Pharmaceutical development of a dosage form will be easier
if a system is developed that exactly mimics the conditions of human body. Unfortunately, till date, such a system does
not exist. Dissolution serves the
purpose to some extent for the prediction of various pharmacokinetic
parameters. Bioavailability is the rate
and extent of absorption of drug whereas dissolution is the rate and extent of
drug that goes into solution. The rate
constant that is calculated in dissolution indicates the rate of absorption of
drug and the extent of dissolution indicates the amount of drug absorbed. A good correlation of invitro values with
invivo values has several advantages.
Bioavailability studies during formulation development can be minimized. It gives support to the bioequivalence
studies that are required during development of generic drug product. Establishing strong IVIC also helps in
approval of scale up and post approval changes (my previous blog). Any small changes like batch size, equipment,
site change that may affect the bioavailability can be justified by strong
IVIC. Regulatory guidance was given by
FDA on IVIC. Five correlation levels have
been given by FDA1.
Level A correlation1: It is the highest degree of
correlation. All the parameters
calculated invitro exactly matches with invivo.
The percentage of drug released exactly matches with the invivo drug
absorbed calculated from methods like Wagner Nelson method or Loo-Reilgman
method. Raw material changes,
manufacturing site or any other small changes in formulation can be justified.
Level B correlation1: It is not exact correlation of the
points and depends on principles of statistical moment analysis. Mean dissolution time, mean residence time
calculated from invitro and invivo data are considered. This correlation cannot
justify manufacturing site change, formulation modification.
Level C correlation1: It is the weakest correlation. At a single point of time, the amount of drug
dissolved is compared with invivo parameter.
Either the values of t 50%, t 90% are compared with AUC or cmax, tmax. This type of correlation is generally useful
during early stages of formulation development.
Multiple - level C correlation1: As the name indicates, AUC
or cmax is compared with amount of drug dissolved at several time points of
dissolution. The time points represent
early, middle and late stages of dissolution.
If the correlation is more at different points, it suggests that level A
correlation can also be achieved.
Level D correlation1:
It is the qualitative analysis and not useful for regulatory purposes but
used during formulation.