Organic Reactions & Processes Optimisation & Scale up
1. Organic Reactions & Processes:
Optimization & Scale up
BY
Mr. Bhavesh Bharat Amrute
(M.Pharmacy-Pharmaceutical Chemistry)
March 20
2. Introduction
March 20
Opimization & Scale up of Organic Reactions & processes, is
problematic area of chemistry and chemical engineering, and
can be costly when it goes wrong.
• By correctly choosing and designing the synthetic route to a
fine chemical or drug substance, as well as controlling the
reaction and work up/product isolation parameters, many of
the difficulties in scale up can be avoided.
• The more complex a process is in terms of chemistry and
unit operations, the more there is to go wrong.
3. Drug Developments
March 20
mg-gm 1 Kg 1-100 kg
Idea
Discovery
Process
Research
Process
development
kilo
lab
Routine
manufacturing
>100Kg
Toxicity
batches/
Phase I
Phase 2 Phase 3
Batch Sizes for compound during Drug Development
4. Drug Development Timeline
March 20
Target
Screen(s) Hit
Lead
Candidate Launch
Patent
Expiration
P A T E N T
D I S C O V E R Y
C L I N I C A L
SAFETY/PHARMACEUTICAL STUDIES
P R O C E S S R E S E A R C H
4.5 yrs 2 yrs
200-300 gms < 100 kg 100-2000 kg
8.2 years
5. Development journey of new drug from discovery
to launch: Phase Study & Activities involved
March 20
Pre-Clinical study: Target molecule identification and animal study
Phase Clinical -1 study: Safety test in healthy humans & Dose
determination
Phase-2 Clinical study : Efficacy study in patients and proof of concept
Phase-3 Clinical study: Extensive studies about excipients, therapy
efficacy and safety
Filing and approval: Regulatory evaluation about efficacy, safety and
manufacturing for claimed use
Market Launch and Phase-4 Study:Post marketing studies about clinical
benefit & monitor events
6. Unit Process
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Unit process is defined as the one in which several unit
operations are combined in sequence to achieve the
objective of Chemical or Physical Process
a) Physical Process: E.g. Mfg. of Common salt
b)Chemical process: e.g. Paracetamol production
from Phenol
7. Chemical Process
March 20
Chemical process operations are of two basic types:
Batch processes, which operate according to batch cycles,
Continuous processes, which operate continuously under
steady conditions.
Chemical processes consist of a number of sequential and
integrated operations carried out in appropriate equipment.
For example chemical reaction carried out in a chemical
reactor.
The precise operations, sequence of operations and equipment
specifications depend on the nature of the process, operating
conditions, materials used and product produced.
9. Chemical Processes
March 20
Operation Equipment
Chemical reaction reactor
Distillation distillation column
Filtration filter units
Drying dryers (various types)
Fluid transport pipes, valves, pumps etc
Process control measurement devices,
controllers, valves
Evaporation evaporators
Centrifugation centrifuges
Heat transfer heat exchangers
Granulation granulator
10. General features
March 20
• Synthetic route selection:
Convergent synthetic route using low cost raw materials
Robustness of the process
Minimal waste output
Suitable for Scale up
• Conditions:
Temperature
Viscosity of solvent
Low solubility of reactants/products/byproducts
Encrustation of raw materials on the vessel walls
11. General Considerations for Process
Chemistry
March 20
Avoid column chromatography
Seeding helps crystallization
Avoid desiccants, use azeotrope
Avoid solvents with flash point < 15 ºC
Ether, hexanes, DCM
Temperature range -40 to 120 ºC
Avoid protecting groups
Impurities of > 0.1% must be analyzed
12. Appropriate Synthetic & Scale up
route
March 20
Cl
Cl
O
OCl
Cl
O
Cl
Cl
OH Dichlorobenzene
AlCl3
1 step process
Route II
Cl
Cl
O
OH
O
Sodium Borohydride
Route I
Benzene;
then Cyclize
Tetralone Intermediate for Sertraline
Succinic Anhydride;
AlCl3
AlCl3
Overall Yield: 60 %
Overall Yield: 80 %
14. March 20
GREEN CHEMISTRY IN SERTRALINE
O
Cl
Cl
Cl
Cl
NCH 3
CH3NH2
ETHANOL
EARLIER ROUTE : METHYLAMINE / TiCl4
GREEN ROUTE : METHYLAMINE / ETHANOL
ELIMINATED USE OF 440 MT. OF TITANIUM DIOXIDE
AND 150 MT. OF 35% HCl
CUT PROCESS SOLVENT FROM 60,000 TO 6000 GALLONS
PER TON OF SERTRALINE
ELIMINATED USE OF 100MT. OF 50% NaOH PER YEAR
PFIZER WON PRESIDENTIAL GREEN CHEM. AWARD IN 2002
REF : CHEM. ENG. NEWS, APRIL 22, 2002.
15. Green Chemistry in
Levetiracetam Synthesis
March 20
Established Approch
Et
NH2
OH
Et
OH
O
BzHN
Et
NH2
NH2
O
Et
N
CH3
O
O
(S)-aminobutanol
i) Benzoyl protection
ii) [o]
N- benzoyl protected (s)-aminobutyric acid
ii) Deprotection
i) Amidation
(S)-aminobutyramide
4-chlorobutyryl chloride
Levetiracetam
Cl
ClO
16. Green Chemistry in
Levetiracetam Synthesis
March 20
ECO -friendly synthesis of Levetiracetan
Et
NH2
OH +
O O
Et
OHN
O
Et
OHN
O
O
Et
NH2
N
O
O
(s)-aminobutanol gamma-butyrolactone
solvent free condensation
Oxidation
acid Intermediate
i) EtOCOCl
ii) NH3
Levetiracetan
Condensed Alcohol
kMNO4 OR
Cat. RuCl2 /NaOCl
17. Synthetic Route Modification
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MODIFIED SULPHONE SYNTHESIS
SH
HO
S
HO
Cl
S
Cl
HO
Cl
S
Cl
HO
O
O
S
OH
HO
O
O
1. NaOH / 2- BROMOETHANOL
2. SOCl2 / PYRIDINE
1. NaOH / 2- BROMOETHANOL
2. OXONE / MeOH
( ROUTE 1 )
( ROUTE 2 )
SOCl2 / PYRIDINE
OXONE / METHANOL
95% 5%
+
58% YIELD IN 3 STEPS ( ROUTE 2 )
90% YIELD IN 3 STEPS ( ROUTE 1 )
18. Optimization of addition Sequence
March 20
ACO
O
OH
NH
CH3 O
O
O
N
ACO
CH3
Key mesylate intermediate in synthesis of Nelfinavir Mesylate
Adding the base last as a key operation of Mesylation. Ratio of Mesylate to oxazoline
( 95:5 ) by minimizing the amount of free base ( Et3N )
sMO
ACO
O
NH
CH3
O
i) 2.5 MsCl
EtOAC
ii)1.5 Et3N
+
Et3N.HCl
Et3N
Mesylate intermideat
Oxazoline
19. Reagent Selection
March 20
Reagents are chosen to minimize cost, minimize
waste, and to maintain safe operations, among other
considerations. Less hazardous reagents may be
chosen in order to minimize time spent wearing PPE
that hinders movement. Substitutes may be sought for
air-sensitive reagents that pose handling constraints.
Less expensive reagents may be employed.
21. Removal of Protecting Group
BOC (t-Butoxycarbonyl)
March 20
N
O N
Cl
BOC
N
H
O N
Cl
p-TsOH/EtOH
88 %
.p-TsOH
Deprotection using TFA:Corrosive; Incineration problem due
to HF generation.Other alternative to TFA are HCl; H2SO4;
Methanesuifonic acid; toluenesulfonic acid. The tosylate
crystallised directly from deprotection & proved to be more
Stable compare to HCl or TFA Salt.
22. Economy of reagent selection
March 20
Peptide bond forming reagent arranged according to decreasing
cost
1. EDC(1-3-Diethylaminopropyl)-3-ethylcarbodimide
2. Vilsmeier reagent (Chloromethylene-dimethylammonium
chloride)
3. DCC (Dicyclohexyl carbodimide)
4. Isobutyl Chloroformate
5. Pivaloyl Chloride
6. Thionyl Chloride
23. Economy of reagent selection
March 20
Relative cost of Alkali in Rs
Sodium Hydroxide: 35-40 per Kg
Potassium Hydroxide: 90-100 per Kg
Lithium Hydroxide: 150-160 per Kg
Sodium Hydroxide; 50%: 35-50 per liter
Cost of Solvent in Rs. Per Kg
Methanol: 20-24
Acetone: 80
Ethanol: 40-100
Ethyl acetate: 72
Toluene: 90
Hexane: 80-82
24. Waste Utilisation
March 20
ALTERNATIVE FEEDSTOCKS
WASTE FROM ONE PROCESS AS FEEDSTOCK FOR ANOTHER
CH3
CH3
SO2Cl
CH3
SO2Cl
ClSO3H
+
FOR TOLBUTAMIDE
CHLORAMIN-T
FOR SACHARIN
SUGARS / CARBOHYDRATES AS REPLACEMENT FOR
PETROCHEMICAL HYDROCARBON
CO2 AS FEEDSTOCK.
AND AS A REAGENT.
25. Solvent free reaction
March 20
Synthesis of acetanilide :
Conventional Procedure:
NHCOCH 3
PYRIDINE
(CH3CO)2O+ CH2Cl2
NH2
Aniline Acetic anhydride Acetanilide
Non-green Components:
Use of chlorinated solvent like CH2Cl2
Pyridine is also not eco-friendly
Acetic anhydride leaves one molecule of acetic acid
unused (not atom-economic)
26. Alternative Green route
March 20
NH2
+ COOHCH3
NHCOCH 3
zinc dust
boil
Chemicals Required:
• Aniline - 10 ml (10.2 g)
• Glacial acetic acid - 30 ml
• Zinc dust - 0.5 g
Green Context:
• Avoids use of acetic anhydride
• Minimizes waste by-products
• Avoids hazardous solvent
28. Commonly used Solvents for
Reactions
March 20
Solvents Commonly Used on Scale
Water DMSO MIBK MTBE
MeOH DMF DME PhCH3
1,2-Propanediol t-BuOH EtOAc Et3N
EtOH NMP THF Xylenes
AcOH Acetone i-PrOAc Heptane
n-BuOH t-AmOH PhCl Cyclohexane
i-PrOH CH2Cl2 2-Me-THF Methylcyclohexane
Acetonitrile Pyridine i-BuOAc
29. General features: Reactions
March 20
Correct dosing regime:
Stoichiometry based on the reaction:
Other factors: rate of addition, mixing, temperature, the solvent
and its purity,Concentration, pH, presence of catalyst or inhibitors
Understanding the Kinetics:
Allow design of process,
Allow correct choice of temperature,
Allow optimum dosing rate for particular scale
For an exothermic reaction, the dosing rate limited by the cooling
capacity of the vessel. So it is important to understand exactly
when the heat is generated in the process.
30. Hazards of Scale up
• Potential for loss of control if reaction is exothermic, since
the change in heat transfer area per unit volume varies with
scale. The consequences of this are increased cycle times
and particularly increased addition times for reagents.
• These changes affects the yield & quality of the product.
• The problem is there if the reagent addition is too fast
compared to heat removal, accumulation can occur & lead
to a runaway reaction if loss of cooling capacity occurs
simultaneously.
• The consequences may be decomposition of the reaction
mixtures or the wastage of the reaction.
March 20
31. Hazards solutions
• Solution for this problems is keeping the CALORIMETER
& monitoring the heat of reaction at proper stage & time.
• From the economic point of view the destruction of plant
facility & loss of human life affects the bottom line so
much more than capital expenditure on calorimeter.
• Calorimetric evaluation can usually pay for itself since it
usually leads to increased yield & quality
March 20
32. Mass transfer issues
• The solid & liquid dosing of the reagent; eg NBS
• The stirrer speed (rpm) & type
• Reactions involving 2 liquid phases, such as phase transfer
catalyst reactions are very sensitive to the position of
agitator as well as agitator type/diameter/shape.
•Maintain the ratio of interfacial area to total volume
constant.
March 20
33. Simple effective workup &
Isolations
March 20
Work-up becomes a major consideration in designing processes for
preparation of all phases of drug development after Phase 1, as “60 to
80% of both capital expenditures and operating costs go to separations.”
Work-up conditions can limit the selection of reagents and routes. Simple
work-ups with a minimal number of transfers decrease the number of
opportunities for physical losses and contamination.
Kilo Lab: Concentration & Evaporation
Concentrating to a residue product can be time-consuming, with the risk
that the product will decompose during a lengthy operation. When a
reaction product is nicely crystalline, adding an anti-solvent may
crystallize the product directly, and this is often preferred for a pilot-plant
campaign and manufacturing.
34. Solvent extraction problems
March 20
• During the extractive workup addition of aqueous phase to
organic or vice versa.
• The problem of emulsion formation & the time of
disengagement of the layers, as well of their separation
efficiency.
• Saturated solution of water in an organic solvent is an
excellent hydrolysis media for the esters and other
hydrolysable groups if traces of base are present. At
extended separation times hydrolysis may then occur leading
to greater amounts of by-products.
• This can effect the yield and also may impact the product
quality.
35. Solvent Extraction
• For this reason the solvent ethyl acetate is a poor choice of
extraction solvent for scale up, particularly in acid/base work-
ups, since the extended times the ethyl acetate is in contact
with water when trace acids/bases are present will initiate
hydrolysis of the solvent, leading to more acid (acetic acid)
which further catalyses hydrolysis. The high solubility of
water in ethyl acetate and vice-versa means that aqueous
layers, unless heavily salted, are rich in organics (and thus
more difficult to dispose of)
March 20
36. Solvent Extraction
• Also the ethyl acetate layers have high water contents and
may need drying before further processing. Isopropyl
acetate and butyl acetate, though more expensive initially,
may actually be more cost effective overall in scale up,
particularly since solvent recovery is easier because the
low water content in the solvent leads to higher recoveries.
• Extraction temperature: 2 to 40 oC, more preferably 50-100
oC in plant extractions
March 20
37. Compatibility with vessel
March 20
• GLR (Etching problem; wear & tear) vs SSR (Metal
contamination)
Case studies: CF3 gp may yield traces of HF
Corrosion testing: Testing of individual components along with
the reaction mixture for compatibility with the materials of
construction of the Vessel.
38. Crystallisation and
polymorphism
• In our country the generic pharmaceutical industry is highly
active in investigating alternative crystalline forms of drugs in
order to circumvent existing patents, or to provide new IP
opportunities. However, consistent manufacture of the desired
form on large scale can be a problem.
• Key parameters controlling which form is produced, and the
particle size distribution, (PSD, which determines filterability
and drying times) include the number and level of trace
impurities in solution (even as low as 0.01%), which may vary
from batch to batch.
March 20
39. Crystallisation and
polymorphism
• The control of a crystallisation process needs exact control of
nucleation (by seeding at a defined supersaturation) and
a programmed cooling programme that allows the crystals
to take up the supersaturation very slowly.
• Reactor or filter/centrifuge contamination from previous
batches of the same substance may impact on the ability
to produce the correct crystal form and PSD of the product.
• Specific physical properties of the product are desired for
further processing, such as formulation, or affect the
stability of the product ( eg. oxygen or light).
March 20
40. Crystallisation and
polymorphism
• Polymorphs and pseudopolymorphs (solvates) may be
discovered for any compound,not just APIs. For instance, more
than 100 solvates have been identified for sulfathiazole
• New forms of a drug candidate can present opportunities for
expanding intellectual property, and may also provide definitive
proof of structure by single-crystal X-ray analysis.
March 20
41. Crystallisation and
polymorphism
• The detection of undesired polymorphs or pseudopolymorphs is
key to avoid interrupted sales of drug product. Ritonavir was
aggressively developed by Abbott and approved by the FDA in
1996 About two years later a new polymorph (Form II) was
discovered in the drug product, and crystallization to give Form I
could not be controlled in any manufacturing plant. The
undesired Form II have been associated with the urethane an
impurity that was present in the optimized route to ritonavir. The
drug product was reformulated to accommodate Forms I and II,
and, fortunately, no market hiatus occurred
March 20
42. Conclusion
• The best way to minimize scale up problems is by data
gathering and detailed process understanding.
• Trained technical staff (chemists and engineers) with up-to-
date knowledge of current thinking can help, design of better
processes with fewer scale up issues.
• Do not hesitate to take the help of professionals in
trouble-shooting persistent manufacturing problems.
March 20
43. References
1. T. Laird “Development and Scale-up of Processes for
the Manufacture of Pharmaceuticals” Comprehensive
Medicinal Chemistry. Vol 1, 1989, Pergamon Press; T.
Laird, The Neglected Science of Chemical
Development, Chemistry in Britain, Dec. 1989,p.1208
2. N.G Anderson, Practical Process Development,
Academic Press 2000
3. K.G. Gadamasetti, Process Chemistry in the
Pharmaceutical Industry, Marcel Dekker, 1999 (Vol 1)
and CRC Press 2007 (Vol 2)
March 20
44. References
4. W. Hoyle, Pilot plants and Scale Up of Chemical
Processes, Royal Society of Chemistry, Vols 1 and 2, 1997
and 1999
5. S. Lee and G Robinson, Process Development: Fine
Chemicals from Grams to Kilograms, Oxford Science,
1992
6. M. Williams and G. Quallich, Chem & Ind, 1990, 315;
G Quallich, Chirality, 2005, 17, S120-S126
7. F. Stoessel, Org Process R&D, 1997, 1, 428
8. F Stoessel, Thermal Safety of Chemical Prrocesses; Risk
Assessment and Process Design, Wiley-VCH, 2008
9. www.csb.gov/assets/document/Morton_Report.pdf
March 20
45. References
10. E.L. Paul, presentation at 2nd International
Conference on Scale Up of Chemical Processses,
Scientific Update, 1996
11. E.L. Paul, Y.A.Atiemo-Obeng and S.M.Kresta,
Handbook of Industrial Mixing, Wiley-Interscience,
2004
12. K.J.Carpenter, Chem Eng Sci, 2001, 56, 305-322
13. J.H Atherton and K.J.Carpenter, Process
Development, Physico-Chemical Concepts, Oxford Science,
2000
March 20
