Enabling Technologies for the Continuous Manufacturing of APIs: Continuous Crystallization
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1 Enabling Technologies for the Continuous Manufacturing of APIs: Continuous Crystallization Bernhardt L. Trout Director, Novartis-MIT Center for Continuous Manufacturing Professor, Department of Chemical Engineering, MIT
2 Crystallization Process Development Process Goals Purity Yield Average Size and Size Distribution Correct Polymorph or Pseudopolymorph Shape 2
3 Road Map for Pharmaceutical Manufacturing Paradigm shifts in manufacturing and quality envisioned Quality by Design Blue Sky Vision: Continuous Manufacturing Traditional Manufacturing Disconnected process steps Process steps and their impact understood Seamlessly integrated and well characterized processes Past Current >
4 Novartis-MIT Blue Sky Vision Integrated Continuous Manufacturing: A radical transformation the ultra LEAN Manufacturing MIT Massachusetts Institute of Technology From start of chemical synthesis through final pharmaceutical dosage form 4
5 Our Definition of Continuous (ultra QbD) Flow Integration (end to end) Systems approach Integrated control strategy 5
6 Novartis-MIT Center for Continuous Manufacturing Phase 1 June 2007-May 2012 Phase 2 June 2012 June MIT students and post-docs 20 Novartis staff and 12 MIT Professors from Chemical Engineering, Chemistry, and Mechanical Engineering Most research performed in each professor s lab Dedicated facility for translational work. 6
7 MIT Continuous Manufacturing Facility 7
8 MIT Pilot Plant VIDEO Courtesy of NVS-MIT Center 8
9 Tablets Produced in Integrated Process 9
10 Batch Versus Continuous Crystallization Continuous Crystallization 10 Built in flexibility for control Does not necessarily discharge at equilibrium conditions Lower cost CSD is broad Polymorph Control? Batch Crystallization Cleaning done between each batch Simplicity of equipment Narrower size distribution Higher cost
11 Novartis-MIT Center for Continuous Manufacturing Important task: demonstration of end-to-end continuous manufacturing platform Used to gain experience about integration and control Involves multiple reactions, workup steps, crystallizations Each crystallization presented unique challenges 11
12 Example 1: Optimization via Modeling of MIT Pilot Plant MSMPR VIDEO Courtesy of NVS-MIT Center 12
13 Example 1: Optimization via Modeling of MIT Pilot Plant MSMPR VIDEO Courtesy of NVS-MIT Center 13
14 Example 1: Optimization via Modeling of MIT Pilot Plant MSMPR VIDEO Courtesy of NVS-MIT Center 14
15 Model for Multistage MSMPR Population Balance: Conservation equation for the number of crystals in a population dni Gt i i ni n (1) i 1 dl Mass Balance n i : population density at stage i t i : residence time at stage i L: crystal size G i : crystal growth rate at stage i B 0 : nucleation rate 15 MT i 1 Crystal Growth Nucleation 3 s kv L ni dl Ci Ci G k B 0 g k C C Cs b s C C Cs s g b (2) (3) (4) M T i : Suspension density at stage i C: steady state solute concentration s : crystal density k v : volume shape factor C s : equilibrium concentration k g, g, k b, b: model parameters to be estimated
16 Kinetics Parameter Estimation a) Convert the experimental values of CSD into Population Density b) Find the values of k g, g, k b, and b that minimize the objective function F : min F Lmax n exp n calc ( L) 0 2 Subject to equations (1) to (4) where = [k g, g, k b, b ] 16
17 Purity % Yield % Modeling Work for Crystallization of Intermediate Modeled how changing temperature and residence time of each stage affects purity and yield Yield, % First Stage residence Time, min Second Stage Residence Time, min
18 Example 2: Tight Control of Continuous Aliskiren Reactive Crystallization O O OH H N NH 2 + a) HCl-gas, ipr 2 O b) NaOH, Me-THF O O O NH 2 OH O H N NH 2 O O NH 2 O O C11 92% C11 92%. 1/2 C11 (SPP-100 FREE BASE) C12(FUMARIC ACID) ALISKIREN (SPP-100) SALT 18
19 % C13 (mass/mass) C13 concnetration in the mother liquor, mass/mass UV control of fumaric acid addition O O OH H N NH 2 + a) HCl-gas, ipr 2 O b) NaOH, Me-THF O O O NH 2 OH O H N NH 2 O O NH 2 O O C11 92% C11 92%. 1/2 C11 (SPP-100 FREE BASE) C12(FUMARIC ACID) ALISKIREN (SPP-100) SALT 6.00% 5.00% 4.00% 3.00% 2.00% 1.00% C13 crystallization is very sensitive to fumaric acid/c11 ratio % Molar Ratio of acid/c11 Molar Ratio of fumaric acid/c11
20 Feed forward control Dilute drug substance UV flowcell Fumaric acid feed Filter & wash Water absorption column Reactive crystallization Solvent dilution Density flowcell R F F B A Drum dryer Silicon dioxide Vacuum dryer Extrusion/ molding Go P5 20
21 fumaric acid/c11; yield FA/C11 molar ration, Yield UV control of fumaric acid addition Vessel 1_FA/C11 molar Ratio Vessel 1_Yield Vessel 2_FA/C11 molar Ratio Vessel 2_Yield Time, day Time, days Tightly controlled Fumaric Acid addition by the control system can reach high yield with satisfactory crystal properties. 21
22 Example 2: Summary Starting from Isolated Freebase to final API Continuous process- effectively telescoped into 2 steps(15 L pilot-plant scale crystallizer), 8 hours total residence time First stage: simultaneous reaction and crystallization Second stage: further growth and nucleation Process Yield of 97% Conti. Process results in significantly shorter processing time compared to batch 22
23 Example 3: Control of Polymorphism in Continuous Crystallization There are limited studies on polymorphism in continuous crystallization Polymorphism impacts product bioavailability and manufacturability There are fundamental differences when moving from batch to continuous crystallization process: 23 Residence time distribution Secondary nucleation Seeding Efficacy Steady state vs. Equilibrium No solvent mediated transformation
24 Case study: L-glutamic acid Polymorphism: α form (metastable), β form (stable) Solvent: Water Characterization: polymorph ratio (Raman, XRD), solute concentration (FTIR) α form β form Business Use Only 24
25 Polymorph specific MSMPR achieved Studying the possibility to control polymorphism via manipulating stage temperature and residence time Residence time = 60 min, Temp = 25 C α form specific Polymorph specific MSMPR observed for the first time pure α form *Mass Ratio= α form/ (α form + β form) Business Use Only 25
26 Control of steady state polymorphism Effect of temperature and residence time on polymorphism: T=25 C T=45 C τ (min) ML conc. (g/kg solvent) Polymorphism α form α form α form α form β form β form Metastable Form Low Temp Short RT Stable Form High Temp Long RT 26 Business Use Only
27 Efficacy of seeding on Polymorphism Experimental Design: Single stage MSMPR (T = 25 C, τ = 60min) the unseeded steady state contains pure α form β polymorph seed added during startup: Seed type β form β form β form Seed mass 5% to M Teq 50% to M Teq 100% to M Teq Final form α form α form α form τ washout 4τ 7τ 9τ Seeding is unable to alter the steady state polymorphism, the seeds are removed in several residence time 27 Business Use Only
28 Example 4: Heterogeneous Crystallization on Patterned Excipients Excipient Chemical/ Biological Synthesis API Solution Continuous Crystallization Continuous Purification API-Excipient Composite Particles Tableting/ Encapsulation Advantages: Manufacturing process Streamlined downstream processing Control over crystallization kinetics through heterogeneous nucleation API properties masked by the excipient to simplify downstream process development Confidential API-excipient composite particles Widely tunable chemical, physical, and mechanical properties Potential to enhance API bioavailability Potential to control drug release profile Applicable to multiple API forms
29 Controlling API nucleation by tuning the nanopore shape No pore 15nm 40nm The scale bar is 200nm 120nm 300nm Polymer surfaces with nanopores of various shapes and sizes were fabricated by Nanoparticle Imprint Lithography (NpIL), as well as Nanoimprint lithography (NIL) 29
30 Aspirin: Crystal orientation suggests nucleation of (011) & (100) from the ledge (011) Crystal orientation verified by XRD (100) Growth direction Empty pores Pores with crystals 100nm Why not (002) & (100)? Scale bar is 100nm 30
31 Nucleation of mefenamic acid in anisole on HPMC surfaces Ln (P) Heteronucleant Type Type A (60 and 120 ) Type B (80 and 100 ) Type C (90 ) Induction time (τ, h) Error (h) Linearity (h) no polymer no pattern spheres Type A 60 and 120 spherical nano-pores Type B 80 and 100 absence of nano-pores Type C Type A Type B Type C -1.0 no polymer no pattern spheres Time 10.0(h)
32 Publication List 1. Zhang, H.; Quon, J.; Alvarez, A. J.; Evans, J.; Myerson, A. S.; Trout, B.; Development of Continuous Anti-Solvent/Cooling Crystallization Process using Cascaded Mixed Suspension, Mixed Product Removal Crystallizers, Organic Process Research & Development, 2012, 16, Quon, J. L.; Zhang, H.; Alvarez, A.; Evans, J.; Myerson, A. S.; Trout, B. L.; Continuous Crystallization of Aliskiren Hemifumarate; Crystal Growth & Design, 2012, 12, Wong, S. Y.; Tatusko, A. P.; Trout, B. L.; Myerson, A. S.; Development of Continuous Crystallization Processes Using a Single-Stage Mixed-Suspension, Mixed-Product Removal Crystallizer with Recycle, Crystal Growth & Design, 2012, 12, Alvarez, A, Singh, A., and Myerson, A.S. (2011). Crystallization of Cyclosporine in a Continuous Multistage MSMPR Crystallizer. Crystal Growth and Design 11, Wong, S.Y., Cui, Y., and Myerson, A.S., (2013). Contact Secondary Nucleation as a Means of Creating Seeds for Continuous Tubular Crystallizers. Crystal Growth and Design 13, Haitao Zhang, Richard Lakerveld, Patrick L. Heider, Mengying Tao, Min Su, Christopher J. Testa, Alyssa N D'Antonio, Paul I Barton, Richard D Braatz, Bernhardt L. Trout, Allan S. Myerson, Klavs F Jansen, James M. B. Evans* (2013). Application of continuous crystallization in an integrated continuous pharmaceutical pilot plant. To be submitted. 7. Ferguson S., Ortner, F., Quon, J., Peeva, L., Livingston, A., Myerson, A.S., (2013). Use of Continuous MSMPR Crystallization with Integrated Nanofiltration Membrane Recycle For Enhanced Yield and Purity in API Crystallization. Crystal Growth and Design (in review). 8. Mascia, S., Heider, P.L., Zhang, H., Lakerveld, R., Benyahia, B., Barton, P.I., Braatz, R.D., Cooney, C.L., Evans, J.M.B., Jamison, T.,Jensen, K.F., Myerson, A.S., and Trout, B.L., (2013). End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation. Angewandte Chemie International Edition (in press). 32
33 Acknowledgements Allan Myerson, Richard Braatz, Paul Barton Students, Postdocs, Staff Scientists Examples 1 & 2: Haitao Zhang, Justin Quon, Alejandro Alvarez, Richard Lakerveld, Sal Mascia, James Evans Example 3: Chris Lai Tsai-ta Example 4: Ying Diao, Vilamli Lopez-Mejias, Li Tan Novartis Pharma 33
34 34
35 35
36 Thank you! Questions?
37 Back-up
38 Polymorph transformation in MSMPR Single Stage MSMPR: 25 C, τ=2hr Seeding condition: 100% MT eq β seed Polymorph transform: β α Pure β form α crystal found State transition Business Use Only 38
39 Polymorph dynamic simulation Case Study objectives: Study the effect of seeding Effect of process parameters (residence time, temperature) on steady state polymorphism and stability Simulation methodology: Population balance equations (partial integro-differential equations) Mass balance between liquid and solids Method of characteristics solves PDE at steady state C feed Obtain steady state yield and polymorphism 300 rpm T=25 C Yield? Polymorph ratio? Business Use Only 39 Confidential
40 Simulation case 1: seeding efficacy Single stage MSMPR, T= 25 C and τ = 60min Regardless of the seeding conditions, steady state polymorphism remains unchanged (stable S.S.) Dynamic Simulation Results Different seed concentration 40
41 Simulation case 2: residence time Polymorph dominance at different τ was studied (25 C): Negligible β stable form at S.S. for τ<400 mins To reach > 50wt% stable form at S.S., τ>800 mins (13 hrs) Steady state polymorphism at different residence time Pure β Pure α 41
42 Implications from polymorph simulations Dynamic simulation can be used to determine the S.S. polymorphism and the S.S. stability Further investigate effect of temperature and residence time Metastable Form Stable Form Low Temp Short RT 13hrs High Temp Long RT May be difficult to obtain desired form at short residence time (>13hrs in the case of the commercial β L-glutamic acid) Design MSMPR system to achieve desired polymorph (β form) while reducing total residence time: Continuous seeding from MSMPR cascade 42 Stable form dominated T 1 T 2
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