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1. NAME:ABDUL
MANNAN KASHIF
ROLL NO:M-CHEM
15E07
PRESENTATION TOPIC:
ROLE OF THERMODYNAMIC IN
STABILITY OF DRUG

2. ROLE OF THEMODYNAMICS AND
MOLECULER KINETICS IN STABILITY OF
DRUG AND DOSAGE FORM
CONTENTS
1-ENTROPY
2-GIBS FREE ENERGY
3-ENERGY OF ACTIVATION
4-TRANSITION STATE THEORY
5-COLLISION THEORY
6-ORDER OF REACTION
7-ELECTROCHEMISTRY

3. 1-ENTROPY:
Definition:
Entropy is the quantitative measurement of
randomness of the system.
When we
move ordered
system to
disordered
system
Melting and boiling points as
like melting of ice
Molecular structural change
from simple to complex

4. Types of entropy

5. 1

6. AMOUNT
GIBS FREE ENERGY
Maximum amount of energy to do work……..

9. • Relationship of Gibbs free energy with
different pharmaceutical parameters. Gibbs
Free Energy And Surface Tension
At constant tempreture and pressure surface tension is equal
to Gibbs free energy ……
G=PdV=YdA
Y = represent the surface
A= Surface area
Contact angle&Surface free energy can also
observed with above relation

11. Gibbs free energy and Solubility
Solubility problem can also solved with the help gibbs free
energy…..and its relevant solubility stability disorders can
detmine before time…
1.heat fusion
2.heat sublimation
And differont other such parameters can be calculated

12. Mathematical relation to calculate
solubility

13. NERNST EQUATION;
Nernst equation is also a application of gibbs free energy as
G=-nFE
n=number of electrons transferred in balance reaction
E= potential difference
F=Faraday s constant 96500C/mol
under stander condition
G0=-nFE0
G=G0+RTlnQ
by putting the value of G
-nFE= -nFE0+RTlnQ by dividing with nF
E=E0+RTlnQ/nF
E=E0+2.303RTlogQ/nF
E=E0+0.0595VlogQ/n

16. Theories of reaction rates
Two theories are more important
1. Collision theory
2. Transition state theory
Collision theory:
collision theory based upon
two postulates
1. Molecules must collides
2. They have least equal to activation energy

18. N
Mathematical form of collision theory
2A P
According to law of mass action
-d[A]/dt=k[A]²=kn²
collision number
, ZAA=1/√2 . ²n²Ĉ
-d[A]/t=ZAA
kn²=ZAA
k=ZAA/n2
now add NA/10³ k= [NA/10³] ZAA/n2

19. k=NA/10³×1 /√2 . ²n²Ĉ
C= √ 8RT/ M
k=Z◦=2NA/10³ ² √ RT/M
Determination Of active molecules;
According to Boltzman energy distribution
law
n*=ne-Ea/RT
n*= number of activated molecules
e-Ea/RT=Boltzman factor

20. MODIFIED FOR COLLISION THEORY;
THIS MODIFIED FORM IS NEEDED ON THE
BEHALF OF FRUITFUL COLLISIONS WHICH
RESULTED INTO PRODUCT AND
MATHEMATICALLY CAN BE GIVEN AS
k=PZºeEa/RT In equatiion P is the
probablity factor as complexty increase what will be
the probablity?
When we compare this Arrhenius equation then
k=AeEa/RT then
A=PZº and P=A/Zº

23. MATHEMATICAL FORM TRANSITION
THEORY;
X+Y X*.Y* PRODUCT
k=RT/Nah.k*
K*=X*/[X][Y]
ΔG=-RTlnK*
lnK*=-ΔG*/RT
K*=e- ΔG*/RT
k=RT/Nah.e- ΔG*/RT

24. PHYSICAL STABILITY OF DRUGS
AND DOSAGE FORM
BY ;ABDUL MANNAN KASHIF
BS(HONS),PHARM.D(PU), CRCP(CTU
KARACHI),M.PHIL

25. •DRUG STABILITY ;
Stability of pharmaceutical
product may be defined as capability of chemical drug
and its particular formulation in a specific
container/closure system to remain within its physical,
chemical ,micobiologicl,therputic and toxicological
specifications
Pharmaceutical product should meet their expected
quality, purity and strenth for specific period of time
under certain conditions(storage conditions)
OR

26. AND
PHYSICAL FACTORS FOR STABILITY OF DRUGS;
PHARMACEUTICAL PRODUCTS EXISTES IN
VARIOUS MICROSCOPIC PHYSICAL STATES WITH
DIFFERONT DEGREE OF ORDERS AS
1.AMORPHOUS STATE
2.CRYSTALLINE STATE
3.HYDRATED STATE
4.SOLVATED STATE
THESE STATES CAN BE CHANGED DUE TO
DIFFERONT CHEMICAL POTENTIALS AND
FACTORS .THE RATE OF CONVERSION DEPENDS
UPON ENERGY BARRIERS AND AVILABLE
FACTORS .

27. PHYSICAL CHANGE;
 APPEARANCE
 MELTIN POINT
 CLARITY AND COLOR OF SOLUTION
 MOISTUR
 CRYSTAL
MODIFICATIONS(POLYMORPHISM)
 PARTICLE SIZE

28. PHYSICAL DEGRADATION;
1.CRYSTALLIZATION OF AMOPHOUS
 Amorphous state is more soluble than crystalline state
 solubility is major problem in different dosage forms
So the amorphous state is mostly considered
 but amorphous substance high in free energy and
entropy and leads towards stability problem
 long term storage of amorphous substance resulted in
change in crystal habit
Stability changes of Nifedipine under different storage
conditions give different dissolutions as represented
graphically

30. Changes in dissolution behavior of nifedipine from
amorphous nifdipine samples exposed to
different storage conditions. Storage period at 40°C: (1) 0,
(2) 3.5, (3) 6 months; (b) storage period at 21°C and
75% RH: (1) 0, (2) 0.5, (3) 1.5, (4) 4 months.
 amorphous nifedipine can coprecipitated with
polyvinylpyrrolidone PVP on storage for long while
Spray drying products also show time dependent changes
in solubility.
The crystallization rate of amorphous frusemide prepared by
spray drying depended onthe preparation temperature;
higher temperatures apparently provided a more stable
amorphous,state with a higher glass-transition temperature (
Tg ).
A similar crystallization rate,dependency on the spray-drying
temperature of macrolide derivatives was seen. Spray drying
in nature

31. TRANSITION IN CRYSTALLINE STATE
 POLYMORPHS ARE THE DIFFERENT CRYSTALLINE
FORMS OF THE SINGLE DRUG.
POLYMORPHIC TRANSITION CAN CHANGE THE
CRITICAL PROPERTYIES OF DRUG.
EXAMPLE 1.TWO CRYSTALLINE FORMS OF
BENOXAPROFEN 2.THREE CRSTALLINE FORMS OF
BROMOVALERYLUREA 3 TWO FORMS OF PYRIDOXAL
CHLORIDE…………
TRANSITION BETWEEN HYDRATED AND
ANHYDRATED FORM EXIST IN VARIOUS DRUGS

32. SE
CRYSTAL FORMATION & GORWTH;
Molecules in crystal, and crystal themselves should
not considered as static.
Crystals can increase or decrease in size and
provide medium across which molecules can move.
 this could be liquid phase or gaseous phase into
which molecules can move.
 drug and excipients may be recrystallize and
sublimes on surface and cous “whiskering”.
 this crystallization may enhanced in porous tablets.

33. VAPOR PHASE TRANSFER INCLUDING
SUBLIMATION;
Pharmaceuticals containing components that
sublime easily may undergo changes in,drug
content owing to the sublimation of the drug
substances or excipients.
EXAMLE ;
Nitroglycerin
THIS TRANSFER CAN STOPED BY
POLYETHYLENEGLYCOL PEG OR OTHER
WATER SOLUBLE NON VOLATILE AGENTS

34. MOISTURE ABSORPTION;
MOISTURE ABSORPTION MOSTLY OBSERVED IN SOLID
DOSAGE FORM.
MOISTURE ADSORPTION CAN COUSE PHYSICAL
INSTABILITY OF DRUGS BY CHANGING,
COLOR AND APPEARANCE
DISSOLUTION
ZOGARFI AND COWORKERS DETERMINE THE W FOR SOLID
DOSAGE FORM
Rhi AND RH0= ARE RELATIVE HUMIDITY FACTORS
C&F= CONDUCTIVE COEFFICIENTS

35. TEMPRATURE AS PHYSICAL FACTOR;
Temperature is one of the primary factor affecting the
stability…..basically it can be explained with arrhenius
equation
k
STBILITY IN FROZEN STATE;
FREEZING IS OFTEN ASSUMED TO SLOW
DEGRADATION PROCESS BUT NOT IN AQOUS
SOLUTIONS,WHERE IT INCREASE DEGRADTION.

37. pH AND pH RATE PROFILE;
The effect of pH on degradation rates of
drug substances in aqueous solutions has
been studied extensively, and the pH
dependency of the degradation rate of be
nzylpenicillin was,reported in the 1940.
The pH degradation effect can be explaine
by catalytic effect of hydroxide and
hydronium ion,
IT CHANGES THE ENERGY BARIERS

38. DIFFERONT pH PROFILES FOR PSEUDO
FIRS ORDER REACTIONS WHERE RATE OF
REACTIONS DEPENDS UPON HYDRONIUM
AND HYDROXIDE
.