iPRD Away Day Agenda

15th May 2009, Weetwood Hall Hotel

8:30 – 9:00Coffee on Arrival

9:00 – 9:30Update on IPRD Progress – AJB

9:30 – 10:30Brainstorm Session 1

11:00 – 11:30Coffee

11:00 – 12:30Brainstorm Session 2

12:30 – 13:30Lunch

13:30 – 14:30Brainstorm Session 3

14:30 – 15:30Brainstorm Session 4

15:00 – 15:30Coffee

15:30 – 17:00Summary Session

Brainstorm Sessions iPRD Away Day 15th May 2009 Weetwood Hall

1)Computational prediction/analysis of whole processes (ie putting a quantitative score on things like route selection, separationand cycle-time – would require integration of synthetic chemistry and process engineering knowledge and/or prediction of material form at each stage, processing considerations etc). Session led by John Blacker.

2)Problematic material properties (could include amorphous materials, gels, viscous oils, metastable solid phases, volatiles, solvents with tunable switchable properties). Session led by Chris Rayner.

3)Difficult phase behaviour in reactors and in flow (includes areas like modelling of multiphase flow systems eg liquid/gas, solid/liquid or even tripartite; innovative catalyst separation techniques eg continuous liquid/liquid extraction for feedback of catalysts). Session led by Steve Marsden.

4)Process analytical design with integratable reaction and downstream processing eg “plug and play kit”. (A number of companies/speakers also identified analytical needs eg detection of trace metals, oxidation states). Session led by Kevin Roberts.

Please refer to notes from Industrial Club “Wish List” for guidance

Session 1 Led by John Blacker

Computational prediction/analysis of whole processes (ie putting a quantitative score on things like route selection, separation and cycle-time – would require integration of synthetic chemistry and process engineering knowledge and/or prediction of material form at each stage, processing considerations etc). Session led by John Blacker.

Convergent route

Software can bring together known information

Scoring of more cited lit routes, quality of journal etc (lower risk)

Can we integrate to engineering earlier – isolations, separations,

Too many routes to quantify early on – need simple qualitative measures early to cut down.

KJR – ought to be possible to predict solubility?

(can we have database of solubilities?)

Physical properties

Identify heat and mass transfer issues

Kinetics (reaction time)?

Thermodynamic databases – do they exist? Should be easy?

Sandia national lab has software for process design (for high temp stuff)

Chris P – cost of catalyst etc; solvents on red list can’t be used etc etc

“Knowledge management” (hits funding bodies)

Idea of scoring process improvements

Toxicity/safety – currently judged against databases by analogy – could do same for eg solubility?

Chris R – environmental metrics well established (Roger Sheldon) – should be incorporated

Chris P – GSK has leading model for this (FLASC programme) (AZ have similar tool)

Type of waste

Pre-determination of toxicity

Use Cambridge database to extract information about solubilisation

(KJR – flags up grand challenge in prediction of manufacturing)

APJ – Beilstein – 10 million cpds – owned by Elsevier – they are looking for partners?

Xue – standardisation of information recording needs standardisation!

Round-up: Interested partners – Chris R, Paddy, Peter J, Gert. Tariq, Kevin, Xaijun Lai, Steve M, Xue

Final comment: Chris P – tool to understand possibilities and record decision-making process. Difficult but well-worth doing!

Kevin R – process modelling has been lost with demerging of larger companies, they’ve had to use commercial software which isn’t fit for purpose!

Rafiq Gani – Denmark – owns the old ICI software (centre for process systems) – perhaps ought to talk to him

Task – check “knowledge management” on EPSRC etc websites (or information management)

Session 2. Led by Chris Rayner

General area: Problematic material properties (could include amorphous materials, gels, viscous oils, metastable solid phases, volatiles, solvents with tunable switchable properties).

Reactions designed to have gaseous and volatile by-products, and handling of volatile reagents

Handling of volatile/gaseous reagents difficult; they are also very hard to mix in conventional systems. If exothermic reactions, large surface area is required for efficient heat transfer, but this leads to increased demands for efficient surface cleaning. Volatiles can be introduced by sparging, but again this is not trivial.

Fluorinated solvents can be difficult. Reactorsneed to be designed to handle volatiles, perhaps lab scale – test bed for scale-up, which would also require some modelling.

Industrial reactors are better equipped to deal with volatiles – ought we to scale down based on this existing knowledge rather than trying to scale-up?

Usually requires knowledge of reactions kinetics/reagent properties; common for commodity chemicals, less so for fine chemicals and Pharma.

Gas/liquid reactions – mass transfer determines reaction efficiency, need to understand properly and maybe devise new ways to enhance gas solubility (e.g. using pressure, or reagents/solvents which may have greater affinity for gas). An alternative suggestion was to get away from mechanical agitation, and perhaps use something like injection mixing.

Design of reactions which only have volatile by-products (e.g. HCl, SO2, CO2, N2 etc.) – particularly useful for difficult reactions which need a thermodynamic push. Can we learn from e.g. BASF Ludwigshafen – make use of by-products! (eg Cativa process)

Containment of volatiles important on scale; ideal if can be used for other processes but requires process integration rather than considering only individual process operations.

Solvent alternatives, e.g. with tunable switchable properties

Fluorinated hydrocarbons are used as delivery vehicles for aerosol drugs – alternatives needed (need to be non-toxic and no environmental issues such as ozone depletion). Talk to some of the atmospheric chemists?

Switchable solvent properties, consider kind of switch - light activation (photochromic materials), pH, gas addition (e.g. CO2), temperature, concentration – e.g. for gelation?

Work-up and pH control of aqueous reactions (e.g. CO2 to change properties – what happens if add CO2 to a reaction to quench it rather than water, or add CO2 to basic reaction medium to raise pH?).

Sustainable solvents is significant issue (e.g. MeTHF, butyrolactone) – where are they going to come from in quantities and qualities needed. Alternatives to dipolar aprotics required but ionic liquids haven’t delivered – any others? Scionix – Leicester – choline-derived/urea derived solvent systems; also Bionix (York), again much lower impact than original ionic liquids and some interest in using them for reactor cleaning. Ammonium formate – volatile salt. Still major issue due to volumes used.

Non-flammable solvents. What is known about organic flame retardants – can they be incorporated into solvents somehow?

Direct drop reactions (no aqueous work-up)

Impact of by-products on solubility; addition of external agents to induce precipitation, e.g. use of volatiles to change solvent (CO2, ammonia etc.).

Change in reaction volume by pressure change (pressure induced crystallisation, or spray drying)

Use of phase tags to facilitate separation of products/catalysts etc.

Electrolysis to remove trace water.

Smart particles to recognise products etc to pull out of solution

Nanofilter membranes work well with aqueous systems but NOT currently with organic solvents – no product yet for industrial scale!

(filtration expertise in Steve Russell’s group in textiles). Identify problems here (materials of construction and processing into membranes/filters)

Huge market for filtration of organic solvents, reliability/reproducibility currently a major issue.

Prediction and control of oiling out

Oiling out – caused by impurities which resist nucleation, or other factors in crystallisation (solvent, concentration, temperature). Comes down to interparticle or intermolecular interactions.

Would be particularly useful to identify exemplars from industry.

Variety of approaches to induce crystallisation were discussed:

  • Pre-treatment of glass (eg like silation), or maybe better with sacrificial plates (don’t want to cause plant cleaning issues by treating whole reactor).
  • Inject bubbles to create surfaces, or use foaming agents
  • Ultrasonics in oils?
  • Self-assembled monolayers
  • Use materials such as zeolites (robust)?
  • Crystalline polymers?
  • Ultrasonics - Xaijun Lai hsa project for summer using Prosonix probe. Do stirrers which are also ultrasonic probes exist?
  • Electrostatics to initiate aggregation

Handling of gels and viscous oils (occurrence, processing or avoidance)

Once formed, the breakdown of gels to a processable solution is a major issue. Gelling out occurs in reactions commonly metal containing (e.g. Al, Ti) or bioreactions.

Can use viscosity to monitor formation (easily done through power to impeller but not currently usually done). But if you know its starting to form, what action can you take to prevent further gelation?

Can you add a gas to expand gel, and maybe induce breakdown?

Can we learn from polymer synthesis e.g. dispersion polymerisation, where prevention of agglomerisation is key; or starch and other sugars?

Uncontrolled foaming (e.g. in bioreactions) an issue; develop novel antifoaming techniques or additives?

Formation of emulsions also problematic during liquid-liquid extractions, usually when solvents/products/reagents have some affinity for water reducing tendency for phase separation. Can we use knowledge of rheological properties and colloid chemistry to understand processes (Simon Biggsshould be able to help with this), then develop approaches to alleviate problem. Also relevant to gelation (SOMS, Amalia Aggeli, Andy Wilson, Michaele Hardie)

Interfacial crud is also a problem in liquid liquid extractions – can this be solved by recycling?

Suggestion of Dr Hamid Golshekan (?), ; 01484 472134 at Huddersfield– expert in liq/liq extractions.

Viscous oils – problem at high concentration and/or solventless reactions

How do people go about pumping syrups, bitumen etc – heating is used for petrochemicals? Friedel-Crafts using AlCl3 in chlorobenzene is very viscous, but also corrosive; may require linings for pipes?

Transfer of oils, how to flush out of reactors/pipes difficult?

Could these oils be expanded under pressure using something like CO2?

Possibility of collapsible vessel/bag/lining within reactor which may be moved rather than requiring pumping– cf disposable fermenters

Alternative approaches include static mixer in flow reactor, screw mixers (cf. Archimedean screw used in powder manufacture)

Can we understand gelling process in the first instance?(SOMS, Amalia, Andy, Michaele)

Crystallisation of viscous oils.

Seeding - learn from clathrate chemistry/inclusion compounds (Chris P – GSK just started project with Rob Price in pharmacology at Bath)

“Self-seeding” – (cycling) crystallise badly, redissolve except minor quantities, then re-crystallise – gives very good product (KR has experience of this)Need improved knowledge of how to control this.

(Can this be improved also by using plate technology as above?)

Milling as a purification tool was suggested, using seeds as a sponge to remove impurities.

Amorphous materials – what pharma really means is sub-100 nm particles – i.e. does not give X-ray diffraction pattern – does not necessarily mean truly amorphous. Such small particles are actually crystal types, i.e. nanocrystals

Analysis on this size scale is a real problem!

Drying technologies

Drying time is significant part of process – can it be shortened? Assay for dryness / residual solvent (invasive – done by sample removal); stability of product to drying conditions also a concern.

Can we use chemical or optical imaging to view effect of various drying techniques on the solid? (access to MRI imaging?). Need to know critical moisture content.

Techniques discussed:

  • Gas filtration and/or active displacement
  • Solvent swap to volatile solvent (e.g. scCO2)
  • Fluidised bed with gentle agitation
  • Tray dryer with tunable microwave
  • Get flux change of liquid in cake by using variable air pressure
  • IR heating – eg to be combined with rotating arm that is used to scrape off top layers?

Filtrate needs washing – otherwise mother liquor adds stuff on (could be slurry washing or displacement washing). Need reproducibility between kit – comes down to analytical (e.g. NIR of off-gases) and control.

Problems with crystal damage may be limitation with some of these.

Key issue: we crystallise large to facilitate filtration, then dry, bag, mill etc etc

Continuous crystallisation – can this help? What is known in literature?

Need to get exemplars of e.g. gelling or oiling reactions from industry

Interested parties: Kevin, Tariq, Steve M, Chris R, Xaijun, Rob,

Session 3 Led by Steve Marsden

Difficult phase behaviour in reactors and in flow (includes areas like modelling of multiphase flow systems eg liquid/gas, solid/liquid or even tripartite; innovative catalyst separation techniques eg continuous liquid/liquid extraction for feedback of catalysts).

AJB – volatile/gaseous reagents difficult

KR – mixing hard, but also issues of cleaning with exothermic reactions – large surface area because of need for heat transfer. Sparging also problematic.

Fluorinateds difficult.

Reactor should be designed to handle volatiles

Lab scale – test bed for scale-up

MODELLING!

Industrial reactors are better equipped to deal with this – ought we to scale down based on this rather than trying to scale-up!

Knowledge of reactions kinetics/reagent properties

Gas/liquid reactions – mass transfer determines this, need to understand.

Suggestion – get away from mechanical agitation, use injection mixing?

Design of reactions which only have volatile by-products

Can we learn from eg BASF Ludwigshafen – make use of by-products! (eg Cativa process)

Containment important on scale

Chris P – fluorinated hydrocarbons used as delivery vehicles for aerosol drugs – alternatives needed

Light activation – eg for gelation?

pH control of aqueous reactions (eg CO2 to change properties)

Sustainable solvents (eg MeTHF, butyrolactone)

Non-flammable solvents (ionic liquids haven’t delivered)

Ammonium formate – volatile salt

(Scionix – Leicester – choline-derived/urea derived solvent systems)

Impact of by-products on solubility

Use of volatiles to change solvent – eg CO2, ammonia

Change in reaction volume by pressure change

Use of phase tags

Electrolysis to remove trace water

Smart particles to recognise products etc to pull out of solution

Nanofilter membranes work well with aqueous systems but NOT currently with organic solvents – no product yet for industrial scale!

(filtration expertise in Steve Russell’s group in textiles)

Huge market for filtration of organic solvents!

Reliability/reproducibility an issue.

Oiling out – caused by impurities which resist nucleation?

Need exemplars – from industry?

Pre-treatment of glass (eg like silation) – maybe better with sacrificial plates (don’t want to cause plant cleaning issues by treating whole reactor)

Inject bubbles to create surfaces, or use foaming agents

Ultrasonics in oils?

Self-assembled monolayers

Can initiation of xtallisation with zeolites (robust)? Or crystalline polymers?

Xaijun Lai – project for summer using Prosonix probe

Electrostatics to initiate aggregation?

Breakdown of gels – issues of gelling out in reactions, esp. metal containing or bioreactions

Comes down to interparticle or intermolecular interactions

(Do stirrers which are also ultrasonic probes exist?)
Chris P – does it come back to monitoring viscosity? (easily done through power to impeller but not currently usually done)

Add gas to expand gel?

Chris P – can we learn from polymer synthesis eg dispersion polymerisation, where prevention of agglomerisation is key? Or starch?

Uncontrolled foaming (eg in bioreactions) an issue

Liquid/liquid extraction – formation of emulsions also problematic

Need understanding of rheological properties (Simon Biggs should be able to do this)

Interfacial crud is a problem in liquid liquid extractions – can this be solved by recycling?

(suggestion of Hamed at Huddersfield – expert in liq/liq extractions)

Viscous oils – problem at high concentration and/or solventless reactions

(how do people go about pumping syrups, bitumen etc – heating is used for petrochemicals) – eg Friedel-Crafts AlCl3 in chlorobenzene, very viscous

Linings for pipes?

Chris P – transfer of oils, how to flush out of reactors/pipes difficult?

CO2 expanded?

Collapsible vessel/bag within reactor – cf disposable fermenters

Static mixer in flow reactor

Screw mixers (Archimedean screw used in powder manufacture)

Can we understand gelling process in the first instance?(SOMS, Amalia, Andy, Michaele)

Seeding - learn from clathrate chemistry/inclusion compounds (Chris P – GSK just started project with Rob Price in pharmacology at Bath)

“Self-seeding” – (cycling) crystallise badly, redissolve except minor quantities, then re-crystallise – gives very good product (KR has experience of this)

Need improved knowledge of how to control this!

(Can this be improved also by using plate technology as above?)

Milling as a purification tool! (using seeds as a sponge to remove impurities)

Amorphous – what pharma really means is sub-100 nm – ie does not give X-ray diffraction pattern – does not necessarily mean . They are actually crystal types, nanocrystals

Analysis on this size scale a real problem!

Session 4 Led by Kevin Roberts

Process analytical design with integratable reaction and downstream processing eg “plug and play kit”. (A number of companies/speakers also identified analytical needs eg detection of trace metals, oxidation states). Session led by Kevin Roberts.

Question for industrial club: is PAT an in-manufacture thing or a pre-manufacture? Debate! Some people think it really needs to be integrated. Chris P – should be part of manufacture so you can react to it

And, furthermore, what do we mean by quality by design? (some people taking to mean just DoE and management). Industry treats QbD as risk management.

Chris P: need to get consensus from industrial club members as to what we mean by QbD

New JEEP beamline at DIAMOND light source

John B – analogy with petrochemicals, where processes are very well understood, and the outcome of any perturbations of any key parameters can be predicted and reacted to. Isn’t QbD trying to get to the same state with the transformations used to make organic molecules?

For some older products process understanding is poor

Delivering QbD in synthesis:

Concentration of reagents, intermediates, by-products

In situ, real-time reaction measurements

Input data from modelling? (QM/MD)

Need analytical techniques to develop trace molecular species

IR – track fingerprint region

Modelling has key role to play (link to informatics of reaction design – APJ?)

So: choose a system we know and apply in a multi-technique study using QbD

IDEA: Chris P – IPRD should become leader in this, partner companies to drive this through

Get someone from MRHA along to discuss

Maybe develop a DTC application around this? “Science-based manufacture”; “science of scale”

Interested: everyone!