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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
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
July 2012, InSciTech 3
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
July 2012, InSciTech 4
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!
July 2012, InSciTech 5
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
July 2012, InSciTech 6
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)
July 2012, InSciTech 7
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:
July 2012, InSciTech 8
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
July 2012, InSciTech 9
TEMPERATURE
S
O
L
U
B
I
L
I
T
Y
Ttransition
MONOTROPIC ENANTIOTROPIC
MOST COMMONLY USED ANALYTICAL METHODS
July 2012, InSciTech 10
THERMAL ANALYTICAL METHODS
SOLID STATE NMR
VIBRATIONAL SPECTROSCOPIC METHODS
SOLUBILITY
CRYSTALLOGRAPHY
XRPD
SINGLE CRYSTAL X-RAY
July 2012, InSciTech 11
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)
July 2012, InSciTech 12
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
July 2012, InSciTech 13
“DRUG-LIKE” PROPERTIES
•BIOPHARMACEUTICAL FACTORS
•STABILITY
•MANUFACTURABILITY
July 2012, InSciTech 14
BIOPHARMACEUTICAL CLASSIFICATION
CLASS SOLUBILITY PERMEABILITY
I HIGH HIGH
II LOW HIGH
III HIGH LOW
IV LOW LOW
EASIER TO DEVELOP
HARDER TO DEVELOP
July 2012, InSciTech 15
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
July 2012, InSciTech 16
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
July 2012, InSciTech 17
WHAT IS A POORLY SOLUBLE DRUG?
July 2012, InSciTech 18
Dose
Solubility Permeability
IMPOSSIBLE TO DEFINE WITHOUT KNOWLEDGE OF
THE DOSE
July 2012, InSciTech 19
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
July 2012, InSciTech 20
CANDIDATE SELECTION FOR DEVELOPMENT
PRELIMINARY SELECTION
COMPOUND
FINAL SELECTION
FORM
July 2012, InSciTech 21
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
July 2012, InSciTech 22
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
July 2012, InSciTech 23
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
July 2012, InSciTech 24
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
July 2012, InSciTech 25
EXAMPLE
DRUG
MOLECULE
HAVING 5
POLYMORPHS
July 2012, InSciTech 26
CONSEQUENCES OF INADEQUATE AQUEOUS SOLUBILITY
•LOW AND VARIABLE ABSORPTION
•POTENTIAL FOOD EFFECTS
•FORMULATION EFFECTS
•POTENTIAL FOR NON-LINEAR ABSORPTION
•TISSUE DISTRIBUTION
•METABOLISM
July 2012, InSciTech 27
IMPACT OF INADEQUATE SOLUBILITY ON DEVELOPMENT
•PRECLINICAL ASSESSMENT
•TOXICOLOGY
•ANALYTICAL METHODS
•FORMULATION DEVELOPMENT
•CLINICAL PERFORMANCE
July 2012, InSciTech 28
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?
July 2012, InSciTech 29
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
July 2012, InSciTech 30
EXAMPLE
EFFECT OF
MILLING
July 2012, InSciTech 31
PRACTICAL EXAMPLES OF POLYMORPHISM
THE GOOD, THE BAD, THE UGLY, THE INDIFFERENT AND THE SOMETIMES
USEFUL
July 2012, InSciTech 32
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
July 2012, InSciTech 33
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
July 2012, InSciTech 34
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
July 2012, InSciTech 35
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……
July 2012, InSciTech 36
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
July 2012, InSciTech 37
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?
July 2012, InSciTech 38
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).
July 2012, InSciTech 39
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
EXAMPLE 5, continued
July 2012, InSciTech 40
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?
July 2012, InSciTech 41
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
July 2012, InSciTech 42
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
July 2012, InSciTech 43
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
July 2012, InSciTech 44
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
July 2012, InSciTech 45
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