Topic under subject APIT in Pharmacy

1. Optimisation of Organic
Reactions

2. Introduction
 Men & medicines cannot be isolated from each
other.
 In today’s era, pharmaceutical industries are
striving hard to provide quality medicines to the
society.
 It is considered that new drug development
requires an average time of 8 to 12 years.
 This drug development is governed by interplay
of financial, governmental and personal
considerations.
 Due to availability of numerous targets like
enzymes and receptors for treatment,
a variety of drug candidates having
complex structure are developed by pharma

3. Purpose of Process Development
 After discovery of new drug, its large scale mfg
requires process research and process
development.
 The route of bulk drug mfg from its discovery is
shown in fig
Drug
Discovery
Process
Research
Laboratory
Process
Development
Laboratory
Synthesi
s up to 1
Synthesis up
to 100kg
Bulk mfg more
than 100 kg

4.  Process research
involves optimising the chemistry of process i.e.
selection of possible synthetic routes.
it involved in synthesising up to 1 kg of
new drug required for regulatory approval.
 Process development
aims optimisation of individual steps so that
method becomes practical.
In process development, themain aim
is to developm cost effective, safe, robust,
reproducible and highly efficient method of
manufacturing.

5. The Purpose of Process Development is to
accomplish the following goals.
1. Cost effectiveness
2. Flexibility and simplicity of process
3. Reproducibility of process
4. Safety
5. Environment friendly process

6. 1. Cost effectiveness
Cost effectiveness in terms of process development
indicates getting highest possible yield with
retention of purity.
High yield of API indicates minimum waste
generated during process.
Sometimes the advantage of obtaining high yield
may be lead of high degree of impurity in the
product.
It is very important to note that obtaining higher
yield with the use of expensive solvents and raw
materials does not follow the criteria of cost

7. 2. Flexibility and simplicity of process
Inexpert workers may pose problem of safety
during process and may result in accidents.
Simplified operations limit undesirable accidents.
To reduce the exposure to hazardous solvents, the
process chemist must find alternate solvents and
make the process more flexible

8. 3. Reproducibility of process
The regulatory requirement for specifications of API
has become stringent day by day.
This demands uniform quality requirements of raw
material used in mfg.
If quality of raw material is uniform in each batch
this ultimately results in reproducible process and
validation of process.

9. 5. Safety
Safety in broad sense is to keep control on all
aspects of the process to limit the release of
harmful materials and energies.
To control heat generated during exothermic
reactions it is always advisable to use continous
process.

10. 6. Environment friendly process
Now a days environmental acceptability of process
depends upon E factor and Atom economy.
E factor- deals with the waste generated per Kg of
end product.
Atom economy- is the ratio of molecular weight of
desired product to sum of the molecular wt. of all
the material reagent

11. Approaches for Optimization
 1. Choice of Raw Material
 2. Selection of appropriate synthetic route
 3. Reagent selection
 4. Solvent selection
 5. Study of effect of reaction variables
 6. In process Control in Process Development
 7. Workup and Product Isolation
 8. Planning for Scale-up
 9. Effluent Minimisation and Control

12. 1. Choice of Raw Material
 Following criteria should be met by the raw
materials for optimization of overall process
 a. Easy availability of raw material with least
price.
 b. Easy availability in various physical forms
 c. Should obey specifications of purity
 d. Should be stable upon storage

13. a. Easy availability of raw material
with least price
 Every process begins with commercially available
raw materials.
 Reaction involving reduction of keto function
using either Lithium aluminium hydride or Lithium
borohydride as reducing agent.
 Lithium borohydride is very expensive reagent
and not available commercialyy.
 Lithium aluminium hydride reacts violently with
substrate reducing all carbonyl group.
 Instead sodium borohydride is considered as
weakest reducing agent and also available
commercially.

14. b. Easy availability in various physical
forms
 Reducing agent like Sodium borohydride is
available in pellet as well as powder form.
 Selection of powder or pellet form depends upon
type of substrate employed for reduction.

15. c. Should obey specifications of purity Purity specifications of raw material must comply
with the standard in pharmacopoeia.
 Impure raw material affects process
characteristics like reproducibility.
 Selection of raw material sometimes depends
upon type of process.
 E.g. a very pure form of Aluminium trichloride is
not useful in friedel-craft reactions,
 Lithium metal which contains sodium and
potassium as chief impurity which are essential
for main activity.

16. d. Should be stable upon storage
 Sodium hydroxide (NaOH) is deliquescent in
nature.
 It reacts with CO2 from air to form NaHCO3 and
Na2CO3.
 It is always stored in plastic containers not the
glass container.
 When stored in glass stoppered bottles,
carbonates crust form at neck of glass makes it
difficult to open.
 If the shelf life of raw material is longer duration
then bulk purchase is always beneficial.

17. 2. Selection of appropriate synthetic
route
 Following basic approaches should be taken into
consideration while selecting the most
appropriate synthetic route.
 a. Chemoselectivity consideration.
 b. Use of protecting groups
 c. Role of enzymes
 d. Green chemistry approach

18. a. Chemoselectivity consideration
 Chemoselectivity can be defined as preferential
reaction of reagent with one functional group in
presence of similar functional group.
Aqs. NaOH

19. b. Use of protecting groups
 A protecting group is introduced into a molecule by
chemical modification of a functional group in order
to obtain subsequent chemical reaction.
 Following three considerations are important in
choosing an appropriate protective group-
i) The nature of the group requiring protection
ii) The reaction conditions under which the protective
group must be stable
iii) The conditions that can be tolerated for removal of
protective group.

20.  In the above reaction acetal (dioxolane)
protecting group has been utilised to obtain
selectivity between two carbonyl groups.

21. c. Role of enzymes
 Advantages of employing enzymews in synthesis
 i) Reactions usually proceed under very mild
conditions than conventional route
 ii) It has low environmental impact.
 iii) Selectivity like enantio and diasterioselectivity
can impart.
 iv)It has Efficient catalysts
 V) A wide variety are now commercially available

23. d. Green chemistry approach
 Green chemistry deals with designing of chemical
products and processes so as to reduce or
eliminate generation of hazardous substances.
 Greener synthetic routes avoid formation of
unwanted side products and therefore are
economic, environment friendly and socially
beneficial.

24.  Following are some of the goals of green
chemistry-
 1. To reduce adverse environmental impact.
 2. To develop processes based on renewable raw
material
 3. To minimize by-products in chemical
transformation
 4. To develop products that degrades more
rapidly in the environment
 5. To reduce the requirement for hazardous
persistent solvents in chemical processes.

25. Principles of green Chemistry pertaining
to selection of synthetic route
 1. Analysis of Waste
As the waste incurs the additional cost for its disposal, it is always
recommended to prevent waste formation.
The greener route has fewest steps involving minimum use of
starting material, reagent, solvents and minimum labor.
e.g. Initially the synthesis of Ibuprofen was performed in six steps
with the production of secondary by-products and waste. With
atom economy 40%
A new synthetic greener route has only three steps, increased atom
economy 77%

26.  2. Atom Economy
Atom economy is the ratio of molecular weight of
desired product to sum of the molecular weights
of all reagent.

27.  3. Less Hazardous Chemical Synthesis
Safety is of prime concern in green chemistry.
Less hazardous chemical synthesis involves very
little formation of toxic substances which can
affect workers involved in manufacturing as well
as environment.

28.  4. Use of Safer Solvents
As solvent as huge impact on processing cost and
environment, green chemistry principles can be
successfully applied to recover and recycle the
solvents.
Green Solvents have been characterized for their
low toxicity, low solubility in water, easily
biodegradable, high boiling point, easy to recycle
after use.

29.  5. Energy Efficient Design
Energy requirements of chemical process should
be recognized for their environmental and
economic impacts and should be minimized.
If possible , synthetic methods should be conducted
at ambient temperature and pressure.

30. 3.Reagent Selection
 Reagent is substance or chemical compound that
transforms a substrate to a product.
 Or reagent is substance added to a system in
order to bring about a chemical reaction.
 An Auxiliary reagent does not contribute to end
structure but it will aid in successful completion of
the reaction.
 Selectivity and efficacy of reagent totally depends
upon reactivity of reagent and substrate

31.  Following are some of the ideal characteristics of reagents-
1. It should bring desired synthetic transformation so that isolation
becomes easier from end product
2. It should not pose any chemical hazard upon use
3. It should not have buying restriction which may consume time to
obtain license.
4. It should be non toxic
5. It should not be obtained from animal sources
6. It should be available with all vendors.
7. It should be inexpensive.
8. It should be stable upon storage and should get readily transferred
into reactor
9. It should not require any specialized equipment or facility for
handling reagent
10. It should be easily recoverable

32. 4. Solvent Selection
 Solvent is a liquid in which a solute is dissolved to
form a solution.
 Solvent plays crucial role in organic reactions
 Use of solvent allows changing the rate of
reaction, concentration, pH and also enables to
control reactions.
 Increase or decrease in polarity of solvent may
affect the rate of reaction.

33.  The following points must taken into consideration
while selecting the solvent for reaction.
 1. Toxicity consideration:
Following table illustrates toxicity associated with solvents.
 ICH has classified solvents depending upon its toxicity to human as Class-
I,II and III
Name of Solvent Toxicity ICH class
Benzene Carcinogenecity Class-I
CCl4 Hepatotoxic Class-I
Chlorinated solvents Contaminate soil and water Class-I
Chloroform Hepatotoxic and Carcinogenic Class-II
Toulene Not easily biodegradable Class-II
Hexane Static electricity generation Class-II
Acetone Less toxic compared with Class-I &II Class-III

34.  2. Environmental Issue:
 Volatile organic solvents pose great environmental
issues.
 Volatile organic solvents contaminate soil, ground
water and when released in the air cause global
warming, especially chlorinated hydrocarbons.

35.  3. Safety Consideration:
 The vapors of flammable liquid catch fire when they come in contact
with an ignition source.
 Only vapours of flammable solvent catches fire and not the liquid.
 Flash point: is the lowest temperature at which the flammable liquid
gives off sufficient concentration of vapors
 Ignition temperature is the minimum temperature necessary to
initiate combustion.
 Many solvents have flash point below room temperature and ignition
temperature more than room temp
 E.g. Carbon disulfide has flash point of -30 °C and ignition
temperature 80 °C

36.  4. Purity consideration
 Impurities in solvents can arise from
manufacturing methods, storage and number of
environmental factors.
 These impurities can affect chemical reaction with
the formation of byproduct.
 Probable impurities in solvents must be kept in
mind before selection of solvent for reaction.

37. 5. Study of the effect of Reaction
Variables
 1. Effect of temperature
 Temperature is one of the important reaction
variables.
 Varying the temperature may have desirable and
undesirable effects.
 An increase in 10 °C doubles the reaction rate
and decrease in temperature slows down the
reaction rate.
 E.g. Cyclohexanone with semicarbazone at R.T.
give 2-Cyclohexylidenehydrazine
 Same reagent at 190 °C give different product
i.e. 2-Furan-2-methylene carboxamide.

38.  2. Effect of Pressure
 Increasing the pressure on a reaction involving
reacting gases or volatile component may
increase the rate of reaction.
 E.g. Hydrogenation reaction requires high
pressure to complete the course of reaction.

39.  3. Effect of pH
 Many times pH governs the solubility of a variety
of starting materials and reagents.
 pH influences the rate of reaction and stability of
functional groups.
 If the proper pH conditions are not maintained, it
may give rise to undesirable side effects.
 Many reactions like ester hydrolysis, oxidation
and reduction are governed by pH.

40. 6. In-Process Control (IPC)
 Objective of IPC is to synthesize quality products
through productive processes.
 IPC methods are key component of quality control in
API mfg plant.
 IPC methods are developed to run designed process
in an effective, efficient and consistent manner.
 Aim of IPC method is to synthesis end product having
quality attribute mentioned by regulatory authorities of
respective country.
 These methods ensure that reaction step conducted
by trained operators will produce a quality chemical
entity with expected yield.
 IPC form an important part known as CMC
(Chemistry, Manufacturing an Control) of New Drug
Application (NDA) which is submitted to regulatory
authorities of various countries.
 To execute IPC methods one has to take help of
instrumental / analytical technique for IPC application.

41.  The following table list the instrumental technique
for IPC with application.
Instrumental Technique Application
Chromatographic Technique
like HPLC/TLC
Used to identify impurity in
starting material as well as
end product
Karl-fischer Titration To find presence of
moisture
pH meter To maintain optimum pH
during reaction
Conductivity meter Removal of salt from end
product
IR spectrocopy To monitor the reaction

42.  Advantages of IPC methods
1. It enables to understand at which point of time
impurities may get incorporated in process
2. It confirms quality of product
3. It identifies areas for process improvement
4. It enables to identify generation of isomer during
process by HPLC
5. It generates valuable information to optimise
overall process

43.  Selection of appropriate IPC method is
challenging task.
 While selecting an IPC method following points
must be taken into consideration
1. IPC method should be convenient to execute at
different phases of process development
2. IPC method should inspect important aspects of
synthetic process clearly.
3. IPC method must able to produce reliable data
after execution.

44.  Some of the simple IPC methods
1. TLC
Simplicity of this method lies in its early
detection of impurities travelling on TLC plate.
Advanced methods like GC, HPLC may
destroy or decompose the sample under study.

45. 2. Near Infrared Spectroscopy (NIR)
This method has advantage –
1. Non –destructive
2. Fast and automated measurment
3. Easy anf flexible process
4. Precise and reproducible results
5. No sample prepration
6. No physical contact with sample.

46. 3. Visual in Process Control Method
Some of the chemical reactions are associated with
change in colour.
For such reaction visual inspection may be the
appropriate IPC method .
Color change indicate that reaction is complete .
When this method is clubbed with other analytical
methods like HPLC, GC and IR it gives valuable
information.

47. 7. Workup and Product Isolation
 Work-up refers to the series of manipulations to
isolates and purify the product of chemical
reaction.
 A well-organised and efficient workup is important
for successful outcome of chemical reaction.
 If workup fails it renders unfit reaction for scale-up
 Selection of workup procedures is governed by
solvents and reagents employed for completion of
reaction.

48.  Work up operation may take various forms
mentioned below-
 Filtration
 Quenching Reaction
 Extraction
 Workup for metals
 Chromatographic isolation

49.  1. Filtration
 For lab scale work up , filtration of reaction
mixture to isolate end product is cost effective
operation.
 Filtration is basically used to remove insoluble
impurities, unreacted reagents and unreacted
starting material.
 Vacuum filtration is one of the technique for
separating a solid product from a solvent or liquid
reaction mixture.
 As filtration proceeds, fine particles may plug
filtrating media leading to accumulation.
 In such cases diatomaceous earth may be used
to improve operation.

50.  2. Quenching Reaction
 Quenching a reaction refers to deactivation of any
unreacted reagents at a particular point of time.
 It is a process of diluting the reaction mixture to
stop the reaction.
 Aim of quenching is to convert reactive
substances to ordinary non hazardous material.
 Quenching neutralizes reactive component of
reaction mixture.
AlCl3 + 3 H2O Al(OH)3 + 3 HCl

51.  3. Extraction
 Extraction is method to separate synthesized
compound based on its relative solubility in two
different immiscible liquids, usually water and an
organic solvent.
 It is preferred over filtration to remove impurities,
 As filtration require additional equipment while
extraction provides a more effective isolation of
product.
 Maximum three extractive processes are
performed to extract desired compound from the
reaction mixture.

52.  4. Workup for Metals
 Contamination of API with transition metals like
iron, titanium, zinc, copper, nickel etc. is major
concern regarding purity.
 Heavy metals in API are not tolerated above
certain limits depending on metal
 Various methods are employed to removing metal
from API
Metal Treatment
Al Rochelle salt
Cu NH4OH
Fe Lactic acid
Mg Citric acid
Zn EDTA

53.  5. Chromatography
 It is separation technique.
 In API industry, it finds wide application starting
from isolation of selected natural agent to
purification of synthesized derivatives.
 Some of the new chromatographic technique like
Simulated Moving Bed (SMB) chromatography is
used for manufacture of sucrose and fructose.
 Chromatography is considered as the most costly
technique of work up.

54. 8. Planning for Scale up
 Before starting actual scale up it is important to
have data from laboratory investigation on
specified process.
 E.g. requirement of temperature condition,
addition sequence, type of mixing , solvent
require and some In Process Control (IPC)
methods.
 Following are some of the basic considerations
for efficient scale-up
1. Safety Issue
2. Temperature issue
3. Phase consideration

55. 9. Effluent Minimisation and Control
 Effluent means stream of waste exiting from
chemical processes usually from chemical
reactors or equipments used for manufacturing
API.
 This waste can be categorized as-
 Corrosive
 Reactive
 Ignitable
 Toxic

56.  Following are some of the means for effluent
minimization:
 Try to recover and maintains the record of recovery of
volatile solvents which can pose great environmental
issues
 Use fractional crystallization to separate stream
containing high TDS
 Install proper exhaust system in mfg area.
 Install alarm system indicating overflow of reactor
 Install pressurized water jet system for cleaning
equipment which saves water.
 Substitute toxic materials like benzene, pyridine and
halogenated solvents with non- toxic materials.
 Increase the operating efficiency of overall process
 Maintain the addition sequence of reagent and
reactant to minimize its waste.
 Use fluidized bed continuous dryer in place of open
tray dryer to reduce energy consumption, drying time

57. Types of Health Hazards in API
Manufacturing
 A hazard is a potential source of harm or adverse
health effect on a person or persons working in
mfg area.
 Pharmaceutical workers faces broad spectrum of
health hazards.
 Various categories of hazards in API mfg are as
follows
1. Chemical hazards
2. Physical hazards
3. Biological hazards

58. 1. Chemical Hazards:
 Chemical hazards generally raised due to
inhalation and skin absorption of chemical or
API
API Health Hazard
Pyridine Short term:- Irritations to nose and throat
Long Term:- Damage to kidneys and liver. Affect brain to
cause confusion
Chlorampheni
col
Affect bone marrow
Cortisone Suppression of adrenocortical hormone
Penicillin Immunological reactions
Quinidine Dermititis

59. 2. Biological Hazards:
These hazards are associated with accidental
ingestion/inhalation of biological materials like
enzymes and microorganisms
These microorganisms and biological material
create acute and chronic health hazards.
e.g. amylase or porcine pancreatic dust is
responsible for bronchial hypersensitization.

60. 3. Physical Hazards
workers are exposed to moving parts of
equipment, high noise, heated surfaces, energy
sources and ionizing radiation which are potential
physical hazards.

61.  TLV (Threshold Limit Value)
American Conference of Governmental Industrial
Hygienists has set TLV concept.
TLV are developed as guideline to assist in the
control of Health Hazard
1. TLV-TWA:- (Threshold Limit Value-Time weighted average)
It is average Exposure on the basis of 8Hr/day
schedule
2. TLV-STEL:- (Threshold Limit Value-Short Term Exposure
Limit)
3. TLV-C :-(Threshold Limit Value)