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

Comparison of orders plotted on Regular Paper: 2nd order is faster than 1st order and 1st order is faster than zero order reaction.

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.

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.

Complex Reaction: Reversible Reaction Rate of change of A with respect to time dA / dt = - K1 [A] + K2 [B] Parallel Reaction

dA / dt = -K1A – K2A 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.

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

pH rate profile: (a) Plot log conc. Vs time at different pH values Determine K values at different pH values

(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

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)

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.

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: Environmental hazards Humidity Sunlight Oxygen Microbial contamination Physical hazards such as storage and transit

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: Glass: Most commonly used packaging material. Advantages: Readily available material

Provides good product presentation Types of Glass Inert i.e. provides excellent product-pack compatibility Provides good product presentation Types of Glass According to pharmacopoeia (USP, EP, BP): Neutral or borosilicate glass Soda glass with surface treatment Soda glass with limited alkalinity Soda glass, non-parenteral general purpose glass Properties of Glass - Only advocated for injectable products or when chemical reaction may occur because it is inert - more expensive - durable

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

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

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

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.

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.

- 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)

Arrhenius plot:

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

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

2- Accelerated stability studies: Methods: Determine K at different temperatures

(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.

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)

Effect of catalyst