This document discusses optimization and scale up of organic reactions and processes. It is important to correctly design the synthetic route and control reaction parameters to avoid difficulties in scale up. The more complex a process, the more that can go wrong during scale up. Simple and effective workups and isolations are important considerations for process design, especially for later drug development phases where separations account for most costs. Hazards like exothermicity must be monitored to avoid runaway reactions at scale. Mass transfer and solvent extraction issues can also impact yields and purity.
Process chemistry AS PER PCI SYLLABUS FOR M.PHARMShikha Popali
pharmaceutical process chemistry is process WHERE FROM THE RESEARCH TO FINISH PRODUCT INCLUDING THE PRODUCT DEVELOPMENT AT LABORATORY LEVEL THAN PILOT PLANT WHERE THE PRODUCT IS MANUFACTURED IN 10X THAN FINAL AT 100X THAT IS SCALE UP PLANT.
Process chemistry AS PER PCI SYLLABUS FOR M.PHARMShikha Popali
pharmaceutical process chemistry is process WHERE FROM THE RESEARCH TO FINISH PRODUCT INCLUDING THE PRODUCT DEVELOPMENT AT LABORATORY LEVEL THAN PILOT PLANT WHERE THE PRODUCT IS MANUFACTURED IN 10X THAN FINAL AT 100X THAT IS SCALE UP PLANT.
Two dimensional Nuclear Magnetic Resonance (2D NMR) refers to a set of multi pulse techniques which were introduced to overcome the complex spectra obtained with NMR.
It is a set of NMR methods which give data plotted in a space defined by two frequency axes rather than one.
This Powerpoint describes what is Flow chemistry, what are its advantages over batch method, Continuous flow reactor and Applications of Continuous flow chemistry.
TEXTILE SLUDGE DEGRADATION USING WATER HYACINTH AND BIOGAS GENERATIONijiert bestjournal
Textile industry is growing on an enormous rate due to the cap ital demand of the product cotton,wool and synthetics. The waste water generated from different manufacturing processes in a point to treat because of its toxicity. The toxici ty mainly comes from pr esence of heavy metals,chemicals and different compounds used in di fferent manufacturing processes;among these heavy metals is of great concerns. The heavy su ch as Pb,Cd,Ni,Cu,As,Cr etc. are found in textile sludge. water hyacinth (Eic hhornia crassipes) has received great attention because of its obstinacy and high productivity.
Two dimensional Nuclear Magnetic Resonance (2D NMR) refers to a set of multi pulse techniques which were introduced to overcome the complex spectra obtained with NMR.
It is a set of NMR methods which give data plotted in a space defined by two frequency axes rather than one.
This Powerpoint describes what is Flow chemistry, what are its advantages over batch method, Continuous flow reactor and Applications of Continuous flow chemistry.
TEXTILE SLUDGE DEGRADATION USING WATER HYACINTH AND BIOGAS GENERATIONijiert bestjournal
Textile industry is growing on an enormous rate due to the cap ital demand of the product cotton,wool and synthetics. The waste water generated from different manufacturing processes in a point to treat because of its toxicity. The toxici ty mainly comes from pr esence of heavy metals,chemicals and different compounds used in di fferent manufacturing processes;among these heavy metals is of great concerns. The heavy su ch as Pb,Cd,Ni,Cu,As,Cr etc. are found in textile sludge. water hyacinth (Eic hhornia crassipes) has received great attention because of its obstinacy and high productivity.
Application on Semi-aerobic Landfill. Technology in in Tropical Climate: Lysi...CRL Asia
Presentation file on Application on Semi-aerobic Landfill. Technology in in Tropical Climate: Lysimeter experiment of Thailand (Created: SWGA Chart Chiemchaisri)
“Local Anaesthetics”
These are agents which upon topical application or local injection cause reversible loss of pain sensation in a restricted area of the body. They act by blocking both sensory and motor nerve conduction to produce temporary loss of sensation without loss of consciousness.
Mechanism of action
These drugs reversibly prevent the generation and propagation of impulses in all excitable membranes including nerve fiber by stabilizing the membrane.
Local anesthetics block the nerve conduction by decreasing the entry of Na+ during action potential. They interact with a receptor situated within the voltage sensitive Na+ channel and raise the threshold of Na+ channel opening.
Therefore, Na+ can’t enter into the cell in response to an impulse which prevents depolarisation. Thus, action potential is not generated.
This action affecting the depolarization which leads to failure of conduction of impulse without affecting the resting membrane potential (RMP) is known as membrane stabilizing effect.
History- Cocaine is a naturally occurring compound indigenous to the Andes Mountains, West Indies, and Java.
It was the first anesthetic to be discovered and is the only naturally occurring local anesthetic; all others are synthetically derived.
Cocaine was introduced into Europe in the 1800s following its isolation from coca beans. Sigmund Freud, the noted Austrian psychoanalyst, used cocaine on his patients and became addicted through self-experimentation.
In the latter half of the 1800s, interest in the drug became widespread, and many of cocaine's pharmacologic actions and adverse effects were elucidated during this time. In the 1880s, Koller introduced cocaine to the field of ophthalmology, and Hall introduced it to dentistry
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones
Slide 1: Title Slide
Extrachromosomal Inheritance
Slide 2: Introduction to Extrachromosomal Inheritance
Definition: Extrachromosomal inheritance refers to the transmission of genetic material that is not found within the nucleus.
Key Components: Involves genes located in mitochondria, chloroplasts, and plasmids.
Slide 3: Mitochondrial Inheritance
Mitochondria: Organelles responsible for energy production.
Mitochondrial DNA (mtDNA): Circular DNA molecule found in mitochondria.
Inheritance Pattern: Maternally inherited, meaning it is passed from mothers to all their offspring.
Diseases: Examples include Leber’s hereditary optic neuropathy (LHON) and mitochondrial myopathy.
Slide 4: Chloroplast Inheritance
Chloroplasts: Organelles responsible for photosynthesis in plants.
Chloroplast DNA (cpDNA): Circular DNA molecule found in chloroplasts.
Inheritance Pattern: Often maternally inherited in most plants, but can vary in some species.
Examples: Variegation in plants, where leaf color patterns are determined by chloroplast DNA.
Slide 5: Plasmid Inheritance
Plasmids: Small, circular DNA molecules found in bacteria and some eukaryotes.
Features: Can carry antibiotic resistance genes and can be transferred between cells through processes like conjugation.
Significance: Important in biotechnology for gene cloning and genetic engineering.
Slide 6: Mechanisms of Extrachromosomal Inheritance
Non-Mendelian Patterns: Do not follow Mendel’s laws of inheritance.
Cytoplasmic Segregation: During cell division, organelles like mitochondria and chloroplasts are randomly distributed to daughter cells.
Heteroplasmy: Presence of more than one type of organellar genome within a cell, leading to variation in expression.
Slide 7: Examples of Extrachromosomal Inheritance
Four O’clock Plant (Mirabilis jalapa): Shows variegated leaves due to different cpDNA in leaf cells.
Petite Mutants in Yeast: Result from mutations in mitochondrial DNA affecting respiration.
Slide 8: Importance of Extrachromosomal Inheritance
Evolution: Provides insight into the evolution of eukaryotic cells.
Medicine: Understanding mitochondrial inheritance helps in diagnosing and treating mitochondrial diseases.
Agriculture: Chloroplast inheritance can be used in plant breeding and genetic modification.
Slide 9: Recent Research and Advances
Gene Editing: Techniques like CRISPR-Cas9 are being used to edit mitochondrial and chloroplast DNA.
Therapies: Development of mitochondrial replacement therapy (MRT) for preventing mitochondrial diseases.
Slide 10: Conclusion
Summary: Extrachromosomal inheritance involves the transmission of genetic material outside the nucleus and plays a crucial role in genetics, medicine, and biotechnology.
Future Directions: Continued research and technological advancements hold promise for new treatments and applications.
Slide 11: Questions and Discussion
Invite Audience: Open the floor for any questions or further discussion on the topic.
The increased availability of biomedical data, particularly in the public domain, offers the opportunity to better understand human health and to develop effective therapeutics for a wide range of unmet medical needs. However, data scientists remain stymied by the fact that data remain hard to find and to productively reuse because data and their metadata i) are wholly inaccessible, ii) are in non-standard or incompatible representations, iii) do not conform to community standards, and iv) have unclear or highly restricted terms and conditions that preclude legitimate reuse. These limitations require a rethink on data can be made machine and AI-ready - the key motivation behind the FAIR Guiding Principles. Concurrently, while recent efforts have explored the use of deep learning to fuse disparate data into predictive models for a wide range of biomedical applications, these models often fail even when the correct answer is already known, and fail to explain individual predictions in terms that data scientists can appreciate. These limitations suggest that new methods to produce practical artificial intelligence are still needed.
In this talk, I will discuss our work in (1) building an integrative knowledge infrastructure to prepare FAIR and "AI-ready" data and services along with (2) neurosymbolic AI methods to improve the quality of predictions and to generate plausible explanations. Attention is given to standards, platforms, and methods to wrangle knowledge into simple, but effective semantic and latent representations, and to make these available into standards-compliant and discoverable interfaces that can be used in model building, validation, and explanation. Our work, and those of others in the field, creates a baseline for building trustworthy and easy to deploy AI models in biomedicine.
Bio
Dr. Michel Dumontier is the Distinguished Professor of Data Science at Maastricht University, founder and executive director of the Institute of Data Science, and co-founder of the FAIR (Findable, Accessible, Interoperable and Reusable) data principles. His research explores socio-technological approaches for responsible discovery science, which includes collaborative multi-modal knowledge graphs, privacy-preserving distributed data mining, and AI methods for drug discovery and personalized medicine. His work is supported through the Dutch National Research Agenda, the Netherlands Organisation for Scientific Research, Horizon Europe, the European Open Science Cloud, the US National Institutes of Health, and a Marie-Curie Innovative Training Network. He is the editor-in-chief for the journal Data Science and is internationally recognized for his contributions in bioinformatics, biomedical informatics, and semantic technologies including ontologies and linked data.
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
Nutraceutical market, scope and growth: Herbal drug technologyLokesh Patil
As consumer awareness of health and wellness rises, the nutraceutical market—which includes goods like functional meals, drinks, and dietary supplements that provide health advantages beyond basic nutrition—is growing significantly. As healthcare expenses rise, the population ages, and people want natural and preventative health solutions more and more, this industry is increasing quickly. Further driving market expansion are product formulation innovations and the use of cutting-edge technology for customized nutrition. With its worldwide reach, the nutraceutical industry is expected to keep growing and provide significant chances for research and investment in a number of categories, including vitamins, minerals, probiotics, and herbal supplements.
Cancer cell metabolism: special Reference to Lactate PathwayAADYARAJPANDEY1
Normal Cell Metabolism:
Cellular respiration describes the series of steps that cells use to break down sugar and other chemicals to get the energy we need to function.
Energy is stored in the bonds of glucose and when glucose is broken down, much of that energy is released.
Cell utilize energy in the form of ATP.
The first step of respiration is called glycolysis. In a series of steps, glycolysis breaks glucose into two smaller molecules - a chemical called pyruvate. A small amount of ATP is formed during this process.
Most healthy cells continue the breakdown in a second process, called the Kreb's cycle. The Kreb's cycle allows cells to “burn” the pyruvates made in glycolysis to get more ATP.
The last step in the breakdown of glucose is called oxidative phosphorylation (Ox-Phos).
It takes place in specialized cell structures called mitochondria. This process produces a large amount of ATP. Importantly, cells need oxygen to complete oxidative phosphorylation.
If a cell completes only glycolysis, only 2 molecules of ATP are made per glucose. However, if the cell completes the entire respiration process (glycolysis - Kreb's - oxidative phosphorylation), about 36 molecules of ATP are created, giving it much more energy to use.
IN CANCER CELL:
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
Unlike healthy cells that "burn" the entire molecule of sugar to capture a large amount of energy as ATP, cancer cells are wasteful.
Cancer cells only partially break down sugar molecules. They overuse the first step of respiration, glycolysis. They frequently do not complete the second step, oxidative phosphorylation.
This results in only 2 molecules of ATP per each glucose molecule instead of the 36 or so ATPs healthy cells gain. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.
introduction to WARBERG PHENOMENA:
WARBURG EFFECT Usually, cancer cells are highly glycolytic (glucose addiction) and take up more glucose than do normal cells from outside.
Otto Heinrich Warburg (; 8 October 1883 – 1 August 1970) In 1931 was awarded the Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme.
WARNBURG EFFECT : cancer cells under aerobic (well-oxygenated) conditions to metabolize glucose to lactate (aerobic glycolysis) is known as the Warburg effect. Warburg made the observation that tumor slices consume glucose and secrete lactate at a higher rate than normal tissues.
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
March 20
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
March 20
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.
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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)
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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
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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
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