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.

Safety Assessment Process

Target Reaction Calorimetry	Research on secondary reactions (thermal stability) of raw materials, intermediates and products
RC1	DSC
Measure Various Thermal Data	Thermal Process Detection of Chemical Raw Materials
Heat Generation Rate	The 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 Progress	Thermal Process Detection of Chemical Process System
Starting Point, Ending Point & Dynamics	Reduce 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-Up	Kinetic 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 Curve	TD24, 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 Risk	Low 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 Danger	Process Risk	Actions Needed
Level 1 & Level 2	Low Process Risk	No Actions Needed
Level 3 & Level 4	Process is Danger	Technical Actions Needed
Level 5	High Process Risk	Redesign the Process

Safety Assessment Laboratory

Automatic Reaction Calorimeter RC1mx（Model: METTLER TOLEDO RC1mx）

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 Reaction	177.5
	After Reaction	190.4
Specific Heat Capacity of Reaction Material Cp(J.g^-1.k^-1)	Before Reaction	2.9843
	After Reaction	3.4922
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

DSC Test Data

Decomposition Heat Evaluation List

	Decomposition Heat (j/g)	Description
1	Decomposition Heat < 400	Potential Explosion Hazard
2	400 < 1200 < 1200 < Decomposition Heat < 1200	The release of heat is large, and the potential explosion risk is high
3	1200 < 3000 < 3000 < Decomposition Heat < 3000	Large heat release, high potential explosion risk
4	Decomposition Heat>3000	The 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 Heat	128.70
Initial Decomposition Temperature	147.12
Pre-reference Factor	20.04+/-0.29/td>
Reaction Activation Energy	91.29+/-1.01
Reaction Level	0.87+/-22.04e-03
TMRad (min)
TD24	57.4

Adiabatic Accelerating Calorimeter ARC

ARC Test Chart and Data

Temperature/Pressure – Antoine Equation Curve

TMR Fitting Curve

Initial Exothermic Temperature	114.5
Initial Temperature Rising Rate	0.022
Maximum Temperature Rising Rate Temperature	188
Maximum Temperature Rising Rate	10.904
Maximum Pressure Rising Rate	14.687
Maximum Temperature	197.1
Maximum Pressure	53.277
Adiabatic Temperature Rise	82.6
Heat Release	1247.47
Specific Heat	207.912
TD24	103.6
Reaction Level	0.84
Activation Energy	160867

FAQs

What is 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.
What are 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.

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