Application to Drug Substance Crystallization Marino Nebuloni

Transcription

1 Application to Drug Substance Crystallization Marino Nebuloni REDOX Monza Parma University

2 Objectives of the presentation 1.Crystallization principles 2.What are QbD (Quality by Designe) and PAT (Process Analytical Technique)? 3.Analytical Techniques for PAT Application 4.Examples of PAT in Crystallization of API 5.Summary

3 Crystallization Processes 1 Crystallization is a core technology of many sectors in the chemical process and allied industries 2 Involves a variety of business sectors, e.g..agrochemicals, catalysts, dyes/pigments, electronics, food/confectionery, health products, nano-materials, nuclear fuel, personal products & pharmaceuticals 3 Processes can involve complex process chemistry together with non-ideal reactor hydrodynamics.hence can be difficult to understand and scale-up from laboratory to production scale operation 4 Crystallization also forms part of a wider process system

4 Crystallization Process Systems

5 CRYSTAL CHARACTERISTICS

6 Phase Equilibria Understanding phase equilibria is crucial to crystallizer operation Solubility-supersolubility diagram

7 Supersaturation Supersaturation, c, is sometimes called the concentration driving force

8 Crystallization Kinetics particle formation processes depend upon supersaturation

9 Process Analytical Technology (PAT) in the assessment and control the Critical Variables in Crystallization Processes

10 The application of PAT to the crystallization means understand IDENTIFICATION MEASUREMENT PAT PREDICTION

11 Scientific Contributions for the application of the PAT Analytical Sensor Quality and Hazard design PAT Process Control Data Data Analysis Analysis

12 Fundamental Approach in Development Traditional Approach Causal Links Predict Performance Quality by Design Scale Up Prediction Real Time Control for Continuous Improvement Decision Based On Univariate Approach Data Derived From Trial & Error Experimentation Modeling for Mechanistic Understanding DOE (Multivariate Systems Approach) Identification of PCCP* PAT PCCP* Process Critical Control Parameter

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14 Impact of On-line Process Analyzers - Crystallization - PAT Raw Material Reaction Purification Crystallization Isolation & Drying API Quality/Productivity Mechanistic & kinetic knowledge Parametric boundary Access to extreme conditions Real time monitoring & control Continuous quality assurance

15 Application for On-line Process Monitoring - Crystallization - SOLID STATE Physical properties intrinsic external Reaction Calorimetry FT-IR/ATR spectroscopy Raman Spectroscopy FBRM -Focuse BeamReflectance Measurements

16 Instrument characteristic requirements for on-line process monitoring

17 Analytical Techniques available on Spectroscopic Techniques the market NIR FT-IR/ATR Raman Light Scattering (laser) Mass-Spectrometry X-ray (Diffraction & Fluorescence) Turbidimetric and Rifractometric Techniques Turbidimetry Densitometry rifractometry Particles physical and morphologic properties Particle Size (FBRM) Photoacustic Etc.

18 Measurement technology review

19 REVIEW

20 Polymorphism and Particle Size modification during a crystallization process controlled by RC1, FT- IR/ATR and FBRM During a crystallization process of an API was observed : at the first step after seeding : * crystals with large Particle Size and polymorphic Form I at the second step (cooling phase): * Increase of small crystals instead of growth and transformation of the solid into polymorphic Form II

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22 First Step : Lab Scale FT-IR/ATR & FBRM (Lasentec) into RC1 calorimeter FT-- IR/ATR FBRM RC1

23 Crystallization Heat of API recorded by RC1 seeding ---- Form I Form I I --- Heat developed on the crystallization Reactor Temperature Conversion Heat Flow time (min)

24 N Totale N Conteggi di Particelle Esempio I Valore medio Crystallization Mean Diameter Profile and and Particles distribution count of byparticles FBRM Mean diameter DIAMETRO MEDIO Seeds Seeds (1) (1) (2) (2) (3) (3) Tr=36-->19 C Time (min) (4) (4) N Particles Maximum Growth Rate Time (min) 50 um 250 um Tr=36-->19 C (5) (5) Diametro Diametro Medio Medio (um) (um)

25 Esempio I FT-IR Polymorphic Form modification during the crystallization controlled by FT-IR/ATR (2) N Particles 0.45 N Totale di Particelle Form I (initial) (1) (3) (4) Tr=36-->19 C Form II (Final) Concentrazione Relativa Seeds (5) Time (min) -0.05

26 Second Step: lab-max & mini plant

27 Reaction Calorimetry RC1 profiles Heat developed on the crystallization Reactor Temperature With only one solvent (standard process) 3 Conversion 2 1 Heat Flow time (min) Seeds addition Crystallization induced by the cosolvent Modify method (with co-solvent) Heat flow Conversion time (min) -0.2

28 Third Step: production scale

29 On-line Control of crystallization of polymorphic forms and Particle Size by FBRM (Lasentec) Active Principle (API) can exist into two polymorphic forms Form I - m.p = 222 C By slow cooling Form II - m.p = 219 C By rapid cooling

30 FBRM (Focused Beam Reflectance Measurement) Probe scheme nicr CSDIR c1ir TuIR c2ir TICR TICR Batch Cooling Crystallizer: Experimental Set-Up c1ir: Concentration Measurement 1 (Oscillating U-Tube Measurement) c2ir: Concentration Measurement 2 (Ultrasound Velocity Measurement) TuIR: Turbidometer (Backscatter Measurement) CSDIR: Crystal size Distribution Measurement (Chord Length Measurement FBRM) jacketed crystallizer

31 Particle Size distribution by FBRM during the cooling steps Cooling step from 90 to 55 C Particle Size distribution on the time at 55 C

32 Final Particle Size distribution in relation to the process temperature

33 FBRM application for monitoring an API crystallization process influenced by ph, concentration, Temperature and Induction time

34 Critical Quality Paramiters Concentration ph Solid state FBRM on line Filtrability Induction Time

35 Information collected on the time during the crystallization

36 Time 0 time Nucleation Growing Induction Time

37 Laboratory Scale-up Production F.B.R.M. F.B.R.M. Definition of CQa Quality Control P.A.T. Optimization

38 Experimental Data N particelle Particelle 1-3 um Particelle 3-5 um Particelle 5-10 um Particelle um Particelle um Particelle um N totale di particelle Inizio 2h Tempo (h)

39 ph= 6.7 concentration : A mg/ml Poor filtrability Design Of Experiment Filtrazione F 7 A F 7 B F 6.7 A F 6.7 B NO F 7 A ph NO F 7 B NO F 6.7 A NO F 6.7 B Concentrazione

40 um 3-5 um 5-10 um um um um N totale particelle N particelle N particelle totali Inizio 3h tempo (h)

41 Final Result Filtrability F 7 A F 7 B 3 h F 6.7 A 2 h F 6.7 B NO F 7 A ph NO F 7 B 0.5 h NO F 6.7 A 0 h NO F 6.7 B Concentration Time

42 Impact of Agitation on Particle Size Distribution

43 Effect of Agitated Drying

44 Monitoring in Tumble Dryer

45 Continuous Crystallization controlled by PAT AIMS 1. To deliver consistent crystal quality (morphology, size and size distribution), not achieved consistently in large batch operations. 1. To investigate additional manufacturing advantages of COBC for crystallisation in continuous or semicontinuous modes 1. Improved filterability; 1. Reduced crystallisation time, space usage and utility and energy consumption; 1. Provision of seeding along the flow path.

46 Continuous Oscillatory Baffled Crystalliser Courteously by Jon-Paul Sherlock, AstraZeneca Continuous Material moves continuously through Oscillatory Although there is a net flow through the unit, the local flow moves back and forth Baffled. Reactor Small baffles are installed along the length to promote turbulence and hence mixing Or crystalliser, or extractor, or

47 How is mixing achieved? Mixing Mechanism Mixing controlled by oscillation Plug flow at relatively low flows Each cell is a CTSR Handles particulates

48 material moves through the crystalliser

49 Well controlled cooling rate

50 Product performance

51 Summary Advantage of PAT application i) Understanding of the uncertainties of the process; ii) Identification and quantification of the failure mechanisms on the crystallization process iii) Estimation of the risks associated with each step of the process. iv) Documentation of physical characteristics for the Regulatory Requirements

52 Thank you for your attention! Marino Nebuloni Parma University