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
 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
 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
 Zero order and first order: most commonly encountered in pharmacy
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
= e
(Ea/R)(1/T + 10) – (1/T)