1. TRD - Your Partner for Technical R&D
Pharmaceutical Preformulation
Wei-Qin (Tony) Tong, Ph.D.
Novartis Pharmaceuticals Corporation
Integrated Drug Product Development Process
(3 day-course), University of Utah
July 17-19, 2006
2. TRD - Your Partner for Technical R&D
IntroductionIntroduction
• Preformulation:
l a stage of development during which the physicochemical properties of
drug substance are characterized
• Some commonly evaluated parameters:
l Solubility
l Dissolution behavior
l Stability
l Partition coefficient
l Ionization constant (pKa)
l Solid state properties such as crystal forms/polymorphs, water sorption
behavior, surface properties, particle size and shape, and other mechanical
properties, et. al.
3. TRD - Your Partner for Technical R&D
Why is Preformulation Important?Why is Preformulation Important?
“It is a capital mistake to theorize before one has data”
- Scandal in Bohemia, Sir Arthur Conan Doyle
l Thorough preformulation work is the foundation of
developing robust formulations.
4. TRD - Your Partner for Technical R&D
Learning before DoingLearning before Doing –– Develop a knowledge baseDevelop a knowledge base
l There are critical differences between
companies at the detailed level of knowledge
and their ability to learn before doing
– knowledge of the underlying variables and their relationship
to performance
– knowledge of the future manufacturing environment and the
new variables introduced by that environment
G. Pisano, “The Development Factory”, Harvard Business School Press, 1996
5. TRD - Your Partner for Technical R&D
l Preformulation
– A case of learning before doing
6. TRD - Your Partner for Technical R&D
Preformulation in the Overall R&D ProcessPreformulation in the Overall R&D Process
Preparation for and
completion of PoC
Study(ies)
Hit validation and
lead selection
Lead optimization
Candidate
selection
process
6 months to 24 months 3 months to 9 months 12 months to 24months3 months to 6 months
Preformulation
NDA
7. TRD - Your Partner for Technical R&D
SolubilitySolubility
l Importance of solubility
l Theoretical and practical considerations in
solubility determination
8. TRD - Your Partner for Technical R&D
0
10
20
30
40
50
60
70
80
90
<-2 -2 -1 0 1 2 3 4 >4
Lipophilicity (cLogP)
NumberofDrugsineachCategory
All Drugs
CNS Drugs
A SURVEY OF 257 MARKETED DRUGS
AND THEIR LIPOPHILICITY
BackgroundBackground
0
4
8
12
16
20
<-1 0 1 2 3 4 5 6 >7
Lipophilicity (cLogP)
Percent
RECENT TRENDS IN DISCOVERY PIPELINE
• Drug candidates are becoming more lipophilic and poorly soluble
9. TRD - Your Partner for Technical R&D
0
10
20
30
40
50
Aqueous Solubility
Percent
<10µg/mL 10-100µg/mL >100µg/mL
Practically Insoluble
BackgroundBackground
• Recent trends in aqueous solubility of discovery compounds
10. TRD - Your Partner for Technical R&D
Formulation Challenges with Poorly Soluble CompoundsFormulation Challenges with Poorly Soluble Compounds
l Poor dissolution rate
l Low and variable bioavailability
l More potential for food effect
l Inability to deliver high doses for tox studies
l Difficulty in developing parenteral formulations
11. TRD - Your Partner for Technical R&D
Tablet
or capsule
Granules
or aggregates
Fine
Particle
Disintegration Deaggregation
Dissolution
Dissolu-
tion Dissolution
Precipitation
Systemic
circulation
Drug
in solution
Fine fine
particle
Dissolution
Absorption
Drug has to be in solution to be absorbed!
12. TRD - Your Partner for Technical R&D
Solubility Criteria: how soluble is soluble enough?
lDependent on dose and permeability
– Dissolution time
– Maximum Absorbable Dose (MAD):
S (mg/mL) x Ka (/min) x SIWV (mL) x SITT (min)
lBiopharmaceutical Classification
13. TRD - Your Partner for Technical R&D
Minimum Acceptable Solubility (mg/mL)
11
55
2121
1010
5252
207207
100100
520520
21002100
0.1
1
10
100
1000
10000
0.1 1 10
Projected Dose in mg/kg
Solubility(µg/ml)
High Pe
Med Pe
Low Pe
11
1010
100100
55
5252
520520
2121
207207
21002100
14. TRD - Your Partner for Technical R&D
Biopharmaceutics Classification System (BCS)
l Classification
– Class I High Permeability, High Solubility
– Class II High Permeability, Low Solubility
– Class III Low Permeability, High Solubility
– Class IV Low Permeability, Low Solubility
l Class Boundaries
l Highly soluble: the highest does is soluble in <250 ml water over a pH range of 1 to 7.5
l Highly permeable: >90% dose absorbed in humans
l Rapidly dissolving: >85% of labeled amount of drug substance dissolves within 30
minutes
15. TRD - Your Partner for Technical R&D
Solubility and BioavailabilitySolubility and Bioavailability
l Dissolution rate limited absorption
– The absolute amount of drug absorbed increases with the
increasing of the dose
– Reduce particle size and using solution formulation should
enhance absorption
l Solubility limited absorption
– The absolute amount of drug absorbed does not increase
with the increasing of the dose
– Increasing dissolution rate does not increase absorption
16. TRD - Your Partner for Technical R&D
Solvents for Solubility Studies
l For developability assessment:
– Simulated gastric fluid (SGF)
– Simulated intestinal fluid (SIF)
– pH 7.4 buffer
– Intrinsic solubility to estimate pH-solubility profile
l For Formulation Development:
– pH solubility profile
– Solubility in solubilization agents/systems
• Co-solvents
• Surfactants
• Complexation agents
• Combinations of techniques
17. TRD - Your Partner for Technical R&D
l High crystallinity/high MP
– Zwitterion formation
– Insoluble salts
– H-bonding networks
l Hydrophobicity/High LogP
– Lack of ionizable groups
– High molecular weight
Factors Causing Poor Solubility
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l Amorphous vs. crystalline
– Differences could be > 1000x
l Polymorphs
Effect of Solid State Form
Equilibration Time (Days)
Solubility(mcg/mL)
0
200
400
600
800
1000
1200
1 2 3 4 5 6 7 8 9
19. TRD - Your Partner for Technical R&D
ExamplesExamples
l Comparison of apparent solubility of amorphous
material (A) and crystalline material (C):
Solute Melting Point (°C) Solubility Ratio
(A/C)
Caffeine 238 5
Theophylline 272 50
Morphine 197 270
Hydrochlorthiazide 273 1.1
Sulfamethoxydiazine 215 1.5
•S. Yalkowsky, Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington D.C. (1999).
20. TRD - Your Partner for Technical R&D
ExamplesExamples
l Comparison of apparent solubility of polymorphs:
Solute ∆ Melting Point
(°C)
Solubility Ratio
(L/H)
Acemetacin 20 2.3
70 4.7
Cyclopenthiazide 41 2
57 3.6
Mebendazole 30 3.6
70 7.4
Spironolactone 05 1.2
10 1.9
•S. Yalkowsky, Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington D.C. (1999).
21. TRD - Your Partner for Technical R&D
l Definition of solubility
– Molarity of the substance in a solution that is at
chemical equilibrium with an excess of the undissolved
substance
l What is kinetic/non-equilibrium solubility?
Equilibrium Solubility vs. Kinetic SolubilityEquilibrium Solubility vs. Kinetic Solubility
22. TRD - Your Partner for Technical R&D
l Effect of intrinsic solubility on the shape of the pH-solubility profile:
l Effect of temperature
pH-Solubility Profile and Effect of Temperature
876543210.0
0.2
0.4
0.6
0.8
1.0
1.2
pKa'
pH
Solubility(mg/mL)
23. TRD - Your Partner for Technical R&D
Solubility of SaltsSolubility of Salts
l Challenges with weak acid or base
– pH of the saturated solution vs. pHmax
– It is only from a solubility experiment at a pH below pHmax
that the solubility of the salt of a weak base can be
estimated.
l Different salts will have different solubility in non-
aqueous systems.
24. TRD - Your Partner for Technical R&D
DissolutionDissolution
l Importance of Dissolution
l Theoretical and practical considerations in
dissolution rate determination
25. TRD - Your Partner for Technical R&D
Importance of DissolutionImportance of Dissolution
l Dissolution rate for poorly soluble compounds may often be
the rate limiting step to absorption
l Examples of drugs with dissolution rate limited absorption:
– Digoxin
– Penicillin V
– Phenytoin
– Quinidine
– Tetracyclines
26. TRD - Your Partner for Technical R&D
Factors Affecting Dissolution RateFactors Affecting Dissolution Rate
l DC/Dt = kd (Cs – C) = KiA/V (Cs-C)
– Kd dissolution rate constant
– Ki intrinsic dissolution rate constant
l Volume of the dissolution medium: dose:solubility ratio
l Intrinsic dissolution rate constant: using rotating disk
apparatus
l Surface area of the solid
– particle size effect
– Effective surface area: the portion in actual contact with the
dissolution medium
27. TRD - Your Partner for Technical R&D
Choice of Dissolution MediumChoice of Dissolution Medium
l Biorelevant dissolution media should be the most
important consideration:
– USP SGF (USP 2000)
– USP SIF (USP 2000)
– Simulated Gastric Fluid-fasted state
– Simulated Intestinal Fluid-fasted state
– Simulated intestinal Fluid-fed state
(Dressman J et al. Pharm Res 15(1) 11-12 (1998))
– Surfactant such Sodium Lauryl Sulfate (SLS)
– Milk
l IVIVC: which comes first?
28. TRD - Your Partner for Technical R&D
Dissolution Rate and Salt SelectionDissolution Rate and Salt Selection
l What really happen in the gut?
– Higher dissolution rate in the gut for soluble salts
– Super-saturation possibility
– Importance of knowing the solubility of the HCl salt
– Potential negative impacts by salts:
• Higher degradation
• Conversion to free base on the surface – impact on the dissolution of
the remaining salts
• Potential toxicity
l Effect of salts on solubility in solubilization
systems
29. TRD - Your Partner for Technical R&D
StabilityStability
l Importance of stability
l Theoretical and practical considerations in
stability determination
30. TRD - Your Partner for Technical R&D
Chemical StabilityChemical Stability
l In SGF and SIF
l pH-stability profile
l Solid state stability
– Effect of moisture
– Effect of solid state form – amorphous vs. crystalline
l Excipient compatibility
– Effect of moisture
– Effect of processing
l Degradation mechanism
– Hydrolysis
– Oxidation potential
– Effect of temperature
31. TRD - Your Partner for Technical R&D
Physical StabilityPhysical Stability
l Characterization of Amorphous Material
– Tg and mobility
– Effect of moisture on Tg
– Solid solubility
l Characterization of hydrates/solvates
– Effect of processing
– Impact on chemical stability and bioavailability
32. TRD - Your Partner for Technical R&D
Solid State PropertiesSolid State Properties
l Importance of Solid State Properties
l Theoretical and practical considerations in
solid state characterization
33. TRD - Your Partner for Technical R&D
Impact on Pharmaceutical PropertiesImpact on Pharmaceutical Properties
l Bioavailability (solubility/dissolution rate)
l Stability (physical and chemical)
l Processing Factors
–Hygroscopicity
–Bulk, mechanical, and rheological properties
–Ease of isolation, filtration, and drying
–Degree of purification
34. TRD - Your Partner for Technical R&D
Risk Assessment Related to Crystal Form IssuesRisk Assessment Related to Crystal Form Issues
l The Fundamental Question:
What will be the consequence should a new
thermodynamically more stable form is discovered?
– 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
35. TRD - Your Partner for Technical R&D
High Risk CompoundsHigh Risk Compounds
l Poorly soluble compounds as defined by the FDA
biopharmaceutical classification system:
Solubility in pH 1-8 solutions x 250 mL < Dose
l Compounds that would require one of the non-
equilibrium methods or semi-solid/liquid formulations to
enhance dissolution rate/ bioavailability
– amorphous
– meta-stable polymorphs
– solid dispersion
– lipid based formulations
l Compounds with parenteral formulations formulated
close to equilibrium solubilities at given temperature
36. TRD - Your Partner for Technical R&D
Potential Risks Due to Salt or Form ChangesPotential Risks Due to Salt or Form Changes
l Additional Studies Required Due to Salt and/or Form
Changes
– PK bridging studies
– Repeated tox (1 month or 3 months)
– Additional considerations due to potential impurity changes
– Bio-equivalent studies
l Risk Associated with Developability Assessment of
Drug Candidate
– Impact on tox formulation
– Impact on bioavailability at clinically relevant doses
37. TRD - Your Partner for Technical R&D
Patent Protection for Potential LCM OpportunitiesPatent Protection for Potential LCM Opportunities
Compound Claimed
1990
Original API
Product Lunch
2001
Polymorphs/Salts
Claimed
1998
Patent expired
2010
Extension
2015
Generic Entry
Generic Entry for
All Other Forms
not Covered
Salts and Polymorphs
PTR
PTR: Patent Term Restoration = half of the investigational period + all of the FDA review period
38. TRD - Your Partner for Technical R&D
Salt and Form Selection StrategySalt and Form Selection Strategy
l Balancing Various Factors:
– Physical stability: the thermodynamically most stable form
is always the preferred choice
– Bioavailability: clinically relevant doses vs. tox coverage
– Process consideration
– Other physicochemical properties such as hygroscopicity,
morphology and chemical stability
l Salt Selection vs. Form Selection
– An integrated process
39. TRD - Your Partner for Technical R&D
Some Practical Considerations in Salt Screening and SelectionSome Practical Considerations in Salt Screening and Selection
l Dosage Form Considerations
– IV vs. oral formulations
– High dose vs. low dose
– Excipient compatibility
– Interaction with other actives in potential combination formulations
l Salts and Other Solubilization Techniques
– Effect of Salts on Complexation Binding Constants
– Effect of Salts on Solublization by Surfactants
– Solubility of Salts in Non-aqueous Solvents
l Toxicological Considerations
40. TRD - Your Partner for Technical R&D
Some Product Specific AspectsSome Product Specific Aspects
l Solid dosage forms
– Effect of micronization and processing such as granulation on solid state
properties and chemical stability
– Effect of excipients on crystallization/nucleation
– Powder flow properties: bulk density, compression properties and particle
size and shapes
l Parenteral Dosage Forms
– Injection site precipitation
– Pain upon injection
– Toxicity of new excipients
– Effect of excipients on crystallization/nucleation
l Suspensions
– Effect of processing and formulation on the physical and chemical stability
– Effect of excipients on crystallization/nucleation
41. TRD - Your Partner for Technical R&D
Automation for Improving Efficiency and ProductivityAutomation for Improving Efficiency and Productivity
l Automation of Common Preformulation Studies:
– Solubility as a function of pH and composition
– Solution stability as a function of pH and composition
– Excipient compatibility studies
– Others
42. TRD - Your Partner for Technical R&D
Example: Platform for Excipient Compatibility StudiesExample: Platform for Excipient Compatibility Studies
43. TRD - Your Partner for Technical R&D
Final ThoughtsFinal Thoughts
l Thorough preformulation work is the
foundation of developing robust formulations.
l Pay now or pay later is a balancing act.
l Organization structures vary, but the science
doesn’t.
l Good science is always the right thing to do!
44. TRD - Your Partner for Technical R&D
Additional ReadingAdditional Reading
l G. Banker and C.T. Rhodes, Modern Pharmaceutics, Marcel Dekker, Inc., 2000.
l H. Brittain, Physical Characterization of Pharmaceutical Solids, Marcel Dekker, Inc., 1995.
l H. Brittain, Polymorphism in Pharmaceutical Solids, Marcel Dekker, Inc., 1999.
l S.R. Byrn, R.R. Pfeiffer and J.G. Stowell, Solid State Chemistry of Drugs, Second Edition, SSCI, Inc.,
1999.
l K.A. Connors, G.L. Amidon, and V.J. Stella. Chemical Stability of Pharmaceuticals (Second Edition),
John Wiley & Sons, Inc., 1986.
l E.F. Fiese and T.A. Hagen, “Preformulation”, Chapter 8 in the Theory and Practice of Industrial
Pharmacy, Lea & Febiger, Philadelphia, 1986.
l M. Gibson, Pharmaceutical Preformulation and Formulation, HIS Health Group, Englewood, CO, 2001.
l D.J.W. Grant and T. Higuchi, Solubility Behavior of Organic Compounds, John Wiley & Sons, Inc., 1990.
l L.F. Huang and W.Q. Tong, Impact of solid state properties on developability assessment of drug
candidates, Advanced Drug Delivery Review, 56 (321-334), 2004.
l L.J. Ravin and G.W. Radebaugh, “Preformulation”, Chapter 75 in Remington’s Pharmaceutical Sciences,
18th edition, Mack Publishing Company, Easton, Pennsylvania, 1990.
l W.Q. Tong, “Preformulation Aspects of Insoluble Compounds” in Water Insoluble Drug Formulation,
Edited by R. Liu, Interpharm Press, 2000.
l J. Wells, Pharmaceutical Preformulation, Ellis Horwood Limited, 1988.
l S. Yalkowsky, Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington
D.C. 1999.