Physical Pharmacy

1. Factor Affecting GI Absorption of
a Drug
Presented By
KAHNU CHARAN PANIGRAHI
Asst. Professor in Pharmaceutics
12/14/2021
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2. CONTENT
PHARMACEUTICAL FACTOR
A. Physiochemical Factor
• Drug solubility and dissolution rate
• Particle size and effective surface area
• Polymorphism, amorphism and Pseudopolymorphism
• Salt form of the drug
• pH partition hypothesis
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3. B. Pharmaco-techanical factor
• Disintegration time (tablets / capsules)
• Manufacturing variables
• Pharmaceutical ingredients (excipients / adjutants)
• Nature and type of dosage form
• Product age and storage conditions
PATIENT-RELATED FACTOR
• Age
• Gastric emptying time
• Intestinal transit time
• Gastro intestinal pH
• Disease status
• Blood flow through GIT
• Gastrointestinal content
• Pre-systemic metabolism
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4. Drug Solubility and Dissolution Rate
RDS RDS
for lipophilic drug for hydrophilic drug
Lipophilic Drug- Grisofulvin, Spirnolactone
Hydrophilic Drug- Neomycin, Cromolyn sodium
Maxmium absorbable dose(MAD) = Ka SGI VGI tr
Ka = intersic absobtion rate
SGI= solubility of drug in GI
VGI = volume of GI fluid
tr = residence time
If clinical dose < MAD , then absorption is not a limiting factor
Solid
drug
Solid
drug
particle
Drug in solution
at absorption
site
Permiation
Drug in
body
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5. Based on the intestinal permeability and solubility of drug,
Amidon et al. developed BCS.
Biopharmaceutical classification system
Class Solubility Permeability Absorption RDS step Example
1 High High High Gastric
emptying
Diltiazem
2 Low High Variable Dissolution Nifidipine
3 High Low Variable Permeability Insulin
4 Low Low Poor Case by case Taxol
Absolute intrinsic solubility: Maximum amount of solute dissolved in a given
solvent.
Dissolution rate: Amount solid substance that goes into solution per unit time
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6. Theories of drug dissolution
1.Diffusion layer model/Film theory
2.Danckwert model/Surface renewal theory
3.Interfacial barrier model/Limited solvation theory
1.Diffusion layer model/Film theory
• Solution of drug form a thin layer at solid liquid inter
face called as stagnant film or diffusion layer-rapid
step.
• Diffusion of soluble solute from stagnant layer to the
bulk solution-slow step or RDS step.
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8. From Noyes-Whitney’s equation of dissolution:
where,
D = diffusion coefficient or diffusivity of the drug molecule
A = surface area of the dissolving solid exposed to the
dissolution medium
KW/o = water/oil partition coefficient of the drug
V = volume of dissolution medium
h = thickness of the stagnant layer
Cs – CB = concentration gradient of the diffusing drug molecule.
dC
dt
DAK C C
Vh
W O S B


/ ( )
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• The previous equation shows a first order equation, the driving
force is concentration gradient i.e. Cs-Cb
• In vitro dissolution is in non-sink condition, and slow down after
some time .
• The in-vivo dissolution is rapid than in vitro dissolution as sink
conditions are maintained by absorption of drug in systemic
circulation i.e. Cb=0
• Thus in vivo no concentration build up occur in bulk solution
i.e. Cs >> Cb and sink condition maintained
• Under sink conditions, if the volume and surface area of the
solid are kept constant, then equation reduces to
dC/dt = K
• This represents that the dissolution rate is constant under sink
conditions and follows zero order kinetics i.e. yields a linear plot.

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To obtain good in vitro-in vivo dissolution rate correlation, the in
vitro dissolution must always be performed under sink conditions.
The in vitro sink conditions are so maintained that Cb is always less
than 10% of Cs.
This can be achieved in one or more of the following ways;
1.Bathing the dissolving solid in fresh solvent from time to time.
2. Increasing the volume of dissolution fluid.
3. Removing the dissolved drug by partitioning it from the aqueous
phase of the dissolution fluid into an organic phase placed either
above or below the dissolution fluid. Ex: hexane or chloroform.
4. Adding a water miscible solvent such as alcohol to the dissolution
fluid.
5. Adding selected adsorbents to remove the dissolved drug.

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Hixson-Crowell’s cubic root law of dissolution takes into account the particle size
decrease and change in surface area;
W0
1/3 – W1/3 = Kt
Where;
W0 = original mass of the drug.
W = mass of drug remaining to dissolve at time t.
Kt = dissolution rate constant.

12. 2.Danckwert model/Surface renewal theory
 Non existence of stagnant layer
 Trubulence in the dissolution media exist at interface
 Danckwert 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
 Solute containing packets are continuously replaced with new
packet of fresh solvent
The Danckwert’s model is expressed by the equation;
Where;
• m = mass of solid dissolved.
• Gamma (γ) = rate of surface renewal.
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13. 3.Interfacial barrier model/Limited solvation theory
Intermediate concentration can exist at the interface as a result of solvation
mechanism and is a function of solubility rather then diffusion
G = Ki (Cs-Cb )
G= dissolution rate per unit area
Ki=effective interfacial transport constant
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14. PARTICLE SIZE AND EFFECTIVE SURFACE AREA
• Particle size and surface area of solid drug are inversely related to
each other.
• Absolute surface area: total area of solid particle, effective surface
area: area of solid surface exposed to dissolution medium
• According to Noyes-Whitney’s equation dissolution of drug
increases with increase in effective surface area
• For hydrophobic drug like griseofluvin,chloramphnicol increase of
effective surface area by micronisation result increase in
absorption.
• For hydrophobic surface drug like aspirin ,phenacetin the effective
surface area decreased by micronisation due to
1. Adsorption of air which inhibit wettability.
2. Reaggregation to form large particle due to high surface free
energy.
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The absolute surface area is converted to effective surface area by
I. use of surfactant which promote wettability eg-polysorbate-80
II. Adding hydrophilic diluent such as PEG,PVP
The effects of particle size on the absorption of phenacetin in man

16. POLYMORPHISIM, AMORPHISM AND PSEUDOPOLYMORPHISIM
INTERNAL STRUCTURE OF COMPOUND
CRYSTALINE
POLYMORPH
ENANTIOTROPIC MONOTROPIC
MOLECULAR ADUCT
STOICHIOMETRIC
(PSEUDOPOLYMORPHISM)
ORGANIC SOLVATE HYDRATES
NONSTOCHIOMETRIC
AMORPHOUS
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17. • When a substance exist in more than one crystalline from, the different form are designated as
polymorph and the phenomenon as polymorphism.
• Two type: Enantiotropic: reversibly changed into one another
Monotropic: unstable at all temperature and pressure
• Each polymorph are differ in their physical properties like solubility, melting point, density,
hardness, compression etc.
• These can be identified by optical crystallography, XRD, DSC etc.
• Increasing order of energy state and melting point
AMORPHOUS < METASTBLE < STABLE
• Increasing order of solubility
STABLE < METASTBLE <AMORPHOUS
• Example: Polymorphic form-III (metastable) of riboflavin is 20 times more water soluble than
the form-I (stable).
Novobiocin amorphous form 10 time more soluble then crystalline form.
• Conversion of metastable form to stable form can be inhibited by using thickening agent like
PVP, CMC, pectin, gelatin etc.
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18. The crystalline form may be either polymorph or molecular adduct.
The stoichimetric type of adduct where the solvent molecules are incorporated
in the crystal lattice which are call as solvates and the solvent as solvent of
crystallisation.
The solvates exist in different crystalline form are called as
pseudopolymorphism.
When the solvent associated is water then solvate are called as hydrate.
Generally anhydrous form has grater water solubility than the hydrates and
organic solvates have better aqueous solubility than anhydrous form.
e.g: The anhydrous form of ampicillin have higher aqueous solubility then
hydrous form but chloroform solvate of griseofluvin have more aqueous
solubility than non-solvate form.
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SALT FORM OF DRUG
• Most drug are either weak acid or weak base, hence these are
converted to their respective salt for in order to improve the
dissolution rate.
• Weakly acidic drug- a strong base salt is prepared e.g-sodium salt
of barbiturate and sulphonamide
• Weakly basic drug-a strong acid salt is prepared e.g-hydrochloride
of alkaloid

20. • For salt of weak acid (p H)d > (p H)b which favor
solubility of free acid similarly for salt of weak base(p
H)d < (p H)b which favor solubility of free base. (d-
diffusion layer, b- bulk of solution)
• The decrease in p H of the diffusion layer is due to
buffer action of strong base cation or strong acid anion.
• Precipitation of free acid occur when diffuses into
acidic medium having less solubility. These are fine
particle having large surface area leads increase
solubility.
Example: Aspirin, Penicillin etc.
• Smaller the size of counter ion greater the solubility
e.g-Ratio of solubility of novobiocin of its sodium salt ,
calcium salt , free acid is 50:25:1
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21. p H PARTITION HYPOTHESIS-
The theory states that For drug compound of molecular
weight grater than 100, which are transported by passive
diffusion, the process of absorption governed by.
• The dissociation constant (pKa) of drug.
• The lipid solubility of unionized drug (K o/w).
• The pH of absorption site.
On simplifying above theory-
• If the p H on either side of the compartment is different
than the compartment whose p H favor ionization of drug
contain grater amount of drug.
• Only unionized drug with sufficient lipophilicity can
permeate the membrane passively.
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22. The above statement of theory based on assumption that-
1. GIT is a simple lipoidal barrier for transport of drug
2. Larger the fraction of unionized drug faster the absorption
3. Greater the lipophilicity greater the absorption
Drug pKa and GI pH
The amount of drug that exists in unionized form is a function of
dissociation constant (pKa) of the drug and pH of the fluid at the
absorption site. By applying Henderson-Hesslback equation :
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23. Considering p H of GIT in between 1-8. 1-3: stomach, 5-8: intestine
CATEGORY DRUG pKa SITE OF ABSORPTION
Very weak acid Phenobarbital >8 Entire GIT
Phenytoin
Moderately weak Ibuprofen 2.5-7.5 STOMACH
Cloxacillin
Strong acid Disodium
cromoglycate
<2.5 Poorly absorbed
Very weak base Thophylline <5 Entire GIT
Dizepam
Moderately weak Reserpine 5-11 INTESTIN
Codeine
Strong base Mecamylamine >11 Poorly absorbed
guanethidine
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24. o For optimum absorption, a drug ideally should have
sufficient aqueous solubility and lipid solubility high
enough to facilitate partitioning of drug in lipoidal
membrane
o So there should be a perfect HLB for optimum
bioavailability
o A P value of range 1-2 sufficient for passive absorption.
P: Partition coefficient
o P value calculated considering octanol /p H 7.4 buffer
Rapid rate absorption Moderate rate Slow rate
Phenylbutazone Aspirin Barbituric acid
thiopental Theophylline sulphaguanidne
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25. LIMITATION :
1.Presence of virtual membrane p H
 An S shaped curve, called the p H absorption
curve denoting dissociation of drug
 For acidic drug – shift to right basic drug-shift
to left
 Suggest a microclimate p H different from the
luminal p H which is called virtual membrane p
H
2.Absorption of ionised drug
 Principle of non ionic diffusion-ionised drug
absorption 3-4 time less then non ionised
 Some drug having large lipophilic group(e.g-
morphin) despite of their ionisation absorbe
passively
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26. 3.Influence of GI surface area and residence
time of drug
 According to PH partition hypothesis acidic
drug best absorbed from stomach while
basic drug absorbed from intestine
 But due to large surface area of lumen and
longer residence time of drug in intestine
both acidic and basic drug absorbed
predominantly
4.Presence of aqueous unstirred diffusion layer
The shift of p H absorption curve suggest
that the drug is not directly in contact with
the membrane, but a barrier called as
aqueous unstirred diffusion layer present in
between them.
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27. RULE 5 :lipinski
 molecular weight < 500
 Lipophilicity logP < 5
 Number of H-bond acceptor < 10
 Number of H-bond donor < 5
Any of the above 2 more then the
specified value then absorption may be
significant problem
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28. B. Pharmaco-techanical factor
1.Disintegration time
Depend on coating, amount of binder
2. Manufacturing variables
 Method of granulation-wet granulation, direct
compression, agglomerative phase communition
 Compression force-in four way
3. Product age and storage conditions
Alter solubility due to conversion of metastble form to
stable form or change in particle size distribution in case of
suspension, increase in excipient hardness e.g - PVP, acacia
and decrees in hardness for binder like CMC
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29. 4.Effect of Excipients on the Pharmacokinetic
1. Vehicle
2. Diluent
3. Binder
4. Disintegrant
5. Lubricant
6. Coating
7. Suspending agent
8. Surfactants
9. Complexing agents
10.Buffers
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30. Parameters of Oral Drug Products
Excipients Example k a T MAX AUC
Disintegrants Avicel, Explotab + - +/0
Lubricants Talc, hydrogenated
vegetable oil
- + -/0
Coating agent Hydroxypropylmethyl
cellulose
0 0 0
Enteric coat Cellulose acetate phthalate - + -/0
Sustained-release
agents
Methylcellulose,
ethylcellulose
- + -/0
Sustained-release
agents (waxy agents)
Castorwax, Carbowax - + -/0
Sustained-release
agents (gum/viscous)
Veegum, Keltrol - + -/0
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31. 5.Nature and type of dosage form
Slowest
A
B
S
O
R
P
T
I
O
N
Fastest
TABLET
CAPSULE
POWDER
(COARSE)
SUSPENSION
EMULSION
SOLUTION
GRANULES
FINE PARTICLES
DRUG IN SOLUTION
DRUG IN BLOOD
Disintegration
Disoslution of capsule shell
Deaggregation
Dissolution
Absorption
Partition form oil
phase to aqueous phase
Biomembrane
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