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Pharmaceutical Research
Safety Assessment Lab of Process Chemistry

Safety Assessment Lab of Process Chemistry

In the development of innovative drugs chemical process research plays a pivotal role. During the synthesis process to the scale up process in the laboratory, errors and risks must be controlled. Therefore, in the development of innovative drugs, the assessment of the safety of chemical processes and equipment is extremely important.

  • In January 2017, the State Administration of Work Safety issued the instructions and guidelines on strengthening the safety risk assessment of fine chemical reactions.
    Enterprises involved in the key supervision of hazardous chemical processes and Grignard reactions, intermittent and semi-batch reactions of metal organic synthesis reactions, in any of the following situations, must carry out a reaction safety risk assessment if:
    The new technology and formula will be used for the first time in China for industrial production or the new process introduced for the first time from overseas and a reaction safety risk assessment has not been carried out.      The existing process route, process parameters or device capabilities are changed, and the safety risk assessment report is not filed.      Production safety accidents have occurred due to reaction process issues.
    Adhering to “Innovation-Driven, Quality First”, Medicilon has established a laboratory research platform focused on evaluating the safety of chemical processes to provide clients with customized, accurate and reliable testing data and safety assessments.
Medicilon diamond icon.pngSafety Assessment Process
  • Target Reaction CalorimetryResearch on secondary reactions (thermal stability) of raw materials, intermediates and products
    RC1DSC
    Measure Various Thermal DataThermal Process Detection of Chemical Raw Materials
    Heat Generation RateThe heat absorption and release, melting point, decomposition temperature, decomposition rate and heat release of a single chemical during the heating process.
    Heat of Reaction
    Reaction ProgressThermal Process Detection of Chemical Process System
    Starting Point, Ending Point & DynamicsReduce the system to the DSC test system according to the actual ratio, test the decomposition temperature, decomposition rate and decomposition heat of the entire system
    Process Safety and Scale-UpKinetic Process of Ddecomposition Reaction
    Determination of Adiabatic Temperature Rise Maximum Temperature MTSR Heat Conversion Rate Specific Heat Capacity Cp Heat Transfer Coefficient: U Heat Accumulation vs Time CurveTD24, Activation Energy Ea, Pre-reference Factor A, Predict and Evaluate the Safety of Chemical Reactions
    Fully Automatic Control
    Mixing\Feeding\Pressure\PH Control
    High Hr, Fast Kinetics
    High RiskLow Risk
    Trigger a second reaction?No further testing required
    Adiabatic Test
    ARC
    Starting Temperature; Pressure Data; Adiabatic Temperature Rise; TMRad; Heat Release; TD24; Heat Release Rate
    Levels of DangerProcess RiskActions Needed
    Level 1 & Level 2Low Process RiskNo Actions Needed
    Level 3 & Level 4Process is DangerTechnical Actions Needed
    Level 5High Process RiskRedesign the Process
Medicilon diamond icon.pngSafety Assessment Laboratory
  • Automatic Reaction Calorimeter RC1mx(Model: METTLER TOLEDO RC1mx)

    METTLER-TOLEDO-RC1mx.jpg

    AP01 - Atmospheric
    Temperature: -73 - 230
    Reaction Volume: 0.5L
    Pressure: 50m bar (Atmospheric)
    HP60 - Autoclave
    Temperature: -10 - 250
    Volume: 1.5L
    Pressure: 60 bar
    RC1 Reaction Calorimetry Test Data list
    Reaction Temperature Tp(℃)48
    Reaction System Quality Mr(g)230.7
    Heat Transfer Coefficient U(W.k-1m-2)Before Reaction177.5
    After Reaction190.4
    Specific Heat Capacity of Reaction Material Cp(J.g-1.k-1)Before Reaction2.9843
    After Reaction3.4922
    Temperature Difference between Reactor and Jacket Tr-Tj(k)2.7
    Maximum Specific Heat Release Rate q’max(w.kg-1)49.0
    Reaction Heat Accumulation Acc(%)5.7
    Reaction Heat Release Q(kJ)83.2
    Reaction Heat Release RatioQ’(KJ.kg-1)360.6
    Molar Reaction Enthalpy-△Hr(kJ.mol-1)213.3    (Calculated based on the molar amount of benzonitrile input)
    Adiabatic Temperature Rise△Tad(K)103.2
    Highest Temperature for Synthesis Reaction MTSR(℃)54.1
    Highest temperature when the Heat Accumulation Degree is 100% for Synthesis Reaction(℃)151.2

  • Differential Scanning Calorimeter DSC

    Differential-Scanning-Calorimeter-DSC.jpg

    DSC Test Data

    DSC-Test-Data.jpg

    Decomposition Heat Evaluation List
    Decomposition Heat (j/g)Description
    1Decomposition Heat < 400Potential Explosion Hazard
    2400 < 1200 < 1200 < Decomposition Heat < 1200The release of heat is large, and the potential explosion risk is high
    31200 < 3000 < 3000 < Decomposition Heat < 3000Large heat release, high potential explosion risk
    4Decomposition Heat>3000The release of heat is very large, and the potential explosion risk is very high
    Sample Size (mg)8.872
    Heat Release (mJ)1141.80
    Specific Heat128.70
    Initial Decomposition Temperature147.12
    Pre-reference Factor20.04+/-0.29/td>
    Reaction Activation Energy91.29+/-1.01
    Reaction Level0.87+/-22.04e-03
    TMRad (min)
    TD2457.4

  • Adiabatic Accelerating Calorimeter ARC

    Adiabatic-Accelerating-Calorimeter-ARC.jpg

    ARC Test Chart and Data

    Antoine-Equation-Curve.jpg

    Temperature/Pressure – Antoine Equation Curve

    TMR-Fitting-Curve.jpg

    TMR Fitting Curve
    Initial Exothermic Temperature114.5
    Initial Temperature Rising Rate0.022
    Maximum Temperature Rising Rate Temperature188
    Maximum Temperature Rising Rate10.904
    Maximum Pressure Rising Rate14.687
    Maximum Temperature197.1
    Maximum Pressure53.277
    Adiabatic Temperature Rise82.6
    Heat Release1247.47
    Specific Heat207.912
    TD24103.6
    Reaction Level0.84
    Activation Energy160867

FAQs
  • Process Development Stage

    1. Literature research, patent evaluation report.

    (1) Gather as much relevant publicly available information as possible.    
    (2) Design multiple possible synthesis routes.    
    (3) Evaluate potential intellectual property risks associated with each synthesis route.

    2. Select a synthesis route and design reactions

    (1) Finalize the design of each reaction step, evaluating profiles, impurity spectra, yield, and quality based on accumulated knowledge.
    (2) Finalize post-treatment designs, including quenching, purification, filtration, and drying.
    (3) RFT (Right First Time).

    3. Process optimization.

    (1) Compare pre- and post-optimization results, identifying "key process points.""   
    (2) Drafting of preliminary quality standards for starting materials and intermediates.

    4. Impurity spectrum study.

    (1) A comprehensive study is not required.   
    (2) There should be an overview of the major impurities.

    5. Analysis of the reaction mechanisms.

    (1) Analyze the reaction mechanism of each step to control side reactions.  
    (2) Optimize conditions favoring primary reaction.

  • Process Research Methods

    DOE and Parallel reaction 

    Optimization of reaction conditions: reagent equivalent, temperature, concentration, reaction time, etc. 

    These methods can significantly improve the efficiency of condition optimization and quickly achieve optimal conditions.

    Destructive test (Stress test) 

    It is essential to do destructive tests for laboratory-scale batches, including the stability of starting materials, intermediates and products. 

    After the initial optimization of the process, it tests the applicable scope of the process.

    The Spiking experiments 

    Verification of process performance, such as assessing the reasonableness of specification settings and the capability to remove impurities.

Relevant laboratoriesRelevant laboratories
  • DSC+TGA
  • Liquid and mass Analysis Laboratory
  • Pharmaceutical Research Lab
  • Infrared XRPD
  • Pharmaceutical Research ICP-MS
  • Pharmaceutical Research TOC equipment
  • Pharmaceutical Research analytical equipment
  • Pharmaceutical Research-LCMS
  • Pharmaceutical Safety Research