Vadas Webcast-Crystal Pharmatech Series- Seventh Street Development Group July 2012

POLYMORPHISM OF DRUGS

CAN WE EXPLOIT PHYSICAL FORM IN THE DEVELOPMENT OF LOW SOLUBILITY

MOLECULES?

Presented by ELIZABETH B. VADAS, PhD

InSciTech Inc. Montreal, Canada

Hosted by Seventh Street Development Group

Sponsored by

www.crystalpharmatech.com

http://www.seventhstreetdev.com/

July 2012, InSciTech 2

DEFINITIONS

CRYSTALLINE SOLIDS – substances that possess a regular, repetitive

internal arrangement of atoms, molecules or ions in a well defined 3

dimensional structure called the crystal lattice

POLYMORPHS – the same chemical entity having different 3 dimensional

arrangements in the solid state

SOLVATES – the crystal lattice contains a solvent

HYDRATES – the solvent contained in the crystal lattice is water

LIQUID CRYSTALS – a chemical entity that has long-range orientational order

but lacks a certain degree of positional order relative to a crystal lattice

AMORPHOUS SOLIDS – the molecules exists in a disordered state and do not

possess a distinguishable long range 3 dimensional order


FDA DEFINITION –ANDA guidance

POLYMORPHIC FORMS – crystalline and amorphous forms as well as

solvates and hydrates

CRYSTALS – possess different arrangements and/or conformations of

the molecules in the crystal lattice

AMORPHOUS MATERIALS – disordered arrangements of molecules

without a distinguishable crystal lattice

SOLVATES – crystal forms containing either stoichiometric or non-

stoichiometric amounts of solvents. If the incorporated solvent is water, it

is referred to as a hydrate

SOME AMBIGUITY


SOME MORE AMBIGUITY

PSEUDOPOLYMORPHS – solvates and hydrates are sometimes

referred to as pseudopolymorphs

Kenneth R. Seddon, Pseudopolymorph: A Polemic

Crystal Growth & Design, 2004, 4(6) p 1087

Abstract: The author argues against the use of the term

“pseudopolymorph”, since the scientific community gains no new

understanding by its introduction, its use is pedagogically misleading,

and a long-established and well-understood term “solvate” already

exists.

AMEN, strike the word from your vocabulary!


WHY IS POLYMORPHISM OF INTEREST TO THE PHARMACEUTICAL INDUSTRY?

Polymorphs are chemically identical, but have different crystal

lattice energies, melting points, intrinsic solubilities, rates of

dissolution, densities, mechanical properties, chemical and

physical stability, hygroscopicity, different crystal habits …..

Polymorphism has implications in biopharmaceutical properties,

formulation/processing aspects, intellectual property

The different intrinsic solubilities may lead to differences in the

rate of absorption – therapeutic implications


CRYSTAL POLYMORPHISM

THE ABILITY OF A SUBSTANCE TO CRYSTALLIZE IN MORE

THAN ONE DISTINCT CRYSTAL STRUCTURE

Different crystal structures will contain different contributions from the

various possible intermolecular interactions such as van der Waals

forces, ionic and hydrogen bonds.

The different crystal structures will have different free energies

resulting in differences in physical, chemical, optical, mechanical

properties such as melting point, solubility, density, hygroscopicity,

compactability, stability.

HOW DIFFERENT IS DIFFERENT?

Graphite, diamond, buckminsterfullerene

(allotropes of carbon)


Drug molecules in different crystal forms may have

different bioavailability (or not) as a result of the

differences in free energy.

THERMODYNAMIC RELATIONSHIP BETWEEN POLYMORPHS:


ENANTIOTROPY AND MONOTROPY

A PAIR OF POLYMORPHS IS CONSIDERED ENANTIOTROPIC IF THERE IS A TRANSITION POINT (TEMPERATURE) AT

WHICH THE TWO POLYMORPHS CAN UNDERGO A REVERSIBLE SOLID-SOLID TRANSFORMATION. AT THE TRANSITION

TEMPERATURE THE TWO POLYMORPHS HAVE EQUAL FREE ENERGY AND THEY ARE AT EQUILIBRIUM WITH EACH

OTHER. BELOW THE TRANSITION TEMPERATURE ONE OF THE TWO POLYMORPHS IS STABLE AND ABOVE IT THE

OTHER.

A PAIR OF POLYMORPHS ARE CONSIDERED MONOTROPIC IF ONE OF THE TWO IS STABLE AT ANY TEMPERATURE

BELOW THE MELTING POINT OF BOTH POLYMORPHS . THE FREE ENERGY OF THE STABLE FORM IS LOWER AT ALL

TEMPERATURES BELOW THE MELTING POINT OF BOTH.

IT IS CRITICAL TO UNDERSTAND THE THERMODYNAMIC RELATIONSHIP OF POLYMORPHS (FIRST EXPERIMENT IS

GENERALLY A SOLUBILITY WITH TEMPERATURE STUDY)

REFERENCE: POLYMORPHISM in the Pharmaceutical Industry, edited by Rolf Hilfiker, Chapter 2 , 2006, Viley-VCH

SCHEMATIC REPRESENTATION OF SOLUBILITY VS TEMPERATURE


TEMPERATURE

S

O

L

U

B

I

L

I

T

Y

Ttransition

MONOTROPIC ENANTIOTROPIC

MOST COMMONLY USED ANALYTICAL METHODS


THERMAL ANALYTICAL METHODS

SOLID STATE NMR

VIBRATIONAL SPECTROSCOPIC METHODS

SOLUBILITY

CRYSTALLOGRAPHY

XRPD

SINGLE CRYSTAL X-RAY


SOME EXAMPLES OF DRUGS EXHIBITING POLYMORPHISM

Steroids

Barbiturates

Sulfonamides

Acetaminophen (analgesic)

Ranitidine Hydrochloride (histamine H2 receptor antagonist)

Loperamide hydrochloride (inhibits GI motility)

Ribavirin (antiviral)

Risperidone (atypical antipsychotic)

Atorvastatin Ca (cholesterol lowering agent)

Famotidine (Histamine H2 antagonist)

Clopidogrel bisulphate (platelet aggregation inhibitor)

Ritanovir (antiviral)


WHY DO COMPOUNDS FAIL IN PRECLINICAL/CLINICAL DEVELOPMENT?

•LACK OF EFFICACY – 30%

•ANIMAL TOXICOLOGY – 11%

•ADVERSE EFFECTS IN HUMANS – 10%

•COMMERCIAL REASONS – 5%

•POOR “DRUG-LIKE” PROPERTIES – 39%

KENNEDY, DRUG DISCOVERY TODAY 2, (1997), 436-444


“DRUG-LIKE” PROPERTIES

•BIOPHARMACEUTICAL FACTORS

•STABILITY

•MANUFACTURABILITY


BIOPHARMACEUTICAL CLASSIFICATION

CLASS SOLUBILITY PERMEABILITY

I HIGH HIGH

II LOW HIGH

III HIGH LOW

IV LOW LOW

EASIER TO DEVELOP

HARDER TO DEVELOP


MARKETED DRUGS vs. CURRENT NCEs IN DEVELOPMENT

MARKETED DRUGS NCEs

Class 1 ~ 35 % ~ 5 %

Class 2 ~ 30 % ~ 70 %

Class 3 ~ 25 % ~ 5 %

Class 4 ~ 10 % ~ 20 %

Data from Les Benet, UCSF


BIOPHARMACEUITCAL CHARACTERIZATION

•BIOPHARMACEUTICAL CLASSIFICATION SYSTEM (BCS)

- FOUR CLASSES BASED ON COMBINATION OF AQUEOUS SOLUBILITY

AND GASTROINTESTINAL PERMEABILITY

- IMPORTANCE OF DOSE WITH RESPECT TO GI VOLUME AND GI

SOLUBILITY

- ROLE OF ABSORPTIVE TRANSPORTERS AND EFFLUX MECHANISMS

AND IMPORTANCE OF METABOLISM

BIOPHARMACEUTICS DRUG DISPOSITION CLASSIFICATION

SYSTEM (BDDCS)

Amidon et al.

Dressman et al.

Benet et al.

AQUEOUS SOLUBILITY

FREELY SOLUBLE: 100-1000 mg/mL

SOLUBLE: 33-100 mg/Ml

SPARINGLY SOLUBLE: 10-33mg/mL

SLIGHTLY SOLUBLE: 1-10 mg/mL

VERY SLIGHTLY SOLUBLE: 0.1-1 mg/mL

PRACTICALLY INSOLUBLE: < 0.1 mg/mL


WHAT IS A POORLY SOLUBLE DRUG?


Dose

Solubility Permeability

IMPOSSIBLE TO DEFINE WITHOUT KNOWLEDGE OF

THE DOSE


WHAT IS A POORLY SOLUBLE DRUG?

Molecule Dose

(mg)

Solubility

(mg/mL)

Volume needed to

dissolve (mL)

Piroxicam 20 0.007 2857

Digoxin 0.5 0.024 21


CANDIDATE SELECTION FOR DEVELOPMENT

PRELIMINARY SELECTION

COMPOUND

FINAL SELECTION

FORM


SELECTION OF FORM OF THE DEVELOPMENT CANDIDATE

CHEMICAL FORM

NEUTRAL MOLECULE

ACID, BASE OR SALT

CO-CRYSTAL

SOLVATE, HYDRATE

PHYSICAL FORM

CRYSTALLINE

POLYMORPHS

LIQUID CRYSTAL

AMORPHOUS

FORM FUNCTION


SELECTION CRITERIA FOR DOSAGE FORM DEVELOPMENT

NEW CHEMICAL

ENTITY

Chemical Form(s) Physical Form(s)

Crystallinity

Polymorphs

Hydrates

Solvates

Neutral cpd Ionizable Group(s)

Salt Forms

SOLUTION

CHARACTERISTICS SOLID STATE

PROPERTIES Aqueous and organic

pH solubility and sol’n.

stability Particle Morphology

Mechanical Properties

ABSORPTION

CHARACTERISTICS


INSULIN

INSULIN IS AVAILABLE IN TWO FORMS FOR INJECTION:

•Insulin suspension containing the amorphous form

•Insulin suspension containing the crystalline form

The two forms have different rates of dissolution resulting in

different response rates


SELECTION CRITERIA FOR THE DEVELOPMENT OF SOLID DOSAGE FORMS

Solid State Properties

Crystalline,

Amorphous,

Solvates/hydrates

Tg

Excipient

Compatibility

Physical

Chemical Temp.

Humidity

Particle size, Shape,

Surface area

Mechanical

properties

Plastic, Brittle

Solid State Stability

Physical

Chemical

Temp.

Light

O2

Humidity


EXAMPLE

DRUG

MOLECULE

HAVING 5

POLYMORPHS


CONSEQUENCES OF INADEQUATE AQUEOUS SOLUBILITY

•LOW AND VARIABLE ABSORPTION

•POTENTIAL FOOD EFFECTS

•FORMULATION EFFECTS

•POTENTIAL FOR NON-LINEAR ABSORPTION

•TISSUE DISTRIBUTION

•METABOLISM


IMPACT OF INADEQUATE SOLUBILITY ON DEVELOPMENT

•PRECLINICAL ASSESSMENT

•TOXICOLOGY

•ANALYTICAL METHODS

•FORMULATION DEVELOPMENT

•CLINICAL PERFORMANCE


BIOPHARMECUTICAL FACTORS

REASONS FOR POOR ORAL ABSORPTION CHARACTERISTICS

POOR AQUEOUS SOLUBILITY (thermodymanics)

SLOW RATE OF DISSOLUTION (kinetics)

PERMEABILITY - EFFLUX

FIRST PASS METABOLISM

CAN WE MITIGATE ANY OF THE ABOVE ?

HOW?


SOLUBILITY AND DISSOLUTION ENHANCEMENT

What can we do?

•LEAD OPTIMIZATION (PERMEABILITY, METABOLISM)

•CRYSTAL MODIFICATIONS

POLYMORPHS, SOLVATES, SALTS,

CO-CRYSTALS, AMORPHOUS FORM

•PARTICLE SIZE REDUCTION

•FORMULATION - USE OF SOLUBILIZING EXCIPIENTS

SOLUTIONS, SEMISOLIDS, SOLID SOLUTIONS,

SOLID DISPERSIONS,SELF EMULSIFYING SYSTEMS,

COMPLEXATION WITH CYCLODEXTRINS


EXAMPLE

EFFECT OF

MILLING


PRACTICAL EXAMPLES OF POLYMORPHISM

THE GOOD, THE BAD, THE UGLY, THE INDIFFERENT AND THE SOMETIMES

USEFUL


EXAMPLE (1)

RITONAVIR –protease inhibitor

•Originally thought to have a single crystal form

Poorly absorbed molecule

Formulated as soft gel capsule containing an

ethanol/water solution of the molecule

•Two years after market introduction several batches

failed dissolution specifications

•A new crystal form precipitated out of solution, this

form had ~ 50% lower intrinsic solubility

•Product had to be withdrawn from market and

reformulated in an oily vehicle


EXAMPLE (2)

FAMOTIDINE – histamine H2 antagonist

Has two polymorphic crystal forms

Melting point difference is < 100 C

Heats of fusion very similar

The two forms are bioequivalent

Polymorphism is an IP and CMC issue here,

no biopharmaceutical consequenses


EXAMPLE 3

CLOPIDOGREL BISULFATE - platelet aggregation inhibitor

US patent 4,847,265, July 11, 1989 – composition of matter,

describes a number of salts, including hydrogen sulfate salt.

Claims pure enantiomers as opposed to a racemix mix. No

mention of polymorphism.

SNDA – March 2000 – bioequivalence between two

polymorphic forms demonstrated, current marketed product

contains new form.

US patent 6,429,210 B1, August 6, 2002 – Polymorphic

Clopidogrel Hydrogensulphate Form


EXAMPLE 3, continued

The 2002 patent describes the differences between two forms of

the molecule based on XRPD, IR, melting point, enthalpy of

fusion, morphology, single crystal data.

FROM I FORM II

Tm = 181.2 C Tm = 176 +/- 3 C

Heat of fusion = 77 J/g Heat of fusion = 87 J/g

Morphology – irregular

plates

Morphology-

agglomerates, less

electrostatic than FORM I

FORM II is “less electrostatic and is hence particularly suited to the

manufacture of pharmaceutical compositions……



US patent 6,504,030 B1, January 2003

Repeats same crystallographic information, same DSC data.

Claims that FORM II has lower solubility, no data provided.

Claims specific methods of preparation.

“FORM II does not convert to FORM I….”

“Mother liquor of FORM I converts to FORM II after 3-6 months if

kept at < 40 C…”

THERMODYNAMICS vs KINETICS


EXAMPLE 4

ATORVASTATIN Ca – cholesterol lowering

To date 27 polymorphic forms are mentioned in the

patent literature

The marketed product contains the amorphous form

IP issue – if any of the claimed polymorphs isolated

during the preparation of the amorphous API – patent

infringement?


EXAMPLE 5

EXPERIMENTAL MOLECULE

Neutral cpd with low aqueous solubility, but initial batch from medicinal

chemistry had acceptable oral absorption characteristics in rats when

administered as a suspension in 0.5% CMC/Tween

Second batch had much reduced oral absorption, < 10% vs ~30%

observed initially – not a particle size effect

Two polymorphic crystal forms identified. The melting point difference

was < 100 C, unlikely to explain the difference in absorption

characteristics. However, the heat of fusion of the better absorbed

form (A) was ~ 2/3 of the new, poorly absorbed form (B).


HOW MUCH ENERGY IS NEEDED TO PULL A

MOLECULE OFF THE FACE OF A CRYSTAL INTO THE

SOLUTION PHASE?

Terada et al., Int.J.Pharmaceutics, 204 (2000) 1-6

Quantitative correlation between initial dissolution rate

and heat of fusion of drug substance




Can we exploit the absorption characteristics of the less stable form to

provide appropriate levels of exposure in IND enabling tox studies and

thus provide adequate safety margins for first in man?

Can process chemistry make the less stable polymorph reliably without

conversion to the more stable form?

Under what conditions can we avoid conversion of the less stable form

to the more stable one? Can we run the tox studies with the less stable

form?

Risk –thermodynamics will drive conversion to the more stable form

Opportunity – is there a kinetic barrier we can exploit?



SOME OF THE EXPERIMENTAL WORK

Process chemistry – crystallization conditions

solvents and solvent mixtures

degree of supersaturation

heating/cooling

mixing rates

Observation – less stable from can be made consistently

XRPD, Tm, solubility



Conversion studies

Expose less stable form to different environments

Temperature, humidity, saturated solvent vapor

solvents favoring one from or the other

mixtures of solvents

Expose less stable form to mechanical stress

Wig-L-Bug high energy milling

Toxicology formulations – suspension studies

CMC and MC

different levels of surfactant

different particle size distributions

Observations – there are conditions under which the less stable

form does not convert to the more stable one.

OUTCOME – IND enabling tox completed with less stable form


CANDIDATE SELECTION FOR DEVELOPMENT

THE BEST CANDIDATE IS NOT NECESSARILY THE IDEAL CANDIDATE FROM EITHER THE

DISCOVERY OR FROM THE DEVELOPMENT SCIENTISTS’ POINT OF VIEW

THE BEST CANDIDATE GENERALLY REPRESENTS THE BEST COMPROMISE

THE SELECTED MOLECULE AND ITS FORM MUST SATISFY A NUMBER OF REQUIREMENTS

COMING FROM A VARIETY OF DIFFERENT DISCIPLINES INVOLVED IN DRUG DEVELOPMENT

RISK ASSESSMENT


WHERE ARE THE OPPORTUNITIES?

An incomplete list

•COMPOUND PROFILING AND SELECTION

•EARLY INTERACTION BETWEEN DISCOVERY AND

DEVELOPMENT

•CRYSTAL ENGINEERING

•SALT SELECTION AND POLYMORPH CHARACTERIZATION

•BIOPHARMACEUTICAL EVALUATION OF FORMS

•TOXICOLOGY FORMULATIONS

•PHASE 0 or MICRODOSING TECHNIQUES

•FIRST INTO MAN FORMULATIONS

•USE OF BIOMARKERS

•PROCESS ANALYTICAL TECHNOLOGIES

•STREAMLINED REGULATORY PROCESSES


POLYMORPHS, HYDRATES AND SOLVATES: Can we exploit their existence?

DIFFERENT FORMS OF A DRUG MOLECULE

REPRESENT AN OPPORTUNITY FOR OPTIMIZED

DRUG DELIVERY

BE SMART, DO NOT BE AFRAID TO EXPERIMENT

DO UNDERSTAND THE THERMODYNAMIC

RELATIONSHIPS AMONG FORMS AND THE KINETICS

OF CONVERSION

CONTINUOUS RISK – BENEFIT ANALYSIS DURING

DEVELOPMENT

Check out the recordings for the Crystal Pharmatech Webcast Series

Hosted by Seventh Street Development Group

Recordings are available at http://www.crystalpharmatech.com/webcast_series.php

The Use of Amorphous Solid Dispersions to Enhance Dissolution, and Oral Bioavailability of Poorly Water-Soluble Pharmaceutical Compounds

George Zografi

University of Wisconsin-Madison

Madison, WI USA

Engineering Cocrystal Solubility and Streamlining Cocrystal Early Development

: Naír Rodríguez-Hornedo

University of Michigan

Ann Arbor, MI, USA

http://www.crystalpharmatech.com/



http://www.seventhstreetdev.com/

http://www.crystalpharmatech.com/webcast_series.php

Documents

Vadas Webcast-Crystal Pharmatech Series- Seventh Street Development Group July 2012