Polymorph screening Why, when and how?
IFF 2013
Karin Liltorp
Particle Analytical ApS
www.particle.dk
Outline
What?
Scientific background
Why?
Cases & guidelines
When?
Risk Assessment - Quality by Design
How?
Examples of polymorph screenings
What - Glossary
Crystal: Solid having, in all three dimensions of
space, a regular repeating internal unit of
structure. Most solid API’s are dosed as crystals.
Polymorphs: Different ways of arranging same
type of molecules in a crystal lattice
Amorphous: Lack of long range pattern
Polymorph screening: Experiments in order to
make new crystal forms/polymorphic forms
Physical properties: Solubility, stability,
dissolution rate etc.
All polymorphs have different physical properties
which might affect patient safety.
What are polymorphic forms?
Examples of polymorphism
What are the difference between
polymorphis forms?
Polymorphic forms differ with regard to:
•Stability (degradation, reactivity, compatibility)
•I.e. impact on storage etc.(impurities)
•Solubility and dissolution rate
•Impact on bioavailability
•Manufacturing properties
•I.e. impact on flowability, blending etc.(content
homogenity)
What are the difference between
polymorphis forms?
Physical:
Kinetic:
Mechanical:
•Solubility/stability
•Melting temperature
•Density
•Morphology
•Hygroscopicity
•Dissolution rate
•Reaction rate
•Rate of
crystallisation
•Flowability
•Tableting properties
•Compactability
•Hardness
Transformation of polymorphic forms
Some ”rules”
•
A metastable form might be
sufficiently stable to use as
active ingredient
•
Spontanous transition from a
metastable to a stable
polymorph is always a risk
•
The relative stability of forms
might change with
temperature or pressure
Safety can be affected if…..
The product
has a new
dissolution
profile
The product
contains
impurities
The product does
not contain the
right amount of
the API
Guidelines based on patient safety!
Main
focus of
the FDA
guideline
Crystal control during manufacturing
• Content of API in product
Inhomogeneous distribution?
New polymorphic form has different particle
properties and behaves different during
manufacturing
• Impurities
Stability? Interactions with excipients?
New polymorphic form has different
stability and might interact differently
with the excipients
’
Particle control in vivo
New dissolution profile?
Change in crystal form gives higher/lower
dissolution rate.
WHY…..
The importance of controlling polymorphy
The ”Ritonavir-case”
Discovery off a new, more stable
polymorph of ritonavir, Form II, with
much a lower solubility.
•
• Abbott had to reintroduce the
product formulated with Form II, but
encountered serious challenges in
maintaining the drug supply of this
life saving treatment for AIDS.
Vermox
New polymorphic
form with reduced
efficiency
Coumadin - recall
Lack of control
of crystal form
Tegretol – clinical
failure due to
crystal
transformation
Norvir - withdrawal
New polymorphic
form
+ many examples
from development….
Neupro - recall
Crystallisation of
new form
Avalid - recall
Lack of control
of crystal form
New example: Lack of control of
crystal forms
FOR IMMEDIATE RELEASE - May 10, 2013 - Weston,
Florida: Apotex Corp. announced today that it is conducting,
on behalf of the manufacturer Hospira, Inc., a voluntary
nationwide recall of 21 lots of Piperacillin and
Tazobactam for Injection, USP 40.5 grams, NDC
number 60505-0773-00 to the hospital / healthcare
provider /user level. The impacted lots of Piperacillin and
Tazobactam for Injection, USP 40.5 grams may show
precipitation / crystallization in IV bag or IV line after
reconstitution.
What do the guidelines say?
ICH guideline
ICH Q6A: Decision Tree
ICH Q6A: Decision Tree
All polymorphic
forms have
different
properties…..but
how different?
Risk
Assessment!
ICH Q6A: Decision Tree
Risk
Assessment!
Read more: Non-binding
recommendations from FDA
“Although the conceptual framework
adopted by these decision trees is
based primarily on the potential for
polymorphic forms to affect drug
product BA/BE, we recommend that
you still consider the influence
polymorphic forms may have on the
ability to manufacture the drug
product and on the stability of the
drug product.”
http://www.fda.gov/downloads/Dru
gs/GuidanceComplianceRegulatoryInf
ormation/Guidances/ucm072866.pdf
Summary: Why perform
polymorph screening?
1. To fulfill guidelines
2. To secure that you have the
stable API – i.e. no risk of
transformation
3. To find a metastable
polymorph that have the
needed properties – and
define the ”stability limits”
4. (To protect IPR)
Polymorph screening
–
When?
When do I start polymorph screening
The earlier the better…..
Potential risk: Repetition of full
development program
Interpretation of results…..
What if lack of efficiency is due to crystallisation?
Consider perfoming a reduced polymorph
screening in very early development
Polymorphy, Quality by Design
and Risk Accessment
”The evaluation of the risk to quality should be
based on scientific knowledge and ultimately link to
the protection of the patient....”
ICH Q8/Q9
Risk Assessment
RISK
Polymorph transition
Probability
that it will happen
Depends on relative
stability of
polymorphic form
Consequence
if it goes wrong
Depends on
therapeutic window,
solubility, etc.
http://www.leonaking.org/risk-management
Impact?
Will a polymorphic
transformation have
significant impact on
product properties?
Maybe not – but you will
have to show
Evaluating risk
M e an Value s of Sys te m ic conce ntrationM
in
e an
plas
Value
m a of
s of Sys te m ic conce ntration in
AA38466_Laba_Xe no_is e f1_5 ove r Tim e AA38466_Laba_Xe no_is e f1_5 ove r Ti
1.60E-01
Systemic concentration
20E-01
00E-01
0E-02
Therapeutic window
0E-02
0E-02
0E-02
0E+00
1.40E-01
1.20E-01
Systemic concentration
40E-01
Systemic Concentration (mg/L)
60E-01
1.00E-01
8.00E-02
Therapeutic window
6.00E-02
4.00E-02
2.00E-02
0.00E+00
0
4
Time (hours)
8
12
Tim e (h)
16
0
20
4
24
8
Time (hours)
Broad therapeutic window and high
solubility: Simple screening
Narrow therapeutic window and low
solubility: Extensive screening and testing
12
Tim e (h)
16
Evaluating risk - guidelines
An integrated set of guidelines:
 Q8 Pharmaceutical Development
 Q9 Quality Risk Management
 Q10 Pharmaceutical Quality Systems
Risk assessment with regard to
bioavailability
1. What is the risk that a much more stable polymorph form
will be discovered?
2. Solubility and dissolution: Is bioavalability dependent on
dissolution (at all physiological pH values)? What if dose
increases?
3. What would be ”worst case” if polymorphic transformation
occured? (± 2% or ± 100%)
4. Would it be discovered if a polymorphic change took place
with the current analytical methods? (dissolution, DVS,
XRD?)
Example
•Form A: Solubility 1.2 mg/ml
•Form B: Solubility 1.4 mg/ml
•(pH independant)
•Dose: 10 mg
•Form A is the stable form (but almost
equal stability)
•Highly soluble at given dose
•”High” risk with regard to transformation
– but no risk in relation to bioavailability
Example
•Form A: Solubility 1.2 mg/ml
•Form B: Solubility 1.4 mg/ml
•(pH independant)
•Dose: 500-1000 mg
•Form A is the stable form (but almost equal
stability)
•Limited solubility
•”High” risk with regard to transformation –
”some” effect in relation to bioavailability
Example
•Form A: Solubility 1.2 mg/ml
•Form B: Solubility 10 mg/ml
•(pH independant)
•Dose: 500-1000 mg
•Form A is the stable form (and very different
stability)
• Limited risk with regard to transformation –
but if it occurs it will have a high influence on
BA.
Polymorph screening – when?
Reduce risk: Perform polymorph
screening with ”all possible” known
risks potentially leading to
transformation
Identified risk: Change in
polymorphic form/ desalting
and thereby a change in
dissolution rate/solubility
h
i
g
h
low
RISK OF TRANSFORMATION
API arrive
from chemist
Initial characterisation
of compound
(crystal form, MP, etc)
Pressure
Solvents
Concentration
heating/cooling
Time line
”Full” polymorph
screening
Polymorph screening – when?
• In early development: In order to minimise the risk of
transformation into more stable form (searching for the
stable form) “ASSURANCE”
• In late development: To protect your compound with
regard to IPR (including search for “all” metastable
forms)
Feared scenario:
The appearance of a new more stable
crystal form in late stage of development
Or after introduction to market
Can polymorph screening be done
”too soon” in regard to IPR?
“The inventiveness of a novel polymorph
form of a pharmaceutically active compound
will be acknowledged only if the novel
polymorph form is associated with an
unexpected pharmaceutical activity”
Polymorph screening
–
How?
”How” according to ICH guideline
Screen: To select, reject, consider, or group
(people, objects, ideas, etc.) by examining systematically
=Stage is free
Setting up the screening
Purpose: To ”stress” the system
in order to crystallise ”all”
possible polymorphic forms of the API
• Challenge: To select relevant
conditions – as it is not possible
to test ”all”.
• The larger the risk – the more
extensive the screening
How to create different
polymorphic forms…
At a given temperature and
pressure, one of these forms is the
stable form.
How to create different polymorphic
forms… Imagination?
How to create different polymorphic
forms… Imagination?
Polar end
Non-polar end
Crystallisation:
High ”local”
concentrations
Solvent mediated
How?
Solvents
Temperature
Wet/dry
New
polymorph?
Special
manufacturing
conditions
Pressure
Case study
• Well known API used to ”test”
simple polymorph screening set-up
–
–
–
–
3 solvents (very different properties)
3 temperatures (hot/cold/intermediate)
Pressure
Humidity
Case study
• Results: 5 polymorphic
forms/solvates found
• 6 polymorphic forms known
from literature:
• Using a very basic set-up
almost all forms were
reproduced!
Setting up ”slim”
screening procedure
• Choose a number of solvents with very
different properties
• Examine effect of temperature, pressure
and humidity
• Examine all known ”risks” from
manufacturing process
aciclovir_200_fyldt digel, 21.05.2012 14:16:54
aciclovir_200_fyldt digel, 15.8634 mg
mg
? Step
Onset
Left Limit
Right Limit
Heating Rate
15.8
-5.1605 %
-0.8186 mg
101.34 °C
29.94 °C
198.37 °C
10.00 °Cmin^-1
15.6
Crystallisation:
Concentration
Temperature
Evaporation rates
Pressure
2
°C
15.4
15.2
All ”precipitates”
15.0
40
60
analysed by XRD
80
100
120
140
160
Pa r tic le An a ly tic a l Ap S: M ETT L ER
– crystalline?
All forms analysed
aciclovir_Si_1
900
by TGA: True
800
700
polymorphic forms
Lin (Counts)
600
or solvates?
500
400
300
200
100
0
5
6
7
8
9
10
11
12
13
14
15
16
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20
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39
2-Theta - Scale
aciclovir_Si_1 - File: accilovir_Si_15min.raw - Type: 2Th/Th locked - Start: 5.000 ° - End: 40.000 ° - Step: 0.020 ° - Step time: 0.5 s - Temp.: 25 °C (Room) - Time Started: 7 s - 2-Theta: 5.000 ° - Theta: 2.500 ° - Chi: 0.00 ° - Phi: 0.00 ° - X: 0.0 mm - Y: 0.0 mm - Z: 0.0 mm - Aux1: 0.0 - Aux2: 0.0 Operations: Import
40
180
°C
ST AR e SW 9 .2 0
A new polymorphic form is
identified by XRD
Intensity (counts)
• Only crystalline material has a diffraction pattern
• All polymorphic forms have unique pattern
10000
6400
3600
1600
400
0
5
10
15
20
25
30
35
40
2Theta (°)
A ”pure” polymorph are distinguished
from a solvent by TGA
• Weight loss upon heating
• Reveals ”loosely bound” components
•  Solvates (hydrates) are identified
120
Weight (%)
100
80
60
40
20
0
50
100
150
200
Temperature (°C)
250
300
350
Universal V4.2E TA Instruments
Relative stability of polymorphs
After initial screening:
Examination of stability
Most stable = lowest solubility
Relative stability might change with temperature
…. but independent on solvent
Solvates might ”slur” the picture
A metastable form will always transform
into the stable form – but it
might take time…..
Why does the stable form not
always precipitate?
Local concentration
Orientation in solvent due to solvent properties
Solvent ”mediated” crystallisation
Kinetics determines the transformation rate
Why is it difficult to find all forms?
Mix acetone and acetonitril
1:1 and add 1.5% of water.
Heat it to 39C for 3 minutes
and cool it with liquid
nitrogen.
”Unpredictable”
Design of Experiment (e.g.
MODDE) very difficult
Dry the sample for >24 hours at 100
C. Expose the sample to EtOH
vapor. Dissolve the the sample in
MeOH and leave for stirring for 10
hours at RT
Dissolution
Need for quantification of
polymorphic form?
Yes…..
• If a high risk of
transformation exist
(remember to include
examination of the
excipients)
• If a possible transformation
has high influence on
bioavailability
ICH 10: Identify sources of variation affecting
process performance and product quality
for potential continual improvement activities to
reduce or control variation;
Methods: XRD, FTIR, DVS, dissolution, DSC
Dissolution
Need for quantification of
polymorphic form?
ICH Q10: Demonstrate product and process
understanding, including effective
use of quality risk management
principles (e.g., ICH Q8 and ICH
Q9).
Opportunity to:
• facilitate science based
pharmaceutical quality
assessment;
• enable innovative approaches to
process validation;
• establish real-time release
mechanisms.
Methods: XRD, FTIR, DVS, dissolution, DSC
Dissolution
Need for ID of polymorphic form in
final product
Q6A: “It is generally
technically very difficult to
measure polymorphic changes
in drug products. A surrogate
test (e.g., dissolution) (see
Decision tree 4(3)) can
generally be used to monitor
product performance, and
polymorph content should
only be used as a test and
acceptance criterion of last
resort.
Not true
Methods: XRD, FTIR, DVS, dissolution, DSC
Does your surrogate test
assure crystalline purity?
Dissolution tests are generally not
validated in order to predict possible
variations in vivo
A dissolution test of polymorphic
changes should be tested in relevant
biological media (pH 1.5 – 7)
Need for ID of polymorphic
form in final product
Down to 3-5% “crystalline impurity” can be detected
by XRD - Even lower with DVS (amorphous)
A surrogate test (dissolution) is generally much less
sensitive in detecting polymorphic changes
Interations with excipients can cause changes from
stable to metastable form!
Identity of crystalline form in final product should
always be validated! (i.e. compatibility study)
Methods: XRD, FTIR, DVS, dissolution, DSC
Summary
What?
Why?
When?
All API’s exist in different crystal forms
with different properties
At some time point a spontaneous
transformation between metastable forms
and the stable form will occur
A polymorph screening will lead to
”increased control”
How?
Summary
What?
Why?
When?
Cases from real life show the need for
screening for polymorphs:
Transformation of polymorphic form
might affect patient safety and
consequences should
be evaluated
The requirement is stated in ICH Q6A
How?
Summary
What?
Why?
When?
How?
•Risk assessment!
•Never too early, but the extent should
correspond to the risk
Summary
What?
Why?
New polymorphic forms can be formed by
changing the surroundings
When?
No such a thing a a ”full” screening
exist – but risk of transformation can be
minimized
How?
Particle Analytical ApS
www.particle.dk
kli@particle.dk