Problems needing attention in synthesis process scaling up

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Problems needing attention in synthesis process scaling up

Many “accidents” encountered in the process of scaling up can be predicted. If you can pay more attention to some details in small tests, do some simple experiments and collect some data, it will be of great help to the future process.

The glass flasks used in the test generally do not have corrosion problems (glass is not resistant to hydrofluoric acid and compounds that may decompose to produce fluorine, hot concentrated alkali). However, the compatibility of materials and materials in production must be considered, which is also the requirement of GMP for equipment selection. If you can consider to do a material corrosion test (in the reaction system to add stainless steel or other material sample) will save the time of equipment selection later. A simple measurement of the heap density of the filter cake is conducive to the estimation of the volume of the product filter cake and the selection of equipment in the future production. There is a certain relationship between the filtration speed and the filtration area and the thickness of the filter cake.

1. Typical amplification problems

The most common problem in process scaling-up is the change of reaction selectivity, which affects the yield and purity of the product. This is mainly due to the inconsistency between the mixing effect and the production in the small test. If the impact of the speed has been evaluated in the small test, the cause will be quickly found when there is a problem. The reaction kettle in the pilot workshop is equipped with frequency conversion speed regulation, which can be adjusted appropriately to determine the appropriate speed.
The appearance of new crystal forms during magnification is also common.
In the process of amplification, the separation of the product will also be problematic. The washing effect of the filter cake in the production is not up to the level of the small test, and impurities cannot be completely washed away. The three-in-one filter, washing and drying equipment with stirring can replace the centrifuge in some technological conditions. The three-in-one equipment can be directly added to the solvent for washing and pulping after filtration. The washing effect is better than that of the centrifuge.

Another reason for the amplification problem is the effect of production operation time. It is necessary to conduct a small test on the effect of time extension on the product. In the actual production, the prolongation of distillation time leads to the decomposition of products, and side reactions occur many times.
Crystallization and mixing are the three most common causes of magnification problems. As we’ll see below, there are a lot of problems related to mixing and heat transfer, but it’s fundamentally about understanding chemistry. What side reactions can occur in addition to the main reactions? What conditions promote the occurrence of side reactions? What changes when you zoom in? What effect will these changes have on reaction selectivity? In production practice, the current heat transfer conditions of the reactor basically cannot be changed (local supercooling/heat can be reduced by controlling the temperature difference between heating, cooling medium and the system in the reactor, and the heating/cooling speed). Mixing can be improved by the choice of speed and propeller type.

2. What to do in magnification

1) Team cooperation

Only the close collaboration of different professionals can produce a stable and scalable process. Chemists have a deep understanding of the effects of variables on the quality of a product. Process engineers have a better understanding of what operations are not feasible or unsafe in production. At the same time, as mentioned above, there are many tests that chemists can perform in the early stages of process development. For example, in drying and distillation experiments, physical parameters such as pressure and density of the system were recorded.

2) Principles of process development and operation

No matter the size of the company, some basic rules need to be established to ensure the safe transfer of the small test process to the kilogram laboratory and pilot plant. Establish clear, strict procedures and documentation required in small interviews, and resist pressure to stick to them even when deadlines are required. These data include production procedures and three batches of pilot tests according to the procedures, at least one batch using the same specifications as the raw materials used in the production. Cleaning verification scheme to avoid the possibility of cross-contamination. Process safety analysis data. Although the above requirements can affect “efficiency”, strict enforcement has resulted in no serious accidents or amplification of failed batches over the years.

3) Equipment accounting

Maintain operation and maintenance log of main equipment (reactor, filter, drier, pump, etc.) in kg laboratory and pilot plant. Includes batch records, cleaning records, verification records and other maintenance records.

4) Sample database

Set up sample database, collect and organize data of each sample (product, wet cake, distillate, process by-product). Including production batch number, collection time, analysis results, etc. These data have important reference value and can be collected and sorted to ensure that the data will not be lost. For research and regulatory reasons, these samples often need to be re-analyzed to determine, and at the same time can be carried out mass constant calculation.

5) Sample storage

With the establishment of sample database, it is necessary to set up a special sample room to preserve samples, and pay attention to drying, light protection and low temperature. The important thing is to set up a system so that samples can be found quickly when needed.

6) fixing process

Identify and resolve issues prior to trial run. It is dangerous to change the process at the last minute before scaling up. Can cause accidents and safety problems.

7) Process risk assessment (HAZOP analysis)

Risk assessment should be carried out before trial production of a new process. There should be an evaluation team composed of personnel from different departments to conduct a detailed review of the entire process safety and preventive measures. There is no 100% safe process, but according to the results of the assessment, the appropriate measures can be adopted to avoid or reduce safety accidents.

8) Determine the reaction energy

Lack of awareness or recognition of the hazards of exothermic reactions may be a major cause of major injuries and accidents. The heat transfer area per unit volume of reactor in production is much smaller than that of small test flask. The heat transfer area of 500ml flask is about 0.02 square meters, while the heat transfer area of 4000L reactor is only 10.7 square meters. So safe scale-up reactions require calorimetry or similar experiments. This aspect of the work is gradually attracting our attention. Although there have been no serious accidents, but in the production of punching happens. Compounds containing high-energy functional groups (e.g., compounds containing multiple amine groups, tetrazoles, hydrazine hydrate) should be avoided in the pilot phase. Reactions that may produce free radicals and gases should be given sufficient attention and described clearly during process transfer.

9) Establish production operation procedures

The importance of production operation procedures need not be said, the important is to ensure the procedures of time, as far as possible to reduce the errors in writing. The use of copy-and-paste in document editing brings convenience, but it also leads to unintended errors. This is also the importance of small test in accordance with the process procedures to repeat experiments.

10) Raw materials

Industrial grade raw materials were used in the experiment, and all raw materials were tested in small scale before production expansion. In this way, if the amplification is not successful, the cause of the raw material can be directly eliminated. In addition to the chemical purity of the raw material, physical properties also have an impact on the reaction, such as the particle size of the solid material.

11) Seize opportunities

Preparing for pilot production requires a lot of labor, time, and money. In many cases, however, only limited data is collected. That’s why it’s important to take advantage of every batch opportunity to learn as much as possible. A detailed sampling and analysis plan can help complete mass balance calculations, identify unanticipated byproducts, and resolve other amplification issues that may arise. Each flow of process logistics (including waste) should be weighed and sampled. There is no other opportunity to collect so much data as the pilot test. All observations should be recorded and samples of isolated intermediates and samples should be kept for use. Take advantage of the opportunity to collect as much amplification data as possible and make a detailed summary and analysis of the production to form a report for future reference. Validation is required at the time of production transfer, before which pilot production should be conducted to familiarize the process and determine the process procedures and operating procedures. If the pilot production is successful, the verification time will be shortened. The smooth trial production depends on the preliminary small test research and development, the pilot stage for the depth of the process problems.

3. What to avoid in magnification

1) Avoid complexity

Make it as simple as possible in process development and scale-up. The simpler it is, the less chance there is for process errors. In practical operation, the more complex the process is not easy for the operator to master, and it is difficult to describe in detail through the operating procedures.
Simplification is not only for safety reasons, but also reduces production cycle time, reduces waste and so on. Avoid reactions using very special equipment. Or reactions that are very dangerous and require safety facilities, such as nitrification, hydrogenation, etc.
The simplification of the process comes from the simplification of the reaction route, and often the route with the least reaction steps is the best route. In the process development stage, it is necessary to consider whether the separation of intermediates and the merging reaction can be avoided, and the type and quantity of solvent used can be reduced.

2) Avoid reheating all raw materials

One of the most dangerous operations in the process is the reheating reaction in which all the reactants are added together. Also do not add the catalyst after the final feed. The danger is that once the reaction mixture reaches the temperature to start the reaction, there’s no way to stop it. Some reactions are highly exothermic and spontaneously heat up to higher and higher temperatures. If the mixture reaches its boiling point it will boil or even flush. Some materials degrade at higher temperatures, and the degradation is self-accelerating and exothermic than the reaction itself. When the reaction needs urgent cooling, switching and cooling is not as convenient and rapid as small test.
Of course, a single input of raw material is acceptable for reactions that have been understood and determined to be safe. However, the first magnification of the process shall be prohibited.
The most common control for exothermic reactions is the drip addition of a reagent. The timing of the drip addition depends on the heat of the reaction and the heat transfer capacity of the reactor. In addition, in order to avoid the accumulation of raw materials, resulting in sudden reaction, it is necessary to add the raw materials at an appropriate temperature, to ensure that the raw materials can react immediately, such as format reaction.

3) Avoid heating without stirring

Heat transfer in the reactor in production mainly depends on stirring. In addition to ensuring safety, good mixing can reduce temperature differences in the kettle, making temperature readings more accurate. Generally, the temperature of the kettle wall is higher than that of the center of the system, which will cause local overheating, decomposition or coking of the product, and ultimately affect the output and quality. Do not stop stirring until the reaction is complete and cooled to a safe temperature.
One accident, for example, was caused by a strong exothermic reaction between organic amines and sulfuric acid. According to the process, the amine is slowly added to the hot sulfuric acid under intense agitation. The reaction is a two-phase system. One day, the operator changed. In the absence of stirring, the amine was added, and the amine precipitation did not react at the bottom of the reaction kettle. Later, another employee found that the mixing was not on, so he started the mixing. At this moment, all the materials reacted instantly, resulting in an explosion.

4) Do not ignore the potential degradation reaction

Do not react in the known degradation temperature of the reactant 50℃, so as not to reaction out of control. In addition to the calorimetric evaluation of exothermic reactions, degradation reactions that can be self-accelerating also need to be investigated. This requires additional experiments, such as an adiabatic reaction calorimetry (ARC), which should be performed if the analysis indicates that the reaction may produce potentially unstable and easily degradable products.
Some degradation reactions may occur too slowly to be identified by routine testing. Even below the initial temperature, the heat release of the reaction will still increase at a small rate. When the temperature is found to rise significantly, the decomposition reaction has occurred.
A domestic raw material pharmaceutical factory in diazotization reaction, in the heat preservation stage, the operator closed the steam valve, leave the post to eat, because the steam valve leakage, resulting in the reaction temperature rise, diazotization salt decomposition. As no one was on duty, the temperature rise was not detected in time. When the workers on duty returned to their post and found the temperature rise abnormally, the reaction could not be controlled, and eventually an explosion occurred, and the whole workshop was 

5) Avoid adding solids to the reaction mixture

Do not put solids into a reaction mixture that is being reflux or heated. This is a common operation in small trials, but difficult to achieve in production. Dosing increments is to control the reaction, which is easy to do in a small test. But in the production of adding solid materials must be opened manhole, the existing solvent steam in the kettle and air will form an explosive mixture of gas. If the material reaction is very fast, it will cause the material liquid to eject the manhole (similar accident happened when sodium hydrogen was thrown).
One improvement is to consider adding solids first and then solvents. But changing the feeding order may affect the selectivity of the reaction. In addition, the solid can be dissolved and added, or even formed slurry and then pressed into the reactor.
If the process cannot be changed, it is necessary to consider how to add under closed conditions from an engineering perspective. Attempts have been made to improve this area, such as the use of vacuum feeding, but there is no economic, good and universally applicable solution, especially for some solid materials and intermediates with corrosion, rapid drugs and poor mobility.

6) Avoid evaporation to dry

The use of rotary evaporation to concentrate the feed liquid to dry operation is very common in small tests. But most reactors in the shop have a minimum stirring volume of about 10-20%. When the feed liquid is concentrated to the end, it is inevitable that the material will be heated without good stirring. The hazards of heating without stirring have been described previously. This can raise safety and quality issues. When the evaporation is to replace the solvent, the use of steam to a certain volume, add the latter solvent repeatedly towing, can avoid concentrating to dry operation, but this needs to see the relative volatility of the two solvents and whether azeotropic. A more efficient way is to use “constant volume distillation”.
The process of concentration to dry is very common in our production. If the process provided by the pilot process is concentrated to dry, the production will be carried out in accordance with it. Concentration to dry may be a simple operation, but it is uncontrollable, unmeasured, and only after subsequent production and quality problems can it be found that the previous steaming was not dry enough. There was fracture of stirring shaft, incomplete replacement of solvent, resulting in a decline in yield, and poor quenching of blanking material after concentration. Therefore, it is necessary to consider whether there is a better process to achieve during research and development.

7) Avoid insufficient estimation of process time

For those who are new to process magnification, perhaps the biggest surprise is that all the operations take so long. It is important to conduct stability assessments for all materials, intermediates and products prior to scale-up. Avoid reactions that must be quenched and separated immediately after the reaction.

8) Avoid ignoring the use of solvents

A solvent with good solubility and easy distillation recovery may be used in a small test. But some of them need to be avoided in production. This includes all solvents of a class, with a flash point below -18 ° C. The flash point of n-hexane is -23℃, and its electrical conductivity is poor. Generally, foreign enterprises are prohibited to use it in production, and heptane is used instead. However, due to the cost problem, it is still used in some processes. The toxicity of dichloromethane is lower than that of other chloro-alkane solvents (chloroform, dichloroethane, etc.), but it should be avoided as far as possible. In some processes, methyl tert-butyl ether and toluene can be used instead.

9) Avoid neglect of quenching and extraction

Many of the problems with magnification come from the post-processing process. So it should be given as much attention as the reaction. The upper layer to avoid delamination is waste liquid. Extraction is often the largest solvent volume step, in order to improve the capacity per unit volume, should minimize the extraction of solvents. With the increase of the number of solvents, the delamination and feeding time also lengthened, and the emulsification phenomenon may be intensified. In weak acid/base environments, prolonged extraction and separation time may lead to the hydrolysis of compounds containing readily hydrolytic functional groups.
When an API intermediate is scaled up to 80 tons/year, one of the one-step extractions requires two extractions of 2000L of solvent, for a total of 4000L of solvent, and the transfer of the solvent takes three to four hours.
As a common extraction solvent, ethyl acetate is easily hydrolyzed to acetic acid in acid/alkaline environment, which enhances the acidity of the system. The more stable isopropyl acetate or butyl acetate can be used instead, and the saturated water content of the solvent is lower and easier to recover.

10) security

Safety is the most important thing. The point here is not to risk reacting a limited amount of raw material all at once. Be prepared for possible failures, especially with new processes. This can be done in two or smaller batches to avoid the suspension of the project when all the raw materials are used up. At the same time, smaller batches have higher unit heat transfer area, which reduces mixing problems and magnification factor.


Experience is important in a timely and successful scale-up process. At the same time, there are many excellent references worth learning and adopting. While it is not possible to predict all contingencies during the first scale-up, the considerations outlined above should lead to further consideration of process development and scale-up, and an awareness of the importance of collaboration should increase the chance of success.