\\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Title-R1d.png CRYSTALLIZATION Petr Beňovský \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION – DIFFERENT DEFINITIONS Crystallization is a phase interconversion of the first order dependent on two parameters – concentration and structure ? 2 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION – DIFFERENT DEFINITIONS C:\Users\pbenovsky\Desktop\caveofcrystals.jpg Crystallization is the natural or artificial process by which a solid forms, where the atoms or molecules are highly organized into a structure known as a crystal. 3 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLUBILITY MEASUREMENT SOLUBILITY Is a measurement of the equilibrium state between a solid and a liquid phase 4 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png EQUILIBRIUM STATES PHASE DIAGRAMS •Can help in the selection of a crystallization method, yield determination and temperature of a crystallization process; •Supersaturation – concentration of a compound in solution is higher than in equilibrium; •Degree of supersaturation – driving force of crystallization, nucleation and crystal growth; • SOLUBILITY CURVES van’t Hoff equation for ideal solutions: Unfortunately, the most of solutions differ from ideal solutions and calculated solubilities of the same compounds for different solvents differ a lot EXPERIMENTALLY OBTAINED SOLUBILITY CURVES 5 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png PHASE DIAGRAM OF ICE POLYMORPHS 6 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLUBILITY CURVE/METASTABILE ZONE FOR PHENACETIN IN ETHANOL 7 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SOLUBILITY MEASUREMENT Possibility of polymorph interconversion Black, S.; Dang, L.; Liu, C.; Wei, H. Org. Process Res. Dev. 17, 486 (2013) 8 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png THE BLACK’S RULE Simon Black (Astra Zeneca) Solubility doubles with every 20 oC increase Could be used for the solvent selection after the initial screening of solvents; In cases, where the prediction according to the Black’s rule significantly differs from experimentally obtained results, always consider possibility of the formation of solvates or different polymorphs; Muller, F.L.; Fielding, M.; Black, S. Org. Process Res. Dev. 13, 1315 (2009) Muller, F.L.; Black, S. Org. Process Res. Dev. 14, 661 (2010) 9 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png THE BLACK’S RULE 10 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png METASTABLE ZONE Metastability – a term introduced by Ostwald Parsons, A.R.; Black, S.N.; Colling, R. Trans IChemE 81, Part A, 700 (2003) Ideal area for the crystal growth on already formed nuclei 11 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png METASTABLE ZONE Metastable zone width – MZW Exert influence on probability of nucleation and seeding options The metastable zone width depends on types of measurement, temperature gradient, presence of impurities, equipment geometry, use of ultrasound, viscosity of solution, stirring mode 12 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png METASTABLE ZONE Solubility curve and metastable zone determination CRYSTALLINE (TECHNOBIS) C:\Users\pbenovsky\Desktop\Work\Crystallization\Solubility\Crystalline picture.jpg 13 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png METASTABLE ZONE Tung, H-H. Org. Process Res. Dev. 17, 445 (2013) 14 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png METASTABLE ZONE (AND WHAT NEXT?) Tung, H-H. Org. Process Res. Dev. 17, 445 (2013) 15 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png INDUCTION TIME Could be roughly correlated with the crystallization kinetics Sangwal, K. Nucleation and Crystal Growth, J.Wiley & Sons, 2018 16 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png TYPES OF CRYSTALLIZATION 1.COOLING CRYSTALLIZATION •Suitable for moderately to high soluble compounds – (100 – 300) g/l; •Positive slope of solubility curve; •Slope of the solubility curve is sufficiently steep; •In the end of crystallization the content of solid product in the reaction mixture should not be higher than 30-35% (vol.); • •Product deposits or scaling could be a problem; •Viscosity of solution; • •During crystallization, the system is NOT in thermodynamic equilibrium, but actual concentration does not differ much from equilibrium concentration → yields can be calculated using solubility curves; •Yields are limited by solubility of a compound at the lowest temperature used → possibility to reprocess mother liquors. 17 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png TYPES OF CRYSTALLIZATION 2. EVAPORATIVE CRYSTALLIZATION •Selected temperature, pressure and concentration of mother liquors are constant; •Solubility is almost independent on pressure, so it can be derived from the solubility curve at atmospheric pressure; •The challenge could be an accumulation of impurities in mother liquors → yield is limited by maximal accepted level of impurities in mother liquors; • 100% yield could be accomplished; •Yield could be calculated from mass balance in a solution and it is directly proportional to the mass of evaporated solvent(s); •Could be used for moderately to highly soluble compounds (100 – 300) g/l; •Could be used for the compounds with the flat solubility curve; •Used for compounds not stable at atmospheric boiling 18 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png TYPES OF CRYSTALLIZATION 3. PRECIPITATION •Used in the case of compounds with very low solubility ((0.001 – 1) g/l); •Two very soluble compounds form together the product with very low solubility; •Very fast process; •Concentration of a product in solution is very low, so the yield can be determined only from its initial concentration; •Mostly, amorphous material is produced, or different polymorphs obtained using different types of crystallization; 19 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png TYPES OF CRYSTALLIZATION 4. ANTI-SOLVENT CRYSTALLIZATION • Solubility of a compound depends on the ratio solvent/antisolvent; • •Addition of antisolvent dilutes a reaction mixture → decrease in solubility should have higher impact than dilution effect; • •Compounds that form hydrates tend to provide compounds with lower number of water molecule in crystal lattice; 20 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SUPERSATURATION Situation, where there is more compound in a solution than in equilibrium state under particular conditions; Nucleation and crystal growth occur in supersaturated solutions; Degree of supersaturation -Mathematical expressions available – it is difficult and demanding to get corresponding data; -Practical expression of degree of supersaturation based on easily available experimental values; - High supersaturation can lead to agglomeration of formed solid phase. 21 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SUPERSATURATION PRACTICAL EXPRESSIONS 22 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SUPERSATURATION G = growth rate; kg = growth rate constant; g = growth order (usually 1-2); ∆C = supersaturation; B = nucleation rate; kb = nucleation rate constant; b = nucleation order(usually 5-10) 23 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png THERMODYNAMIC MODELS 24 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SUPERSATURATION – PRACTICAL EXAMPLE Malwade, C.R.; Qu, H. Org. Process Res. Dev. 22, 697 (2018) 25 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png NUCLEATION Nucleation control is essential for obtaining of desired polymorph and particle size distribution; Homogeneous primary nucleation -New phase is formed by a statistical fluctuation of entities of dissolved compound that agglomerate; Heterogeneous primary nucleation -New phase is formed in the presence of tiny, invisible particles of dust or impurities; Secondary nucleation -Supersaturated solution already contains crystals of crystallized compound – the only observed mechanism for cooling crystallizations or evaporative crystallizations (already present crystals and their growth decrease the value of supersaturation to the extent that primary nucleation is ruled out); - Cluster formation by combination and detachment of particular entities of a dissolved compound – subsequent combination of clusters – cluster concentration is much lower than concentration of dissolved compound – critical size of clusters 26 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png NUCLEATION Homogeneous nucleation is practically very rare (it is extremely difficult to remove majority of dust particles) – therefore, crystallization mostly starts with heterogeneous nucleation mechanism; Induction time – can be used as a measure of tendency of the system to remain in metastable state and therefore, can be used to determine the metastability limit ; Induction time could be used for an estimation of nucleation rates. Nucleation generally requires relatively large amount of energy and proceeds better in highly oversaturated solution. 27 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png NUCLEATION 28 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png NUCLEATION 29 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTAL GROWTH The most important factors influencing crystal growth: • supersaturation • • ambient phase (melt or solution?) • • interaction energy between dissolved compound and solvent • • the presence of impurities • Crystal growth rate depends on the size of crystals – the smaller crystals grow slower to a certain limit size than larger crystals 30 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTAL GROWTH OSTWALD RIPENING A phenomenon observed in solid solutions or liquid sols that describes the change of an inhomogeneous structure over time, i.e., small crystals or sol particles dissolve, and redeposit onto larger crystals or sol particles. Dissolution of small crystals or sol particles and the redeposition of the dissolved species on the surface of larger crystals or sol particles was first described by Wilhelm Ostwald in 1896. C:\Users\pbenovsky\Desktop\Work\Crystallization\Icecream.jpg C:\Users\pbenovsky\Desktop\Work\Crystallization\Pastis.jpg 31 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTAL GROWTH Example of Ostwald ripening utilization for the modification of particle size distribution: > Problems with the crystallization of the salt (strict control of water content); Free base and succinic acid dissolved in water/acetone mixture with lower amount of acetone than required for crystallization at 45 oC, filtered through 1 µm filter, acetone added to required ratio; Slow stirring and cooling to 43 oC, seeding with 1% of the product, stirred at 43 oC for 2 h and then cooled to 20 oC over 1 h. The mixture was again heated to 38 oC over 1 h, slowly stirred for 1 h and cooled down to 33 oC in 3 h and cycles repeated in similar mode three times. By this approach PSD (100-200) µm instead of original (10-15) µm was obtained. Brown Ripin, D.H. et al Org. Process Res. Dev. 9, 440 (2005) 32 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTAL GROWTH Practical example of crystal healing process: Codan, L.; Sirota, E.; Cote, A. Org. Process Res. Dev. 22, 1131 (2018) 33 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SEEDING C:\Users\pbenovsky\Desktop\Work\Crystallization\Sower.jpg 34 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SEEDING Main reasons for the seeding during crystallization: •initiation of crystallization in the systems where crystallization is difficult and where the systems tend to oil out; • •particle size distribution control with the aim to get larger crystals with narrower particle size distribution; • •elimination of encrustation (scaling) caused by spontaneous nucleation, and also the preparation of a desired polymorph; • • preparation of a single crystal. 35 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SEEDING Operation, that could principally influence: • progress of crystallization • product purity • particle size distribution of the product • surface area • orderliness (less disorders in a crystal lattice) • polymorphism • rate of crystallization • Based on many experiments it was observed and verified that without seeding about 30 – 50% of the product quickly precipitate from the solution during spontaneous crystallization. Thus, very large number of tiny crystals is formed with broad particle size distribution. Subsequently, possible crystal growth occurs on the surface of these tiny crystals (depending on concentration). Ideal crystallization – additon of crystal seeds on which (and only there) the crystal growth occurs – number of crystals thus remains the same as in the beginning of crystallization 36 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SEEDING Very important operation of the crystallization process that principally influences various attributes of the solid product; DEVIL IS HIDDEN IN DETAILS The amount of seed (seed loading), particle size distribution of the seed can dramatically affect the result of crystallization; Generally, it is close to ideal to seed in the region of lower oversaturation, and thus eliminate primary or secondary nucleation; Based on the assumption that no primary and secondary nucleation occurs the number of crystals is the same as the number of seed crystals (on every seed crystal additional deposits of solid material is accumulated); Cs = seed loading ratio 37 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SEEDING Theoretically, for desired particle size of a product, it is possible to calculate seed particle size (direct proporsion); Practically, there are certain limitations: •In the case Cs is too low → insufficient seed loading → small surface area → leads to large oversaturation and primary and secondary nucleation → not robust and small particle size → frequent agglomeration; • •In the case Cs is too high → excessive seed loading → not economical. • CRITICAL SEED LOADING RATIO CS* The lowest possible seed loading at which no nucleation occurs When CS* is used, unimodal particle size distribution is obtained regardless used temperature gradient, yield and volume of a crystallizer (under circumstances that no primary and secondary nucleation occurs – low oversaturation is maintained). 38 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SEEDING CS* = 2,17 x 10-6 x LSEED2 i = 1 (needles), 2 (plates) or 3 (cubes) 39 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SEEDING Timing of seed addition • critical factor for a successful process; • • too early → seeds could be dissolved; • • too late → spontaneous nucleation might occur • • • Seed quality • narrow particle size distribution as much as possible; • •always add seed as a suspension in slightly undersaturated solution; • • always use seed with the highest possible purity. 40 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SEEDING Seed loading Paul, E.L.; Tung, H.-H.; Midler, M. Powder Tech, 150, 133 (2005) „Pinch“ – used mostly in early phase of development on small scale with limited amount of material. Rarely effective or reliable on larger scale. Small (< 1%) – aid in more controlled crystallization, but not adequate to achieve primarily growth on scale-up. Large (5-10%) – to improve the probability of growth with the possibility of preventing further nucleation and bimodal distribution. Massive – mostly used in continuous operations. Provides maximum opportunity for all growth. 41 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png SEEDING Practical example of seeding: Beckmann, W. Org. Process Res. Dev. 4, 372 (2000) Beckmann, W.; Nickisch, K.; Budde, U. Org. Process Res. Dev. 2, 298 (1998) 42 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION TRAJECTORY Which crystallization trajectory is actually ideal?? - Particular crystallization conditions have significant impact on the yield, size and shape of crystals, polymorphism etc.; - Various ways how to control crystallization •Natural cooling – the simplest, but mostly high degree of supersaturation occur and very small crystals are formed; •Linear cooling – often similar results are obtained as for natural cooling; 43 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION TRAJECTORY •Constant supersaturation – maintained by a regulated control of cooling/heating, evaporation or antisolvent addition – could bring technical challenges; •Optimal trajectory for a certain purpose – a control system tries to create the best conditions for a certain phase of crystallization, and to get required attributes of crystalline product; Open loop control – optimal trajectory is calculated by mathematical models and algorithms and is used by a control system – very difficult to control and calculate the impact of various factors and requested attributes (content of impurities, residual solvents, crystal habit etc.); Closed loop control – the optimal operating policy is continuously updated during a run taking into account in-line process measurements; Direct design – usually starts with a supersaturation trajectory determined from an open-loop method. The supersaturation is experimentally determined in the course of the process and possibly corrected according to values measured in real time (ATR-FTIR) – can be used to improve for the next batches. 44 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION TRAJECTORY Direct nucleation control (DNC) Formation of crystalline entities/seeds directly in the system without external seeds (very useful for highly toxic compounds); Does not require any information on the crystallization kinetics; Overall number and size distribution of formed crystalline entities/seeds is controlled (FBRM) and parameters that influence these attributes are modified in the course of crystallization (temperature, antisolvent addition, solvent evaporation); Thus, relatively narrow distribution of crystal size can be obtained – by appropriate temperature control fractions of very small crystals are dissolved again; 45 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION TRAJECTORY Direct nucleation control (DNC) 46 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION TRAJECTORY Direct nucleation control (DNC) Practical example of application: Abu Bakar, M.R.; Nagy, Z.K.; Saleemi, A.N.; Rielly Ch.D. Crystal Growth Design 9, 1378 (2009) Liotta, V.; Sabesan, V. Org. Process Res. Dev. 8, 488 (2004) Saleemi, A.N.; Steele, G.; Pedge, N.I.; Freeman, A.; Nagy, Z.K. Int. J. Pharm. 430, 56 (2012) 47 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png APPROACHES USED IN THE OPTIMIZATION OF CRYSTALLIZATION Gao, Z.; Rohani, S.; Gong, J.; Wang, J. Engineering 3, 343 (2017) 48 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Title-R1d.png DUTCH RESOLUTION, ATTRITION ENHANCED DERACEMIZATION Petr Beňovský \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES RACEMIC MIXTURE (CONGLOMERATE) A mechanical mixture of enantiomerically pure crystals of one enantiomer and its opposite; RACEMIC COMPOUNDS The crystallographic unit cell contains both enantiomers in ordered 1 : 1 ratio; RACEMIC SOLID SOLUTIONS The crystallographic unit contains molecules of each enantiomer in a random order. 50 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES Sogutoglu, L.-C. et al Chem. Soc. Rev. 44, 6723 (2015) 51 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES CRYSTAL GROWTH Step-wise growth Spiral growth 52 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES CRYSTAL GROWTH Step-wise growth Spiral growth 53 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES CRYSTAL HABITS (ICE CRYSTALS) 54 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES CRYSTAL HABIT MODIFIERS Present impurities or deliberately added compounds that have profound effect on growth rate of one or more faces even at very low concentrations; 55 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES CRYSTAL HABIT MODIFIERS MoO3 a – urea; b – PEG 200; c – EDTA; d – sorbitol Parviz, D. et al J. Nanopart. Res. 12, 1509 (2010) 56 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES NUCLEATION INHIBITORS Some compounds can efficiently block (or dramatically slow down) crystal growth or nucleation of crystals; The metastable zone width is thus enlarged; If we want to crystallize just one enantiomer from a racemic conglomerate we must block nucleation and crystal growth of the opposite one; Inhibitor in that case must be homochiral; Inhibitor must be the same enantiomorph 57 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES OPTICAL RESOLUTION VIA DIASTEREOMERIC SALTS Single enantiomer drugs - $147 billion worldwide sale (2001) Optical resolution (besides utilization of chiral pool and asymmetric synthesis) is the most frequent used industrial method for obtaining single enantiomers; 1882 – Louis Pasteur demonstrated that by seeding a supersaturated solution of ammonium sodium tartrate with a d-crystals on one side of the reactor and a l-crystals on the opposite side, crystals of opposite handedness formed on the opposite sides of the reactor. 58 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES OPTICAL RESOLUTION VIA DIASTEREOMERIC SALTS Peachey-Pope Resolution Instead of one equivalent of homochiral resolving agent, only one half equivalent of resolving agent is used and supplemented with one half equivalent of an achiral, low cost acid or base (e.g. HCl, NaOH) to make the system neutral. The achiral supplement should provide very soluble salts with the racemate so this will not crystallize and ruin the resolution. The less soluble (desired) salt will start to crystallize and will consume most of a chiral resolving agent thus leaving only small amount of a chiral resolving agent for the more soluble diastereomer which, in ideal case, will not crystallize. The solubility difference between two diastereomeric salts can be relatively small. 59 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES OPTICAL RESOLUTION VIA DIASTEREOMERIC SALTS Peachey-Pope Resolution Harrington, P.J. Org.Process Res. Dev. 1, 72 (1997) – naproxen example 60 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES OPTICAL RESOLUTION VIA DIASTEREOMERIC SALTS Dutch Resolution •The use of mixtures of resolving agents (families); •The family members should bear strong structural similarity and are stereochemically homogeneous; •2 or 3 family members are used in a resolution; •Usually, such resolutions proceed rapidly with high diastereomeric excess; •Often, this combination of resolving agents brings better resolution than with just one resolution agent; •Sometimes, all resolution agents are incorporated into the crystal lattice, but sometimes at least one of them serves as a nucleation inhibitor; • 61 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES OPTICAL RESOLUTION VIA DIASTEREOMERIC SALTS Dutch Resolution 62 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES OPTICAL RESOLUTION VIA DIASTEREOMERIC SALTS Dutch Resolution Dalmolen, J. et al Chem. Eur. J. 11, 5619 (2005) Kellogg, R.M. Synthesis (10), 1626 (2003) 63 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES ATTRITION ENHANCED DERACEMIZATION Viedma Ripening 1.Racemisation in solution 2. 2.Ostwald ripening 3. 3.Enantioselective growing 4. 4.Attrition Sogutoglu, L.-C. et al Chem. Soc. Rev. 44, 6723 (2015) 64 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES ATTRITION ENHANCED DERACEMIZATION Viedma Ripening Hachiya, S. Chem. Commun. 49, 4776 (2013) 65 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES ATTRITION ENHANCED DERACEMIZATION Noorduin, W.L. et al Org. Process Res. Dev. 14, 908 (2010) Upscaled synthesis of Clopidogrel (Plavix) using a bead mill 66 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES ATTRITION ENHANCED DERACEMIZATION Noorduin, W.L. et al Org. Process Res. Dev. 14, 908 (2010) Upscaled synthesis of Clopidogrel (Plavix) using a bead mill 67 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png CRYSTALLIZATION OF ENANTIOMERS FROM RACEMIC MIXTURES ATTRITION ENHANCED DERACEMIZATION Noorduin, W.L. et al Org. Process Res. Dev. 14, 908 (2010) Upscaled synthesis of Clopidogrel (Plavix) intermediate using a bead mill 68 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png WHAT NEXT?? Solubility determination using very small amounts Peybernes, G.; Grossier, R.; Villard, F.; Letellier, P.; Lagaize, M.; Candoni, N.; Veesler, S. Org. Process Res. Dev. 22, 1856 (2018) Membrane crystallizations Drioli, E.; Di Profio, G.; Curcio, E. Curr. Opinion Chem. Eng. 1, 178 (2012) Continuous reaction including crystallizations on microscale Song, H.; Chen, D.L.; Ismagilov, F. Angew. Chem. Int. Ed. 45, 7336 (2006) 69 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png WHAT NEXT?? MSMPR (Mixed Suspension Mixed Product Removal) Crystallization Zhang, D. et al Engineering 3, 354 (2017) Nagy, Z.K. et al Chem. Eng. Res. Des. 135, 112 (2018) 70 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png WHAT NEXT?? MSMPR (Mixed Suspension Mixed Product Removal) Crystallization MSMPR equipment in Eli Lilly; Crystallization was the most important element of their control strategy for low impurity profile; Purity of a crystallized compound was higher than 99.8 %. 71 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png WHAT NEXT?? Plug Flow Crystallization (PFC) Kwon, J.S. et al Chem. Eng. Sci. 119, 30 (2014) 72 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png WHAT NEXT?? AIRLIFT CRYSTALLIZERS 73 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png WHAT NEXT?? Microfluid Crystallizations Crystallization in droplets – every droplet with nanoliter volume is independent crystallizer Ildefonso, M.; Candoni, N.; Veesler, S. Org. Process Res. Dev. 16, 556 (2012) 74 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png WHAT NEXT?? OSCILLATORY BAFFLED CRYSTALLIZATION NiTech Solutions 75 \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png WHAT NEXT?? OSCILLATORY BAFFLED CRYSTALLIZATION Practical example NiTech Solutions Lawton, S.; Shering, P.; Zhao, L.; Laird, I.; Ni, X-W. Org. Process Res. Dev. 13, 1357 (2009) 76