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
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Solubility
Dissolution behavior
Stability
Partition coefficient
Ionization constant (pKa)
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
Preformulation
A case of learning before doing
Preformulation in the Overall R&D Process
Hit validation and

lead selection
Lead optimization
Candidate
selection
process
Preparation for and

completion of PoC
Study(ies)
NDA
3 months to 6 months
12 months to 24months
Preformulation
Solubility
l
Importance of solubility
Theoretical and practical considerations in

solubility determination
Background
Drug candidates are becoming more lipophilic and poorly soluble
RECENT TRENDS IN DISCOVERY PIPELINE
90
80
All Drugs
20
70
CNS Drugs
16
60
50
40
30
Percent
Number of Drugs in each Category
A SURVEY OF 257 MARKETED DRUGS

AND THEIR LIPOPHILICITY
12
8
4
20
10
0
<-2
-2
-1
1
2
3
4
Lipophilicity (cLogP)
>4
<-1
Lipophilicity (cLogP)
>7
Background
Recent trends in aqueous solubility of discovery compounds
50
Percent
40
Practically Insoluble
30
20
10
0
<10g/mL
10-100g/mL
>100g/mL
Aqueous Solubility
Formulation Challenges with Poorly Soluble Compounds
Poor dissolution rate
Low and variable bioavailability
More potential for food effect
Inability to deliver high doses for tox studies
Difficulty in developing parenteral formulations
Drug has to be in solution to be absorbed!

Deaggregation
Disintegration
Tablet
or capsule
Dissolution
Granules
or aggregates
Fine
Particle
Dissolution
Dissolution
Precipitation
Fine fine
particle
Drug
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)
Solubility (g/ml)
10000
1000
207
207
52
52
100
21
21
10
1
55
1
2100
2100
520
520
100
100
Med Pe
10
10
Low Pe
0.1
0.1
High Pe
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
Highly soluble: the highest does is soluble in <250 ml water over a pH range of 1 to 7.5
Highly permeable: >90% dose absorbed in humans
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
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
Solubility (mcg/mL)
l Polymorphs
1200
1000
800
600
400
200
0
Equilibration Time (Days)
Examples
l Comparison
of apparent solubility of amorphous

material (A) and crystalline material (C):
Solute
Caffeine
Theophylline
Morphine
Hydrochlorthiazide
Sulfamethoxydiazine
Melting Point (C)

238
272
197
273
215
Solubility Ratio
(A/C)
5
50
270
1.1
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
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).
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

Effect of intrinsic solubility on the shape of the pH-solubility profile:
Solubility (mg/mL)
1.2
1.0
0.8
0.6
0.4
pKa'
0.2
0.0 1
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 nonaqueous systems.
Dissolution
l
Importance of Dissolution
Theoretical and practical considerations in

dissolution rate determination
Importance of Dissolution
l
l
Dissolution rate for poorly soluble compounds may often be

the rate limiting step to absorption
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
Volume of the dissolution medium: dose:solubility ratio
Intrinsic dissolution rate constant: using rotating disk

apparatus
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
l Theoretical
of stability
and practical considerations in

stability determination
Chemical Stability
l
In SGF and SIF
pH-stability profile
Solid state stability

Effect of moisture
Effect of solid state form amorphous vs. crystalline
Excipient compatibility
Effect of moisture
Effect of processing
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
l Theoretical
of Solid State Properties
and practical considerations in

solid state characterization
Impact on Pharmaceutical Properties

l Bioavailability
l Stability
(solubility/dissolution rate)
(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
Compounds that would require one of the nonequilibrium methods or semi-solid/liquid formulations to
enhance dissolution rate/ bioavailability
amorphous
meta-stable polymorphs
solid dispersion
lipid based formulations
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
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
1990
2001
Original API
Patent expired
2010
Extension
2015
PTR
Salts and Polymorphs
Polymorphs/Salts
Claimed
1998
Generic Entry for

All Other Forms
not Covered
PTR: Patent Term Restoration = half of the investigational period + all of the FDA review period
Generic Entry
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
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
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
Toxicological Considerations
Some Product Specific Aspects

l
Solid dosage forms
Parenteral 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
Injection site precipitation
Pain upon injection
Toxicity of new excipients
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.
Pay now or pay later is a balancing act.
Organization structures vary, but the science

doesnt.
Good science is always the right thing to do!
Additional Reading
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G. Banker and C.T. Rhodes, Modern Pharmaceutics, Marcel Dekker, Inc., 2000.
H. Brittain, Physical Characterization of Pharmaceutical Solids, Marcel Dekker, Inc., 1995.
H. Brittain, Polymorphism in Pharmaceutical Solids, Marcel Dekker, Inc., 1999.
S.R. Byrn, R.R. Pfeiffer and J.G. Stowell, Solid State Chemistry of Drugs, Second Edition, SSCI, Inc.,
1999.
K.A. Connors, G.L. Amidon, and V.J. Stella. Chemical Stability of Pharmaceuticals (Second Edition),
John Wiley & Sons, Inc., 1986.
E.F. Fiese and T.A. Hagen, Preformulation, Chapter 8 in the Theory and Practice of Industrial
Pharmacy, Lea & Febiger, Philadelphia, 1986.
M. Gibson, Pharmaceutical Preformulation and Formulation, HIS Health Group, Englewood, CO, 2001.
D.J.W. Grant and T. Higuchi, Solubility Behavior of Organic Compounds, John Wiley & Sons, Inc., 1990.
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.J. Ravin and G.W. Radebaugh, Preformulation, Chapter 75 in Remingtons Pharmaceutical Sciences,
18th edition, Mack Publishing Company, Easton, Pennsylvania, 1990.
W.Q. Tong, Preformulation Aspects of Insoluble Compounds in Water Insoluble Drug Formulation,
Edited by R. Liu, Interpharm Press, 2000.
J. Wells, Pharmaceutical Preformulation, Ellis Horwood Limited, 1988.
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

TRD - Your Partner for Technical R&D

a stage of development during which the physicochemical properties of

Some commonly evaluated parameters:

TRD - Your Partner for Technical R&D

Why is Preformulation Important?

Thorough preformulation work is the foundation of

TRD - Your Partner for Technical R&D

Learning before Doing Develop a knowledge base

There are critical differences between

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

TRD - Your Partner for Technical R&D

TRD - Your Partner for Technical R&D

Preformulation in the Overall R&D Process

Hit validation and

Preparation for and

TRD - Your Partner for Technical R&D

Theoretical and practical considerations in

TRD - Your Partner for Technical R&D

Number of Drugs in each Category

A SURVEY OF 257 MARKETED DRUGS

TRD - Your Partner for Technical R&D

TRD - Your Partner for Technical R&D

Formulation Challenges with Poorly Soluble Compounds

Poor dissolution rate

Low and variable bioavailability

More potential for food effect

Inability to deliver high doses for tox studies

Difficulty in developing parenteral formulations

TRD - Your Partner for Technical R&D

Drug has to be in solution to be absorbed!

TRD - Your Partner for Technical R&D

Solubility Criteria: how soluble is soluble enough?

on dose and permeability

TRD - Your Partner for Technical R&D

Minimum Acceptable Solubility (mg/mL)

Projected Dose in mg/kg

TRD - Your Partner for Technical R&D

Biopharmaceutics Classification System (BCS)

High Permeability, High Solubility

High Permeability, Low Solubility

Low Permeability, High Solubility

Low Permeability, Low Solubility

Highly permeable: >90% dose absorbed in humans

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

TRD - Your Partner for Technical R&D

Solubility and Bioavailability

rate limited absorption

The absolute amount of drug absorbed increases with the

The absolute amount of drug absorbed does not increase

TRD - Your Partner for Technical R&D

Solvents for Solubility Studies

For developability assessment:

For Formulation Development:

TRD - Your Partner for Technical R&D

Factors Causing Poor Solubility

Lack of ionizable groups

TRD - Your Partner for Technical R&D

Effect of Solid State Form

Differences could be > 1000x

Equilibration Time (Days)

TRD - Your Partner for Technical R&D

of apparent solubility of amorphous

Melting Point (C)