Dissolution Seminar Series

The Fundamentals of Dissolution
Agilent Dissolution Seminar Series
Welcome
Agilent Dissolution
Seminar Series
Terry Way BPharm MAPS
Dissolution Science Consultant
Agilent Technologies
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The Fundamentals of Dissolution
Program Outline
1. The Dissolution Technique
2. Dissolution Automation - Sampling
3. Dissolution Automation - Direct Measurements
4. Dissolution Apparatus Qualification
5. Fundamental Principles of Drug Release
6. Current Trends in Dissolution Testing
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AN OVERVIEW OF THE
DISSOLUTION TECHNIQUE
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The Fundamentals of Dissolution
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 performed
on traditional tablets and capsules.
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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 granules
ointments, creams, gels
transdermal patches
implants, stents
medicated contact lenses
wound care products
bone cement
powders for inhalation
chewing gums, etc….
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The Fundamentals of Dissolution
Dissolution - Definition
Google search:
Search Results
Dissolution - Glossary page - UK Parliament
www.parliament.uk › Site information › GlossaryCached - Similar
Dissolution is the official term for the end of a Parliament. After the Fixed Term Parliament Act was passed on 15 September 2011, the date of the...
[PDF] Dissolution and Removal from the Register of Charities - Charity ...
www.charitycommission.gov.uk/library/guidance/csd1077a.pdf
File Format: PDF/Adobe Acrobat - Quick View
Egypt's dissolution of parliament is a counter-revolution in all but ...
www.guardian.co.uk/.../egypt-dissolution-parliament-counter-revolut...Cached
Jun 15, 2012 – David Hearst: Will the coup by the old regime, and its attempt to install Ahmed Shafiq as president reignite Egypt's revolutionary forces?
Early Dissolution
www.insolvencydirect.bis.gov.uk/.../Dissolution/EarlyDissolution.ht...Cached
The dissolution of a company ends its legal existence. Its property then either belongs to the Crown, ...
Company Law: Voluntary dissolution
www.companylawclub.co.uk/topics/voluntary_dissolution.shtml Cached
Voluntary dissolution. Introduction The application. Notifying interested parties. Objections Dissolution by Companies House and its effects.
The Dissolution of the Monasteries
www.historylearningsite.co.uk › Tudor EnglandCached - Similar
The dissolution of the monasteries was a major event in the reign of Henry VIII. The dissolution effectively ended the power of the monasteries...
[PDF] D183 - About divorce/dissolution - Family Law
www.familylaw.co.uk/system/uploads/attachments/0002/.../D183.pdf
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What is the difference between a divorce and a dissolution? ...
[PDF] BR20 - Pension and divorce or dissolution - Gov.uk
www.direct.gov.uk/prod_consum_dg/groups/.../dg_180317.pdf Similar
File Format: PDF/Adobe Acrobat - Quick View
Pensions and divorce or dissolution.
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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.
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The Fundamentals of Dissolution
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.
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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.
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The Fundamentals of Dissolution
An Overview of Dissolution
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 ~0.5m2
Small Intestine ~200m2
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An Overview of Dissolution
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.
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The Fundamentals of Dissolution
An Overview of Dissolution
Basically, the dissolution test mimics the first few 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
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An Overview of Dissolution
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
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The Fundamentals of Dissolution
An Overview of Dissolution
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.
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An Overview of Dissolution
Dissolution assesses the performance of drug products
To be effective, the test should be:
•
•
•
•
Predictive
Comparative
Discriminatory
Reproducible
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The Fundamentals of Dissolution
COMPENDIAL
DISSOLUTION TESTING
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Compendial Requirements
The requirements for dissolution testing were harmonised through the ICH
Q4B Guidelines in 2006:
The pharmacopœial texts are based on the original USP General Chapters <711>
and <724> but, despite “harmonisation” there are still various regional differences.
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The Fundamentals of Dissolution
Apparatus
A general description of the assembly which is common to both Apparatus 1
and 2 is included in the description for Apparatus 1:
Vessels
• glass or other inert, transparent material
• cylindrical with hemispherical bottom
• partially immersed in a water bath or heated by a heating jacket
• 1L, 2L or 4L nominal capacity
• a fitted cover may be used to retard evaporation
Motor with speed-regulating device
An apparatus that permits observation of the specimen and stirring element
during the test is preferable.
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Dissolution Vessels
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.
The 1L vessel has dimensions of 98 -106mm i.d. and 160 - 210mm in height.
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The Fundamentals of Dissolution
Dissolution Vessels
Large volume vessels have been required for testing APIs with low
solubility and also larger veterinary formulations
• 2-Liter vessel has dimensions of 98-106mm id and 280-300mm in height.
• 4-Liter vessel has dimensions of 145-155mm id and 280-300mm in height.
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Apparatus 1 - Baskets
Used for testing tablets and capsules where disintegrated granules or beads
would pass through the 10# of the disintegration test but would be retained
on the 40# of the dissolution basket - dissolution progressing inside the
basket.
The original acceptance criteria required
75% dissolution within a specified period.
Beyond this time, particles could be small
enough to pass through the basket mesh
and fall to the bottom of the vessel.
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The Fundamentals of Dissolution
Apparatus 1 - Baskets
More commonly used today for non-disintegrating products.
The basket mesh must remain clear throughout the test but is prone to
occlusion by bubbles and undissolved materials such as gelatinous or waxy
excipients which inhibit the flow of media through the basket.
Often used for testing enteric products where the pH must be changed.
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USP Apparatus 1
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The Fundamentals of Dissolution
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.”
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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
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The Fundamentals of Dissolution
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 a protective case.
Carefully inspect for damage or excessive wear since defective or misshaped
baskets will affect test results.
A basket with gold coating 2.5 µm thick (0.0001 inch) is an allowable
variation of the standard 40-mesh basket.
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The Fundamentals of Dissolution
USP Apparatus 1
Starting a dissolution test with baskets:
The product is placed in a dry basket and attached to the shaft.
The shaft is lowered into the vessel to the correct height.
Then rotation is started.
Dissolution should occur within the basket.
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Apparatus 2 - Paddles
Baskets are unsuitable for testing products that release small
particles e.g. tablets made by direct compression or powderfilled capsules. Hence, paddles were introduced as an
alternative test.
Also used for testing powders and suspensions.
The dissolution process should occur throughout the
dissolution medium with good mixing provided by adequate
speed - usually 50-75rpm.
pH change can be achieved by addition of buffer concentrates.
With slower speeds (and for some hydrophobic products)
coning is a problem:
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The Fundamentals of Dissolution
USP Apparatus 2
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USP Apparatus 2
The paddle apparatus consists of a metallic or suitably inert, rigid blade and
shaft comprising a single entity.
A suitable two-part detachable design may be used provided the assembly
remains firmly engaged during the test.
The paddle blade and shaft may
be coated with a suitable inert
material.
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The Fundamentals of Dissolution
USP Apparatus 2
Starting a dissolution test with paddles:
The dosage unit must be allowed to settle to the bottom of the vessel prior to
rotating the paddle.
Unfortunately some types of dosage forms may float to the surface,
especially capsules.
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Apparatus 2 - Paddles
Sinkers are often used to prevent products floating:
• A small, loose piece of nonreactive material,
such as not more than a few turns of wire helix,
may be attached to dosage units that would otherwise
float. (“USP Sinker”)
• An alternative sinker device :
(“Japanese Sinker”)
• Other validated sinker
devices may be used.
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The Fundamentals of Dissolution
Special Apparatus
• Stationary Basket assembly
• Basket for USP Felodipine
Extended Release Tablets
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Non-Compendial Dissolution Apparatus
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.
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The Fundamentals of Dissolution
Non-Compendial Dissolution Apparatus
•Mini-Paddle Apparatus
•Mini-Basket Apparatus
•Based on USP Apparatus 1&2
•100 or 200 mL vessels
• Minimum volume ~30 ml
•Tablets, Capsules
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Non-Compendial Dissolution Apparatus
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The Fundamentals of Dissolution
THE DISSOLUTION TEST
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The Dissolution Environment
A very sturdy surface should be used to support the dissolution
apparatus.
The apparatus with full water bath and full vessels may weigh
up to 100 kg.
Benches should not impart vibration on the dissolution
apparatus.
• Vibration has been shown to have a significant effect on dissolution rates.
• Effects of both higher and lower dissolution rates have been seen.
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The Fundamentals of Dissolution
The Dissolution Environment –
Sources of Vibration
•Fume hoods
•Bench top centrifuges
•Vacuum pumps
•Ultrasonic baths
•Construction
•Heater circulators or pumps
•Mechanical shakers
•Worn parts or bearings
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The Dissolution Environment
Lighting should be sufficient to perform visual observations.
• Visual observations may offer clues to dissolution behavior.
• Unusual observations should be documented
• Considerations should be made for light sensitive products.
Local sinks and purified water sources for media prep and
disposal
Media handling and preparation equipment must not impart
vibration to the dissolution apparatus
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The Fundamentals of Dissolution
The Dissolution Environment
•Suitable media degassing equipment
•Dedicated vessels and shafts (each apparatus)
•Sufficient bench space for sample handling and analytical
measurement
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The Dissolution Test
The analyst is responsible for verification of the physical
parameters.
- including that the equipment is clean.
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The Fundamentals of Dissolution
The Dissolution Test
Prepare dissolution media
and properly deaerate.
USP Method: Heat media to
41°C, vacuum filter through
0.45µm filter, continue to pull
vacuum for 5 additional
minutes.
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The Dissolution Test
Care must be taken in measuring
the dissolution media to maintain
the volumetric accuracy at ±1%.
Volumetric accuracy is based on
dissolution media measured at
room temperature.
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The Fundamentals of Dissolution
The Dissolution Test
Alternatively, dissolution media may be weighed.
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The Dissolution Test
Measure and carefully
introduce dissolution
media to the vessel.
Have materials ready
for the test including
all sampling
equipment.
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The Fundamentals of Dissolution
The Dissolution Test
Allow media in each vessel to
reach 37 C  0.5 C and use
immediately.
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The Dissolution Test
Always handle dosage units
with gloves (not cotton),
forceps or tweezers which
will not scratch or damage
the surface of the dosage
unit.
Examine the six dosage
units. Do not use chipped,
cracked or capped tablets
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The Fundamentals of Dissolution
The Dissolution Test
Option: Record the dosage
unit weights? Weight is for
information and investigation
purposes only.
Dosage units are to be
chosen at random and may
not be selected or discarded
based on weight.
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The Dissolution Test
Have analyst notebook or
dissolution worksheets for
recording information. All
information must be
recorded directly into
analyst notebooks or
official batch record
worksheets.
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The Fundamentals of Dissolution
The Dissolution Test
Prepare to drop tablets. Lower
paddles to proper height, or
suspend baskets until ready to
begin the test.
Note: Apparatus 1 baskets
should be tested immediately
after placing the tablet inside
and clipping to the shaft.
Exposure to humidity can alter
test results.
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The Dissolution Test
Prepare calibrated timer.
Record times as tablets are dropped.
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The Fundamentals of Dissolution
The Dissolution Test
For the paddle apparatus, drop the dosage units into non-rotating medium.
They must settle to the bottom of the vessel before rotation of the shaft
begins. Then start rotation.
Visually inspect the dosage forms for air bubbles immediately after dropping.
For the basket apparatus, lower the baskets into non-rotating medium.
When at the correct height, immediately start rotation.
Record any unusual observations.
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The Dissolution Test
Most immediate release tablets
disintegrate very rapidly and will
reaggregate in the form of a cone
on the bottom of the vessel.
As the active drug goes into
solution during the dissolution
process, some excipient material
may be visible on the bottom of
the vessel at the end of the test.
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The Fundamentals of Dissolution
The Dissolution Test
Withdraw sample at the proper time 
2% (a 30 minute sample must be
pulled within  36 seconds) and filter
immediately.
Temperature must be taken a second
time at least, generally after the last
sample is pulled and before the shaft
has stopped
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The Dissolution Test
The samples are withdrawn at a
depth halfway between the top of the
paddle (or basket) and the top of the
medium and not less than 1cm from
the wall of the vessel.
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The Fundamentals of Dissolution
The Dissolution Test
Filtration stops the dissolution process
and defines the end of the first phase of
the test which is basically a sample
preparation period executed under strictly
controlled physical parameters.
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The Dissolution Test
Once the sample has been filtered the second phase of the testing begins to
determine the analytical concentration of the sample.
Analytical concentration is generally determined through UV-Vis
spectroscopy or HPLC analysis. HPLC is primarily used for drug products
containing multiple active components or for stability testing.
The responses from the analytical finish will be used to calculate the amount
of sample released from the dosage form within the specific time interval.
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The Fundamentals of Dissolution
USP <711> Acceptance Table
Immediate Release Forms
Stage
Number Tested
Acceptance Criteria
S1
6
Each unit is  Q + 5%.
S2
6
Average of 12 units (S1 + S2) is  Q and no
unit is < Q – 15%.
S3
12
Average of 24 units (S1 + S2 + S3) is  Q,
not more than 2 units are < Q – 15% and no
single unit is less than Q – 25%.
If a sample fails either Stage S1 or S2, proceed to the next stage and test
the number of units indicated.
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What is Q?
Q, as it relates to dissolution is commonly used in the USP for
immediate release and delayed release dosage forms.
The quantity of Q is the amount of dissolved active ingredient
specified in the individual monograph expressed as a
percentage of the labeled content.
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The Fundamentals of Dissolution
CONCEPTS OF DISSOLUTION
AUTOMATION
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The Concept of Automation
•Where a sufficiently large number of similar units are to be
subjected routinely to the same type of examination, automated
methods of analysis may be far more efficient and precise than
manual methods.
•USP<16> Automated Methods
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The Fundamentals of Dissolution
The Concept of Dissolution Automation
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The Concept of Dissolution Automation
•Dissolution consists of a series of unit operations.
•Traditionally, these unit operations, when performed manually,
are quite technique-dependant which may cause
inconsistencies in test results.
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The Fundamentals of Dissolution
The Concept of Dissolution Automation
•The entire dissolution test is a series of unit operations, any
one of which may be manual or automatic:
• Setup
• The dissolution test
• Sampling
• Analysis and data reduction
• Cleanup and changeover
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Advantages and Limitations of Automation
Advantages of Automated Dissolution
Accuracy
Precision
Time saving “buying time”
Throughput – cycle time reduction
Documentation of events
Data capture
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The Fundamentals of Dissolution
Limitations of Dissolution Automation
Limitations of Automated Dissolution
Personnel
Synchronizing & sequential time demands
Evaporation
Altered hydrodynamics
Sample archiving
Validation
21 CFR Part 11
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Future Challenges for Automation of Dissolution
• Network control of dissolution systems
• Video monitoring and recording
• Remote data processing and report generation
• Remote control of laboratory operations from home
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The Fundamentals of Dissolution
Early Dissolution Automation
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Simple Automation of Sample Collection
A fraction collector with peristaltic pump.
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The Fundamentals of Dissolution
Multi-test Automation with Sample Collection
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Advanced Automation of Sample Collection
New 850-DS Sampler
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The Fundamentals of Dissolution
850-DS Dissolution Sampling Station
Overview
•
Integrated syringe pump and fraction
collector
•
Streamlined design for ease of use and
reliable, repeatable operation
•
One sampler per dissolution apparatus
for ultimate flexibility
•
Built-in options and components for all
types of dissolution methods
•
Data export features ideal for paperless
environments
850-DS Dissolution Sampling Station
Options – Printer, Filter Module
Standard:
• Media replacement
• Automated cleaning
Optional:
• Built-in printer
• Filter module (for dissolution
methods requiring 0.45µm
filtration)
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The Fundamentals of Dissolution
850-DS Dissolution Sampling Station
Options – Sample Trays
Standard:
• 16 x 100 mm (up to 14 mL) – 96 positions
Optional:
• 12 x 32 mm (2 mL vials) – 96 positions
• Agilent HPLC tray* – 100 positions
• Well plate (dual)* – 192 positions
• 2 mL vials (dual)* – 108 positions
*Requires needle block adjustment
850-DS Dissolution Sampling Station
Features – Color Touch Screen
Real-time display of method progress…
Icons appear for key alerts
… and remaining time points.
Active tray format displayed prominently
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The Fundamentals of Dissolution
850-DS Dissolution Sampling Station
Features – Pump and Filtration
Filter module incorporated to
save valuable bench space
Easily disable filtration when not required
• Faster pump = more frequent time points
• Stored volume calibration for repeatable precision
and accuracy
Improved sampling needle to prevent
clogging / coring of septa
850-DS Dissolution Sampling Station
Features – Replacement Media and Cleaning
Automated cleaning and media replacement
is standard on all 850-DS sampling stations
An automated cleaning cycle can be added to the
end of any method to keep the system operating
properly and extend the life of internal components.
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The Fundamentals of Dissolution
850-DS Dissolution Sampling Station
Features – User Levels and Data Export
Place instrument in specific “Mode” to
restrict changes / access.
Three (3) data export options:
Printer, Serial Port, SD Card
Useful for method transfer (to another
850-DS) or LIMS integration.
Data export options:
SD Card or RS232
850-DS Dissolution Sampling Station
System Configurations
Dissolution Workstation Software
708-DS Dissolution Apparatus
850-DS Sampling Station (with Filter Module)
Cary 60 UV-Vis Spectrophotometer
8454 Diode-Array Spectrophotometer
Bio-Dis Reciprocating Holder or
Apparatus 7 Reciprocating Cylinder
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The Fundamentals of Dissolution
Automated Dissolution Analysis
UV-Visible Spectroscopy
HPLC
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UV-Visible Spectroscopy
Pros
• Fast
• Reliable
• Robust
• Cost
• Validation
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The Fundamentals of Dissolution
UV-Visible Spectroscopy
Cons
• Traditionally single component
• Timing demands
• Staggering starts
• Excipient interference
• Dilution
• Cell pathlength
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Fibre Optic Dissolution
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The Fundamentals of Dissolution
Fibre-Optic Dissolution Testing
•
•
The use of fibre-optics for the determination of drug
concentrations during a dissolution test has
become a useful alternative to conventional
sampling techniques in research and development
as well as quality control environments.
First used in the late 1980s, several publications
appeared in 1995 and full commercial systems
became available by 1999.
Fibre-Optic Dissolution Testing
•
•
•
The system allows continuous in-situ analysis of
drug concentrations without the need for sample
withdrawal and preparation.
More comprehensive data can be obtained at a
faster rate and the results can be interpreted
instantaneously.
Taking spectroscopy to the vessel:
•
•
the “flow-cell” is immersed directly in the dissolution medium
“pump light not liquid”
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The Fundamentals of Dissolution
Advantages of Fibre Optics
• No Sampling
– Analysis in real time, igh speed collection
– Increase in amount of collectable data
• No Fluidics
– pumps, valves
– tubing
– flow cells
• No issues with liquid handling systems
– carryover
– leaking
– adsorption / desorption
Procedure
• Measure medium blanks
• Measure Standards
• Staggered start
• Static or non-resident probes?
• Optional post-run standards
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The Fundamentals of Dissolution
Basics of Fibre-Optics
• Quartz fibre transmits light by total internal reflection
– Flexible (within limits)
• Two fibres per probe
– One coupled to source of mono-/poly-chromatic light
– One coupled to detector
Direct Transmittance
Transreflectance
Transreflectance Dip Probe
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The Fundamentals of Dissolution
Dip Probe in-situ
Multiplexed Scanning Spectrophotometer
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The Fundamentals of Dissolution
Multiplexed Scanning Spectrophotometer
One scanning spectrophotometer reading all fibres/vessels
Advantages
•
•
•
•
Only one detector/spectrometer to validate
Highest dynamic range
No stray light
Minimum solarization
– Uses only low wavelengths when needed.
– Use of a pulsed lamp allows light to be on only when
measuring.
Disadvantages
• Sequential data collection
Typical Dissolution
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The Fundamentals of Dissolution
Considerations for Fibre-Optics
• Excipient and bubble interference
• Sticky residues
• Cell path length
• Optical fouling
• Ease of blanking and standardization of each
probe
• Filters (or lack thereof)
• Validation
Significance of Probe Positioning
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The Fundamentals of Dissolution
Problems
• Interference in light path
– Bubbles
• degassing essential
• No Filtration
– Particles
– Excipients
Baseline Correction
Typical Drug Spectrum
0.5
Absorbance
0.4
0.3
0.2
0.1
0
230
250
270
290
310
330
350
370
390
Wavelength (nm)
True drug absorption = measured - excipients
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The Fundamentals of Dissolution
Baseline Correction
The spectrum of the interference should be flat to properly
perform the correction.
It only works as long as the total absorbance of the active, the
excipients, and the fibers is less than the maximum absorbance
limit of the spectrophotometer.
• Active + Excipients + Fibers < Maximum Absorbance
Baseline Correction
3
ABS (AU)
2.5
2
1.5
1
0.5
0
Active
Excipients
Fibers
Total
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The Fundamentals of Dissolution
Fibre-Optic Dissolution
Some products are suitable …..
and some are not
Agilent Cary 60 with Fibre-Optics
•
Linear over 3.5 absorbance units.
•
Room light immune.
•
Split beam dual Si diode detectors.
•
High intensity Xenon flash lamp.
•
80 readings a second.
•
Scanning speed up to 24,000 nm/min
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The Fundamentals of Dissolution
Agilent Cary 60 with Fibre-Optics
• Very large dynamic working range,
0.0001 – 3.5 AU
• Lamp only flashes when taking a reading
giving it an extremely long life.
• Very low baseline noise
• Fast monochromotor, does not
photobleach samples or fibres.
Agilent Cary 60 with Fibre-Optics
• No warm up or stabilisation time for the
lamp
• Full UV-Vis 190 – 1100nm range.
Monochromator
Detector
• Dedicated fibre optic dissolution software.
Sample
Exit slit
• Full suite of stand-alone applications.
Fast Dispersion
element
Xe Light
source
Entrance
slit
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The Fundamentals of Dissolution
Agilent 616 Fibre Optic Multiplexer
• 16 channel system for dual bath
capability.
• Purpose built for dissolution testing &
Cary 60.
• Each fibre is individually connected to the
multiplexer.
• Highest optical transmission of any
system on the market allowing it to easily
read in high turbidity solutions.
Agilent 616 Fibre Optic Multiplexer
• High precision & high speed channel to
channel movement.
• Raw absorbances on a single channel @
80 readings a second
• Raw absorbances on multiple channels
@ 6 readings every second
• Full dissolution reports, graphs, and
% dissolved data @ 6 readings every 30
seconds.
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The Fundamentals of Dissolution
Agilent Fibre Optic Probes.
• Specially designed for dissolution
testing.
• 600 micron silica/silica fibers for
optimised transmission down to
190 nm.
• 1, 2, 5, 10, 20 & 50 mm tips
available.
• Streamlined to minimize
hydrodynamic influence.
Agilent UV Dissolution Software
A full suite of applications is included
such as:
• Simple/Advanced Reads
• Scan
• Concentration
• Scanning Kinetics
• Validate
• Align
• UV Dissolution
•Fibre Optic Multiplexer is fully compatible with all applications
110
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The Fundamentals of Dissolution
UV Dissolution – Hardware Configuration
Compatible equipment includes:
• All Agilent dissolution apparatus
705, 708, 709, 7000, 7010, 7025 &
7030.
• Non-Agilent dissolution apparatus
may also be used with a resident
probe setup.
111
UV Dissolution - Method Setup
• Fully flexible timepoints
• Actual times
(HHH:MM:SS) or intervals are
entered
• No limit to number of stages
112
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The Fundamentals of Dissolution
UV Dissolution - Method Setup
Tester Settings:
– Apparatus type
– Initial spin (RPM & time)
– Spindle (RPM)
– Infinity spin (RPM & time)
• The Temperature page includes the
bath and vessel temperature
settings as well as tolerance
specifications
113
UV Dissolution - Method Setup
Standard Options:
• Several online standard options
are available including: Pre &
Post Cycle Standard, Bridged
Mean, and Running Mean
• Enhanced flexibility for
percentage and mg dissolved
calculations
• Capsule Blank correction is also
available
114
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The Fundamentals of Dissolution
UV Dissolution - Method Setup
Standard Options:
• An option to measure a Check
Standard with a variable
tolerance field
• Control Limits may be set up
to flag any out-of-tolerance
standards measured at any
time throughout the test
115
UV Dissolution - Method Setup
Analysis Options:
• Analysis is possible using a single
wavelength, a scan range, or single
and scan
• Scan analysis offers the choice
between mean or second derivative
• Single and scan analysis allows you
to specify a wavelength for analysis,
and collect data at surrounding
wavelengths for possible
recalculation.
116
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The Fundamentals of Dissolution
UV Dissolution - Method Setup
Analysis Options:
• Full background Correction is
available using a single wavelength
or mean values of a scan range, to
correct for excipients in your solution.
117
UV Dissolution: Fiber Optic
• The probe can be programmed to
dwell slightly under the vessel
media surface between time points.
This prevents drying of particles
and bubble formation while
minimizing hydro-dynamic
disturbance.
118
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The Fundamentals of Dissolution
UV Dissolution: Fiber Optic
• Multiplexer calibration and
probe performance is
monitored through the FO Mux
Calibration application.
119
Cary 60 Tests - Validate
• Easy setup and execution of
routine calibration
• Quick tests to monitor
instrument performance
and/or troubleshoot
• Complete record of all tests
with time/date stamp
120
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The Fundamentals of Dissolution
UV Dissolution: 21 CFR 11 Compliance
21 CFR Part 11 Compliance
121
UV Dissolution: 21 CFR 11 Compliance.
– Spectroscopy Database
Administrator (SDA)
– Spectroscopy Configuration
Manager (SCM)
Can be installed on a central
server or the local PC
• The Win UV Dissolution software
runs off the local PC with
Windows® 7 32- or 64- bit
122
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The Fundamentals of Dissolution
Agilent Dissolution Seminar Series
Welcome
Replacement Media - 20 mL
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The Fundamentals of Dissolution
No Replacement Media - 10 mL
QUALIFICATION OF DISSOLUTION
APPARATUS
126
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The Fundamentals of Dissolution
Analytical Instrument Qualification
Good Manufacturing Practices (GMP) regulations
(e.g. FDA’s 21 CFR 211.160 (b)(4)) require companies to
establish procedures ensuring the fitness for use of instruments
that generate data supporting regulated product testing.
• No definitive guidance for the qualification of analytical
instruments.
USP proposed a General Chapter <1058> on Analytical
Instrument Qualification in 2005
127
Published in USP-NF in 2009
128
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The Fundamentals of Dissolution
Analytical Instrument Qualification
USP <1058> provides a scientific approach to AIQ and
considers AIQ as one of the major components required for
generating reliable and consistent data.
• “AIQ is the collection of documented evidence showing that an instrument
performs suitably for its intended purpose.”
• Users of analytical equipment should:
– validate their procedures
– calibrate their instruments
– perform additional instrument checks
• System suitability tests
• In-process control samples
129
USP <1058> definitions:
Design Qualification (DQ)
• documented collection of activities that define the functional and
operational specifications of the instrument and criteria for selection of the
vendor, based on the intended purpose of the instrument.
• Prior to purchase
Installation Qualification (IQ)
• documented collection of activities necessary to establish that an
instrument is delivered as designed and specified, and is properly installed
in the selected environment, and that this environment is suitable for the
instrument.
• performed at time of installation
130
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The Fundamentals of Dissolution
USP <1058> definitions:
Operational Qualification (OQ)
• documented collection of activities necessary to demonstrate that an
instrument will function according to its operational specification in the
selected environment.
• After installation or major repair
Performance Qualification (PQ)
• documented collection of activities necessary to demonstrate that an
instrument consistently performs according to the specifications defined by
the user, and is appropriate for the intended use
• Performed after completion of OQ and periodically at specified intervals for
each instrument
131
USP <1058> definitions:
Performance Qualification (PQ):
• Usually based on the instrument’s application and may consist
of analyzing known components or standards
• PQ tests may be modular or holistic
• PQ tests should be based on good science and reflect the
general intended use of the instrument
• When an instrument fails to meet PQ test specifications, it
requires maintenance or repair
132
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The Fundamentals of Dissolution
Requirements for dissolution equipment
OQ
• after installation or repair
– conformance to mechanical specifications
PQ
• after installation, repair and at regular intervals
– conformance to mechanical specifications
– Performance Verification Test
133
Qualification of Dissolution Apparatus
USP requirements for pharmacopœial dissolution tests were first
introduced in 1970 for 6 monographs.
The basic concepts of the dissolution apparatus were established by
empirical means rather than sound scientific and engineering
considerations.
It very quickly became obvious that tests with different apparatus
produced different results
• apparatus was often custom-made
• control of mechanical parameters was inadequate
• vibration was thought to be a key factor but couldn’t be conveniently quantified
at the time.
Use of a “calibrator” was suggested
134
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The Fundamentals of Dissolution
Mechanical Qualification
Specifications and tolerances for the apparatus itself are given in the
General Chapters
Tolerances for operating parameters are also provided,
some more specific than others, e.g.
• speed ±4%
• temperature ±0.5°C
• rotation without significant wobble
• no significant vibration
These specifications and tolerances are the minimum standards
allowable and have since been supplemented by tighter standards
published by various authorities including USP, FDA, ASTM, FIP
135
Mechanical Qualification
FDA published “The Use of Mechanical Calibration of
Dissolution Apparatus 1 and 2” in 2006:
• Enhanced Mechanical Calibration (MC or MQ) of dissolution apparatus
may be used as an alternative to the current Apparatus Suitability
procedure for Dissolution Apparatus 1 and 2 described in USP <711>
• The Mechanical Calibration procedure should specify the frequency at
which each calibration step is performed
• Either the USP procedure or an appropriate Mechanical Calibration
method executed according to a written procedure will satisfy the CGMP
requirement for calibration of the laboratory apparatus…
136
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The Fundamentals of Dissolution
Mechanical Qualification
In collaboration with FDA, in 2007 ASTM published “Standard
Practice for Qualification of Basket and Paddle Dissolution Apparatus”
• outlines the procedures and tolerances for enhanced mechanical calibration
2.2 Once a unit meets all of the mechanical specifications included in
this practice, it is considered calibrated and further calibration with
dissolution calibrator tablets is not required.
• Moore et al published an “Implementation Guidance” document in 2010
Abstract: This guidance is intended to serve as a companion document for ASTM
Standard E 2503-07, “Standard Practice for Qualification of Basket and Paddle
Dissolution Apparatus”, by providing practical information useful for the
implementation of mechanical calibration. Particular focus is placed on use of the
The Open Drug Delivery Journal, 2010, 4, 14-20
available tools to make the required measurements.
137
Mechanical Qualification
In 2007, USP published the “Dissolution Toolkit - Procedures for
Mechanical Calibration and Performance Verification Test”
This provides
• “...a description of best practices associated with the mechanical
calibration and performance verification test for the USP basket and paddle
dissolution apparatuses and test assemblies.”
• very detailed mechanical calibration procedure along with measuring
techniques, tools required, and frequency of measurement
• detailed procedures for the use and interpretation of the USP Performance
Verification Test (PVT)
138
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The Fundamentals of Dissolution
Mechanical Qualification
139
Specifications and Tolerances
Parameter
ICH
(USP, JP, EP)
FDA
DPA-LOP.002
ASTM
E2503-07
USP
Toolkit Ver 2.0
Basket and
Paddle Depth
25 ± 2 mm
25 ± 2 mm
25 ± 2 mm
(or <8%)
23-27 mm
Rotational
Speed
± 4% of
specified rate
± 2 rpm of
target
Larger of ± 2
rpm or within
2% of target
± 1 rpm of target
Shaft Wobble
No significant
wobble
≤ 1.0 mm total
runout
≤ 1.0 mm total ≤ 1.0 mm total
runout
wobble
Shaft
Verticality
Not measured
≤ 0.5° from
vertical
Within Bubble
Basket
Wobble
± 1 mm
≤ 1.0 mm total
runout
≤ 1.0 mm total ≤ 1.0 mm total
runout
wobble
NMT 0.5° from
vertical
140
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The Fundamentals of Dissolution
Specifications and Tolerances
Parameter
ICH
(USP, JP, EP)
FDA
DPA-LOP.002
ASTM
E2503-07
USP
Toolkit Ver 2.0
Vessel/Shaft
Centering
NMT 2 mm
from center
axis
≤ 1.0 mm from
center line
≤ 1.0 mm from
center line
NMT 2.0 mm
difference (4 90° positions)
Vessel
Verticality
Not Measured
≤ 1.0° from
vertical (2 - 90°
positions)
≤ 1.0° from
vertical (2 90° positions)
NMT 0.5° from
vertical
Vessel Plate
Level
Not Measured
Not Measured
Not Measured
NMT 0.5° from
horizontal
Performance
Verification
Test (PVT)
USP
Prednisone
Tablets RS
Not Measured
Not Measured
USP
Prednisone
Tablets RS
141
Apparatus Suitability
Initially, the primary purpose of the USP Apparatus Suitability
test with Prednisone and Salicylic Acid tablets was to indicate
the influence of environmental factors and vibration on the
apparatus since most other parameters could be controlled by
mechanical measurements
The original test became known as “Calibration” although this
was not a true indication of the test being performed; later
changed to “Performance Verification Test” (PVT)
The PVT, has been responsible for detecting problems
associated with dissolution apparatus that are found to be within
mechanical tolerances
142
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The Fundamentals of Dissolution
Apparatus Suitability
The Apparatus Suitability Test became a USP requirement for all
dissolution equipment in 1978
Determine the acceptable performance of the dissolution test assembly
periodically. The suitability for the individual apparatus is demonstrated
by the Apparatus Suitability Test.
Apparatus Suitability Test, Apparatus 1 and 2— Individually test 1
tablet of the USP Dissolution Calibrator, Disintegrating Type and 1 tablet
of USP Dissolution Calibrator, Nondisintegrating Type, according to the
operating conditions specified. The apparatus is suitable if the results
obtained are within the acceptable range stated in the certificate for that
calibrator in the apparatus tested.
143
Apparatus Suitability
Initially, 8 tests required:
• 50mg Prednisone Calibrator Tablets - disintegrating
– baskets and paddles both at 50 and 100rpm
– tested in 900ml water for 30 minutes
• 300mg Salicylic Acid Calibrator Tablets - non-disintegrating
– baskets and paddles both at 50 and 100rpm
– tested in 900ml phosphate buffer for 30 minutes
• Acceptance criteria (upper and lower limits ) applied to each individual
position.
• Variation between positions was not considered.
144
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The Fundamentals of Dissolution
Apparatus Suitability
USP rationalised the requirements in 1997:
• With experience of the tests, it was found that just testing at a single speed
gave sufficient information.
• If the equipment was only used with one apparatus (baskets or paddles)
then the tests were only required with that apparatus.
In 1999, a new 10mg Prednisone tablet formulation was
introduced
• tested in 500ml water
• this formulation was found to be extremely sensitive to mechanical
variations in the apparatus and also to experimental procedures such as
degassing of the medium.
145
Apparatus Suitability
With these new tablets, industry started to have problems
meeting the requirements and the credibility of the test was
doubted.
After many experiments, it was found that there was no
significant problem attributable to the tablets themselves and
the procedure was shown to be a very sensitive, holistic test for
qualification of dissolution equipment.
It was also concluded that sufficient information was obtained
from the Prednisone tablet tests and additional testing with the
Salicylic Acid tablets was no longer necessary
• the requirement to test with Salicylic Acid tablets was withdrawn in
December 2009.
146
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The Fundamentals of Dissolution
Apparatus Suitability
The problem with the original requirement to evaluate individual
positions:
65.0
60.0
55.0
50.0
45.0
- Is this acceptable?
40.0
35.0
30.0
25.0
0
1
1
2
147
Apparatus Suitability
The procedure and requirements for the Apparatus Suitability
Test have been the subject of extensive review over several
years.
USP revised the concept of the test from a test on each
individual position in a dissolution tester to the ISO approach of
“instrument proficiency testing” based on tests on the whole
instrument.
This introduced Performance Verification Testing (PVT)
148
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The Fundamentals of Dissolution
Apparatus Suitability
Performance Verification Testing (PVT)
• Statistical analysis of the results of tests on all positions of an apparatus
now required.
• Both the Mean of the results and the % Coefficient of Variation must pass
the acceptance criteria.
• The Prednisone tablets were renamed as “Reference Standard Tablets” to
remove the implication of “calibration”.
149
2009 revision to USP <711>
APPARATUS SUITABILITY
The determination of suitability of a test assembly to perform
dissolution testing must include conformance to the
dimensions and tolerances of the apparatus as given above.
Determine the acceptable performance of the dissolution test
assembly periodically. The suitability for the individual
apparatus is demonstrated by the Performance Verification
Test.
Performance Verification Test, Apparatus 1 and 2—
Test USP Prednisone Tablets RS according to the operating
conditions specified. The apparatus is suitable if the results
obtained are within the acceptable range stated in the
technical data sheet specific to the lot used and the apparatus
tested.
150
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The Fundamentals of Dissolution
Ph. Eur. 2.9.3
Apparatus suitability. The determination of suitability of a test assembly to
perform dissolution testing must include conformance to the dimensions
and tolerances of the apparatus as given above.
Determine the acceptable performance of the dissolution test assembly
periodically.
J.P. 6.10
Apparatus suitability— The determination of suitability of a test assembly
to perform dissolution testing must include conformance to the dimensions
and tolerances of the apparatus as given above.
Determine the acceptable performance of the dissolution test assembly
periodically.
151
Apparatus Suitability
USP has always regarded mechanical calibration as a prerequisite for the Apparatus Suitability Test
• not an alternative as implied by FDA
The new approach with the statistical evaluation of the
Performance Verification Test has shown that much dissolution
apparatus has been inadequately controlled in the past.
152
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The Fundamentals of Dissolution
USP Performance Verification Test
PVT provides experimental proof that the dissolution test
assembly is suitable for dissolution testing
• Apparatus 1 and Apparatus 2
– Prednisone RS tablets
• Apparatus 3
– Chlorpheniramine Maleate Extended Release RS tablets
(requirement withdrawn from end of February 2012)
• Apparatus 4
– currently not available (no monographs used App. 4 until 2013)
153
USP Performance Verification Test
154
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The Fundamentals of Dissolution
The USP ISO-based PVT Test
PVT now designed as a Single-Stage testing approach i.e. two
consecutive runs using all positions of an instrument
• Collect the results as % prednisone dissolved at 30 min of two consecutive
runs on the dissolution assembly
• Calculate the overall geometric mean (GM) and the mean of the variances
of both runs
• Compare the obtained results with the applicable acceptance limits
PVT passes if both values meet acceptance criteria
155
Optional Two-Stage testing
Possibility of stopping after the first step
Step 1:
• Perform one test with all positions of the dissolution assembly and
calculate % prednisone dissolved at 30 min
• Determine the geometric mean (GM) and percent coefficient of variation
(%CV)
• Compare the GM and %CV to the acceptance criteria.
If both values meet acceptance criteria, test finished
• If not, go to Step 2
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The Fundamentals of Dissolution
Optional Two-Stage testing
Step 2:
• Perform an additional test and record the percent dissolved value
• Determine the geometric mean (GM) and percent coefficient of variation
(%CV) for this second test
• Compute a pooled (from Step 1 and 2) GM and the mean of the variances
of both runs
• Compare to the acceptance criteria.
If both values meet acceptance criteria, PVT passed
If GM and/or %CV do not meet the acceptance criteria the test
has failed and further work is needed.
USP does not offer guidance as to which approach to use.
157
Acceptance Limits for the PVT with Prednisone
tablets (July 2015):
158
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The Fundamentals of Dissolution
From experience...
The most common causes of failure are:
• procedural
– improper degassing
– inaccurate dispensing
– resident sampling probes and/or thermometers
– sampling technique
• equipment (this is the purpose of the test)
– poor quality vessels
– apparatus alignment
– vibrations
159
Causes of failure
The most common cause of PVT failures due to the procedure
is degassing.
The recommended degassing technique is simple and efficient
• Heat media to 41-45°C
• Vacuum filter (<100mBar)
through 0.45µm filter
• Continue to pull vacuum for
5 additional minutes.
160
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The Fundamentals of Dissolution
De-aerated vs. Non-de-aerated Medium
161
The Prednisone Test
Cone formation is an essential and critical characteristic of the
test
• dissolution occurs at the surface of the cone
• saturated solution in the centre
• any disturbance of the cone changes the results
162
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The Fundamentals of Dissolution
Dispensing
The medium should be used immediately after degassing
• temperature should not fall below 37°C
• dispense gravimetrically
163
Sampling
Samples should be taken at the correct time from the correct
position
• 30 minutes ±2% (±36 seconds)
• mid-point between surface of
medium and top of paddle or
basket, at least 1cm from vessel wall
• take a large sample (20-30ml)
• filter immediately
164
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The Fundamentals of Dissolution
Vessels
The most common cause of PVT failures due to the apparatus is
the vessels.
Vessels usually made by traditional glass-blowing techniques
• Each vessel is more or less unique since they are essentially hand-made,
individual flaws add to hydrodynamic variability
• Modern manufacture of vessels is better controlled and individual vessels
may be certified
165
Vessels
The compendial specification is not well-defined:
… made of glass or other inert, transparent material
… cylindrical with a hemispherical bottom
… sides are flanged at the top
… for a nominal capacity of 1 liter, the height is 160mm to 210mm
and its inside diameter is 98mm to 106mm
166
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The Fundamentals of Dissolution
Vessels
Even with perfect manufacture, “within specification” differences are significant
98mm ID
for 900ml
Surface
Area
106mm ID
+17%
Volume of -10%
Cylinder
Volume of +27%
Hemisphere
Such differences can change dissolution results
167
Vessels
Vessel Dimensions – Inner Diameter
• Sets of 6 vessels from 10 different manufacturers
105
Average Inner Diameter (mm)
104
103
102
101
100
99
0
2
4
6
8
10
12
Source
168
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The Fundamentals of Dissolution
MECHANICAL QUALIFICATION STANDARDS
169
Dissolution Mechanical Qualification Standard
Requirements
General MQ Requirements:
•Check vessel, basket and paddle dimensions on receipt
•Perform maintenance procedures recommended by
manufacturer
•Perform mechanical qualification:
• After apparatus is moved
• After apparatus is repaired
• After 6-months from previous calibration
•Perform “Operational Checks” at each time of use
170
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The Fundamentals of Dissolution
Dissolution Mechanical Qualification Standard
Requirements
Check Dimensions Upon Receipt:
Paddle, Basket/Shaft, and Vessel
apparatus components must be verified
that they conform with the harmonized
standard USP <711> Dissolution (USP,
JP, EP)
• Individual measurements for each
dimension of each component must
be documented
• Certificates of Conformance (COC)
may be obtained from Agilent to
document conformance.
• Otherwise, measurements must be
documented by the end user.
171
Dissolution Mechanical Qualification Standard
Requirements
Perform Maintenance Procedures:
•Lubricate moving parts
•Check belt for wear and proper
tension
•Check power cords and cable
connections for wear
•Check alignment of belt, pulleys and
spindle housing
•Clean water bath, replace tubing if
necessary and use algaecide
approved for heater/circulators
172
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The Fundamentals of Dissolution
Dissolution Mechanical Qualification Standard
Requirements
Mechanical Qualification Requirements:
•Shaft Wobble
•Paddle/Basket Shaft Verticality
•Basket Wobble
•Vessel Centering
•Vessel Verticality
•Paddle/Basket Depth
•Rotational Speed
173
Dissolution Mechanical Qualification Standard
Requirements
Operational Checks (document each time of use):
•Basket/shaft examination
•Paddle examination
•Vessel examination
•Vessel Temperature
•Vibration
174
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The Fundamentals of Dissolution
Dissolution Mechanical Qualification Standard
Requirements
Basket and Basket Shaft, must be free from:
• Defects
• Rusting
• Corrosion
• Loose wires
• Clogged mesh openings
• Dented sides or bottom
• Knicks, dents or misshapen appearance
• O-ring are not compliant; three clips required
175
Dissolution Mechanical Qualification Standard
Requirements
Paddle Examination, must be free from:
• Defects
• Rusting
• Corrosion
• Peeling or loose coating
• Knicks, dents or misshapen appearance
176
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The Fundamentals of Dissolution
Dissolution Mechanical Qualification Standard
Requirements
Vessel Examination, must be free from:
• Scratches
• Cracks
• Pits
• Residue
• Surface irregularities
177
TOOLS FOR MECHANICAL QUALIFICATION
178
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The Fundamentals of Dissolution
Mechanical Qualification
Height:
Wobble:
179
Mechanical Qualification
Temperature
Level
180
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The Fundamentals of Dissolution
…The Agilent 280-DS
Fast – less than 35 minutes
Simple – only two devices
Easy to Use - software prompts
every measurement
Data Capture - standardized
reporting, historical tracking and
trending by serial number (instrument,
vessel, paddle, basket, etc)
21 CFR Part 11 Compliant Certificates of Conformance - storage
and tracking
Control - Agilent dissolution
apparatus during measurement
181
280-DS Mechanical Qualification System
Components
Vessel Module
Instrument Module
Temperature Probe
Software
Personal Computer
(Optionally Supplied)
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The Fundamentals of Dissolution
280-DS Mechanical Qualification System
Vessel Module (VM)
Once placed in the vessel
this will measure:
• Spindle Speed (RPM)
• Shaft Wobble
• Basket Wobble
• Shaft Verticality
• Vessel Verticality
• Vessel Centering
• Basket/Paddle height
280-DS Mechanical Qualification System
Instrument Module (IM)
The Instrument Module (IM) is placed on
the vessel plate to measure:
Vessel Plate Level
Vibration
Temperature
184
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The Fundamentals of Dissolution
280-DS Mechanical Qualification System
How it Works
185
280-DS Mechanical Qualification System
Software Capabilities
• Configuration files maintain all relevant
apparatus data including serial numbers of
critical components
• Method files may be chosen from a pre-loaded
list of regulated procedures or customized based
on specific internal requirements
• All necessary controls available for use in a 21
CFR Part 11 environment including User
Groups, Audit Trails, etc.
• Text directions as well as graphics instruct the
user how and when to perform each
measurement
• All results are stored within a database that may
be created locally or on a secure network
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The Fundamentals of Dissolution
280-DS Mechanical Qualification System
Software Capabilities
•Select specific positions to be tested for quick investigations
•Record exact orientation of vessel within the data file
•Filter past reports using various criteria including dates, operator,
apparatus, etc.
•Conveniently monitor system and/or method changes with built-in audit
trail reports
•Inspect individual position measurements
using the data trending capability
•Certificates for all components can be
stored and linked within Apparatus file.
280-DS Mechanical Qualification System
Software Capabilities
Comprehensive Reporting:
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The Fundamentals of Dissolution
280-DS Mechanical Qualification System
Vibration Monitoring
PVT OR MQ
WHAT IS RIGHT FOR YOUR LABORATORY?
190
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The Fundamentals of Dissolution
PVT or MQ
What Is Right For Your Laboratory?
PVT Advantages:
•Holistic test with actual controlled tablets
•Conforms closely to USP <1058> Analytical Instrument
Qualification, requirement for Performance Qualification
•New USP Acceptance Criteria provide statistical interpretation
of results for an instrument as a whole.
•Detects issues with Vessel Quality
•Detects environmental issues
•PhRMA studies showed PVT should be maintained until a
definitive vibration specification is developed
191
PVT or MQ
What Is Right For Your Laboratory?
When a PVT failure is
observed it is a situation that
requires investigation.
The PVT does not tell us
exactly what is wrong but if we
proceed without resolution, the
consequences may be
catastrophic!
192
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The Fundamentals of Dissolution
PVT or MQ
What Is Right For Your Laboratory?
PVT Disadvantages:
• Time – takes significant time to perform
• Expense:
• Cost of USP prednisone tablets
• Cost of USP reference standards
• Analyst’s time away from production
• Expertise - requires training and experience
• FDA claims of USP tablet variability
193
PVT or MQ
What Is Right For Your Laboratory?
Time Savings (35-min vs a few hours with PVT)
Ease of use allows shorter qualification intervals
Data that helps you pinpoint possible problems
Now have the ability to trend parameter variation over time
No guesswork associated with manual
and analog gauges
No standards or tablets to purchase
Provides instant failure investigation
information
Reports exact information required by
Enhanced MQ Standards
194
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The Fundamentals of Dissolution
PVT or MQ
What Is Right For Your Laboratory?
MQ Disadvantages:
• Misinterpretation of Certificates of Conformance for
components – These are not to be confused with
manufacturing conformance certificates which state parts are
manufactured according to USP specifications
• Subjectivity of Component Examination at time of use
• Does not account for:
•
•
•
•
Vessel Quality
Vibration
Deaeration
Other Laboratory Environment Issues
196
PVT or MQ
What Is Right For Your Laboratory?
Primary reason customers transition to MQ:
• Anticipated savings for time and money
• Anticipated reduction in frequency and intensity of
investigations
Common misconceptions about transition from PVT to MQ:
• Perceived variability in USP Prednisone PVT – cited by FDA
• Requirement for individual component “Certificates of
Conformance” is not necessary
• MQ will reduce apparatus variability, however, vessel quality
and effects of vibration will not be challenged
197
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The Fundamentals of Dissolution
Current Situation with PVT vs EMC
PVT is only a USP requirement
• Conformance to USP is only required for products with USP monographs
marketed in the USA
• USP General Notices 6.30 allows alternative validated procedures
• Federal law states that FDA should enforce USP requirements
• FDA inspectors have issued 483s to companies who have just abandoned
PVT with no documented justification of EMC as an alternative procedure
198
Current Situation with PVT vs EMC
There has recently been debate around the industry about the
necessity of PVT using the Prednisone Tablets.
FDA and FIP have indicated that they do not consider PVT
essential if there is an adequate enhanced mechanical
calibration regime.
PVT is required by the USP but is only suggested by other
pharmacopœias.
• USP states that enhanced mechanical calibration is an essential prerequisite to PVT.
199
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The Fundamentals of Dissolution
FUNDAMENTALS OF DRUG
RELEASE
- BIOPHARMACEUTICS
Bioavailability and Bioequivalence
FDA Definitions
Pharmaceutical Equivalence
• Same active drug ingredient; same strength; same dosage form and route
of administration; comparable labeling; meets compendial or other
applicable standards of strength, quality, purity, and identity.
Bioavailability
• The rate and extent to which the active ingredient or active moiety is
absorbed from a drug product and becomes available at the site of action.
Bioequivalence
• Two pharmaceutical equivalent drug products are bioequivalent if after
drug administration, the bioavailabilities (rate and extent of drug
availability) provide similar effects with respect to efficacy and safety.
201
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The Fundamentals of Dissolution
Bioavailability and Bioequivalence
WHO Definitions
Pharmaceutical Alternative Products
• They contain the same molar amount of the same pharmaceutical
ingredient but differ in dosage form and/or chemical form and are
administered by the same route.
Therapeutic Equivalence
• They are pharmaceutically equivalent or alternatives and their safety and
efficacy are the same when administered by the same route..
Interchangeable Pharmaceutical Product
• Therapeutically equivalent to a comparator product.
202
Biopharmaceutics Classification System (BCS)
The BCS is a scientific framework for classifying drug
substances based on their aqueous solubility and intestinal
permeability
When combined with the dissolution of the drug product, the
BCS takes into account three major factors that govern the rate
and extent of drug absorption from IR solid oral dosage forms:
• solubility, intestinal permeability and dissolution
203
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The Fundamentals of Dissolution
Biopharmaceutics Classification System - BCS
The BCS is effectively a risk tool adopted by regulatory agencies
which:
• characterises the absorption properties of a drug
• characterises the likely clinical performance (PharmacoKinetics) of new and
old formulations
BCS terminology is a useful way to describe the biopharmaceutical
properties of a compound.
In August 2000 the FDA introduced this into guidance, which:
• Sets solubility, permeability and dissolution limits
• Allowed ‘biowaivers’ (removal of bioequivalence studies) for ‘Class 1’
compounds/products – due to their lower level of biopharmaceutical risk
204/112
Biopharmaceutics Classification System - BCS
High
Dose soluble in
250 mL pH 1 to 7.5
High
Extent of
absorption
>90%
Permeability
Low
Extent of
absorption
<90%
1
3
Solubility
Low
Dose NOT soluble in
250 mL pH 1 to 7.5
2
4
• For drugs in the Class 1 category, if dissolution >85% in 30mins, the
FDA may waive the requirements for BA/BE studies.
205/112
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The Fundamentals of Dissolution
Biopharmaceutics Classification System - BCS
Examples
Class 1: High Solubility
High Permeability
• Verapamil
• Propranolol
• Metoprolol
Class 3: High Solubility
Low Permeability
• Ranitidine
• Cimetidine
• Atenolol
Class 2: Low Solubility
High Permeability
• Ketoprofen
• Naproxen
• Carbamazepine
Class 4: Low Solubility
Low Permeability
• Furosemide
• Hydrochlorthiazide
206/112
BCS - Solubility
The solubility class boundary is based on the highest dose strength of
an IR product that is the subject of a biowaiver request
A drug substance is considered highly soluble when the highest dose
strength is soluble in 250 ml or less of aqueous media over the pH
range of 1-7.5
The volume estimate of 250 ml is derived from typical BE study
protocols that prescribe administration of a drug product to fasting
human volunteers with a glass
(about 8 ounces) of water
207
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The Fundamentals of Dissolution
BCS - Permeability
The permeability class boundary is based
•
directly on the rate of mass transfer of a drug substance in humans
across human intestinal membrane
•
Alternatively, non-human systems capable of predicting the extent
of drug absorption in humans can be used (e.g.; in vitro epithelial
cell culture methods, CaCo2 cells)
•
In the absence of evidence suggesting instability in the
gastrointestinal tract, a drug substance is considered to be highly
permeable when the extent of absorption in humans is determined
to be 90% or more of an administered dose based on a mass
balance determination or in comparison to an intravenous reference
dose
208
BCS - Dissolution
An IR drug product is considered rapidly dissolving when no less than
85% of the labeled amount of the drug substance dissolves within 30
minutes using
•
USP Apparatus I (basket) at 100 rpm,
or Apparatus II (paddle) at 50 rpm
•
A volume of 900 ml or less in each of the following media:
– 0.1 N HCl or Simulated Gastric Fluid USP without enzymes
– pH 4.5 buffer
– pH 6.8 buffer or Simulated Intestinal Fluid USP without
enzymes
209
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The Fundamentals of Dissolution
In Vitro – In Vivo Correlation?
In Vitro
In Vivo
210/112
In Vitro – In Vivo Correlation
• Early practice was to develop dissolution requirements based on the in
vitro performance of clinically successful formulations.
• Similarity in dissolution behavior has long been sought from the
perspectives of both bioavailability and quality control considerations.
• The goal of the pharmaceutical scientist is to find a relationship between an
in vitro characteristic of a dosage form and its in vivo performance.
• In vitro–in vivo correlation, IVIVC, refers to the establishment of a rational
relationship between a biological property, or a parameter derived from a
biological property produced by a dosage form, and a physicochemical
property or characteristic of the same dosage form.
– USP <1088> In Vitro And In Vivo Evaluation Of Dosage Forms
211
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The Fundamentals of Dissolution
Parameters to be Correlated
In Vivo data is taken from human pharmacokinetic studies
•
Overlapping of kinetic subprocesses
•
Apparent in vivo dissolution needs to be deconvoluted
– at least distribution and elimination taken into account
•
Prerequisite is that in vivo dissolution is rate limiting step
In Vitro data is taken from dissolution experiments
•
Experimental design determines primary data
– closed models (paddle) provide cumulative profiles
– Open models (flow-through cell) provide fractionated profiles
•
No preference for model, profiles a convertible
212
In Vivo
Transformation of plasma levels to “in vivo dissolution”
213
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The Fundamentals of Dissolution
In Vitro – In Vivo Correlation
The biological properties most commonly used are one or more
pharmacokinetic parameters obtained following the administration of the
dosage form
•
AUC
•
Cmax
The physicochemical property most commonly used is a dosage form's
in vitro dissolution behavior
•
% drug released under a given set of conditions
The relationship between the two properties, biological and physicochemical,
is then expressed quantitatively
214
IVIVC Correlation Levels according to USP <1088>
Level A
•
Highest category of correlation
•
Represents a point-to-point relationship between in vitro dissolution
and the in vivo input rate of the drug from the dosage form
•
Compares the % drug released versus % drug absorbed
215
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The Fundamentals of Dissolution
IVIVC Correlation Levels
Level A – Advantages:
•
•
•
•
A point-to-point correlation is developed
– All in vitro dissolution data and all the in vivo plasma drug
concentration profile data are used
An in vitro dissolution curve can serve as a surrogate for in vivo
performance
– A change in manufacturing site, method of manufacture, raw
material supplies, minor formulation modification, and even
product strength using the same formulation can be justified
without the need for additional human studies
A truly meaningful (in vivo indicating) quality control procedure,
which is predictive of a dosage form's performance, is defined
Can justify quality control limits
216
Level A IVIVC Example
Bioavailability from two
different tablet formulations
Plasma Concentration (ng/mL)
Dissolution profiles for two
different tablet formulations
Percent drug released (%)
100
Formulation 1
Formulation 2
80
60
40
20
0
0
1
2
Time (hr)
3
4
8
Formulation 1
Formulation 2
6
4
2
0
0
2
4
6
8
10
12
Time (hr)
217
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The Fundamentals of Dissolution
IVIVC Correlation Levels
Level B
•
Utilizes the principles of statistical moment analysis
•
Compares the mean in vitro dissolution time, MDT, to either the
mean residence time, MRT (mean time that the drug molecules
stay in the body), or the mean in vivo dissolution time
•
Utilizes all of the in vitro and in vivo data
•
Not considered to be a point-to-point correlation because it does
not reflect the actual in vivo plasma level curve
•
Cannot rely upon a Level B correlation alone to justify formulation
modification, manufacturing site change, excipient source change,
batch-to-batch quality, etc.
•
Cannot justify quality control limits
218
Level B Correlation
In Vitro - In Vivo Correlation of Mean Dissolution Times
2.5
MDTvivo [h]
2
1.5
1
0.5
R
T1
0
T2
T3
-0.5
-0.1
0
0.1
0.2
0.3
MDTvitro [h]
0.4
0.5
0.6
MDTvivo, tablet = MRTtablet - MRTsolution
219
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The Fundamentals of Dissolution
IVIVC Correlation Levels
Level C
•
Relates one dissolution time point (t50%, t90%, etc.) to one
pharmacokinetic parameter such as AUC, Cmax, or Tmax
•
Single point correlation
•
Does not reflect the complete shape of the plasma level, which
is the critical factor that defines the performance of finished
drug products
•
Has limited usefulness in predicting in vivo drug performance
•
Cannot be used to justify formulation modification,
manufacturing site change, excipient source change, batch-tobatch quality, etc. or quality control limits
220
Level C Correlation
Tmax vs. 30 minute dissolution (different formulation
variables)
221
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The Fundamentals of Dissolution
Level C Correlation
Cmax vs. 30 and 60 minute dissolution (different
formulation variables)
222
In Vitro – In Vivo Correlation
Immediate release and rapidly dissolving drug products
•
Difficult to obtain an IVIVC due to relationship of dissolution and
absorption in vivo
– Rapid dissolution - may only obtain one or two dissolution
samples within short time period (e.g.; <30mins) unless e.g.;
profiling with the use of fiber-optics
– Rapid systemic absorption - may only obtain a few plasma
drug concentration values prior to Tmax (e.g.; Tmax < 1 hr)
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The Fundamentals of Dissolution
In Vitro – In Vivo Correlation
Extended release drug products
•
IVIVC works best for ER drug products where in vivo drug
release is rate limiting step by design
•
Need to compare at least two formulation variables to set
specification ranges
– More rapid drug release
– Less rapid drug release
– Alternatively target vs. upper/lower side batches
•
Need to consider different USP Apparatus and/or different
dissolution conditions
224
In Vitro – In Vivo Correlation
IVIVC is drug formulation dependent under specific dissolution
conditions
Generic drug products containing same pharmaceutical
ingredients may not have the same IVIVC
225
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The Fundamentals of Dissolution
Lack of In Vitro-In Vivo Correlation
May not be able to obtain an IVIVC for your drug product where :
•
Systemic drug absorption is the rate-limiting step for absorption
– Variations in drug dissolution/release are not reflected in
variations in drug absorption
– Dissolution is not rate limiting step
•
Drug dissolution test is not discriminating
– May need to modify dissolution conditions
226
Lack of In Vitro-In Vivo Correlation
Bioindicative dissolution method needed
Dissolution media do not reflect physiological conditions in the GI tract
•
•
pH in different regions of GI tract
Contents of GI tract
– Liquids and solids
– Fed or fasted state
– Normal digestive enzymes
– Water content
Other factors affecting systemic drug absorption
•
•
•
GI transit time
Pre-systemic drug elimination (first pass effects)
Enterohepatic circulation
227
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The Fundamentals of Dissolution
Waiver of In Vivo Bioequivalence Requirement
A sponsor of a new drug product may request a waiver of in vivo
bioequivalence requirement for lower strength drug products under
certain conditions
In vitro dissolution testing can be used in place of performing an in vivo BE
study on all dosage strengths
228
Waiver of In Vivo Bioequivalence Requirement
Formulation proportionality
•
The in vivo BE requirements can be waived for lower strength drug
products provided
– the lower strengths of the same dosage form are proportionally
similar in their active and inactive ingredients
– dissolution profiles have sufficient similarity
Example
•
200 mg tablet BE study performed
•
100 mg and 50 mg tablets dissolution profiles performed
•
Beads in capsules
229
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The Fundamentals of Dissolution
Waiver of In Vivo Bioequivalence Requirement
Drug Products intended for Systemic Action
for which In Vivo
Bioequivalence Studies may be Waived
Condition
Example
Comments
Drug products for
which bioavailability
is self evident
Oral solutions
Drug bioavailability
from a true solution is
considered self-evident.
Highly viscous solutions
may have bioavailability
problems
In vivo-in vitro
correlation (IVIVC)
Modified release drug
products
The dissolution of the
drug from the drug
product in vitro must be
highly correlated to the
in vivo bio- availability
of the drug
230
Waiver of In Vivo Bioequivalence Requirement
Drug Products for which In Vivo
Bioequivalence Studies may be Waived
Condition
Example
Comments
Biopharmaceutics
classification system
(BCS)
Immediate release
(IR) solid oral drug
products
Drug must be a highly
soluble and highly
permeable substance
that is in a rapidly
dissolving dosage form
Biowaiver
Drug products
containing a higher
or lower dose
strength (e.g., 200
mg, 100 mg and 50
mg IR tablets)
Drug products in the
same dosage form and
proportionately similar
in active and inactive
ingredients. Similar
dissolution profiles at
different pH values
231
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The Fundamentals of Dissolution
Scale-Up and Post Approval Changes (SUPAC)
After a drug product is approved for marketing by the FDA, the manufacturer
may want to make a manufacturing change. SUPAC guidance are
published by the FDA for manufacturers of approved drug products who
want to change:
•
a component and composition of the drug product
•
the batch size
•
the manufacturing site
•
the manufacturing process or equipment
•
packaging
232
Scale-Up and Post Approval Changes (SUPAC)
The SUPAC guidance describe various levels of postapproval changes according to whether the change is
likely to impact on the quality and performance of the
drug product. The level of change is classified by the
FDA as the likelihood that a change in the drug product
might affect the quality of the product
233
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The Fundamentals of Dissolution
Scale-Up and Post Approval Changes (SUPAC)
Change
Level
Example
Comment
Level 1
Change in batch size
<10 times bio-batch
Level 1 changes are those that are
unlikely to have any detectable
impact on formulation quality and
performance
Level 2
Quantitative change in
excipients greater than
allowed in a Level 1
change
Level 2 changes are those that could
have a significant impact on
formulation quality and performance
Level 3
Process change
Level 3 changes are those that are
likely to have a significant impact on
formulation quality and performance.
A Level 3 change may require in vivo
bioequivalence testing
234
Scale-Up and Post Approval Changes (SUPAC)
Change
Level
Change
Example
Level 1
Level of excipient:
Disintegrant
Binder
Lubricant
Starch ±3% Other ±1%
(any) ±0.5%
Magnesium Stearate ±0.25% Other ±1%
Level 2
Level of excipient:
Disintegrant
Binder
Lubricant
Starch ±6% Other ±2%
(any) ±1%
Magnesium Stearate ±0. 5% Other ±2%
Grade of excipient
Avicel PH102 to Avicel PH200
Level 3
Excipient >Level 1 changes
Excipient >Level 2 changes
Process
For narrow therapeutic range drugs and
low permeability drugs all drugs
Wet granulation to direct compression
235
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The Fundamentals of Dissolution
Comparing Dissolution Data
f1 and f2 Calculations
In vitro data:
•
All in vitro data to be generated with the same method
•
Differences to be taken at the same sampling times
•
Differences taken from average values (profiles) with low data
variability
Acceptable difference
•
Up to 10% average difference in the profiles is assumed to
reflect sameness in product performance in patients, i.e.;
bioequivalence
236
f1 Difference Factor
“Proportional to the average difference between two profiles”
Normalized to percent, acceptance value based on 10% average
difference between profiles
Identical profiles have an f1 value of 0, profiles are considered to be not
different if f1 is between 0 and 15
  Rn  Tn
f1  
 R
n


 100


237
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The Fundamentals of Dissolution
f2 Similarity Factor
“Inversely proportional to the average squared difference between two profiles“
Normalized to percent, acceptance value based on 10% average difference
between profiles
Identical profiles lead to an f2 factor of 100, profiles are considered not different
if the f2 value is between 50 and 100

f 2  50 log 1  1 N  Rn  Tn 
2

 0.5

 100
238
Helpful Remarks
Profiles need to belong to same curve type
Average profile based on 12 individual determinations, CV below 10% (up
to 20% at early values)
At least 3 data pairs are necessary, better more
The data points should preferably be spread out such that they represent
the profile appropriately
Only one release value above 85% permissible (either test or reference)
Profiles from rapidly dissolving IR formulations (85%/15min) do not need to
be compared by f1 or f2 factors, they are by definition similar / not
different
239
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The Fundamentals of Dissolution
Example 1
Are the profiles similar?
F1, F2 comparison: Example 1
Reference and Test
% released R
% released T
R-T
0
0
0
0
1
23
18
5
2
40
29
11
3
52
40
12
4
62
50
12
5
71
60
11
6
79
68
11
7
85
75
10
8
91
82
9
9
96
88
8
10
99
92
7
100
80
% Released
Time (h)
60
40
%released R
20
%released T
0
0
2
Time
4
(h) 6
8
10
240
Example 1
The profiles are not similar
F1, F2 comparison: Example 1
Time
% released R % released T
0
0
0
1
23
18
2
40
29
3
52
40
4
62
50
5
71
60
6
79
68
7
85
75
8
91
82
9
96
88
10
99
92
7
412
Difference factor f1:
Similarity factor f2:
17,48
48,78
R-T
0
5
11
12
12
11
11
10
9
8
7
(R-T)2
0
25
121
144
144
121
121
100
81
64
49
72
776
Reference and Test
100
80
% Released
obs
0
1
2
3
4
5
6
7
8
9
10
60
40
% released R
20
% released T
0
0
2
4Time (h) 6
8
10
241
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The Fundamentals of Dissolution
Example 2
Are the profiles similar?
% released R
0
21
36
48
58
67
74
80
86
91
96
% released T
0
13
23
36
57
73
80
85
89
91
93
R-T
0
8
13
12
1
6
6
5
3
0
3
Reference and Test
100
80
% Released
Time (h)
0
1
2
3
4
5
6
7
8
9
10
60
40
%released R
%released T
20
0
0
2
Time
4
(h) 6
8
10
242
Example 2
The profiles are similar, but different release kinetics
obs
0
1
2
3
4
5
6
7
8
9
10
Time
0
1
2
3
4
5
6
7
8
9
10
% released R
0
21
36
48
58
67
74
80
86
91
96
7
% released T
0
13
23
36
57
73
80
85
89
91
93
384
Difference factor f1:
Similarity factor f2:
R-T
0
8
13
12
1
6
6
5
3
0
3
(R-T)2
0
64
169
144
1
36
36
25
9
0
9
51
475
13,28
54,05
243
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The Fundamentals of Dissolution
Example 3
Are the profiles similar?
% released T
0
25
44
58
70
81
89
95
99
100
100
Reference and Test
R-T
0
2
5
7
9
10
10
10
8
5
1
100
80
% Released
% released R
0
23
39
51
61
71
79
85
91
95
99
60
40
% released R
20
% released T
0
0
2
4
6
Time (h)
8
10
244
Example 3
The profiles are similar
obs
0
1
2
3
4
5
6
7
8
9
10
Time
0
1
2
3
4
5
6
7
8
9
10
% released R
0
23
39
51
61
71
79
85
91
95
99
6
% released T
0
25
44
58
70
81
89
95
99
100
100
324
Difference factor f1:
Similarity factor f2:
R-T
0
2
5
7
9
10
10
10
8
5
1
(R-T)2
0
4
25
49
81
100
100
100
64
25
1
43
359
13,27
55,40
245
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The Fundamentals of Dissolution
Medium Selection
The Concept of Biorelevant Medium
Similar to the human physiological fluid
Where is the drug product dissolved and then absorbed?
Dissolution usually takes place in acid in stomach
• Rare to be absorbed in stomach
Then is emptied into the intestine after 20 minutes
Absorbed in the intestinal tract
• Range of pH from 5-7
• Typical 6.8 pH
Ionic strength, pH, wetting properties, and solubilization in physiological
range are also critical
Sink Conditions
Quantity of medium should be not less than 3 times that
required to form a saturated solution of drug substance.
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The Fundamentals of Dissolution
Justification of Medium
Medium other than the typical acids and buffers need
justification
Justification will be data that show how typical media do not give
adequate drug solubility, good profile, or stable dissolution
results
Dissolution media for in vitro testing
0.1 N HCl
• Surfactants may be added as needed
USP Simulated Gastric Fluid pH 1.2 – SGF
• pepsin may be added as needed
• surfactants
USP Simulated Intestinal Fluid pH 6.8– SIF
• 0.05M phosphate buffer
• Pancreatin may be added as needed
• Surfactants may be added as needed
Buffer solution pH 4.5
• Acetate buffer solution
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The Fundamentals of Dissolution
Simulated Biological Fluids
Simulated Gastric Fluid – fasted state: FaSSGF
• pH 1.6
• Pepsin: 0.1 mg/mL
• Na-taurocholate: 80 µM
• Lecithin: 20 µM
Simulated Gastric Fluid – fed state: FeSSGF
• pH value : 6 – 3 (early – late)
• Osmolality :600 – 300 mOsmol/kg (early – late)
Simulated Biological Fluids
Simulated Intestinal Fluid – fasted state: FaSSIF
•
•
•
•
pH value : 6.5
Osmolality 180 mOsmol/kg
Na-taurocholate :3mM
Lecithin: 0.2 mM
Simulated Intestinal Fluid – fed state: FeSSIF
•
•
•
•
•
pH value : 6.5 – 5.8 (early – late)
Osmolality :400 mOsmol/kg
Na-taurocholate: 10 – 4.5 mM
Lecithin: 3 -0.5 mM
Glyceryl monocholate: 6.5 – 1 mM
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Dissolution media for in vitro testing
In vitro dose dumping of ER oral drug products
• 0.1 N HCl
• 0%, 5%, 20%, and 40% ethanol added
• 2 h test with sampling time each 15 min
Surfactants
Wetting Agents
Used just to decrease surface tension
Concentration will be below the critical micelle concentration
(CMC) of the surfactant
• Sodium lauryl sulfate is less than 0.23% w/v
Solubilizing Agents
Surfactants that are above their CMC
Actually increase solubility of the drug substance
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Surfactants
Surfactant Concentrations
Concentrations typically go from 0.01 to 4.0%
Must justify amount used with dissolution profiles above and
below chosen %
Regulators do not want more than necessary to achieve sink
conditions
Surfactants
Typical Surfactants
Sodium lauryl sulfate (SLS)
Polysorbate 20-80 (Tween)
Cetrimide (Ctab)
Lauryl dimethylamine oxide
Bile salts
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Choice of Media
Combinations of surfactants and buffers/acids
• Useful for combining pH control and increasing solubility. For example, if a
molecule is stable only at a certain pH yet poorly soluble in that pH,
surfactant may increase solubility.
Other Media
With justification
• Mixture of aqueous and organic (<20%, usually isopropyl alcohol but
propanol and octanol have been used)
• Above pH 8
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In Vivo Simulation
In Vivo Simulation
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CURRENT TRENDS IN
DISSOLUTION TESTING
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MODIFICATION OF USP APPARATUS 7 FOR
DRUG ELUTING STENTS
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What is a Stent
A stent is a wire metal mesh tube
used to prop open an artery during
angioplasty.
The stent is collapsed to a small
diameter on a balloon catheter. It is
then moved into the area of blockage,
When the balloon is inflated, the stent
expands, locks in place as a scaffold.
This holds the artery open.
The stent stays in the artery
permanently, holds it open, improves
the blood flow and relieves the
symptoms
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Angioplasty
A tiny balloon that presses the plaque
blockage against the artery so that
blood may flow more freely through
the vessel
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Stenting
A stent is inserted into an artery after
angioplasty to help ensure that blood
continues to flow freely through the
vessel and to reduce the chance that
plaque will block the artery again.
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Development of Coated and Drug-Eluting Stents
Physicians and companies began
testing a variety of drugs that were
known to interrupt the biological
processes that caused restenosis.
Stents were coated with these drugs,
sometimes imbedded in a thin
polymer for time-release, and clinical
trials were begun.
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Case Study
Drug Eluting Stents
• Initially, most drug eluting stent
manufacturers utilized a rocking
“incubator,” shaker tables or USP
Apparatus 4 or 7 as their
instruments of choice.
• Modifications to App 7 allowed
smaller volumes and automated
sampling.
• Custom holders had been designed
for various stents and other medical
devices.
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Challenges with Traditional Apparatus 7
• Instrument was not originally designed for extremely low volumes.
• Evaporation control was difficult due to reciprocating rod (which held the
dosage form/device). Many methods allowed for media addition (“top up”)
prior to analysis.
• Initial design was difficult to automate The smaller volume tubes had
smaller diameter openings; as a result, clearance was tight for sample and
return lines.
• The requirement for testing 12 stents at a time lead to the development of a
12 place collector.
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Early Development
Proof of Concept Unit
The intent was to develop a
prototype inexpensively in order to
test:
1) theory of operation
2) conformance with USP
specifications and
3) eliminate problems associated
with past units.
Utilized existing hardware with
modified firmware.
The unit was built for manual
testing, sampling and media
changes where done by hand
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Proof of Concept
Apparatus 7 with Magnetic Drive
How did it work?
• Each rack was designed for a specific size stent/tube
• The rack reciprocated the USP specified 2 cm distance
• Each rack had a magnetic plate which drove the stent holder within
each tube
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Design Advantages
• Matched USP specifications for
Apparatus 7
• Able to handle small volumes (5 50mls)
• Inert materials used in design
allowed solvents to be used
• Able to change DPM to more
closely match in-vivo release
• Provided a tool for IVIVC work as
well as accelerated QC release
testing
• High throughput in a single tester
(customize the number of available
rows)
• Excellent temperature control,
allows elevated temperatures
• Sealed system; essentially no
evaporation
• Disposable tubes (no dead volume
or cleaning issues to contend with)
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Small Volume Drug Release Apparatus Prototype
to Commercial Product
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Agilent 400-DS
• Parent module has the ability to
test 13 samples and incorporates
the ability to access up to four
types of media.
• Sample collection is built into each
module.
• Additional modules, each capable
of testing 13 samples, can be
added to the parent module to
extend testing capacity to 52
samples.
• Each unit is individually operated
and controlled via the software
provided.
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400-DS: Dissolution Cell Design
Dissolution Cell
Heater
Jacket
• A glass tube (dissolution cell), open at both ends, is
placed atop a base seal
• A heating jacket fits around each tube (no water bath is
used)
• The sample holder is inserted and the tube is capped
• All media fill and sampling is done via the bottom of
the tube via the media/sample port
Media / Sample
Port
Temperature
Probe
• Media temperature is recorded and controlled through
the built-in temperature probe
• Dissolution cells are disposable and can be readily
replaced when necessary
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400-DS Temperature Control
• External jacket designed to provide
uniform heating of the test media
• Temperature feedback provided by
internal temperature probe in the base
of each chamber
• No water bath!
Heater jackets
surround the
dissolution cells
Dissolution cells 5 mL and 10 mL
Reciprocating holder for
drug-eluting stents of
various lengths
Temperature probe and
sampling port at bottom of
the dissolution cells
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400-DS – Improved Test Performance
The 400-DS successfully addresses the many challenges associated with
the testing of combination products:
• Small Volume
• Low Evaporative Loss
• Use of organic solvent media
• Automated Sampling and Media Replacement
• Bathless
• Regulatory Compliance
• Small footprint
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400-DS Reciprocating Holder Options
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400-DS Contact Lens Holder
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The Fundamentals of Dissolution
400-DS Holder for Micro-Particulates
TESTING OF SEMI-SOLIDS AND
OTHER NON-ORAL DOSAGE
FORMS
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Semi-Solids
The requirement for testing the release rate of drugs from semisolid dosage forms has increased in recent years.
Products tested include
ointments
creams
pastes
gels
lotions
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Semi-Solids
A new USP General Chapter <1724> “Semisolid Drug Products
- Performance Tests” became official in August 2013. This
provides general information on testing semi-solids including
descriptions of three apparatus:
– Vertical Diffusion Cells
– Immersion Cell
– Insert for Apparatus 4
USP also proposes to include specific procedures and
acceptance criteria in a revised General Chapter <724>
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USP Vertical Diffusion Cell
Three versions of this apparatus are described based on the
classic Franz cell.
Model A
• volume ~7ml
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USP Vertical Diffusion Cell
Model B
• - volume ~5ml
Model C
- volume ~10ml
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USP Vertical Diffusion Cell
Recommended stirring speed is 600rpm
Test period 4-6 hours
Commercial apparatus for performing these tests is now
becoming available.
PermeGear, Inc.
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Immersion Cell Method
Used in conventional dissolution testers with a special vessel
and “mini-paddle”.
Volume of medium: 50-200ml
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Immersion Cell Method
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Flow-Through Cell Method
Used in Apparatus 4 equipment
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Rectal / Vaginal Preparations
Preparations include suppositories, pessaries, vaginal tablets
and vaginal rings.
These dosage forms are usually designed to soften and/or melt
to release the drug.
Currently the only compendial requirements are described in
Ph. Eur.
Typical apparatus for testing includes:
• Apparatus 1 - Baskets
• Apparatus 2 - Paddles (using Stationary Baskets)
• Apparatus 4 - using special cell (Ph. Eur.)
• Swirling conical flasks
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Rectal / Vaginal Preparations
The problem with the basket-type tests is that the mesh can be
blocked as the product melts.
This is overcome with special Palmeri baskets
• these are sometimes used with beads to enclose the product and provide a
simulation of the physiological environment.
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Rectal / Vaginal Preparations
The Ph. Eur. device is used in conventional Apparatus 4 Flowthrough Cell systems.
This is designed to separate the flowing medium from the
molten lipophilic excipients.
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Rectal / Vaginal Preparations
Vaginal rings are often tested in swirling flask apparatus in
incubators
• typically in 250ml saline at 130rpm for 12 hours
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Chewing Gums
Medicated chewing gums have become popular especially
for Nicotine.
Ph. Eur. describes one apparatus in 2.9.40
- Dissolution Test for Medicated Chewing Gums
• “The gum is artificially chewed by the horizontal
pistons, and the vertical piston ensures that the
gum stays in the right place between chews.”
• Volume of medium ~20ml
• “60 chews per minute”
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Chewing Gums
USP has an Advisory Panel looking into a suitable procedure
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Inhalations
There are currently no requirements for dissolution testing of
particulates from MDI/DPI aerosol products.
A USP Advisory Committee agreed that there was no necessity
to publish standards for dissolution testing of such products
(PF34-4, 2008).
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Inhalations
Various devices have been used for research purposes:
• Powder cell in Apparatus 4 using whole formulation
• Collected fractions from Anderson Cascade Impactor:
– filters from each fraction placed between membranes in a special cell for
Apparatus 4
• Using NGI apparatus, special collection cups are covered with a
membrane and dissolution measured in Apparatus 2:
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SOURCES OF INFORMATION…
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Sources of Information
Dissolution Discussion Group
www.dissolution.com
•
•
•
•
Worldwide users group for dissolution chemists
Free, on-line, interactive bulletin board
Provides annual and regional meetings around the world
Place for practical answers to everyday questions on
dissolution
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Sources of Information
FDA
www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
USP
www.usp.org
www.usppf.com
Controlled Release Society
www.controlledreleasesociety.org
www.ukicrs.org
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Sources of Information
Dissolution Technologies
www.dissolutiontech.com
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Sources of Information
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QUESTIONS?
Thank you!
Terry Way
[email protected]
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