1

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

2

Comparison of orders plotted on Regular Paper:

2nd order is faster than 1st order and 1st order is faster than zero orderreaction.

3

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.

4

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.

5

Complex Reaction:

1. Reversible Reaction

Rate of change of A with respect to time

dA / dt = - K1 [A] + K2 [B]

2. Parallel Reaction

6

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.

7

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

8

pH rate profile:

(a) Plot log conc. Vs time at different pH values

Determine K values at different pH values

9

(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

10

• Storage at low temperature:Generally lower temperature will increase stabilityException: Emulsion should not be frozen.

• Solvent selection:Instead of using only water, use water in combination with other organic co-solventsExample: 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)

11

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.

12

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 Humidity Sunlight Oxygen Microbial contamination

(b) Physical hazards such as storage and transit

13

(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

14

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

15

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

16

(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

17

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

18

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.

19

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.

20

- 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)

21

Arrhenius plot:

22

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:

Ea = ln (K1/K2) x

Ln K1 = [(1/T2) – (1/T1)] + Ln K2

Example: a drug decomposes with the following first order rate constants at the given temperatures.,

K (days-1) 0.0132 0.0336

T (oC) 40 50

Calculate Ea and shelf life at 20oC

R

(1/T2) – (1/T1)

Ea

R

23

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

24

2- Accelerated stability studies:

Methods:

(a) Determine K at different temperatures

25

(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.

26

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)

27

Effect of catalyst