1. 1 Advisory Committee for Pharmaceutical Science May 3, 2005 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 Lawrence X. Yu, Ph. D. Director for Science Office of Generic Drugs Food and Drug Administration

2. 2 Presentation Outline l In Vitro Dissolution Testing l Limits to Oral Drug Absorption l Challenges to Regulatory Evaluation l In Vitro Dissolution Testing l Limits to Oral Drug Absorption l Challenges to Regulatory Evaluation

3. 3 Oral Drug Absorption Gastric Emptying Transit Permeation Dissolution Metabolism

4. 4 What Does Dissolution Measure? Solid drug particle stagnant layer (h) with a concentration = C s bulk solution with a concentration = C t = X d /V Bulk Solvent          V X C h DA dt dX DR d s

5. 5 Quality Control: Pharmaceutical Solid Polymorphism Form II Form I

6. 6 In Vivo Bioequivalence: IVIVC 0 30 60 90 120 0510152025 Time (hrs.) % Absorbed Regular Fast Slow 0 30 60 90 120 051015202530 Time (hrs.) % Dissolved Regular Fast Slow Dissolution Profiles Fraction Absorption Profiles

7. 7 Presentation Outline l In Vitro Dissolution Testing l Limits to Oral Drug Absorption l Challenges to Regulatory Evaluation l In Vitro Dissolution Testing l Limits to Oral Drug Absorption l Challenges to Regulatory Evaluation

8. 8 Disintegration Dissolution… … …..….. What Affects Dissolution? Drug Substance Factors

9. 9 In Vivo and In Vitro Relationship: Scientific Issues l Limits to oral drug absorption u Dissolution-limited u Solubility-limited u Permeability-limited l Limits to oral drug absorption u Dissolution-limited u Solubility-limited u Permeability-limited Gastric Emptying Transit Permeation Dissolution Metabolism Solubility DissolutionPermeation Conc  Solubility

10. 10 Quantitative Estimation of Absorption Dose Volume Dissolution Time Absorbable Dose

11. 11 Limits to Oral Drug Absorption (Yu, Pharm. Res. 16:1884-1888 (1999)) Rate-limiting Steps ConditionsComments Dissolution limiting T diss > 199 min P eff > 2  10 -4 cm/sec D abs >> Dose The absolute amount of absorbed drug increases with the increased dose. Permeability limiting T diss < 50 min P eff < 2  10 -4 cm/sec D abs >> Dose The absolute amount of absorbed drug increases with the increased dose. Solubility limiting T diss < 50 min P eff > 2  10 -4 cm/sec D abs < Dose The absolute amount of absorbed drug does not increase with the increased dose.

12. 12 CAT Model: Extent of Intestinal Drug Absorption (Permeability-limited) (Yu et al. Int. J. Pharm. 186:119-125 (1999))

13. 13 Digoxin: Dissolution-limited (Yu, Pharm. Res. 16:1884-1888 (1999))

14. 14 Griseofulvin: Solubility-limited (Yu, Pharm. Res. 16:1884-1888 (1999))

15. 15 Applications of Predictive Absorption Model in Drug Discovery

16. 16 Disintegration Dissolution… … …..….. What Affects Dissolution? Dosage Form Factors

17. 17 Plasma Concentration Profile of a Drug from an Oral Solution 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 Plasma Conc time (hr) Oral Solution Data Oral Solution Simulation

18. 18 Dissolution Profile from a Drug from A Solid Oral Dosage Form 0 0.2 0.4 0.6 0.8 1 0 2 4 6 8 10 12 fraction dissolved time (hr) Slow Medium Fast

19. 19 0 1 2 3 4 5 6 7 8 9 0 2 4 6 8 10 Plasma Conc time (hr) Slow Medium Fast Plasma Concentration Profile of a Drug from a Solid Oral Dosage Form

20. 20 Dissolution Profile of a Drug with Different Protective Coating 0 0.2 0.4 0.6 0.8 1 0 2 4 6 8 10 12 fraction dissolved time (hr) Slow Medium Fast

21. 21 PK Profile of a Drug with Different Protective Coating 0 0.01 0.02 0.03 0.04 0.05 0 5 10 15 20 Plasma Conc time (hr) Measured Slow Medium Fast

22. 22 Presentation Outline l In Vitro Dissolution Testing l Limits to Oral Drug Absorption l Challenges to Regulatory Evaluation l In Vitro Dissolution Testing l Limits to Oral Drug Absorption l Challenges to Regulatory Evaluation

23. 23 Dissolution and Limits to Oral Absorption l When dissolution is rapid and, therefore, not the rate determining step, drug levels in blood/plasma may not reflect dissolution differences u Dissolution-limited absorption v IVIVC possible for IR/ER products v In vivo fraction absorption profile is not always possible; Deconvolution-based IVIVC methods u Solubility-limited absorption u Permeability-limited absorption l Convolution-based IVIVC methods l When dissolution is rapid and, therefore, not the rate determining step, drug levels in blood/plasma may not reflect dissolution differences u Dissolution-limited absorption v IVIVC possible for IR/ER products v In vivo fraction absorption profile is not always possible; Deconvolution-based IVIVC methods u Solubility-limited absorption u Permeability-limited absorption l Convolution-based IVIVC methods

24. 24 Dissolution Profile Comparison    }100])TR( n 1 (1{[log50 2 f 5.02 tt l f 2 = ‘Similarity’ Factor. Values are scaled between 0-100. l f 2 values greater than 50 (50-100) reflect a 10% or less, ‘overall’ or ‘global’ difference between the two curves. l f 2 = ‘Similarity’ Factor. Values are scaled between 0-100. l f 2 values greater than 50 (50-100) reflect a 10% or less, ‘overall’ or ‘global’ difference between the two curves.

25. 25 In Vitro and In Vivo l Dissolution testing is “non-discriminating” u Dissolution - limited absorption u Others l Dissolution testing is “over discriminating” u Solubility - limited absorption u Permeability - limited absorption l Dissolution testing is “non-discriminating” u Dissolution - limited absorption u Others l Dissolution testing is “over discriminating” u Solubility - limited absorption u Permeability - limited absorption “f 2 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.”

26. 26 Role of Dissolution Testing l A quality control tool to monitor batch-to-batch consistency of the drug release from a product l An in vitro surrogate for product performance that can guide formulation development and ascertain the need for bioequivalence tests Are these goals consistent? l A quality control tool to monitor batch-to-batch consistency of the drug release from a product l An in vitro surrogate for product performance that can guide formulation development and ascertain the need for bioequivalence tests Are these goals consistent?

27. 27 Hydrodynamic Conditions l Current Paddle Speeds Result in Re: u Re = 4688 (50 RPM) u Re = 9375 (100 RPM) l Some evidence that current speeds are correlated with in vivo dissolution l Slower laminar flows would lead to much more reproducible hydrodynamics, but may not correlate with in vivo hydrodynamics. l Current Paddle Speeds Result in Re: u Re = 4688 (50 RPM) u Re = 9375 (100 RPM) l Some evidence that current speeds are correlated with in vivo dissolution l 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

28. 28 Medium l Product Specific Medium u Allows full dissolution for all products in a finite time and dissolution volume l Universal/Biorelevant Media u A true in vivo correlation should use the same media for all products l Product Specific Medium u Allows full dissolution for all products in a finite time and dissolution volume l Universal/Biorelevant Media u A true in vivo correlation should use the same media for all products

29. 29 Role of Dissolution l Should the roles be separated? l Is single point acceptance criterion relevant for either role? l Do the multiple roles impede the reduction of variability? l Should the roles be separated? l Is single point acceptance criterion relevant for either role? l Do the multiple roles impede the reduction of variability?

30. 30 Dissolution for Quality Control l A product specific quality control test u The hydrodynamics and medium for this test are chosen for reproducibility and detection of product changes u The design of this test is not constrained by a desire to mimic in vivo conditions. l A product specific quality control test u The hydrodynamics and medium for this test are chosen for reproducibility and detection of product changes u The design of this test is not constrained by a desire to mimic in vivo conditions.

31. 31 Dissolution for In Vivo Performance l A biorelevant dissolution test u 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 u The biorelevant dissolution test is a one-time test to provide a baseline for product performance u Any biowaivers should rely on the biorelevant dissolution testing u Biorelevant dissolution testing as a quality control test l A biorelevant dissolution test u 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 u The biorelevant dissolution test is a one-time test to provide a baseline for product performance u Any biowaivers should rely on the biorelevant dissolution testing u Biorelevant dissolution testing as a quality control test

32. 32 Summary l In Vitro Dissolution Testing - Over discriminating/Non-discriminating dissolution - Not sufficient to assure bioequivalence/bioavailability l Limits to Oral Drug Absorption - Dissolution/Solubility/Permeability-limited absorption l Challenges to Regulatory Evaluation u Dissolution Profile Comparison u Role of Dissolution Testing l In Vitro Dissolution Testing - Over discriminating/Non-discriminating dissolution - Not sufficient to assure bioequivalence/bioavailability l Limits to Oral Drug Absorption - Dissolution/Solubility/Permeability-limited absorption l Challenges to Regulatory Evaluation u Dissolution Profile Comparison u Role of Dissolution Testing