Pre Formulation

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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


IntroductionIntroduction

• Preformulation:l a stage of development during which the physicochemical properties of

drug substance are characterized

• Some commonly evaluated parameters:l Solubilityl Dissolution behaviorl Stabilityl Partition coefficientl 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?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 Learning before Doing –– Develop a knowledge baseDevelop 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 ProcessPreformulation in the Overall R&D Process

Preparation for and completion of PoC

Study(ies)

Hit validation and lead selection Lead optimization

Candidate selection process

6 months to 24 months 3 months to 9 months 12 months to 24months3 months to 6 months

Preformulation

NDA


SolubilitySolubility

l Importance of solubility

l Theoretical and practical considerations in solubility determination


0

10

20

30

40

50

60

70

80

90

<-2 -2 -1 0 1 2 3 4 >4Lipophilicity (cLogP)

Num

ber

of D

rugs

in e

ach

Cat

egor

y

All Drugs

CNS Drugs

A SURVEY OF 257 MARKETED DRUGS AND THEIR LIPOPHILICITY

BackgroundBackground

0

4

812

16

20

<-1 0 1 2 3 4 5 6 >7

Lipophilicity (cLogP)

Per

cen

t

RECENT TRENDS IN DISCOVERY PIPELINE

• Drug candidates are becoming more lipophilic and poorly soluble


0

10

20

30

40

50

Aqueous Solubility

Per

cen

t

<10µg/mL 10-100µg/mL >100µg/mL

Practically Insoluble

BackgroundBackground

• Recent trends in aqueous solubility of discovery compounds


Formulation Challenges with Poorly Soluble CompoundsFormulation 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


Tabletor capsule

Granules or aggregates

FineParticle

Disintegration Deaggregation

DissolutionDissolu-tion Dissolution

Precipitation

Systemiccirculation

Drugin solution

Fine fineparticle

Dissolution

Absorption

Drug has to be in solution to be absorbed!


Solubility Criteria: how soluble is soluble enough?

lDependent on dose and permeability

– Dissolution time

– Maximum Absorbable Dose (MAD):

S (mg/mL) x Ka (/min) x SIWV (mL) x SITT (min)

lBiopharmaceutical Classification


Minimum Acceptable Solubility (mg/mL)

1155

2121 10105252

207207100100

52052021002100

0.1

1

10

100

1000

10000

0.1 1 10

Projected Dose in mg/kg

So

lub

ility

( µg

/ml)

High Pe

Med Pe

Low Pe

11

1010

100100

55

5252

520520

2121

207207

21002100


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 Boundariesl 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 BioavailabilitySolubility 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


l High crystallinity/high MP– Zwitterion formation

– Insoluble salts

– H-bonding networks

l Hydrophobicity/High LogP– Lack of ionizable groups

– High molecular weight

Factors Causing Poor Solubility


l Amorphous vs. crystalline

– Differences could be > 1000x

l Polymorphs

Effect of Solid State Form

Equilibration Time (Days)

Solu

bilit

y (m

cg/m

L)

0

200

400

600

800

1000

1200

1 2 3 4 5 6 7 8 9


ExamplesExamples

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).


ExamplesExamples

l Comparison of apparent solubility of polymorphs:

Solute ∆ Melting Point

(°C) Solubility Ratio

(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).


l Definition of solubility– Molarity of the substance in a solution that is at

chemical equilibrium with an excess of the undissolved substance

lWhat is kinetic/non-equilibrium solubility?

Equilibrium Solubility vs. Kinetic SolubilityEquilibrium Solubility vs. Kinetic Solubility


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

l Effect of temperature

pH-Solubility Profile and Effect of Temperature

8 7 6 5 4 3 2 1 0.0

0.2

0.4

0.6

0.8

1.0

1.2

pKa'

pH

Sol

ubili

ty (

mg/

mL)


Solubility of SaltsSolubility 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.


DissolutionDissolution

l Importance of Dissolution

l Theoretical and practical considerations in dissolution rate determination


Importance of DissolutionImportance 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 RateFactors 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 MediumChoice 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 SelectionDissolution Rate and Salt Selection

lWhat 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


StabilityStability

l Importance of stability

lTheoretical and practical considerations in stability determination


Chemical StabilityChemical 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 StabilityPhysical 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 PropertiesSolid State Properties

l Importance of Solid State Properties

lTheoretical and practical considerations in solid state characterization


Impact on Pharmaceutical PropertiesImpact on Pharmaceutical Properties

lBioavailability (solubility/dissolution rate)

lStability (physical and chemical)

lProcessing Factors– Hygroscopicity

– Bulk, mechanical, and rheological properties

– Ease of isolation, filtration, and drying

– Degree of purification


Risk Assessment Related to Crystal Form IssuesRisk 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 CompoundsHigh Risk Compounds

l Poorly soluble compounds as defined by the FDA biopharmaceutical classification system:

Solubility in pH 1-8 solutions x 250 mL < Dosel 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 ChangesPotential 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 OpportunitiesPatent Protection for Potential LCM Opportunities

Compound Claimed

1990

Original API

Product Lunch

2001

Polymorphs/Salts Claimed

1998

Patent expired

2010

Extension

2015

Generic Entry

Generic Entry for All Other Forms

not Covered

Salts and Polymorphs

PTR

PTR: Patent Term Restoration = half of the investigational period + all of the FDA review period


Salt and Form Selection StrategySalt 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 SelectionSome 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 AspectsSome 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– Effect of excipients on crystallization/nucleation

l Suspensions– Effect of processing and formulation on the physical and chemical stability– Effect of excipients on crystallization/nucleation


Automation for Improving Efficiency and ProductivityAutomation 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 StudiesExample: Platform for Excipient Compatibility Studies


Final ThoughtsFinal 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 ReadingAdditional Readingl 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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