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.
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
| 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 | |
| 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 |
| 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 |
FAQs1. 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.
• 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 laboratories
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