Chemical Reaction Safety in the Pharmaceutical … · Chemical Reaction Safety in the Pharmaceutical Research Laboratory Steve Stefanick Scientific Director – Technical Integration

Janssen Research & Development

Chemical Reaction Safety in the Pharmaceutical Research Laboratory

Steve Stefanick

Scientific Director – Technical Integration

API Small Molecules - Reaction Safety Lab

Pharmaceutical Development and Manufacturing Sciences

Janssen Pharmaceutical Companies of Johnson & Johnson

1000 Route 202

Raritan, NJ 08869


Some Pharma Background

Consumer MDD

Pharma

Johnson & Johnson

Phases of Drug Development

I IIa IIb III IV

Research Development ManufacturingDiscovery Lab Pilot Plant and Plant Commercial and 2nd gen process


Reaction Safety Lab

NaH/DMF; Hydrazine; DiBAL-H, Peroxides, DMSO, ……


Famous Last Words

• I didn’t see an exotherm in the lab

• I only saw a little bit of foaming

• It turns brown if you leave it in the oven too long


Objective

Identify those situations/substances that have the potential for chemical reactions where the reaction energy / products will not be safely absorbed by the reaction environment.

Learn what key tools are available to help identify chemical reactivity hazards in the research laboratory


Legislative AspectsServeso Directive

1974 - Flixborough England Cylcohexane explosion

1976 - Serveso Italy - Dioxane release

Clean Air Act Ammendment

1984 - Mexico City- LP gas explosion

1984 - Bohpal India - MIC release

1985 - W. Virginia - aldicarb oxime release

1999 – Concept Sciences Inc, Hydroxylamine explosion

OSHA Standard Title 29 CFR 1910.110


Concept Sciences Inc.

Catastrophichydroxylamine (HA)explosion that occurredon February 19, 1999, atthe Concept Sciences,Inc. (CSI), facility inHanover Township,Lehigh County,Pennsylvania. Four CSIemployees and oneemployee of an adjacentbusiness were killed; 14people were injured.

1. Reaction of HA sulfate and potassium hydroxide to produce a 30 wt-percent HAand potassium sulfate aqueous slurry:HAS + 2 KOH HA + K2SO4 + 2 H2Owhere:HAS = (NH2OH)2*H2SO4HA = (NH2OH).2. Filtration of the slurry to removeprecipitated potassium sulfate solids.3. Vacuum distillation of Hafrom the 30 wt percentsolution to separate it from thedissolved potassium sulfate and producea 50 wt-percent HA distillate.4. Purification of the distillate through ionexchange cylinders.


Types of Hazards

Chemical reaction hazards

Exothermic reactions - boiling, decomposition and gas evolution

Thermal instability of materials, mixture and product

Mechanical hazards

Fire and explosion

Ignition and grounding

Static

Shock sensitivity


Incident HistoryPrime causes:

Process Chemistry -No knowledge of the heat of reaction

Reaction mixture decomposed during reaction / workup

Unstable or shock sensitive product

Batch vs semi batch reaction

Too concentrated

Reaction temperature too low – accumulation

Catalysis by equipment materials of construction

Impure starting materials


Incident History

Prime causes cont’d:

Plant operation and design -

Poor temperature control - loss of cooling, too much heat

Temperature probe placement

Inadequate stirring or failure

Added wrong amount of reactants, solvents, catalyst or added in wrong order

Equipment leaks from reactor jacket / condenser

Human factors and operator error


Assessment

Chemicals - Literature, calculations, DSC

Reaction rate Equipment

Accelerating Rate Calorimetry Heating/cooling

Reaction calorimetry capacity

Vent sizes


Assessment - Chemicals

Find reactivity hazard information on MSDS

MSDS Definitions from literature sourcesMSDS: - section 5: fire-fighting measures:

water reactivity + consequences of heating- section 10: Stability + reactivity:

chemical stability, conditions to avoid, incompatibility, decomposition or polymerization

- section 14: Transport:look for the hazardous material description, hazard class, UN/NA id. Number

- section 16: Other information:look for hazard ratings

! MSDS’s often contain incomplete or contradictory information; do not rely on a single source in emergency situations !


Reactivity Information (Worksheets)

Bretherick’s and other literature

Chemical Reactivity Worksheet http://response.restoration.noaa.gov

CAMEO Chemicals Worksheethttp://cameochemicals.noaa.gov/

Is this substance Reactive?What might happen if these 2 substances are combined?

Chemical Reactivity Worksheet: looking at reactive groups- Only binary combinations- Consequences are predicted for ambient conditions of T and P.- Possible effects of catalysts, contaminants, .. are not included- Reaction products are not predicted, though flammable and toxic

gas generation may be suggested.

http://response.restoration.noaa.gov/

http://cameochemicals.noaa.gov/


Chemical Reactivity Worksheet• Chemicals in this mixture:

ACETONE mixed with SULFURIC ACID

• Reaction proceeds with explosive violence and/or forms explosive products

• Spontaneous ignition of reactants or products due to reaction heat

• Exothermic reaction. May generate heat and/or cause pressurization

• Combination liberates gaseous products, at least one of which is toxic. May cause pressurization

• Possible Gases: – Nitrogen Oxides– Sulfur Oxides – Halogen Oxides – Carbon Dioxide


Reactivity Information (Wiser database)

• WISER provides a wide range of information on hazardous substances, including substance identification support, physical characteristics, human health information, and containment and suppression guidance.

• Access to 400+ substances to see detailed information on over 4,700 critical hazardous substances

• Rapid access to the most important information about a hazardous substance

First Responder Hazmat Specialist EMS Specialist

PPE Physical Properties Summary Treatment

Protective Distance PPE Health Effects

Fire Procedures IDLH Toxicity Summary

Reactivities Flammability Limits IDLH

Treatment NFPA 704 Classification NFPA 704 Classification

Download at http://wiser.nlm.nih.gov/about.html

ftp://ftp.orr.noaa.gov/pub/hazmat/reactivity/react95.exe

http://wiser.nlm.nih.gov/about.html


Classification of Materials

Several types of reactive chemicals: - self reactions- reactions with common environmental

substances- incompatibilities

Some chemicals have many ways they can get involved in out-of-control

situations.

! Whether a chemical hazard actually exists will always depend, not just on the kind of chemical that is present, but whether or not the reaction energy and products will be safely absorbed by the reaction environment.


Classification of MaterialsReactivity Hazard Definition Examples Measures

UNSTABLE- decomposing- thermally sensitive- shock sensitive- explosive

Has the tendency to break down over time or when exposed to conditions such as heat, sunlight, shock, friction, or a catalyst with the resulting decomposition products often being toxic or flammable. Decomposition can be rapid enough to give an explosive energy release and can generate enough heat and gases for fires/explosions.

TNTdibenzoyl peroxideethylene oxideacetylenepicric acidhydrogen peroxide

- DSC- SS test:*unstable group/stressed rings * oxidant, reductant mixture * DSC (> 1000 J/g)

POLYMERIZING Has the tendency to self-react to form larger molecules, while possible generating enough heat/gases to burst a container

styrene1,3-butadieneacrylic acid

PYROPHORIC Will ignite spontaneously when exposed to air phosphorussilane

See Bretherick’s


Classification of MaterialsReactivity Hazard Definition Examples Measures

PEROXIDE FORMER Has the tendency to slowly react with oxygen, such as from being exposed to air, to form unstable organic peroxides

isopropyl ether1,3-butadiene

- Note date on opening bottle- Purge N2- Avoid higher temp./concentrate- clean up (dresser dry)+dilute with absorbent

WATER REACTIVE Will react with water or moisture. Some react slowly; others violently. Heat and flammable/toxic gases may be produced.

SodiumSulfuric acidAcetic anhydride

OXIDIZER Will give up oxygen easily or readily oxidize other materials.

Chlorinenitric acid

INCOMPATIBLE Readily reacts with other chemicals hydrazine+metalAcetone + H2O2


Highly Energetic Compounds

C-C and C-N triple bonds and metal salts

(acetylenic compounds)

Adjacent N-O atoms (nitro, nitroso compounds)

Adjacent and consecutive O-O pairs (peroxides)

Adjacent and consecutive N-N compounds

(diazo compounds)

Adjacent C atoms bridged by O or N (epoxides)

O-X pairs (perchlorates)

N-metal pairs


Reactive Chemical Groups






Peroxide Forming SolventsAcetaladehyde Acrylaldehyde Allyl ethel ether 1-Allyloxy-2,3-epoxypropane Bis(2-ethoxyethyl) ether Bis-(2-methoxyethyl) ether 1,3-Butadiene 1,3-Butadiyne 2-Butanol Buten-3-yne Butyl ethyl ether Butyl vinyl ether 2-Chloro-1,3-butadiene Chloroethylene 2-Chloroethyl vinyl ether Cinnamaldehyde Crotonaldehyde Cyclopropyl methyl ether Diallyl ether Dibenzyl ether Dibutyl ether 1,1-Dichloroethylene 1,1-Diethoxyethane 1,2-Diethoxyethane

3,3-Diethoxypropene Diethyl ether Diethylketene 2,3-Dihydrofuran Diisopropyl ether 1,1-Dimethoxyethane 1,2-Diethoxyethane 3,3-Diethoxypropene 1,3-Dioxane 1,4-Dioxane 1,3-Dioxol-4-en-2-one Dipropyl ether Di(2-propynyl) ether Divinyl ether 2-Ethoxyethanol 1-Ethoxy-2-propyne 2-Ethylacrylaldehyde oxime 2-Ethylbutanal 2-Ethylhexanal Ethyl isopropyl ether Ethyl propenyl ether Ethyl vinyl ether 2-Furaldehyde Furan 2,4-Hexadien-2yn-1-ol

2,5-Hexenal 2-Indanecarboxaldehyde 2-Isopropylacrylaldehyde Isobutyraldehyde Isopropyl vinyl ether Isovaleraldehyde Limonene 1,5-p-Menthadiene Methoxy-1,3,5,7-cyclooctatetraene 2-Methoxyethanol 2-Methoxyethyl vinyl ether 4-Methyl-2-pentanone 2-(1-Methylheptyl)-4,6-dinitrophenyl crotonate2-3-Methyl-2-methylenebutanal 2-Methyltetrahydrofuran Methyl vinyl ether Alpha-Pentylcinnamaldehyde Propionaldehyde Sodium 5,8,11,14-eicosatetraenoate Sodium ethoxyacetylide 1,1,2,3-Tetrachloro-1,3-butadiene Tetrahydrofuran


Minimizing risks in the lab

• Segregated storage: avoid confusion of wrong chemicals:- base / acid- explosives / oxidizers

• Correct labelling of chemicals: avoid abbreviations

• Read the labels !

• Correct use of units (ml - g)

• Systematically look up of the properties of chemicals

• Look up compatibilities of mixtures (catalyst, metals,…)

• Correct use of protective equipment: fume hood, PPE’s


Strategies

Lab Scale Pilot Plant Manufacturing

Literature Evaluate chemical Evaluate equipment Search reaction hazards hazards

Desktop Define influence of Define critical calculations operating hazards parameters

Laboratory Process Safety Review HAZOPTesting


Chemical reaction

Desired chemistry Unwanted chemistry

Normal limits Adiabatic Adiabatic temperature temperature

rise of reaction rise of decomposition


Reaction rate - Laboratory Testing

Property to evaluate Typical Instrumentation

Thermal stability of raw Differential Scanning materials Calorimetry

(DSC)

Normal reaction conditions Reaction Calorimetry (RC-1)

Minimum exothermic Accelerating Rate Calorimetryrunaway temperature (ARC)

Runaway reaction consequences Accelerating Rate Calorimetry (ARC)

Reaction Calorimetry (RC-1 pressure)


Reaction Safety GuidelinesOperating Guidelines - When and what to test

4 stages of evaluation

Stage 1 - A chemical procedure run at any scale that requires thestorage and use of a key raw material, intermediate, reagent, solventthat contains a known hazardous chemical functionality or is itselfsuspected or known to be hazardous or unstable.

Stage 2 - A chemical procedure that displays any observed thermal orpressure event, unexpected eruption or degassing, venting orspilling, viscosity increase, darkening or polymerization duringlaboratory scale experimentation or initial scale up.

Stage 3 - A chemical procedure that is representative of a final syntheticroute and may not be fully optimized. This chemical procedure hasbeen performed and duplicated minimally on a 500 mL reactionscale.

Stage 4 - A chemical procedure that is optimized at the laboratory scaleand ready for introduction into large scale equipment.


Reaction Safety Review (RSR)• “HAZOP” - RSR (via in person, phone, or e-mail)

• Formal review of the “mechanics” of the procedure

– Review available data - MSDS, literature, RC-1, DSC, etc.

– What equipment is being used

– How you do things – “mechanics of the procedure”– Heat or cool (Mantle or ice)– Monitor temperature, pressure, etc– Monitor reaction– Work-up reaction (extract, rotovap, filter)– Isolate product– Is additional testing required to scale safely ?


Reaction Safety Testing Protocol

2-5 mg of materialQuick screening test

25°C to 300°C

DSC TestEvaluate the thermal stability

of all raw mateirals used

3-5 grams of materialMore sensitive than DSC

Time to Maximum Rate/pressuresRunaway reaction potential

ARC TestEvaluate the thermal stability

of raw materials, reaction mixturesunder adiabatic conditions

1.0 L scale"Any chemistry" can be tested-90°C to 250°C, under pressure

ReactIR, kinetics, "optimization"

RC-1 CalorimetryEvaluate the Heat of Reaction

and worst case temperature riseunder actual reaction conditions

* Any Reaction to be run onequal/greater than 5L scale that

requires ice bath cooling(other than for chemical quality)


Differential Scanning Calorimetry DSC

Typical sample size = 1-10 mgScanning rate = 5οC/min to 300οC

100o/50o ruleTMR24AKTS


DSC Example

FastSmall sample sizeBroad temperature range

Representative sample ?No mixing (heterogeneous)No pressure data


DSC Example


Accelerating Rate Calorimeter

Typical sample size = 3- 5 gramsHeat / wait / search to 400οC


ARC Example

TBAP salt TBAP reaction mixture


EasyMax and MultiMax

Preliminary chemistry screening, observing Tr-Tj behaviorSmall scale, easy and fastCrystallization study and optimization


Reaction Calorimeter (RC-1)


RC-1 iCSafety

R OH

O

R OCH3

O


Reactor heat transfer specific cooling specific ΔT needed on jacketcoëfficiënt area heat transfer to cool 30 W/L

U (W/m2K) (m2/m3) U . A / V (W/lK)

500 ml flask 200 86 17.2 2RC1 1L vessel 150 40 6 5250 L reactor 250 6,8 1,70 16

1000 L reactor 250 4,6 1,15 266300 L reactor 250 2,6 0,65 44

Cooling capacities for different reaction vessels

** ALWAYS OBSERVE AND REPORTTEMPERATURE CHANGES


Typical Heat of Reaction Values

Bromination: < 50kJ/moleFriedel-Crafts: 53 kJ/moleAcid/Base Neutralization: 56 kJ/moleEsterification: 67 kJ/moleNaBH4 Reduction: 150 kJ/moleOxidation: 300kJ/moleGrignard: 400 kJ/moleHydrogenation (NO2): 560 kJ/moleNitration: 130 kJ/moleEpoxidation: 96 kJ/moleAmination: 120 kJ/moleDiazotization: 117 kJ/mole

0-50 kJ = Weak50-100 kJ = Medium150-300 kJ = Strong300 kJ = Very Strong


Mettler FTIR Model iC10


Reaction Calorimeter and ReactIR


We have the information

Now what ??

Some Examples

Chemical Reaction Hazards


Example # 1

A Critical Parameter in the Development of a

Scaleable Synthesis of 2,3-Bis-chloromethylpyridine Hydrochloride

Source: Stephen Stefanick et al, Organic Process Research and Development, 2002, 6, 938-942


Reaction Safety Issues

1. Potential runaway chemical reaction2. Reaction done in neat thionyl chloride3. Difficult temperature control on larger reaction scale4. “Troublesome” isolation of product5. Waste disposal

Reaction Scheme

N

OH

N

Cl

Cl

x HCl

SOCl2OH

N

OH

Cl

SOCl2



Dosing loop

Charge reactor at set temperaturethen add thionyl chloride via dosing loop or manually

Reaction Flow Diagram


Heat Flow Curve - MTBE at 25°C

Issues: ExothermicInduction period, accumulation of SOCl2En-mass reaction, uncontrolled out-gassing

Add thionyl chloride at 25oC over 40 minutes



Issues: ExothermicStill did not initiate, accumulationSimilar to MTBE reaction at 25 CSO2 and isobutylene (CRC90e at 40 C)

Heat Flow Curve - MTBE at 45°C




Re-think our Strategy

Issues:

Reaction will not initiate in MTBE at 25oC and 45oC

Serious accumulation of thionyl chloride

Uncontrolled outgassing – SO2

Solvent decomposition issues – Isobutylene

Action Plan:

Evaluate new solvent / conditions



Heat Flow Curve - Toluene at 25°C

Issues: ExothermicInduction period, accumulation of SOCl2En-mass reaction, uncontrolled out-gassing




Heat Flow Curve - Toluene at 45°C

Issues: ExothermicStill did not initiate, accumulationSpontaneous reaction as 2nd equivalent of SOCl2 is added




Heat Flow – MTBE/DMF at 25°C

Issues: Exothermic, feed controlledReaction initiates, controlled out-gassingPossible isobutylene formation from MTBE

Add thionyl chloride portion-wise at 25oC over 40 minutes



Heat Flow – Toluene/DMF at 25°C

Issues: Exothermic, feed controlledReaction initiates, controlled out-gassingIsobutylene formation not possible

Add thionyl chloride portion-wise at 25oC over 45 minutes



Why the Chemistry is DifferentChlorination via "Vilsmeier Intermediates"

N CH2Cl

CH2

N CH2Cl

CH2Cl

3.

x HCl

x HCl

H NMe2

OSOCl2

H NMe2 + Cl-

OSO2Cl

H NMe2 + Cl-

Clor

"Vilsmeier Intermediate"

N CH2OH

CH2OH

2.

x HCl

N CH2

CH2OHx HCl

N CH2Cl

CH2OHx HCl

H NMe2

O+

H NMe2 + Cl-

X X = Cl or OSO2Cl

"monochloro"

+

H NMe2

O

O

NMe2+

H

Cl-

O H

NMe2+Cl-

-HCl, -SO2



Conclusions

• Reaction in Toluene with catalytic DMF is SAFE

• Optimized thionyl chloride• Simplified product isolation• Minimal Waste Disposal concerns

Chemical reaction safety testing in tandem with reaction optimization has led to a safe, acceptable and environmentally friendly synthesis able to produce >3.0 kg of material for use in the preparation of final product.

N

OH

N

Cl

Cl

x HCl

SOCl2OH

N

OH

Cl

SOCl2



Improved Reductive Cyclization Procedure for the Preparation of 3,4-

Dihydro-1H-[1,4]oxazino[3,4-c][1,4]benzodiazepine-6,12(11H, 12aH)-

dione with Iron in Acetic Acid

Example # 2

Source: Stephen Stefanick et al, Organic Process Research and Development, 2003, 67 1067-1070


IntroductionFor an ongoing project, we needed toprepare kilograms of 3,4-dihydro-1H-[1,4]-oxazino[3,4-c][1,4]benzodiazepine-6,12(11H,12aH)-dione

Our original procedure involved thereductive cyclization of 4-(2-nitrobenzoyl)morpholine-3-carboxylatemethyl ester 1 by simply adding iron powderto 1 in glacial acetic acid and refluxing.

NH

N OO

O

Fe (powder)HOAc, reflux

21

N

OH

O

CO2MeNH2

N

OH

O

CO2MeNO2



Results

A brief examination of the original procedure presented several challenges to scale-up……

• Dilute reaction concentration [5% w(g)/v(mL)] required a large volume of glacial acetic acid

• The use of 6.3 equivalents of iron pellets resulted in a significant agitation problem.

• The reaction needed 20 hours to achieve completion.• A prolonged workup and silica gel chromatographic purification

was necessary to isolate the product.• The mass yield was only 62%.



Our Initial Process Work Resulted In Several Improvements…..

• Double reaction concentration [10% w(g)/v(mL)] therefore cut the use of glacial acetic acid.

• Reduce the amount of Fe powder (2.5 equivalent, 325 mesh size).

• Shorten the reaction time to 1.5 hours.• The product is precipitated from water after removal of acetic

acid.• The HPLC assay yield is increased to 84%.• Low iron content (50-100 ppm) in the product is crucial for the

subsequent reactions.



However We Observed…

…An uncontrollable exotherm: after heating to 50-60 °C, the reaction temperature increased to reflux in less than 1 minute (115-116 °C)!

…The reaction mixture thickened - almost stopping the agitation.

…After 5-10 minutes, the reaction mixture thinned out to a more stirrable suspension.

…A potential chemical reaction hazard!!



Evaluation Using Reaction Calorimetry; How About Portion-wise Addition of Iron

powder?

Adding iron powder in fourportions to a heated solution of 1in acetic acid resulted in thefollowing heat flow curve.

• Heat flow curve from RC-1 reaction calorimeter.

• Red = Heat flow

• Blue = Tj Jacket temperature

• Green = Iron addition



From Portion-wise Addition, We Observed…

• Each iron addition step is exothermic.

• Thickening of reaction mixture and poor agitation were observed.

• Large calculated temperature rise (198 °C) existed.

• If loss of cooling/agitation and mischarge of all the iron powder, vigorous reflux and spewing of reaction mixture from reaction vessel might occur.

• A potential chemical reaction hazard still existed.



How About Reverse Addition?

A solution of 1 in acetic acid was added slowly to a stirring mixture of iron powder (325 mesh) and acetic acid at 75 °C.

• Heat flow curve from RC-1 reaction calorimeter.

• Yellow = Thermal conversion to product

• Red = Heat flow

• Blue = Tj Jacket temperature

• Green = Starting nitro ester 1 addition



From Reverse Addition, We Observed…

• The reaction is still exothermic but feed controllable.

• No thickening or poor agitation was observed.

• Large calculated temperature rise (158°C) existed.

• If loss of cooling/stirring and mischarge of all solution of 1 in acetic acid , vigorous reflux and spewing of reaction mixture from reaction vessel might occur.

• A chemical reaction hazard existed; however,…...



The Reverse Addition Is Our Choice

• Feed controlled addition with metering pumps of the acetic acid solution of 1 prevents accidental full mischarge of 1 thus minimizing the reaction hazard.

• The “continuous” heat flow resulting from the reverse addition is far more controllable than the “portion-wise” heat flow.

• No thickening or poor agitation leads to a much improved heat transfer.

• The reverse addition method offers a substantial improvement compared to other conditions.



SummaryThrough the use of RC-1 reaction calorimetry, we evaluated reaction safety and our scale-up process.

The improved reverse addition conditions allows us to safely prepare multi kilograms of 3,4-dihydro-1H-[1,4]-oxazino[3,4-c][1,4]benzodiazepine-6,12(11H,12aH)-dione 2 in high yield and high purity.

NH

N OO

O

Fe (powder)HOAc, reflux

21

N

OH

O

CO2MeNH2

N

OH

O

CO2MeNO2



Oxidation of 4-Halo-2-nitrotoluene with Tetrabutylammonium Permanganate in Pyridine:

Development and SafetyEvaluation

Introduction- RC1e used for safety assessment of

modified conditions that resulted in an improved and safer procedure

Target molecule needed in multigram quantities for a drug discovery projectTypical KMnO4 oxidation in water not satisfying Variations of conditions did not yield good enough resultsTBAP more soluble, relatively stable, gives better results

Source: Xiaohu Deng, Stephen Stefanick et al, Organic Process Research and Development, 2006, 10, 1287-1291


Scale-Up Difficulties

- Induction period from hours to days- Very fast reaction once initiated- Cause of induction unclear- DSC and ARC test run before

increasing temperature to 60⁰C


Implemented changes and safety study- Slow addition of a cold

TBAP/pyridine solution to a 60°C solution of bromonitrotoluene

- Still induction period- Feed controlled exotherm- Reaction complete in 2.5 h, 80%

isolated yield- Reaction enthalpy: 575kJ/mol; worst

case temperature rise 72°CConclusion

- Unpredictable induction period- Reaction vigorously exothermic- Pose a serious safety concern- Safe for multigram- Not recommended for larger scale



Thermal Safety of Chemical Processes by Francis Stoessel

Chemical Reaction Hazards, John Barton and Richard Rogers, Institution of Chemical Engineers, 1993

•Guidelines for Chemical Reactivity Evaluation and Application to Process Design, Center for Chemical Process Safety of the American Institute of Chemical Engineers,1995

•Bretherick’s Handbook of Reactive Chemical Hazards

•Chilworth Technology

Acknowledgements

Dr. Cynthia A. MaryanoffDr. Kirk SorgiDr. Dave Palmer Mr. Mitul PatelDr. Xini Zhang

Dr. Fuqiang LiuMr. Jeff GrimmXiaohu DengDan PippelNeelakandha Mani

References:


Conclusions

Find reactivity hazard information.

Know the existence of databases - programs to search for safety information.

Know when Lab Testing of chemicals & mixtures is needed.

Know how to minimize risks in the lab.


THANK YOU FOR YOUR ATTENTION

Documents

Chemical Reaction Safety in the Pharmaceutical … · Chemical Reaction Safety in the Pharmaceutical Research Laboratory Steve Stefanick Scientific Director – Technical Integration