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Pharmaceutical Solid Form Screening, Characterization, and Selection - Yuchuan Gong

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<ul><li> 1. Pharmaceutical Solid FormScreening, Characterization,and SelectionEnhancing Drug Bioavailability and SolubilityYuchuan Gong, Ph.D.Boston, MA, Jan. 25, 2012</li></ul><p> 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 &lt; GI GIII &lt; 0Phase II is more stable Phase I II is a spontaneous processGII &gt; GI GIII &gt; 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 &lt; GI GIII &lt; 0Phase II is more stable Phase II has less solubilityGII &gt; GI GIII &gt; 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) &gt; aH 2O(g) or p &gt; pt , hydrate is more stable caH 2O(g) &lt; aH 2O(g) or p &lt; 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 &amp; 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: &gt; Form II: &gt;Form I:Stagner &amp; 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 &amp; 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-Aminosalicy...</p>