© 2017 H. Lundbeck A/S – All Rights Reserved

LUNDBECK PHARMACEUTICALS ITALY

Applicazione della spettroscopia Raman in-line nell’ottimizzazione di processi di cristallizzazione di principi attivi farmaceutici e loro intermedi sintetici Florian Huber Process R&D Department

Workshop Quality by design Un’opportunità per l’industria farmaceutica Venerdì 3 Febbraio 2017 - Archivio Antico, Palazzo Bo

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Lundbeck is an international pharmaceutical company engaged in discovering, developing and commercializing new and innovative treatments for psychiatric and neurological disorders Headquarters at Copenhagen. Two Chemical Production Sites (Denmark and Italy).

Lundbeck Pharmaceuticals Italy SpA (LUPI) / Padova • 115 employees (18 in Process R&D) • API production • Custom Manufacturing • Generics

LUNDBECK IN BRIEF

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Process Analytical Technology (PAT)

a definition (FDA / Food and Drug Administration): “A system for designing, analyzing, 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.”

PAT – a QbD Tool

• Analytical instruments used to measure those parameters over

time • Example: In-line monitorning using Raman spectroscopy

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Monitoring: In-line (Probe), On-line, At-line, Off-line

In-line

On-line (by-pass loop)

At-line Off-line

Laboratory Setup:

immersion probe

Laboratory Setup:

sample chamber

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Process Optimisation using the Raman Probe

Process monitoring

Process understanding

Identification of Critical Process Parameters (CPPs) that affect Critical Quality Attributes (CQA)

Process optimisation in terms of yield, purity and robustness

The Raman probe is used in laboratory and not in full scale production.

“Render the process so robust, that monitoring in production is not necessary.”

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Raman Spectroscopy

Principles of the Raman Spectroscopy Equipment (Hardware and Software) Applications and Case Studies

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Raman Spectroscopy

Principles of the Raman Spectroscopy

Equipment (Hardware and Software) Applications and Case Studies

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(Very) Basic Principles

SCATTERING phenomenon characterized by a change of frequency RAMAN scattering is related almost exclusively to VIBRATIONAL energy levels

1 in 10 million photons

1 %

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Spectral Information

IR Spectrum

Raman Spectrum

Courtesy of Kaiser Optical Systems, Inc.

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How does a Raman spectrometer work?

Note: Lenses not shown Fixed Holographic Transmission Grating

Laser

Sample

Slit

Notch Filter

Low λ: 120-1900 cm-1

High λ: 1900 – 3450 cm-1

Simultaneous collection on Peltier cooled CCD Detector Quick "One-Shot" Analysis

Courtesy of Kaiser Optical Systems, Inc.

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Principal Features

Low intrinsic sensitivity of this techniques can be now overcome with powerful laser and new detectors.

Raman spectra can be measured irrespective of the state of substance (solution – suspension - solid).

Small quantities are necessary.

Raman intensity proportional to concentration.

Can be used in aqueous environments (contrary to IR).

A serious drawback can be the fluorescent interference.

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Raman spectroscopy

Principles of the Raman Spectroscopy

Equipment (Hardware and Software) Applications and Case Studies

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Raman Spectrometer

C. Venkata Raman The Raman effect was first reported by C.V. Raman and K.S. Krishnan in 1928. Raman received the Nobel Prize (Physics) in 1930 for his work on the scattering of light.

Courtesy of the Indian Association for the Cultivation of Science.

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Raman Spectrometer

Raman Analyzer RXN2 Kaiser Optical Systems

Immersion probe Optical fibre cable (cavo fibra ottica)

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Raman Spectroscopy

Principles of the Raman Spectroscopy

Equipment (Hardware and Software) Applications and Case Studies

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Milling

Produce Drug (API)

Reaction Monitoring

Crystallization Drying

Raman Probe

Granulation

Raman Probes

Blending

Raman Probe

Coating

Raman Probe

Pharma X

Tableting

Raman Probe

Typical Manufacturing Process

Courtesy of Kaiser Optical Systems, Inc.

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Case Studies and Applications

CASE 1: Classical resolution (crystallisation) CASE 2: Transformation of polymorphs in

suspension monitored by Raman spectroscopy

Case 1: QdB/PAT application in the optimization of a resolution process

Escitalopram (Cipralex ®, Lexapro ®) is a Lundbeck CNS antidepressant

obtained industrially from the enantiomeric separation of its key racemic-diol intermediate via diasteromeric salts (classical resolution process)

ONC

F

N

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NC

F

N

OH

OH

D-(+)-di-p-toluoyl-L-tartaric acid

OO

COOH

HOOC

O

O

D-DTTA

NC

F

N

OH

OHO

OCOOH

HOOC

O

O+

rac-DIOL

S-DIOL D-DTTA saltDIASTEREOMERIC SALT A

NC

F

N

OH

OHO

OCOOH

HOOC

O

O

R-DIOL D-DTTA salt

DIASTEREOMERIC SALT BLundbeck Patent: US8022232B2

Process optimisation using the Raman probe in-line Monitoring of diasteromeric salt crystallisation

Small differences in the solubilities of salt A (wanted) and salt B (unwanted) in alcohol. Diastereomeric salts A precipitates first, then afterwards also the undesired salts B precipitates. Resolution process is therefore kinetically and not thermodynamically controlled. Isolation of diastereomeric salt A has to be done prior to precipitation of B.

Goals of optimisation using the Raman probe:

• Increase process robustness by delaying precipitation of unwanted diastereomeric salt B as much as possible in order to obtain highly pure salt A (quality issue!)

• Optimisation of crystallisation yield.

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Comparison of Raman spectra: spot the differences

0

100000

200000

300000

400000

500000

600000

Inte

nsity

2004006008001000120014001600180020002200240026002800300032003400

RamanShift (cm-1)

15201540156015801600162016401660168017001720174017601780

RamanShift (cm-1)

tems / METTLER TOLEDO

Raman spectroscopy proved to be the only (available) technique able to distinguish between the two diastereomeric salts in suspension of the resolution mixture.

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Raman Spectra of Single Compounds

“diagnostic” Raman wave-number region at 1700 cm-1:

Red: salt A (wanted)

Blue: salt B (unwanted)

Green: 50:50 mixture

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During crystallisation record many spectra over time (sequence of single spectra)

3-D surface ‘bird-view’

Correlation of Raman spectra with chiral HPLC data (in process samples taken throughout experiment)

IPC1 97.5% IPC2 87.6% IPC3 74.3% IPC4 66.6% IPC5 60.0%

A model can be built with the Raman software correlating: Peak Area Ratios (RAMAN) vs. enantiomeric purity (HPLC) of isolated in-process samples (composition A vs. B) A linear correlation with excellent fit (R squared = 0.999) was obtained

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Stacked RAMAN spectra Chiral HPLC

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Trend graph based on optical purity model

Dia

ster

omer

ic s

alt A

(en

anti

omer

ic p

uri

ty %

)

time

50%

100%

Precipitation of unwanted salt A

The built model can be applied in a new resolution experiment, thus the crystallization can thus be followed in real time viewing the new trend graph.

The enantiomeric purity of the precipitated diastereomeric salts – expressed as % of salt A - is given in real time.

Levels of salt B lower than 5% can be detected. A second model was then build for the yield. Time window

1 hour

Final optimisation (PAT, DoE, MVA)

Combination of PAT with DoE (output: enantiomeric purity, how big is the time window, yield) and MVA (plant data). The monitoring with Raman helped Process R&D to increase the process understanding with the assessment of the Critical Process Parameters (CPPs) and definition of their proven acceptable ranges (PAR).

Crystallisation temperature is critical, since a decrease of only 2°C during the first part of the crystallisation influences the crystallization robustness anticipating the unwanted salt B precipitation.

Presence of traces of water and/or some organic solvents delays unwanted salt B precipitation, but do not lead to any yield increase.

A higher stirring rate anticipates the unwanted salt B precipitation.

Temperature and time of final ‘aging’ influence product yield, as expected. Longer aging time and lower temperatures increases the yield but are detrimental to the optical purity (a compromise must be taken).

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Case 2: Transformation of Polymorphs in Suspension

Two polymorphs* can be formed in the final crystallisation of an API: alpha and beta.

Reinvestigation of Critical Process Parameters (old data based on in-process samples and DSC analysis): stirring speed, temperature, choice of solvent. Polymorph beta (unwanted): Kinetic product. Polymorph alpha: more stable form (desired crystal form in API).

Transformation of beta into alpha occurs: How fast? (lack of data).

* Polymorphism is the ability of a solid material to exist in more than one form or crystal structure.

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Comparison alpha vs. beta polymorph

70075080085090095010001050110011501200125013001350140014501500

RamanShift (cm-1)

119512001205121012151220122512301235

RamanShift (cm-1)

Ra

ma

nS

hift

(cm

-1)=

12

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20336-4 4/8/2011 4:38:53 PM=484,978.13

Spectrum of solid in-process sample (beta form in red) vs. solid API lot (alpha form in blue)

Also a very small shift in Raman wave numbers (3-4 cm-1) distinguishes the two forms.

beta alpha

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Transformation of polymorphs in suspension monitored by Raman spectroscopy

129000

130000

131000

132000

133000

134000

135000

136000

137000

138000

rew

119912001201120212031204120512061207120812091210121112121213

RamanShift (cm-1)

Ram

anS

hift

(cm

-1)=

1204

20392 4/15/2011 12:28:57 PM=137,800.07

0

0.02

0.04

0.06

-0.02

-0.04

-0.06

-0.08

-0.1

-0.12Pe

ak

01:00:00 01:10:00 01:20:00 01:30:00 01:40:00 01:50:00 02:00:00 02:10:00 02:20:00 02:30:00

Relative Time

Elap

sed

time=

01:2

4:56

alpha form

beta form

beta form alpha form

30 min

Single Raman spectra showing the transformation of beta into alpha polymorph, monitored by the Raman in-line probe.

Trend graph (based on peak integration) showing in green the disappearance of the beta polymorph and in blue the formation of the alpha polymorph.

Conclusion: at a certain temperature the transformation is fast. “Just wait to isolate the product”.

DOMANDE?

Book recommendation

Pharmaceutcial Applications of Raman Spectroscopy Slobodon Šašić Wiley-Interscience 2008 ISBN 978-0-8138-1013-3