Anthony crasto manufacturing presentation of API and organic chemicals

1. By
DR ANTHONY MELVIN CRASTO

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

3. Journey

5. 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 semi-
works 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.

6. 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?

7. * 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?
*

8. 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?

9. 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.

10. 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.

11. 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.

12. SYMBOLS, CONVENTIONS

18. EXAMPLES OF DIAGRAMS

26. MANUFACTURING ESSENCE

27. What about
manufacturing?

28. Discovery Development Marketing Manufacturing

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

38. EQUIPMENTS

39. 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.

40. 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 that’s why known for
perfect mixing.
 Compositions at outlet and inside reactor are same.
 Best suitable for liquid phase reactions

42. Reactor with Internal Coils

43. Jacketed Reactor and its types

44. Sparkler Filter System
Sparkler Filter System

45. The Agitated nutsche filter is a versatile
machine used for drying as well as filtering.

46. What about PROCESS
WATER?
46

47. WATER

48. 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.

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

51. Water for Pharmaceutical Use
Pretreatment –
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

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

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

54. Typical 2-stage RO schematic
Water from softener or de-ioniser
Second 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

55. 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 light
circulating Outlets
Heat Exchanger
Ozone Generator Hygienic pump Air break
to drain

56. BIGGER SIZED EQUIPMENTS

57. A rotary vacuum dryer

58. 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

59. 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.

60. A high steam granulator

61. Turb mixer

62. anchor

64. BIO

66. Industrial fermenters

67. Sunlight H2
Sunlight 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

69. CASE SUDIES

70. 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 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

71. Development of a Novel Catalytic Distillation Process for Cyclohexanol Production: Mini Plant Experiments and
Complementary Process Simulations
Rakesh 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,
Germany
Org. Process Res. Dev., 2011, 15 (3), pp 527–539
DOI: 10.1021/op1001879
Publication Date (Web): March 14, 2011

72. 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.

73. 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.

77. H&R Guide to Fragrance Ingredients

78. H&R Guide to Fragrance Ingredients

79. H&R Guide to Fragrance Ingredients

80. H&R Guide to Fragrance Ingredients

81. Microreactors

85. 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).

86. 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).

87. Thanks
DR ANTHONY MELVIN CRASTO Ph.D
amcrasto@gmail.com
MOBILE-+91 9323115463
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
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