Pharmaceutical process chemistry m pharm second semester pharma chemistry

1. Reaction Progress Kinetic
Analysis
PHARMACEUTICAL PROCESS CHEMISTRY
PRESENTED BY
Mr. Darshan N U B Pharm ( M Pharm)
M Pharmacy II Semester
Dept. of Pharmaceutical Chemistry
SACCP
PRESENTING TO
Mr. Purushotham K N M Pharm ( Ph.D)
ASST. Professor
Dept. of Pharmaceutical Chemistry
SACCP
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2. Reaction progress
• Route selection is at the foundation of developing new products and processes.
Selecting the optimal route to make molecules can have a major impact on
environment and cost of product. Usually there are many synthetic pathways, or
routes, to synthesize a given structure. For each given route there is choice of starting
materials, intermediates reagents and solvents to synthesize the products.
• Route selection is a complex process, and synthetic routes can change during the
development pipeline of an API, and post launch as part of life cycle management
activity.
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3. • For route selection following factors should be considered:
1. Environmental impact: the volume and nature of waste.
2. Legal: ensuring intellectual property rights (breach anyone's patents).
3. Economics: lower cost of target molecule.
4. Control: Meet the quality specifications.
5. Throughput: The availability of raw materials, manufacturing time, make enough
material to satisfy commercial demand.
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4. • Expedient route
1.Familiarity: time and availability of reagent
2.Technical feasibility- Technology known
3.Availability of equipment
4.By this route target molecule can be produced on large scale
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5. Characteristics of Cost-effective Routes
1.Technical Feasibility : robust method is produce and control parameter like PH ,
raw material , equipment, temperature , reaction time .
2.Availability of Suitable Equipment : specilised equipment or produce from vendor.
3.Long-Term Availability of inexpensive Reagents and Starting Materials : select
supplier providing good quality reagent. Cost, quality, and reliable delivery are
critical parameters.
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6. • Strategies for Selection of Optimal Routes/Cost effective Routes
1.Use less intermediate and less steps in synthesis .
2.Using Telescopic Work-up - It is called one step synthesis in this intermediate are isolated and
purified to increase product quality and time for synthesis .
3.Minimizing Impact from Protecting Groups - Protective group temporary block active sites of
compound and avoid unwanted reactions .
4.Use of Enzymatic transformations- it removes protecting groups Minimized Number of Steps:
reduce step to decrease time, cost
5. Double reaction, Tandem Reaction, Multiple reaction Avoiding Adjusting Oxidation States: Use
intermediates at the suitable oxidation level.
6.Minimized Environmental Impact - waste generated, incorporate Green Chemistry
Enantiospecific and Stereospecific Reactions: Chemo selective, Regioselective , Enantioselective,
Diastereoselective.
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7. • Selection of raw material
A)Reagent selection - After route is selected then important step is to select the correct reagent for
selected route. Reagent selection can have a critical effect upon reaction scale-up safety, especially if
things go wrong.
The ideal reagent should produce: The desired product in high yield in the expected time frame
 Minimal effort needed for work-up and isolation of the product.
 Decreased Cost and easy availability, ease of handling and waste disposal considerations
Impurity profiles vary from lot to lot and from manufacturer to manufacturer. Perform front-runs first
to verify results before proceeding.
If using large equivalent excesses of a reagent, try running a more concentrated reaction with less
equivalents.
Use reagents that allow for better stoichiometric control and safer chemical handling and storage.
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8. Examples:
o Use NH4Cl and base rather than NH3 dissolved in Dioxane.
o Use NH4NO3 and H2SO4 rather than HNO3 and H2SO4
o Use dimethylamine hydrochloride and base rather than dimethylamine dissolved in water,
THF, or methanol.
o Use TMS diazomethane or generate diazomethane in diethyl ether rather than distilling
diazomethane.
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9. Avoid sensitive intermediates. Carefully determine how you will drive a reaction to
completion. Use reactions that will allow you to easily add more reagents (to drive
reactions forward) rather than having to create more of an intermediate.
If possible, use reagents that can make workups and purifications cleaner and easier.
This can lead to cleaner reactions, less intensive purifications, lower flammable solvent
usage, lower fire hazard, and less expenditure of time. Ultimately, efficiency
• and safety are increased. Examples:
oFor Mitsunobu or Wittig reactions, use Me3P (1M solution) rather than Ph3P;
Me3P=O is water-soluble and can be washed away; Ph3P=O is sometimes difficult to
remove during purification.
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10. o Use N,N-Dimethylethylenediamine (CAS# 108-00-9) to scavenge excess acid chlorides,
acrylates, mixed anhydrides. Then wash away with a simple acid
• wash during workup.
N,N-Dimethylethylenediamine
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11. • Solvents selection
• Be aware of the flammability of solvents around the equipment you choose, and take
the appropriate precautions.
 If possible, choose solvents that will boil before the product decomposes. This helps
to prevent the formation of tar, impurities, and other side products.
 Be aware of the dangers (explosions) from concentrating peroxide-forming solvents.
When working with >1000 ml of peroxide-forming solvent, check peroxide levels
• when the volume of solvent has been reduced to 10-20% of the original volume.
 Use freshly distilled or purchased solvents, especially if anhydrous conditions are
needed.
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12.  Avoid highly volatile solvents with low boiling points and peroxide-forming issues. Use of these solvents poses
fire and explosion hazards, especially during operations involving transfers, heating, and concentrating. Highly
volatile solvents are also prone to concentration changes (e.g., running the reaction vessel dry).
o Avoid THF and use 2-MeTHF (less peroxide issues, slightly higher b.p., and more environmentally
friendly);
o Avoid Et2O and use t-BuOMe (less volatile, higher b.p., less peroxide issues);
o Avoid hexanes and use heptanes (higher b.p., less toxic, less volatile)
o Avoid CH2Cl2 & CHCl3 and use 1,2-dichloroethane (higher b.p., ALL halogenated solvents have toxicity
issues).
 When performing air-sensitive reactions (e.g., Suzuki, Buchwald) sparge the solvents (run a steady stream of
bubbling inert gas through the solvent via a 12-18” needle while in the reaction vessel). This is safer and works
better than degassing with vacuum (freeze-pump-thaw method). Sparge solvent mixture for 30 minutes with
• stirring before adding sensitive reagents, then sparge for another 5-10 minutes after addition but before heating.
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13. • Families of Reagents Useful For Scale-up
1. Reagents for Deprotonation - n-Butyl lithium, NaH are most commonly used for deprotonation of
weakly acidic molecules
2. Alkoxide Bases – potassium tertiary buroxide is often used as a moderately strong base
3. Amine Bases – Triethylamine, Bu3N commonly used to scavenge acids generated during reactions.
4. Oxidations – most troublesome reactions to scale up due to toxicity and hazardous CrO3, Pt/O2,
H2O2
5. Reductants – Pt/H2, NaBH4
6. Catalytic reagents - Sharply decrease costs of both reagents and waste disposal and can increase
productivity. – catalytic hydrogenation is used for scale up in industries. Rh-TPPTS (3,3′,3″-
Phosphane triyltris(benzenesulfonic acid) trisodium salt)
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14. 7. Polymeric reagents – ion exchange resins- convenient filtration
removes the polymers and facilitates work-up.
8. Biocatalysts as Preparative Reagents- often used to prepare molecules
with two or more chiral centre.
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15. Reference
• https://www.slideshare.net/ShikhaPopali1/process-chemistry-
199354290
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16. THANK YOU
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