DISSOLUTION METHODS
FORMULATION AND PROCESSING FACTORS
IVIVC’S DATA
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DEFINITION
➢DISSOLUTION: is a process in which a solid substances
solubilizes in a given solvent i.e. mass transfer from the
solid to the liquid phase.
➢DISSOLUTION RATE: Is the amount of solid
substance that goes in to solution per unit time under
standard condition of temperature, pH and solvent
composition and constant solid surface area.
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DISSOLUTION APPARATUS
➢ There are two types of dissolution apparatuses.
1. Closed compartment apparatus:
➢ limited volume apparatus
➢Operating under non-sink condition.
➢e.g : Beaker type apparatus such as rotating basket and paddle.
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).
➢A third type called a dialysis systems are used for very poorly
aqueous soluble drugs for which maintenance of sink condition
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would otherwise require large volume of dissolution fluid.
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IDEAL FEATURES OF DISSOLUTION
APPARATUS
➢ The apparatus must be simple and easy to operate
under variety of conditions.
➢ The dimensions and position of all the components
must be precisely specified
➢ The apparatus must yield repeatable results
➢ The apparatus must be sensitive enough to reveal
process variations
➢ The apparatus should permit a uniform and non-
turbulent liquid agitation
➢ The apparatus should provide minimum mechanical
abrasion to the dosage form 4
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➢ Evaporation of solvent medium must be eliminated.
➢ Medium must be maintained at a fixed temperature within a
specified narrow range
➢ Nearly perfect sink condition should be maintained
➢ Samples should be easily withdrawn without interrupting the
flow of the liquid
➢ The apparatus should be versatile and capable of evaluating
disintegrating, dense or floating tablets, or capsules, and
finely powdered drugs
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Apparatus 1- Basket
➢ It was first discovered by PERNAROWSKI. It is
basically closed compartment, beaker type comprising of
a cylindrical vessel with apparatus hemispherical bottom
of one litre capacity partially immersed in a water bath to
maintain the temperature at 37°C.
➢A basket made of 22 mesh to hold the dosage form is
located centrally in the vessel at a distance of 2cm from
the bottom and rotated by a variable speed motor through
a shaft.
➢The tablet is placed in a dry
basket. 7
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A. Cylindrical vessel
B. Variable speed motor
C. Basket
D. Withdrawl ports
E. Waterbath
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Useful for :
➢Tablets
➢Capsules
➢Suppositories
➢Delayed/enteric coated dosage forms
➢Floating dosage forms
Agitation :
Stainless steel 316
Usual speed: 50 to 100 rpm
ADVANTAGES: limited area, capsules are placed in a basket-
float, used for non-official test such as suppositories &
microencapsulated particles.
DISADVANTAGES: clogged, light particles float, corroded in
presence of Hcl solution. 9
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Apparatus 2 – Paddle
➢The assembly is same as that for apparatus 1 except that the
rotating basket is replaced with a paddle which acts as a stirrer.
➢This method was first discovered by levy & Hayes.
➢The dosage form is allowed to sink to the bottom of the vessel.
➢SINKERS are recommended to prevent floating of the
capsules and other floatable forms.
➢The tablet is allowed to sink to the bottom of the vessel prior
to the rotation of the paddle, if the tablet floats, a wire or glass
helix is used.
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Useful for :
• Tablets
• Capsules
Agitation:
✓ Rotating stirrer
✓ Usual speed: 25 to 75 rpm
Standard volume: 900/1000 ml
Advantages:
✓Easy to use
✓Paddle method produces greater turbulence compared to
basket method .
Disadvantages:
✓Some tablets and capsules tend to float . Hence sinkers have to
be used.
✓Orientation of paddle is very important, else result vary. 12
✓pH/media often change is difficult
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Apparatus 3 – Reciprocating cylinder
➢The apparatus consists of a set of cylindrical flat –
bottomed glass vessel equipped with glass reciprocating
cylinders.
➢stainless steel fittings and screens that are made of
suitable non adsorbing and nonreactive material(poly
propylene).
➢That are designed to fit the tops and bottoms of the
reciprocating cylinders, and a motor and drive assembly
to reciprocate the cylinders vertically inside the vessel. 13
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➢The vessels are partially immersed in a suitable water bath of
any convenient size that permits holding the temperature at
37°c ± 0.5°c during the test.
➢The dosage unit is placed in reciprocating cylinder & the
cylinder is allowed to move in upward and downward
direction constantly.
➢Release of drug into solvent within the cylinder vessel.
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Useful for: Tablets, controlled release bead-type
formulations.
Standard volume: 200-250 ml.
Advantages:
1) Design is technically easy
2) Medium can be changed easily by removing the
dosage unit(inner cylinder) and placing it in another
medium. Easily automated.
Disadvantages:
1) small volume (max. 250 ml).
2) Little experience.
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Apparatus 4 – Flow Through Cell
➢The assembly consists of a reservoir and a pump for the
dissolution medium.
➢A water bath that maintains the dissolution medium at
37°c ± 0.5°c.
➢ The pump forces the Dissolution Medium upwards flow
through the cell holding the test sample.
➢It may be used in either:
➢closed mode – where the fluid is re-circulated and by
necessity is of fixed volume.
➢open mode – when there is continuous replenishment of
the fluids.
➢The material under test is placed in the vertically
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mounted dissolution cell, which permits fresh solvent to
be pumped in from the bottom.
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➢The system allows a large quantity of medium to be used which is
an advantage for low solubility drugs requiring a large amount of
medium reaching the sink condition.
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Useful for:
➢Low solubility drugs.
➢Implants.
➢Powder granules.
➢Capsules.
Advantages:
➢1. Easy to change the pH.
➢2. Feasibility of using large volume of dissolution fluid.
➢3. Easy to maintaining Sink conditions.
Disadvantages:
➢1. clogging of filter creates difficulties.
➢2. High volumes of media.
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Apparatus 5 – Paddle Over Disk
➢ Use of the paddle and vessel assembly from Apparatus 2 with
the addition of a stainless steel disk assembly designed for
holding the transdermal system is placed at the bottom of the
vessel.
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➢The disk assembly holds the transdermal system flat and is
positioned such that the release surface is parallel with the
bottom of the paddle blade
➢The vessel may be covered during the test to minimize
evaporation.
Advantages:
➢ Less expensive
➢Standard equipment (available with the manufacture)i.e.
apparatus can be modified and utilized apparatus 5.
Disadvantages:
➢ Disk assembly restricts the patch size.
➢ 17 mesh is standard (others available )
➢ Accommodates patches of up to 90mm
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Apparatus 6 – Rotating Cylinder
➢Use the vessel assembly from Apparatus 1 except to
replace the basket and shaft with a stainless steel cylinder
stirring element.
➢The temperature is maintained at 32°C ± 0.5°C
➢The dosage unit is placed on the cylinder at the beginning
of each test, to the exterior of the cylinder such that the
long axis of the system fits around the circumference of
the cylinder & removes trapped air bubbles.
➢Place the cylinder in the apparatus, and immediately
rotate at the rate specified in the individual monograph.
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DESIGN:
➢Vessel – In place of basket cylinder is used
➢Shaft- stainless steel 316
➢Sample-mounted to cuprophan (inner porous cellulosic
material) an entire system adheres to cylinder
➢Dosage unit is placed in cylinder and release from side
out
➢Used for transdermal patches
➢Dis Adv: large volume of medium
is required. Drugs gets diluted and
causes difficulties in analysis of drug.
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Apparatus 7 – Reciprocating Holder
➢The samples are placed on
disc-shaped holders using inert
porous cellulosic support which
reciprocates vertically by means
of a drive inside a glass container
containing dissolution medium.
➢The test is carried out at 320C
and reciprocating frequency of
30 cycles/min.
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➢Apparatus 7 is applied to transdermal patches and solid
oral dosage forms.
➢It is particularly used for the drug release from osmotic
pumps and extended release tablets.
➢Adv:
➢This method is for selecting the volume of the medium
and for maximizing the drug conc. that is suitable for
drug analysis. It can be automated.
➢Dis Adv: Invetsment on dissolution apparatus is high,
because the design is totally different from std. equipment
already available in the industry.
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FORMULATION AND PROCESSING FACTORS
➢ Formulation factors:
a. Vehicle g. Suspending agents
b. Diluents h. Surfactants
c. Binders & granulating agents i. Buffers
d. Disintegrants j. Complexing agents
e. Lubricants k. Colorants
f. Coatings l. Anti-Precipitant
➢ Processing factors:
a. Method of granulation
b. Compression force
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1)VEHICLES:
➢ vehicle or solvent system is the major component of liquid orals
and parenterals.
3 categories of vehicle:
➢Aqueous vehicle-water, syrup, etc.
➢Non-aqueous water miscible vehicle-propylene glygol, glycerol,
sorbitol.
➢Non-aqueous water immiscible vehicle- vegetable oils.
2)DILUENTS(fillers)
➢Diluents are commonly added to the tablet and capsule formulation
if the required dose is inadequate to produce the necessary bulk.
➢Diluents may be organic or inorganic.
➢Organic-carbohydrates are widely used Eg:starch,lactose, MCC etc.
➢Inorganic- dicalcium phosphate(DCP) is the most common.
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➢Eg: drug-diluent tetracycline and DCP.
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3)DISINTEGRANTS
➢These agent overcome the cohesive strength of tablet & break
them up on contact with water.
➢A decrease in the amount of disintegrant – lower dissolution.
➢Disintegrants like bentonite and veegum should be avoided
with low dose drugs like digoxin, alkaloids & steroids.
➢Microcrystalline cellulose is a very good disintegrating agent
but at high compression force, it may retard drug dissolution.
➢Starch is not only an excellent diluents but also superior
disintegrant – hydrophilicity and swelling property.
4)BINDERS OR GRANULATING AGENTS
➢ These materials are used to hold powders together to form
granules or promote cohesiveness for directly compressible
materials.
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➢The hydrophilic (aqueous) binder increase dissolution rate of
poorly wettable drug.eg: phenacetin
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➢Large amount of binder increase hardness & decrease
disintegration /dissolution rate of tablet.
➢PEG6000 –deleterious binder for phenobarbital –it forms poorly
soluble complex with drug.
➢Non aqueous binders such as ethyl cellulose also retard the
dissolution rate of drug.
5)LUBRICANTS/ANTIFRICTIONAL AGENTS:
➢To aid flow of granules
➢To reduce interparticle friction
➢Sticking or adhesion of particles to dies and punches
➢Lubricants are hydrophobic in nature (several metallic stearate
& waxes) which inhibit wettability, penetration of water into
tablet.
➢The best alternative use of soluble lubricants like SLS and
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Carbowaxes which promote drug dissolution.
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6)COATINGS:
➢The effect of various coatings on drug dissolution from a tablet
dosage form is in following order:
➢Enteric coat > sugar coat > Non-enteric film coat
➢The dissolution profile of certain coating materials change on
aging;
➢Eg: shellac coated tablets, on prolonged storage dissolve more
slowly in the intestine.
➢This can be prevented by incorporating little PVP in the coating
formulation.
7)SUSPENDING AGENTS/VISCOSITY BINDERS:
➢Popular suspending agents are hydrophilic polymers like
vegetable gums (acacia,tragacanth,etc..)
➢Semi-synthetic gums(CMC,MC) and synthetic gums which
primarily stabilize the solid drug particles by reducing their rate 29
– increase in the viscosity medium.
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➢These agents and some sugars are also used as a viscosity
imparters to affect palatability and pourability.
➢The macromolecular gums often form unabsorbable
complexes with drugs Eg: sodium CMC forms a poorly
soluble complex with amphetamine.
8)SURFACTANTS
➢ They enhance the dissolution rate of poorly soluble drug –
lowering of interfacial tension, increasing effective surface
area – faster dissolution rate.
➢ E.g. Non-ionic surfactant Polysorbate 80 increase dissolution
rate of Phenacetin granules.
➢Low conc. Of surfactant= decrease the surface tension and
increase the rate of dissolution.
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➢High conc. Of surfactant= tend to form micelles with the
drug and decrease the rate of dissolution.
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9)BUFFERS:
➢Buffers of different pHs are used in the dosage forms for the
following reason:
1)Buffers provide right atmosphere for drug dissolution.
e.g. buffered aspirin tablets.
2)Buffers provide right atmospheric condition for better
stability of drug. E.g. buffered pilocarpine solution.
➢However, certain buffer systems containing potassium cations
inhibit the drug absorption as seen with vit-B2 &
sulphanilamide.
➢Buffer system for a salt of drug should contain the same
cation as the drug salt & no introduction of additional cations
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10)COMPLEXING AGENTS:
• Complex formation has been used to alter the
physicochemical and biopharmaceutical properties of a drug.
• The complexed drug may have altered stability, solubility,
molecular size, partition coefficient and diffusion coefficient
• Eg: complexation has been used to enhance drug
bioavailability
• Enhanced dissolution through formation of soluble complex
Eg: ergotamine tartarate-caffeine complex and hydroquinone-
digoxin complex.
• Enhanced lipophilicity for better membrane permeability Eg:
caffeine-PABA complex.
• Enhanced membrane permeability Eg: enhanced GI
absorption of heparin (normally not absorbed from the GIT)
in presence of EDTA which chelates Ca and Mg ions of
membrane. 32
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11)COLORANTS:
➢Even a very low conc. of water-soluble dye can have a
inhibitory effect on dissolution of several crystalline drugs.
➢The dye molecules get adsorbed onto the crystal faces and
inhibit drug dissolution Eg: brilliant blue retards dissolution of
sulphathiazole.
➢cationic dyes are more reactive than the anaionic ones due to
their greater power for adsorption on primary particles.
12)PRECIPITATION/CRYSTAL GROWTH INHIBITORS:
➢Precipitation or crystal growth inhibitors such as
PEG,HPMC,PVA and such hydrophilic polymers prolong
supersaturation thus preventing precipitation or crystallization
by-
1)Increasing the viscosity of the vehicle 33
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2)Preventing conversion of a high energy metastable
polymorph in to stable, less soluble polymorph.
3)Adsorbing on the faces of crystal thus reducing the crystal
growth.
PROCESSING FACTORS
1. METHOD OF GRANULATION
➢ Wet granulation process is the most conventional technique
and thought to yield tablets that dissolve faster than those
made by other granulation methods.
LIMITATIONS:
1. Formation of crystal bridge by the presence of liquid
2. Liquid may act as a medium for affecting chemical
reactions such as hydrolysis.
3. Drying step may harm the thermolabile substances 34
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• The method of direct compression has been utilized to yield
tablets that dissolve at a faster rate.
• One of the recent method is agglomerative phase of
communition(APOC).
• This process involves grinding of drugs in an ball mill for
time long enough to affect spontaneous agglomeration
• Tablets were stronger and showed rapid dissolution
2. COMPRESSION FORCE
➢The compression force is applied during tabletting that
influences density, porosity, hardness, disintegration time &
dissolution of tablet.
➢4 different types of curves are obtained by plotting
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compression force (vs) rate of dissolution.
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• On the one hand: higher compression force increase the
density & hardness of the tablet, decrease porosity hence
penetrability of the solvent into the tablet, retards wettability
by forming a firmer & more effective sealing layer by the
lubricant, so decrease dissolution rate of tablet.
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➢On the other hand: higher compression force cause
deformation, crushing or fracture of the drug particles into
smaller one or convert spherical granules into disc shaped
particles – increase in the effective surface area so increase
in dissolution rate.
➢A combination of both the curves A and B is also possible as
shown in curves C and D.
➢In short, the influence of compression force on the
dissolution is difficult to predict and a thorough study on
each formulation should be made to ensure better dissolution
and drug absorption.
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IN VITRO IN VIVO CORRELATION
➢In vitro dissolution refers to the process of dissolution (release)
of drug from a dosage form as measured in an in vitro
dissolution apparatus.
➢In vivo dissolution refers to the process of dissolution of drug
in the GIT.
➢Correlation is a relationship between in vitro dissolution rate
and in vivo input (absorption rate) as used in bioequivalence
guidance.
➢In vitro-in vivo correlation is a predictive mathematical model
describing the relationship b/w in vitro property (release from a
dosage form, usually rate and extent of drug dissolution or
release) and a relevant in vivo response (plasma drug conc. Or 38
amount of drug absorbed).
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➢The in vitro method must reflect the bioavailability (in vivo)
profile of the dosage form, in order to assure biologic response.
➢For Eg: plasma drug conc. or amount of drug absorbed.
➢The drug product should exhibit the same specifications
throughout the shelf life.
APPLICATIONS
➢ In vitro dissolution testing is important for:
• Providing process control and quality assurance.
• Determining consistent release characteristics of the product
over time.
• To ensure batch-to-batch consistency in the physiological
performance of a drug product by use of such in vitro values. 39
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• To serve as a tool in the development of a new dosage form
with desired in vivo performance.
• To assist in validating or setting dissolution specifications (i.e.
the dissolution specifications are based on the performance of
product in vivo).
APPROACHES
➢2 basic approaches by which the correlation b/w dissolution
testing and bioavailability are,
1. By establishing a relationship, usually linear, between the in
vitro dissolution and the in vivo bioavailability parameters.
2. Modifying the dissolution methodology on the basis of
existing bioavailability and clinical data. 40
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PARAMETERS FOR CORRELATION
In vitro In vivo
Dissolution rate Absorption rate (or absorption time)
Percent of drug dissolved Percent of drug absorbed
Max. plasma conc.(C max)
Serum drug conc.
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GENERAL PRINCIPLES OF IVIVC
➢ IVIVC should be developed using two or more formulations
with different release rates
-only one release rate is sufficient if dissolution is
condition-independent.
➢ Invitro dissolution profiles should be generated using an
appropriate dissolution methodology.
-dissolution method used should be same for all the
formulations
➢ A bioavailability study should be conducted to determine
the in vivo plasma concentration time profiles for each of
the formulations
➢ In vivo absorption profile is plotted against the in vitro
dissolution profile to obtain a correlation. 42
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FOUR CATEGORIES OF IVIVC
LEVEL A:
➢A level A correlation represents a point-to-point relationship between
the in vitro dissolution and the in vivo rate of absorption (or in vivo
dissolution)
➢i.e. the in vitro dissolution and in vivo absorption rate curves are
superimposable and the mathematical description for both the curve
is same.
LEVEL B:
➢A level B correlation uses the principles of statistical moment
analysis.
➢The mean in vitro dissolution time is compared with the mean in vivo
dissolution
➢This type of correlation uses all of the in vitro and in vivo data, it is
not considered as a point-to-point correlation .
➢It does not uniquely reflect the actual in vivo plasma drug level 43
curve.
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LEVEL C:
➢A level C correlation establishes a single point relationship
between one dissolution parameter (e.g. t50% dissolved 4 hr in
the dissolution test is correlated) and one pharmacokinetic
parameter (e.g. AUC or Cmax).
➢This level does not reflect the complete shape of the plasma
concentration-time curve.
➢This type of correlation can be useful in early formulation
development and in-process quality control procedure.
MULTIPLE LEVEL C:
➢A multiple level C correlation involving one or several
pharmacokinetic parameters to the amount of drug dissolved at
various time points.
➢This level can be useful as level A IVIVC from a regulatory
perspective.
➢If the drug is highly permeable and in vitro dissolution is the 44
rate limiting step
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TRANSPORT MODEL
PERMEABILITY-SOLUBILITY-CHARGE STATE AND pH
PARTITION HYPOTHESIS
The theory expresses the interrelationship of dissociation constant
and the partition coefficient of the drugs with the GIT pH for the
prediction of drug absorption.
• The theory states that for drug compounds of molecular weight
greater than 100, which are primarily transported across the
biomembrane by passive diffusion the process of absorption is
governed by:
1. The dissociation constant (pKa) of the drug.
2. The lipid solubility of the unionized drug (a function of drug
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Ko/w).
3. The pH at the absorption site.
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• This theory of drug absorption is based on that GIT is a
simple lipid barrier to the transport of drugs and chemicals.
• Accordingly the unionized form of an acid or basic drug, is
sufficiently absorbed but the ionized form is not.
• The larger the fraction of drug in unionized form at a specific
absorption site, the faster is the absorption.
PROPERTIES OF GASTRO INTESTINAL TRACT
GIT is a tube of about nine meters long that runs through the
middle of the body from the mouth to the anus and includes ;
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• throat (pharynx),
• esophagus,
• stomach,
• small intestine
– duodenum
– jejunum
– ileum
• large intestine
• The surface area available for absorption is highest in the
jejunum and the ileum, accounting for more than 99% of
the total.
• In the fasted state, the pH in the stomach is 1.7.
• The acidified contents of the stomach are neutralized in
the duodenum by the infusion of bicarbonate ions through 47
the pancreatic duct.
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Physical properties of the GIT, with approximate values
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pH MICROCLIMATE
• Mechanisms maintaining a low-pH microclimate in the
intestine. The thickness of this microclimate was estimated
to be 700 microns, comparable with that described for the
unstirred water layer. Maintenance of the low
pH compartment is due to the presence of a mucus coating
rather than hydrogen ion secretion.
• The apparent pKa values observed in the absorption–pH
curve in some cases were shifted to higher values for acids
and to lower values for bases, compared with the true pKa
values. Such deviations could be explained by the effect of
an acid layer on the apical side of cells, the so-called acid
pH microclimate
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INTRACELLULAR pH ENVIRONMENT
• The physiological pH in the cytosol is maintained by plasma
membrane-bound H+-ATPase, ion exchangers, as well as
the Na+/K+-ATPase pumps. Inside the organelles, pH
microenvironments are maintained by a balance between ion
pumps, leaks, and internal ionic equilibria
INTRACELLULAR pH ENVIRONMENT
• Mitocondria 8.0
• Cytosol 7.2–7.4
• Endoplasmic reticulum 7.1–7.2
• Golgi 6.2–7.0
• Endosomes 5.5–6.0
• Secretory granules 5.0–6.0
• Lysosomes 4.5–5.0 50
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TIGHT JUNCTIONS
• Tight junctions, also known as occluding
junctions or zonulae occludentes (singular, zonula
occludens) are multiprotein junctional complexes whose
general function is to prevent leakage of transported solutes
and water and seals the paracellular pathway.
• Tight junctions may also serve as leaky pathways by
forming selective channels for small cations, anions, or
water.
• Tight junctions are present only in vertebrates. The
corresponding junctions that occur in invertebrates are
septate junction
• Tight junctions are composed of a branching network of
sealing strands, each strand acting independently from
others. 51
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• There are at least 40 different proteins composing the tight
junctions. These proteins consist of both transmembrane and
cytoplasmic proteins. The three major transmembrane
proteins are occludins, claudins and junction adhesion
molecule (JAM) proteins.
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FUNCTIONS OF TIGHT JUNCTIONS
• They hold cells together.
• Barrier function
• Tight junctions help to maintain the polarity of the cells
by preventing the lateral diffusion of integral membrane
proteins between the apical and lateral /basal surfaces.
• It prevents the passage of molecules and ions through the
space between plasma membranes of adjacent cells.
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REFERENCE
➢Leon shargel, susanna wu-pong, Andrew B.C YU, applied
biopharmaceutics & pharmacokinetics,
5th edition pg.no. 411-452.
➢CVS Subrahmanyam textbook of biopharmaceutics &
pharmacokinetics-concept & applications first edition 2010
pg.no. 49-57,163-171.
➢D M Brahmankar, Sunil B.Jaiswal Biopharmaceutics and
Pharmacokinetics-A treatise third edition 2015 pg.no.52-59,
335-339.
➢Absorption and drug development solubility, permeability and
charge state, Alex Avdeef pg.no.7-22. 54
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THANK YOU…
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