POLYMORPHISM OF DRUGS

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 July 2012, InSciTech 2

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 July 2012, InSciTech 3

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 4

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 5

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. July 2012, InSciTech 6

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. July 2012, InSciTech 7

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 July 2012, InSciTech 8

SCHEMATIC REPRESENTATION OF SOLUBILITY VS TEMPERATURE S O L U B I L I T Y MONOTROPIC ENANTIOTROPIC TEMPERATURE Ttransition July 2012, InSciTech 9

MOST COMMONLY USED ANALYTICAL METHODS THERMAL ANALYTICAL METHODS SOLID STATE NMR VIBRATIONAL SPECTROSCOPIC METHODS SOLUBILITY CRYSTALLOGRAPHY XRPD SINGLE CRYSTAL X-RAY July 2012, InSciTech 10

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 11

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 12

DRUG-LIKE PROPERTIES BIOPHARMACEUTICAL FACTORS STABILITY MANUFACTURABILITY July 2012, InSciTech 13

BIOPHARMACEUTICAL CLASSIFICATION CLASS SOLUBILITY PERMEABILITY EASIER TO DEVELOP I HIGH HIGH II LOW HIGH III HIGH LOW HARDER TO DEVELOP IV LOW LOW July 2012, InSciTech 14

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 15

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. July 2012, InSciTech 16

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? Dose Solubility Permeability IMPOSSIBLE TO DEFINE WITHOUT KNOWLEDGE OF THE DOSE July 2012, InSciTech 18

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 19

CANDIDATE SELECTION FOR DEVELOPMENT PRELIMINARY SELECTION COMPOUND FINAL SELECTION FORM July 2012, InSciTech 20

SELECTION OF FORM OF THE DEVELOPMENT CANDIDATE CHEMICAL FORM PHYSICAL FORM NEUTRAL MOLECULE ACID, BASE OR SALT CO-CRYSTAL SOLVATE, HYDRATE CRYSTALLINE POLYMORPHS LIQUID CRYSTAL AMORPHOUS FORM FUNCTION July 2012, InSciTech 21

SELECTION CRITERIA FOR DOSAGE FORM DEVELOPMENT Chemical Form(s) Neutral cpd Ionizable Group(s) Salt Forms SOLUTION CHARACTERISTICS Aqueous and organic ph solubility and sol n. stability NEW CHEMICAL ENTITY ABSORPTION CHARACTERISTICS Physical Form(s) Crystallinity Polymorphs Hydrates Solvates SOLID STATE PROPERTIES Particle Morphology Mechanical Properties July 2012, InSciTech 22

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 23

SELECTION CRITERIA FOR THE DEVELOPMENT OF SOLID DOSAGE FORMS Solid State Properties Crystalline, Amorphous, Solvates/hydrates Particle size, Shape, Surface area Tg Temp. Humidity Excipient Compatibility Physical Chemical Mechanical properties Plastic, Brittle Solid State Stability Physical Chemical Temp. Light O 2 Humidity July 2012, InSciTech 24

EXAMPLE DRUG MOLECULE HAVING 5 POLYMORPHS July 2012, InSciTech 25

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 26

IMPACT OF INADEQUATE SOLUBILITY ON DEVELOPMENT PRECLINICAL ASSESSMENT TOXICOLOGY ANALYTICAL METHODS FORMULATION DEVELOPMENT CLINICAL PERFORMANCE July 2012, InSciTech 27

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 28

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 29

EXAMPLE EFFECT OF MILLING July 2012, InSciTech 30

PRACTICAL EXAMPLES OF POLYMORPHISM THE GOOD, THE BAD, THE UGLY, THE INDIFFERENT AND THE SOMETIMES USEFUL July 2012, InSciTech 31

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 32

EXAMPLE (2) FAMOTIDINE histamine H2 antagonist Has two polymorphic crystal forms Melting point difference is < 10 0 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 33

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 34

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 Morphology irregular plates FORM II Tm = 176 +/- 3 C Heat of fusion = 87 J/g Morphologyagglomerates, less electrostatic than FORM I FORM II is less electrostatic and is hence particularly suited to the manufacture of pharmaceutical compositions July 2012, InSciTech 35

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 36

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 37

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 < 10 0 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 38

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 July 2012, InSciTech 39

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 40

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 41

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 42

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 43

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 44

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 July 2012, InSciTech 45

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 : Naír Rodríguez-Hornedo University of Michigan Ann Arbor, MI, USA Recordings are available at http://www.crystalpharmatech.com/webcast_series.php