Biomedical Engineering Reference
In-Depth Information
Table 2
List of preformulation studies
Study
Comment
Ionization constant (pKa)
Information helpful to improve aqueous
solubility, assess BCS classification,
and identify best candidate.
Partition/distribution coefficient (Log D/P)
Lipophilicity. Information helpful to assess
BCS classification and identify best
candidate for development.
Solubility
Intrinsic solubility.
pH solubility (preferred pH 4-8).
Effect of solubilizers
Surfactant.
Cosolvent.
Complexing agents.
Surfactant/cosolvent combination.
Cosolvent/complexing agent combination.
Cosolvent/surfactant/complexing agent
combination.
Effect of common ions on solubility
With appropriate salts.
Solution stability
pH stability (preferred pH 4-8).
Arrhenius study (pH 5 and 7).
Oxidation study with oxidants.
Photostability
Under ICH light condition (preferred pH 4-8).
Crystal properties and polymorphism,
solid-state characterization, evaluate
relative stability of known solid forms
Conduct study to determine the most stable
crystal form. Important for suspension
formulation.
Excipient compatibility
With excipients commonly used in ophthalmic
formulations.
Effect of sterilization
Determine the best method of sterilization
(dry heat, gamma, autoclave slurry, ETO).
Packaging compatibility
Assess packaging compatibility (as appropriate
and needed).
The impurities should be specified in the drug substance speci-
fication section. Furthermore, a rationale for inclusion/exclusion
of impurities should also be included in the submission. A decision
tree for identification and qualification of impurities is also provided
in the guidance.
These are generally assessed and if necessary qualified following
compendia or other suitable procedures. Discussion in the submis-
sion should be provided on inclusion/exclusion requirement of
3.3.2 Inorganic
Impurities
