crystals_JLiangXtal

Small Molecule Crystalliza tion Jessica K. Liang Department of Chemical Engineering Illinois Institute of Technology ACS Summer School July 2003 Chicago IL Overview ØBasic Crystal Science ØCrystallization Process ØOur Research Projects ØLab Tour New Y orkWhat is a Cr ystal? Crystal Amor phous London Ø Solid with short and long range order with atoms or molecules in a fi xed lattice arrangement Definition of Crystal Ø The distinction between a crystal and an amorphous solid is that between order and disorder over large distances Ø Internal structure of crystals accessible by x-ray dif fraction analysis Crystal Str uctur e Unit cell parameters: a, b, c, α, β, γ Seven Cr ystal Systems Space Gr oups Ø 230 space groups Ø For organic molecules, statistics shows that 95% of all compounds crystallize out in these 16 space groups• P21/c monoclinic • P21 monoclinic • P21/m monoclinic • P2/c monoclinic • C2/c monoclinic • C2/m monoclinic • Cc monoclinic • C2 monoclinic • P-1 triclinic • P1 triclinic • P212121 orthorhombic • Pbca orthorhombic • Pnma orthorhombic • Pna21 orthorhombic • Pbcn orthorhombic • Pca21 orthorhombic • P21212 orthorhombic X-Ray Dif fraction Structure Determination Ø Need good quality single crystal Send to Crystallographer . ØThey determine lattice type, parameters i.e. a, b, c, α, β, γ atom positions and space group Ø Space groups relate crystal symmetry on an atomic scale to possible arrangement of atom which possess that symmetry . Ø Given systems and space group you can calculate all possible arrangement of atoms which meet this symmetry . Types of Crystals Ø Ionic – Charged ions held in place on lattice by electrostatic forces (NaCl) Ø Covalent – Atoms connected by framework of covalent bonds (Diamond) Ø Molecular Crystals – Usually organic, composed of discrete molecules held together by weak attractive forces (Urea) Ø Metallic Crystals – Ordered arrays of identical cations (Copper) Morpholog y and Ha bit ØCrystal morphology is defi ned as the general appearance of crystals described by the Miller indices of the faces that show and give the crystals their characteristic shape ØCrystal habit means the general shape of a crystal as given by the relative length of the various major axes. ØBoth morphology and habit depend on growth conditions and can vary under dif ferent process conditions. Morpholog y and Ha bit Same morphological form but dif ferent habit Different morphological form but same habit Crystal Siz e Distribution Ø CSD: the most widely applied quality test of a crystalline product Ø Many industrial processes demand a narrow range of particle size as this results in good fi ltering, drying and free- flow ability Sizing Method On-lined sizing Polymor phism ØThe phenomenon of a chemical species having more than one possible crystal form e.g. Carbon (graphite: top and pencil and diamond: bottom) whilst remaining chemically identical ØDifferent forms maybe signifi cantly dif ferent in terms of both their structures and physical & chemical properties Reference: Yu, L.; Stephenson, G. A.; Mitchell, C. A.; Bunnell, C. A.; Snorek, S. V.; Bowyer , J. J.; Borchardt, T. B.; Stowell, J. G; Byrn, S. R. J. Am. Chem. Soc . 2000, 122, 585 .5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile “ROY” 6 Polymorph Forms McCr one’s Law ‘Every compound has dif ferent polymorphic forms, and that, in general,the number of forms known for a given compound is proportional to the time and money spent in research on that compound.’ McCrone, W.C. Polymorphism in Physics and Chemistry of the Organic Solid State , Ed. by Fox D, Labes MM, Weissber ger A1965, Vol. II, pp. 726-767 , Wiley Interscience New York. Types of Polymor phism Packing Polymorphism Ø Packing and bonding arrangement of the structure in its different forms are signifi cantly dif ferent Conformational Polymorphism Ø The existence of dif ferent conformers of the same molecule in dif ferent polymorphic modifi cations Ø Low energy dif ference between various conformations Pseudopolymorphism Ø A new structure of a compound that is hydrated or solvated Packing P olymor phism Glycine (C2H5NO2) Albrecht G and Corey RB J. Am. Chem. Soc ., 1931 , 61, 1037. Y. Iitaka, Proc. Jap. Acad . 1954 ; Vol. 30,109-1 12 Hexagonal Monoclinic Conformational Polymor phism Koch MH, Acta Cryst B29, 1973 , 379. Azibi M et al., J. Pharm Sci ., 72, 1983 , 232.Spiperone (C23H26FN3O2) Polymor phic Pr operties Packing Properties Ø Molar volume, density , refractive index, conductivity , hygroscopicity Thermodynamic Properties Ø Melting and sublimation temperature, structural energy , Enthalpy , Heat capacity , Entropy , Free energy and chemical potential, Thermodynamic activity , Vapor pressure, Solubility Kinetic Properties Ø Dissolution rates, rates of solid state reactions, stability Spectroscopic Properties Surface Properties Ø Surface free energy , interfacial tension, morphology Mechanical Properties Ø Hardness, tensile strength, compactability , handling, fl ow Bioavailability Char acteriza tion Methods Crystallography: X-Ray Dif fraction Ø Single Crystal X-Ray Dif fraction Ø X-Ray Powder Dif fraction Morphology: Microscopy Ø Polarizing Optical Microscopy Ø Thermal Microscopy Phase Transitions: Thermal Methods of Analysis Ø Thermogravimetry Ø Differential Thermal Analysis Ø Differential Scanning Calorimetry Molecular Motion: V ibrational Spectroscopy Ø Infrared Absorption Spectroscopy Ø Raman Spectroscopy Chemical Environment: Nuclear Magnetic Resonance SpectrometryOn-lined Monotr opic System ØOne form is metastable relative to the other at all temperatures below the melting point ØPolymorphs are not interconvertible ØSolubility of the stable form is always lower than the metastable form Monotr opic System β−form α−form L-glutamic acid C 5H9NO4 Enantiotr opic System ØPolymorphic form dependent upon the temperature and pressure of the system ØReversible transition point where relative thermodynamic stabilities change ØTransition point below melting point for any of the solid phase L-Phenylalanine Monohydrat e stable Anhydrate stable38o CØ Metastable form may exist for a long time; Ø Presence of the stable form results in solvent mediated phase transformation Crystalliza tion ØFormation of a crystalline phase from a parent phase, e.g. solution ØOne of the oldest and most important unit operations, e.g. extracting salt crystals from sea water ØOver 90% of all pharmaceutical products contain drug substances in crystalline form Crystalliza tion Pr ocess Final ProductLiquid MixtureNucleation: Birth of Solid PhaseCrystal GrowthGeneration of Supersaturatio n:Driving force Solid Form (Polymorph,Hydrate )Ratio of Rate of Nucleation to Growth Controls Final Product Size DistributionCrystal Habit, Crystal Purity Definition of Super saturation C* : equilibrium concentration for a given temperature C : solution concentration; T*: saturated temperature; Tcry: Crystallization temperatureSupercooling Gener ation of Super saturation Mode Supersaturation generation method Cooling Reduction in temperature Evaporation Lost of solvent Dilution Adding anti-solvent Reaction Generation of solute Vacuum Cooling, fl ashing evaporation Ø Supersaturated zone: Spontaneous nucleation is expected Ø Metastable zone: Spontaneous nucleation is impossible Ø Stable zone: Nucleation is impossible Metasta ble Zone Solubility & Supersolubility Diagram Metasta ble Zone W idth Ø MSZW is a nucleation kinetic-limited parameter that is highly dependent on process conditions Ø Many factors may infl uence the value of MSZW , e.g. rate of cooling, agitation, the presence of foreign particles and impuritiesØ Metastable zone width (MSZW) is a critical parameter in the crystallisation process as it reveals the nucleation behaviour of the system Effects of Cooling Ra te & Agita tion Ø MSZW decreases as stirrer speed increases Ø MSZW widens at N>400rpm Ø MSZW widens as cooling rate rises Cooling crystallization of aqueous L-glutamic acid solutions200 250 300 400 500152025303540455055 0.2°C/min 0.5°C/min0.3°C/min Nucleation Homogeneous: SpontaneousHeterogeneous: Induced by the presence of foreign particlesPrimary Nucleation: Nucleation in crystal free systemSecondary Nucleation: Induced by the presence of crystals Homogenous Nuc leation r: radius of cluster vm: specifi c volume of solute molecules SB: supersaturation of the solution γ: solid-liquid interfacial tensionGibbs Free Energy Change Free Energy Diagram Metastable Unstable Stable AGs i 3ry Bi c 2' 8 ——— Workofbringing g wate &see ie thebodytothe_ omens ips unstable state 3 Za TTS Rainer? a oe Bo: 2 Displacement _! $ |pNuelira if Embryos |Growing crystals ve t Workofnuclei { Xcritical nucteus Size ~ Size ofnucleus, r Particle size Heter ogeneous Nuc leation Ø Heterogeneous nucleation: caused by dust, dirt, rough spots on walls, etc Ø In industrial processes, homogeneous nucleation is rare Ø Nucleation is usually heterogeneous and/or secondary Heter ogeneous Nuc leation Ø Lower energy barrier Energy Ratio Contact angle Empirical Nuc leation Model J :Nucleation rate kn:Nucleation rate constant m:Nucleation order C*:equilibrium concentration at nucleation temperature C:solution concentration Secondar y Nuc leation Stirring rateSuspension densityØ Nucleation caused by interaction of existing crystals with vessel, impeller or by collisions Ø The main source of nuclei in many industrial applications Ø Empirical model: B secondary nucleation rate Secondar y Nuc leation Supersaturation Stirr er speed Secondary Nucleation of Potassium Chloride Secondar y Nuc leation Ø Higher secondary nucleation rate using steel impeller Ø Secondary nucleation rate increases as agitator speed rises Crystal Gr owth (1)Transport from bulk to boundary layer (2)Dif fusion to crystal surface (3) Absorb onto surface and partial desolvation (4)Dif fusion to energetically favorable sites(4*) Diffusion away (5) Integration at a kink and total desolvatio n Molecule Incor poration Single molecule incorporation on fl at areas of a crystal face is not energetically favorable Molecule is bonded both to a step face as well as to the surfaceMost energetically favorable: three sides of molecular cube are bonded ( kink site) Surface Structur e of a Gr owing Crystal Ø Where do the steps come from? Ø What is the rate control factor in determining the crystal growth rate?Crystal Gr owth T heories BCF (Bur ton Ca brera Frank) T heor y Ø Dislocations in the crystal are the source of new steps (dislocations are a certain type of irregularity in the structure of the crystal lattice) Ø Screw dislocation provides a way for the steps to grow continuously Spiral Growth from a Screw Dislocation Empirical Gr owth Model Mass Deposition Rate g: Growth order is generally between 0 and 2.5, most commonly equal to 1; kG: Overall rate constant,depends on temperature, crystal size, hydrodynamics and presence of impurities; AT: Total surface area of the crystals m: Mass of the crystals; L : Mean crystal size; α, β : volume and area shape factors; ρ : Crystal densityOverall Linear Growth Rate “Designer” ParticlesParticle Engineering Bioavailability (solubility) Chemical and physical stability Physicochemical Chemical purity Crystal Habit Crystal Structure (Polymorphism/ hydrate/imperfe- ction) Thermodynamic propertiesPhysicotechnical Mechanical properties (compressibility) packing & fl owability Particulate Properties Crystal size, shape & surface Seeding T echnolog y Objectives: Ø Design the crystallization process to achieve a certain fi nal product size using seeds Ø By seeding the preferable polymorph form, obtain desired crystal morphology and polymorph or pseudo-polymorph Approach MultiMax reactor system 4x50 ml scale Temperature Stirring rate Dosing rate PXRD Polymorphic formLasentec FBRM In-situ particle sizingBET Particle surface area Model Population balance equation Crystal growth Nucleation Super- saturation balance Solubility Seed properties: size, shape, mass, surface areaNucleation and crystal growth kinetic parameters Population Balance Model Simulated fi nal crystal size distribution & yieldMeasured fi nal crystal size distribution VerificationOptimization & design What do w e do? Ø Crystallization process development and optimization Ø Nonphotochemical laser-induced nucleation of small molecules and proteins Ø Template-directed nucleation and growth of molecular crystals Ø Electrodynamic levitation of single solution droplet to study the activity of supersaturated small molecule and protein solutions