1. 1 Crystallization: Concepts, Development & Manufacturing Strategies

2. 2 Agenda Crystallization in the Pharmaceutical Industry Crystallization in the Pharmaceutical Industry Crystallization kinetics Crystallization kinetics Crystallization development Crystallization development Particle size engineering Particle size engineering Analytical tools – Lasentec Analytical tools – Lasentec Practical examples Practical examples

3. 3 Crystallization in the Pharma Industry Most of the Active Product Ingredients (API’s) and the intermediate products form stable crystalline compounds at room temperature. Most of the Active Product Ingredients (API’s) and the intermediate products form stable crystalline compounds at room temperature. Crystallization is an efficient process to isolate these compounds with high productivity and high purity. Crystallization is an efficient process to isolate these compounds with high productivity and high purity.

4. 4 Crystallization in the Pharma Industry (contd) Batch Crystallization Process Batch Crystallization Process Formation of solid particles within a homogeneous phase by modifying the solubility of the component of interest Formation of solid particles within a homogeneous phase by modifying the solubility of the component of interest The change in solubility is accomplished by: The change in solubility is accomplished by: decreasing the temperature of the solution (cooldown Xon) decreasing the temperature of the solution (cooldown Xon) Changing composition of solvent by adding a solvent in which the compound is insoluble (antisovent crystallization) Changing composition of solvent by adding a solvent in which the compound is insoluble (antisovent crystallization) In some cases crystallization is not achieved by a change in solubility →reactive crystallization In some cases crystallization is not achieved by a change in solubility →reactive crystallization

5. 5 Isolate substrate Isolate substrate FiltrationPSD, Crystal habit FiltrationPSD, Crystal habit DryingSolvent Selection, PSD DryingSolvent Selection, PSD YieldSolubility, T YieldSolubility, T Purify Substrate Purify Substrate Impurity RejectionRelative Solubility Impurity RejectionRelative Solubility Solvent removalPSD Solvent removalPSD Washing PropertiesCake porosity Washing PropertiesCake porosity Downstream Manufacturability Downstream Manufacturability Flow Properties of productPSD Flow Properties of productPSD Filtration (specific cake resistance)PSD, habit, agglomeration Filtration (specific cake resistance)PSD, habit, agglomeration Drying rate/LODPSD, habit, solvate Drying rate/LODPSD, habit, solvate Physical AttributesPSD, Polymorph Physical AttributesPSD, Polymorph Crystallization Objectives

6. 6 Crystallization Kinetics: Supersaturation Temperature Concentration Undersaturated Solution Equilibrium Solubility “Spontaneous” Nucleation Curve Metastable Region TIME

7. 7 Two common types of nucleation mechanisms Primary nucleation: Primary nucleation: Homegeneous: occurs at the onset of crystallization, when the concentration of the solvent exceeds the metastable region. Homegeneous: occurs at the onset of crystallization, when the concentration of the solvent exceeds the metastable region. Heterogeneous:occurs when solid particles of foreign substances cause an increase in the rate of nucleation. Heterogeneous:occurs when solid particles of foreign substances cause an increase in the rate of nucleation. Secondary nucleation: is caused by contacts between a crystal and another surface, and occurs within the metastable region (difficult to scale up) Secondary nucleation: is caused by contacts between a crystal and another surface, and occurs within the metastable region (difficult to scale up) Crystallization Kinetics: Nucleation

8. 8 Typically follows an initial stage of either homogeneous or heterogeneous nucleation, unless a "seed" crystal, purposely added to start the growth, was already present. Typically follows an initial stage of either homogeneous or heterogeneous nucleation, unless a "seed" crystal, purposely added to start the growth, was already present. Addition of solute to faces of crystal Addition of solute to faces of crystal For controlled growth operate crystallization under low supersaturation levels For controlled growth operate crystallization under low supersaturation levels Growth & nucleation are competing processes! Growth & nucleation are competing processes! Crystallization Kinetics: Growth

9. 9 Crystallization development Requirement to isolate as many solid forms as possible in order to select the form with best attribute for further development (screening of polymorphs) Requirement to isolate as many solid forms as possible in order to select the form with best attribute for further development (screening of polymorphs) Develop best crystallization procedure with means available at hand to enable scale-up for New Drug Toxicology and other campaigns. Develop best crystallization procedure with means available at hand to enable scale-up for New Drug Toxicology and other campaigns.

10. 10 Crystallization development (contd) Determine solubility of the substance in common solvents Determine solubility of the substance in common solvents Where: VGS: very good solvent, GS: good solvent, AS: acceptable solvent, B: bad solvent, Scc: Solvent for cooling crystallization, AS: anti-solvent.

11. 11 Crystallization development (contd) Crystallization method development Crystallization method development

12. 12 Crystallization- Engineering Particle size reduction Particle size reduction Greater surface area Greater surface area Faster dissolution Faster dissolution Better bioavailability Better bioavailability Better compactibility Better compactibility Particle size distribution: Particle size increase Particle size increase Faster filtration/drying Faster filtration/drying Better handling Better handling Better flowability Better flowability Crystal shape: - Influence the flowability of the resulting powder.

13. 13 Crystallization/Particle Engineering Particle Size Enhancement: Particle Size Enhancement: Cubic Crystallization Cubic Crystallization Strategic Seeding Strategic Seeding Thermal methods Thermal methods Target Property Improvements Target Property Improvements Flowability Flowability Filtration Filtration Bulk density Bulk density Drying rate Drying rate Thermal cycleLinear cooling

14. 14 Crystallization/Particle Engineering Particle Size Reduction Particle Size Reduction Wet Milling Wet Milling Ultrasounds Ultrasounds High-shear Polymorph Transformation High-shear Polymorph Transformation Dry milling Dry milling Target Property Improvements Target Property Improvements Dissolution rate Dissolution rate Exposure, bioavailability Exposure, bioavailability PSD PSD Compactability/ Compressibility Compactability/ Compressibility Wet milling Dry milling

15. 15 Particle size reduction Why not just mill all the API’s? Usually undesired in manufacturing Usually undesired in manufacturing Safety issues related to dust explosion potential Safety issues related to dust explosion potential Issues of physical stability of crystals--potential loss of crystallinity due to stresses applied to crystals Issues of physical stability of crystals--potential loss of crystallinity due to stresses applied to crystals Wide particle size distribution, more fines Wide particle size distribution, more fines Possibility of reduced yield Possibility of reduced yield Noise Noise Another unit operation Another unit operation Productivity, equipment/facility issues Productivity, equipment/facility issues

16. 16 Particle size increase From linear crystallizationFrom cubic crystallization Salt crystallization at low supersaturation by cubic addition of sulfuric acid into the solution with seeds Cubic addition: addition at a variable rate, slow at first and gradually faster towards the end as the surface area for growth increases Increased filtration rate and wash efficiency

17. 17 Particle shape modification To improve flowability, bulk density, and handling To improve flowability, bulk density, and handling To increase filtration rate To increase filtration rate “Needles to bricks” or “plates” to “cubes” “Needles to bricks” or “plates” to “cubes”

18. 18 Shape modification - Example Particle engineering of "needles” into “bricks” using series of sonication and temperature cycling 100 um

19. 19 Spherical agglomeration Uniform agglomerates sized 20-100  m consisting of smaller primary crystals Uniform agglomerates sized 20-100  m consisting of smaller primary crystals Excellent flowability and handling Excellent flowability and handling Compactibility needs to be tested Compactibility needs to be tested

20. 20 Spherical Agglomeration Can be triggered by temperature 45°C56°C <1h56°C 1h56°C 8h 53-56°C >1dcooled to 48°C cooled to 20°C and aged back to 53°C

21. 21 Spherical Agglomeration Can also be triggered by by-product or a 3 rd solvent (e.g. Toluene) Not necessarily spherical in shape

22. 22 Particle size Particle size distribution Crystallization kinetics Crystallization Analytical Tools —In- Process PSD by Lasentec FBRM

23. 23 Lasentec FBRM applications Practical case 1: low flowability Practical case 1: low flowability 2007 campaign: 30% batches did not meet flow specifications 2007 campaign: 30% batches did not meet flow specifications 2008 campaign: modifications done into crystallization protocol→17% batches did not meet flow spec 2008 campaign: modifications done into crystallization protocol→17% batches did not meet flow spec 2009 campaign:modifications done into crystallization protocol→All the batches met the flow specifications 2009 campaign:modifications done into crystallization protocol→All the batches met the flow specifications 2010: Same crystallization protocol as per 2008→25% batches did not meet flow specifications 2010: Same crystallization protocol as per 2008→25% batches did not meet flow specifications 2011: investigation on-going 2011: investigation on-going

24. 24 Practical case 1: low flowability (contd) Compound A Crystallisation is pH and temperature controlled. Compound A Crystallisation is pH and temperature controlled. Crystallisation sequence starts when pH is lowered below pH6 Crystallisation sequence starts when pH is lowered below pH6 Controlled HCl charge rates for pH <6.0 are used to control saturation, nucleation and crystal growth Controlled HCl charge rates for pH <6.0 are used to control saturation, nucleation and crystal growth Crystal growth is achieved by a combination of controlled HCl charge rates, specific pH ranges & seeding coupled with short hold periods at constant temperature for optimal, controlled crystal growth. Crystal growth is achieved by a combination of controlled HCl charge rates, specific pH ranges & seeding coupled with short hold periods at constant temperature for optimal, controlled crystal growth.

25. 25 Practical case 1: low flowability (contd) Multiple changes done over years based on Lasentec data analysis and pH and Temperature trends comparison. Multiple changes done over years based on Lasentec data analysis and pH and Temperature trends comparison. Good flowability Bad flowability

26. 26 Practical case 1: low flowability (contd) Typical Lasentec data for good and bad batches Typical Lasentec data for good and bad batches Poor flowability < 6 g/s Number of fines #/sec between 1 and 21 μm Good flowability > 6 g/s

27. 27 Practical case 1: low flowability (contd) Lasentec data at nucleation point Lasentec data at nucleation point

28. 28 Practical case 1: low flowability (contd) Lasentec data post nucleation, bad flow, high number of fines

29. 29 Lasentec data post nucleation, bad flow, high number of fines Practical case 1: low flowability (contd)

30. 30 Practical case 2: Slow filtrations Seed Type Flux (L/m 2 h) No seeds 1200 Unmilled1560 Thermal Ramp option 2230 Jet-milled4160 Wet-milled3480 unseeded 32 hr isolation wet-milled seeds 11 hr isolation

31. 31 Q&A Q&A