Process Analytical Technology Applications in Crystallisation Development

Transcription

1 Process Analytical Technology Applications in Crystallisation Development Amy Gillon-Robertson Process Engineering, Process R&D, AstraZeneca R&D Charnwood, Loughborough, UK

2 Overview Process Analytical Technology (PAT) Introduction Summary of PAT techniques Case Study 1 Applications of ATR UV/Vis spectroscopy in crystallisation Open and closed loop systems Supersaturation feedback control Case Study 2 Sibenadet Hydrochloride Structure solution Crystallisation investigations using FBRM Conclusions

3 Solid State Analytical Techniques Off-line techniques routinely used to investigate the solid form Remacemide HCl Batch: 102/ Cps Theta /1757, :42:59 1/1757, mg Integral mj normalized Jg^-1 P eak C Left Limit C Right Limit C 20 mw C min Weight (%) % ( mg) % ( mg) Temperature ( C)

4 Process Analytical Technology (PAT) FDA definition of PAT A system for designing, analysing and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality Developed further within PAT guidance to include risk analysis, statistical process control and design of experiments In-line Measurements Automated measurements conducted on samples in the process vessel

5 Focused Beam Reflectance Measurement - FBRM Crystal size distribution dissolution cloud clear crystallisation

6 Particle Vision Monitor (PVM) Lasentec in-process video PVM700 microscope and imageanalysis system for use in high-solidsconcentration slurries % solids conc. 5um 1mm size range Image analysis possible to measure crystal size and aspect ratios in situ

7 ATR UV/vis Probe Hellma ATR UV/Vis probe and Zeiss MCS 500 spectrometer used The ATR probe uses a 3- bounce sapphire ATR crystal, which is directly immersed into the solution to be measured. Evanscent wave penetrates only a few microns into solution-does not see crystals

8 ATR UV/Vis Crystallisation UV / ATR absorbance measurements are often temperature dependant but so is the solute concentration. To derive accurate concentrations from absorbance measurements, they must first be corrected for temperature. Calibration data by HPLC d2y/dx2 (Absorbance) x C elc ius 15 Celcius 25 Celcius 35 Celcius 45 Celcius 55 Celcius As temperature decreases, absorbance increases x onset of crystallisatio n Compound dissolving Absorbance at 273nm compound is fully dissolved in this region Temperature (Celcius)

9 PAT Techniques Automated measurements on samples in the process vessel (in-line) Turbidity FBRM PVM ATR-UV/Vis Spectroscopy ATR-FTIR spectroscopy Raman Spectroscopy NIR These are used in conjunction with: At-line Optical microscopy Off-line Environmental scanning electron microscopy (ESEM) X-ray powder diffraction, DSC, TGA etc.

10 PAT Benefits Obtain solubility data (Turbidity, FBRM) Monitor and control solution concentration (UV/vis) Monitor polymorphic transformations (Raman, FBRM) In-situ microscopy (PVM) In-situ particle characterisation (PVM, FBRM) Increase process understanding Demonstrate batch to batch consistency or provide information on variability Optimum process design

11 Laboratory Crystallisers

12 Case Study 1 Applications of ATR UV/Vis Spectroscopy in Crystallisation

13 Open and Closed Loop Feedback Control Open loop strategies - control of supersaturation is by a previously entered cooling profile Closed Loop strategies - feeding back information on the supersaturation level during a crystallisation and using this information to vary the temperature to keep the supersaturation at a specified level.

14 Cooling Crystallisations T a b c Natural cooling (a) Process reaches high supersaturation Linear cooling (b) Supersaturation is not constant supersaturaion Natural cooling time Linear Controlled Time Non-linear cooling (c) Supersaturation is constant Crystallising from constant supersaturation Maximise growth, minimisation nucleation/secondary nucleation/agglomeration

15 Recrystallisation of Compound X Compound X is polymorphic Forms A-G identified 2 solvates H and I identified A G Form A is crystallised in the crude stage Form G is recrystallised from Form A in IMS:Water 2:1 (10 vols) Requirements: Increase yield from 80% Solvent system with a wider MSZ Maintain form, purity and morphology CPS AR_D119137XX_85.raw AR_D119137XX_83.raw AR_D119137XX_31.raw AR_D119137XX_28.raw AR_D119137XX_21.raw AR_D119137XX_9.raw AR_D119137XX_8.raw AR_D119137XX_5.raw AR_D119137XX_1.raw Deg.

16 Solubility Measurements MEK and acetonitrile alone, and with water added, exhibit higher solubility then the current IMS/water system which would result in a lower product yield. Gravimetric solubility studies at elevated temperatures demonstrated potential benefits for an n-propanol/water system over other alcohol/water due to the ability to heat to higher temperatures before reaching reflux. Solubility AZD3342 (mg/m l) Solubility (mg/ml) % a lcoh ol n-propanol Ethanol IMS iso-propanol Compound X (mg/10 rel vol) Temperature (ºC) 67% IMS 50% 1-propanol

17 In-line ATR-UV/vis Approximate concentration (3 point calibration curve) Data Manipulation: Baseline zero 1 st derivative over 11 point interval multiplied by 1 Value at 235nm used Linear temperature correction applied

18 Experimental DoE methodology. Experiments carried out on a 200ml scale monitored by ATR UV/vis probe Individual experiments scaled to 750ml monitored by FBRM, PVM seeded and unseeded experiments linear and cubic cooling profiles

19 Results Unseeded Crystallisation Spontaneous crystallisation using a linear cooling profile produced agglomerates growth Lasentec data agglomeration Concentration B A nucleation Large crystals C Temperatu re crystals aggregate agglomeration

20 Results Seeded Crystallisation Non-linear cubic cooling seeded crystallisation produced large unagglomerated crystals FBRM (#/sec) time (hours) Temperature (ºC) #/s 1-10 Median sq Mean Sq wt #/s 1-5 #/s 5-25 #/s #/s #/s Tj Tr

21 Seeded vs unseeded (linear unseeded cool) (seeded cubic cool) Concentration (m g/m l) heating cooling MSZW Temperature (ºC) Concentration (mg/ml) heating cooling Temperature (ºC)

22 Open Loop Summary New solvent system 1:1 propan-1-ol:water Optimised cooling profile and rates Optimised seed loading and seeding temperature Robust process to crystallise the correct polymorphic form, of suitable purity and size and improved yield

23 Feedback Control of Supersaturation FTIR/UV/vis FBRM crystalliser spectra calibration Reactor temperature control supersaturation concentration If S<S max then T If S>S max then T In batch crystallisation, usually the feedback controller is designed to follow a temperature profile rather than a supersaturation profile simply because of ease of measurement An alternative approach is to follow the supersaturation profile in the metastable zone using UV-Vis measurements, i.e. closed loop control applies a feedback strategy to calculate the desired control effect.

24 SSF T vs C Profile Concentration (mg/ml) Temp C linear 0.3C/min solubility SSF0.5 SSF0.2 SSF0.8 SSF0.1

25 SSF0.1 SSF0.2 SSF0.5 SSF C/min Amy Gillon-Robertson

26 Temperature and Supersaturation Profiles SSTCvsTemp SSF Temp SSF0.1 SSF0.2 SSF0.8

27 Benefits of Feedback Control Direct Control Improved control of polymorphs Potential to engineer size and shape of crystals by controlling desupersaturation rates Potential to avoid secondary ops i.e. milling Avoid lengthy aging times.

28 Case Study 2 Sibenadet Hydrochloride

29 Sibenadet Hydrochloride HO N H S O H.HCl N O S O O Form I From the earliest batches some variation in the solid-state properties of the HCl salt were observed -particularly the DSC thermograms Other techniques, eg (XRPD) also showed differences Form II Implied the existence of polymorphs

30 XRPD Data Long spacings Short spacings Lin (Counts) Form I + II Form I mix Form I Theta - Scale Regular reflections indicate a layer type structure common in long-chain molecules, eg. alkanes Form II Form II

31 Crystal Structure Determination Crystals consist of small, very thin plates (<1μm)- not suitable for laboratory single crystal determination K Ab initio structure solution from powder diffraction data using DASH (in collaboration with Rutherford Appleton laboratory) was unsuccessful due to problems with indexing normalised intensity theta High resolution XRPD data for Form I obtained from synchrotron (Daresbury) RT

32 Crystal Structure Form I Determined using a microcrystal on station 9.8 of the Synchrotron Radiation Source, CLRC Daresbury laboratory Space group: P2 1 /n Unit cell: a= 5.349(4) b = 81.91(8) c = (4) β= Model confirmed disorder in phenyl groups Cosgrove et al. J Pharm Sci (2005), 2403

33 Crystal Structure..HNH.Cl.HNH linkage (CO..HN) H-bonded dimer motif

34 Crystallisation Turbidity (%) Methanol/HCl/water (0.15 C) Temperature-solubility curve cooling MSZW heating Solubility mg/ml MeOH/H+ Expon Temp/ C -20 Temperature ( C) Temperature ( C) MSZW as function of cooling/heating rate Cooling/heating rate ( C/min) Recrystallisation based on a cooling crystallisation 40 C metastable zone width means solution will substantially supersaturate before crystallisation will lead to small crystals Seed!

35 Crystallisation FBRM Data

36 Control Measures Because of the wide metastable zone spontaneous crystallisation was to be avoided Therefore seed added (3.1% w/w (minimum) added between C Controlled cooling profile (0.1 C/min)

37 Conclusions PAT Provides process understanding and can reduce process failures Can identify the root causes of process deviations Two applications of an ATR UV/vis probe have been demonstrated. In the open loop experiments the probe was used to monitor the changes in concentration with predetermined temperature profiles enabling the optimum cooling profile to be selected In the closed loop experiments the probe was used to monitor the concentration in solution and feed the information to the temperature control to allow the supersaturation factor to be kept at a predetermined value FBRM data was used to explain the occurrence of very small crystals of Sibenadet Hydrochloride

38 Acknowledgments Gerry Steele Case Study 1 Richard Bell, Peter Morgan Case Study 2 Steve Cosgrove, Nayna Govind, Phil Plumb, David O Sullivan, Talbir Austin, Mel Giles, Steve Eyely, Colin Thomson, Birgitta Stensland, AstraZeneca Elizabeth MacLean and Simon Teat, CCLRC Kevin Roberts (currently University of Leeds) and Elena Ferrari (currently University of Milan)