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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

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Introduction
Preformulation:
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a stage of development during which the physicochemical properties of

drug substance are characterized

Some commonly evaluated parameters:

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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.

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Why is Preformulation Important?

It is a capital mistake to theorize before one has data
- Scandal in Bohemia, Sir Arthur Conan Doyle
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Thorough preformulation work is the foundation of

developing robust formulations.

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Learning before Doing Develop a knowledge base

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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

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Preformulation
A case of learning before doing

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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

6 months to 24 months

3 months to 9 months

12 months to 24months

Preformulation

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Solubility
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Importance of solubility

Theoretical and practical considerations in

solubility determination

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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

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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

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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

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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

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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

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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

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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

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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

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Solvents for Solubility Studies

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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

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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

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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)

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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).

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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).

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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?

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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

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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.

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Dissolution
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Importance of Dissolution

Theoretical and practical considerations in

dissolution rate determination

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Importance of Dissolution
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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

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Factors Affecting Dissolution Rate

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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

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Choice of Dissolution Medium

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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
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IVIVC: which comes first?

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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

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Stability
l Importance

l Theoretical

of stability

and practical considerations in

stability determination

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Chemical Stability
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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

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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

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Solid State Properties

l Importance

l Theoretical

of Solid State Properties

and practical considerations in

solid state characterization

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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

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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

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High Risk Compounds

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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

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Potential Risks Due to Salt or Form Changes

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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

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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

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Salt and Form Selection Strategy

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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

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Some Practical Considerations in Salt Screening and Selection

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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

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Some Product Specific Aspects

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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
Effect of excipients on crystallization/nucleation

Suspensions

Effect of processing and formulation on the physical and chemical stability

Effect of excipients on crystallization/nucleation

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Automation for Improving Efficiency and Productivity

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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

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Example: Platform for Excipient Compatibility Studies

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Final Thoughts
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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!

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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.