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
Introduction
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?
βIt is a capital mistake to theorize before one has dataβ
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 Doing β Develop a knowledge base
l There are critical differences between
companies at the detailed level of knowledge
and their ability to learn before doing
β knowledge of the underlying variables and their relationship
to performance
β knowledge of the future manufacturing environment and the
new variables introduced by that environment
G. Pisano, βThe Development Factoryβ, Harvard Business School Press, 1996
5. TRD - Your Partner for Technical R&D
l Preformulation
β A case of learning before doing
6. TRD - Your Partner for Technical R&D
Preformulation in the Overall R&D Process
Candidate Preparation for and
Hit validation and
Lead optimization selection completion of PoC
lead selection
process Study(ies)
NDA
3 months to 6 months 6 months to 24 months 3 months to 9 months 12 months to 24months
Preformulation
7. TRD - Your Partner for Technical R&D
Solubility
l Importance of solubility
l Theoretical and practical considerations in
solubility determination
8. TRD - Your Partner for Technical R&D
Background
Drug candidates are becoming more lipophilic and poorly soluble
A SURVEY OF 257 MARKETED DRUGS RECENT TRENDS IN DISCOVERY PIPELINE
AND THEIR LIPOPHILICITY
90
80 All Drugs 20
70 CNS Drugs 16
Percent
60
50 12
40
8
30
20 4
10
0
0
<-2 -2 -1 0 1 2 3 4 >4 <-1 0 1 2 3 4 5 6 >7
Lipophilicity (cLogP)
Lipophilicity (cLogP)
9. TRD - Your Partner for Technical R&D
Background
β’ Recent trends in aqueous solubility of discovery compounds
50
Practically Insoluble
40
Percent
30
20
10
0
<10Β΅g/mL 10-100Β΅g/mL >100Β΅g/mL
Aqueous Solubility
10. TRD - Your Partner for Technical R&D
ormulation 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
Drug has to be in solution to be absorbed!
Disintegration Deaggregation
Tablet Granules Fine
or capsule or aggregates Particle
Dissolu-
Dissolution tion Dissolution
Precipitation
Fine fine
Drug
particle
in solution
Dissolution
Absorption
Systemic
circulation
12. TRD - Your Partner for Technical R&D
Solubility Criteria: how soluble is soluble enough?
l Dependent on dose and permeability
β Dissolution time
β Maximum Absorbable Dose (MAD):
S (mg/mL) x Ka (/min) x SIWV (mL) x SITT (min)
l Biopharmaceutical Classification
13. TRD - Your Partner for Technical R&D
Minimum Acceptable Solubility (mg/mL)
10000
Solubility ( g/ml)
2100
1000 2100
520
207 520
207
Β΅
100 100
100 High Pe
52
52
21
21 Med Pe
10 10
10
Low Pe
55
1 1 1
0.1
0.1 1 10
Projected Dose in mg/kg
14. TRD - Your Partner for Technical R&D
Biopharmaceutics Classification System (BCS)
l Classification
β Class I High Permeability, High Solubility
β Class II High Permeability, Low Solubility
β Class III Low Permeability, High Solubility
β 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 Bioavailability
l Dissolution rate limited absorption
β The absolute amount of drug absorbed increases with the
increasing of the dose
β Reduce particle size and using solution formulation should
enhance absorption
l Solubility limited absorption
β The absolute amount of drug absorbed does not increase
with the increasing of the dose
β Increasing dissolution rate does not increase absorption
16. TRD - Your Partner for Technical R&D
Solvents for Solubility Studies
l For developability assessment:
β Simulated gastric fluid (SGF)
β Simulated intestinal fluid (SIF)
β pH 7.4 buffer
β Intrinsic solubility to estimate pH-solubility profile
l For Formulation Development:
β pH solubility profile
β Solubility in solubilization agents/systems
β’ Co-solvents
β’ Surfactants
β’ Complexation agents
β’ Combinations of techniques
17. TRD - Your Partner for Technical R&D
Factors Causing Poor Solubility
l High crystallinity/high MP
β Zwitterion formation
β Insoluble salts
β H-bonding networks
l Hydrophobicity/High LogP
β Lack of ionizable groups
β High molecular weight
18. TRD - Your Partner for Technical R&D
Effect of Solid State Form
l Amorphous vs. crystalline
β Differences could be > 1000x
l Polymorphs
1200
Solubility (mcg/mL)
1000
800
600
400
200
0
1 2 3 4 5 6 7 8 9
Equilibration Time (Days)
19. TRD - Your Partner for Technical R&D
Examples
l Comparison of apparent solubility of amorphous
material (A) and crystalline material (C):
Solute Melting Point (Β°C) Solubility Ratio
(A/C)
Caffeine 238 5
Theophylline 272 50
Morphine 197 270
Hydrochlorthiazide 273 1.1
Sulfamethoxydiazine 215 1.5
β’S. Yalkowsky, Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington D.C. (1999).
20. TRD - Your Partner for Technical R&D
Examples
l Comparison of apparent solubility of polymorphs:
Solute β Melting Point Solubility Ratio
(Β°C) (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
β’S. Yalkowsky, Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington D.C. (1999).
21. TRD - Your Partner for Technical R&D
Equilibrium Solubility vs. Kinetic Solubility
l Definition of solubility
β 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?
22. TRD - Your Partner for Technical R&D
pH-Solubility Profile and Effect of Temperature
l Effect of intrinsic solubility on the shape of the pH-solubility profile:
1.2
Solubility (mg/mL)
1.0
0.8
0.6
0.4
pKa'
0.2
0.0 1 2 3 4 5 6 7 8
pH
l Effect of temperature
23. TRD - Your Partner for Technical R&D
Solubility of Salts
l Challenges with weak acid or base
β pH of the saturated solution vs. pHmax
β 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
Dissolution
l Importance of Dissolution
l Theoretical and practical considerations in
dissolution rate determination
25. TRD - Your Partner for Technical R&D
Importance 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:
β Digoxin
β Penicillin V
β Phenytoin
β Quinidine
β Tetracyclines
26. TRD - Your Partner for Technical R&D
Factors Affecting Dissolution Rate
l DC/Dt = kd (Cs β C) = KiA/V (Cs-C)
β Kd dissolution rate constant
β 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
β particle size effect
β Effective surface area: the portion in actual contact with the
dissolution medium
27. TRD - Your Partner for Technical R&D
Choice of Dissolution Medium
l Biorelevant dissolution media should be the most
important consideration:
β USP SGF (USP 2000)
β USP SIF (USP 2000)
β Simulated Gastric Fluid-fasted state
β Simulated Intestinal Fluid-fasted state
β Simulated intestinal Fluid-fed state
(Dressman J et al. Pharm Res 15(1) 11-12 (1998))
β Surfactant such Sodium Lauryl Sulfate (SLS)
β Milk
l IVIVC: which comes first?
28. TRD - Your Partner for Technical R&D
Dissolution Rate and Salt Selection
l What really happen in the gut?
β Higher dissolution rate in the gut for soluble salts
β Super-saturation possibility
β Importance of knowing the solubility of the HCl salt
β Potential negative impacts by salts:
β’ Higher degradation
β’ Conversion to free base on the surface β impact on the dissolution of
the remaining salts
β’ Potential toxicity
l Effect
of salts on solubility in solubilization
systems
29. TRD - Your Partner for Technical R&D
Stability
l Importance of stability
l Theoretical and practical considerations in
stability determination
30. TRD - Your Partner for Technical R&D
Chemical Stability
l In SGF and SIF
l pH-stability profile
l Solid state stability
β Effect of moisture
β Effect of solid state form β amorphous vs. crystalline
l Excipient compatibility
β Effect of moisture
β Effect of processing
l Degradation mechanism
β Hydrolysis
β Oxidation potential
β Effect of temperature
31. TRD - Your Partner for Technical R&D
Physical Stability
l Characterization of Amorphous Material
β Tg and mobility
β Effect of moisture on Tg
β Solid solubility
l Characterization of hydrates/solvates
β Effect of processing
β Impact on chemical stability and bioavailability
32. TRD - Your Partner for Technical R&D
Solid 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 Properties
l Bioavailability (solubility/dissolution rate)
l Stability (physical and chemical)
l Processing Factors
β Hygroscopicity
β Bulk, mechanical, and rheological properties
β Ease of isolation, filtration, and drying
β Degree of purification
34. TRD - Your Partner for Technical R&D
Risk Assessment Related to Crystal Form Issues
l The Fundamental Question:
What will be the consequence should a new
thermodynamically more stable form is discovered?
β High risk if this could lead to significant delay in the
overall project timeline or product failure
β Low risk if impact on timeline and resources are minimum
35. TRD - Your Partner for Technical R&D
High 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
β amorphous
β meta-stable polymorphs
β solid dispersion
β 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 Changes
l Additional Studies Required Due to Salt and/or Form
Changes
β PK bridging studies
β Repeated tox (1 month or 3 months)
β Additional considerations due to potential impurity changes
β Bio-equivalent studies
l Risk Associated with Developability Assessment of
Drug Candidate
β Impact on tox formulation
β Impact on bioavailability at clinically relevant doses
37. TRD - Your Partner for Technical R&D
Patent Protection for Potential LCM Opportunities
Compound Claimed Product Lunch Patent expired Extension
1990 2001 2010 2015
Original API PTR
Salts and Polymorphs Generic Entry
Polymorphs/Salts
Claimed Generic Entry for
All Other Forms
1998 not Covered
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 Strategy
l Balancing Various Factors:
β Physical stability: the thermodynamically most stable form
is always the preferred choice
β Bioavailability: clinically relevant doses vs. tox coverage
β Process consideration
β Other physicochemical properties such as hygroscopicity,
morphology and chemical stability
l Salt Selection vs. Form Selection
β An integrated process
39. TRD - Your Partner for Technical R&D
Some Practical Considerations in Salt Screening and Selection
l Dosage Form Considerations
β IV vs. oral formulations
β High dose vs. low dose
β Excipient compatibility
β Interaction with other actives in potential combination formulations
l Salts and Other Solubilization Techniques
β Effect of Salts on Complexation Binding Constants
β Effect of Salts on Solublization by Surfactants
β Solubility of Salts in Non-aqueous Solvents
l Toxicological Considerations
40. TRD - Your Partner for Technical R&D
Some Product Specific Aspects
l Solid dosage forms
β Effect of micronization and processing such as granulation on solid state
properties and chemical stability
β Effect of excipients on crystallization/nucleation
β Powder flow properties: bulk density, compression properties and particle
size and shapes
l Parenteral Dosage Forms
β Injection site precipitation
β Pain upon injection
β Toxicity of new excipients
β Effect of excipients on crystallization/nucleation
l Suspensions
β Effect of processing and formulation on the physical and chemical stability
β Effect of excipients on crystallization/nucleation
41. TRD - Your Partner for Technical R&D
Automation for Improving Efficiency and Productivity
l Automation of Common Preformulation Studies:
β Solubility as a function of pH and composition
β Solution stability as a function of pH and composition
β Excipient compatibility studies
β Others
42. TRD - Your Partner for Technical R&D
Example: Platform for Excipient Compatibility Studies
43. TRD - Your Partner for Technical R&D
Final 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
doesnβt.
l Good science is always the right thing to do!
44. TRD - Your Partner for Technical R&D
Additional 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, βPreformulationβ, 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, βPreformulationβ, Chapter 75 in Remingtonβs Pharmaceutical Sciences,
18th edition, Mack Publishing Company, Easton, Pennsylvania, 1990.
l W.Q. Tong, βPreformulation Aspects of Insoluble Compoundsβ 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.