1. Pharmaceutical Solid FormScreening, Characterization,and SelectionEnhancing Drug Bioavailability and SolubilityYuchuan Gong, Ph.D.Boston, MA, Jan. 25, 2012

2. Outline 1. Solid Forms Solid Forms Solid State Thermodynamics 2. Impact of Solid Form Solubility/Dissolution Stability Morphology/Processing 3. Solid Form Development Solid Form Screening Solid State Characterization Solid Form SelectionPharmaceutical Solid Form Screening, Characterization, and Selection2Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 3. Outline 1. Solid Forms Solid Forms Solid State Thermodynamics 2. Impact of Solid Form Solubility/Dissolution Stability Morphology/Processing 3. Solid Form Development Solid Form Screening Solid State Characterization Solid Form SelectionPharmaceutical Solid Form Screening, Characterization, and Selection3Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 4. Why Solid? Solid is more stable than its liquid counterpart APIs are usually manufactured, transported, and stored as solid Most drugs are marketed in solid dosage forms Common Dosage FormsPhase of API in DrugTabletsolid Capsulesolid, liquid Powder, granulesolid Ointment, cream, gel solid Transdermalsolid Suppositorysolid Solutionliquid Disperse solid, liquidPharmaceutical Solid Form Screening, Characterization, and Selection4Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 5. Types of Solid FormsSolidlong range order short range order CrystallineLiquid Crystalline Amorphous singlemultiple component components ionic non-ionicPolymorphs Salt + Molecular Adducts Solvate/HydrateCo-crystalPharmaceutical Solid Form Screening, Characterization, and Selection 5Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 6. Solid Forms (Polymorphs)Polymorphs:crystalline forms with the same chemical compositionbutdifferent internal structures (packing, conformation, etc.) Packing: Conformational: H-Bonding OOH Tautomeric:NH N More than 80% of the pharmaceutical solids exhibit polymorphsPharmaceutical Solid Form Screening, Characterization, and Selection6Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 7. Solid Forms (Polymorphs)metastableThe thermodynamically most stable form of apharmaceutical solid is less soluble, but more stableA metastable polymorph is more soluble, but less stablestableRitonavirThe thermodynamically most stable form of a pharmaceutical solid is normallypreferred on account of its greatest stabilityA metastable polymorph is sometimes developed, when it can provide anacceptable balance between processability and stability Pharmaceutical Solid Form Screening, Characterization, and Selection7 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 8. Solid Forms (Solvates/Hydrates)Solvates / Hydrates Molecular adducts that incorporate solvent molecules in their crystal lattices; Solvent is water Hydrates Solvent is other solventsSolvates Non-solvatedSolvatePharmaceutical Solid Form Screening, Characterization, and Selection8Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 9. Solid Forms (Solvates)Common organic solvents in solvates Methanol, ethanol, 1-propanol, IPA, 1-butanol, hexane, cyclohexane, acetone, MEK,benzene, toluene, acetonitrile,ethyl acetate, diethyl ether, THF, dioxane, dichloromethane acetic aciddimethylformamide Solvates are not acceptable for API (except ethanol solvate)Solvate is the most stable form in the particular solvent Knowing if a solvate can form in a particular solvent is essential to processing. Solvate formation can be used for purification Solvate may be used to prepare a desolvated solid formPharmaceutical Solid Form Screening, Characterization, and Selection9Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 10. Solid Forms (Hydrates)Organic compounds frequently form hydrates in presence of water due to Small molecular size of water The multidirectional hydrogen bonding capability of water Distribution of stoichiometry of hydrates among 6000 non-organometalliccompounds (3.8% of all) in Cambridge Crystallographic Database 3000Number of Occurences 2500 2000 1500 100050000.5 1 2 3 45 6 7 8 9 Hydration NumberPharmaceutical Solid Form Screening, Characterization, and Selection10Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 11. Solid Forms (Hydrates) Hydrate is the most stable solid form in water,least soluble form in GI environmentNon-hydrous solid form is usually favored over hydratesHowever, Stable hydrates with acceptable bioavailability can be developed: may have better physicochemical properties may be the only crystalline form of a APIPharmaceutical Solid Form Screening, Characterization, and Selection11Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 12. Solid Forms (Salts / Co-crystals)Crystalline Salts and Co-crystalscontain two or more components in the same latticeOO RR1 R R1O- HN+ R2O H NR2Salt Co-crystal Differentiation is debatable:1. Interaction between the components2. Proton transferPharmaceutical Solid Form Screening, Characterization, and Selection12Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 13. Solid Forms (Salts / Co-crystals)Salt / co-crystal formation of API are investigated ingreat frequency becausePowder dissolutionCrystallization tool:PurificationProperty modification:Dissolution rateChemical and physical stabilityCrystallinityHygroscopicityBulk properties Density, particle size, flowability, etc. Manufacturability drying, filtrability Childs et al., J Am Chem Soc 126:13335-13342, 2004.Pharmaceutical Solid Form Screening, Characterization, and Selection13Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 14. Solid Forms (Amorphous)Amorphous solid solid in which there is no long-range order of the positions of molecules/atoms. Amorphous Crystalline Amorphous solid has higher free energy than its corresponding crystalline solids, therefore, higher apparent solubility and dissolution rate Law et al., J. Pharm. Sci. 93:563, 2004Pharmaceutical Solid Form Screening, Characterization, and Selection14Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 15. Types of Solid Forms (Stoichiometry)Solidlong range order short range order CrystallineLiquid Crystalline Amorphous singlemultiple component components ionic non-ionicPolymorphs Salt + Molecular Adducts Solvate/HydrateCo-crystalstoichiometricnon-stoichiometricPharmaceutical Solid Form Screening, Characterization, and Selection 15Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 16. Solid State Thermodynamics Gibbs free energy: G = H TS where: G : Gibbs free energy (KJ/mol)H : enthalpy (KJ/mol)T : temperature (K)S : entropy (J/molK)Free Energy: measure of thermodynamic potentialEnthalpy: Internal energyEntropy: measure of disordernessPharmaceutical Solid Form Screening, Characterization, and Selection16Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 17. Solid State Thermodynamics (Polymorph) Why does the same chemical identity of different solid forms have different G? G = H TSEnthalpy is the heat needed to create something from nothingnessTherefore, different solid forms have different enthalpy due todifferent bonding/interactions between molecules in the solid formsEntropy is a measure of disorderness Therefore, solid forms have different entropy due to internal arrangement The higher the disorder, the higher the entropy Any system tends to change towards the direction of lower disorderPharmaceutical Solid Form Screening, Characterization, and Selection17Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 18. Solid State Thermodynamics (Polymorph) Free energy:Only quantity that determines the thermodynamic relationship (relative stability) between phases GIII = GII GI = HIII TSIIIGII < GI GIII < 0Phase II is more stable Phase I II is a spontaneous processGII > GI GIII > 0Phase II is less stable Phase II I is a spontaneous processGII = GI GIII = 0Phase I and II is equally stable Phase I and II are in equilibriumPharmaceutical Solid Form Screening, Characterization, and Selection18Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 19. Solid State Thermodynamics (Polymorph) Solubility (Activity): GIII = GII GI = RT ln(aII/aI) = RT ln(IICsII/ ICsI) = RT ln(II/ICsII/CsI)* In dilute solutions, I = II RT ln(CsII/CsI)*where CsI and CsII : solubility of solid form I and II;I and II : activity coefficients at CsI and CsII.GII < GI GIII < 0Phase II is more stable Phase II has less solubilityGII > GI GIII > 0Phase II is less stable Phase II has higher solubilityGII = GI GIII = 0Phase I and II is equally stable Phase I and II are in equilibriumPharmaceutical Solid Form Screening, Characterization, and Selection19Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 20. Solid State Thermodynamics (Polymorph) G liqu idCIMonotropicC II GI S b u o y t i l G E FG II g n e y r , G = H TS T m, I T m, IITemperature, T Temperature, TGIII = HIII TSIII C II G liquid CI Enantiotropic S b u o y t i lG II G E F g n e y r ,GI TtT m, II T m, ITtTemperature, TTemperature, TPharmaceutical Solid Form Screening, Characterization, and Selection 20Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 21. Solid State Thermodynamics (Hydrate/Solvate) The equilibrium between the anhydrous and hydrate forms of a drug D can be represented as K , p H D nH 2O( solid ) D( solid ) + nH 2O( gas )d t, tr[aD(s) ][aH 2O(g) ]ncp Therefore Kd == [aH 2O(g) ]n = [ pt ]n = [ RH ]n c[aDnH 2O(s) ] s aH 2O(g) > aH 2O(g) or p > pt , hydrate is more stable caH 2O(g) < aH 2O(g) or p < pt , anhydrate is more stablecaH 2O(g) = aH 2O(g) or p = pt , anhydrate and hydrate arec equally stable* Solvates are treated similarlyPharmaceutical Solid Form Screening, Characterization, and Selection21Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 22. Solid State Thermodynamics (Hydrate/Solvate)Relative stability of hydrates at various RH 9H2OOuabain 100 Copper Sulfate 8H20Penta% Weight Water Oubain.nH2O Tri 2H2OMono00 04.5 30 47 1000 100Relative Humidity Temperature (oC)Pharmaceutical Solid Form Screening, Characterization, and Selection22Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 23. Solid State Thermodynamics (Hydrate/Solvate) Temperature dependence of hydrate stability Apply vant Hoff equation to KdH tr ln(ac H 2O(g) 2 ) ln( ac) =H 2O(g) 1nR ( T12 T1 )1 Critical water activity increase withHigher T temperatureLn(Critical Water Activity) Hydrate is less stable at higher temperatures Hydrate is more stable at lower temperatures Keep the hydrate under cool and humid conditions!Lower T1/T (1/K)Pharmaceutical Solid Form Screening, Characterization, and Selection 23Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 24. Solid State Thermodynamics (Amorphous) Amorphous: glass, no long-range order between molecules Important concepts:uidLiqTm melting temperature Tg glass transition temperature led oo ercup id S u Tk Kauzmann temperature LiqG la ss 1 Re la xa tion2 Gla ssMobilitymEVpahneuoyt,lC ryst a llin e RelaxationCrystallizationTk TgTm TemperaturePharmaceutical Solid Form Screening, Characterization, and Selection24Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 25. Outline 1. Solid Forms Solid Forms Solid State Thermodynamics 2. Impact of Solid Form Solubility/Dissolution Stability Morphology/Processing 3. Solid Form Development Solid Form Screening Solid State Characterization Solid Form SelectionPharmaceutical Solid Form Screening, Characterization, and Selection25Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 26. Impact of Solid Forms Different solid forms show different physical, chemical, and mechanical properties Melting point Stability (physical & chemical) Spectral properties Dissolution rate SolubilityBioavailability Druggability Density Hygroscopicity HardnessBulk properties Crystal shape Manufacturability .Pharmaceutical Solid Form Screening, Characterization, and Selection26Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 27. Impact of Solid Forms (Solubility / Dissolution) Hydrates Lower solubility in water Higher solubility in other solvents Amorphous Always has higher solubility than its crystalline counterparts Salts Modify solubility by adjusting pH Consideration: Thermodynamic Solubility v.s. Apparent SolubilityPharmaceutical Solid Form Screening, Characterization, and Selection27Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 28. Impact of Solid Forms (Solubility)SulfamerazineH2 NO N MeS NHON Form I Metastable Form II Most StableS Form I= 1.2S Form IISolubility at 25oCGong, et. al, 2008.Pharmaceutical Solid Form Screening, Characterization, and Selection28Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 29. Impact of Solid Forms (Dissolution)Whitney-Noyes equation:Driving forcedM DSD S Cs= ( Cs C ) dt hhWhere dM/dt :dissolution rate;M: mass of solute dissolved;D: diffusion coefficient;S: surface area of the exposed solid;h: thickness of the diffusion layer;Cs : solubility;C: concentrationDiffusion layer Bulk solution Concentration/solubilitySolid State CSCbulkDistance from Solid SurfacePharmaceutical Solid Form Screening, Characterization, and Selection29Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 30. Impact of Solid Forms (Dissolution) Iopanoic acidPowder dissolution Intrinsic dissolutionAmorphous AmorphousForm II Form II Form I Form IAmorphous: > Form II: >Form I:Stagner & Guillory, 1963.Pharmaceutical Solid Form Screening, Characterization, and Selection30Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 31. Impact of Solid Forms (Dissolution)Succinyl sulfathiazole, in ~0.001 N H2SO4 solution at 20CO N NH SO SO NH C CH 2 CH 2 CO 2 H Shefter & Huguchi , 1963.Pharmaceutical Solid Form Screening, Characterization, and Selection31Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 32. Impact of Solid Forms (Dissolution) Salt 2 Salt 1 pKa pHmaxSubstantial increase in apparent solubility by salt formation, which will lead to theenhancement in dissolution rateDifferent salt forms will have different extent of apparent solubility improvementPharmaceutical Solid Form Screening, Characterization, and Selection32Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 33. dM DS= ( Cs C ) D S C sImpact of Solid Forms (Dissolution)dt hh H2 Np-Aminosalicylic acid: antibacterial CO 2 HOHParentForbes et al, 1995Pharmaceutical Solid Form Screening, Characterization, and Selection33Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 34. Impact of Solid Forms (Dissolution) Dissolution enhancement of salt may be jeopardized by the precipitation of the parent API Solid StateDiffusion layerBulk solution pHmax HAA-A-HABH+A-pHSolidA- HA HA A- pHbulk CS CSaltConcentration/solubilityA-HA Cbulk CFADistance from Solid Surface Pharmaceutical Solid Form Screening, Characterization, and Selection34 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 35. Impact of Solid Forms (Chemical Stability)Compound AFB:Photo-sensitive Forming crystalline salts can improve photo-stability of API at ambient temperaturesPharmaceutical Solid Form Screening, Characterization, and Selection35Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 36. Impact of Solid Forms (Morphology)Compound B Morphology may have great impact on processing of API and formulationPharmaceutical Solid Form Screening, Characterization, and Selection36Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 37. Outline 1. Solid Forms Solid Forms Solid State Thermodynamics 2. Impact of Solid Form Solubility/Dissolution Stability Morphology/Processing 3. Solid Form Development Solid Form Screening Solid State Characterization Solid Form SelectionPharmaceutical Solid Form Screening, Characterization, and Selection37Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 38. Solid Form Development Work FlowHit Identification Crystallization of Parent Manual salt/co-crystal screeningHit Scale-Up Thermodynamically most stable form of hitsLeadIdentification SingleDetailed SS characterization CrystalStructureLead Scale-UpLead Verification Pharmaceutical Evaluation Manufacturability EvaluationSolid Form SelectionPolymorph ScreeningPharmaceutical Solid Form Screening, Characterization, and Selection 38Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 39. Salt/Cocrystal Screening (Guest Selection)Safety is the overriding considerationCocrystals: hydrogen bonding potentialSalts: the strength of acids/bases: pKa 2** Salt/cocrystal continuum: pKa 1 3 could result in salt or cocrystal 2,6-dihydroxybenzoic acid(pKa: 1.3) Caffeine (pKa: 0.7) pKa = -0.6Personal conversation with Dr. Geoff Zhang The property of the solid is more important than the differentiation of salt vs. cocrystal no need to worry about the pKa differencesPharmaceutical Solid Form Screening, Characterization, and Selection39Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 40. Salt/Cocrystal Screening (Crystallization)Common Crystallization TechniquesReactiveAntisolvent addition GenerateSolvent evaporation SupersaturationTemperature gradientSlurryShould we consider the ability to scale up? At early stage, scale up is less of a concern As the candidate moves to later stages, the ability to performcrystallization at larger scale becomes increasingly important Preferred industrial crystallization usually involves reactive, antisolvent,and temperature gradientPharmaceutical Solid Form Screening, Characterization, and Selection40Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 41. Solution Crystallization CrystallizationNucleation Crystal Growth Secondary Primary(induced by crystals) Heterogeneous Homogeneous(induced by foreign surfaces)(spontaneous) Can be controlled by either nucleation or crystal growth Usually nucleation the slowest, rate-limiting step Mullin, 1992. Pharmaceutical Solid Form Screening, Characterization, and Selection 41 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 42. Crystallization (Solvent Evaporation)From a single solventAdvantage: Easy Column of solvent decreases Potential Problem: Concentration increases Evaporation rate is too high Solubility remains same Solubility is too high 100 10000908070 Concentration (mg/mL) Volume (mL)6050 100040302010 Supersaturation 0100 S 0 2 46 8 10 02 4 68 10Time (hr) Time (hr)Pharmaceutical Solid Form Screening, Characterization, and Selection 42Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 43. Crystallization (Solvent Evaporation)From a solvent mixture Advantage:Volume of solvent decreasesAdjustable solubility Dual effect on supersaturationConcentration of API increases Potential Problem:Solubility of API decreases Complex solvent system100250 Concentration Solubility 80 Concentration or Solubility (mg/mL) 200 Volume (mL) or % SolventBad Solvent (A) 60150 40100 Good Solvent (B) Supersaturation 20 Volume 50Solvent A %Solvent B %0 S 00 1 2 3450 1 2 345Time (hr)Time (hr)Pharmaceutical Solid Form Screening, Characterization, and Selection43Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 44. Crystallization (Heat & Cool)Heat & Cool Advantage:Temperature drops Moderate solubilityBetter yieldSolubility of API decreasesPotential Problem:Concentration remains sameDegradationConcentrationC0TempSupersaturationS Time High TempLow TempPharmaceutical Solid Form Screening, Characterization, and Selection44Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 45. Crystallization (Anti-solvent) Anti-solventAdvantage: More solvent options% bad solvent increases High yieldSolubility of API decreasesPotential Problem:Concentration of API decreases Complex solvent system Titration rate SConcentrationABad Solvent %BSupersaturation Time Good Solvent %Pharmaceutical Solid Form Screening, Characterization, and Selection45Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 46. Crystallization (pH Adjustment)pH Adjustment (Salt formation)At higher pH, apparent solubility of ionic API increasesAt pH > pHmax, concentration of API > Solubility of saltDriving force of the crystallization of the salt increases Supersaturation Ssalt pKa pHmaxPharmaceutical Solid Form Screening, Characterization, and Selection46Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 47. Crystallization (SMPT)Solution-MediatedSolution Concentration SMetastable Phase Transformation SStable GI > GII CI > CIISlurry of I1 23 100% Metastable PhaseSolid Composition Supersaturation of IICrystallization of II100% Stable PhaseTimePharmaceutical Solid Form Screening, Characterization, and Selection 47Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 48. Crystallization (SMPT)Crystallization ofHydrate: various water activityCo-crystal: maximum co-crystal former activityIdentity of the Crystal FormIdentity of the Crystal Form Drug stable Co-crystalHydrateregion stable regionCo-crystalCritical Water Critical Co-crystalActivity (aw,c)Former Activity (aCCF,c) Anhydrate Drug0 (0%) 1 (100%)0 1 Water Activity (aw) or Relative Humidity (RH) Co-crystal Former Activity (aCCF) Pharmaceutical Solid Form Screening, Characterization, and Selection 48 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 49. Solution Crystallization Factors may impact Additives (impurity, other additives) Solvent (solubility, viscosity, solute-solvent interaction etc.) Rate of reaching supersaturation(evaporation rate, cooling rate, anti-solvent addition rate) Temperature Mechanical impact (agitation, sonication) Solid/solvent ratio (SMPT) Particle size/surface area (SMPT) etc.Only trick to success is keep tryingPharmaceutical Solid Form Screening, Characterization, and Selection49Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 50. Solid Form Development Work FlowHit Identification Crystallization of Parent Manual salt/co-crystal screeningHit Scale-Up Thermodynamically most stable form of hitsLeadIdentification SingleDetailed SS characterization CrystalStructureLead Scale-UpLead Verification Pharmaceutical Evaluation Manufacturability EvaluationSolid Form SelectionPolymorph ScreeningPharmaceutical Solid Form Screening, Characterization, and Selection 50Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 51. Solid Form CharacterizationCrystalline solidsCharacterizationsTechniques Chemical identityNMR, IC Crystalline solid form identification Microscopy, PXRD, Raman, IR, DSCMelting temperature DSC MorphologyMicroscopy Solvate/hydrate identification DSC, TGA/MS, PXRDHygroscopicity Moisture sorption balanceDissolution rate-DissAmorphous solidsPhysical stability assessment (Tg, relaxation kinetics, crystallization kinetics)Pharmaceutical Solid Form Screening, Characterization, and Selection51Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 52. Solid Form Characterization (PXRD) Braggs Law 2d sin = n Each d corresponds to a ddsin d dsinPharmaceutical Solid Form Screening, Characterization, and Selection52Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 53. Solid Form Characterization (PXRD) PXRD is the most commonly used technique to identify solid form Different solid forms generally have different PXRD patterns PXRD can not be used to distinguish the chemical identity of the solids, unless the solid forms of each compound are known Single crystal structure is the most direct way to determine the nature of a crystalline solid. Single crystal X-ray data can be used to calculate the PXRD patternPharmaceutical Solid Form Screening, Characterization, and Selection53Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 54. Solid Form Characterization (PXRD) Be very careful with two solids having same PXRD patternsAre they really same or very similar?Pharmaceutical Solid Form Screening, Characterization, and Selection54Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 55. Solid Form Characterization (PXRD) Be very careful with hydrates/solvates as they may be missed due to quick dehydration/desolvation Conversion rate of the solvates: Methanol > Ethanol > IPAPharmaceutical Solid Form Screening, Characterization, and Selection55Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 56. Solid Form Characterization (NMR / IC) Solution NMR Determine the chemical identity / purity Determine the stoichiometry of solvates/co-crystals Determine the stoichiometry of salts with organic counter ions Ion Chromatography Determine the stoichiometry of salts with inorganic counter ionsPharmaceutical Solid Form Screening, Characterization, and Selection56Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 57. Solid Form Characterization (Spectroscopy) Raman and IR Spectroscopy Most commonly used in characterizing pharmaceutical solids Small sample requirement Simple sample preparation /Can be used in-situ Not everything is Raman or IR active (Raman) may be not representative / Fluorescence / Burning (IR) low spatial resolution (XY&Z) / less information at low wavelength Flufenamic Acid Metastable StablePharmaceutical Solid Form Screening, Characterization, and Selection57Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 58. Solid Form Characterization (Thermal)Advantages:Small sample sizeInformation on melting point and phase transition (DSC)Information on enthalpy differenceStoichiometry for solvates and hydrates (TGA)Disadvantages: Destructive Method Thermal manipulation Interference (other components, thermal products, etc.) Black box (total heat exchange)Pharmaceutical Solid Form Screening, Characterization, and Selection58Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 59. Solid Form Characterization (Thermal-DSC)DSC is used to monitor heat exchange when the sample isheated/cooled or maintained isothermally Endothermic EventsExothermic Events Solid-solid transitionsSolid-solid transitions DegradationDegradationMelting, boiling, sublimation, vaporizationCrystallization Desolvation Baseline ShiftGlass transitionPharmaceutical Solid Form Screening, Characterization, and Selection 59Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 60. DSC Applications of DSC DSC Melting temperature Heat of fusion Impurity Solid state solubility Dehydration/desolvation Chemical reaction Polymorphism etc.Pharmaceutical Solid Form Screening, Characterization, and Selection60Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 61. DSC (Melting)DSC is commonly used to measure melting temperature of crystallinesolidsSample: IndiumFile: S:3SGongINDIUM.001Size: 3.2640 x 0.0000 mgDSC Operator: YGMethod: Temperature (C)Run Date: 24-Apr-2008 14:59Melting Point:Comment: Cell constant calibrationTm of IndiumInstrument: DSC Q2000 V24.2 Build 107 Sharpness reflects the 0 158.03C28.42J/g chemical purity Onset Temp Defined by extrapolated-1 onset temperature (pure)Heat Flow (W/g) Reported using peak-2 temperature (with impurity) May overlap with other-3 physical processes Peak Temp (recrystallization, solid-solid 158.76C transition, etc.) and-4145155165 chemical processes Exo Up Temperature (C) Universal V4.4A TA Instru (decomposition etc.)Pharmaceutical Solid Form Screening, Characterization, and Selection61Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 62. DSC (Heat of fusion) DSC is commonly used to measure the heat of fusion of a crystalline solid Sample: IndiumFile: S:3SGongINDIUM.001 Size: 3.2640 x 0.0000 mgDSC Operator: YG Method: Temperature (C)Run Date: 24-Apr-2008 14:59 Comment: Cell constant calibration Tm of Indium Instrument: DSC Q2000 V24.2 Build 107 0 158.03C 28.42J/g Heat of Fusion: Integrated area under -1Hf melting curve Heat Flow (W/g) May overlap with-2 recrystallization May overlap with-3 decomposition and158.76C sublimation -4 145155165 Exo Up Temperature (C) Universal V4.4A TA InstrumentsPharmaceutical Solid Form Screening, Characterization, and Selection 62Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 63. DSC (Melting without decomposition) Melting is a thermodynamic phenomenon,therefore, melting point does not change much with heating rate Higher heating rateSame Tm Thomas, L. http://www.tainstruments.com/pdf/literature/TA315.pdfPharmaceutical Solid Form Screening, Characterization, and Selection63Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 64. DSC (Melting with decomposition) Decomposition is a kinetic phenomenon, therefore, melting/decomposition temperature changes with heating rate Higher heating rateHigher Tm Thomas, L. http://www.tainstruments.com/pdf/literature/TA315.pdfPharmaceutical Solid Form Screening, Characterization, and Selection64Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 65. DSC (Dehydration/desolvation) DSC is used to determine dehydration/desolvation Carbamazepine dihydrate- Usually at lower temperatures- Large enthalpy because of theevaporation of releasedwater/solvent- May result in lower hydrates,anhydrous phases, oramorphous phaseLi Y. et al., Pharm. Dev. Tech., 2000. 5, 257.Pharmaceutical Solid Form Screening, Characterization, and Selection65Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 66. DSC (Polymorphism)Different polymorphs usually havedifferent melting temperatures and heat of fusionsMonotropicEnantiotropic HLHL H f, IIH f, I H f, IH f, II HIHIG liquid G liquidH II H IIT m, I T m, II G H E g e n yTt ) ( r ,TtGHE T m, IIgenG IIy G II)(r, GI T m, IGITemperature, TTemperature, T Heat of Fusion Rule higher melting form; higher Hf higher melting form; lower HfPharmaceutical Solid Form Screening, Characterization, and Selection66Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 67. DSC (Polymorphism)IIPhase transitions ofIILMonotropic PolymorphsLIIIIL IILHL H f, II IILIIH f, IHIG liquidIILH III IIIT m, IIIL TtGHET m, IIgeny G II)(r, GITemperature, TPharmaceutical Solid Form Screening, Characterization, and Selection 67Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 68. DSC (Polymorphism) IIIII ILPhase transitions ofEnantiotropic Polymorphs IILLIHL IIIL H f, IIIL H f, II HIG liquid IIIILIILH II IIII IIIT m, IIGHEgeny)(r, Tt G IIILT m, IGI Temperature, TPharmaceutical Solid Form Screening, Characterization, and Selection 68Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 69. MDSC (Theory) Modulated DSC (MDSC) applies a sinusoidal heating program on top of a linear heating rate in order to measure the heat flow that responds to the changing heating rate MDSC separates the total heat flow response into the reversing and non- reversing componentsMudunuri P. Ph.D. Thesis., 2007 Paul G. et. al. Pharm. Res., 1998, 15(7), 1117Pharmaceutical Solid Form Screening, Characterization, and Selection69Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 70. MDSC (Glass transition, Phase separation) MDSC reversing heat flow scans of trehalose-dextran mixture (40/60) stored 50oC/75%RH34 days23 days 13 days4 days2 days Measured Tg can be used to determine0 day phase homogeneity Single Tg: Single phase Multiple Tgs: phase separation Mudunuri P. Ph.D. Thesis., 2007Vasanthavada M. et. al. Pharm. Res., 2004, 21(9), 1598Pharmaceutical Solid Form Screening, Characterization, and Selection70Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 71. DSC/MDSC (Solid-State Solubility) DSC is used to determine solubility of crystalline small moleculein polymerTend TendTgTend and Tg as a function of D-mannitol concentration in PVP Jing T. et al. Pharm. Res. 2009, 26(4) 855Pharmaceutical Solid Form Screening, Characterization, and Selection71Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 72. Solid Form Characterization (TAM)Pros Excellent isothermal condition High sensitivityCons Disturbance when the experiment starts Limited temperature rangeApplications Recrystallization(heat and/or moisture induced) Excipient compatibility Slow reactions Bystrom. Thermometric Application Note 22004, 1990Pharmaceutical Solid Form Screening, Characterization, and Selection72Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 73. Solid Form Characterization (Thermal-TGA) Thermogravimetric Analysis:Measures the thermally induced weight change of a material as afunction of temperature Ref Pan Sample Pan - provides information on volatile content - type of purge gas and purge rate can affect curveFurnacePurge GasPharmaceutical Solid Form Screening, Characterization, and Selection73Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 74. TGA (Dehydration / Desolvation)TGA is often used to measure the weight loss upon heating, from which stoichiometry of hydrate and solvate TGA be determined can Sample: Erythromycin A dihydrate Size: 24.3160 mg Method: to 200 @ 10 File: P:...GeoffEryA T06110301 Ery.2H2O Operator: Geoff Run Date: 11-Jun-2003 14:45 Comment: Lot 86-434-CDInstrument: 2950 TGA HR V5.3C 100 0.4M% weight loss 0.398 4.660% (1.133mg) Deriv. Weight (%/C)MWeight (%) MWSolventX =96 0.2100 MMWDrug94 0.1Ramp 10.00 C/min to 200.00 C920.0 2040 60 80100120140 160 180 200Temperature (C)Universal V4.0C TA InstrumentsPharmaceutical Solid Form Screening, Characterization, and Selection74Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 75. TGA (Degradation) TGA is often used to determine the thermal stability of sampleThermal profiles of polymers (PVC, PMMA, HDPE, PTFE, and PI) http://www.tainstruments.com/pdf/brochure/TGA_IR_Brochure.pdfPharmaceutical Solid Form Screening, Characterization, and Selection75Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 76. Solid Form Characterization (Thermal)Advantages:Small sample sizeInformation on melting point and phase transition (DSC)Information on enthalpy differenceStoichiometry for solvates and hydrates (TGA)Disadvantages: Destructive Method Thermal manipulation Interference (other components, thermal products, etc.) Black box (total heat exchange)Pharmaceutical Solid Form Screening, Characterization, and Selection76Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 77. Solid Form Characterization (Thermal) Hyphenated Thermal Techniques:Other techniques, e.g. microscopy, diffraction, and spectroscopy, are combined with thermal analysis methods to characterization solid phase changes Common Hyphenated Thermal Techniques: DSC/TGA Hot-stage Microscopy VT-PXRD TGA-MS, TGA-FTIR etc. Giron D. J of Therm Anal Calori, 2002. 68, 335Pharmaceutical Solid Form Screening, Characterization, and Selection77Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 78. Solid Form Characterization (Moisture Sorption)Determine moisture uptake at various water activity / Relative humidity Sorption Isotherm Types AA: monolayer adsorptionB: multi-layer adsorption BC: deliquescence CPharmaceutical Solid Form Screening, Characterization, and Selection78Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012 79. Solid Form Characterization (Moisture Sorption) Monitor formation of hydrates (Nedocromil Sodium)Sorption:90%RH: Heptahemi-hydrateDesorption:>10%RH: Heptahemi-hydrate