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Agilent Dissolution Seminar Series

1© - 2013 All Rights Reserved


Terry Way

Dissolution Science Consultant

Agilent Technologies

Terry Way BSc MAPS

….qualified at the Portsmouth School of Pharmacy, England, specialising in

pharmaceutical analysis. He worked in both QC and development laboratories of several pharmaceutical manufacturers and then became

directly involved with analytical instrumentation. He has been responsible for

the design and implementation of specialised systems and software for dissolution testing as well as chromatography and spectroscopy including

validation and qualification of both old and new technologies.

Training has become a speciality and he has taught classes and lectured at

conferences in many countries. During the past 6 years he was a senior international representative for the U.S. Pharmacopeia and used his

experience of a wide range of compendial techniques to provide advice and

guidance to the industry.

He now works as an independent consultant providing training and

consultancy for pharmaceutical analysis and compendial affairs. He is a member of the UK Academy of Pharmaceutical Sciences and a member of

the Royal Society of Medicine.

Program Outline

1. Overview of Dissolution

2. Dissolution Apparatus - Types and Purposes

3. Dissolution Technique

4. Drug Release Apparatus 3-7

5. Testing Novel Dosage Forms

6. Testing of Semi-Solids and Other Non-Oral Dosage Forms

7. Dissolution Apparatus Qualification

8. Concepts of Dissolution Automation

9. Dissolution in the Regulatory Environment

AN OVERVIEW OF IN VITRO DISSOLUTION AND DRUG RELEASE

Introduction

The dissolution test has evolved to become a definitive tool used to characterize the performance characteristics of solid oral dosage forms.

As dosage forms have become more unique over the last fifty years, the dissolution apparatus has required continuous improvement and modification to provide suitable conditions for performance testing of a wide

variety of products.

However, probably 99% of

dissolution testing is performedon traditional tablets and capsules.

What do we test?

Dissolution is not just about orally ingested products such as tablets and capsules.

We also test :suspensions and powders coated beads and granulesointments, creams, gelstransdermal patches

implants, stentsmedicated contact lenseswound care productsbone cementpowders for inhalation

chewing gums, etc….

Introduction

6 / 17



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Dissolution - Definition

Academic definition:

Dissolution is the process by which a solid substance enters into a

solvent to form a solution.

Pharmaceutical definition:

Dissolution is a test used throughout the life cycle of a pharmaceutical product to evaluate the rate of release of a drug substance from the

dosage form.

Introduction

8 / 17

Tablet Compression An Overview of Dissolution

Generally, active pharmaceutical ingredients (API) are mixed with

inactive excipient materials and

pressed into a tablet or filled into a capsule.

An Overview of Dissolution

In the body, a pharmaceutical active ingredient must be “in solution” before it can be absorbed by the blood and ultimately carried to the receptor site to

render a therapeutic effect.

Dissolution is the process by which that active ingredient enters into a

solvent to yield a solution.


Solid oral dosage forms typically begin to disintegrate and dissolve in

the stomach.

The resulting solution passes into the

small intestine where dissolution

continues.

Surface areas:Stomach ~0.05m2

Small Intestine ~200m2




The dissolved active ingredient is absorbed into the blood stream

through the walls of the small

intestine.

The blood carries the active

ingredient to the site of therapeutic effect.


Basically, the dissolution test mimics the first several stages of this process under very controlled laboratory conditions (in vitro).

• For immediate release products:

– Wetting in the stomach

– Disintegration in the stomach

– Deaggregation in the stomach

– Dissolution in the stomach and intestine

– Permeation through the intestinal wall

– Absorption into the blood stream

– Transit to the therapeutic site (via liver)

– Decomposition and elimination


Dissolution is an important tool for characterizing the biopharmaceutical properties of a pharmaceutical product at different stages throughout its life

cycle.

• Product Development

– API characterisation, Formulation evaluation, Stability testing

• Bioavailability / Bioequivalence

– In Vitro / In Vivo Relationships

• Quality Control

– Pass / Fail product release

• Scale-Up and Post-Approval Changes

– Raw materials, Formulation, Process, Manufacturing site

Introduction

15 / 17


Dissolution is one the three primary tests used to release a finished drug product:

• Assay – determines the overall potency of the batch and ensures the accuracy of the finished drug product.

• Dose Uniformity – determines the consistency among the individual dosage units and ensures the precision of the manufacturing process.

• Dissolution – ensures that the performance of the finished drug product is consistent with the release rates of the API as determined in bioavailability

studies during the clinical trials.

Applications of Dissolution within the Drug Development Life Cycle

Little to no dissolutionDiscovery

Intrinsic Dissolution

Characterization

Disso Method Development

Drug Development

IVIVCClinical Trials

QC of every batch Manufacturing

Stability Testing

SUPACPost

release

Post Patent Bioequivalence

Testing


Dissolution assesses the performance of drug products

To be effective, the test should be:

• Predictive

• Comparative

• Discriminatory

• Reproducible

Introduction

18 / 17



An Overview of the Dissolution Performance Test

The dissolution apparatus usually consists of:

• An inert vessel

• A dissolution solvent (medium)

• A moving element which provides

the hydrodynamic flow of the

solvent across the surface of the dosage form

The dissolution apparatus must maintain these three components

in terms of alignment, stability and isolation from the environment

An Overview of the Dissolution Performance Test

Most dissolution testers contain at least six positions so that six dosage units may be tested at one time.

HISTORICAL DEVELOPMENT OF THE DISSOLUTION TEST

1897

• Noyes and Whitney publish a paper of “The Rate of Solution of Solid Substances in Their Own Solution” suggesting dissolution rate is controlled by a layer of saturated solution that forms instantly around a solid particle.

• They developed the Noyes-Whitney equation which is still used today to determine dissolution rate constants.

1897

• Noyes and Whitney paper relates dissolution rate to concentration as solutions approach saturation

Journal of the American Chemical Society, Vol. 19 1897

1897: Noyes and Whitney



1897: Noyes and Whitney 1897

Pharmaceutical industry just becoming established

Pills – previously hand-made – made onmachines as tablets

Gelatin capsules hadjust been introduced

Tablet manufacturing room

1900

• Brunner and Tolloczko prove that dissolution rate depends on the chemical and physical structures of the solid, the surface area exposed to the medium, agitation speed, medium temperature and the overall design of the dissolution

apparatus.

• They further refined the Noyes-Whitney equation to consider the surface area of the active pharmaceutical ingredient.

1904

• Nernst and Brunner used Fick’s laws of diffusion to introduce a new relationship between the dissolution rate constant and the diffusion coefficient of the solute.

• Their studies focused on the boundary (saturated) layer between the active pharmaceutical ingredient and the solvent.

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dMs

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1930 - 1933

• Experiments begin with in vitro / in vivo correlation and bioavailability.

• Hixson and Crowell develop a mathematical model describing the dissolution process.

• They expressed the dissolution rate as a function of both concentration and surface area.

• The Solvometer is introduced by Klein and modified by Elliott

in 1933. Chemical substances were compressed into a tablet of uniform surface area to study surface rate dissolution … the forerunner of modern intrinsic studies.

1934

• Pharmacopoeia Helvetica in Bern Switzerland is the first regulatory body to incorporate a disintegration test for tablets.

1950 - 1955

• The disintegration test becomes an official USP method.

• USP XV requires the disintegration test for most solid dosage forms.



1957

• The first experimentation to investigate the correlation between bioavailability and dissolution was conducted by Nelson. He was able to confirm that the intrinsic dissolution rate of theophylline salts was the controlling factor that

determined the concentration and rate of buildup in the blood.

1958

• Rotating bottle method developed to study timed-release formulations.

1958 - 1960

• Levy and Hayes, utilizing a beaker and three-blade stirrer at 30 - 60 RPM, found significant differences in the in vitrodissolution rate of different brands of aspirin tablets and link them to the incidence of gastrointestinal irritation caused by

various brands of aspirin tablets due to their slow dissolution rates.

1960’s

• It becomes apparent that disintegration has little to do with biological activity. Disintegration was important, but de-aggregation was essential for bioavailability.

• USP-NF Joint Panel recognizes a need for a dissolution test.

• William Mader and Dr. Lee T. Gradey, with the U.S. Drug Standards Laboratory, experiment with a variety of basket and stirring devices.

• Kefauver-Harris Drug Amendments passed to ensure drug efficacy and greater drug safety. For the first time, drug manufacturers are required to prove to FDA the effectiveness of their products before marketing them.

1968 – 1969

• The “rotating basket assembly” was developed by Pernarowski

• The “paddle method” of dissolution was developed by Poole

• The circulating “flow through cell” was developed in Europe by

Dr Langenbucher.

1970

• USP XVII incorporates the first official “dissolution test” for solid dosage forms.

• Twelve monographs are published in USP - NF with the official dissolution test - rotating basket.

Early 1970s

• Scientists evaluate variability seen in dissolution results from one apparatus to another.

• NCDA (FDA) finds variability from apparatus-to-apparatus and from lab-to-lab.

• FDA and USP push for standardization of dissolution testing.

• The USP Revision Subcommittee on General Chapters begins development of calibrators for dissolution testing.

• The USP Subcommittee recommends two apparatus:

• Rotating basket

• Rotating paddle



1978

• FDA publishes “Guidelines for Dissolution Testing.”

• USP publishes Pharmaceutical Manufacturers Association

(PMA) Collaborative Study results for three calibrators:

• Prednisone (disintegrating) Hoffman - LaRoche

• Salicylic Acid (non-disintegrating) Upjohn

• Nitrofurantion (disintegrating) Parke-Davis (unsuitable)

• USP proposed conditions:

• 50, 100, and 150 RPM for baskets

• 50 and 100 RPM for paddles

• Time points: 15, 30, 45, and 60 minutes (40 tests)

1990

• Transdermal dissolution methods incorporated into USP XXII:

• Apparatus 3 - paddle over disk

• Apparatus 4 - cylinder

• Apparatus 5 - reciprocating disk

1995

• USP XXIII adds two extended release methods and re-numbers apparatus:

• 1 - basket

• 2 - paddle

• 3 - reciprocating cylinder

• 4 - flow through cell

• 5 - paddle over disk

• 6 - cylinder

• 7 - reciprocating disk

• FDA Guidance for Industry “Scale-Up and PostapprovalChanges for Immediate Release Solid Oral Dosage Forms “SUPAC-IR” released

1997

• Pooled sampling is added to USP XXIII Seventh Supplement.

• Calibration requirements were reduced to 4 tests total

• Disintegrating and non-disintegrating tablets

• 50 and 100 RPM – one speed each apparatus

• Each test had individual acceptance ranges (4 total).

• Apparatus dedicated for paddle or basket require only 2 tests

1997

• FDA Guidance for Industry Documents introduced:

– “Dissolution Testing of Immediate Release Solid Oral Dosage Forms”

(August)

– “Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations” (September)

– Scale-Up and Postapproval Changes for Modified Release Solid Oral Dosage Forms “SUPAC-MR” (September)

2000

• FDA Guidance for Industry “Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System (BCS)”



2006

• EP, JP and USP Harmonized

• As part of the International Conference on Harmonization (ICH) effort USP 29 incorporates two of the following drug release tests into the <711> Dissolution chapter from the <724> Drug Release chapter:

• Apparatus 1 – Basket (Specification Change)

• Apparatus 2 – Paddle

• Apparatus 3 – Reciprocating Cylinder

• Apparatus 4 – Flow-Through Cell

• <724> Drug Release chapter now contains:

• Apparatus 5 – Paddle over Disk

• Apparatus 6 – Rotating Cylinder

• Apparatus 7 – Reciprocating Holder

THE DISSOLUTION APPARATUS

Dissolution Apparatus Overview Dissolution Apparatus Overview

Over the past forty years two basic techniques have evolved for in vitro dissolution testing:

• Stirred beaker method

• Flow through procedure

Dissolution Apparatus Overview

Stirred Beaker Method

This system places the test specimen and a fixed volume of fluid in a vessel,

and stirring provides mechanical (hydrodynamic) agitation.

This system was adopted as the official dissolution method in USP XVIII in 1970 and described as the rotating basket method, USP apparatus 1.

The rotating paddle method was adopted as an official dissolution method by the USP several years later and became USP Apparatus 2.


Flow Through Procedure

Two new apparatus were added to the USP in 1990 to overcome some of the

experimental difficulties from the use of the single vessel methodology:

• USP Apparatus 3 – Reciprocating Cylinder

• USP Apparatus 4 – Flow-through cell




Flow Through Procedure

Some of the needs for the flow-through type apparatus included a change of

pH or any other change in the dissolution medium.

Difficulties had also arisen for a number of sparingly soluble drugs which were difficult to investigate with a limited volume of media.

The flow-through system was first adopted by the DeutscherArzneimittelcodex (German Pharmaceutical Codex, DAC) in 1981.


The most common dissolution apparatus used throughout the world are (1) the basket method and (2) the paddle method.

These methods are simple and robust and are generally flexible enough to allow dissolution testing for a wide variety of drug products.


For this reason, Apparatus 1 and 2 should be used for dissolution method development unless shown to be unsatisfactory.

Other in vitro dissolution apparatus such as (3) the reciprocating cylinder and (4) a flow-through cell system described in the USP may be considered if

needed.

This workshop will deal primarily with the functional aspects of Apparatus 1

(paddle) and Apparatus 2 (basket)

THE HARMONIZED DISSOLUTION APPARATUS: APPARATUS 1 (BASKET)

AND APPARATUS 2 (PADDLE)

USP Apparatus 1

General apparatus 1 description

Vessels

Baskets

Current physical parameters and tolerances

Proposed physical parameters and tolerances

USP calibration requirements

Typical products tested

Allowable variations

Non-Compendial variations

USP Apparatus 1

General Apparatus 1 Description

The rotating basket shaft and basket components are fabricated from 316

stainless steel. Unless otherwise specified in a monograph, a 40-mesh basket is used.

The basket shaft assembly containing the product is lowered into a 1000 mL

vessel and rotated at a specific speed within media which is maintained at a

specific temperature.



USP Apparatus 1


The rotating basket method is routinely used at an agitation speed of 50 to

100 rpm.

Rates outside a range of 50 to 150 rpm are generally unacceptable because of irreproducibility of the hydrodynamics below 50 rpm and turbulence above

150 rpm.

High turbulence in the vessel leads to a loss of discriminatory power

associated with the method.

USP Apparatus 1

Vessels

Apparatus 1 and 2 typically use a 1000mL hemispheric shaped vessel made

of glass or suitably inert material.

Media volume should be between 500 and 1000mL with 900mL used historically.

1L Vessels are tubing based with dimensions of 98 -106 mm id and 160 - 210 mm in height.

Dissolution Vessels

Large volume vessels have been required to handle veterinary bolus formulations

Vessels shown left to right

• 4-Liter vessel has dimensions of 145-155 mm id and 280-300mm in height.

• 2-Liter vessel has dimensions of 98-106 mm id and 280-300mm in height.

• The 1 liter and 500mL vessels are shown at right

Dissolution Vessels

Peak Vessel

• The peak vessel reduces the inherent inconsistencies in the hydrodynamics of standard hemispherical dissolution vessels.

• An inverted peak is incorporated into the bottom of the vessel, displacing the unstirred zone, preventing cone formation

• Especially useful for bead formulations requiring exposure to fresh dissolution medium

USP Apparatus 1

Baskets

The historical USP 40 mesh dissolution basket has 40 openings per linear

inch. Openings are equal in both directions producing a standard square weave. USP specifies that 40 mesh (40 x 40) screen be manufactured with

wire having a nominal 0.25mm diameter.

Harmonized basket specifications are now referred to as “0.22-0.31 mm wire

diameter with wire openings of 0.36-0.44 mm.”

USP vs. JP Basket

USP 40-mesh Basket JP 36-mesh Basket

• Microscopic comparison in identical scale show the JP basket with

larger wire and fewer openings

• Test results under identical conditions reveal lower results for

Prednisone calibrator tablets tested in the JP basket

60



USP Apparatus 1

Baskets

Dissolution baskets are fragile and require proper handling and care.

Attachment or removal from the basket shaft requires holding the upper rim. When not in use, store in supplied protective case. Carefully inspect for

damage or excessive wear since defective or misshaped baskets will affect

test results.

USP Apparatus 1

Current Harmonized Physical Parameters and Tolerances

Wobble “not significant”

Dimensions per USP

Height 25 mm ± 2 mm above bottom of vessel

Centering ± 2 mm center line

Speed ± 4% of set speed

Media Temp. 37 ± 0.5 °C

Timepoints ± 2% of specified time

USP Apparatus 1

Optional Parameters and Tolerances (Enhanced Mechanical Parameters)

Shaft wobble ≤ 1.0 mm total runout

Basket wobble ≤ 1.0 mm total runout (lower rim)

Vessel/shaft centering ≤ 1.0 mm from centerline

Basket exam No defects at time of use

Shaft verticality Vertical using bubble level (≤ 0.5º)

Vessel verticality ≤ 1.0º from vertical

Speed Larger of ± 2% or ± 2 RPM of set speed

Vibration “Not significant”; analyst to control

USP Apparatus 1

Typical Products Tested

• Capsules

• Tablets

• Floaters

• Modified release

• Beads

• Suppositories (modified Palmeri basket)



USP Apparatus 1

Allowable Variations

A basket with gold coating 2.5 µm thick (0.0001 inch) is an allowable

variation of the standard 40-mesh basket.

Larger vessels accommodating up to two and four liters are now allowable variations in the USP. Such vessels are advantageous for poorly soluble

drugs.

USP Apparatus 2

General apparatus 2 description

Sinkers

Current physical parameters

USP calibration requirements

Typical products tested

Non-Compendial variations

USP Apparatus 2


USP Apparatus 2, the rotating paddle method, followed the development of the rotating basket method with better stirring characteristics.

The paddle blade is fixed to the bottom of the shaft and rotates at a height of 25mm from the inner bottom of the vessel.

USP Apparatus 2


The paddle apparatus consists of a metallic or suitably inert, rigid blade and shaft comprising a single entity.

The paddle blade and shaft may be coated with a suitable inert material.

USP Apparatus 2


The paddle is lowered into a 1L vessel and rotated at a specific speed within

media which is maintained at a specific temperature.

The rotating paddle method is routinely used at an agitation speed of 25 to 75 rpm.

Rates outside a range of 25 to 75 rpm are generally unacceptable because of irreproducibility of the hydrodynamics below 25 rpm and turbulence above

100 rpm.

High turbulence in the vessel leads to a loss of discriminatory power

associated with the method.



USP Apparatus 2


Agitation rates around 25 rpm but less that 50 rpm are acceptable for

suspensions.

For solid dosage forms with excessive coning, rotational speeds around 75 rpm may be necessary to improve the data.

As with any variance from normal operating parameters, atypical conditions must be supported with data from normally accepted conditions for

justification.

USP Apparatus 2


When profiles exhibit inappropriately dissolving drug substance which are too

fast or slow adjustments to the rotational speed may be warranted.

Per USP, the dosage unit must be allowed to settle to the bottom of the vessel prior to rotating the paddle.

USP Apparatus 2


A small, loose piece of non-reactive material such as not more that a few turns of wire helix may be attached to dosage units that would otherwise float.

USP Apparatus 2

Sinkers

In addition to sinking floating dosage forms, sinkers may assist in keeping a

dosage form from sticking to the vessel inappropriately as in the case with some film coated tablets.

Sinkers must be adequately described in the method to eliminate

hydrodynamic variation associated with different sinker devices.

USP Apparatus 2

USP <1092>: Sinkers may be fabricated by wrapping 20 gauge (0.032 inch) wire around a cork bore.

USP Apparatus 2

Other validated sinker devices may be used.



USP Apparatus 2

Current Harmonized Physical Parameters and Tolerances

Wobble not specified in current harmonized pharmacopeias

Dimensions per USP

Height 25 mm ± 2 mm above bottom of vessel

Centering ± 2 mm center line

Speed ± 4% of set speed

Media Temp. 37 ± 0.5°C

Timepoints ± 2% of specified time

USP Apparatus 2

Optional Parameters and Tolerances (Enhanced Mechanical Parameters)

Shaft wobble ≤ 1.0 mm total runout

Vessel/shaft centering ≤ 1.0 mm from centerline

Paddle exam No defects at time of use

Shaft verticality Vertical using bubble level (≤ 0.5º)

Vessel verticality ≤ 1.0º from vertical

Speed Larger of ± 2% or ± 2 RPM of set speed

Vibration No specification; analyst to control

USP Apparatus 2

Typical Products Tested

• Tablets

• Capsules (with sinkers)

• Hydrogels

• Suspensions

• Powders

• Microparticles

• Transdermals (USP Apparatus 5)

Alternative Dissolution Apparatus

Suspended Basket Method

• Place each tablet in basket

• Place tablet cover horizontally

• Mount in the evaporation cover

• Adjust bottom of basket to 1 cm above the top of the paddle

• Orient the large side of the basket with the flow stream with the tablet standing on its edge

• Operate paddle at 50 rpm– USP Monograph for Felodipine Extended-

Release Tablets

Non-Compendial Dissolution Apparatus

•Mini-Paddle Apparatus

•Mini-Basket Apparatus

•Based on USP Apparatus 1&2

•100 or 200 mL vessels

•Operational minimum 30 mLvolume

•Tablets, Capsules



Non-Compendial Dissolution Apparatus Non-Compendial Dissolution Apparatus

Rotating Bottle

• Developed in 1958

• Vessel volumes 500, 250, 100, 50, 15, 4mL

• No evaporative loss

• Long term extended release testing

• Tablets, Capsules, Suspensions, Implants

Intrinsic Dissolution Apparatus

• USP <1087>

• Intrinsic dissolution is defined as the dissolution of a pure drug substance from a specified constant surface area.

• A special punch and die is used to compress pure drug substances into a disk or tablet.

• The disk is placed into a special holder that allows only one flat surface to come in contact with a dissolution media at any time during the test.

Intrinsic Dissolution

• Intrinsic dissolution data is generally used in drug screening but can provide helpful solubility information for method development.

• Rates lower than 0.1 mg/min/cm2 generally mean that bioavailability will be determined by the dissolution rate.

• Rates higher than 1 mg/min/cm2 mean that bioavailability will most likely be determined by the drug permeability.

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