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Solubility boston-2012-published

The document discusses different types of solid forms that active pharmaceutical ingredients can take, including polymorphs, solvates, hydrates, salts, co-crystals, and the amorphous form. It notes that over 80% of pharmaceutical solids exhibit polymorphism. The thermodynamically most stable polymorph is generally preferred for stability reasons, though a metastable polymorph may be developed to provide a balance between processability and stability. Hydrates and solvates are discussed, with hydrates being the most common type of solvate. Salt and co-crystal formation can impact properties like dissolution and stability. The amorphous form lacks long-range order.

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Pharmaceutical Solid Form Screening, Characterization, and Selection Enhancing Drug Bioavailability and Solubility Yuchuan 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 Selection Pharmaceutical Solid Form Screening, Characterization, and Selection 2 Enhancing 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 Selection Pharmaceutical Solid Form Screening, Characterization, and Selection 3 Enhancing 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, liquid Pharmaceutical Solid Form Screening, Characterization, and Selection 4 Enhancing 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-ionic Polymorphs Salt + Molecular Adducts Solvate/Hydrate Co-crystal Pharmaceutical Solid Form Screening, Characterization, and Selection 5 Enhancing 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 polymorphs Pharmaceutical Solid Form Screening, Characterization, and Selection 6 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
Solid Forms (Polymorphs) metastable The thermodynamically most stable form of a pharmaceutical solid is less soluble, but more stable A metastable polymorph is more soluble, but less stable stable Ritonavir The thermodynamically most stable form of a pharmaceutical solid is normally preferred on account of its greatest stability A metastable polymorph is sometimes developed, when it can provide an acceptable 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 Solvate Pharmaceutical Solid Form Screening, Characterization, and Selection 8 Enhancing 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 form Pharmaceutical Solid Form Screening, Characterization, and Selection 9 Enhancing 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 Number Pharmaceutical Solid Form Screening, Characterization, and Selection 10 Enhancing 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 API Pharmaceutical Solid Form Screening, Characterization, and Selection 11 Enhancing 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 transfer Pharmaceutical Solid Form Screening, Characterization, and Selection 12 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
Solid Forms (Salts / Co-crystals) Salt / co-crystal formation of API are investigated in great frequency because Powder dissolution Crystallization tool: Purification Property 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 13 Enhancing 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, 2004 Pharmaceutical Solid Form Screening, Characterization, and Selection 14 Enhancing 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-ionic Polymorphs Salt + Molecular Adducts Solvate/Hydrate Co-crystal stoichiometric non-stoichiometric Pharmaceutical Solid Form Screening, Characterization, and Selection 15 Enhancing 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 16 Enhancing 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 disorder Pharmaceutical Solid Form Screening, Characterization, and Selection 17 Enhancing 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 equilibrium Pharmaceutical Solid Form Screening, Characterization, and Selection 18 Enhancing 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 equilibrium Pharmaceutical Solid Form Screening, Characterization, and Selection 19 Enhancing 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 similarly Pharmaceutical Solid Form Screening, Characterization, and Selection 21 Enhancing 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 22 Enhancing 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 23 Enhancing 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 Temperature Pharmaceutical Solid Form Screening, Characterization, and Selection 24 Enhancing 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 Selection Pharmaceutical Solid Form Screening, Characterization, and Selection 25 Enhancing 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 26 Enhancing 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 Solubility Pharmaceutical Solid Form Screening, Characterization, and Selection 27 Enhancing 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 28 Enhancing 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 Surface Pharmaceutical Solid Form Screening, Characterization, and Selection 29 Enhancing 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 30 Enhancing 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 31 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
Impact of Solid Forms (Dissolution) Salt 2 Salt 1 pKa pHmax Substantial increase in apparent solubility by salt formation, which will lead to the enhancement in dissolution rate Different salt forms will have different extent of apparent solubility improvement Pharmaceutical Solid Form Screening, Characterization, and Selection 32 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
dM DS = ( Cs − C ) ≈ D S C s Impact of Solid Forms (Dissolution) dt h h H2 N p-Aminosalicylic acid: antibacterial CO 2 H OH Parent Forbes et al, 1995 Pharmaceutical Solid Form Screening, Characterization, and Selection 33 Enhancing 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 CSalt Concentration/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 temperatures Pharmaceutical Solid Form Screening, Characterization, and Selection 35 Enhancing 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 formulation Pharmaceutical Solid Form Screening, Characterization, and Selection 36 Enhancing 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 Selection Pharmaceutical Solid Form Screening, Characterization, and Selection 37 Enhancing 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 Crystal Structure 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 consideration Cocrystals: hydrogen bonding potential Salts: 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 differences Pharmaceutical Solid Form Screening, Characterization, and Selection 39 Enhancing 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 • Slurry Should 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 gradient Pharmaceutical Solid Form Screening, Characterization, and Selection 40 Enhancing 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 42 Enhancing 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 43 Enhancing 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 C0 Temp Supersaturation S Time High Temp Low Temp Pharmaceutical Solid Form Screening, Characterization, and Selection 44 Enhancing 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 A Bad Solvent % B Supersaturation Time Good Solvent % Pharmaceutical Solid Form Screening, Characterization, and Selection 45 Enhancing 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 pHmax Pharmaceutical Solid Form Screening, Characterization, and Selection 46 Enhancing 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 Time Pharmaceutical Solid Form Screening, Characterization, and Selection 47 Enhancing 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 Form Identity 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 49 Enhancing 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 Crystal Structure 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 Characterization Crystalline 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-Diss Amorphous solids Physical stability assessment (Tg, relaxation kinetics, crystallization kinetics) Pharmaceutical Solid Form Screening, Characterization, and Selection 51 Enhancing 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 52 Enhancing 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 pattern Pharmaceutical Solid Form Screening, Characterization, and Selection 53 Enhancing 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 54 Enhancing 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 > IPA Pharmaceutical Solid Form Screening, Characterization, and Selection 55 Enhancing 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 ions Pharmaceutical Solid Form Screening, Characterization, and Selection 56 Enhancing 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 Stable Pharmaceutical Solid Form Screening, Characterization, and Selection 57 Enhancing 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 58 Enhancing 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 is heated/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 transition Pharmaceutical Solid Form Screening, Characterization, and Selection 59 Enhancing 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 60 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
DSC (Melting) DSC is commonly used to measure melting temperature of crystalline solids 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 Melting 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 61 Enhancing 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 Instruments Pharmaceutical Solid Form Screening, Characterization, and Selection 62 Enhancing 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.pdf Pharmaceutical Solid Form Screening, Characterization, and Selection 63 Enhancing 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.pdf Pharmaceutical Solid Form Screening, Characterization, and Selection 64 Enhancing 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 65 Enhancing 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 ∆Hf Pharmaceutical Solid Form Screening, Characterization, and Selection 66 Enhancing 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 Tt G H E T m, II g e n y 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, II G H E g e n y ) ( 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), 1117 Pharmaceutical Solid Form Screening, Characterization, and Selection 69 Enhancing 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), 1598 Pharmaceutical Solid Form Screening, Characterization, and Selection 70 Enhancing 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) 855 Pharmaceutical Solid Form Screening, Characterization, and Selection 71 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
Solid Form Characterization (TAM) Pros • Excellent isothermal condition • High sensitivity Cons • Disturbance when the experiment starts • Limited temperature range Applications • Recrystallization (heat and/or moisture induced) • Excipient compatibility • Slow reactions Bystrom. Thermometric Application Note 22004, 1990 Pharmaceutical Solid Form Screening, Characterization, and Selection 72 Enhancing 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 Gas Pharmaceutical Solid Form Screening, Characterization, and Selection 73 Enhancing 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 (%) MWSolvent X = 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 Instruments Pharmaceutical Solid Form Screening, Characterization, and Selection 74 Enhancing 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.pdf Pharmaceutical Solid Form Screening, Characterization, and Selection 75 Enhancing 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 76 Enhancing 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, 335 Pharmaceutical Solid Form Screening, Characterization, and Selection 77 Enhancing 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 C Pharmaceutical Solid Form Screening, Characterization, and Selection 78 Enhancing 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: monohydrate Pharmaceutical Solid Form Screening, Characterization, and Selection 79 Enhancing 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 Crystal Structure 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 81 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
Decision Making (Solid From Selection) Stability Cross-functional Decision Some key properties are inter-related Hygroscopicity Crystallinity • Crystallinity & Hygroscopcity Certain properties have higher priority Apparent Solubility • Chemical stability v.s. Polymorphism Dissolution Rate Project/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. salt Pharmaceutical Solid Form Screening, Characterization, and Selection 82 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
Approaches: Early vs. Late How early is early? • Before the nomination of the development candidate Pros 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 selection Pharmaceutical Solid Form Screening, Characterization, and Selection 83 Enhancing 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 considerations Pros 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 consumption The “best” approaches will lay between the two extremes – Timing, intrinsic properties of the compound, availability of material…… Pharmaceutical Solid Form Screening, Characterization, and Selection 84 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
Approaches: Robotic vs. Manual Pros 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 methods Pharmaceutical Solid Form Screening, Characterization, and Selection 85 Enhancing 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 Crystal Structure 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 Screening Pharmaceutical Solid Form Screening, Characterization, and Selection 87 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
Summary Screening, characterizing, and selecting a solid form is an essential/critical task in drug product development Logical screening and selection processes will result in good solid forms with less material, time, and labor; ultimately efficiency in solid form selection and formulation development Solid form selection has strong impact on the product development due to various pharmaceutically relevant properties of solid forms – Solid state, pharmaceutical, manufacturing properties Communication – Multi-functional team, requires constant dialogue/discussion/negotiation within the team The future of solid form selection: Incorporate formulation/processing (i.e. Materials Science) considerations Pharmaceutical Solid Form Screening, Characterization, and Selection 88 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
89

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Solubility boston-2012-published

  • 1.
    Pharmaceutical Solid Form Screening,Characterization, and Selection Enhancing Drug Bioavailability and Solubility Yuchuan 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 Selection Pharmaceutical Solid Form Screening, Characterization, and Selection 2 Enhancing 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 Selection Pharmaceutical Solid Form Screening, Characterization, and Selection 3 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 4.
    Why Solid? Solidis 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, liquid Pharmaceutical Solid Form Screening, Characterization, and Selection 4 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 5.
    Types of SolidForms Solid long range order short range order Crystalline Liquid Crystalline Amorphous single multiple component components ionic non-ionic Polymorphs Salt + Molecular Adducts Solvate/Hydrate Co-crystal Pharmaceutical Solid Form Screening, Characterization, and Selection 5 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 6.
    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 polymorphs Pharmaceutical Solid Form Screening, Characterization, and Selection 6 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 7.
    Solid Forms (Polymorphs) metastable The thermodynamically most stable form of a pharmaceutical solid is less soluble, but more stable A metastable polymorph is more soluble, but less stable stable Ritonavir The thermodynamically most stable form of a pharmaceutical solid is normally preferred on account of its greatest stability A metastable polymorph is sometimes developed, when it can provide an acceptable balance between processability and stability Pharmaceutical Solid Form Screening, Characterization, and Selection 7 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 solvents Solvates Non-solvated Solvate Pharmaceutical Solid Form Screening, Characterization, and Selection 8 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 9.
    Solid Forms (Solvates) Commonorganic 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 form Pharmaceutical Solid Form Screening, Characterization, and Selection 9 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 10.
    Solid Forms (Hydrates) Organiccompounds 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 Number Pharmaceutical Solid Form Screening, Characterization, and Selection 10 Enhancing 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 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 API Pharmaceutical Solid Form Screening, Characterization, and Selection 11 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 12.
    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 transfer Pharmaceutical Solid Form Screening, Characterization, and Selection 12 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 13.
    Solid Forms (Salts/ Co-crystals) Salt / co-crystal formation of API are investigated in great frequency because Powder dissolution Crystallization tool: Purification Property 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 13 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 14.
    Solid Forms (Amorphous) Amorphoussolid 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, 2004 Pharmaceutical Solid Form Screening, Characterization, and Selection 14 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 15.
    Types of SolidForms (Stoichiometry) Solid long range order short range order Crystalline Liquid Crystalline Amorphous single multiple component components ionic non-ionic Polymorphs Salt + Molecular Adducts Solvate/Hydrate Co-crystal stoichiometric non-stoichiometric Pharmaceutical Solid Form Screening, Characterization, and Selection 15 Enhancing 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/mol·K) Free Energy: measure of thermodynamic potential Enthalpy: Internal energy Entropy: measure of “disorderness” Pharmaceutical Solid Form Screening, Characterization, and Selection 16 Enhancing 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 – 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 disorder Pharmaceutical Solid Form Screening, Characterization, and Selection 17 Enhancing 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 ∆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 equilibrium Pharmaceutical Solid Form Screening, Characterization, and Selection 18 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 19.
    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 equilibrium Pharmaceutical Solid Form Screening, Characterization, and Selection 19 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 20.
    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
  • 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) ]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 similarly Pharmaceutical Solid Form Screening, Characterization, and Selection 21 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 22.
    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 22 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 23.
    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 23 Enhancing 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: 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 Temperature Pharmaceutical Solid Form Screening, Characterization, and Selection 24 Enhancing 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 Selection Pharmaceutical Solid Form Screening, Characterization, and Selection 25 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 26.
    Impact of SolidForms 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 26 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 27.
    Impact of SolidForms (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 Solubility Pharmaceutical Solid Form Screening, Characterization, and Selection 27 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 28.
    Impact of SolidForms (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 28 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 29.
    Impact of SolidForms (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 Surface Pharmaceutical Solid Form Screening, Characterization, and Selection 29 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 30.
    Impact of SolidForms (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 30 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 31.
    Impact of SolidForms (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 31 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 32.
    Impact of SolidForms (Dissolution) Salt 2 Salt 1 pKa pHmax Substantial increase in apparent solubility by salt formation, which will lead to the enhancement in dissolution rate Different salt forms will have different extent of apparent solubility improvement Pharmaceutical Solid Form Screening, Characterization, and Selection 32 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 33.
    dM DS = ( Cs − C ) ≈ D S C s Impact of Solid Forms (Dissolution) dt h h H2 N p-Aminosalicylic acid: antibacterial CO 2 H OH Parent Forbes et al, 1995 Pharmaceutical Solid Form Screening, Characterization, and Selection 33 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 34.
    Impact of SolidForms (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 CSalt Concentration/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
  • 35.
    Impact of SolidForms (Chemical Stability) Compound A FB: Photo-sensitive Forming crystalline salts can improve photo-stability of API at ambient temperatures Pharmaceutical Solid Form Screening, Characterization, and Selection 35 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 36.
    Impact of SolidForms (Morphology) Compound B  Morphology may have great impact on processing of API and formulation Pharmaceutical Solid Form Screening, Characterization, and Selection 36 Enhancing 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 Selection Pharmaceutical Solid Form Screening, Characterization, and Selection 37 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 38.
    Solid Form DevelopmentWork 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 Crystal Structure 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
  • 39.
    Salt/Cocrystal Screening (GuestSelection) Safety is the overriding consideration Cocrystals: hydrogen bonding potential Salts: 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 differences Pharmaceutical Solid Form Screening, Characterization, and Selection 39 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 40.
    Salt/Cocrystal Screening (Crystallization) CommonCrystallization Techniques • Reactive • Antisolvent addition Generate • Solvent evaporation Supersaturation • Temperature gradient • Slurry Should 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 gradient Pharmaceutical Solid Form Screening, Characterization, and Selection 40 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 41.
    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
  • 42.
    Crystallization (Solvent Evaporation) Froma 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 42 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 43.
    Crystallization (Solvent Evaporation) Froma 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 43 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 44.
    Crystallization (Heat &Cool) Heat & Cool Advantage: Temperature drops Moderate solubility Better yield Solubility of API decreases Potential Problem: Concentration remains same Degradation Concentration C0 Temp Supersaturation S Time High Temp Low Temp Pharmaceutical Solid Form Screening, Characterization, and Selection 44 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 45.
    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 A Bad Solvent % B Supersaturation Time Good Solvent % Pharmaceutical Solid Form Screening, Characterization, and Selection 45 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 46.
    Crystallization (pH Adjustment) pHAdjustment (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 pHmax Pharmaceutical Solid Form Screening, Characterization, and Selection 46 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 47.
    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 Time Pharmaceutical Solid Form Screening, Characterization, and Selection 47 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 48.
    Crystallization (SMPT) Crystallization of Hydrate: various water activity Co-crystal: maximum co-crystal former activity Identity of the Crystal Form Identity 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
  • 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 trying” Pharmaceutical Solid Form Screening, Characterization, and Selection 49 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 50.
    Solid Form DevelopmentWork 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 Crystal Structure 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
  • 51.
    Solid Form Characterization Crystallinesolids 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-Diss Amorphous solids Physical stability assessment (Tg, relaxation kinetics, crystallization kinetics) Pharmaceutical Solid Form Screening, Characterization, and Selection 51 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 52.
    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 52 Enhancing 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 pattern Pharmaceutical Solid Form Screening, Characterization, and Selection 53 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 54.
    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 54 Enhancing 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 > IPA Pharmaceutical Solid Form Screening, Characterization, and Selection 55 Enhancing 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 ions Pharmaceutical Solid Form Screening, Characterization, and Selection 56 Enhancing 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 Stable Pharmaceutical Solid Form Screening, Characterization, and Selection 57 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 58.
    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 58 Enhancing 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 is heated/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 transition Pharmaceutical Solid Form Screening, Characterization, and Selection 59 Enhancing 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 Selection 60 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 61.
    DSC (Melting) DSC iscommonly used to measure melting temperature of crystalline solids 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 Melting 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 61 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 62.
    DSC (Heat offusion) 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 Instruments Pharmaceutical Solid Form Screening, Characterization, and Selection 62 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 63.
    DSC (Melting withoutdecomposition) 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.pdf Pharmaceutical Solid Form Screening, Characterization, and Selection 63 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 64.
    DSC (Melting withdecomposition) 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.pdf Pharmaceutical Solid Form Screening, Characterization, and Selection 64 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 65.
    DSC (Dehydration/desolvation) DSCis 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 65 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 66.
    DSC (Polymorphism) Different polymorphsusually 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 ∆Hf Pharmaceutical Solid Form Screening, Characterization, and Selection 66 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 67.
    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 Tt G H E T m, II g e n y 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
  • 68.
    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, II G H E g e n y ) ( 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
  • 69.
    MDSC (Theory) ModulatedDSC (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), 1117 Pharmaceutical Solid Form Screening, Characterization, and Selection 69 Enhancing 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%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), 1598 Pharmaceutical Solid Form Screening, Characterization, and Selection 70 Enhancing 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 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) 855 Pharmaceutical Solid Form Screening, Characterization, and Selection 71 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 72.
    Solid Form Characterization(TAM) Pros • Excellent isothermal condition • High sensitivity Cons • Disturbance when the experiment starts • Limited temperature range Applications • Recrystallization (heat and/or moisture induced) • Excipient compatibility • Slow reactions Bystrom. Thermometric Application Note 22004, 1990 Pharmaceutical Solid Form Screening, Characterization, and Selection 72 Enhancing 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 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 Gas Pharmaceutical Solid Form Screening, Characterization, and Selection 73 Enhancing 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-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 (%) MWSolvent X = 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 Instruments Pharmaceutical Solid Form Screening, Characterization, and Selection 74 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 75.
    TGA (Degradation) TGAis 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.pdf Pharmaceutical Solid Form Screening, Characterization, and Selection 75 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 76.
    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 76 Enhancing 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, 335 Pharmaceutical Solid Form Screening, Characterization, and Selection 77 Enhancing 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 A A: monolayer adsorption B: multi-layer adsorption B C: deliquescence C Pharmaceutical Solid Form Screening, Characterization, and Selection 78 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 79.
    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: monohydrate Pharmaceutical Solid Form Screening, Characterization, and Selection 79 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 80.
    Solid Form DevelopmentWork 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 Crystal Structure 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
  • 81.
    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 81 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 82.
    Decision Making (SolidFrom Selection) Stability Cross-functional Decision Some key properties are inter-related Hygroscopicity Crystallinity • Crystallinity & Hygroscopcity Certain properties have higher priority Apparent Solubility • Chemical stability v.s. Polymorphism Dissolution Rate Project/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. salt Pharmaceutical Solid Form Screening, Characterization, and Selection 82 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 83.
    Approaches: Early vs.Late How early is early? • Before the nomination of the development candidate Pros 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 selection Pharmaceutical Solid Form Screening, Characterization, and Selection 83 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 84.
    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 considerations Pros 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 consumption The “best” approaches will lay between the two extremes – Timing, intrinsic properties of the compound, availability of material…… Pharmaceutical Solid Form Screening, Characterization, and Selection 84 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 85.
    Approaches: Robotic vs.Manual Pros 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 methods Pharmaceutical Solid Form Screening, Characterization, and Selection 85 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 86.
    Solid Form DevelopmentWork 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 Crystal Structure 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
  • 87.
    Polymorph Screening Pharmaceutical SolidForm Screening, Characterization, and Selection 87 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 88.
    Summary Screening, characterizing, andselecting a solid form is an essential/critical task in drug product development Logical screening and selection processes will result in good solid forms with less material, time, and labor; ultimately efficiency in solid form selection and formulation development Solid form selection has strong impact on the product development due to various pharmaceutically relevant properties of solid forms – Solid state, pharmaceutical, manufacturing properties Communication – Multi-functional team, requires constant dialogue/discussion/negotiation within the team The future of solid form selection: Incorporate formulation/processing (i.e. Materials Science) considerations Pharmaceutical Solid Form Screening, Characterization, and Selection 88 Enhancing Drug Bioavailability and Solubility, Boston, MA, Jan. 25 - 26, 2012
  • 89.