The Chemistry of Process Development in Pharmaceutical Industry 1

7/31/2019 The Chemistry of Process Development in Pharmaceutical Industry 1

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The Chemistry of ProcessThe Chemistry of Process

Development inDevelopment inPharmaceutical IndustryPharmaceutical Industry

Venugopal Rao VEERAMANENI,Venugopal Rao VEERAMANENI,

Ph.D.Ph.D.

Indus BioSciences (P) Ltd.Indus BioSciences (P) Ltd.



Highlights of PresentationHighlights of Presentation

• Introduction & Steps in Drug DiscoveryIntroduction & Steps in Drug Discovery

• Introduction & Role PR&D Role in DrugIntroduction & Role PR&D Role in Drug

DiscoveryDiscovery

• Challenges, Significance and Criteria of PChallenges, Significance and Criteria of P

R&DR&D

• Steps in Practical Process Research &Steps in Practical Process Research &

DevelopmentDevelopment



Steps in Drug DiscoverySteps in Drug Discovery

TargetDiscover

y

Informatics &

Genomics

LeadDiscover

y

MedicinalChemistr

y

Cellular&

Molecular Level

Preclinical

Development

Target

Identification

Bioinfor

matics

Assay

Development

Library

Development

Invitro

DrugActivity

Pharmac

oKinetics

TargetValidatio

n

Genomics HTS StructureBased

DD

CellularDiseaseModels

In VivoPharmac

ology

AssayDevelop

ment

Proteomics

Biochemistry/Enzymology

MedicinalChemistr

y

DrugMechanis

m

Toxicology/SafetyPharmac

olgy



Steps in Drug DiscoverySteps in Drug Discovery

3-4 Years3-4 YearsDiscovery &Discovery &

EarlyEarly

DevelopmentDevelopment

6-8 Years6-8 YearsClinical DevelopmentClinical Development

LaunchLaunch

&&

MarketiMarketi

ngng

1 Year1 YearSubmissiSubmissi

onon

Pre Clin

Study

Phase 1 Phase 2 Phase 3Filling &

Approval

Phase IV

Lunch

TargetTargetIdentifiIdentifi

cation;cation;

LG & LOLG & LO

Safety;Safety;

PK/PD.PK/PD.DetermiDetermi

ne dosene dose

forfor

Phase 2Phase 2

EfficacyEfficacy; Proof ; Proof

of of

conceptconcept

ExtensiExtensi

veve

StudiesStudies

;;

EfficacyEfficacy

&&

SafetySafety

RegulatRegulat

oryory

ReviewReview

;;

EfficacyEfficacy

&&

Safety.Safety.

PlanninPlannin

g forg for

ManufaManufa

PostPost

MarketiMarketi

ngng

Studies.Studies.

PostPost

approvaapprova

ll

changechange

s ins in

ManufaManufa



OvercomeOvercome

Patent Infringement

Inconsistent Raw Material Quality andSupply Hazardous or Non-Regulated RawMaterials

Costly Raw Materials Unsafe or Environmentally HazardousReactions Low Yields Difficult-To-Achieve Levels of Purity

(e.g., for enantiomers) Scale-up

Difficult-To-Handle Processes -



ChallengesChallenges

Current cost of bringing newCurrent cost of bringing newdrug to market:drug to market: >$800 million>$800 million

Success rate:Success rate: 1 in 101 in 10

Time to Market:Time to Market: 10 to 15 years10 to 15 years

Highly competitiveHighly competitive Highly regulatedHighly regulated



P R&DP R&D SignificanceSignificance

SafetySafety&&

SpeedSpeed

QualityQuality&&

QuantitQuantit

yy

EnvironEnviron

mentalmental

ImpactImpact

Cost &Cost &

TimeTime

Bulk Bulk

OperatiOperati

onon



P R&DP R&D PhilosophyPhilosophy

Subject Environmentally Thinking Economically ThinkingAtomEconomy

Minimal by Product Formation More from Less - Incorporate Total Value of Materials

Solvent

reduction

Less Solvent Waste Higher throughput, Less

EnergyReagentOptimization

Catalytic, Low Stoichometry,Recyclable Reagents,Minimize Us age

Higher Efficiency - HigherSelectivity

Convergency Due to Increased ProcessedEfficiency

Higher Efficiency .

EnergyReduction

From Power Generation, Transport and Use

Reduced Energy , IncreasedEfficiency, Shorter Processand Mild Conditions

Safety Non-Hazardous MaterialsReduce Risk of Exposure,

Release, Explosions & Fire

Worker Safety and ReducedDown Time. Reduced Time

on Special Control Measures



,,HarderHarder

Meet the Challenges by executing fundamental changes

to the development and manufacturing approach

Integrated scientific,manufacturing, &commercial objectives

Development of the best

route with full intrinsicprocess knowledge

Apply new technologies for

effective utilization of

Scienc

e

Integration

Manufacturing



Targetfrom

Discovery

PR&D -PR&D - The Work FlowThe Work Flow

IDEA RoutineManufaturing

RD PR PD

DrugDisc

overy

Phase 1

Phase 2

Phase 3

BestSynthetic

Route

Optimized Route

Technology

Transfer





oa ap – ua y yoa a – ua y yDesignDesign

Chemistry

Selection

Designing for the API Manufacturing

Deliverables

Process

Modeling

Process

Devel.

Process

Control

Process

Scale Up

Evaluate Design Predict Verify Control

BestProduction

Chemistry

IntrinsicProcess

Knowledge

OptimizedUnit

Operations

DemonstratedProduction

Process

Real TimeContinuous

Improvements

QualityBy

Design

Science of Design Manufacturing Science

=



Viewpoint of Out-SourcingViewpoint of Out-Sourcing

FirmsFirmsCriteria Considerations

Reagents Cost, Purity, Availability. Specialized equipment neededToxicity: restricting exposure requires additional PPE andmonitoring. Chemical hazard: liability worse with scale-up

Solvent Safety; Ease of work-up; Ease of removing solvent from finalproduct

Work-up &Isolations

Minimal reliance on chromatography; No concentrations todrynessMinimal number of repeated steps (extractions; solventdisplacements); Controlled crystallization preferred overprecipitation.

ReactionRuggedness

Exotherms and gas evolution: liability worse with scale-up.Cryogenic or very high temp. require specialized equipment.Control of reaction conditions (temp. or pH). Excluding moistureor oxygen may require additional considerations. Rapidadditions and short reaction times require nonstandardequipment

Yield Low yields require that more intermediates be prepared for



Steps in Practical ProcessSteps in Practical Process

ResearchResearch Approaches to ProcessApproaches to Process

Development.Development.

Route Selection.Route Selection.

Reagent Selection.Reagent Selection.

Solvent Selection.Solvent Selection.

Running the Reaction.Running the Reaction. Effects of Water.Effects of Water.

In-Process Controls.In-Process Controls.

Optimizing the Reaction byOptimizing the Reaction by



Optimizing Catalytic ReactionsOptimizing Catalytic Reactions Work-UpWork-Up

Tools for Purifying the Product Tools for Purifying the Product

Column Chromatography &Column Chromatography &

CrystallizationCrystallization

Final Product Form and ImpurityFinal Product Form and Impurity

Considerations.Considerations. Vessels and Mixing.Vessels and Mixing.

Preparing for and Implementing thePreparing for and Implementing the

Scale-u Run.Scale-u Run.

Steps in Practical ProcessSteps in Practical Process

ResearchResearch



PR&D -PR&D - ApproachesApproaches

Introduction

Importance of scale-up

operations

Importance of team work

Determining operations Safety Considerations

Take Advantage of Good

pproac espproac es mpor ance ompor ance o



–– pproac es -pproac es - mpor ance ompor ance oTeam Work Team Work

OperatioOperatio

nsns

ProcessProcess

EngineeriEngineeringng

ManufactManufact

uringuring

PharmacPharmac

euticaleutical

ChemChemRegulatorRegulator

yy

QualityQuality

ControlControl

QualityQuality

AnalysisAnalysis

A R&DA R&D

ProcessProcess

ChemistrChemistr

yy

pproac espproac es mpor ance ompor ance o



S.No. Department Key Responsibilities

1 Discovery

Chemistry

To discovering the new molecule

2 ProcessChemistry

Initially develop chemical process

3 ProcessDevelopment

Optimizing process for pilot plant &manufacturing

4 Processengineering

To Identify practical considerations needed foreffective scale up

5 Operations/Operators

To carry out scale up operations and preparelarge quantities of materials

6 Manufacturing To Manufacture drug substance in multi Kg level

7 PharmaceuticalChem.

To formulate drug substance from drug product

8 Regulatory To Interface with FDA and other regulatoryauthorities

9 Quality Documentation & Interface with DR&D and

–– pproac es -pproac es - mpor ance ompor ance oTeam Work Team Work



Operation Lab Scale On Scale

Common Easy toeffect

Common Easy toeffect

Rotary evaporation;Concentration to dryness

X X

Use of Highly Flammable

solvents

X X

Column Chromatography &Drying over agents

X X X

Azeotropic drying X X X

Addition of dangerous

reagents &

X X X X

Maintaining Cryogenictemperature & Rapid

quenching

X X X

Fine controlling Heating &

Cooling

X X X X

– –Comparison of Lab Scale & PlantComparison of Lab Scale & Plant

ScaleScale



ReferenceCompound

Use of most expeditious route,minimal optimization & purification by

chromatography

Kilo lab batches Cost of raw materials may be fairly high,invest time to decrease risk of poor yields

& meeting deadline is primary concern

Pilot plant batches Expensive to occupy equipment, sooptimize for reasonably smooth

processing. Cost of raw material may besignificant, so optimize to obtain significant

yields. Preferably to solve any processingproblems in lab

Manufacturing High cost and value of raw materials andintermediates. Small change in yield or

quality has major financial impact..

Expensive efforts to fine tune process are

– –Focus of Efforts for PreparingFocus of Efforts for Preparing

BatchesBatches



PR&D -PR&D - Route SelectionRoute Selection

Introduction

Characteristics of Appropriate

Route

Characteristics of Cost-Effective

Route

Planning for Ultimate Route



PR&D -PR&D - Route Selection –Route Selection – SummarySummary

of Route Characteristicsof Route CharacteristicsCriteria Time Eff.

Route

Cost-

Eff.Route

Comments

Appropriate X Appropriate early in drugdevelopment

Familiarity X X Familiarity developed duringscale up

Fits Equipment X X Practicality is key

Exp. Reagents X Availability ?

Optimized Work up X Optimize the productivity

Protecting group X Minimize number & sizeMin. No. of Steps X Optimize productivity

High Overall Yield X May include statisticaloptimization

Technically Feasibly X X Reliability on scale

Minimize reagents X



A+B A-B A-B-C

Step1 Step1

CA-B-C-D

Step1

DA-B-C-D-E

Step1

E

A-B-C-D-E-F

Step1

F

A-B-C-D-E-F-G

Step1

G

A-B-C-D-E-F-G-HStep1

H

A-B-C-D-E-F-G-H-IStep1

I

A+B A-BStep1

C+DStep1

C-D

Step1

A-B-C-D

E+F E-FStep1

G+H Step1

G-H

Step1

E-F-G-H

A-B-C-D-E-F-G-HStep1 A-B-C-D-E-F-G-H-IStep1

I

PR&D -PR&D - Route Selection –Route Selection – CriteriaCriteria



PR&D -PR&D - Reagent SelectionReagent Selection

Introduction The Ideal Reagent for Scale-Up Types of Reagents Reagents for deprotanation

Alkoxides Amine Bases Oxidations

Reductants Catalytic Reagents Polymeric reagents

Biocatalysts

& S l i



PR&D -PR&D - Reagent Selection –Reagent Selection –

Characteristics of Ideal ReagentsCharacteristics of Ideal ReagentsCharacteristics Comments

Specific for desired synthetictransformation

With increased reactivity, shortenedreaction times, reaction selectivity

Nontoxic to operators andanalysts

More time required for handling more toxicreagents

Poses no chemical reactions

hazard to personal

Consider the safety of operators,

equipment and the community

Inexpensive Minimize over all cost of product

Readily available Consider outsourcing specializedcompounds

Consistent quality from batch to

batch

May eliminates the needs for use-tests

Stable with good self life Good stability at room temperaturepreferred

Readily generated and used if notstable

Reproducible generation minimizes

Readily transferred into reactors Liquids and solutions are preferred



PR&D -PR&D - Solvent SelectionSolvent Selection

Introduction

Selecting Solvents Based on Physical

Characteristics

Selected Solvent Impurities

Choosing Solvents

Alternatives to Classical Solvents



Solvents Alternative SolventsPolarity Must be compatible with and encourage the desiredchemistry

Freezing Point May limit range of low-temperature reactions

Boiling Point A higher bp extends the temperature range of reaction

without using pressurized reactor. A lower boiling solventsis easier to remove by distillation.

Flash Point Temperature at which a liquid produces ignitable vapors .Lower boiling solvents/compounds typically have lowerflash point.

PeroxideFormation Occurs primarily in etheric solvents. Slower in ketones &amides. Solvents with tendency for peroxide formationshould be monitered

Viscosity Solvents with increased viscosity display slower filtrationrates

Water-Miscibility

Solvents with low water-miscibility allow for easierextractive work-ups

PR&D -PR&D - Solvent Selection –Solvent Selection – PrimaryPrimary

Physical Characteristics of solventsPhysical Characteristics of solvents

for Scale-upfor Scale-up



Goal Impact on ProcessingIncrease the desired reactionrate

Increased productivity often throughhomogeneous reaction conditions

Provide homogeneousreaction conditions

Increase reaction rate and decrease by-products

Increasing strirrability of reactions

Minimize localized heating minimize by-productformation, increase ability to transfer slurries tofilters

Remove impurities bydistillation

Increase productivity, yield & quality

Remove impurities by theaddition of immisciblesolvents (Water)


Purify product bycrystalization


Increase of safety operationsProtect operators, analysts and plant facilities

PR&D -PR&D - Solvent Selection –Solvent Selection – ProcessProcess

Design ReasonsDesign Reasons



Solvents UndesirableCharacteristic AlternativeSolvents

Diethylether Flammable MTBE

Isopropyleth

er

Flammable/Peroxide

formation

MTBE

HMPA Toxicity NMP

Pentane Flammable Heptane

Hexane Electrostatic discharge Heptane

Chloroform Mutagenicity, Toxicity MDC, ACN, Toluene, DMF,nBuOH

CCl4 & EDC Mutagenicity MDC

Benzene Carcinogen Toluene

Dioxane Carcinogen THF

Acetonitrile Animal tertogen IPA

PR&D -PR&D - Solvent Selection –Solvent Selection –

Avoided/Minized on ScaleAvoided/Minized on Scale

& S l S l i



Water DMSO MIBK

Methanol DMF DME

Propane diol tButanol Ethyl acetate

Ethanol NMP THF

Acetic acid Acetone iPropylacetatenButanol Amylalcohol Chlorobenzene

iPropanol Dichloromethane

2-Me-THF

Acetonitrile Pyridine iButylacetate

MTBE Toluene Triethyl amine

Xylenes Heptane Cyclohexane

Pyridine 1,4-Dioxane Cyclohexane

PR&D -PR&D - Solvent Selection –Solvent Selection –

Commonly used in Large ScaleCommonly used in Large Scale

unn ng e



-- unn ng eReactionReaction

Introduction

Determining Reaction Safety Assessing Safe Operating Conditions in theLab Selecting the Reaction Scale

Choosing Equivalents of Reagents, StartingMaterials & etc Plan for Inert Condition if needed Charge Starting Materials and Solvents Select Reaction Temperature Select Duration & Sequence of Additions Select Reaction Pressure

Adjust Stirring



PR&D -PR&D - Effects of WaterEffects of Water

Introduction

Detecting and Quantitating Water

Removing Water from Routine Organic

Processing

Entry of Water through Processing Air

Entry Water through Solvents

Entry Water through Reagents

Formation of Water as a By-Product & Its

Removal



PR&D -PR&D - In-Process ControlsIn-Process Controls

Introduction

The Importance of IPC for Process Filed with the

FDA Choosing the Appropriate IPC

Generating Reproducible IPC

Obtaining a Representative Sample of Process

Stream

Reproducible Sample Preparation

Generating Reproducible Assay Data

-- n- rocess on ro s-



-- n- rocess on ro s –- –Useful.Useful.

Analytical

Method

To

Monitor

Quantit

ative

IPC

Suitability

Comments

HPLC R & W X X Very Useful

GC R & S X X Rapid Assays

GC-MS R & S X X

TLC R X X Inexpensive

IR R X X Good for Assay

UV R X X Rapid Assays

H NMR R X X

C NMR R

P NMR R X X

MC S & Rg X X Rapid Assays

Titrations Re X X

Density Sol X X

-



-Reaction by MinimizingReaction by Minimizing

ImpuritiesImpurities

Introduction Steps to Optimize the Reactions Optimizing Reaction Temperature Optimizing Reagent Equivalents

Optimizing Addition of Reagents Optimizing Use of Solvents and Cosolvents Optimizing Reaction Concentration Changing Reagents and Intermediates Optimizing Catalysts and Ligands

Optimizing Stirring Importance of Extending Reaction Times

Minimizing Impurity Formation by IndentifyingImpurities First



&D - Optimizing Catalytic Reaction

Introduction Catalyst & Ligand Selection

Optimizing Catalyst Concentration

Generating Active Catalysts

Importance of Extended Additions

Influence of Co-Catalysts & Impurities Catalyst Decomposition

Non-Linear Catalyst Effect



PR&D - Work-Up

Introduction

Aspects of Work-up

Quench

Extraction

Activated Carbon Treatment

Filtration

Concentrating Solution/Solvent

Displacement

Deionization and Removing Metals

Destruction of Process Streems

PR&D -PR&D - Tools for Purifying theTools for Purifying the



PR&D -PR&D - Tools for Purifying theTools for Purifying theProductProduct

Introduction Purification by column

chromatography

Crystallization

Theory & Process

Classification of solids Salt Selection

Washing & Drying Solid Products

PR&D -PR&D - Final Product FormFinal Product Form



PR&D -PR&D - Final Product FormFinal Product Formand Impurityand Impurity

ConsiderationsConsiderations Introduction

The Importance of Solid State Characteristics

Stability Testing The importance of Controlling Particle Size of a Drug

Substance

Preparing and Selecting the Polymorph Varying Crystallization Condition in order to Prepare

Polymorph

Purit and Im urit Considerations – Freezin



PR&D -PR&D - Vessels and MixingVessels and Mixing

Introduction Batch Vs Continuous Process Batch Processing Continuous Operations Semi continuous Operations

Use of Continuous Flow Reactors Static MixturesImmobilized Catalysts Photochemical Reactors

Microwave Reactors Sonochemical Reactors Plug Flow Reactors Electrochemical Reactors

--



--Implementing the Scale-upImplementing the Scale-up

RunRun

Introduction Anticipating Scale-Up Problems Scale-Up Considerations Identify the Goals of Scale-Up

Safety Considerations Identify Critical Processing Steps Define Equipment Limitations Develop Contingency Plan for Incomplete & RunawayReactions Know Effects of Extended and Interrupted Processing Identify Cleaning and Waste Disposable Procedures Guidelines for Documentation: Efficient Process

Transfer

Implementing the Scale-Up Run

PR&D T bl h i



PR&D -PR&D - TroubleshootingTroubleshooting

Introduction Physical and Chemical Causes of ProcessingProblem Steps for Troubleshooting A Process

Confirm that there is Problem Determine Whether the problem is Serious EnoughSpend Time Compare Processing Steps to those used in

Successful Batches Identify as assay to monitor key Processing Confirm that the cause of the problem has beenidentified Propose alternative treatments to eliminate theproblem

Case StudyCase Study



Case StudyCase StudyManufacturing of Intermediate for AntiManufacturing of Intermediate for Anti

Ulcer AgentsUlcer Agents

N

O

S

O

NH

N

O

Omeprazole N

O

S

O

NH

N

O

Esomeprazole

N

O

S

O

N

H

N

O

Lansoprazole

F

F

FF

F

N

O

S

O

NH

N

O

Rabeprazole

F

F

O

N

OO

S

O

N

H

N

O

Pentoprazole

F

F

N

R1

OR

Cl




Case StudyCase StudyManufacturing of Intermediate for AntiManufacturing of Intermediate for Anti

Ulcer AgentsUlcer Agents

N

R1

N

R1

O

N

R1

O

NO1

N

R1

O

Cl

N

R1

O

R

N

R1

O

R

ClIII III IV

Step IV Modified by Changing chlorinationreagent Acetyl chloride in ethanol used instead of HCl,

Thionyl Chloride, and etc 30Kg scale performed without any issues




Case StudyCase StudyImproved Process for Pioglitazone – AntiImproved Process for Pioglitazone – Anti

DiabeticDiabetic

N ONH

S

O

O

Pioglitazone

N OH N OR N O

O

N ONH

S

O

O

Pioglitazone

I II

III

IV

Step I Step II Step III Step IV

Med ChemRoute

Tosyl group NaOH/MDCor K 2CO3

Piperidine/Ethanol

Pd/H2 , Dioxane

ImprovedRoute(Feasibility)

1 eq MsCl1eq TEA,PhCH3 7 Vol

1eq K 2CO3

PhMe 7.4Vol

0.72 eq of Piperidine, MeOH13 times

1.2 eq of NaBH4

0.4eq of DMGH2O:MeOH:DMF

ImprovedRoute 1.12 eq MsCl1.25eq TEA, 1.07 eqK 2CO30.83 eq of Piperidine, MeOH 1.2 eq of NaBH4

0.4eq of DMG

C S dC St d



Cl

NH1

N MgBr

O O

O

NH

N

Cl

O N

N

Cl

O

O

N

NH

Cl

O

O

N

NH

NH

Cl

O

N

NH

NH

Cl

O

N

Case StudyCase StudySynthesis of Synthesis of Efavirenz Analogue (NNRTI)

C S dC St d



NH

N

Cl

O

N

NHCl

N

NH

NHCl

O

N

Deprotection

Resolution

O

Cl

NH1

BCl1/AlCl1

NCl

Cl

NH1

O

Cl

NH1

O

Cl

KOCN

N

N

Cl

O

Case StudyCase StudySynthesis of Synthesis of Efavirenz Analogue (NNRTI)

C St d P D l t f



Case Study - Process Development of Hexahydrofuro[2,3-b]furan-3-ol moiety

O

O

OHHexahydrofuro[1,1-b]furan-1-ol

(Bisfuran Alcohol)

NHHO

O

N

O

O

O

H1N

S

OO

Darunavir

(TMC-111

)

NHHO

O

N

O

O

O

S

O

O

Brecanavir (GW111111)

OO

N

S

O

HN

HO

O

N

O

O

O

H1N

SO

O

GS-1111

HN

P

O

O

O

O

O

C St d P D l t f




CO1Et

EtO1C

OH Br

LDA CO1Et

CO1Et

OH

LAH

OH

HO

OH

HO

Acetone

PTSA

O

O

O

MeO

Oxidation

CHO

O

OCSA

MeOH

O

MeO

O

O1 CSA

MeOH

O

O

HO

OH OH

Enantioselective Synthesis

Reported synthetic routeReported synthetic route

roblems with enantiomeric puritycalability

C St d P D l t f




OOH

O

O

O

O O

O

O

OOH O

I

O

1) Cobaloxime

NaBH1 /NaOH

CH1Cl1 /1°C

O

O

O

1) NaIO1K1OsO1(OH)1

O

O

HO

NaBH1

O

O

HO

Enzymatic

ResolutionAcetylation(1) (1) (1)(1)

NIS

(1)

O

O

AcO

Synthesis and Optical Resolution




Case StudyCase StudyManufacturing of Sertraline byManufacturing of Sertraline by

PfizerPfizerSertraline-Active Ingredient in Zoloft (Treatment for Depression)Sertraline-Active Ingredient in Zoloft (Treatment for Depression)Pfizer’s Conventional 3 step process Reduced to a Single StepPfizer’s Conventional 3 step process Reduced to a Single Step

OHCl

Cl

O

Cl

Cl

NMe

Cl

Cl

NMe

Cl

Cl

TiCl1 /MeNH1Tolene/Hexane

MeNH1EtOH

Isolated

NHMe

ClCl Isolated

NHMe

Cl

Cl

Pd/C, H1D-Mandelicacid

Sertralinemandelate

NHMe

Cl

Cl

D-Mandelicacid

NHMe

Cl

Cl

Sertralinemandelate

Pd/CaCO1

EtOH

THF

Not Isolated

Solvent use reduced from 60,000 to 6,000 gallons per ton of sertraline

Eliminated the use of 440 metric tons of titanium dioxide per

year



L/kg111

Discovery Route

L/kg11

st Commercial1

L/kg11

nd Commercial1

L/kg22

rd Commercial1

L/kg1

Chiral Tetralone

Methanol

Ethyl acetate

Ethanol

THF

Hexane

Toluene

Methylene chlorid






Case StudyCase StudyManufacturing of Sildenafil byManufacturing of Sildenafil by

PfizerPfizer

Pd/C & HPd/C & H22 Used for reduction of nitro to amine instead of Used for reduction of nitro to amine instead of

SnCl/EtOHSnCl/EtOH During Sulfonation, thionyl chloride used to convert sulfonicDuring Sulfonation, thionyl chloride used to convert sulfonic

acid (intermedite) to Sulfonyl chlorideacid (intermedite) to Sulfonyl chloride

Sulfonamide formation was performed in aq. NaOHSulfonamide formation was performed in aq. NaOH

CDI used in the formation of amide (coupling) instead of CDI used in the formation of amide (coupling) instead of Oxalyl chlorideOxalyl chloride

N

NH1N

O

Pr O1N

N

NH1N

O

Pr

H1N

OEt OH

O

N

NHN

O

Pr

N

OEt

S

N

O O

N

Pd-C/H1

ClSO1H

SOCl1

OEt

OH

O

SO1Cl

OEt

OH

O

S NaOH/H1O

N

O O

N

CDI

OEt O

S

N

O O

N

N

N

H1NO

Pr

NH

KOBut/tBuOH




Case StudyCase StudyManufacturing of Sildenafil byManufacturing of Sildenafil by

PfizerPfizer



1816 L/kg

Medicinal

Chemistry

1990

139 L/kg

Optimized

Med. Chemistry

1994

31 L/kg

Commercial Route

(1997)

10 L/kg

Commercial Route

following solvent

recovery

Pyridine

Toluene

t-Butanol

2-Butanone

Ethyl Acetate

Ether

Methanol

Ethanol

Acetone

Methylene Chloride




yyManufacturing of Ibuprofen byManufacturing of Ibuprofen by

BHCBHCIbuprofen (Pain Killer,) discovered in 1961Ibuprofen (Pain Killer,) discovered in 1961

Traditional Synthesis (by Boots) involves 6 steps. Traditional Synthesis (by Boots) involves 6 steps.

And atom utilization is only 40%And atom utilization is only 40%

Excess AlCl3 is used old process and which gave 20,000 tones of

solid waste.

AlCl1/Ac1O

O

ClCH1CO1Et

NaOEt

O

CO1Et

H1O

CHO

CHNOH CN CO1H




yyManufacturing of Ibuprofen byManufacturing of Ibuprofen by

BHCBHCBHC Redesigned in 1990 (after patent expire in 1984)BHC Redesigned in 1990 (after patent expire in 1984)Catalytic Synthesis, completed in 3 stepsCatalytic Synthesis, completed in 3 steps

77% Atom Utilization77% Atom Utilization

Catalytic amount of Hydrofluoric acid used instead of AlCl3.

Catalyst Reused in Next Batch.

Acetic acid is by product in first step, was converted to Ac2O

(99% of recovered)

HF/Ac1O

OOH

CO1H

H1

R-Ni

Pd

CO



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The Chemistry of Process Development in Pharmaceutical Industry 1