Factors Impacting Drug Dissolution and Absorption : Current State of Science

Factors Impacting Drug Dissolution and Absorption: Current State of Science Lawrence X. Yu, Ph. D. Director for Science Office of Generic Drugs Food and Drug Administration Advisory Committee for Pharmaceutical Science May 3, 2005

Presentation Outline • In Vitro Dissolution Testing • Limits to Oral Drug Absorption • Challenges to Regulatory Evaluation

Oral Drug Absorption Gastric Emptying Metabolism Transit Permeation Dissolution

× æ ö dX A D X d = = × - ç ÷ DR C s dt h V è ø What Does Dissolution Measure? Solid drug particle stagnant layer (h) with a concentration = Cs bulk solution with a concentration = Ct = Xd/V Bulk Solvent

Quality Control: Pharmaceutical Solid Polymorphism Form II Form I

120 120 90 90 Regular Regular % Dissolved 60 Fast % Absorbed 60 Fast Slow Slow 30 30 0 0 0 5 10 15 20 25 0 5 10 15 20 25 30 Time (hrs.) Time (hrs.) In Vivo Bioequivalence: IVIVC Dissolution Profiles Fraction Absorption Profiles

…… …..….. …….. Disintegration Dissolution What Affects Dissolution? Drug Substance Factors

Gastric Emptying Metabolism Transit Permeation Solubility Dissolution Permeation Dissolution Conc  Solubility In Vivo and In Vitro Relationship: Scientific Issues • Limits to oral drug absorption • Dissolution-limited • Solubility-limited • Permeability-limited

Quantitative Estimation of Absorption

Limits to Oral Drug Absorption(Yu, Pharm. Res. 16:1884-1888 (1999))

CAT Model: Extent of Intestinal Drug Absorption (Permeability-limited)(Yu et al. Int. J. Pharm. 186:119-125 (1999))

Digoxin: Dissolution-limited (Yu, Pharm. Res. 16:1884-1888 (1999))

Griseofulvin: Solubility-limited(Yu, Pharm. Res. 16:1884-1888 (1999))

Applications of Predictive Absorption Model in Drug Discovery

…… …..….. …….. Disintegration Dissolution What Affects Dissolution? Dosage Form Factors

Plasma Concentration Profile of a Drug from an Oral Solution 14 12 10 8 Plasma Conc 6 4 2 Oral Solution Data Oral Solution Simulation 0 0 2 4 6 8 10 12 time (hr)

1 0.8 0.6 fraction dissolved 0.4 0.2 Slow Medium Fast 0 0 2 4 6 8 10 12 time (hr) Dissolution Profile from a Drug from A Solid Oral Dosage Form

9 Slow Medium 8 Fast 7 6 5 Plasma Conc 4 3 2 1 0 0 2 4 6 8 10 time (hr) Plasma Concentration Profile of a Drug from a Solid Oral Dosage Form

1 0.8 0.6 fraction dissolved 0.4 0.2 Slow Medium Fast 0 0 2 4 6 8 10 12 time (hr) Dissolution Profile of a Drug with Different Protective Coating

PK Profile of a Drug with Different Protective Coating 0.05 Measured Slow Medium 0.04 Fast 0.03 Plasma Conc 0.02 0.01 0 0 5 10 15 20 time (hr)

Dissolution and Limits to Oral Absorption • When dissolution is rapid and, therefore, not the rate determining step, drug levels in blood/plasma may not reflect dissolution differences • Dissolution-limited absorption • IVIVC possible for IR/ER products • In vivo fraction absorption profile is not always possible; Deconvolution-based IVIVC methods • Solubility-limited absorption • Permeability-limited absorption • Convolution-based IVIVC methods

f2= ‘Similarity’ Factor. Values are scaled between 0-100. f2 values greater than 50 (50-100) reflect a 10% or less, ‘overall’ or ‘global’ difference between the two curves. 1 å - = · + - · 2 0 . 5 f 2 50 log {[ 1 ( ( R T ) ] 100 } t t n Dissolution Profile Comparison

Dissolution testing is “non-discriminating” Dissolution - limited absorption Others Dissolution testing is “over discriminating” Solubility - limited absorption Permeability - limited absorption In Vitro and In Vivo “f2 values greater than 50 (50-100) ensure sameness or equivalence of the two curves and, thus, of the performance of the test (post -change) and reference (pre-change) products.”

Role of Dissolution Testing • A quality control tool to monitor batch-to-batch consistency of the drug release from a product • An in vitro surrogate for product performance that can guide formulation development and ascertain the need for bioequivalence tests Are these goals consistent?

Hydrodynamic Conditions • Current Paddle Speeds Result in Re: • Re = 4688 (50 RPM) • Re = 9375 (100 RPM) • Some evidence that current speeds are correlated with in vivo dissolution • Slower laminar flows would lead to much more reproducible hydrodynamics, but may not correlate with in vivo hydrodynamics. A. Scholz, E. Kostewicz, B. Abrahamsson and J. B. Dressman Can the USP paddle method be used to represent in-vivo hydrodynamics? Journal of Pharmacy and Pharmacology 55 (2003) 443-451

Medium • Product Specific Medium • Allows full dissolution for all products in a finite time and dissolution volume • Universal/Biorelevant Media • A true in vivo correlation should use the same media for all products

Role of Dissolution • Should the roles be separated? • Is single point acceptance criterion relevant for either role? • Do the multiple roles impede the reduction of variability?

Dissolution for Quality Control • A product specific quality control test • The hydrodynamics and medium for this test are chosen for reproducibility and detection of product changes • The design of this test is not constrained by a desire to mimic in vivo conditions.

Dissolution for In Vivo Performance • A biorelevant dissolution test • All products should undergo dissolution testing in the same device and same media (corresponding to stomach and intestine under fed and fasted conditions) that gives the best possibility to correlate with in vivo dissolution • The biorelevant dissolution test is a one-time test to provide a baseline for product performance • Any biowaivers should rely on the biorelevant dissolution testing • Biorelevant dissolution testing as a quality control test

Summary • In Vitro Dissolution Testing - Over discriminating/Non-discriminating dissolution - Not sufficient to assure bioequivalence/bioavailability • Limits to Oral Drug Absorption - Dissolution/Solubility/Permeability-limited absorption • Challenges to Regulatory Evaluation • Dissolution Profile Comparison • Role of Dissolution Testing

Factors Impacting Drug Dissolution and Absorption : Current State of Science