Pharmaceutical Preformulation: Wei-Qin (Tony) Tong, PH.D

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 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.
Some commonly evaluated parameters:

l l l l l l
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 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
A SURVEY OF 257 MARKETED DRUGS AND THEIR LIPOPHILICITY RECENT TRENDS IN DISCOVERY PIPELINE
90 80 70 60 50 40 30 20 10 0 <-2 -2 -1 0 1 2 3 4 Lipophilicity (cLogP) >4
All Drugs
20 Percent 16 12 8 4 0 <-1 0 1 2 3 4 5 6 >7 Lipophilicity (cLogP)
CNS Drugs
Background
Recent trends in aqueous solubility of discovery compounds
50 40
Practically Insoluble
Percent
30 20 10 0
<10g/mL 10-100g/mL >100g/mL
Aqueous Solubility
ormulation Challenges with Poorly Soluble Compounds
l l l l l
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!

Disintegration Tablet or capsule Dissolution Deaggregation Granules or aggregates Dissolution Fine Particle
Dissolution
Precipitation Drug in solution Dissolution Absorption Fine fine particle
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 ( g/ml)
1000 100 10 1 0.1 0.1 1

1 21 21 55 10 10
207 52 52
207
2100 2100 520 520 100 100
High Pe Med Pe Low Pe
10
Projected Dose in mg/kg
Biopharmaceutics Classification System (BCS)

l Classification
Class I Class II Class III Class IV High Permeability, High Solubility High Permeability, Low Solubility Low Permeability, High Solubility Low Permeability, Low Solubility
l Class
l l l
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 rate limited absorption
l Dissolution
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

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

l Polymorphs
Solubility (mcg/mL)
1200 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 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 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
l Comparison
S. Yalkowsky, Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington D.C. (1999).
Equilibrium Solubility vs. Kinetic Solubility of solubility
l Definition
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
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
l l l
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
of stability
l Theoretical
and practical considerations in stability determination
Chemical Stability
l l 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
of Solid State Properties
l Theoretical
and practical considerations in solid state characterization
Impact on Pharmaceutical Properties

l Bioavailability l Stability
(solubility/dissolution rate)
(physical and chemical) Factors
l Processing
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 1990 Product Lunch 2001 Patent expired 2010 Extension 2015
Original API
PTR Salts and Polymorphs Generic Entry
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
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

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 Effect of processing and formulation on the physical and chemical stability Effect of excipients on crystallization/nucleation
Parenteral Dosage Forms

Suspensions

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
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
l l l l l l l l l l l l l
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

Some commonly evaluated parameters:

TRD - Your Partner for Technical R&D

Why is Preformulation Important?

Thorough preformulation work is the foundation of developing robust formulations.

TRD - Your Partner for Technical R&D

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

TRD - Your Partner for Technical R&D

Preformulation A case of learning before doing

TRD - Your Partner for Technical R&D

Preformulation in the Overall R&D Process

Hit validation and lead selection

Candidate selection process

Preparation for and completion of PoC Study(ies)

TRD - Your Partner for Technical R&D

Importance of solubility Theoretical and practical considerations in solubility determination

TRD - Your Partner for Technical R&D

90 80 70 60 50 40 30 20 10 0 <-2 -2 -1 0 1 2 3 4 Lipophilicity (cLogP) >4

20 Percent 16 12 8 4 0 <-1 0 1 2 3 4 5 6 >7 Lipophilicity (cLogP)

TRD - Your Partner for Technical R&D

TRD - Your Partner for Technical R&D

ormulation Challenges with Poorly Soluble Compounds

TRD - Your Partner for Technical R&D

Drug has to be in solution to be absorbed!

Precipitation Drug in solution Dissolution Absorption Fine fine particle

TRD - Your Partner for Technical R&D

Solubility Criteria: how soluble is soluble enough?

on dose and permeability

Dissolution time Maximum Absorbable Dose (MAD):

TRD - Your Partner for Technical R&D

Minimum Acceptable Solubility (mg/mL)

1000 100 10 1 0.1 0.1 1

2100 2100 520 520 100 100

High Pe Med Pe Low Pe

Projected Dose in mg/kg

TRD - Your Partner for Technical R&D

Biopharmaceutics Classification System (BCS)

TRD - Your Partner for Technical R&D

Solubility and Bioavailability rate limited absorption

TRD - Your Partner for Technical R&D

Solvents for Solubility Studies

For Formulation Development:

TRD - Your Partner for Technical R&D

Factors Causing Poor Solubility

Zwitterion formation Insoluble salts H-bonding networks

Lack of ionizable groups High molecular weight

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 material (A) and crystalline material (C):

TRD - Your Partner for Technical R&D

Examples of apparent solubility of polymorphs:

TRD - Your Partner for Technical R&D

Equilibrium Solubility vs. Kinetic Solubility of solubility

TRD - Your Partner for Technical R&D

pH-Solubility Profile and Effect of Temperature

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

TRD - Your Partner for Technical R&D

with weak acid or base

salts will have different solubility in nonaqueous systems.