Organic Solvent Nanofiltration (OSN) in Pharmaceutical...
Transcript of Organic Solvent Nanofiltration (OSN) in Pharmaceutical...
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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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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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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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)