between
solvent and drug. In order to prevent turbulence and sustain a reproducible laminar flow, which
is essential for obtaining reliable results, agitation should be maintained at a relatively low rate.
 Thus, in general relatively low agitation should be applied.
I. BASKET METHOD- 100 rpm
II. PADDLE METHOD- 50-75 rpm
4.2) STIRRING ELEMENT ALIGNMENT
 The USP / NF XV states that the axis of the stirring element must not deviate more than 0.2 mm
from the axis of the dissolution vessel which defines centering of stirring shaft to within ±2 mm.
 Studies indicant that significant increase in dissolution rate up to 13% occurs if shaft is offset 2-6
mm from the center axis of the flask.
 Tilt in excess of 1.5 0 may increase dissolution rate from 2 to 25%.
4.3) SAMPLING PROBE POSITION & FILTER
 Sampling probe can affect the hydrodynamic of the system & so that change in dissolution rate.
 For position of sampling, USP / NF states that sample should be removed at approximately half
the distance from the basket or paddle to the dissolution medium and not closer than 1 cm to
the side of the flask.
 Filter material must be saturated with the drug by repeated passage to avoid losses that might
go undetected during the test sampling.
 Accumulation of the particulate matter on the surface may cause significant error in the
dissolution testing.

5. FACTORS RELATING DISSOLUTION TEST PARAMETERS

5.1) TEMPERATURE
 Drug solubility is temperature dependent, therefore careful temperature control during
dissolution process is extremely important.
 Generally, a temp of 37º ± 0.5 is maintained during dissolution determination of oral dosage
forms and suppositories. However, for topical preparations temp as low as 30º and 25º have
been used
5.2) DISSOLUTION MEDIUM
It is very imp factor affecting dissolution and is itself affected by number of factors such as:
A. Effect of pH
 Weak acids, dissoln. rate increases with increase in pH whereas for weak bases, increase with
decrease in pH.
[Link] of dissolution medium and sink conditions
 Volume generally 500, 900 or 1,000 ml.
 Simulated gastric fluid(SGF) - pH 1.2.
 Simulated intestinal fluid (SIF)- pH 6.8 (not exceed pH 8.0).
 The need for enzymes should be evaluated case-by-case like…. (Pepsin with SGF and pancreatin
with SIF
 If drug is poorly soluble, a relatively large amount of fluid should be used if complete dissolution
is to be expected.
  In order to minimize the effect of conc. gradient and maintain sink conditions, the conc. of drug
should not exceed 10-15% of its max. Solubility in dissoln. medium selected. For most of the
drugs about 1 L is more than sufficient to maintain sink conditions.
 However, some insoluble drug present a problem as to handling of huge volume of dissoln.
medium that would be required to maintain the sink conditions. For these, different approaches
have been tried like….
1. Continous flow method where fresh solvent is pumped continuously into dissoln flask
at a fixed flow rate while maintaining a constant volume.
2. Use of non-ionic surfactant in conc. above CMC.
3. Use of alcoholic solution (10-30%).
C. Deaeration of dissolution medium
 Dissolved air in distilled water could significantly lower its pH and consequently affect the
dissolution rate of drugs that are sensitive to pH changes, weak acids.
 Another effect is to be released from the medium in form of tiny air bubbles. These bubbles
collect at the surface of the dosage forms, thereby acting as a hydrophobic barrier between
solvent and solid surface. This inhibits wetting and reduction of S.A. and lower dissoln. rate.