Pre Formulation

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
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.
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.
Learning before Doing – Develop 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

l Preformulation
– A case of learning before doing
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
Solubility
l Importance of solubility
l Theoretical and practical considerations in

solubility determination
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
Number of Drugs in each Category
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)
Background
• Recent trends in aqueous solubility of discovery compounds
50
Practically Insoluble
40
Percent
30
20
10
0
<10µg/mL 10-100µg/mL >100µg/mL
Aqueous Solubility
Formulation 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

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
Solubility Criteria: how soluble is soluble enough?
l Dependent on dose and permeability

– Dissolution time
– Maximum Absorbable Dose (MAD):

S (mg/mL) x Ka (/min) x SIWV (mL) x SITT (min)
l Biopharmaceutical Classification
Minimum Acceptable Solubility (mg/mL)
10000
Solubility (µg/ml)
2100
1000 2100
520
207 520
100
207 100 High Pe
52
52 100
21
21 Med Pe
10 10
10
Low Pe
55
1 1 1
0.1
0.1 1 10
Projected Dose in mg/kg

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
Solubility 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
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
Factors Causing Poor Solubility
l High crystallinity/high MP
– Zwitterion formation
– Insoluble salts
– H-bonding networks
l Hydrophobicity/High LogP
– Lack of ionizable groups
– High molecular weight
Effect of Solid State Form
l Amorphous vs. crystalline

– 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)

Examples
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).
Examples
l Comparison of apparent solubility of polymorphs:
Solute ∆ Melting Point Solubility Ratio

(°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
•S. Yalkowsky, Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington D.C. (1999).
Equilibrium Solubility vs. Kinetic Solubility
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?

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
Solubility 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.
Dissolution
l Importance of Dissolution

dissolution rate determination
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:
– Digoxin
– Penicillin V
– Phenytoin
– Quinidine
– Tetracyclines
Factors 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
Choice 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?
Dissolution 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
Stability
l Importance of stability

stability determination
Chemical 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
Physical 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
Solid State Properties
l Importance of Solid State Properties

solid state characterization
Impact 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
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?
– 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
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
Potential 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
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
Salt 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
Some 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
Some 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
l Suspensions
– Effect of processing and formulation on the physical and chemical stability
Automation 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
Example: Platform for Excipient Compatibility Studies

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
doesn’t.
l Good science is always the right thing to do!
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, “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.

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TRD - Your Partner for Technical R&D

Wei-Qin (Tony) Tong, Ph.D.

Integrated Drug Product Development Process

Why is Preformulation Important?

“It is a capital mistake to theorize before one has data”

l Thorough preformulation work is the foundation of

Learning before Doing – Develop a knowledge base

l There are critical differences between

G. Pisano, “The Development Factory”, Harvard Business School Press, 1996

Preformulation in the Overall R&D Process

Candidate Preparation for and

3 months to 6 months 6 months to 24 months 3 months to 9 months 12 months to 24months

l Theoretical and practical considerations in

• Drug candidates are becoming more lipophilic and poorly soluble

A SURVEY OF 257 MARKETED DRUGS RECENT TRENDS IN DISCOVERY PIPELINE

• Recent trends in aqueous solubility of discovery compounds

Formulation 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

Drug has to be in solution to be absorbed!

Tablet Granules Fine

Solubility Criteria: how soluble is soluble enough?

l Dependent on dose and permeability

– Maximum Absorbable Dose (MAD):

Minimum Acceptable Solubility (mg/mL)

Projected Dose in mg/kg

Biopharmaceutics Classification System (BCS)

– Class II High Permeability, Low Solubility

– Class III Low Permeability, High Solubility

– Class IV Low Permeability, Low Solubility

l Highly permeable: >90% dose absorbed in humans

l Rapidly dissolving: >85% of labeled amount of drug substance dissolves within 30

Solubility and Bioavailability

l Dissolution rate limited absorption

Solvents for Solubility Studies

l For developability assessment:

Factors Causing Poor Solubility

Effect of Solid State Form

l Amorphous vs. crystalline

Equilibration Time (Days)

l Comparison of apparent solubility of amorphous

Solute Melting Point (°C) Solubility Ratio

l Comparison of apparent solubility of polymorphs:

Solute ∆ Melting Point Solubility Ratio

Equilibrium Solubility vs. Kinetic Solubility

l What is kinetic/non-equilibrium solubility?

pH-Solubility Profile and Effect of Temperature

l Effect of intrinsic solubility on the shape of the pH-solubility profile:

l Challenges with weak acid or base

l Theoretical and practical considerations in

l Dissolution rate for poorly soluble compounds may often be

Factors Affecting Dissolution Rate

l DC/Dt = kd (Cs – C) = KiA/V (Cs-C)

Choice of Dissolution Medium

l Biorelevant dissolution media should be the most

– Surfactant such Sodium Lauryl Sulfate (SLS)

Dissolution Rate and Salt Selection

l What really happen in the gut?

l Theoretical and practical considerations in

l In SGF and SIF