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Pharmaceutical Solid Form

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

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

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    Pharmaceutical Solid Form Pharmaceutical Solid Form Presentation Transcript

    • Pharmaceutical Solid FormScreening, Characterization,and SelectionEnhancing Drug Bioavailability and SolubilityYuchuan Gong, Ph.D.Boston, MA, Jan. 25, 2012
    • 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 Selection 2Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 Selection 3Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Why Solid? Solid is more stable than its liquid counterpart API’s are usually manufactured, transported, and stored as solid Most drugs are marketed in solid dosage forms Common Dosage Forms Phase of API in Drug Tablet solid Capsule solid, liquid Powder, granule solid Ointment, cream, gel solid Transdermal solid Suppository solid Solution liquid Disperse solid, liquidPharmaceutical Solid Form Screening, Characterization, and Selection 4Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Types of Solid Forms Solid long range order short range order Crystalline Liquid Crystalline Amorphous single multiple component components ionic non-ionicPolymorphs Salt + Molecular Adducts Solvate/Hydrate Co-crystalPharmaceutical Solid Form Screening, Characterization, and Selection 5Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Forms (Polymorphs)Polymorphs: crystalline forms with the same chemical composition but different internal structures (packing, conformation, etc.) Packing: Conformational: H-Bonding O OH Tautomeric: NH N More than 80% of the pharmaceutical solids exhibit polymorphsPharmaceutical Solid Form Screening, Characterization, and Selection 6Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Forms (Polymorphs) metastableThe thermodynamically most stable form of apharmaceutical solid is less soluble, but more stableA metastable polymorph is more soluble, but less stablestable RitonavirThe 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 Selection 7 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Forms (Solvates/Hydrates)Solvates / Hydrates Molecular adducts that incorporate solvent molecules in their crystal lattices; Solvent is water Hydrates Solvent is other solvents Solvates Non-solvated SolvatePharmaceutical Solid Form Screening, Characterization, and Selection 8Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 acid dimethylformamide …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 Selection 9Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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-organometallic compounds (3.8% of all) in Cambridge Crystallographic Database 3000 Number of Occurences 2500 2000 1500 1000 500 0 0.5 1 2 3 4 5 6 7 8 9 Hydration NumberPharmaceutical Solid Form Screening, Characterization, and Selection 10Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Forms (Hydrates) Hydrate is the most stable solid form in water, least soluble form in GI environment Non-hydrous solid form is usually favored over hydrates However, 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 Selection 11Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Forms (Salts / Co-crystals)Crystalline Salts and Co-crystals contain two or more components in the same lattice O O R R1 R R1 O- H N+ R2 O H N R2 Salt Co-crystal Differentiation is debatable: 1. Interaction between the components 2. Proton transferPharmaceutical Solid Form Screening, Characterization, and Selection 12Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Forms (Salts / Co-crystals)Salt / co-crystal formation of API are investigated ingreat frequency because Powder dissolutionCrystallization tool: PurificationProperty modification: Dissolution rate Chemical and physical stability Crystallinity Hygroscopicity Bulk 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 Selection 13Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 Selection 14Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Types of Solid Forms (Stoichiometry) Solid long range order short range order Crystalline Liquid Crystalline Amorphous single multiple component components ionic non-ionicPolymorphs Salt + Molecular Adducts Solvate/Hydrate Co-crystal stoichiometric non-stoichiometricPharmaceutical Solid Form Screening, Characterization, and Selection 15Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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/mol·K) Free Energy: measure of thermodynamic potential Enthalpy: Internal energy Entropy: measure of “disorderness”Pharmaceutical Solid Form Screening, Characterization, and Selection 16Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid State Thermodynamics (Polymorph) Why does the same chemical identity of different solid forms have different G? G = H – TS Enthalpy is the heat needed to create something from “nothingness” Therefore, different solid forms have different enthalpy due to different bonding/interactions between molecules in the solid forms Entropy 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 Selection 17Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid State Thermodynamics (Polymorph) Free energy: Only quantity that determines the thermodynamic relationship (relative stability) between phases ∆GIII = GII – GI = ∆HIII – T∆SIII GII < GI ⇒ ∆GIII < 0 Phase II is more stable ⇒ Phase I  II is a spontaneous process GII > GI ⇒ ∆GIII > 0 Phase II is less stable ⇒ Phase II  I is a spontaneous process GII = GI ⇒ ∆GIII = 0 Phase I and II is equally stable ⇒ Phase I and II are in equilibriumPharmaceutical Solid Form Screening, Characterization, and Selection 18Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid State Thermodynamics (Polymorph) Solubility (Activity): ∆GIII = GII – GI = RT ln(aII/aI) = RT ln(γIICsII/ γICsI) = RT ln(γII/γI·CsII/CsI) * In dilute solutions, γI = γII ≈ RT ln(CsII/CsI)* where CsI and CsII : solubility of solid form I and II; γI and γII : activity coefficients at CsI and CsII. GII < GI ⇒ ∆GIII < 0 Phase II is more stable ⇒ Phase II has less solubility GII > GI ⇒ ∆GIII > 0 Phase II is less stable ⇒ Phase II has higher solubility GII = GI ⇒ ∆GIII = 0 Phase I and II is equally stable ⇒ Phase I and II are in equilibriumPharmaceutical Solid Form Screening, Characterization, and Selection 19Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid State Thermodynamics (Polymorph) G liqu id CI Monotropic C II GI S b u o y t i l G E F G II g n e y r , G = H – TS T m, I T m, II Temperature, T Temperature, T∆GIII = ∆HIII – T∆SIII C II G liquid CI Enantiotropic S b u o y t i l G II G E F g n e y r , GI Tt T m, II T m, I Tt Temperature, T Temperature, T Pharmaceutical Solid Form Screening, Characterization, and Selection 20 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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) ]n c p Therefore Kd = = [aH 2O(g) ]n = [ pt ]n = [ RH ]n c [aD⋅nH 2O(s) ] s aH 2O(g) > aH 2O(g) or p > pt , hydrate is more stable c aH 2O(g) < aH 2O(g) or p < pt , anhydrate is more stable c aH 2O(g) = aH 2O(g) or p = pt , anhydrate and hydrate are c equally stable * Solvates are treated similarlyPharmaceutical Solid Form Screening, Characterization, and Selection 21Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid State Thermodynamics (Hydrate/Solvate)Relative stability of hydrates at various RH 9H2O Ouabain 100 Copper Sulfate 8H20 Penta % Weight Water Oubain.nH2O Tri 2H2O Mono 0 0 04.5 30 47 100 0 100 Relative Humidity Temperature (oC)Pharmaceutical Solid Form Screening, Characterization, and Selection 22Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid State Thermodynamics (Hydrate/Solvate) Temperature dependence of hydrate stability Apply van’t Hoff equation to Kd ∆H tr ln(a c H 2O(g) 2 ) − ln( a c ) =− H 2O(g) 1 nR ( T12 − T1 ) 1 Critical water activity increase with Higher T temperature Ln(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 T 1/T (1/K)Pharmaceutical Solid Form Screening, Characterization, and Selection 23Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid State Thermodynamics (Amorphous) Amorphous: “glass”, no long-range order between molecules Important concepts: uid Liq Tm – melting temperature Tg – glass transition temperature led oo erc up id S u Tk – Kauzmann temperature Liq G la ss 1 Re la xa tion 2 Gla ss Mobility m E V p a h n e u o y t , l C ryst a llin e Relaxation Crystallization Tk Tg Tm TemperaturePharmaceutical Solid Form Screening, Characterization, and Selection 24Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 Selection 25Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Impact of Solid Forms Different solid forms show different physical, chemical, and mechanical properties Melting point Stability (physical & chemical) Spectral properties Dissolution rate Solubility Bioavailability “Druggability” Density Hygroscopicity Hardness Bulk properties Crystal shape Manufacturability ….Pharmaceutical Solid Form Screening, Characterization, and Selection 26Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 Selection 27Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Impact of Solid Forms (Solubility)Sulfamerazine H2 N O N Me S NH O N Form I – Metastable Form II –Most Stable S Form I = 1.2 S Form II Solubility at 25oC Gong, et. al, 2008.Pharmaceutical Solid Form Screening, Characterization, and Selection 28Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Impact of Solid Forms (Dissolution) Whitney-Noyes equation: Driving force dM DS D S Cs = ( Cs − C ) ≈ dt h h Where 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: concentration Diffusion layer Bulk solution Concentration/solubility Solid State CS Cbulk Distance from Solid SurfacePharmaceutical Solid Form Screening, Characterization, and Selection 29Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Impact of Solid Forms (Dissolution) Iopanoic acid Powder dissolution Intrinsic dissolution Amorphous Amorphous Form II Form II Form I Form I Amorphous: > Form II: > Form I: Stagner & Guillory, 1963.Pharmaceutical Solid Form Screening, Characterization, and Selection 30Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Impact of Solid Forms (Dissolution)Succinyl sulfathiazole, in ~0.001 N H2SO4 solution at 20°C O N NH S O S O NH C CH 2 CH 2 CO 2 H Shefter & Huguchi , 1963.Pharmaceutical Solid Form Screening, Characterization, and Selection 31Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 Selection 32Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • dM DS = ( Cs − C ) ≈ D S C sImpact of Solid Forms (Dissolution) dt h h H2 Np-Aminosalicylic acid: antibacterial CO 2 H OH Parent Forbes et al, 1995Pharmaceutical Solid Form Screening, Characterization, and Selection 33Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Impact of Solid Forms (Dissolution) Dissolution enhancement of salt may be jeopardized by the precipitation of the parent API Solid State Diffusion layer Bulk solution pHmax HA A- A- HA BH+A-pH Solid A- HA HA A- pHbulk CS CSaltConcentration/solubility A- HA Cbulk CFA Distance from Solid Surface Pharmaceutical Solid Form Screening, Characterization, and Selection 34 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Impact of Solid Forms (Chemical Stability)Compound A FB: Photo-sensitive Forming crystalline salts can improve photo-stability of API at ambient temperaturesPharmaceutical Solid Form Screening, Characterization, and Selection 35Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Impact of Solid Forms (Morphology)Compound B  Morphology may have great impact on processing of API and formulationPharmaceutical Solid Form Screening, Characterization, and Selection 36Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 Selection 37Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Form Development Work Flow Hit Identification Crystallization of Parent Manual salt/co-crystal screening Hit Scale-Up Thermodynamically most stable form of hits Lead Identification Single Detailed SS characterization CrystalStructure Lead Scale-Up Lead Verification Pharmaceutical Evaluation Manufacturability Evaluation Solid Form Selection Polymorph Screening Pharmaceutical Solid Form Screening, Characterization, and Selection 38 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 = -0.6 Personal 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 Selection 39Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Salt/Cocrystal Screening (Crystallization)Common Crystallization Techniques• Reactive• Antisolvent addition Generate• Solvent evaporation Supersaturation• Temperature gradient• SlurryShould 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 perform crystallization at larger scale becomes increasingly important• Preferred industrial crystallization usually involves reactive, antisolvent, and temperature gradientPharmaceutical Solid Form Screening, Characterization, and Selection 40Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solution Crystallization Crystallization Nucleation 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
    • Crystallization (Solvent Evaporation)From a single solvent Advantage: Easy Column of solvent decreases Potential Problem: Concentration increases Evaporation rate is too high Solubility remains same Solubility is too high 100 10000 90 80 70 Concentration (mg/mL) Volume (mL) 60 50 1000 40 30 20 10 Supersaturation 0 100 S 0 2 4 6 8 10 0 2 4 6 8 10 Time (hr) Time (hr)Pharmaceutical Solid Form Screening, Characterization, and Selection 42Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Crystallization (Solvent Evaporation)From a solvent mixture Advantage: Volume of solvent decreases Adjustable solubility Dual effect on supersaturation Concentration of API increases Potential Problem: Solubility of API decreases Complex solvent system 100 250 Concentration Solubility 80 Concentration or Solubility (mg/mL) 200 Volume (mL) or % Solvent Bad Solvent (A) 60 150 40 100 Good Solvent (B) Supersaturation 20 Volume 50 Solvent A % Solvent B % 0 S 0 0 1 2 3 4 5 0 1 2 3 4 5 Time (hr) Time (hr)Pharmaceutical Solid Form Screening, Characterization, and Selection 43Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Crystallization (Heat & Cool)Heat & Cool Advantage: Temperature drops Moderate solubility Better yield Solubility of API decreases Potential Problem: Concentration remains same Degradation Concentration C0Temp Supersaturation S Time High Temp Low TempPharmaceutical Solid Form Screening, Characterization, and Selection 44Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Crystallization (Anti-solvent) Anti-solvent Advantage: More solvent options % bad solvent increases High yield Solubility of API decreases Potential Problem: Concentration of API decreases Complex solvent system Titration rate S Concentration ABad Solvent % B Supersaturation Time Good Solvent %Pharmaceutical Solid Form Screening, Characterization, and Selection 45Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Crystallization (pH Adjustment)pH Adjustment (Salt formation) At higher pH, apparent solubility of ionic API increases At pH > pHmax, concentration of API > Solubility of salt Driving force of the crystallization of the salt increases Supersaturation Ssalt pKa pHmaxPharmaceutical Solid Form Screening, Characterization, and Selection 46Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Crystallization (SMPT)Solution-Mediated Solution Concentration SMetastable Phase Transformation SStable GI > GII CI > CII Slurry of I 1 2 3 100% Metastable Phase Solid Composition Supersaturation of II Crystallization of II 100% Stable Phase TimePharmaceutical Solid Form Screening, Characterization, and Selection 47Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Crystallization (SMPT) Crystallization of Hydrate: various water activity Co-crystal: maximum co-crystal former activity Identity of the Crystal FormIdentity of the Crystal Form Drug stable Co-crystal Hydrate region stable region Co-crystal Critical Water Critical Co-crystal Activity (aw,c) Former Activity (aCCF,c) Anhydrate Drug 0 (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
    • 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 trying”Pharmaceutical Solid Form Screening, Characterization, and Selection 49Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Form Development Work Flow Hit Identification Crystallization of Parent Manual salt/co-crystal screening Hit Scale-Up Thermodynamically most stable form of hits Lead Identification Single Detailed SS characterization CrystalStructure Lead Scale-Up Lead Verification Pharmaceutical Evaluation Manufacturability Evaluation Solid Form Selection Polymorph Screening Pharmaceutical Solid Form Screening, Characterization, and Selection 50 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Form CharacterizationCrystalline solids Characterizations Techniques Chemical identity NMR, IC Crystalline solid form identification Microscopy, PXRD, Raman, IR, DSC Melting temperature DSC Morphology Microscopy Solvate/hydrate identification DSC, TGA/MS, PXRD Hygroscopicity Moisture sorption balance Dissolution rate µ-DissAmorphous solids Physical stability assessment (Tg, relaxation kinetics, crystallization kinetics)Pharmaceutical Solid Form Screening, Characterization, and Selection 51Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Form Characterization (PXRD) Bragg’s Law 2d sin θ = nλ Each d corresponds to a θ θ d dsinθ θ’ d’ dsinθ’Pharmaceutical Solid Form Screening, Characterization, and Selection 52Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 Selection 53Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Form Characterization (PXRD) Be very careful with two solids having “same” PXRD patterns Are they really “same” or “very similar”?Pharmaceutical Solid Form Screening, Characterization, and Selection 54Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 Selection 55Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 Selection 56Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 Selection 57Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Form Characterization (Thermal) Advantages: • Small sample size • Information on melting point and phase transition (DSC) • Information on enthalpy difference • Stoichiometry 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 Selection 58Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Form Characterization (Thermal-DSC)DSC is used to monitor heat exchange when the sample isheated/cooled or maintained isothermally Endothermic Events Exothermic Events Solid-solid transitions Solid-solid transitions Degradation Degradation Melting, boiling, sublimation, vaporization Crystallization Desolvation Baseline Shift Glass transitionPharmaceutical Solid Form Screening, Characterization, and Selection 59Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 Selection 60Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • DSC (Melting)DSC is commonly used to measure melting temperature of crystallinesolids Sample: Indium File: S:3SGongINDIUM.001 Size: 3.2640 x 0.0000 mg DSC Operator: YG Method: Temperature (°C) Run Date: 24-Apr-2008 14:59Melting Point: Comment: Cell constant calibration Tm of Indium Instrument: DSC Q2000 V24.2 Build 107 – Sharpness reflects the 0 158.03°C 28.42J/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 158.76°C transition, etc.) and -4 145 155 165 chemical processes Exo Up Temperature (°C) Universal V4.4A TA Instru (decomposition etc.)Pharmaceutical Solid Form Screening, Characterization, and Selection 61Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • DSC (Heat of fusion) DSC is commonly used to measure the heat of fusion of a crystalline solid Sample: Indium File: S:3SGongINDIUM.001 Size: 3.2640 x 0.0000 mg DSC 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 0 158.03°C 28.42J/g Heat of Fusion: – Integrated area under -1 ∆Hf melting curve Heat Flow (W/g) – May overlap with -2 recrystallization – May overlap with -3 decomposition and 158.76°C sublimation -4 145 155 165 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
    • DSC (Melting without decomposition) Melting is a thermodynamic phenomenon, therefore, melting point does not change much with heating rate Higher heating rate Same Tm Thomas, L. http://www.tainstruments.com/pdf/literature/TA315.pdfPharmaceutical Solid Form Screening, Characterization, and Selection 63Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • DSC (Melting with decomposition) Decomposition is a kinetic phenomenon, therefore, melting/decomposition temperature changes with heating rate Higher heating rate Higher “Tm” Thomas, L. http://www.tainstruments.com/pdf/literature/TA315.pdfPharmaceutical Solid Form Screening, Characterization, and Selection 64Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • DSC (Dehydration/desolvation) DSC is used to determine dehydration/desolvation Carbamazepine dihydrate- Usually at lower temperatures- Large enthalpy because of the evaporation of released water/solvent- May result in lower hydrates, anhydrous phases, or amorphous phase Li Y. et al., Pharm. Dev. Tech., 2000. 5, 257.Pharmaceutical Solid Form Screening, Characterization, and Selection 65Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • DSC (Polymorphism)Different polymorphs usually have different melting temperatures and heat of fusions Monotropic Enantiotropic HL HL ∆H f, II ∆H f, I ∆H f, I ∆H f, II HI HI G liquid G liquid H II H II T m, I T m, II G H E g e n y Tt ) ( r , Tt G H E T m, II g e n G II y G II ) ( r , GI T m, I GI Temperature, T Temperature, T Heat of Fusion Rule higher melting form; higher ∆Hf higher melting form; lower ∆HfPharmaceutical Solid Form Screening, Characterization, and Selection 66Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • DSC (Polymorphism) II Phase transitions of IIL Monotropic Polymorphs LII I IL IIL HL ∆H f, II I ILII ∆H f, I HI G liquid IIL H II I III T m, I IIL TtGHE T m, IIgeny G II)(r, GI Temperature, T Pharmaceutical Solid Form Screening, Characterization, and Selection 67 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • DSC (Polymorphism) II III IL Phase transitions of Enantiotropic Polymorphs I IL LI HL II IL ∆H f, I IIL ∆H f, II HI G liquid II IILI IL H II I III III T m, IIGHEgeny)(r, Tt G II IL T m, I GI Temperature, T Pharmaceutical Solid Form Screening, Characterization, and Selection 68 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 components Mudunuri P. Ph.D. Thesis., 2007 Paul G. et. al. Pharm. Res., 1998, 15(7), 1117Pharmaceutical Solid Form Screening, Characterization, and Selection 69Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • MDSC (Glass transition, Phase separation) MDSC reversing heat flow scans of trehalose-dextran mixture (40/60) stored 50oC/75%RH 34 days 23 days 13 days 4 days 2 days Measured Tg can be used to determine 0 day phase homogeneity Single Tg: Single phase Multiple Tg’s: phase separation Mudunuri P. Ph.D. Thesis., 2007 Vasanthavada M. et. al. Pharm. Res., 2004, 21(9), 1598Pharmaceutical Solid Form Screening, Characterization, and Selection 70Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • DSC/MDSC (Solid-State Solubility) DSC is used to determine solubility of crystalline small molecule in polymer Tend Tend Tg Tend 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 Selection 71Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 Selection 72Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Form Characterization (Thermal-TGA) Thermogravimetric Analysis: Measures the thermally induced weight change of a material as a function of temperature Ref Pan Sample Pan - provides information on volatile content - type of purge gas and purge rate can affect curve Furnace Purge GasPharmaceutical Solid Form Screening, Characterization, and Selection 73Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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-CD Instrument: 2950 TGA HR V5.3C 100 0.4 M% weight loss 0.3 98 4.660% (1.133mg) Deriv. Weight (%/°C) M Weight (%) MWSolventX = 96 0.2 100− M MWDrug 94 0.1 Ramp 10.00 °C/min to 200.00 °C 92 0.0 20 40 60 80 100 120 140 160 180 200 Temperature (°C) Universal V4.0C TA InstrumentsPharmaceutical Solid Form Screening, Characterization, and Selection 74Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • TGA (Degradation) TGA is often used to determine the thermal stability of sample Thermal profiles of polymers (PVC, PMMA, HDPE, PTFE, and PI) http://www.tainstruments.com/pdf/brochure/TGA_IR_Brochure.pdfPharmaceutical Solid Form Screening, Characterization, and Selection 75Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Form Characterization (Thermal) Advantages: • Small sample size • Information on melting point and phase transition (DSC) • Information on enthalpy difference • Stoichiometry 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 Selection 76Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • 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 Selection 77Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Form Characterization (Moisture Sorption)Determine moisture uptake at various water activity / Relative humidity Sorption Isotherm Types A A: monolayer adsorption B: multi-layer adsorption B C: deliquescence CPharmaceutical Solid Form Screening, Characterization, and Selection 78Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Form Characterization (Moisture Sorption) Monitor formation of hydrates (Nedocromil Sodium) Sorption: <10%RH : monohydrate 10% - 90%RH: Trihydrate >90%RH: Heptahemi-hydrate Desorption: >10%RH: Heptahemi-hydrate <10%RH: monohydratePharmaceutical Solid Form Screening, Characterization, and Selection 79Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Form Development Work Flow Hit Identification Crystallization of Parent Manual salt/co-crystal screening Hit Scale-Up Thermodynamically most stable form of hits Lead Identification Single Detailed SS characterization CrystalStructure Lead Scale-Up Lead Verification Pharmaceutical Evaluation Manufacturability Evaluation Solid Form Selection Polymorph Screening Pharmaceutical Solid Form Screening, Characterization, and Selection 80 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid State Selection• Solid state PXRD Moisture sorption DSC isotherm – is highly crystalline Polymorph, solvate, – is not hygroscopic (<2% weight across 0-80% RH) hydrate screening and characterization – has a melting point > 150 °C DSC – does not exhibit complex polymorphic behavior or solvate formation – does not have a labile hydrate TGA – is physically stable In vitro: solubility, Stable at ambient dissolution, physical conditions stability in suspension• Pharmaceutical In vivo (animal) – is bioavailable (sufficient dissolution rate/solubility) – is chemically stable Screen solvents for solubility Accelerated Evaluate feasibility at smaller scale stability Initial assessment of control: induction time,• Manufacturing desupersaturation rate, size and distribution – Can be prepared in large scale with robust stoichiometric control and acceptable yield, volume, and purity (chemical and physical) – does not exhibit a strongly anisotropic morphology (needle/flask)Pharmaceutical Solid Form Screening, Characterization, and Selection 81Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Decision Making (Solid From Selection) StabilityCross-functional DecisionSome key properties are inter-related Hygroscopicity Crystallinity• Crystallinity & HygroscopcityCertain properties have higher priority Apparent Solubility• Chemical stability v.s. Polymorphism Dissolution RateProject/Compound specific properties• Dissolution enhancement (insoluble API)• Chemical stability (strong amines)Candidates with good properties all-around is a “no-brainer”. But,Balancing/compromising is often required• “Must have” vs. “nice to have”• Formulation/delivery: parent vs. saltPharmaceutical Solid Form Screening, Characterization, and Selection 82Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Approaches: Early vs. LateHow early is early?• Before the nomination of the development candidatePros and Cons• Pros (Early) – less likely to switch salt during later development – better definition of formulation approach at candidate nomination – likely to enable fast formulation development• Cons (Early) – Resources could be “wasted” – Less flexibility in formulation design and process selectionPharmaceutical Solid Form Screening, Characterization, and Selection 83Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Approaches: Integrated v.s. Tiered Integrated Tiered salt 1 salt 2 salt 3 salt 4 Tier 1 Crystallinity crystallinity Crystallization from different solvents Aqueous solubility hygroscopicity Tier 2 Evaluation of crystalline form melting point Thermal properties polymorphism Hygroscopicity physical stability Tier 3 humidity/temperature-dependent solubility/dissolution changes in crystal form chemical stability Tier 4 bioavailability screening stress stability manufacturability scale-up considerationsPros and Cons Morris et al, 1994• Pros (Integrated) Serajuddin and Pudipeddi, 2008 – Polymorphism considered early – Fair comparison among the candidates• Cons (Integrated) Polymorph screening – Resource-intensive, time-consuming, and material consumptionThe “best” approaches will lay between the two extremes – Timing, intrinsic properties of the compound, availability of material……Pharmaceutical Solid Form Screening, Characterization, and Selection 84Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Approaches: Robotic vs. ManualPros and Cons• Pros (Robotic) – Hundreds of salts/cocrystals crystallization simultaneously – Less labor• Cons (Robotic) – Many unsuccessful crystallization – Less characterization, especially the confirmation of the chemical make-up – Requires more material for typical compounds Based on material availability Develop new robotic methodsPharmaceutical Solid Form Screening, Characterization, and Selection 85Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Solid Form Development Work Flow Hit Identification Crystallization of Parent Manual salt/co-crystal screening Hit Scale-Up Thermodynamically most stable form of hits Lead Identification Single Detailed SS characterization CrystalStructure Lead Scale-Up Lead Verification Pharmaceutical Evaluation Manufacturability Evaluation Solid Form Selection Polymorph Screening Pharmaceutical Solid Form Screening, Characterization, and Selection 86 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • Polymorph ScreeningPharmaceutical Solid Form Screening, Characterization, and Selection 87Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
    • SummaryScreening, characterizing, and selecting a solid form is an essential/criticaltask in drug product developmentLogical screening and selection processes will result in good solid formswith less material, time, and labor; ultimately efficiency in solid formselection and formulation developmentSolid form selection has strong impact on the product development due tovarious pharmaceutically relevant properties of solid forms – Solid state, pharmaceutical, manufacturing propertiesCommunication – Multi-functional team, requires constant dialogue/discussion/negotiation within the teamThe future of solid form selection:Incorporate formulation/processing (i.e. Materials Science) considerationsPharmaceutical Solid Form Screening, Characterization, and Selection 88Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
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