Method Development Challenges

1
Method Development - Challenges

• Tahseen Mirza, Ph.D.Associate Director,
  Pharmaceutical and
• Analytical Development
• Pfizer Research Center, Groton
• April 29, 2005

2
Method Devlopment Hydrodynamic Artifacts

Evaluation of Dissolution Hydrodynamics in the
USP, PeakTM and Flat-Bottom Vessels Using
Different Solubility Drugs Tahseen Mirza, Ph.D.1,
Yatindra Joshi, Ph.D, Qian (Julie) Liu, Ph.D.
and Richard Vivilecchia, Ph.D. - Dissolution
Technologies, Volume 12, issue 1, Feb 2005, pp.
11- 16 Literature Several articles in the past
three years
3
Dissolution Artifacts Hydrodynamics, Apparatus
1 and 2

• Confirmation of Existence of the dead zone

4
Plot of Prednisone tablets perturbation study(
prednisone released vs vessel tilt
PhRMA Collaborative performed a similar study -
1999
5
Box and Whisker Plots of the Prednisone tablets
perturbation study( prednisone released vs
vessel tilt)
6
Release rates of LS (low solubility) and HS (high
solubility) drugs with normal set up at paddle
speeds of 50, 60 and 75 rpm, and at the perturbed
condition (vessel tilt of 4.5 mm)
7
Release rate of LS (low solubility drug) at
different agitation rates in the USP vessel
operated under normal set up and perturbed
conditions
8
Release rate of HS (high solubility drug) at
different agitation rates in the USP vessel
operated under normal set up and perturbed
conditions
9
Release rates of LS (low solubility) and HS (high
solubility) drugs from USP, flat-bottomed and
Peak vessels
10
Release rate of LS (Low Solubility) and HS (high
solubility drug) from USP, Peak and Flat-bottom
vessels
11
Other Method Development IssuesBio-relevant
Media

• How do you make a method bio-relevant?
• What is a bio-relevant method?
• Does it have to be physiologically similar?
• Can it be anything that imagination allows?
• How do regulator agency look at newer methods?

12
Use of different software

• Models to simulate conditions
• Softwares are highly model dependent
• Gastroplus (Simulations-Plus, CA)??
• DDS (Simulations-Plus, CA) Allows calibration
  with experimental data

13
Dissolution Methods for Different Phases of
Development

• CSF
• Phase II
• Phase III
• Specification and crtieria
• IVIVC?

14
Low Solubility Drugs

• Use of surfactants
• SLS, Tween, CPC etc., very few choices
• Lack of systematic approach
• Combination of surfactants??
• Single vs. multiple points
• Other Options Increased rpms
• - Other solvents besides water