Developability Assessment Supporting
Drug Candidate Selection
Wei-Qin (Tony) Tong, Ph.D.
Novartis Pharmaceuticals Corporation
Integrated Drug Product Development Process
(3 day-course), University of Utah
July 17-19, 2006
Introduction
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New Trends and Challenges in Drug R&D:
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Business Challenges
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Patent expirations
Mounting cost of drug development
Generic competition
Price controls
Scientific Challenges
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Combinatorial chemistry and high-throughput screening result
in many more hits and more development candidates
Properties of NCEs become less favorable for development
Success rate in clinical studies continue to be low
Introduction
How to Maximize efficiency and minimize risks?
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To profile biopharmaceutical and pharmaceutical
properties early in the discovery process so that
n certain desirable properties can be incorporate into
molecule design
n lead compounds that are most likely to survive in the
pipeline can be selected
n development risks can be identified early
Key Developability Criteria
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Solubility
–
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as related to bioavailability for oral dosage
form
for solution formulations
Stability
n Solid State Properties
n Biopharmaceutical Properties
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Solubility
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Why is solubility so important?
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How do the solid state properties impact
solubility?
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How do we ensure quality of the solubility
data supporting intended decision-making?
Drug has to be in solution to be absorbed
Disintegration
Deaggregation
Granules
or aggregates
Tablet
or capsule
Dissolution
Dissolution
Fine
Particle
Dissolution
Precipitation
Drug
in solution
Absorption
Dissolution
Systemic
circulation
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–
Dissolution rate limited absorption
Solubility limited absorption
Fine fine
particle
Formulation Challenges with Poorly
Soluble Compounds
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Poor dissolution rate
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Low and variable bioavailability
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More potential for food effect
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Inability to deliver high doses for tox studies
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Difficulty in developing parenteral formulations
Solubility Criteria: how soluble is soluble
enough?
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Dependent on Dose and Permeability
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Dissolution Time
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Maximum Absorbable Dose (MAD):
S (mg/mL) x Ka (/min) x SIWV (mL) x SITT (min)
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Biopharmaceutical Classification
Minimum Acceptable Solubility
Solubility (µ g/ml)
10000
1000
207
100
21
21
10
1
55
207
52
5
10 2
10
2100
2100
520
520
100
100
Med Pe
§
Low Pe
11
0.1
0.1
1
High Pe
10
Projected Dose in mg/kg
Factors Causing Poor Solubility
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High crystallinity/high MP
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Zwitterion formation
Insoluble salts
H-bonding networks
Hydrophobicity/High LogP
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Lack of ionizable groups
High molecular weight
Effect of Solid State Form
Amorphous vs. crystalline
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Differences could be > 1000x
Polymorphs
Solubility (mcg/mL)
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1200
1000
800
600
400
200
0
1
2
3
4
5
6
7
8
Equilibration Time (Days)
9
Examples
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Comparison of apparent solubility of amorphous
material (A) and crystalline material (C):
Solute
Caffeine
Theophylline
Morphine
Hydrochlorthiazide
Sulfamethoxydiazine
Melting Point Solubility Ratio
(A/C)
(°C)
238
5
272
50
197
270
273
1.1
215
1.5
•S. Yalkowsky, Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington D.C. (1999).
Examples
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Comparison of apparent solubility of polymorphs:
Solute
Acemetacin
Cyclopenthiazide
Mebendazole
Spironolactone
∆ Melting Point
(°C)
20
70
41
57
30
70
05
10
Solubility Ratio
(L/H)
2.3
4.7
2
3.6
3.6
7.4
1.2
1.9
•S. Yalkowsky, Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington D.C. (1999).
Issues with kinetic solubility
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Solubility data are time-dependent!
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Dissolving material in organic solvents does not
necessarily normalize the effect of crystal form.
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It is difficult to predict whether significant
differences are expected between non-equilibrium
and equilibrium solubility data.
Correlation between equilibrium solubility
and kinetic solubility
Compound
Solubility (mcg/mL)
From solid From DMSO From
by HPLC soln by HPLC nephelometry
Benzthiazide
11
20
27
Progesterone
6
15
20
Butylparaben
139
88
97
Betamethasone
63
> 196
> 196
Oxyphenbutanzone > 500
<1
40
Phenyl salicylate
16
<1
> 107
Propylparaben
273
89
> 89
•C. Bevan and R. Lloyd, Anal. Chem. 72:1781-1787 (2000).
Structure-Solubility Correlations
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Only equilibrium solubility is considered as the
intrinsic property of a particular molecule.
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Both intrinsic solubility of the unionized form and
pKa should be considered.
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Building correlation within the same structure
series
Structure-Bioavailability Correlations
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Bioavailability is formulation dependent!
Formulation strategies for better structurebioavailability correlation
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pH adjusted solution (in situ salt)
Lipid based formulation
Dissolution rate vs. equilibrium solubility:
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equilibrium solubility is still important
Solubility Study Strategies
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Formulation development for discovery compounds:
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Lead Optimization:
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Visual observation method is typically sufficient
In vitro dilution studies can be very useful
Computational alert/in silico profiling
Identify if solubility is a contributor to poor absorption through
carefully designed PK studies
Equilibrium solubility determination of representative lead
compounds with significant structure changes: e.g. MW and
pKa changes
Candidate Evaluation/Selection:
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Miniaturized preformulation studies including salt screening
Throughput Considerations
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Can equilibrium solubility determination be high
throughput?
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Time required for equilibration
Automation possibility and challenges
Importance of checking residual solid of solubility samples
Do we need automation or high throughput?
Does high throughput really add value?
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Careful studying of representative lead compounds vs. massive
screening
Experimental measurement vs. solubility prediction
Most compounds with MW>500 and without any ionizable group
or with ionizable group but have poor solubility
Stability
How do the solid state properties impact
stability?
n How does solution stability impact solid
dosage form development?
n How do we ensure quality of the stability
data supporting intended decision-making?
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Impact on Chemical Stability
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Amorphous material is typically less stable than
crystalline material
Higher melting point typically results in better
stability
Hygroscopicity also plays an important role
Example:
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NCEX: 2 forms (160ºC and 140ºC)
% degradation observed after 4 weeks at 40ºC/75%RH
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Form 1: 0.3%
Form 2: 6%
Amorphous: 20%
Physical Stability
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Amorphous Material/Solid Dispersion
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Tg and mobility
Effect of moisture on Tg
Solid solubility
Hydrates/solvates
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Effect of processing
Impact on chemical stability and bioavailability
Stability Screening Strategies
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Formulation development for discovery compounds:
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Lead optimization:
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Need for stability data depends on stages
Structure analysis
Stability in SGF and SIF
Stability screening of key lead compounds in each structure series
Identify the degradation mechanism and define the screening
method
Candidate evaluation and selection
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Miniaturized preformulation studies including salt screening
Solid State Properties
Bioavailability (solubility/dissolution rate)
n Stability (physical and chemical)
n Processing Factors
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Hygroscopicity
Bulk, mechanical, and rheological properties
Ease of isolation, filtration, and drying
Degree of purification
Risk Assessment Related to Crystal
Form Issues
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The Fundamental Question:
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What will be the consequence should a new
thermodynamically more stable form is
discovered?
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High risk if this could lead to significant delay in the overall
project timeline or product failure
Low risk if impact on timeline and resources are minimum
High Risk Compounds
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Poorly soluble compounds as defined by the FDA
biopharmaceutical classification system
Compounds that would require one of the non-equilibrium
methods or semi-solid/liquid formulations to enhance
dissolution rate/ bioavailability
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amorphous
meta-stable polymorphs
solid dispersion
lipid based formulations
Compounds with parenteral formulations formulated close
to equilibrium solubilities at given temperature
Phase Appropriate Screening
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Lead Optimization Stage
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Monitor solid state form by microscopic examination
(and DSC if possible)
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Small scale limited crystal form screening as needed
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In situ salt screening as needed
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Potential impact
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pharmacokinetics (PK) results
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in vivo efficacy studies
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solubility results
Phase Appropriate Screening
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Candidate Evaluation/Selection Stage
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Risk assessment for crystal form issue
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Continue monitoring the key properties of new batches
of drug substance
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Preliminary screening followed by comprehensive
screenings for salt and polymorphs
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Identify or finalize the “most” desirable salt and form
for further development prior to GLP tox
High Throughput Salt and Crystal
Form Screening
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Automation of manual steps and enhancement in
data handling ability:
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not a solution for all
Still require intellectual input
Broader crystallization space but not possible to cover
all
What about time for crystallization and
combination of various methods?
Analytical methods consideration
Drug substance requirement: quantity and purity
Conclusion
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Solid state properties have profound impact on solubility
and stability.
This impact should be taken into account in designing
solubility and stability experiments and assessing
developability of drug candidates.
Phase appropriate characterization strategies to address
solid state related issues should balance the need of speed
and throughput with the quality of data.
Careful planning and a clear decision making process are
key for ensuring doing the right work at the right time for
ensuring developability.
Case Study 1: Solubility in Lead
Optimization
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Compound A:
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R'''
Structures:
''R
N
R''''
'R
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n
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Amorphous material: solubility in the range of 0.5-1 mg/mL
Poor metabolic stability
Moderate permeability
poor bioavailability (from aqueous solution)
Key Question: should we improve solubility as part of the
chemistry effort to improve PK?
Case Study 1 -Continued
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Strategy:
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Structure analysis: Benzimidazole plane type structure can result in
high crystallinity, so will the crystalline material have low
solubility?
Crystalline material
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n
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High melting
Solubility in SIF (fasted): ~ 0.001 mg/mL
Recommendation: Improving solubility as well as metabolic
stability
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Addition of ionizable group (improving pKa)
Disruption of the plane structure
Case Study 1 -Continued
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Strategy:
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Monitor solid state form and conduct micro-scale screening
Using in-situly prepared salt to maximize exposure in the efficacy
studies
Determine equilibrium solubility of crystalline material and only
use equilibrium solubility together with DSC results for structuresolubility correlation
Result: Bioavailability in rat improved from 2-5% to
40%
Case Study 2: Impact of Formulation on
Bioavailability
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Compound B:
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Basic properties:
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Solubility:
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Weak acid with pKa ~ 4.0
Melting point of form 1: ~ 170ºC
Permeability: moderate
Phosphate buffer (pH 7.4): < 0.001 mg/mL
SGF (pH 1.2): < 0.001 mg/mL
Ph 6.4-6.8 FaSSiF: ~ 0.03 mg/mL
Estimated clinical dose: 1-10 mg/mL
Bioavailability in rat:
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Suspension of free acid (micronized form 1): ~ 15%
Solution in NaOH (in situ Na salt): ~ 85%
Case Study 3: Candidate Evaluation and Selection
Phase – Salt and Crystal Form Screening
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Compound C:
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Containing a group that can undergo acid catalyzed hydrolysis
T1/2 in 0.1 M HCl: < 30 min
Solubility in 0.1M HCl: < 0.001 mg/mL
Key Question:
Strategies:
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Small scale crystal form screening
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should we improve stability as part of the chemistry effort?
Form I: very fine needle with MP of 160C (Form I)
Form II: MP of 140C
Stability (40/75%RH for 4 weeks)
Amorphous 20% degradation
Form I: 0.3%
Form II: 6%
Decision: Include stability enhancement as part of lead optimization whenever
possible
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Results:
candidate with significantly enhanced stability identified.
ACKNOWLEDGMENT
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Johnson and Johnson:
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GlaxoSmithkline:
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Om Dhingra
Graham Whitesell
Richard Winnike
Joel Sutton
University of Iowa
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Lian F. Huang
Keith Guillory
Novartis:
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Abu Serajuddin
Madhu Pudipuddi
Yatindra Joshi
Alan Royce