Organic Solvent Nanofiltration (OSN) in Pharmaceutical Processing

NYM – Sept 2012

Dr. Chris Pink, Elin Rundquist

Presentation Overview

Introduction:

–Background to GSK –Potential applications of OSN to the pharmaceutical industry

Case studies: –Application 1 – Removal of Genotoxic Impurities (API purification) –Application 2 – Application in Liquid Chromatography (solvent swap) –Application 3 – OSN as an Alternative to Distillation (solvent recovery)

GlaxoSmithKline

1. https://pharmaview.decisionresources.com/TherapyArea/5/Overview

GSK are world leaders in the sales of respiratory drugs and vaccines (currently 24%, and 22% of the market share respectively)1

Sales for Top 7 Companies

GSK’s biggest drug brands include:

Advair/Seretide for asthma Flovent / Flixotide for asthma

Infanrix/Pediarix a combination vaccine Hepatitis vaccines

GSK’s biggest consumer brands include:

Lucozade - Sports drink NiQuitin - Nicotine products

Aquafresh - Toothpaste Sensodyne - Toothpaste

Panadol - Painkiller

API Manufacturing Process Overview

Reactions and Separations Particle Forming Unit Operations Reaction

Extraction

Distillation

Crystallisation

Filtration

Drying

•GSK’s Environmental Sustainability Strategy is increasing mass efficiency targets.

•Production plants increasing focus on process energy efficiency as well as mass efficiency.

OSN Introduction

Purification – MW A>B – Constant volume diafiltration – Gradual addition of fresh solvent – Smaller solutes are gradually washed out

Concentration – Removal of solvent, retention of API. – Can potentially be combined with solvent recovery or purification step – Ideally require 100% rejection of desired compound

Impurity removal through constant volume diafiltration Concentration of process solution

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Potential OSN Applications

Reaction

Extraction

Distillation

Crystallisation

Filtration

Drying

Post reaction purification?

Solvent recovery?

Solvent swaps?

API lost in crystallisation liquors, and cake washes can total 5-25% of batch yield

Solvent/ API recovery?

Solvent/ API recovery?

Applications in Waste Treatment

Waste Water Treatment (biological)

–Odorous compounds need to be removed (if plant is open air)

–Low concentrations of organic solvents (roughly under 10% but depends on solvent)

Waste Solvent Incineration

–No traces of silyl compounds, removal using membranes?

–Ideally high calorific value streams

Application 1: Genotoxin removal API Purification

Process stream 1: – API ≈ 500 g mol-1 – Acetamide (59.1 g mol-1) – Ethyl acetate – API rejection: 97.7% – GTI rejection: 1.3% – Flux: 21 L m-2 h-1 – Separation potential: 96% – Target: 5% wt. acetamide – Solvent requirement: 2.7 DV

Process stream 2: – API ≈ 500 g mol-1 – Benzyl 2-Bromoethyl ether (215.1 g mol-1) – N-propanol – API rejection: 99.7% – GTI rejection: 30.0% – Flux: 4 L m-2 h-1 – Separation potential: 70% – Target: 5% wt. Benzyl 2-Bromoethyl ether – Solvent requirement: 4.2 DV

Concentration in feed solution during diafiltration (using Duramem 200) for process stream 1 (left) and 2 (right)

API Genotoxin

API Genotoxin

Application 1: Genotoxin Removal Process Comparison and Conclusion

Process Comparison and Conclusions: Genotoxin Removal – API losses can be significant even at high rejections – OSN can be a solvent intensity technique – High flux is desirable to minimise processing time and required membrane area – Benefits to OSN application has to be evaluated on an individual project basis

compared to purification method currently in use

Comparison parameter Process Stream 1 Process Stream 2 Impurity target (% wt.) 5 5 Separating potential (%) 96 70 Yield loss (%) 6.0 1.2 Solvent requirement (L g-1 purified API) 0.6 0.8 Processing time (h L-1m-2) 0.07 0.3

Process comparison data for OSN genotoxin removal

Application 1: Genotoxin Removal Solvent Recycle Through Adsorbent Loop

Objective: Solvent Recycle – Address OSN solvent intensity through solvent recycle through an adsorbent loop

Process Considerations: Solvent Recycle – Selectivity is enabled through membrane application – High loading capacity desirable – Generic adsorbent selection can be used for application (minimised screening work)

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OSN (standalone) OSN and adsorbent combination

OSN

FeedTank

Freshsolvent

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OSN as a standalone technique and in combination with adsorbent solvent recycle loop

Application 1: Genotoxin Removal Solvent Recycle Through Adsorbent Loop

Conclusions: Solvent Recycle – To maintain a constant volume the flow rate is set to equal diafiltration flux – Acetamide is not being fully adsorbed by the column resulting in a slower removal rate

compared to using OSN only (target reached after 4 rather than 3.7 DV) – API is also by-passing column resulting in an increased overall yield – No additional solvent was required to reach desired target

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Diafiltration volumes (-)

API (OSN only)API (Solvent recycle)Impurity (OSN only)Impurity (Solvent recycle)Target

API and acetamide levels for OSN as a standalone technique and in combination with adsorbents

Application 2: OSN in Chromatography

Solvent Swap and Solvent Recovery

Counter Current Chromatography A chromatographic separation method where both the stationary and mobile phase are immiscible liquids. Stationary phase is retained in the column using centripetal acceleration. Compounds migrate through the column at rates dependant on their partition coefficient of the stationary and mobile phase.

CCC

5. Fresh CCC mobile phase

6. CCC stationary phase

7. Recovered CCC mobile phase

1. Multi-component feed stream

2. CCC Mobile phase solvent

OSN 1

8. a. Concentrated API solution8. b. Concentrated impurity solution

Sample Preparation Solvent Recovery3. CCC Mobile phase solvent

4. Waste

OSN 2

Process schematic of combined OSN and counter-current chromatography (CCC) processing

Objective: OSN Application in Chromatography Investigate the feasibility of using OSN to:

Facilitate solvent swap required for counter-current chromatography (CCC) Improve overall CCC mass-efficiency through recovery of mobile phase

Application 2: OSN in Chromatography Solvent Swap and Solvent Recovery

Application 2: OSN in Chromatography Membrane Screening

Screening Solutions: 1. CCC mobile phase

– 67.32% heptane, 30.29% ethyl acetate, 2.16% methanol and 0.24% water

2. Pure ethyl acetate 3. Mother liquors

Membrane Parameters:

– Solvent stability – Flux and Rejection

Membrane MWCO (Da) 1. Rejection (%) 2. Rejection (%) 3. Rejection (%) Duramem™150 150 76.1 99.1 99.2

Duramem™200 200 21.7 91.6 96.5

Starmem™122 220 83.1 99.8 98.4

Starmem™240 400 98.5 99.5 98.9

Puramem™280 280 86.7 99.6 98.2

Puramem™S 420 66.7 - -

Summary of measured rejections for screening solutions 1-3

Application 2: OSN in Chromatography Solvent Swap and Sample Preparation

CCC Sample Preparation and Separation – Put-and-take diafiltration with a 70% concentration level – Target: 99.997% Ethyl acetate, maximum traces of 0.01% for other solvents – Solvent level reached after 5.9 volumes of ethyl acetate has been added – Solvent composition correspond to mass-balance based on 0% solvent rejection – Difficult distillation as mother liquor solvent is higher boiling point than ethyl acetate – Enable swap between any miscible solvents with no azeotrope formation

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HPLC

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Impurities

API

Composition in retentate during swap CCC separation using OSN sample

ML solvent 1 ML solvent 2 ML solvent 3 Ethylacetate

Application 2: OSN in Chromatography Mobile Phase (MP) Recovery

OSN Mobile Phase Recovery – Solvent was recovered from API (F6-F10) and low conc. impurity fractions (F0, F3-F5) – 70% of the mobile phase could be recovered (1985mL out of 2915mL) – Recovered solvent was within solvent specification stated as 99% (a/a) – Solvent composition was maintained over the membrane

Solvent composition and purity based on GC and Karl Fisher data

Fraction Heptane (% v/v)

Ethyl acetate (% v/v)

Methanol (% v/v)

Water (% v/v)

Imps. (% a/a)

Volume (mL)

F0 66.6 30.6 2.2 0.3 0.46 435 F3-F5 67.8 29.8 2.1 0.3 0.47 660

F6-F10 67.6 30.4 1.7 0.3 0.45 890 Combined permeate 67.7 30.2 1.9 0.3 0.46 1985 Desired composition 67.32 30.29 2.16 0.24 - -

Application 2: OSN in Chromatography Chromatography and MP Recycle

Conclusion – Demonstrated feasibility for CCC separation with sample prepared using OSN – Consistent performance was observed for operation using fresh and recycled MP

demonstrating an improvement in mass efficiency for CCC

Further Reading – E. Rundquist, C. Pink, E. Vilminot, A. Livingston, J. Chromatogr. A., 1229 (2012) 156-163

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OSN Sample and Fresh MPOSN Sample and Recycled MP

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CCC separation for operation on OSN sample using fresh and recycled MP respectively

Application 3: OSN in Solvent Recovery Introduction and Objective

Objective: OSN in Solvent Recovery – Investigate capability of using OSN for solvent recovery from crystallisation liquors – Study potential to use recovered solvent for further processing – Process comparison of OSN and current technique used; distillation

Process schematic of OSN and distillation for solvent recovery

Intermediate grade API

IPAc

Application 3: OSN in Solvent Recovery Membrane Screening

Crystallisation Liquor: – Crystallisation liquor and cake washes from final stage API crystallisation. – Isopropyl acetate (IPAc) containing ~2g L-1 API (MW ≈ 700g mol-1), >40 different

organic impurities and potential traces of water, methanol and IPA

Screening data:

– Ideal membrane performance: 100% API and impurity rejection – Selected membrane Puramem™280 operated at 60bar – GMP support files

Membrane Papplied (bar) API R (%) Flux (Lm-2h-1)

Starmem™122 30 >99.9 36

Starmem™122 60 >99.9 40

Puramem™280 30 99.6 45

Puramem™280 60 99.8 54

Starmem™240 30 99.7 60

Starmem™240 60 99.8 65

Screening data for API mother liquor

Application 3: OSN in Solvent Recovery Solvent Specification and Recovery

Solvent Specification: – Minimum of 99% (area by GC) IPAc – < 0.87% (w/v) water

Solvent Recovery – All permeate samples are within the solvent specification – Impurity trace marginally higher for OSN compared to distillation

Component PMa SMb Dc

IPAc (% a/a) 99.4 99.6 99.7 Imps.(% a/a) 0.6 0.4 0.3 MeOH(% a/a) 0.01 0.02 0.02 IPA (% a/a) 0.03 0.02 0.03 Water (% w/v) 0.19 0.18 0.19

Composition of recovered solvent apermeate from Puramem™280 bpermeate from Starmem™122

cdistillate

HPLC Chromatogram of feed solution and recovered solvent

Application 3: OSN in Solvent Recovery Solvent Recycle/API Crystallisation

API Specification: – Impurity 1 not greater than 0.3% (a/a) – Impurity 2 not greater than 0.15% (a/a) – Any unspecific impurity not greater than 0.1% (a/a) – Total impurities not greater than 1.0% (a/a)

Solvent recovery:

– API rejection remain consistent at 99.8% for solvent recovery 1-3 – Solvent remain within specification and no build-up in solvent traces or impurities can

be observed during subsequent recycle

HPLC data for crystallisation batches aLargest unspecific impurity present

bExpected value between 84-90%

Batch Impurity 1 (% a/a)

Impurity 2 (% a/a)

Unspecifica (% a/a)

Total (% a/a)

Within spec.

Yieldb

(%) Fresh solvent 0.06 0.05 0.04 0.21 Yes 86.5 OSN Recovery 1 0.08 0.05 0.08 0.49 Yes 87.3 OSN Recovery 2 0.03 0.06 0.05 0.33 Yes 87.6 OSN recovery 3 0.03 0.04 0.09 0.27 Yes 87.5

Application 3: OSN in Solvent Recovery Scale-Up

Scale-up OSN solvent Recovery – 18L processed with 14L recovered (7 x 2.0L) equivalent to 80% recovery level – Consistent API rejection and solvent composition throughout run – OSN recovered solvent was within solvent specification

Solvent composition and impurity content for recovered solvent aPuramem™280, baverage for 7×2.0L fractions collected

Component IPAc (% HPLC)

API (%HPLC)

Imps. (%HPLC)

Methanol (% GC)

IPA (%GC)

Water (% wt.)

Distillate 99.9 <0.1 0.1 0.03 0.005 0.18 Lab-scale (PMa) 99.7 <0.1 0.3 0.04 0.002 0.14 Pilot-scaleb (PMa) 98.8 0.6 0.6 0.03 0.005 0.15

Application 3: OSN in Solvent Recovery Process Comparison and Conclusion

Energy requirements: – E factor = Total mass waste generated / Mass of product produced – OSN recovery limited by solubility of solutes present – Hybrid = OSN for 80% recovery and distillation for final 10%

Run time and energy requirements for OSN and distillation solvent recovery

Parameter No recovery OSN Distillation Hybrid Solvent recovered (%) 0 80 90 90 E factor (-) 9.7 4.8 4.2 4.2 Total energy required (MJ) N/A 2.1 66.8 9.6 Energy required per L recovered solvent (MJ L-1)

N/A 0.03 0.74 0.08

Application 3: OSN in Solvent Recovery Conclusion

Conclusion:

– Recovered solvent was within the solvent specification and feasibility for OSN solvent recovery can be considered proven

– Consistent membrane performance was observed with regards to both flux and rejection during scale-up to spiral wound modules

– Through variation of the selected membrane, OSN solvent recovery can be extended to include a range of process streams

– OSN commonly require a lower amount of energy per litre of recovered solvent and can provide benefits with regards to improved energy-efficiency.

Thanks for listening

CURRENTLY RECRUITING - CHEMICAL ENGINEERS in south England

http://www.gsk.com/careers/uk-saa-jobsearch.htm search req ID 72138A

Mention Chris Pink in your cover letter CLOSING DATE - 15th OCT 2012

Acknowledgement: Elin Rundquist (Marie Curie funded PhD student) Andrew Livingston (Imperial College, London) Keith Freebairn (GSK, Stevenage) Chris Thickitt (GSK Stevenage) Nathalie Douillet (GSK, Stevenage) Elsa Vilminot (GSK, Stevenage)