By DR ANTHONY MELVIN CRASTO

Declaration Academic presentation and will not not be used for commercial purposes. Will be freely distributed Free download for industry and academics

Journey

Many new chemical, particularly batch operations, can be scaled up directly from the bench to the plant by developing the process and performing lab testing with the scaleup in mind.

MANY COSTLY AND TIME-CONSUMING startup problems can be avoided if key scaleup issues are understood and resolved during the development of a new chemical process.
Processes are often scaled up in stages from the lab to the pilot plant or semiworks scale to obtain engineering data for commercial plant design. However, this staged scaleup strategy is not always practical for specialty chemicals, which are often characterized by multi-step batch syntheses and relatively low volume, and where speed to market and rapid ramp-up are essential for commercial success.

Scaleup is defined as "The successful startup and operation of a commercial size unit whose design and operating procedures are in part based upon experimentation and demonstration at a smaller scale of operation" (1). Many factors must be considered when selecting the scaleup strategy. Answering a few 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 or equipment being considered? * How novel is the new process? Have similar reactions or processing steps been successfully scaled up? * Will the new process be run in batch, semi-batch or continuous mode? Business factors * Does the commercial success of the project depend on a flawless initial production campaign? * Is there an alternative supply of material in case start-up problems limit the production rate? * Are project economics sensitive to yield or to the ability to recover and recycle some of the streams at relatively high levels?
*

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

Scaleup issues Some of the most common and difficult types of problems encountered during scaleup are particle formation and isolation, liquid/liquid separation, agitation, heat history and trace impurities. (Reaction scaleup is widely discussed in the literature and will not be covered here, and it is assumed that a sound chemical route has already been selected.) Often, scaleup problems are a combination of several of these factors (2). Particle formation and isolation Solids can form as a result of precipitation, often duirng a reaction, or be produced intentionally, such as by crystallization. Generally, the goal is to form large, uniform particles, which will be filtered, washed and dried more efficiently, and are of higher purity, than fine particles.

In almost all cases, understanding and controlling the particle growth environment will result in better particles (3). Many reactions are run in a semi-batch or continuous addition mode, where one of the reactants is metered into the reactor and the product formed is a solid. The order of addition, rate of addition and feed location, as well as the intensity and design of the agitation system, can all affect the particle formation process. It is also important to consider the physical aspects in addition to the chemical aspects of the reaction, and how these affect the particle growth environment.

Crystallization processes involve creating a state of supersaturation, typically by cooling, evaporation, chemical reaction or anti-solvent addition, which drives nucleation and particle growth.

These processes are governed by the conditions of the environment immediately next to the particle. A basic understanding of the solubility curve and supersaturation limit is quite helpful. Changing the solvent phase composition can have a significant effect on the solubility curve.

Tools such as Fourier transform infrared (PTIR) spectroscopy, optical density probes, and microscopes are very useful for studying and optimizing crystallization processes.

It is a good idea to determine the crystal size distribution (CSD), shape, strength and whether multiple polymorphs exist. The latter is particularly important in the pharmaceutical industry.

SYMBOLS, CONVENTIONS

EXAMPLES OF DIAGRAMS

MANUFACTURING ESSENCE

What about

manufacturing?

Discovery

Development

Marketing

Manufacturing

Scaling up is not easy

bench
Simple

commercial
Complex

Quick
Inexpensive Milligrams

Long lead times - 4-5 years

Expensive - $150 million Kilograms

EQUIPMENTS

Types of Reactors
Batch 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 Reactors
Continuous 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 thats 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 versatile machine used for drying as well as filtering.

What about PROCESS

WATER?

46

WATER

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 products regenerating 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 be mentioned: 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 to eliminate 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

If D=25mm & distance X is greater than 50mm, we have a dead leg that is too long.

<2D

Sanitary Valve Water scours deadleg

Water for Pharmaceutical Use

Pretreatment schematic drawing

float operated valve excess water recycled from deioniser air filter spray ball sand filter activated carbon filter

To water softener & DI plant

Water is kept circulating

raw water in

break tank

air break to drain

centrifugal pump

cartridge filter 5 micrometers

S trap to sewer

Typical de-ionizer schematic

from water softener HCl NaOH

6
5 4 3 2 1

6 5 4 3 2 1

Water must be UV light kept circulating

Cationic column

Anionic column

Cartridge filter 5 m

Cartridge filter 1 m Ozone generator

Eluates to neutralization plant Hygienic pump Return to de-ioniser

Outlets or storage.
Drain line Air break to sewer

Reverse osmosis (RO) theory

High pressure Low pressure

Semi-permeable membrane

Feed water under pressure

raw water

Purified water

drain or recycle

Reject water

Permeate water

Typical 2-stage RO schematic

Water from softener or de-ioniser

Second stage reject water goes back to first stage buffer tank
Branch

First stage RO cartridge

Branch

1st stage buffer tank

1st stage reject concentrate

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 Second stage RO water meets Pharmacopoeia standards

Cartridge filter 1 m

Hygienic pump

Water returns to 1st stage buffer tank Outlets or storage

Typical water storage and distribution schematic

Feed Water from DI or RO Hydrophobic air filter & burst disc Cartridge filter 1 m

Spray ball

Water must be kept circulating

Optional in-line filter 0,2 m UV light 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 of batch vacuum filtration requirements as often encountered in kilo lab operation, chemical product development and pharmaceutical intermediate manufacturing.

A high steam granulator

Turb mixer

anchor

BIO

Industrial fermenters

Sunlight

co2 o2

Sunlight

H2

Algae production Bioreactor (Light Aerobic)

Algae Concentra tor and adapter (DarkAnaerobic )

A L G A E

H2

Photobioreactor (light aerobic)

H2
H2

Nutrient recycle
Algae Recycle

Fig:- Schematic of Hydrogenase mediated Biophotolysis process

CASE SUDIES

Scalable in Situ Diazomethane Generation in Continuous-Flow Reactors Emiliano Rossi, et al

Corning European Technology Center, Padova, Italy Org. Process Res. Dev., Article ASAP DOI: 10.1021/op200110a Publication Date (Web): December 12, 2011

Diazomethane is a valuable derivatizing agent but very difficult to handle for largescale 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 d1of diazomethane, at a total flow rate of 53 mL min

Development of a Novel Catalytic Distillation Process for Cyclohexanol Production: Mini Plant Experiments and Complementary Process Simulations Rakesh Kumar, Amit Katariya, Hannsjorg 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, Universitatsplatz 1, 39106 Magdeburg, Germany Org. Process Res. Dev., 2011, 15 (3), pp 527539 DOI: 10.1021/op1001879 Publication Date (Web): March 14, 2011

A new, two-step process concept for the production of cyclohexanol by indirect hydration of cyclohexene using formic acid as a reactive entrainer is suggested, and its principle technical feasibility is demonstrated. The first step of this process is based on an ester formation reaction of cyclohexene with formic acid. This reaction was carried out in a mini plant stainless steel catalytic distillation column of 2.35 m height. The column was packed with noncatalytic structured packings (SULZER-DX) and catalytic structured packings (KATAPAK-S). The experiments were conducted under low-pressure conditions (<0.6 bar) to avoid formic acid decomposition. Concentration and temperature profiles were obtained under steady-state conditions.

Up to 98.3% conversion of cyclohexene and 75.5 mol % ester concentration in the bottom product of the column was obtained. In a similar manner, the second step of the process, i.e. the hydrolysis of the cyclohexyl formate formed in the first step, was investigated experimentally in a continuous catalytic distillation column under low-pressure conditions (<0.4 bar). Important process design parameters such as the feed mole ratio of the reactants, the reboiler duty, the feed flow rate, and the column pressure were investigated with regard to their effect on the cyclohexene conversion and the purity of the bottom product. Furthermore, the experimental data were compared with results obtained from steady-state simulations of the catalytic distillation process.

H&R Guide to Fragrance Ingredients

H&R Guide to Fragrance Ingredients

H&R Guide to Fragrance Ingredients

H&R Guide to Fragrance Ingredients

Microreactors

REFERENCE Literature Cited 1. 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., "Perry's Chemical Engineers' Handbook," 6th ed., 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 Feed Blending," Chem. Eng. Progress, 87 (12), pp. 46-52 (Dec. 1991). Further Reading Sharnatt, 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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