Process development

Exam: 2.5 h. you can use notes

Drugs
- Webster’s Dictionary defines a drug as “a substance intended for use in the diagnosis, cure,
mitigation, treatment, or prevention of disease”.
- Collins Dictionary give defines a drug as “any synthetic or natural chemical substance used in
the treatment, prevention or diagnosis of disease”.
Glossary
• API = Active Pharmaceutical Ingredient
• NCE = New Chemical Entity
• DS = Drug Substance (The Active Ingredient)
• DP = Drug Product (The Formulated Drug)
• IND = Investigational New Drug
• NDA = New Drug Application
• IPC = In-Process Control
• ICH = International Conference on Harmonization
• FDA = Food & Drug Administration (US)
• EMA = European Medicine Agency (EU)
New medicine timeline

preclinical development
The aim of preclinical development is to satisfy all the requirements that must be met before a
new compound is considered ready to be tested for the first time in humans.
The preclinical studies involve in vitro (test tube or cell culture) and in vivo (animal) experiments
using wide-ranging doses of the drug to obtain preliminary efficacy, toxicity and pharmacokinetic
information. The work falls in four categories:
• Pharmacological testing
• Preliminary toxicological testing
• Pharmacokinetic testing
• Chemical and Pharmaceutical development
Clinical development

Phase 4 studies
Comprise the obligatory post marketing (i.e., the period following marketing) surveillance designed
to detect any rare or long-term adverse effects resulting from the use of the drug in a clinical
setting in many thousands of patients.
Different formulations, dosages, duration of treatment, medicine interactions, and other medicine
comparisons may also be evaluated with new age groups, races, and other types of patients can be
studied.
If a marketed medicine is to be evaluated for another (i.e., new) indication, then those clinical
trials are considered Phase II clinical trials.
Types of drugs
- Generic drugs
- Branded
- Over the counter (OTC)
Generic Drug is a copy of a Branded Drug present on the market whose exclusivity protection
expired. It is “equivalent” to the branded (with some different chemicals and crystalline form) and
can be used in alternative to the branded.
Because the drugs are off patent, the innovator companies have little incentive to modify the
chemistry, and the generic companies produce the drugs largely by following the existing patents
with minimal changes.
OTC (Over The Counter) Drugs are medicines that may be sold directly to a consumer without
prescription from the health care professional, as compared to prescription drugs, which may only
be sold to consumers possessing a valid prescription.
Scale-up

Like overnight or slowly added. You must quantify

it

Usually, reactants are more concentrated

because solvent costs a lot

Process flow diagram (block diagram)

Block flow diagrams show vessel used, input and outputs of each unit
operation
A process flow diagram is a tool to help organize and visualize information
about a manufacturing process. boxes - or specific symbols – to represent the
unit operations in a process, an arrows to represent material.
 Type of reactor Time to do that operation

Reagent in order of
addition It must be specified
and with the range

Indicate the occupied volume in

the reaction. Total volume must
be thought taking to account the
following additions

In this time the reactor at what

condition must be?
The three basic component of process development:
 Select and implement the best synthesis route.
 Develop it into a smooth, safe and efficient process.
 Engineer it and scale it up in a plant.
A Synthesis is the description of all reactants, reagents, solvents and conditions necessary for each
step.
A Process is the description of all operations necessary to perform the synthesis in a plant,
including modes of addition, type of equipment, work-up operations, separations, purifications,
isolations, timing, waste and any other operation that needs to be specified in a Batch Record.
A Batch Record is a document, drawn up by technicians, which explains step by step how the
product will be obtained in the plant to certify that is always done with the same quality and safety
Generally, a synthesis is selected before a process is defines, but it is always designed with the final
process in mind.
Scale-up
Usually, the trigger for development to start is when a compound has been identified as having
desirable properties (e.g. a herbicide, pharmaceutical agent or other “effect chemical”) and there
is potential for sales of the materials.
Before the Scale-up the compound will have been synthesized in only relatively small quantities
(e.g. few grams) in the research laboratory using conventional laboratory glassware.
As soon as the compound is selected for development, suddenly very much larger quantities are
required for further evaluation as rapidly as possible as to confirm the desired effect, but also to
enable a full assessment of the toxicological properties of the compound to be made.
This ensures that it will be safe for the proposed use and no adverse side effects will be observed.
In the case of a proposed pharmaceutical agent some studies are necessary over a period of
several years to satisfy the requirements of regulatory authorities before a licence to sell the
compound can be granted and the quantity needed are far beyond the scope of a research
laboratory.
In the early development phase of a new compound, speed and feasibility of manufacture can be
more important than overall chemical efficiency.
The importance of the teamwork
The process chemist must interact with people of
many other disciplines, communication and
teamwork are crucial.
For devising pragmatic, cost-effective processes, the
chemist is well advised to consult engineers and those
who are responsible for preparing drug substances on
scale.
The process chemist should explain processes to the
analysts, so that methods can be developed to assay
for anticipated impurities.
Analytical chemists in Analytical R&D and Quality
Control often detect new impurities, which can lead to alterations in the process.
Scale-up issues
Some operations routinely performed in an (academic) research laboratory are avoided on scale
due to their time-consuming and often redundant nature, including such operations in a process
extends processing times and drives up operating costs.
Additional steps (operations) present risks of physical losses, decreased yields, and the possibility
of increased worker exposure to dangerous conditions and chemicals and, in addition, with more
steps there is an increased chance of contaminating batches, which poses increased difficulties for
making material in compliance with current good manufacturing practice (cGMP).
 Vessel
The content of the vessel is viewed through
the sight glass in the manway.
Instrumental, not visual, endpoints are
generally preferred for in-process monitoring.
Manual access to the vessel during operations
is limited through the manway, making
physical manipulation of a batch
cumbersome.
Liquids can be added to the reactor through
the nozzles connected to dedicated lines.
Vertical elements called baffles minimize
vortexing and allow for more even distribution
of the content.
The agitator (impeller) is raised above the
bottom of the vessel.
The minimum agitation volume is about 10%
of the nominal volume of the vessel.

Type of Vessel
Stainless Steel Reactors
Pro
- Low temperature cons
- High Temperature
- Heat transfer - Incompatibility with some organics (NH2NH2)
- Agitation - Corrosion by: AlCl3, Nitric acid, Phosphoric
- Organometallics acid, Sulfuric acid, Hydrogen chloride dry
- Alkali and aqueous, Trichloroacetic acid, Sodium
Chlorite, Caustic molten NaOH
Glass lined reactors
they are blue because inner glass is linked to the outer stainless steel with a cobalt linker alloyed.
F e hifh pH corrode the glass
Pro Cons
- Temperature from 30 °C to 150 °C - Corrosion by: Alkaline conditions,
- Acidic conditions (HCl, NH4Cl etc.) Complexing agents (tartaric acid),
Fluorides, Tetrafluoborates
Hastelloy reactors
Hastelloy is a registered trademark name of Haynes International, Inc.
The Hastelloy trademark is applied as the prefix name of a range of corrosion-resistant metal alloys
under the material term “superalloys” or “high-performance alloys”.
Within corrosion applications Hastelloy alloys are often chosen due to their relatively attractive
price/performance ratio.
The predominant Hastelloy component is metal nickel and other alloying ingredients are added to
Hastelloy including varying percentages of the elements: molybdenum, chromium, cobalt, iron,
copper, manganese, titanium, zirconium, aluminium, carbon and tungsten.

The primary function of the Hastelloy alloys is that of effective survival under high temperature,
high-stress service in a moderately to severely corrosive, and/or erosion prone environment.
Hastelloy alloys are used for many applications including pressure vessels, nuclear reactors,
chemical reactors, as pipes and valves in chemical industry, but are very expensive
- Hastelloy C-22
✓ Excellent heat transfer characteristics
✓ Corrosion resistant (oxidative test: Ferric Sulphate, HCl / NaCl)
✗ Very expensive.
- Hastelloy C-276
✓resistant to:
mineral acids at moderate temperature in the absence of oxidants like O 2 or Fe(III)
oxidation by Cu (II) and Fe (III) in the absence HCl
halogens, halogenidric acids.

Operation units
Rotary Evaporation
Concentrating a large amount of a solution or a solid to dryness requires considerable time and is
inefficient on a large scale.
Commercial equipment is available for rotary evaporation of solution in 100-liter flasks, but half-
filled 22-liter round-bottom flask is as much as most individuals can conveniently and safely handle
without external support of the flask.
On scale there is no immediate analogy to a rotary evaporator. Most concentrations are carried
out in stirred vessels.
Distillation
Most solvent can be removed readily from process streams by distillation on scale.
Distillation of a product can be very labour-intensive and may require specialized equipment.
Once suitable equipment has been installed, processing can be relatively trouble-free, especially
if an appropriate control equipment is used.
Many high-molecular weight molecules are too unstable to distil, making crystalline intermediates
and products necessary for convenient operations.
Evaporation to Dryness
The reactor vessel contains a stirrer, but this can only stir effectively when the liquid content is at
least 10% of the total vessel volume and the removal of solvent by distillation will leave substantial
quantities of solvent behind and evaporation to dryness is not always possible.
This is especially true in the case of glass-lined reactors but can be achieved with all the other
vessels only under strict controlled conditions.
Due to the small surface area-to-volume ratio of large equipment, heat transfer and distillation
take longer than similar operations in laboratory.
Decomposition may occur with extended heating, especially if there is uneven heat distribution.
The main problem is that mixing It’s not enough good and at a certain point the impeller can’t mix
properly and also solid product probably remain on the walls.
Furthermore, I can’t use it If I have to change the solvent.
Solvent Displacement by Evaporation/Distillation (Solvent Chasing)
To replace a lower-boiling solvent with a higher-boiling on scale, usually the process stream is
concentrated and the higher-boiling solvent is added to the concentrate.
Then evaporation/distillation is continued, with the second solvent “chasing” the first.
Flammable Solvents
Using high flammable solvents on scale requires considerable planning for safe operations.
Equipment must be grounded to prevent static discharge and induction of fires.
To avoid accumulation of volatilized solvents, the head space of equipment must be swept with
inert gases.
Personnel and operating areas often must be monitored to avoid accumulation of and exposure to
dangerous solvents.
Such extensive precautions often delay or preclude use of solvents such as pentane and Et 2O but I
can use alternative solvents include heptane and methyl t-butyl ether (MTBE).
Decanting and Siphoning
Heavy, bulky, or stationary equipment cannot be manipulated to pour off supernatants, so a better
alternative is siphoning.
Removing a supernatant by siphoning often is cumbersome on scale, because controlled
manipulation of the suction hose becomes difficult as the liquid level nears the top of the
suspended solids.
It may be advisable to invest time in developing a protocol for siphoning if the process is to be run
repeatedly in dedicated equipment.
Drying over Solid Desiccants
Drying solutions over Na2SO4, MgSO4, or molecular sieves is an operation rarely used on scale, with
azeotropic drying being preferred.
Using drying agent means that I produce waste and other steps, furthermore it’s not easy to
calculate how much agent I need.
A fixed bed of molecular sieves may be used if the solute is heat-sensitive or if other
considerations such as the time and processing costs of a heated distillation preclude drying by
azeotropic distillation.
Drying Solutions by Azeotropic Distillation
Solvents with dissimilar polarities often form a minimum-boiling azeotrope upon heating to distil.
This
operation can
be used to
remove
dissolved or
suspended water
from some
solvents and
solutions.

Column Chromatography for Purification

This technique is highly efficient and is widely used in the research laboratory. It is however
extremely difficult to scale up beyond a moderate scale.
There are two major limitations:
1) The technique is dilute and requires large volumes of solvent to purify modest amounts of
material.
2) A large amount of solid support is needed to prevent overloading of the column. This requires
use of large diameter columns.
The difficulty of effecting purification by chromatography on scale encourages the process chemist
to devise routes with crystalline intermediates, to upgrade quality by recrystallizing.
Consequently, chromatography is used on scale when other forms of purification are ineffective
and if the products purified by chromatography have relatively low production volume and high
value after processing, and they usually display biological activity at very low dosages.
Trituring
Physically mixing a residue with a solvent (that solves only the impurities), or trituring, is an old
mean of effecting some purification.
Usually, the residue is a viscous oil or a solid, and the mixing is performed by hand with a spatula in
lab glassware.
If the residue cannot be readily dispersed in the solvent, attempts to triturate on scale will be
difficult to carry out.
Recrystallization and reslurrying solids are effective alternatives.
Reslurry
Solids may be stirred in a solvent and recovered by filtration, without ever effecting complete
dissolution.
Reslurrying can be an effective purification, by removing impurities adsorbed to the surface of the
crystals and change the morphic state of the solids.
Reslurry is less efficient operation than crystallization but it’s faster.
Addition of Dangerous Reagents
Setting up safe reaction conditions under which to use toxic reagents is relatively easy in the
controlled environment of fume hoods, but considerable thought must be given to using such
materials on scale.
Once suitable conditions have been put in place for operating on scale, it is often easy and quite
safe to effect such reactions.
For example a reagent can be transferred to the reactor through inert, leak-free lines with
permanent connections (such plumbing is called “hard-piping”).
Thorough analysis of operating conditions is necessary to protect the operators, the plant, and the
community.
Charge Starting Materials and Solvents
The sequence of adding starting materials, reagents, and solvents usually must be optimized for
each reaction.
 In general, adding liquids is easier than adding solids
 during scale-up operations solvents and liquids are usually pumped or pressurized into the
reactor or are drawn into the reactor by partial vacuum.
 Liquids are generally measured more accurately by weight than by volume, as the densities of
liquids and solutions can change significantly due to sample temperature.
Thinking in terms of weight of material added is good training for introducing a process to the
pilot plant or manufacturing plant, where most measurements also are by weight.
 Solvent may be added last for safety reasons: often the solvent is the most flammable and
most volatile component of the reaction.
 Solvent also may be added last to minimize vapor loss.
 Adding the solvent last may cause mixing difficulties, and so solvent is possibly added before
the starting materials and reagents.
 For instance, a starting material may be poorly soluble in the solvent, so if the solvent is added
after the starting materials have been charged, it may be difficult to disperse the solids
effectively.
This is particularly true if the vessel agitator is situated above the charged solids, in such cases,
while the solvent is stirred, the solids may be charged to the reactor, perhaps in portions to
ease their dispersal.
 If the solvent is added first, splashing up toward the operator, when solid reaction components
are added through open manways, can be avoided if the solids are drawn into the reactor by
partial vacuum.
Employ Inert Conditions if Needed
An inert atmosphere is applied to reactions to remove oxygen and to keep out O 2 and H2O from
the reaction.
Usual oxygen content in the plant is 1-3% and it’s sufficient for most reactions
Removing oxygen is necessary for the safe operations of many reactions:
- Hydrogenations.
- Reactions with functional groups readily oxidized with O2, such as mercaptans, tetravalent
phosphorous compounds, and some amines. Anions may also react with dissolved O 2, leading
to impurities during alkylation of these anions.
Several approaches are used to remove oxygen from reactions:

- Reactors may be flushed with N2 and a slight positive pressure of N2 (a “nitrogen blanket”) may
be applied to the reactor to exclude the entry of atmospheric O 2 (and H2O).
- Solvents in the reactor may be purged with purified
- Solvent or reaction may be heated to reflux under N2 and cooled under N2.
Nitrogen tanks with pre-mixed oxygen levels are available and easy to use.
Water can enter a reaction as a part of the air, solvents, reagents, or by-products of a reaction, or
it can enter as a contaminant in equipment.
Since water is the impurity most likely to be found in all stages of processing, its presence and
effects should always be considered.

Select Reaction Temperature

Reaction rates slow with decreasing temperatures, and the rule of thumb is that increasing the
reaction temperature by 10 °C will usually double the reaction rate.
In a pilot plant most reactions can be readily conducted in a range of -40°C to +120°C and
temperature outside this range may require specialized equipment.
To develop processes that can readily be introduced to scale-up facilities, it is better to try to run
the reactions in the range.
“Cryogenic” temperature are those of about -50 °Cand cooler, in the lab, reactions are readily
cooled by immersing a reaction vessel in a dry ice solvent bath.
For longer reactions or those requiring close control of the reaction temperature, the reactor may
be cooled by solvent from recirculating cooling bath (chillers) or direct injection of liquid nitrogen
into a reaction can afford another alternative.
For efficient operations at temperature ranges about -70 °C, metal reactors are preferred:
commonly used glass-steel reactors are relatively poor heat conductors, and glass linings may
crack at low temperatures due to different thermal contraction of glass and metal.
In general, lower reaction temperature are used to increase selectivity and to avoid side reactions.
Fine Control of Heating and Cooling
Once the considerable mass of a large reactor and the solution it contains have reached the
desired temperature range, maintaining a reaction temperature can be relatively easy.
However, if the reaction is moderately exothermic, removing heat from the mass will require
additional time due to the decreased surface area-to-volume ratio on scale, and additions may
take longer while maintaining the desired temperature range.

Repeated operations on scale may justify the installation of equipment to monitor and control the
temperature and the addition of critical components, thus simplifying operations.
Fine control of heating and cooling (± 2 °C) may be necessary for reproducible crystallizations on
scale.
Extended Additions
 In most academic settings, addition times are rarely extended unless high dilution is known to
be advantageous.
 Syringe pumps are often used for this operation in the lab, and this equipment is a wise
addition to the process lab, bur on scale it is not uncommon for an addition to require 30
minutes to 3 hours or longer in order to maintain the desired reaction rate, temperature, or
ratio of catalyst to substrate.
 Addition rates are easy to control on scale by using metering pumps or metering valves.
 Adding a reagent to the reactor containing the starting material often results in an exothermic
reaction, and the chemist usually wants to maintain the reaction within a desired temperature
range. To reduce the rate heat is evolved, one can add the reagent in portions or at a steady
rate over an extended period.
 Generally, the key is to balance the heat generated by the addition against the cooling provided
by the vessel utilities.
 Sometimes the addition is extended to prevent accumulation of the reagent and formation of
side-products.
 For convenience in controlling the addition rate, ideally the last reagent is a liquid or is added
as solution.
 For good control of reaction temperature and hence reproducible, and safe reactions, additions
must be considered as occurring over a defined period of time.
 Anticipate probable addition times on scale, and if appropriate add the key reagent in
laboratory experiments over this length of time.
 Adding reagents at low temperatures can create problems if the freezing point of the reagent is
above the temperature of the reaction.
 For instance, oxalyl chloride (mp -10 to -8 °C) is often used for Swern oxidations of secondary
alcohols. Typically this reaction is conducted at -78 to -70 °C, and oxalyl chloride is added to the
surface of the reaction. Under these conditions oxalyl chloride may freeze at the point it exits
the addition line.
 Diluting with solvents allows compounds with relatively high freezing points to be added to
cold reactions.
reactors
batch
There are three approaches to processing operations:
batch, continuous and semibatch or semicontinuous.
A Batch process is conducted charging all reactants,
solvent and everything is needed into the reactor at the
beginning and the the system is allowed to react at a
fixed temperature.
The product from a batch process is isolated at the end of
an opeartions cycle and can always be readily correlated
with input materials.
Unit operations, such as crystallization, can be finely
controlled on scale for the entire batch.
For these reasons batch processing is used to make most drug substances and intermediates.
In case of unexpected temperature rise, the only method to cool down the system is to lower the
jacket temperature.
Continuous
Continuous processes are generally used for large-
volume products in which reactions are closely
monitored to achieve maximal productivity.
Such processes are carried out on scale by allowing a
reaction to pass through a small reactor.
The products are usually made by reactions completed
in minutes, which allows for fine control of process
conditions.
Reactions requiring longer times may be used in
continuous operations if the reaction products are
stable enough to permit recycling a reaction stream
through the reactor.
Product is isolated throughout the operation cycle.
Continuous operations are used for the manufacture of bulk chemicals and agricultural chemicals.

Semi-batch
A semi-batch process is conducted charging one or
more reactants at the very beginning (solvents,
catalyst…) and the remaining components are added
gradually along a defined time, controlling the
kinetic of reaction.
None of the reaction mixture is displaced through
overflow.
The total volume of a vessel usually increases as the
reaction progresses, and the product is isolated at
the end of the cycle.
During a dosage, in case the temperature rose over a
specified value, the stop of dosage may be effective to avoid a further temperature increase.
Semi-batch processes for strongly exothermic chemical reactions are, in principle, inherently safer
than batch processes especially in vessel with limited heat transfer capacity.
ROUTE SELECTION
Routes to pharmaceuticals and fine chemicals can be characterized by two extremes: expedient
routes, and optimal routes.

Expedient routes are employed early in the development of a drug candidate to expedite (speed
up) the preparation of material that is required for initial testing (in vitro screening). Making this
material in a timely fashion is necessary to promptly assess the feasibility of developing the
compound.
- Often the initial route used to prepare gram amounts of material is scaled up by numerical
factors, with only minimal development efforts.
- Chromatographic purification and other labour-intensive steps may be incorporated in defence
to the goal of preparing the desired amount of drug candidate by the deadline
- Preparing large amounts of product using an “expedient” route can be an exhausting exercise.
- Such routes are rarely incorporated into a final manufacturing process.
Practical route
Once a compound has been identified as a promising drug candidate, process research
investigations are made to develop a practical route for preparing larger amounts of material to
fuel additional studies, including toxicological and formulation ones, and perhaps early testing in
humans (Phase I). The key is to prepare enough material to enable the scheduled studies. The
discovery route is often employed.
Efficient routes
For full-scale development, efficient routes are developed in the laboratory and tested in the pilot
plant. Materials prepared through pilot plant runs will be used for further studies in humans
(Phase II and III) and to develop optimal formulations of the active ingredient into dosage forms.
Research may occur simultaneously to develop routes that are practical enough to make the
kilogram amounts of product, and to develop more optimal routes.
Optimal routes
Optimal routes are developed to manufacture inexpensive bulk drug substances or final product
over the lifetime of a patent or longer.
Optimal routes usually require appreciable time to develop.
The development of these cost-effective routes can justify the expense of many years of work.
Laboratory processes are developed and examined on scale, and they evolve into optimal
routes that are cost-effective and rugged.
The optimal routes are filed with the FDA (Regulatory Agency) but may not be disclosed
elsewhere.

Technical Feasibility
One goal for scale-up operations is to develop and demonstrate rugged and forgiving (robust)
processes.
A rugged process is one that is understood well enough to produce reproducible quality and yields
without resorting to unexpected problem-solving.
In a rugged process, critical processing parameters have been identified, and the ranges that are
known to be acceptable may be relatively narrow.
Parameters to be considered include:
• quality of input materials
• addition times
• reaction times
• temperatures
• undercharging and overcharging chemicals
• pH during reaction work-up
• extended processing, and interrupted processing.
A forgiving or robust process is one that will provide the expected quality and yield of product over
a wide range of operating conditions.
The better a process is understood, the greater the technical feasibility.
Availability of Suitable Equipment
Often routes are chosen in order to use existing large-scale equipment because of the great costs
of buying and installing new equipment and plants and purchasing specialized equipment is usually
approved only after detailed cost analyses.
Special equipment will be required to scale up some reactions, such as those requiring:
- photolysis
- sonication
- electrochemistry
- specialized crystallization
- intimate mixing of heterogeneous reactions
- tight temperature control of highly exothermic reations
- extremely rapid quenching.

Long-Term Availability of Inexpensive Reagents and Starting Materials

- To avoid having to depend on the supplier, companies are wise to identify several sources of
key reagents, starting materials, and intermediates.
- Cost, quality, and reliable delivery are crucial parameters.
- The cost of a material is determined in part by the market demand.
- The overall development cost of a drug can decrease markedly if process research and
development begin with the most appropriate, inexpensive starting material.
- To ease production schedules, key intermediates may be outsourced from vendors.
- Reliable delivery of outsourced materials is crucial to making key production goals.
- As the success of and demand for the production rise, a company may qualify several suppliers
to ensure continue supply of key intermediates.
CHARACTERISTICS OF COST-EFFECTIVE ROUTES
Convergent and linear synthesis
In a linear synthesis all is done in sequence

In a convergent plan various parts of the target molecule are assembled separately and
independently and then linked together near the end of the synthesis.

If we use more than one reactor, we observe improved throughput* and yield.
There are several advantages to incorporating convergency into synthetic route:
1. As the total amount of intermediates decreases, smaller amounts of reagents and starting
materials are needed, decreasing costs.
2. Smaller batches are needed, which increases flexibility by permitting the use of smaller vessels.
But, if larger equipment is used, fewer batches are needed, which permits equipment and
personnel to be used for other purposes.
3. With extended linear syntheses the middle and late intermediates become “increasingly
precious”, and introducing covergency decreases the value of intermediates and liability from
scale-up errors.
But it is the case of paying attention to where drawing the bounderies of the evaluation of the real
cost-effectiveness of the linear vs convergent route design.

Based on yield, the chemist would undoubtedly choose the convergent synthesis: there are fewer
steps, and the overall yield of the final product is higher.
But is this really an accurate measure of how good the synthesis is? It’s better calculate the
consistency.

Identify all building blocks (commodity chemicals available from multiple suppliers, usually
extremely cheap). Label 1,2…n
- Affixations (a) are represented by forks joining
two intermediates or starting materials.
- Cyclizations (Δr) are represented by a double
bond.
- Refunctionalizations (e) are represented by a
single bond.
a+ Δr
consistency C=
a+ Δ r +e

Bigger is the C better is the process

Telescopic Work-ups
Isolating intermediates has many potential disadvantages:
- Cost (personnel and equipment time)
- Some loss of valuable materials
The additional handling required increases both the
exposure of operators to pharmacologically potent
materials and the opportunities for contamination
of batches and loss of valuable product.
Intermediates may be isolated to ensure key
purifications or to fulfil protocols filed with the FDA
or other regulatory agencies.
Telescoping (concatenation or through-processes)
is the process of carrying the product of a reaction
without purification into the next step.
1 brackets means that there isn't a purification step
Inappropriate telescoping can worsen the difficulties in isolating a reaction product that is
sufficiently pure from the subsequent step, BUT appropriate telescoping can greatly increase
overall yields.
Telescoping enhanced operator safety by reducing possible exposure to potent compounds: dried
solids were handled only twice in the telescoped process, as compared to 18 times with the
original route.
Minimized Number of Steps
To decrease the number of operations, an obvious remedy is to redefine the route by using
different starting materials that require fewer steps to produce the product.
Another similar time-saving approach is to carry out more than one synthetic transformation in
one step.
Avoiding Adjusting Oxidation States
Adjusting oxidation levels causes unnecessary expenses of time and money if instead
intermediates at the suitable oxidation level can be used in the synthetic sequence.
Reductions, including reactions with NaBH4 and other hydrides, use or generate hydrogen, either
during the reaction or upon work-up.
Whenever hydrogen is present, the potential exists for fires and explosions. High-pressure reactors
and specially designed reactor suites with blow-out walls may be needed.
The expense of preparing specialized facilities to accommodate the presence of hydrogen can limit
the number of sites available for processing and hence limit product throughput.
In the case of metal-derived oxidants, waste disposal costs can significantly drive-up product cost.
(in genera, metal reactions are done in the first steps to have time and steps to purity them
Incorporating Rearrangements
Rearrangements can also be used to incorporate key elements of stereochemistry and
regiochemistry from simpler molecules.
Focusing on a Common Penultimate or Key Intermediate
Considerable process research and development may occur on several different routes over times.
Usually, these routes converge at the penultimate intermediate or key late intermediates.
If a drug candidate has been filed with the FDA or other regulatory agency, the characterization of
the drug candidate and its penultimate intermediates is of primary importance (months-long bulk
stability studies and detailed analyses).
If reaction conditions to prepare a drug substance are different from those previously disclosed to
the FDA, bulk stability studies must be repeated to confirm that the quality is the same as or better
than that of the drug substance prepared by the filed route.
Filing a new route is simplified if the new reaction(s) leads to intermediates that are part of a filed
process. Then it is necessary to demonstrate that high-quality intermediates are produced and any
new impurities generating in preparing the penultimate do not have an adverse impact on the
quality of the drug substance.

Facile Rework for Final Product and Intermediates

The expected quality of final product and intermediates is not always achieved.
Often the products are again subjected to the final crystallization and isolation conditions.
In other cases, the chemist develops a purification procedure to upgrade batches contaminated
with specific impurities.
To ease the purification of final product, cost-effective routes are designed to incorporate key
intermediates that can be readily upgraded without chromatography.
Usually a sequence of dissolution followed by hot filtration and crystallization is employed, but
on-scale compounds may be also purified by reslurring, extraction and reisolation.
Enantiospecific and Stereospecific Reactions
Resolution of enantiomeric materials returns at best only 50% of the mass input, and the
remaining material must be converted to product or sent for disposal.
If only one chiral centre is present, the “wrong” enantiomer can often be racemized, and the
desired enantiomer can be isolated by resolution.
However, if more than one chiral center is present, racemization of the wrong enantiomer and
recovery of the desired one are often not feasible.
NOTE THAT: any reaction that is not enantiospecific or stereospecific should be positioned at the
beginning of a synthetic sequence in order to minimize wasted processing downstream.
METHODS FOR THE RESOLUTION OF RACEMATES
Resolving Agents
• Ready availability • Low molecular weight
• Stability of supply • Availability in high enantiomeric purity
• Stability in use and storage • Availability of both enantiomers
• Low price or easy separation • Low toxicity
• Ease of recovery and reuse • Reasonable solubility
Regulatory background
Route selection
Route selection is one of the most important decisions to be taken when a new drug candidate
moves into development.
Many factors will determine whether the route selected is ultimately good or not. A large number
of factors have to be taken into account, the acronym “SELECT” has been proposed for the
important parameters that need to be considered during the route selection process.
SELECT stands for:
 Safety
• Environment
• Legal
• Economics
• Control
• Throughput: The amount of product that can be made per reactor volume per day
Safety issues
Main issues associated with process and worker safety are as follows:
• Thermal runaway • Acute toxicity
• Gas evolution • Chronic toxicity
• Potential explosive, shock sensitive • Genotoxicity
materials • Pyrophoric and highly flammable
• Highly corrosive materials materials
Safety data will be obtainable from MSDS (Material Safety Data Sheet) and other sources such as
Sax’s Hazardous Properties of Industrial Chemicals.
To minimize the risk a three-tier system:
- Substitute the chemical with a less hazardous one
- If the above it is not possible: reduce the quantity
- Use Personal Protective Equipment
Three major chemical reaction hazards below:
- The thermal instability of reactants, reaction mixtures, waste streams, and products including
intermediates.
- Exotermic reactions that raise the reaction temperature to produce decomposition reactions or
uncontrolled boiling.
- Gas evolution, either from the desired chemistry or via a decomposition pathway, which can
cause reactor over-pressurization and possible explosion.
The potential for explosion should be eliminated as soon as possible.
Environmental issues
Way to work Environmental Impact Sustainability
- Prevention - Toxicity (Human, plant - Depletion of natural
- Minimization and animals) resources
- Render Harmless - Ozone depletion - High mass of materials
- Climate change used and waste
generated
- Energy-inefficient
processes

Options to manage Environmental Issues:

• Telescoping • Avoid protection (waste
• Avoiding drying (energy) • Reaction high concentration
• Removing stoichiometric reagents • Work up high concentration
• Avoid the use of dipolar solvents (water • Remove toxic reagents
problem) • Design a new “Greener” Route
Legal issues
- Patents opportunity
- Patent infringement by using materials, technology or processes that potentially infringe
current and valid third party intellectual property
- Extensive patent search has to be conducted
- In case of potential infringement: seek a licensing agreement or find an alternative no
infringing synthetic route (patent application is secret for 18 months)
- Although a new route may provide a process patent, it tells competitors the process and helps
them find ways to get round the patent.
- The pros and cons of patenting a process are still being discussed.
- The philosophy of developing a good process after a compound has been launched extends this
patent coverage period. However, a good company does not stop looking at new methods and
processes to commercial drugs as new methodologies are developed.
- With the rapid development of new synthetic methods and technologies, the chances are high
that a new approach will have been developed before the drug becomes generic.
- Use of regulated substances (controlled or banned)
- The international Narcotics Control Board monitors government control over chemicals that
may be used in the illicit manufacture of drugs.
- Use of unacceptable quantities of COMAH* (Control of Major Accident Hazards, EU legislation)
listed chemicals (Chlorine, Explosives, As2O5 etc.)
- Transportation of certain hazardous or non registered materials European Inventory of Existing
Commercial Substances (EINECS): before REACH regulation (December 2006)
Registration, evaluation and authorization of chemicals (REACH) is being implemented in EU to
cover some legal aspects as well as safety, and use of, or movement of, large amounts of materials
may trigger the need for a registration.
REACH applies to all chemicals imported or produced in the EU.
• It is an European Union regulation dating from 18 December 2006.
• It deals with the production and use of chemical substances, and their potential impacts on
both human health and the environment.
• Its 849 pages took seven years to pass, and it has been described as the most complex
legislation in the Union's history and the most important in 20 years.
• It is the strictest law to date regulating chemical substances and will affect industries
throughout the world.
• REACH entered into force on 1 June 2007, with a phased implementation over the next decade.
The regulation also established the European Chemicals Agency (ECHA), which manages the
technical, scientific and administrative aspects of REACH.
Economic issues
The economic variables of a Drug Product include: Drug Substance (API manufacture), Formulation
and packaging and the cost of goods is 25% ca of total product sales, thus 75% of product sales
contribute to:
• Marketing costs
• Research and Development
• Operating costs
• Profit margin
The components that affect commercial manufacturing costs of an API are:
• Product Volume • Waste
• Asset Costs and Depreciation • Raw Materials and Reagents
• Manpower • Licensing costs (if any)
• Maintenance • Supplier Profit Margin
• Utilities (water, electricity, gas, etc.) • Throughput*
Control issues
It is necessary to manufacture API according to FDA guidelines and in compliance with ICH
(International Council of Harmonisation) guidelines (or any EU equivalent guidelines).
These guidelines serve to protect patient safety and this is achieved through setting appropriate
quality criteria in the API specification and through working to GMP (Good Manufacturing
Practice).
Control of API quality is achieved through control of chemical and physical parameters in the
process.
Identification of:
• Non-selective reactions (chemo-regio and stereo) which might generate process related
impurities.
• Chemical stability and physical properties of each intermediate and reagent (in particular, labile
functional groups and chiral centers, stability toward heat, moisture, and oxygen, hygroscopicity,
viscosity and crystallinity) .
• Number and efficiency of potential purification points.
The goal is: “Quality by design”. Rather than developing a process that wholly relies on removal of
impurities it is better to identify the cause of the impurity.
Throughput issues
Throughput of a process defines the “amount of material that can be manufactured in unit time”.
The key variables that influence throughput are:
• Chemical yield • Low availability of starting material or
• Capacity and number of available vessel reagent

• Cycle time for a step (reaction time, work- • Use of specialized equipment and
up time including crystallization time, techniques
distillations, drying, and cleaning) • Production campaign strategy
• Concentrations and volumes • Supply chain strategy
• Use of high molecular weight protecting
groups
Supply chain management is the management of the flow of goods and services and includes all
processes that transform raw materials into final products.
It involves the active streamlining of a business's supply-side activities to maximize customer value,
and gain a competitive advantage in the marketplace.