Application to Drug Substance Crystallization Marino Nebuloni REDOX Monza Parma University
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
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
Crystallization Process Systems
CRYSTAL CHARACTERISTICS
Phase Equilibria Understanding phase equilibria is crucial to crystallizer operation Solubility-supersolubility diagram
Supersaturation Supersaturation, c, is sometimes called the concentration driving force
Crystallization Kinetics particle formation processes depend upon supersaturation
Process Analytical Technology (PAT) in the assessment and control the Critical Variables in Crystallization Processes
The application of PAT to the crystallization means understand IDENTIFICATION MEASUREMENT PAT PREDICTION
Scientific Contributions for the application of the PAT Analytical Sensor Quality and Hazard design PAT Process Control Data Data Analysis Analysis
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
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
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
Instrument characteristic requirements for on-line process monitoring
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.
Measurement technology review
REVIEW
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
First Step : Lab Scale FT-IR/ATR & FBRM (Lasentec) into RC1 calorimeter FT-- IR/ATR FBRM RC1
Crystallization Heat of API recorded by RC1 seeding ---- Form I --------- Form I I --- Heat developed on the crystallization 5 40 4 Reactor Temperature 35 30 3 2 Conversion 25 20 1 0 Heat Flow 15 10 5-1 50 100 150 200 250 300 0 time (min)
N Totale N Conteggi di Particelle 45000 450 40000 400 35000 350 30000 300 25000 250 20000 200 15000 150 10000 100 5000 50 0 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 50 100 150 200 250 300 350 0 Time (min) 50 100 150 200 250 300 350 (4) (4) N Particles Maximum Growth Rate Time (min) 50 um 250 um Tr=36-->19 C (5) (5) 40 40 35 35 30 30 25 25 20 20 15 15 10 10 5 5 0 0 Diametro Diametro Medio Medio (um) (um)
Esempio I FT-IR Polymorphic Form modification during the crystallization controlled by FT-IR/ATR 45000 0.5 40000 (2) N Particles 0.45 N Totale di Particelle 35000 30000 25000 20000 15000 Form I (initial) (1) (3) (4) Tr=36-->19 C Form II (Final) 0.4 0.35 0.3 0.25 0.2 0.15 Concentrazione Relativa 10000 Seeds (5) 0.1 0.05 5000 0 0 50 100 150 200 250 300 350 Time (min) -0.05
Second Step: lab-max & mini plant
Reaction Calorimetry RC1 profiles Heat developed on the crystallization 5 40 4 Reactor Temperature 35 30 With only one solvent (standard process) 3 Conversion 2 1 Heat Flow 0-1 50 100 150 200 250 300 time (min) 25 20 15 10 5 0 Seeds addition Crystallization induced by the cosolvent Modify method (with co-solvent) 18 16 14 12 10 8 6 Heat flow Conversion 1.2 1 0.8 0.6 0.4 4 0.2 2 0 0-2 100 120 140 160 180 200 220 240 260 280 time (min) -0.2
Third Step: production scale
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
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
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
Final Particle Size distribution in relation to the process temperature
FBRM application for monitoring an API crystallization process influenced by ph, concentration, Temperature and Induction time
Critical Quality Paramiters Concentration ph Solid state FBRM on line Filtrability Induction Time
Information collected on the time during the crystallization
Time 0 time Nucleation Growing Induction Time
Laboratory Scale-up Production F.B.R.M. F.B.R.M. Definition of CQa Quality Control P.A.T. Optimization
Experimental Data 8000 30000 N particelle 7000 6000 5000 4000 3000 Particelle 1-3 um Particelle 3-5 um Particelle 5-10 um Particelle 10-21 um Particelle 23-50 um Particelle 54-100 um N totale di particelle 25000 20000 15000 10000 2000 1000 Inizio 2h 5000 0 0 0.00.00 2.24.00 4.48.00 7.12.00 9.36.00 12.00.00 14.24.00 16.48.00 19.12.00 Tempo (h)
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
6000 25000 5000 4000 1-2 um 3-5 um 5-10 um 10-21 um 21-50 um 54-100 um N totale particelle 20000 N particelle 3000 15000 10000 N particelle totali 2000 1000 Inizio 3h 5000 0 0 0.00.00 2.24.00 4.48.00 7.12.00 9.36.00 12.00.00 14.24.00 16.48.00 19.12.00 tempo (h)
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
Impact of Agitation on Particle Size Distribution
Effect of Agitated Drying
Monitoring in Tumble Dryer
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.
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
How is mixing achieved? Mixing Mechanism Mixing controlled by oscillation Plug flow at relatively low flows Each cell is a CTSR Handles particulates
material moves through the crystalliser
Well controlled cooling rate
Product performance
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
Thank you for your attention! Marino Nebuloni Parma University