Biopharmaceutic factors in dosage form design and theories of dissolution

Biopharmaceutic factors in
Dosage Form Design and
Theories of Dissolution
By: Dr. (Mrs)Suvarna Phadatare
Associate Professor
NCRD’s Sterling Institute of Pharmacy,
Nerul, Navi mumbai

Biopharmaceutic factors in Dosage Form
Design OR Factors influencing GI absorption of
a Drug
A. PHARMACEUTICAL FACTORS
a. Physicochem props of drug substance
Drug Soly &Dissoln rate,
Pcle size and Surface area
Polymorphism, Hydrates/ solvates
Salt form, Drug stability
Stereochemical nature of drug
Lipophilicity, pKa of drug –pH partition theory
b. Pharmacotechnical factors – DT, Manufacturing
variables, Excipients,Nature and type of D.F.,
Storage and aging
S.P. Phadtare, SIP, Navi Mumbai.

Factors influencing GI absorption
of a Drug
B. PATIENT RELATED FACTORS (8)
Age ,gastric emptying time, pH, Disease
states, GI contents, Presystemic
metabolism

A. PHARMACEUTICAL FACTORS
Physicochem props of drug substance
1. Drug solubility and Dissolution rate
Rate Determining Steps
1. Rate of dissolution (RDS -
______drugs)
* drug product drug substance in solutn
2. membrane transport (permeatn
across bio. Membrane) (RDS-
__________drugs)
*  drug substance in the system
* simplified mechanistic view of bioavailability

Physicochem props Drug
solubility and Dissolution rate
Correlation between Therap. Doses and
desired solubilty
DOSE
(mg/kg)
DESIRED SOLUBILITY VALUES (mg/ml) FOR
DRUGS WITH
High permeability Medium
permeability
Low
permeability
0.1 1 5 21
1 10 52 207
10 100 520 2100

Physicochem props Drug solubility and
Dissolution rate
Concept of Max. Absorbable Dose (MAD):
MAD = Ka SGI VGI tr
Where,
Ka = intrinsic absorptn rate const
SGI = Soly of drug in GI fluid
VGI = Volume of GI fluid
tr = Residence of drug in GI
Key parameters that have limiting effect on drug
absorption
1. Solubility of drug in the GIT.
2. Intrinsic absorption rate constant specific to drug in
solution.
Eg. - 2 drugs,same Ka, one with greater SGI - ??_MAD
In General, if projected clinical dose << MAD, then D.
Absorptn as limitng factor . If dose >> MAD, then

Biopharmaceutics Classification System (BCS) for
drugs
SOLUBLT
Y
PERMBLTY BCS Class & eg. Absorpn
Pattern
RDS in
Absorptn
High High I (Diltiazam,
Propranolol)
Well
absobed as
no limitn
Gastric
emptying
Low High II ( Nifedipine,
Glibenclamide)
Variable Dissolution
High Low III (Insulin,
Atenolol)
Variable Permeabilty
Low Low IV (Taxol,
Azathioprine)
Poorly
absorbed
Case by
case (both
limtns)

Biopharmaceutics Classification
System (BCS) for drugs
High solubility
 the highest single dose is completely soluble in
250 ml or less of aqueous solution at pH 1 - 6.8
(37 °C)
 generate a pH-solubility profile
High permeability
♦ EU guidance: “Linear and complete absorption
reduces the possibility of an IR dosage form
influencing the bioavailability”
♦ FDA guidance: absolute BA >90 %
♦ WHO guidance: at least 85 % absorption in
humans

Physico chemical factors affecting GI
absorption of a Drug
Definition-
 Dissolution is a process in which a solid
substance solubilizes in a given solvent i.e.
mass transfer from the solid surface to the
liquid phase.
 Abs / Intrinsic Solubility: Max amt of solute
dissolved in a given solvent under std
conditions of temp, pressure and pH.
 Rate of dissolution is the amount of drug
substance that goes in solution per unit time
under standardized conditions of liquid/solid
interface, temperature and solvent composition.

Theories of Drug Dissolution
I. Diffusion layer model/Film Theory
II. Danckwert’s model/Penetration or surface
renewal Theory
III. Interfacial barrier model/Double barrier or
Limited solvation theory.

I. Diffusion layer model/Film Theory
:-
* It involves two steps :-
a. Solution of the solid to form stagnant film or
diffusive layer which is saturated with the drug
b. Diffusion of the soluble solute from the stagnant
layer to the bulk of the solution; slower so this is
r.d.s in drug dissolution.

* The rate of dissolution is given by Noyes and
Whitney:
 dc = k (Cs- Cb)
 dt
dc/dt= dissolution rate of the drug
K= dissolution rate constant
Cs= concentration of drug in stagnant layer
Cb= concentration of drug in the bulk of the
solution at time t

Modified Noyes-Whitney’s
Equation -
 dC 
 dt
 Where,
 D= diffusion coefficient of drug.
 A= surface area of dissolving solid.
 Kw/o= water/oil partition coefficient of drug.
 V= volume of dissolution medium.
 h= thickness of stagnant layer.
 (Cs – Cb )= conc. gradient for diffusion of drug.
DAKw/o (Cs – Cb )
Vh

 This is first order dissolution rate process, for
which the driving force is concentration gradient.
 This is true for in-vitro dissolution which is
characterized by non-sink conditions.
 The in-vivo dissolution is rapid as sink conditions
are maintained by absorption of drug in systemic
circulation i.e. Cb=0 and rate of dissolution is
maximum.

 Under sink conditions, if the volume and
surface area of the solid are kept
constant, then
dC 
dt
 This represents that the dissolution rate
is constant under sink conditions and
follows zero order kinetics.
K

Dissolution rate under non-sink
and sink conditions.
Time
Dissolution rate under non-
sink and sink conditions.
zero order dissolution
under sink condition
Conc
of
dissolved
drug

 Hixon-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.

Danckwert’s model / Penetration
or surface renewal Theory :-
 Dankwert 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.

 The Danckwert’s model is expressed by
equation
Where,
m = mass of solid dissolved
Gamma (γ) = rate of surface renewal
dC
dt
=
V
dm
dt
= A (Cs-Cb). γ D

III. Interfacial barrier model/Double
barrier or Limited solvation theory
 It is based on solvation mecha-
intermediate concn exists at interface
and is a function of soly, not diffusion
(not mass transport).
 The concept of this theory is explained
by following equation-
G = Ki (Cs - Cb)
Where,
G = dissolution rate per unit area,
Ki = effective interfacial transport constant.

Factors affecting Drug Dissolution :
A.Factors relating to physico-chemical
properties of drug.
Pcle size and Surface area
Polymorphism, Hydrates/ solvates
Salt form, Drug stability
Stereochemical nature of drug
Lipophilicity, pKa of drug –pH partition
theory
B. Dosage form related Factors-
DT, Mfg variables,Excipients,Nature and type
of D.F., Storage and aging.

A.Factors affecting Dissoln : relating to
physico-chemical properties of drug.
1.* Solubility:Solubility plays important role in
controlling dissolution from dosage form. All
factors –affect drug solubility.
Noyes-Whitney equation: it shows that
aqueous solubility of drug which determines its
dissolution rate.
Empirical relation for prediction of dissoln
rate from solubility :
Disoln rate R= dC/dt = 2.24 Cs
Drug should have a min aq solubty of 1% to
avoid bioavalblty problems.

2. Pcle size and Surface area of the drug –
 Particle size and surface area are
inversely related to each other.
Two types of surface area –
Absolute surface area which is the total
surface area of any particle.
Effective surface area which is the area of
solid surface exposed to the dissolution
medium.
Modified Noyes whitney eqn
Disoln rate directly proportnl to A

 Effective surface area is directly related to
the dissolution rate.
 Greater the effective surface area, more
intimate the contact between the solid
surface and the aqueous solvent,
increased interaction with solvent and
faster the dissolution.
  in SA by  pcle size- Micronizn to < 0.1
for poorly water sol drugs eg. griseofulvin,
chloramphenicol, tetracycline salts

3.Polymorphism and amorphism –
 When a substance exists in more than
one crystalline form, the different forms
are designated as polymorphs and the
phenomenon as Polymorphism.
 Stable polymorphs has lower energy
state, higher M.P. and least aqueous
solubility.
 Metastable polymorphs has higher energy
state, lower M.P. and higher aqueous
solubility

 Amorphous form of drug which has no
internal crystal structure represents
higher energy state and greater aqueous
solubility than crystalline forms.
 E.g.- amorphous form of novobiocin is
10 times more soluble than the
crystalline form.
 Thus, the order for dissolution of different
solid forms of drug is –
amorphous > metastable > stable

4.Hydrates/solvates –
 The stoichiometric type of adducts where
the solvent molecules are incorporated in
the crystal lattice of the solid are called as
the solvates.When the solvent in
association with the drug is water, the
solvate is known as hydrate.
 Anhydrous form- greater aq solubility...?
eg anhyd theophylline (vs monohyd) &
ampicillin(vs trihydrate)
 The organic (non aq)solvates have greater
aqueous solubility than the nonsolvates.
 E.g. – chloroform solvates of griseofulvin is more
water soluble than their nonsolvated forms

5.Salt form of the drug-
 Dissolution rate of weak acids and
weak bases can be enhance by
converting them into their salt form.
 With weakly acidic drugs, a strong base
salt is prepared eg. sodium and
potassium salts of barbiturates and
sulfonamides.
 With weakly basic drugs, a strong acid
salt is prepared like the hydrochloride
or sulfate salts of alkaloidal drugs.

Factors affecting Dissolution :
Pharmaceutical excipients –
 Vehicle
 Diluents
 Lubricants
 Binders
 Surfactants
 colorants

Factors affecting Dissolution :
Manufacturing processes -
Method of granulation –
Wet granulation
Direct compression
Agglomerative phase of communication
(APOC)

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