Anthony crasto manufacturing presentation

ByDR ANTHONY MELVIN CRASTO

DeclarationAcademic presentation and will notnot be used for commercialpurposes. Will be freely distributedFree download for industry andacademics

Journey

Many new chemical, particularly batch operations, can be scaled up directlyfrom the bench to the plant by developing the process and performing labtesting with the scaleup in mind.MANY COSTLY AND TIME-CONSUMING startup problems can be avoided ifkey scaleup issues are understood and resolved during the development of a newchemical process.Processes are often scaled up in stages from the lab to the pilot plant or semi-works scale to obtain engineering data for commercial plant design.However, this staged scaleup strategy is not always practical for specialtychemicals, which are often characterized by multi-step batch syntheses andrelatively low volume, and where speed to market and rapid ramp-up areessential for commercial success.

Scaleup is defined as "The successful startup and operation of a commercial size unitwhose design and operating procedures are in part based upon experimentation anddemonstration at a smaller scale of operation"(1). Many factors must be considered when selecting the scaleup strategy. Answering afew process-specific and business-related questions early is key to a successful startup. Process factors •What are the critical factors of the new chemistry and process? Are extreme temperatures, pressures or other conditions required? Are operating instructions complicated? * Does the process involve a single reaction, or is it a multi-step synthesis? If the last step in a multi-step process will be piloted, will it be necessary to also make intermediates at the pilot-plant scale, or are they commercially available?

* Are new chemical technologies, unit operations orequipment being considered?* How novel is the new process? Have similar reactions orprocessing steps been successfully scaled up?* Will the new process be run in batch, semi-batch orcontinuous mode?Business factors* Does the commercial success of the project depend on aflawless initial production campaign?* Is there an alternative supply of material in case start-upproblems limit the production rate?* Are project economics sensitive to yield or to the ability torecover and recycle some of the streams at relatively highlevels?*

What is the commercial timeline? Is there enough time todesign, build and operate a pilot plant to generate scaleupdata and still meet the planned commercial launch?* If the startup is delayed, what is the impact on the productlaunch strategy and project economics?* Are significant quantities needed for the launch of theproduct, or will it be introduced into the market slowly?* Are development samples needed over a period of timeleading up to the launch?* If a pilot-plant campaign is being considered, will thebusiness support the cost and human resources needed toperform this activity?

Scaleup issuesSome of the most common and difficult types of problemsencountered during scaleup are particle formation andisolation, liquid/liquid separation, agitation, heat history andtrace impurities. (Reaction scaleup is widely discussed in theliterature and will not be covered here, and it is assumed thata sound chemical route has already been selected.) Often,scaleup problems are a combination of several of thesefactors (2).Particle formation and isolationSolids can form as a result of precipitation, often duirng areaction, or be produced intentionally, such as bycrystallization. Generally, the goal is to form large, uniformparticles, which will be filtered, washed and dried moreefficiently, and are of higher purity, than fine particles.

In almost all cases, understanding and controlling theparticle growth environment will result in better particles(3).Many reactions are run in a semi-batch or continuousaddition mode, where one of the reactants is meteredinto the reactor and the product formed is a solid. Theorder of addition, rate of addition and feed location, aswell as the intensity and design of the agitation system,can all affect the particle formation process. It is alsoimportant to consider the physical aspects in addition tothe chemical aspects of the reaction, and how theseaffect the particle growth environment.

Crystallization processes involve creating a state of supersaturation, typically bycooling, evaporation, chemical reaction or anti-solvent addition, which drivesnucleation and particle growth.These processes are governed by the conditions of the environmentimmediately next to the particle. A basic understanding of the solubility curveand supersaturation limit is quite helpful. Changing the solvent phasecomposition can have a significant effect on the solubility curve.Tools such as Fourier transform infrared (PTIR) spectroscopy, optical densityprobes, and microscopes are very useful for studying and optimizingcrystallization processes.It is a good idea to determine the crystal size distribution (CSD), shape,strength and whether multiple polymorphs exist. The latter is particularlyimportant in the pharmaceutical industry.

SYMBOLS, CONVENTIONS

EXAMPLES OF DIAGRAMS

MANUFACTURING ESSENCE

What aboutmanufacturing?

Discovery Development Marketing Manufacturing

Scaling up is not easy bench commercial  Simple  Complex  Long lead times - 4-5  Quick years  Inexpensive  Expensive - $150 +  Milligrams million  Kilograms

EQUIPMENTS

Types of ReactorsBatch Reactor (BR, STR) The reactants are initially charged into the vessel and are well mixed and left to react for a certain period of time. The resultant mixture is then discharged. This is an unsteady operation where the composition changes with time but is uniform throughout the reactor at a specific time.

Continuous ReactorsContinuous stirred tank reactor (CSTR, MFR, BMFR)  An agitator is introduced to disperse the reactants thoroughly into the reaction mixture immediately they enter the reactor.  Product is continuously drawn out and that’s why known for perfect mixing.  Compositions at outlet and inside reactor are same.  Best suitable for liquid phase reactions

Reactor with Internal Coils

Jacketed Reactor and its types

Sparkler Filter System Sparkler Filter System

The Agitated nutsche filter is a versatilemachine used for drying as well as filtering.

What about PROCESSWATER? 46

The type of resin to be used should be defined by the resin producer depending on the requirements.These ion exchange resins need to be regenerated periodically depending on water and resin characteristics. The productsregenerating these resins are caustic soda for the anion exchange resin and hydrochloric acid for the cation exchange resin.Regeneration processes must be defined by the resin producer, but, in general, three steps for the anion resin can bementioned:1.Backwash rinsing with water to eliminate fines and any particle coming from the water flow,2.Injection of a 4% aqueous caustic soda solution in Mg2+ and Ca2+ free water to avoid precipitation on the resin bed,3.Rinsing with about 3 times the resin volumes to eliminate the caustic soda in two progressive phases, a slow one toeliminate the greater part of the caustic soda and a fast one to eliminate the last residue.

Water system design (1) There should be no dead legs D Flow direction arrows on pipes are important Deadleg section X <2DIf D=25mm & distance X isgreater than 50mm, we havea dead leg that is too long. Sanitary Valve Water scours deadleg

Water for Pharmaceutical UsePretreatment –schematic drawing float operated excess water recycled activated To water valve from deioniser carbon air filter sand filter filter softener & DI plant spray ball Water is kept raw water in break tank circulating cartridge filter centrifugal pump 5 micrometers air break to drain « S” trap to sewer

Typical de-ionizer schematic from water softener HCl NaOH 6 6 5 5 4 4 3 3 2 2 1 1Watermust be Cationic column Anionic column Cartridge Cartridgekept UV light filter 5 µm filter 1 µmcirculating Eluates to Ozone generator neutralization plant Hygienic pump Return to de-ioniser Outlets or storage. Drain line Air break to sewer

Reverse osmosis (RO) theoryHigh pressure Low pressure Semi-permeable membrane Feed water under Purified water pressure raw water Reject Permeate water water drain or recycle

Typical 2-stage RO schematic Water from softener or de-ioniserSecond stage reject water goes back to first stage buffer tank 1st stage buffer tank Branch First stage RO cartridge 1st stage reject concentrate Branch First stage filtrate feeds second stage RO . with excess back to 1st stage buffer tank Air break to sewer 2nd stage buffer tank Second stage RO cartridge High pressure pump Cartridge filter 1 µm Hygienic pump Second stage RO water meets Pharmacopoeia Water returns to 1st stage buffer tank standards Outlets or storage

Typical water storage and distribution schematic Hydrophobic air filter Feed Water & burst disc from DI or RO Cartridge filter 1 µm Spray ball Water Optional in-line filter must be 0,2 µm kept UV lightcirculating Outlets Heat Exchanger Ozone Generator Hygienic pump Air break to drain

BIGGER SIZED EQUIPMENTS

A rotary vacuum dryer

Glass-Lined Nutsche Filter Nutsche filter offers faster and more efficient operation than an open vessel because it can be operated under pressure or vacuum

The glass nutsche facilitates a variety ofbatch vacuum filtration requirements asoften encountered in kilo lab operation,chemical product development andpharmaceutical intermediatemanufacturing.

A high steam granulator

Turb mixer

anchor

Industrial fermenters

Sunlight H2Sunlight co2 o2 Algae A Concentra L tor and G Algae adapter A production H2 (Dark- E Bioreactor H2 Anaerobic Photobioreactor (Light (light aerobic) ) Aerobic) H2 Nutrient recycle Algae Recycle Fig:- Schematic of Hydrogenase mediated Biophotolysis process

CASE SUDIES

Scalable in Situ Diazomethane Generation in Continuous-Flow ReactorsEmiliano Rossi†, et al†Corning European Technology Center, Padova, ItalyOrg. Process Res. Dev., Article ASAPDOI: 10.1021/op200110aPublication Date (Web): December 12, 2011 Diazomethane is a valuable derivatizing agent but very difficult to handle for large- scale chemical transformations. This report indicates the base-induced decomposition of N-methyl-N-nitrosourea under continuous-flow conditions that enables the production up to 19 mol d–1of diazomethane, at a total flow rate of 53 mL min

Development of a Novel Catalytic Distillation Process for Cyclohexanol Production: Mini Plant Experiments andComplementary Process SimulationsRakesh Kumar†, Amit Katariya†, Hannsjörg Freund*†, and Kai Sundmacher†‡† Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstrasse 1, 39106 Magdeburg, Germany‡ Process Systems Engineering, Otto-von-Guericke University Magdeburg, Universitätsplatz 1, 39106 Magdeburg,GermanyOrg. Process Res. Dev., 2011, 15 (3), pp 527–539DOI: 10.1021/op1001879Publication Date (Web): March 14, 2011

A new, two-step process concept for the production ofcyclohexanol by indirect hydration of cyclohexene usingformic acid as a reactive entrainer is suggested, and itsprinciple technical feasibility is demonstrated. The first stepof this process is based on an ester formation reaction ofcyclohexene with formic acid. This reaction was carried outin a mini plant stainless steel catalytic distillation column of2.35 m height. The column was packed with noncatalyticstructured packings (SULZER-DX) and catalytic structuredpackings (KATAPAK-S). The experiments were conductedunder low-pressure conditions (<0.6 bar) to avoid formic aciddecomposition. Concentration and temperature profiles wereobtained under steady-state conditions.

Up to 98.3% conversion of cyclohexene and 75.5 mol % esterconcentration in the bottom product of the column wasobtained. In a similar manner, the second step of theprocess, i.e. the hydrolysis of the cyclohexyl formate formedin the first step, was investigated experimentally in acontinuous catalytic distillation column under low-pressureconditions (<0.4 bar). Important process design parameterssuch as the feed mole ratio of the reactants, the reboilerduty, the feed flow rate, and the column pressure wereinvestigated with regard to their effect on the cyclohexeneconversion and the purity of the bottom product.Furthermore, the experimental data were compared withresults obtained from steady-state simulations of thecatalytic distillation process.

H&R Guide to Fragrance Ingredients

Microreactors

REFERENCELiterature Cited1. Bisio, A., and R. L. Kabel, "Scaleup of Chemical Process," Wiley, Hoboken, NJ, p. 3(1985).2. Anderson, N. G., "Practical Process Research and Development," Academic Press,San Diego, CA (2000).3. Myerson, A. S., "Handbook of Industrial Crystallization," Butterworth-Heinemann,Newton, MA, pp. 15-19 (1993).4. Perry, R. H. and D. W. Green, eds., "Perrys Chemical Engineers Handbook," 6thed., Chapter 19, pp. 65-103, McGraw-Hill, New York, NY (1984).5. Purchas, D. B., ed., "Solid-Liquid Separation Equipment Scaleup," Uplands Press,London, pp. 493-553 (1977).6. Osmonics, Inc., "Liquid/Liquid and Gas/Liquid Coalescing Handbook," Ninnetoka,MN (1991).7. Paul, E. L., et al, eds., "Handbook of Industrial Mixing," Wiley, Hoboken, NJ (2004).

8. Fasano, J. B., and W. R. Penney, "Cut Reaction Byproducts by Proper FeedBlending," Chem. Eng. Progress, 87 (12), pp. 46-52 (Dec. 1991).Further ReadingSharnatt, P. N., "Pilot Plants and Scale-up of Chemical Processes," Hoyle, W., ed.,Royal Society of Chemistry, Cambridge, UK, pp. 13-21, 1-30, 655-690 (1997).

Thanks DR ANTHONY MELVIN CRASTO Ph.D amcrasto@gmail.com MOBILE-+91 9323115463 GLENMARK SCIENTIST , NAVIMUMBAI, INDIA web links http://anthonycrasto.jimdo.com/ http://www.anthonymelvincrasto.yolasite.com/ http://www.slidestaxx.com/anthony-melvin-crasto-phd https://sites.google.com/site/anthonycrastoorganicchemistry/s ites---my-own-on-the-net http://anthonycrasto.wordpress.com/ http://organicchemistrysite.blogspot.com/ http://www.mendeley.com/profiles/anthony-melvin-crasto/ Congratulations! Your presentation titled "Anthony Crasto Glenmark scientist, helping millions with websites" has just crossed MILLION views.

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Anthony crasto manufacturing presentation

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