# Presentation: 909160

## Factors Impacting Drug Dissolution and Absorption: Current State of Science

**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***

## Presentation Outline

***In Vitro***** Dissolution Testing **
**Limits to Oral Drug Absorption**
**Challenges to Regulatory Evaluation**

## Oral Drug Absorption

**Gastric Emptying**

**Transit**

**Permeation**

**Dissolution**

**Metabolism**

## 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**

## In Vivo Bioequivalence: IVIVC

**Dissolution Profiles                                Fraction Absorption Profiles**

## Presentation Outline

***In Vitro***** Dissolution Testing**** **
**Limits to Oral Drug Absorption**
**Challenges to Regulatory Evaluation**

## What Affects Dissolution?

**What Affects Dissolution?**

**Drug Substance Factors**

## In Vivo and In Vitro Relationship: Scientific Issues

**Limits to oral drug absorption**
**Dissolution-limited **
**Solubility-limited**
**Permeability-limited**

## Quantitative Estimation of Absorption

| Dose Volume |  |
| --- | --- |
| Dissolution Time |  |
| Absorbable Dose |  |

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

| Rate-limiting
Steps | Conditions | Comments |
| --- | --- | --- |
| Dissolution limiting  | Tdiss > 199 min
Peff  > 2  10-4 cm/sec
Dabs >> Dose  | The absolute amount of absorbed drug increases with the increased dose.  |
| Permeability limiting  | Tdiss < 50 min
Peff < 2  10-4 cm/sec
Dabs >> Dose  | The absolute amount of absorbed drug increases with the increased dose.  |
| Solubility 
limiting  | Tdiss < 50 min
Peff > 2  10-4 cm/sec
Dabs < Dose  | The absolute amount of absorbed drug does not increase with the increased dose.  |

## 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

## What Affects Dissolution?

**What Affects Dissolution?**

**Dosage Form Factors**

## 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

## Dissolution Profile from a Drug from A Solid Oral Dosage Form

## Plasma Concentration Profile of a Drug from a Solid Oral Dosage Form

**Plasma Concentration Profile of a Drug from a Solid Oral Dosage Form**

## Dissolution Profile of a Drug with Different Protective Coating

## 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

## Presentation Outline

***In Vitro***** Dissolution Testing**** **
**Limits to Oral Drug Absorption**
**Challenges to Regulatory Evaluation**

## 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 **

## Dissolution Profile Comparison

**f****2****= ‘Similarity’ Factor. Values are scaled between 0-100. **
**f****2**** values greater than 50 (50-100) reflect a ****10%**** or less, ‘overall’ or ‘global’ difference between the two curves. **

## In Vitro and In Vivo

**Dissolution testing is “non-discriminating”**
**Dissolution - limited absorption**
**Others**
**Dissolution testing is “over discriminating”**
**Solubility - limited absorption**
**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.”**

## 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