Pg.

108-124
Partition Coefficient
Inherent in this procedure is the selection of appropriate extraction solvents, drug stability, use
of salting-out additives, and environmental concerns
Octanol-partition coefficient is commonly used in formulation development
pKa or Dissociation Constants
Extent of dissociation or ionization of drug substances
Extent of ionization: important effect on the formulation and pharmacokinetic parameters of
the drug
Extent of ionization also has a strong effect on absorption, distribution, and elimination
pKa: usually determined by potentiometric titration
Drug and drug product stability
Evaluation of the physical and chemical stability of the pure drug substance
Drug stability: mechanisms of degradations
Chemical instability of medical agents may take many forms because the drugs in use today are
such diverse chemical constitution.
Hydrolysis and Oxidation: most frequently encountered destructive processes (chemically)
Hydrolysis: solvolysis process in which (drug) molecules interact with water molecules to yield
breakdown products
Hydrolysis most important single cause of drug decomposition: this is due to the great
number of medicinal agents are esters or contain such other groupings as substituted amides,
lactones, and lactams, which are susceptible to the hydrolytic process
Oxidation: loss of electrons from atom or molecule. Each electron is accepted by other
molecule, the recipient
Oxidation is synonymous to the loss of hydrogen (dehydrogenation) from a molecule
Free chemical radicals: molecules or atoms containing one or more unpaired electrons such as
O2 and free OH; these chemicals tend to take electrons from other chemicals, thus oxidizing the
donor
Many of the oxidative changes in pharmaceutical preparations have the character of
autoxidation: autoxidation occur spontaneously under the initial influence of atmospheric
oxygen and proceed SLOWLY and then more RAPIDLY
Autoxidation: a type of chain reaction commencing with the union of oxygen with the drug
molecule and continuing with a free radical of this oxidized molecule participating in the
destruction of other drug molecules and so forth
Decomposition may be prevented in other liquid drugs by suspending them in a nonaqueous
vehicle rather than dissolving them in an aqueous solvent
Antioxidants: reacts with one or more compounds in the drug to prevent progress of the chain
reaction, thus diverting the oxidative process and preserving the stability of the drug
Antioxidants act by being the molecule oxidized rather than the drug being protected
For easily oxidizable drugs, the formulation pharmacist may stabilize the preparation by the
selective exclusion from the system of oxygen, oxidizing agents, trace metals, light, heat and
other chemical catalysts
Antioxidants, chelating agents, and buffering agents may be added to create and maintain a
favorable pH
Kinetics and shelf life
Stability is the extent to which a product retains within specified limits and throughout its period
of storage and use the same properties and characteristics that it possessed at the time of its
manufacture
Half-life: the time taken for the radioactivity of a specified isotope to fall to half its original value
Five Types of Stability
Chemical: each active ingredient retains its chemical integrity and labeled potency within the
specified limits.
Physical: the original physical properties including appearance, palatability, uniformity,
dissolution and suspendability are retained.
Microbiology: sterility or resistance to microbial growth is retained according to the specified
requirements. Antimicrobial agents retain effectiveness within specified limits.
Therapeutic: The therapeutic effect remains unchanged.
Toxicologic: no significant increase in toxicity occurs.
Reaction rate
Description of the drug concentration with respect to the time
Order: the exponent of the individual concentration term in the rate expression
Overall order: Sum of the order of the exponents of the concentration terms of the rate
expression
Zero order and first order: most commonly encountered in pharmacy
Q
10
method of shelf life estimation
Lets the pharmacist estimate shelf life for a product that has been stored or is going to be stored
under different set of conditions
Q
10
= e
(Ea/R)(1/T + 10) (1/T)