DRUG DESIGN AND DEVELOPMENT Stages 1) Identify target disease 2) Identify drug target 3) Establish...

DRUG DESIGN AND DEVELOPMENTDRUG DESIGN AND DEVELOPMENT

StagesStages 1) Identify target disease 2) Identify drug target 3) Establish testing procedures 4) Find a lead compound 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 9) Preclinical trials10) Chemical development and process development11) Patenting and regulatory affairs12) Clinical trials

Note:Note: Stages 9-11 are usually carried out in parallelStages 9-11 are usually carried out in parallel

Drug metabolismIdentification of drug metabolites in test animals Properties of drug metabolites

ToxicologyIn vivo and in vitro tests for acute and chronic

toxicity

PharmacologySelectivity of action at drug target

FormulationStability testsMethods of delivery

PRECLINICAL TRIALSPRECLINICAL TRIALS

DefinitionDevelopment of a synthesis suitable for large scale production up to 100kg

CHEMICAL DEVELOPMENTCHEMICAL DEVELOPMENT

Priorities •To optimise the final synthetic step and the purification procedures •To define the product specifications •To produce a product that consistently passes the purity specifications •To produce a high quality product in high yield using a synthesis that is cheap and efficient. •To produce a synthesis that is safe and environmentally friendly with a minimum number of steps

PhasesPhases

•Synthesis of 1 kg for initial preclinical testing (often a scale up of the original synthesis) •Synthesis of 10 kg for toxicological studies, formulation and initial clinical trials•Synthesis of 100 kg for clinical trials

Notes•Chemical development is more than just scaling up the original synthesis•Different reaction conditions or synthetic routes often required•Time period can be up to 5 years•Need to balance long term aims of developing a large scale synthesis versus short term need for batches for preclinical trials•The product produced by the fully developed route must meet the same specifications as defined at phase 1

CHEMICAL DEVELOPMENTCHEMICAL DEVELOPMENT

The initial synthesis was designed in the research lab

Characteristics•Designed to synthesise as many different compounds as quickly as possible •Designed to identify a range of active compounds•Yield and cost are low priorities•Usually done on small scale

Likely problems related to the original synthesis•The use of hazardous starting materials and reagents •Experimental procedures which are impractical on large scale•The number of reaction steps involved•Yield and cost

Scale up •Original synthesis is often scaled up for the first 1 kg of product, but is then modified or altered completely for larger quantities

THE INITIAL SYNTHESISTHE INITIAL SYNTHESIS

The initial synthesis of fexofenadine (anti-asthmatic)The initial synthesis of fexofenadine (anti-asthmatic)

•Fexofenadine synthesised by the same route used for terfenadine•Unsatisfactory since the Friedel Crafts reaction gives the meta isomer as well•Requires chromatography to remove the meta isomer


C

R

Me

MeC

R2N

O

Reduction NHO

PhPh

HO

C

R

Me

Me

R= Me; TerfenadineR=CO2H; Fexofenadine

C

R

Me

Me

CO

Cl

ClC

R

Me

MeC

Cl

O

Friedel CraftsAcylation

R2NH

Revised synthesis of fexofenadineRevised synthesis of fexofenadine

•More practical and efficient synthesis using easily available starting materials•No ‘awkward’ isomers are formed•No chromatography required for purification

CCO2Et

Me

Me

Me

Oxidation

CCO2Et

Me

OHC

Me

O

O

MgBr

NHHO

Ph

Ph1)

2) NaBH4

NHO

PhPh

HO

C

CO2Et

Me

Me

CCO2Et

MeMe

OH

O

O

CO2Et

MeMe

O

HO

Esterhydrolysis

Fexofenadine

Amberlyst


Aims To optimise the yield and purity of product from each reaction

Notes•Maximum yield does not necessarily mean maximum purity•May need to accept less than the maximum yield to achieve an acceptable purity •Need to consider cost and safety

FactorsTemperature, reaction time, stirring rate, pH, pressure, catalysts, order and rate of addition of reactants and reagents, purification procedure.

OPTIMIZATION OF REACTIONSOPTIMIZATION OF REACTIONS

•Optimum temperature is the temperature at which the rate of reaction is maximised with a minimum of side reactions•Increasing the temperature increases the reaction rate•Increasing the temperature may increase side reactions and increase impurities•Compromise is often required


TemperatureTemperature

•Increased pressure (> 5 kilobar) accelerates some reactions •Involves reactions where the transition state occupies a smaller volume than the starting materials• Useful if increased heating causes side reactions

Examples of reactions accelerated by pressure Esterifications; amine quaternisation; ester hydrolysis; Claisen and Cope rearrangements; nucleophilic substitutions; Diels Alder reactions


ExampleEsterification of acetic acid with ethanol - proceeds 5 times faster at 2 kbar than at 1 atm.- proceeds 26 times faster at 4 kbar

PressurePressure

Br

OO

PPh3

PPh3

OO

benzene-toluene20oC / 15,000atm

•Good yield at 20oC and 15 kbar•No reaction at 20oC and 1 atmosphere•Decomposition at 80oC and 1 atmosphere


Example 1

Example 2•Hydrolysis of chiral esters using base with heating may cause racemisation•Can be carried out at room temperature with pressure instead

PressurePressure

•Optimum reaction time is the time required to get the best yield consistent with high purity. •Monitor reactions to find the optimum time•Use TLC, gas chromatography, IR, NMR, HPLC•If reaction goes to completion, optimum time is often the time required to reach completion•If reaction reaches equilibrium, optimum time is often the time required to reach equilibrium•Optimum time may not be the same as the time to reach completion or equilibrium if side reactions take place•Excess reaction times increase the chances of side reactions and the formation of impurities.•Reaction times greater than 15 hr should be avoided (costly at production level)

OPTIMIZATION OF REACTIONSOPTIMIZATION OF REACTIONSReaction timeReaction time

•Important to outcome, yield and purity•Should normally be capable of dissolving reactants and reagents•Insolubility of a product in solvent may improve yields by shifting an equilibrium reaction to its products •Insolubility may be a problem with catalysts


C

HN

NH

O

O

OO

O

OH

H

H H2 Pd/C

EtOH/H2O

H3NNH

O

O

O

OH

H

H

•Poor yield in ethanol - product precipitates and coats the catalyst•Poor yield in water - reactant poorly soluble•Quantitative yield in ethanol-water; 1:1

Example

SolventSolvent


•Should have a suitable boiling point if one wishes to heat the reaction at a constant temperature (heating to reflux)

•Should be compatible with the reaction being carried out

•Solvents are classed as polar (EtOH, H2O, acetone) or nonpolar (toluene, chloroform)

•Polar solvents are classed as protic (EtOH, H2O) or aprotic (DMF, DMSO)

•Protic solvents are capable of H-bonding

•The polarity and the H-bonding ability of the solvent may affect the reaction

Solvent

•Solvent DMSO; reaction time 1-2 hours•Solvent aq. ethanol; reaction time 1-4 days•DMSO solvates cations but leaves anions relatively unsolvated•Nucleophile is more reactive in DMSO

R

Cl

R

CNNaCNDMSO


ExampleExample

•Protic solvents give higher rates for SN1 reactions but not for SN2 reactions - they aid departure of anion in the rate determining step•Dipolar aprotic solvents (DMSO) are better for SN2 reactions

SN2 reaction

SolventSolvent

•High concentration favors increased reaction rate but may increase chance of side reactions

•Low concentrations are useful for exothermic reactions (solvent acts as a ‘heat sink’)

OPTIMIZATION OF REACTIONSOPTIMIZATION OF REACTIONSConcentrationConcentration

•Increase rate at which reactions reach equilibrium•Classed as heterogeneous or homogeneous•Choice of catalyst can influence type of product obtained and yield

R C C R R C C R

H

H

H

H

H2 Pd/C


ExampleExample

R C C R C C

R

H

R

H

H2 Pd/CaCO 3

Poisonedcatalyst

CatalystsCatalysts

R Cl RC

O

R

CR

O

Lewis acid

Vary Lewis acid catalysts (e.g. AlCl3 or ZnCl2) to optimize yield and purity


ExampleExample

CatalystsCatalysts

•Shifts equilibrium to products if reaction is thermodynamically controlled•Excess reactant must be cheap, readily available and easily separated from product•May also affect outcome of reaction

Ph O

O

H2NNH2

HN

NH2C

O

Ph

O

+ HN

NH

C

O

C

O

Excess diamine is used to increase the proportion of mono-acylated product


ExampleExample

Excess reactantsExcess reactants

•Removing a product shifts the equilibrium to products if the reaction is in equilibrium•Can remove a product by precipitation, distillation or crystallisation

Removing water by distillation shifts equilibrium to right


R R

O

HOOH

R R

OO+

Ptsa catalyst

+ H2O

ExampleExample

Removing a productRemoving a product

•Adding one reactant or reagent slowly to another helps to control the temperature of fast exothermic reactions

•Stirring rates may be crucial to prevent localized regions of high concentration

•Dilution of reactant or reagent in solvent before addition helps to prevent localized areas of high concentration

•Order of addition may influence the outcome and yield

OPTIMIZATION OF REACTIONSOPTIMIZATION OF REACTIONSMethods of additionMethods of addition

•Impurity is formed when butyl lithium is added to the phosphonate•Phosphonate anion reacts with unreacted phosphonate to form impurity•No impurity is formed if the phosphonate is added to butyl lithium


N

Ar

P

O

OMe

OMeN

Ar

R N

Ar

R

1) nBuLi2) RCHO

impurity

+

ExampleExample

Methods of additionMethods of addition

Less reactive reagents may affect the outcome of the reaction

•A 1:1 mixture of mono and diacylated products is obtained even when benzyl chloride is added to the diamine•Using less reactive benzoic anhydride gives a ratio of mono to diacylated product of 1.86:0.14


Cl

O

H2NNH2

HN

NH2C

O

+ HN

NH

C

O

C

O

ExampleExample

Reactivity of reagents and reactantsReactivity of reagents and reactants

Priorities Cost, safety and practicality

SCALING UP A REACTIONSCALING UP A REACTION

Factors to consider Reagents, reactants and intermediates, solvents, side products, temperature, promoters, procedures, physical parameters

•Reagents used in the initial synthesis are often unsuitable due to cost or hazards. •Hazardous by products may be formed from certain reagents (e.g. mercuric acetate from mercury)•Reagents may be unsuitable on environmental grounds (e.g. smell)•Reagents may be unsuitable to handle on large scale (e.g. hygroscopic or lachrymatory compounds)

H

RR

H H

RR

H

Zn/CuEt2OCH2I2

ExampleExample

•Zn/Cu amalgam is too expensive for scale up •Replace with zinc powder

SCALING UP A REACTIONSCALING UP A REACTION ReagentsReagents

•Above reactions should be avoided for scale up•Palladium chloride and pyridinium chlorochromate are both carcinogenic•Synthetic route would be rejected by regulatory authorities if carcinogenic reagents are used near the end of the synthetic route

ExamplesExamples

N

O

PdCl2

X

N

X

R

OH

N

H

CrO3Cl

R C

O

H

SCALING UP A REACTIONSCALING UP A REACTION ReagentsReagents

•m-Chloroperbenzoic acid is preferred over cheaper peroxide reagents m-Chloroperbenzoic acid is preferred over cheaper peroxide reagents •Mcpba has a higher decomposition temperature Mcpba has a higher decomposition temperature •Safer to useSafer to use

Choice may need to be made between cost and safety


CCH3

OO

OH

O

Cl CO

O

CH3

ExampleExample

ReagentsReagents

•Starting materials should be cheap and readily available

•Hazards of starting materials and intermediates must be considered (e.g. diazonium salts are explosive and best avoided)

•May have to alter synthesis to avoid hazardous intermediates

SCALING UP A REACTIONSCALING UP A REACTIONReactants and intermediatesReactants and intermediates

•Solvents must not be excessively costly, flammable or toxic

•Unsuitable solvents include diethyl ether, chloroform, dioxane, benzene, and hexamethylphosphoric triamide

•Concentrations used in the research lab are relatively dilute

•Concentration is normally increased during scale up to avoid large volumes of solvent (solvent:solute ratio 5:1 or less)

•Increased concentrations means less solvent, less hazards, greater economy and increased reaction rates

•Changing solvent can affect outcome or yield

•Not feasible to purify solvents on production scale

SCALING UP A REACTIONSCALING UP A REACTIONSolventsSolvents


•Ignition temperature - temperature at which solvent ignites

•Flash point - temperature at which vapors of the solvent ignite in the presence of an ignition source (spark or flame)

•Vapor pressure - measure of a solvent’s volatility

•Vapor density - measure of whether vapors of the solvent rise or creep along the floor

SolventsSolvents

Solvent properties to be considered


•Solvents which are flammable at a low solvent/air mixture and over a wide range of solvent/air mixtures

•Solvents with a flash point less than -18oC (e.g. diethyl ether and carbon disulfide)

•Diethyl ether has a flammable solvent/air range of 2-36%, is heavier than air and can creep along plant floors to ignite on hot pipes

Hazardous solvents

SolventsSolvents


•Dimethoxyethane for diethyl ether (less flammable, higher BP and higher heat capacity)

•t-Butyl methyl ether for diethyl ether (cheaper, safer and does not form peroxides)

•Heptane for pentane and hexane (less flammable)

•Ethyl acetate for chlorinated solvents (less toxic)

•Toluene for benzene (less carcinogenic)

•Xylene for benzene (less carcinogenic)

•Tetrahydrofuran for dioxane (less carcinogenic)

Alternative solvents for common research solvents

SolventsSolvents

•Reactions producing hazardous side products are unsuitable for scale up.•May need to consider different reagents

•Preparation of a phosphonate produces methyl chloride •Methyl chloride is gaseous, toxic and an alkylating agent. •Trimethyl phosphite stinks•Sodium dimethyl phosphonate results in the formation of non-toxic NaCl

SCALING UP A REACTIONSCALING UP A REACTIONSide productsSide products

R

Cl

R

P

O

OMe

OMe

P(OMe)3+ CH3Cl

R

Cl

R

P

O

OMe

OMe

NaH

HPO(OMe)2

+ NaCl

ExampleExample

Temperature

Must be practical for reaction vessels in the production plant


•Certain chemicals can sometimes be added at a catalytic level to promote reactions on large scale•May remove impurities in commercial solvents and reagents


Example 1•RedAl used as a promoter in cyclopropanation reaction with zinc•Removes zinc oxides from the surface of the zinc•Removes water from the solvent•Removes peroxides from the solvent

Example 2•Methyl magnesium iodide is used as a promoter for the Grignard reaction

PromotersPromoters

Some experimental procedures carried out on small scale may be impractical on large scale

Examples:•Scraping solids out of flasks•Concentrating solutions to dryness•Rotary evaporators•Vacuum ovens to dry oils•Chromatography for purification•Drying agents (e.g. sodium sulfate)•Addition of reagents within short time spans•Use of separating funnels for washing and extracting

SCALING UP A REACTIONSCALING UP A REACTIONExperimental proceduresExperimental procedures

•Drying organic solutions - add a suitable solvent and azeotrope off the water- extract with brine

•Concentrating solutions- carried out under normal distillation conditions

•Purification- crystallization preferred

•Washing and extracting solutions- stirring solvent phases in large reaction vessels- countercurrent extraction


Some alternative procedures suitable for large scale

Experimental proceduresExperimental procedures

May play an important role in the outcome and yieldParameters involved

- stirring efficiency- surface area to volume ratio of reactor vessel- rate of heat transfer- temperature gradient between the center of the reaction

and the walls

SCALING UP A REACTIONSCALING UP A REACTION Physical parametersPhysical parameters

DefinitionDevelopment of the overall synthetic route to make it suitable for the production site, such that it can produce batches of product in ton quantities with consistent yield and purity

Priorities•Minimizing the number of reaction steps•The use of convergent synthesis•Minimizing the number of operations•Integration of the overall reaction scheme•Safety - chemical hazards•Safety - reaction hazards•Minimizing the number of purification steps•Environmental issues•Cost

PROCESS DEVELOPMENTPROCESS DEVELOPMENT

Number of reaction steps

•Minimizing the number of reaction steps may increase the overall yield

•Requires a good understanding of synthetic organic chemistry


•Product synthesised in two halves then linked•Preferable to linear synthesis•Higher yields

R S T U V

M N O P Q

K

L

CONVERGENT SYNTHESIS

A B C D E F G H I J K

LINEAR SYNTHESIS

Overall yield =10.7% assuming an 80% yield per reaction

Overall yield = 26.2% from L assuming an 80% yield per reaction Overall yield from R = 32.8%

PROCESS DEVELOPMENTPROCESS DEVELOPMENTConvergent synthesesConvergent syntheses

•Minimize the number of operations to increase the overall yield•Avoid isolation and purification of the intermediates•Keep intermediates in solution for transfer from one reaction vessel to another•Use a solvent which is common to a series of reactions in the process


•Alkyl halide is not isolated•Transferred in solution to the next reaction vessel for the Wittig reaction

Number of operationsNumber of operations

Alcohol Alkyl halide Wittig reagentSOCl2 PPh3

Example

•Assess the potential hazards of all chemicals, solvents, intermediates and residues in the process.

•Introduce proper monitoring and controls to minimize the risks

PROCESS DEVELOPMENTPROCESS DEVELOPMENTSafety - chemical hazardsSafety - chemical hazards

Toxicity •Compounds must not have an LD50 less than 100mg/kg (teaspoon)

Flammability •Avoid high risk solvents. •Medium risk solvents require precautions to avoid static electricity

Explosiveness •Dust explosion test - determines whether a spark ignites a dust cloud of the compound•Hammer test - determines whether dropping a weight on the compound produces sound or light

Thermal instability •Reaction process must not use temperatures higher than decomposition temperatures

PROCESS DEVELOPMENTPROCESS DEVELOPMENTMain hazardsMain hazards

•Assess the potential hazards of all reactions.

•Carefully monitor any exothermic reactions.

•Control exothermic reactions by cooling and/or the rate at which reactants are added

•The rate of stirring can be crucial and must be monitored

•Autocatalytic reactions are potentially dangerous

PROCESS DEVELOPMENTPROCESS DEVELOPMENTSafety - reaction hazardsSafety - reaction hazards

•Keep the number of purifications to a minimum to enhance the overall yield

•Chromatography is often impractical

•Ideally, purification is carried out by crystallizing the final product of the process

•Crystallization conditions must be controlled to ensure consistent purity, crystal form and size

•Crystallization conditions must be monitored for cooling rate and stirring rate

•Crystals which are too large may trap solvent

•Crystals which are too fine may clog up filters

•Hot filtrations prior to crystallization must be done at least 15oC above the crystallization temperature

PROCESS DEVELOPMENTPROCESS DEVELOPMENT PurificationsPurifications

•Chemicals should be disposed of safely or recycled

•Solvents should be recycled and re-used

•Avoid mixed solvents - difficult to recycle

•Avoid solvents with low BP’s to avoid escape into the atmosphere

•Water is the preferred solvent

•Spent reagents should be made safe before disposal

•Use catalysts whenever relevant

•Use ‘clean’ technology whenever possible (e.g. electrochemistry, photochemistry, ultrasound, microwaves)

PROCESS DEVELOPMENTPROCESS DEVELOPMENT Environmental issuesEnvironmental issues

•Keep cost to a minimum

•Maximize the overall yield

•Minimize the cost of raw materials

•Minimize the cost of labor and overhead by producing large batches on each run

PROCESS DEVELOPMENTPROCESS DEVELOPMENT CostCost

Definition•Specifications define a product’s properties and purity•All batches must pass the predetermined specification limits

Troubleshooting •Necessary if any batches fail the specifications•Identify any impurities present and their source•Identify methods of removing impurities or preventing their formation

Sources of Impurities•Impure reagents and reactants•Reaction conditions•Order of reagent addition•Troublesome by products•The synthetic route

SPECIFICATIONSSPECIFICATIONS

•Includes MP, color of solution, particle size, polymorphism, pH, chemical and stereochemical purity.

•Impurities present are defined and quantified

•Residual solvents present are defined and quantified

•Acceptable limits of impurities and solvents are defined

•Acceptable limits are dependent on toxicity (e.g. ethanol 2%, methanol 0.05%)

•Carcinogenic impurities must be absent

•Carcinogenic compounds must not be used in the final stage of synthesis

SPECIFICATIONSSPECIFICATIONSProperties and purityProperties and purity

•Isolate, purify and identify all impurities

•Methods of analysis include HPLC, NMR spectroscopy, and mass spectrometry

•Identify the source of any impurity

•Alter the purification at the final stage, the reaction concerned or the reaction conditions

SPECIFICATIONSSPECIFICATIONS ImpuritiesImpurities

•Introduce a purification to remove any impurities at the end of the reaction sequence or after the offending reaction

•Methods of purification Crystallisation

Distillation Precipitation of impurity from solution Precipitation of product from solution

SPECIFICATIONSSPECIFICATIONSPurificationsPurifications

•Commercially available reagents or reactants contain impurities

•Impurities introduced early on in the synthetic route may survive the synthetic route and contaminate the product

•An impurity at an early stage of the synthetic route may undergo the same reactions as the starting material and contaminate the final product

SPECIFICATIONSSPECIFICATIONSImpure reagents/reactantsImpure reagents/reactants


Synthesis of fluvostatinSynthesis of fluvostatin

ExampleExample

F

Cl

O

Cl

AlCl3F

O

Cl

a) PhNHCH(CH3)2b) ZnCl2

N

H3CCH3

F

PhMeN

H

O

POCl3CH3CN

N

Ar

H3CCH3

O

HtBuOAcAc/THFnBuLi/hexaneNaH

N

Ar

H3CCH3

OH O tBu

OO

N

Ar

H3CCH3

OH O tBu

OHO

N

Ar

H3CCH3

OH O Na

OHO

Fluvostatin

NaOHEtOHH2O

a) NaBH4Et2BOCH3THF/MeOHb) H2O2


N

Ar

H3CCH3

OH O Na

OHO

Fluvostatin

NH

NHCH2CH3

N-Ethylaniline

Impurity

N

Ar

H3C

OH O Na

OH

O

N-Ethyl analogue of fluvostatin

Impurity

•Vary the reaction conditions to minimize any impurities(e.g. solvent, catalyst, ratio of reactants and reagents)

•Consider reaction kinetics and thermodynamicsHeating favors the thermodynamic product Rapid addition of reactant favors the kinetic product

•Consider sensitivity of a reagent to air and to oxidationN-Butyllithium oxidizes in air to lithium butoxideBenzaldehyde oxidizes to benzoic acidConsider using fresh reagents or a nitrogen atmosphere

SPECIFICATIONSSPECIFICATIONSReaction conditionsReaction conditions

Order in which reagents added may result in impurities


R O R Br

H

R O

R

H Br+

Mechanism of impurity formationMechanism of impurity formation

Occurs when PBr3 is added to the alcohol but not when the alcohol is added to PBr3

ImpurityR OH

PBr3R Br R O

R

+

ExampleExample

Order of additionOrder of addition

•By-products formed in some reactions may prove difficult to remove•Change the reaction or the reagent to get less troublesome by-products


Example - Wittig reaction

R CH2BrPPh3

R CH2PPh3 Br

R' C

O

H

Wittigreaction

R' C

C

H

H

RP Ph

O

Ph

Ph+

Triphenylphosphineoxide

•By-product = triphenylphosphine oxide •Removal requires chromatography

Troublesome by-productsTroublesome by-products

Horner-Emmons reaction - alternative reaction


•By-product = phosphonate ester •Soluble in water •Removed by aqueous wash

R CH2Br R

R' C

O

H

H P

O

OMe

OMe P O

MeO

MeO

nBuLi

Horner-Emmonsreaction

R' C

C

H

H

R P OMe

O

MeO

O

+

Phosphonate ester

Troublesome by-productsTroublesome by-products

Changing a synthesisChanging a synthesisSPECIFICATIONSSPECIFICATIONS

Example- Grignard synthesis

CH3

MgBrC COCl

H3C

H3C

H3C

CH3

C

CH3

OO C

CH3

CH3

CH3

C

O

CH3

CH3CH3

+

Ester impurity

•The ester impurity is formed by oxidation of the Grignard reagent to a phenol which then reacts with the acid chloride•Avoidable by adding Grignard reagent to the acid chloride but...•Not easy on large scale due to air sensitivity and poor solubility of the Grignard reagent


Different routes to same product

CH3

CCH3

CH3

CH3

CCl

O

CCH3

CH3

CH3

BrMg

Lewis acid

CH3

CO C

CH3

CH3

CH3

CH3

CO

CCH3

CH3

CH3

Li

Cl

CH3

CHN C

CH3

CH3

CH3

CH3

CN

CCH3

CH3

CH3

BrMgCH3

CO C

CH3

CH3

CH3

hydrolysis

Changing a synthesisChanging a synthesis

CH3

CHN C

CH3

CH3

CH3

CH3

CN

CCH3

CH3

CH3

BrMgCH3

CO C

CH3

CH3

CH3

hydrolysis

Inorganic impuritiesInorganic impurities SPECIFICATIONSSPECIFICATIONS

•The final product must be checked for inorganic impurities (e.g. metal salts)

•Deionized water may need to be used if the desired compounds are metal ion chelators or are isolated from water

Patenting

•Carried out as soon as a potentially useful drug is identified

•Carried out before preclinical and clinical trials

•Several years of patent protection are lost due to trials

•Cannot specify the exact structure that is likely to reach market

•Patent a group of compounds rather than an individual structure

•Also patent production method

PATENTING AND REGULATORY AFFAIRSPATENTING AND REGULATORY AFFAIRS

Regulatory affairs

•Drug must be approved by regulatory bodiesFood and Drugs Administration (FDA)European Agency for the Evaluation of Medicinal Products

(EMEA)

•Proper record keeping is essential

•GLP - Good Laboratory Practice

•GMP - Good Manufacturing Practice

•GCP - Good Clinical Practice

PATENTING AND REGULATORY AFFAIRSPATENTING AND REGULATORY AFFAIRS

Phase 1•Carried out on healthy volunteers•Useful in establishing dose levels•Useful for studying pharmacokinetics, including drug metabolism

CLINICAL TRIALSCLINICAL TRIALS

Phase 2•Carried out on patients•Carried out as double blind studies •Demonstrates whether a drug is therapeutically useful•Establishes a dosing regime•Identifies side effects

Phase 3Phase 3•Carried out on a larger number of patientsCarried out on a larger number of patients•Establishes statistical proof for efficacy and safetyEstablishes statistical proof for efficacy and safety

CLINICAL TRIALSCLINICAL TRIALS

Phase 4•Continued after a drug reaches the market•Studies long term effects when used chronically•Identifies unusual side effects

DRUG DESIGN AND DEVELOPMENT Stages 1) Identify target disease 2) Identify drug target 3) Establish...

Documents

Transcript of DRUG DESIGN AND DEVELOPMENT Stages 1) Identify target disease 2) Identify drug target 3) Establish...