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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 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:
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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 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

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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
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

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Background
• Recent trends in aqueous solubility of discovery compounds
50 40

Practically Insoluble

Percent

30 20 10 0
<10µg/mL 10-100µg/mL >100µg/mL

Aqueous Solubility

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ormulation Challenges with Poorly Soluble Compounds

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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!
Disintegration Tablet or capsule Dissolution Deaggregation Granules or aggregates Dissolution Fine Particle

Dissolution

Precipitation Drug in solution Dissolution Absorption Fine fine particle

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)

10000

Solubility ( µg/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

1

10

Projected Dose in mg/kg

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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
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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 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

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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

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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
l Polymorphs
Solubility (mcg/mL)
1200 1000 800 600 400 200 0 1 2 3 4 5 6 7 8 9

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 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).

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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?

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pH-Solubility Profile and Effect of Temperature

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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

2

3

4

5

6

7

8

pH

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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

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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

of stability

l Theoretical

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

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Excipient compatibility
– Effect of moisture – Effect of processing

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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

of Solid State Properties

l Theoretical

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) Factors

l Processing

– 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

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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

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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 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

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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

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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

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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

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Toxicological Considerations

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Some Product Specific Aspects
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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

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Parenteral Dosage Forms
– – – –

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Suspensions
– –

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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 doesn’t. 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 Remington’s 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.