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Chemical Synthesis, Engineering, and PAT From Development to Manufacturing
Reac
tion
Engi
neer
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Addressing Today's ChallengesFrom Research to Manufacturing
Chem
ical
Syn
thes
is, E
ngin
eerin
g, a
nd P
AT
Chemical and biopharmaceutical companies are under increasing pressure to bring products to market faster, at lower costs and with higher quality. Companies must identify the best new product opportunities, conduct research and development, and develop a process and scale with minimal resources under ever-increasing time pressures. To be successful, they must create numerous oppor-tunities, evaluate them quickly, and eliminate poor candidates. This requires the capability to generate critical data and then use this data to determine feasibility as quickly as possible.
METTLER TOLEDO provides the enabling technology, software and people that can help build a seam-less workflow to translate bench scale chemistry into a commercial process. For more than 20 years, our enabling tools and services have been a strategic resource pro-viding critical information for thou-sands of development scientists and engineers. Companies have used that knowledge to accelerate the discovery, development and scale-up of new chemical pro-cesses spanning the chemical and biopharmaceutical industries.
Early Phase Development Design and Process Development
Scale-up and Manufacturing
•Speedthedevelopmentofnewcompounds
•Quickly,butsafely,providegramsto kilograms of material
•Rapidlyestablishcosteffective synthetic routes
•Speedthedevelopmentofenvironmentallyfriendly, safe and robust processes
•Buildqualityintotheprocess/rightfirsttime scale-up
•Supportthedevelopmentofcontinuousprocesses
•Increasedqualityandquantityof process knowledge via combination of automated lab reactors and real-time analytics that provide chemical, thermodynamic and particle character-ization of your processes
•IndustrystandardRC1reaction calorimeter helps ensure safe and high performing processes
•Increasedprocessknowledgeenablesengineers to quickly scale-up processes while simultaneously eliminating scale-up failures
•Eliminatebatchfailures•Ensureprocessesdeliverhigheryields
with lower costs•ImprovecycletimeCh
alle
nges
•Usingsmallvolume,semi-automatedlab reactors with integrated analytics, processes can be screened and characterized with limited amount of precious starting materials
•Earlyunderstandingofprocessscale-up issues allows chemists and engineers to eliminate candidates early in development, saving money and opportunity costs
•Allowsearlydetectionofnon-scalablefactors
MET
TLER
TOL
EDO
Solu
tions •RealizethebenefitsofQualityby
Design(QbD)throughthedeliveryofmore robust, lower cost processes to manufacturing
•Optimizefactorythroughputbyimproved understanding of reaction kinetics and endpoint
•Ensureprocessiswithinboundariesthrough utilization of PAT tools
•Reducedownstreamprocessingissuesto improve total process efficiency
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Chem
ical
Syn
thes
is, E
ngin
eerin
g, a
nd P
AT The Complete Solution to FacilitateImprovedProcessR&D
Characterize Your Particle Systems In-processFBRM® and PVM® enable scientists and engineers to optimize crystal-lization and particulate process development by understanding particle dimension and shape in process.
Analyze Your Reaction ChemistryReactIR™FTIRbasedreactionanalysis systems provide real-time composition analysis allowing the monitoring of key reaction species in situ – eliminating the need for grab sampling.
iC Software – Ties it All TogetheriC software integrates your entire experimental workflow and resultant data making it easy to visualize, interpret and report your results
Expand Your Productivity Using Controlled Lab ReactorsAutomated lab reactors provide 'plant like' temperature, mixing and dosing control in addition to critical thermo-dynamic information about processes.
•Ensuresconsistentdownstreamprocessing leading to fewer reworks and batch failure
•Guaranteestargetparticledistri-bution for optimum cycle time
•Ensuresdeliveryofsafescalablecommercial process
•Saveslimitedresourcesand materials
•Enablesprojectcompletionwithfewer experiments
•Quicklyprovidesincreasedprocess understanding
•Allowsfastdeliveryofoptimalsynthetic chemical route for commercial synthesis
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•Enablesfaster,moreinformed decision making that leads to fewer experiments
•Providesfastercommercialroutedevelopment through increased process knowledge
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FBRM® and PVM® allow chemists and engineers to quickly screen crystallization parameters to develop a scalable process – avoidingmajorredesignslater in process development and scale-up.
Screen Potential Routes while Saving Precious Materials
EasyMax™andMiniBlock® are a new generation of synthetic chemistry tools that allow chem-ists to rapidly establish potential routes and identify starting materials and conditions. Byprovidingreproduciblecondi-tions, these tools allow for unattended operation and un-attended data logging.
Quickly Determine Performance and Viability of Process Steps
Early Determination of Crystallization Scalability
ReactIR™ allows the synthetic organic chemist to quickly under-stand if the desired reaction occurred and provides associated endpoint determination without offline analysis. Inaddition,activityandperfor-mance can be quickly screened to eliminate suboptimal catalysts.
Finding Your RouteFrommgstokgs–QuicklyandSafely
Our tools and software enable your innovation efforts in synthetic chemis-try and catalysis by helping to invent viable routes for new products.By quickly evaluating various potential routes, starting materials, building blocks, and reaction conditions, chemists can safely generate the desired quantity of the target compound. Additionally, this work will provide valuable, early process knowledge that facilitates late phase process development efforts.
METTLER TOLEDO provides en-abling technologies that support the development and manufac-turing of biopharmaceutical products. Following the principles ofQualitybyDesign(QbD),ourtechnologies provide the capability to rapidly and efficiently develop an understanding of the appro-priate design space using state of the art automated lab reactors for accurate control of test conditions, and in situ Process Analytical Technologies(PAT)forreal-timemonitoring and control of Critical QualityAttributes(CQA).These solutions can be applied to boththeAPIandfinalformulatedproduct applications.
•Organicsynthesis•Crystallization•Fermentationandbio-processing•Processdevelopmentand scale-up•Processsafety•Formulationsandproduct
development•Pilotplantandproduction
monitoring•Asymmetriccatalysis•Halogenations•Enzymaticcatalysis•Crosscouplingreactions
For the bio/pharmaceutical industries, we offer solutions in these specific application areas:
Industry Focus: Pharmaceuticals
Example Case StudyRapid Crystallization Development 1
www.mt.com/ac-pharma
•Organometalllicchemistry•Solutionphaseand
heterogeneous catalysis•Lithiumchemistry•Grignards•Hydrogenations
Goal of StudyQuicklydeveloparobustpharmaceuticalcrystallizationwhileengineeringparticle size and shape distributions, ensuring correct crystal form, and optimizing product yield and purity
kinetics at each seeding tempera-ture, thereby enabling chemists to engineer a targeted particle dis-tribution, critical for downstream product and process quality.
Value/ROIIntwoshortexperimentsFBRM® and PVM® saved months of costly development time – ensuring consistent yield, purity and particle dimension while increasing the probability of scale-up success. This resulted in a reduction in crystallization development costs by 50%.
For more application examples visit www.mt.com/ac-webinars
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MethodThe crystallization of an active pharmaceutical ingredient from ethanol/watermixtureswas studiedusinginsituFBRM® and PVM® technology. Two experiments were performed with identical cool-ing profiles but different seeding temperatures.
Key Results InsituPVM® discovered phase separation(oiling-out)atoneofthe seed temperatures. This imme-diately identified a point in the design space where yield, purity and scalability would be negatively affected.InsituFBRM® monitored crystal growth and nucleation
1)Lafferrereetal.CrystalGrowth&Design,Vol. 4, No. 6, 2004.
100µm
PVM®imageofphaseseparation(oilingout)
FBRM® trends showing crystal growth and nucleation kinetics
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Proc
ess
Dev
elop
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FBRM® and PVM® enable real-time crystallization process optimization by providing particle dimension, shape and count measurements in situ eliminating the need for grab sampling. This ensures the most representative measurement. The utilization of FBRM®leadstobetterdesignedcrystallization processes that can be scaled to production – providing the desired crystal size, distribution, yield and purity.
Develop Your Chemistry Under Plant-like Conditions
RC1e™ is the industry standard reaction calorimeter for safety engineers worldwide to create safe and economically competi-tive processes from bench scale tomanufacturing.TheRC1e™ ensures processes are developed and tested under the safest work-ing conditions due to the ultrafast cooling and control capabilities of the system's thermostat.
Directly Determine Reaction Kinetics and Endpoints
Real-time Optimization of the Crystallization Process
ReactIR™isanFTIRbasedreac-tion analysis system that provides real-time, in situ composition monitoring to track all key reac-tion species including transient intermediates and by-products. Since the analysis is conducted right in the vessel, errors asso-ciated with grab sampling, such as catalyst poisoning and equilib-rium changes, are eliminated.
Optimized Process DevelopmentRight First Time
With thousands of installations across the pharmaceutical, chemical, and polymer industry worldwide, METTLER TOLEDO automated lab reactors, reaction calorimeters, in situ reaction analysis tools, and particle system characterization instruments are considered industry standard for enabling the development of safe, robust chemical processes.
METTLER TOLEDO provides inno-vative solutions supporting the development and manufacturing of fine and specialty chemical prod-ucts.Inthedevelopmentofnewbatch or continuous processes, our technologies enable scientists and engineers to rapidly optimize processes to deliver maximum economic returns while helping to ensure safe operation from labora-tory to production.
Scientists and engineers in the chemical industry face difficult challenges in optimizing processes due to the hazardous nature of
their chemistry. Our automated labreactorsandinsituFTIRandparticle characterization technolo-gies allow full characterization and optimization of the process while ensuring the user is protected from toxic chemical reactions.
Our extensive experience, from hundreds of installations across the chemical industry (many at elevated temperature and pres-sure),ensuresthatsystemsandprobe designs meet the safety, robustness and performance requirements to withstand these highly corrosive conditions.
Industry Focus: Chemicals
Example Case StudyOptimizationofaHighlyHazardousReaction
•Intermediates•Surfactants•Flavorsand
fragrances•Coating/pigments•Agrochemicals•Initiators•Bulkchemicals
•Isocyanates•EO/PO•Highlyoxidizing
reactions•Biotransformations•Catalyticprocesses•Phosgenations•Esterifications
Typical installations have involved a wide range of chemical industries and applications:
www.mt.com/ac-chemical
Goal of StudyReduce production cost of a highly hazardous reaction - decreasing batch time and solvent consumption
Value/ROI •Thebatchtimeisdecreased
from nine to four hours•Solventconsumptionis
cut by 50%•Overallproductioncostsare loweredby10%
•Saferprocessasaresult of reduced accumulation and efficient evaporation cooling
For more application examples visit www.mt.com/ac-webinars
Key ResultsUtilizingtheRC1e™ reaction calorimeter, batch time, solvent consumption, accumulation and runaway potential of the reaction mass were thoroughly investigated. As a result, the process condi-tions, such as the addition rate, concentration of the reactants, and process temperature of the current production process, were modified.
An increase in process temperature and concentration led to:•Increasedreactionrate•ReductionoftheaccumulationandareductionoftheΔTad
•Reducedsolventconsumption•Moreefficientcoolingconcept
Time
Dosing 1 Dosing 2
Time
Original process with batch time >8h – shows accumulation in dosing steps
Modified process with batch time <4h – reaction now dosing controlled
Hazardouspotential(DSCcurveofthereactionmass)
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Scal
e-up
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ufac
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QbD* Provides Complete Understanding of the Process
For more than 20 years, METTLER TOLEDO has been actively involved in providing PAT solutions for the information rich, real-time measurement of key process parameters in the reactor and associated unit operations such as granulation and drying.
Quantitative Monitoring of Key Reaction Components
Real-time Monitoring of Particle and Droplet Count and Dimension
ReactIR™ provides non-destruc-tive, rapid, quantitative chemical analysis of key reaction compo-nents in the reactor. Continuous process monitoring identifies process upsets, quickly eliminating batch failures and costly re-works. Moreover, reac-tion endpoints are accurately determined resulting in optimized process time and yields.
Successful Process TransferQualityDesigned-In
Process Analytical Technology (PAT) is being implemented throughout the chemical and pharmaceutical industries at an increasing rate. During the development phase, PAT tools such as in situ FTIR and FBRM® support the design of safe and robust processes that build quality into the commer-cial process. This allows process consistency, batch repeatability and eliminates failures at the manufacturing scale.
FBRM® provides the ability to immediately optimize and control the particle distribution in a manufacturing process by linking upstream process control parameters (such as addition rate,mixingortemperature) to downstream process efficiency (filtration/separationsefficiency,reducedcycletime)andoptimizedproduct quality (yield and purity, particle size specifica-tion and bulkdensity).
*(QbD)QualitybyDesign
Example Case StudyImprovetheSelectivityandReactivityof aHydrogenationProcess
www.mt.com/ac-petrochem
Typical installations have involved a wide range of applications that include:•Emulsionpolymerizations•Urethanes/polyurethanes•Monomers•Acrylates•Homoandheterogeneouscatalysis•Hydroformylations•Functionalpolymerizations•Water/oilseparations•Biofuels•Gashydrates
providing critical information about catalyst activity and reaction species.
Polymer chemistry typically requires precise reaction control to generate products with the desired performance characteristics. The required level of control can only be provided by high quality AutomatedLabReactors(ALR). The combination of our automated lab reactors and real-time ana- lytics enable scientists to speed the development of high performance, functional polymers by measuring and optimizing the relative uptake of monomers for production of copolymer with targeted product characteristics.
Industry Focus: Polymers and PetrochemicalsMETTLER TOLEDO solutions are applied across a wide range of chemistries and applications in the petroleum, petrochemical and polymer industries.
Petrochemical processes are often carried out under extreme tempera-ture and pressure conditions using catalysts that are sensitive to con-tamination by unwanted outside influences. As a result, classical analytical techniques are typically inadequate to monitor these difficult reactions.
OurReactIR™ system analyzes these catalytic processes in real-time under reaction conditions
NH
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Goal of StudyUnderstandthereactionkineticsandselectivitytodevelopasafe,efficientand scalable manufacturing process for the hydrogenation of pyrazine carboxamide to form piperazine carboxamide
Value/ROI InsituFTIRreactionanalysisallowed the identification of the intermediate species and its reac-tivity which allowed scientists to develop a safe and efficient manufacturing process. As a result, significant savings in process development time were realized by determining, in real-time, the impact that changes in critical pro-cess parameters had on process performance.
For more application examples visitwww.mt.com/ac-webinars
Key ResultsReal-time in situ information from theReactIR™ showed that the tetra-hydro intermediate formed rapidly at 60 °C and reacted very quickly to generate the final product. This highly exothermic event needed tobeavoided.Whenthereactionwascarriedoutat35°C,ReactIR™ determined that the tetrahydro inter-mediate was stable, but product formation was very slow.
The specificity of the mid-infrared allowed for full understanding of the reaction kinetics and selectivity that led to the rapid development of a safe, scalable process.
PyrazineCarboxymidereactswithtwoequivalentsofH2 to form Piperazine Carboxamide
Reaction trends at 35 °C show stable tetrahydro intermediate(blue),butslowproductformation(purple)
Real-timeinsituinformationfromReactIR™ show fast reacting tetrahydro intermediate at 60 °C
12 13
Softw
are
and
Life
time
Supp
ort Simply Powerful Software
TransformsDatatoInformation
iC software integrates your entire experimental workflow making it simple to visualize, interpret and report your results. Our unified approach supports lab and plant applications for spectroscopy, particle system characterization, precise reactor control and calorimetry. In each iC product, powerful algorithms and visualization tools are controlled with a simple user interface enabling scientists to gain deeper process understanding with less effort.
Enabling Faster and Better Decision Making iC software helps scientists distill information-rich data into valuable process understanding through the integration of chemometrics and informatics that identify and characterize critical process parameters.
www.mt.com/iC
ConcIRT™ speeds and simplifies the development of high-value compounds by automatically identifying and quantifying key reagents, intermediates and products in real-time or post process.
Time
Temperature
Tprocess
normal process
∆Tad desired reaction
∆Tad secondary reaction
desired reaction
RC1
secondary reaction
DSC,ARC,TAM...
TMRad
MTSR
cooling failure
iC User Interface:Consistent, Intuitive, Effective
All iC products look and work similarly and include extensive data exchange capabilities to minimize training time and maximize productivity.
Data to Information Example: Thermal Risk Assessment
Data to Information Example:Reaction Characterization
iC Safety™ speeds and simplifies thermal risk assessments for safe process design and scale-up by transforming reaction calorimetry data into an easy-to-understand graphical format providing critical safety data and supporting calculations.
iC
RC1eFBRM
EasyMax
IR
LabMax
Raman
Our Commitment BestPeople.BestTools.BestService.
METTLER TOLEDO ServiceXXL® offers a variety of solutions tailored to keep systems running at opti-mum performance. Our expert con-sulting and service professionals focus on your system results and reliability so you can focus on your chemistry. The support relationship begins with scheduling instrument installation and continues through-out its lifetime.
Our offerings include initial qualifi-cationpackages(IPac)fornon-regulated environments and equip-
mentqualificationpackages(EQPac)forcustomersfallingunderGLPorGMPguidelines.Theyguar-antee instrument readiness and provide a logbook for maintenance and calibration activities through-out the life of the instrument.
Our application consultants help define the instrument configuration that produces valuable results from the start, and develop partnerships to ensure ongoing success. As information-enabledprojectsuc-cesses grow, so will the demand
for your instruments. Our range of service programs – from calibra-tion and preventive maintenance to comprehensive contracts – offer solutions that keep your instru-ments performing while meeting budgetandriskneeds.Inaddition,our iCare software maintenance program assures all systems are current and compatible. As your instruments age, our team will assist in planning for obsolescence and upgrading to the next genera-tion technology.
www.mt.com/ac-service
•IPac•EQPac•Commissioning•Instrumentfamiliarization•Maintenanceplanning
•Consultingservices•Application-specific
configuration•Partneringforresults
•Expanduserbaseforresults and capabilities
•Continuingtraining•Distributedsoftware
support
•Endoflife assessment
•Trade-incredits•Technology
upgrade
Installation Application Training
Calibration Obsolescence Planning
Maintenance and Support
•Serviceagreements•PM
•Depotrepair•Spares
•Compliancesupport•Remotediagnosis
•iCaresoftware maintenance
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Lab
Solu
tions Intelligent Lab Solutions
ToImproveYourProductivity
Highest Accuracy in Analytical Weighing
Flexible pH and ion Measurement
Leading Technology in Thermal Analysis
One-click™ Titration
Today, laboratory instruments from METTLER TOLEDO build the foundation of laboratories all over the world. They help to improve the processes and results in research, process development and quality control. In fact, the success of our laboratory instruments is the result of intense research and development to achieve high-level efficiency, usability, and time-saving features over many years.
A Wide Range of Lab InstrumentationMETTLER TOLEDO is well known for its market-leading balance port-folio. Apart from that we also offer solutions for many other measure-ment and analytical applcations, fromtitrationtopHmeasurementand pipetting to sophisticated materials characterization solu-tions.
Focus on Performance and Ease of UseMETTLER TOLEDO stands for superior quality and ruggedness.
Weareinvestingsubstantialeffortsin pushing the envelope for our measurement technologies – be it for the further development of the unique mono bloc weighing technology or for new, innovative evaluation techniques in thermal analysis such as TOPEM™. These technologies do not only support you in achieving better results, they also help you to get them quicker than ever.
A modern researcher has to use a wealth of different instruments. Wehavegreatfocusoncreating
optimized user interfaces: fewer keypresses, self-explanatory menus and intuitive workflows are important goals of our product development.Inaddition,manyofour instruments offer touch-screen operation and can therefore largely be customized and optimized for any application.
Automated Density and Refractive Index Measurement
Ergonomic Pipetting
QUANTOS – the Ultimate Solution for Efficient Solid DispensingQUANTOSistheworld'sfirst benchtop system for automatically dispensing small sample quantities of powders. At its heart is an intel-ligent dispensing head including a storage container for dispensing highly potent or hazardous pow-dery substances such as catalysts and precious starting materials. QUANTOSisyouridealpartnerforsample preparation for synthesis or analyticalmethodssuchasHPLC.
Dispense Duplicate Samples with High RepeatabilityEven the most skillful hands never achieve this level of precision: QUANTOSdosesto0.5mg–with0.005 mg accuracy. The intelligent dosing head with built-in radio frequencyidentification(RFID)immediately saves all data. Even the first sample is within your tolerance limits – guaranteed.
Save Precious MaterialQUANTOS provides highly accurate dosingatlowquantities(10mg accordingtoUSP).Thisallows preparationofsmallerquantities/ volumes of material at the equiva-lent concentration levels.
For more informationwww.mt.com/autochemMettler-ToledoAutoChemInc.
7075 Samuel Morse DriveColumbia,MD21046,USAPhone +1-4109108500Fax +1-4109108600
Mettler-ToledoAG,AutoChemSonnenbergstrasse 74CH-8603Schwerzenbach,SwitzerlandPhone +41-448067711Fax +41-448067290
Internet www.mt.com/autochemE-Mail [email protected]
Subjecttotechnicalchanges.©02/2009Mettler-ToledoAGPrintedinSwitzerland,ME-51725144
Ourliveandon-demandwebinars(webseminars)provideapplicationand industry information relevant to you. These interactive presentations, provided by industry experts and our own applications team, give you an opportunity to learn more about your specific area of interest.
Topics include:•Improvingcrystallizationandprecipitationprocesses•Theimportanceofmixinginprocessdevelopment•Avoidingincidentsduringscale-up•Reducingtheriskofhighlyreactivechemistry•Improvingsoliddoseformulationsdevelopment•Calorimetrybestpractices:fromLaPlacetoLavoisier•Optimizationofhighshearwetgranulation•Characterizationofcatalytichydrogenations•FTIRasaPATtoolfororganicchemists•Plusmanyotherapplicationsincludingtopicsingreenchemistry,
organic synthesis, fermentation, high pressure chemistry and more
Theon-demandwebinarlibraryisavailable24/7enablingyoutoviewthe extensive list of webinars at your own convenience.
Learn More with our TechnicalWebinarProgram
www.mt.com/ac-webinars