5) Determination of reaction orders
Graphical Method:
 Zero order give a straight line if we plot conc. Vs time
 1st order gives straight line if we plot log conc. Vs time
 2nd order gives straight line if we plot 1 / C Vs time
1
Comparison of orders plotted on Regular Paper:
2nd order is faster than 1st order and 1st order is faster than zero order
reaction.
2
6) Shelf life (t0.9)
It is defined based on potency or concentration of drug as the
time required for the product to decrease in potency to 90% of the initial
labeled potency (concentration). i.e., it is determined according to drug
concentration.
Other criteria for the determination of Shelf life
Toxicity and safety study:
 Urea is diuretic. In aqueous solution, 1% degradation gives very
toxic ammonia (increase pH) and CO2, which can cause ampoule to
explode due to limited solubility in water. Therefore shelf life is
based on 1% not 10% degradation.
 Product elegance: Solution of epinephrine becomes dark in color
due to oxidation before 1% degradation has taken place. Degraded
product is therapeutically acceptable but not accepted by patient i.e
t90% is appearance of dark color.
3
7) Overage
It is over loading the dosage form with more drug than
100% (i.e 110% or more) to give more time to get 90% potency i.e.
shelf life is longer.
Rational:

Shelf lives are usually a maximum of 5 years and it takes a
product up to 2 years to reach customer

Reduced shelf lives are seen in liquid products e.g, antibiotics and
ophthalmics because they are unstable in presence of moisture

Some drugs are inherently unstable e.g, vitamins. Therefore, they
are over loaded.
4
Complex Reaction:
1.
Reversible Reaction
Rate of change of A with respect to time
dA / dt = - K1 [A] + K2 [B]
2.
Parallel Reaction
5
dA / dt = -K1A – K2A
3.
Consecutive Reaction
dA / dt = - K1 [A]
dB / dt = K1 [A] -K2 [B]
dC / dt = K2 [B]
8) Degradation Pathways

Hydrolysis
Degradation caused by presence of water molecules in the
formulation.
6
Method of protection from Hydrolysis:
 Replace liquid dosage forms with solid dosage
forms e.g, tablet, capsules, powders etc.
 Lyophilize liquid dosage forms and reconstitute prior
to administration.
Lyophilization (Freeze drying) i.e sublimation or
evaporation of water from solid state to gaseous
state.
 Control of pH: optimum pH for stability can be
obtained from pH-rate profile
7
pH rate profile:
(a) Plot log conc. Vs time at different pH values
Determine K values at different pH values
8
(b) Plot log K vs pH and this plot is called pH-rate profile
Lowest K value is highest time needed for degradation i.e,
highest Stability but Limitation of pH is solubility
9
• Storage at low temperature:
Generally lower temperature will increase stability
Exception: Emulsion should not be frozen.
• Solvent selection:
Instead of using only water, use water in
combination with other organic co-solvents
Example: ethanol, Propylene glycol, Polyethylene
glycol etc.
 Oxidation
Degradation caused by O2 molecules leading to
formation of free radicals (molecules having a pair of
free electrons) in presence of certain metal ions
(Ferrous or cupric ions)
10
Method of Protection From oxidation:
1- Exclusion of O2
 Sealing of ampoules under inert N2 gas or Argon
 Deoxygenate (boil) water
 Use hermectic strip for tablets and capsules
2- Protect from light:
 Protect from uv and visible light have ionizing radiation leading
to oxidation and formation of free radicals called photolysis
3- Use of chelators:
 Chelators such as EDTA and citric acid are used to remove
metal ions from the solution
4- Use of antioxidants such as water soluble ascorbic acid (Vit-C)
and water insoluble antioxidant - Vitamin-E. They are called O2
scavengers because they are more readily oxidized than active
drugs.
11
9)
Influence of packaging on drug stability
Faulty packaging of pharmaceutical dosage forms can
invalidate the most stable formulation.
Package: It is defined as an economical means of providing
protection, presentation, identification and convenience for a
product until the product is completely used.
Protection from:
(a)
Environmental hazards




(b)
Humidity
Sunlight
Oxygen
Microbial contamination
Physical hazards such as storage and transit
12
(c)
Harmful effects caused by the pack itself i.e.
product and pack must be compatible.
The pack should not leach out and Material should not
absorb constituent from the formulation.
Failure of protection of pharmaceuticals leads to:
- Product may deteriorate by losing activity
- Product may give rise to harmful products.
Types of materials used for containers and closures:
(i)
Glass: Most commonly used packaging material.
Advantages:

Readily available material
13

Inert i.e. provides excellent product-pack compatibility

Provides good product presentation
Types of Glass
According to pharmacopoeia (USP, EP, BP):
1.
Neutral or borosilicate glass
2.
Soda glass with surface treatment
3.
Soda glass with limited alkalinity
4.
Soda glass, non-parenteral general purpose glass
Properties of Glass
1.
Neutral or borosilicate glass
- Only advocated for injectable products or when chemical
reaction may occur because it is inert
- more expensive
- durable
14
2.
Soda glass (three types)
Suitable for product not affected by the slight alkalinity of
the surface
(ii)
Plastic
Advantages

Lighter than glass or metal

Can be used in thinner section

Less prone to breakage and in case breakage occurs,
fragments are less hazardous
Disadvantages

Low chemical inertness compared to glass

More permeable than glass

Low resistance to high temperature compared to glass

For topical ointments, vaccines and transfusion bottles,
flexible plastic called polyolefins are used
15
(iii)
Metal
Advantages

Strong material

Opaque

Impermeable to liquids, gases, odors and bacteria

Resistant to both low and high temperature
Types of metal materials
- Aluminum
- Tin
- Steel
- Tinplate
16
Disadvantages
 Chemical reaction with drug products i.e. not inert
 Corrosion might occur from inside or outside. To overcome
corrosion
metal substances are coated e.g. Tinplate, made by coating low
carbon steel sheet electronically with pure tin
 Most commonly used metal packaging material is Aluminum
because:
- it can be used uncoated
- it is light weight
- it is ductible
- it is non-toxic
- resistant to corrosion
- sterilizable
- can be shaped into rigid, semi rigid or collapsible
containers
17
Closures:
Most effective closure for glass ampoules is sealing by
fusion because product is in contact with only one material.
Requirements for Closures:
 Must be compatible with the product. Closures are made of
metal, plastic or rubber bungs.
 Rubber bungs are used for parenterals that require multiple or
single piercing for multiple use without any detachment of
particles by fragmentation.
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10) Influence of temperature on reaction rate
Basis: Reaction rates are proportional to the number of
collisions per unit time (of reactant molecules). The
number of collisions increases as the temperature
increases. Therefore, the reaction rate increases as the
temperature increases according to Arrhenius equation.
19
- Hump is called Quizi equilibrium point
- Ea is magnitude of hump called activation energy and
defined as: minimal amount of energy that should be given to
molecules to take them to top of hump.
when Ea2 >> Ea1, this is a spontaneous reaction and reversible.
- for a spontaneous reaction Ea comes from surrounding.
Arrhenius equation:
K = reaction rate constant
A = frequency factor constant i.e maximum number of
collisions at infinite temperature
Ea = Energy of activation
T = absolute temperature (Kelvin)
20
Arrhenius plot:
21
Applications:
1- Determine Ea and shelf life if two reaction rate constants K1 and
K2 at two temperatures T1 and T2 are known, use equation:
R
Ea = ln (K1/K2) x
Ln K1 =
Ea
R
(1/T2) – (1/T1)
[(1/T2) – (1/T1)] + Ln K2
Example: a drug decomposes with the following first order rate
constants at the given temperatures.,
K (days-1)
T (oC)
0.0132
40
0.0336
50
Calculate Ea and shelf life at 20oC
22
Ea = ln (0.0132/0.0336) x (1.987 / 1/323- 1/313)
Ea = ln 0.393 x (1.987 / 0.0031-0.0032)
Ea = - 0.934 x - 19870
Ea = 18558.6 cal/ mol.deg
to determine K at 20o C:
ln K1 = Ea/R [(1/T2) – (1/T1)] + Ln K2
ln K1 = 18558.6/1.987 (1/323-1/293) + ln 0.0336
ln K1 = 9340 (0.0031-0.0034) – 3.39
ln K1 = - 2.802 – 3.39
ln K1
= - 6.192
K1 = 0.002 days-1
 Shelf life t90% at 20o C = 0.105/K = 0.1052/0.002 = 52.5 days
23
2- Accelerated stability studies:
Methods:
(a) Determine K at different temperatures
24
(b) Plot log K Vs 1/T
(c) Determine log K from graph at the required temperature (room
temperature or at 20o C ) then determine K and t1/2 and t90% from first
order equations.
25
11) Influence of catalysts on reaction rate
Catalysis:
A catalyst is a substance which.,
 Increase rate of reaction
 Not consumed by reaction i.e not reactant
 Does not alter the yield of reaction
- a catalyst that decreases the reaction rate is called negative
catalyst (inhibitor)
26
Effect of catalyst
27