POLYMORPHISM OF DRUGS

CAN WE EXPLOIT PHYSICAL FORM IN THE DEVELOPMENT OF LOW SOLUBILITY MOLECULES?

Sponsored by
www.crystalpharmatech.com

Presented by ELIZABETH B. VADAS, PhD

InSciTech Inc. Montreal, Canada
Hosted by Seventh Street Development Group

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
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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 nonstoichiometric amounts of solvents. If the incorporated solvent is water, it is referred to as a hydrate SOME AMBIGUITY
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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!

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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

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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.

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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.

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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

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SCHEMATIC REPRESENTATION OF SOLUBILITY VS TEMPERATURE

S O L U B I L I T Y
MONOTROPIC ENANTIOTROPIC

Ttransition

TEMPERATURE

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MOST COMMONLY USED ANALYTICAL METHODS

THERMAL ANALYTICAL METHODS SOLID STATE NMR VIBRATIONAL SPECTROSCOPIC METHODS SOLUBILITY CRYSTALLOGRAPHY XRPD SINGLE CRYSTAL X-RAY

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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)

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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

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DRUG-LIKE PROPERTIES

BIOPHARMACEUTICAL FACTORS STABILITY MANUFACTURABILITY

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BIOPHARMACEUTICAL CLASSIFICATION
CLASS
EASIER TO DEVELOP

SOLUBILITY PERMEABILITY HIGH LOW HIGH HIGH

I II

III
HARDER TO DEVELOP

HIGH
LOW

LOW
LOW

IV

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MARKETED DRUGS vs. CURRENT NCEs IN DEVELOPMENT

MARKETED DRUGS NCEs

Class 1
Class 2 Class 3 Class 4

~ 35 %
~ 30 % ~ 25 % ~ 10 %

~ 5%
~ 70 % ~ 5% ~ 20 %
Data from Les Benet, UCSF

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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.
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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

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WHAT IS A POORLY SOLUBLE DRUG?

Dose

Solubility

Permeability

IMPOSSIBLE TO DEFINE WITHOUT KNOWLEDGE OF THE DOSE

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WHAT IS A POORLY SOLUBLE DRUG?

Molecule Piroxicam Digoxin

Dose (mg) 20 0.5

Solubility (mg/mL) 0.007 0.024

Volume needed to dissolve (mL) 2857 21

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CANDIDATE SELECTION FOR DEVELOPMENT

PRELIMINARY SELECTION

COMPOUND
FINAL SELECTION FORM

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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
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FUNCTION
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SELECTION CRITERIA FOR DOSAGE FORM DEVELOPMENT

NEW CHEMICAL ENTITY

Chemical Form(s)

Neutral cpd

Ionizable Group(s)
Salt Forms

Physical Form(s) Crystallinity Polymorphs Hydrates Solvates

SOLID STATE PROPERTIES

SOLUTION CHARACTERISTICS

Aqueous and organic pH solubility and soln. ABSORPTION stability CHARACTERISTICS

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Particle Morphology Mechanical Properties

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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

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SELECTION CRITERIA FOR THE DEVELOPMENT OF SOLID DOSAGE FORMS

Solid State Properties
Crystalline, Amorphous, Solvates/hydrates Tg
Excipient Compatibility Physical Chemical Mechanical properties Plastic, Brittle Particle size, Shape, Surface area

Temp. Humidity
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Solid State Stability Physical Chemical

Temp. Light O2 Humidity

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EXAMPLE
DRUG MOLECULE HAVING 5 POLYMORPHS

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CONSEQUENCES OF INADEQUATE AQUEOUS SOLUBILITY

LOW AND VARIABLE ABSORPTION
POTENTIAL FOOD EFFECTS FORMULATION EFFECTS POTENTIAL FOR NON-LINEAR ABSORPTION TISSUE DISTRIBUTION

METABOLISM

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IMPACT OF INADEQUATE SOLUBILITY ON DEVELOPMENT

PRECLINICAL ASSESSMENT TOXICOLOGY ANALYTICAL METHODS FORMULATION DEVELOPMENT CLINICAL PERFORMANCE

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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?
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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

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EXAMPLE
EFFECT OF MILLING

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PRACTICAL EXAMPLES OF POLYMORPHISM

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

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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

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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

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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

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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 Tm = 181.2 C Heat of fusion = 77 J/g

FORM II Tm = 176 +/- 3 C Heat of fusion = 87 J/g

Morphology irregular plates

Morphologyagglomerates, less electrostatic than FORM I

FORM II is less electrostatic and is hence particularly suited to the manufacture of pharmaceutical compositions
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EXAMPLE 3, continued
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

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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?

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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).

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EXAMPLE 5, continued
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

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EXAMPLE 5, continued
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?
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EXAMPLE 5, continued
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

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EXAMPLE 5, continued
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
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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

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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

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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

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Check out the recordings for the Crystal Pharmatech Webcast Series
Hosted by Seventh Street Development Group
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 Nar Rodrguez-Hornedo University of Michigan Ann Arbor, MI, USA
:

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