In Process Monitoring of Polymorphic Form Conversion by Raman Spectroscopy

S Barnes, J Anderson, J Chen, D Ertl, J Rydzak

Outline

Background / Introduction

– Crystallization and crystal form

– In-situ techniques to monitor form conversionIn-line versus traditional off-line measurements

In-situ Raman spectroscopy to monitor solvent mediated form conversion

– In-situ measurements of reaction kinetics and Induction times

– Data analysis approaches – Multivariate Curve Resolution (MCR)

– Comparison of Raman spectroscopy and turbidity measurements

Conclusion

Introduction; Crystallization

Pharmaceutical crystallization is a common unit operation to stabilise and purify process intermediates and finished products.

Crystallization can separate very similar molecules relatively cheaply and easily.

Can control crystal size distribution, crystal morphology and polymorphic form

Particle size and shape affect down stream formulation and bioavailability

Solubility curve for a typical cooling crystallization

Active Pharmaceutical Ingredients (APIs) are found in different polymorphic forms

Polymorphs have different properties: solubility, dissolution, stability, bioavailability.

Develop robust process to consistently make desired form for secondary processing

Full characterization of phase diagram identifies most stable crystal form at any operating condition

Thermodynamic Temperature

Solvent concentration

Purity

Kinetic Hold time at isolation temperature

Cooling rate

Equipment; mixing, heat transfer

Seed

Introduction; Crystal Form

Off-line Measurement of Polymorphic Form

Different polymorphs identified by a number of off-line analytical methods FTIR Raman XRPD DSC

Off-line techniques provide no continuous information Sampling delay Form can be very fast or can occur over night to days

Change in processing history isolation, drying

MonohydrateAnhydrateMethanol solvate 1

Methanol solvate 2

XRPD traces; all four forms

In-Situ Spectroscopic Analysis of Crystal Form

In-line monitoring techniques can be applied for analysis of:

– De-super saturation (ATR-FTIR)– Particle size (FBRM)– Particle shape (lasentec PVM)– Polymorphic form (Raman, NIR)

In-situ Raman spectroscopy can be applied to monitor form transformations

– Rapid sampling; no delay– No sample preparation– Non-destructive measurements. – Kinetic and thermodynamic information– Versatile sampling interface

Raman data provides molecular specific data

– Turbidity– Lasentec / FBRM

 

Experimental Details

Raman data acquired using a Kaiser Rxn-1 system– 785 nm laser– Short focus immersion probe, 18” long, ½ “ dim – Data acquisition time of 10 seconds (10 sec exposure 1

accumulation)

In-situ data obtained from slurry samples in 1L JLR

– Methanol / water solvent system – Rapid agitation of slurry with temperatures ranging from 0 – 70 o C

Data analyzed in real-time

– Real-time analysis in HoloReact– Trending of peak areas / derivatives– Application of MCR

Results supported by off-line analysis of grab samples

– FTIR– XRPD– Optical Microscopy

Raman probe

Off-line Data; Four Crystal Forms

AnhydrateMonohydrate

Methanolate 1 Methanolate 2

Four polymorphic forms identified Anhydrate, monohydrate, 2 methanolate forms

Form obtained dependant on a number of factors

Solids added

Slurry temperature

Solvent content

Hold time before isolation

Optical microscopy Standard method form identification

Change in crystal structure and particle size observed between forms

Physical properties Processability

Off-line Raman Spectra of Crystal Forms

Off-line Raman spectra of the monohydrate, anhydrate and methanolate in powder form

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Raman shift (cm-1)

HYDRATEMETHANOLATE (M1)ANHYDRATE

Distinct differences in spectral features of the three forms in solid state

Off-line Raman Spectra of Methanol Solvates

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Spectral differences for two methanolate forms (M1 and M2)

METHANOLATE (M1)METHANOLATE (M2)

Strong differences in spectral data of solid samples

Differences in in-line data more subtle due to strong solvent bands Identification of isolated features ascribed to each form

In-line Raman Data of Form Conversion at 25 C

Methanolate (M1)

Anhydrate

Time (days)

Waterfall plots of in-situ Raman data acquired over time during form conversion from anhydrate to methanolate at 25 C

Data acquired over 2 days Induction time 12 hours First methanolate form observed

Wavenumber shifts Appearance of new features

1148 cm-1

Emergence of peak at 1148 cm-1 on formation of the methanolate

Change in baseline integrated peak area over time used to map form change in real-time

Methanolate

Anhydrate

Anhydrate

Methanolate (M1)

Real-time Data Analysis: HoloReact

MCR Analysis of Raman Data

Data analyzed in real-time using HoloReact– Data clipped (1100 – 1500 cm-1)– Persons Baseline correction– 1st derivative

2 Principal components

Excellent agreement between trend plots and PCs from MCR

– MCR for form change profiles– Real-time kinetics information

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Raman Data for Form Conversion at 0 C

In-situ Raman data acquired during form conversion from anhydrate to methanolate 2 at 0 C

Spectrum no.

Anhydrate

Methanolate 2

Integrated area of feature at 1200 cm-1 used to map form

Conversion confirmed by XRPD and FTIR

Raman and Turbidity Data for Form Conversion

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Turbidity data

Seeding Anhydrate at 0C

Methanolate 2, 0C

Dissolution

Excellent correlation between data from turbidity and Raman measurements

Both techniques sensitive to change in form from anhydrate to M1 at 25 C

Turbidity sensitive to change in particle size during form conversion

Raman Data of Transformation kinetics

Raman measurements of form change induction time as a function of isolation temperature

Temp of Isolation (C) Induction time for 1st Trace of Solvate

Solvate form produced on holding

20 C 25 hrs M110 C 12 hr M2

3 C 9 hr M2

0 C 7 hr M2

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Lower temperature reduces induction time for conversion to solvate

Data shows a decrease in the time for isolation and recovery of the API at lower temperatures

Determination of induction time and form change kinetics

Raman Data; Phase Diagram

Thermodynamic Stability of Forms A, H and M1 and M2

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Phase diagram showing stability of all four forms as a function of temperature and water content

Raman data used to gain knowledge of the process over range of solvent compositions and temperatures

Removes / reduces need for off-line samples

Data acquisition less labor intensive

Develop understanding of the design space for a cooled seeded crystallization in this solvent system

Summary

Raman is an effective technique for in-situ identification of polymorphic form– Kinetic measurements of form transformation– No sample preparation– Less labor / time intensive

Application of in-situ Raman allowed process understanding of the final crystallization step

– Affect in solvent composition and temperature on form– Time for API isolation before form conversion at each temperature

Excellent agreement between Raman and turbidity measurements for measurement of form transformation

– Raman molecular specific but more expensive – Turbidity – inferential measurement but simple to implement

Software interface allows Raman to be used extensively in the lab as an in-situ diagnostic tool

– MCR and peak integration methods developed for simplified routine analysis

Acknowledgments

Jason Gillian

Delphi Burton

Ann Diedrich

Duncan Thompson

Colleagues in US PAT&C

FACSS organization for the opportunity to present

Thank you for your attention

Questions?