Technical traps to avoid during process scale-up

Avoiding various problems that may arise during process scale-up, focusing on the accumulation of experience during scale-up, integrating standardized procedures and avoidable issues during scale-up, and recognizing the importance of collaboration will ensure smoother scale-up of API processes.

1. Avoid Complex Processes

During process development and scale-up, keep processes as simple as possible. The simpler, the less likely process errors will occur. In practice, more complex processes are more difficult for operators to master and difficult to describe in detail through operating procedures.

Simplification is not only for safety reasons, but also can reduce production cycle times and waste. Avoid reactions that require highly specialized equipment or are extremely dangerous and require safety equipment, such as nitration and hydrogenation.

Process simplification stems from simplifying the reaction route. Often, the route with the fewest steps is the best route. During the process development phase, consider whether it is possible to avoid the isolation of intermediates, combine reactions, and reduce the type and amount of solvents used.

2. Avoid Adding All Raw Materials and Then Heating

One of the most dangerous operations in a process is adding all reactants at once and then heating the reaction. Similarly, avoid adding catalysts after adding all raw materials at the end. The danger is that once the reaction mixture reaches the reaction temperature and begins, there is no way to stop the reaction. Some reactions are highly exothermic and will spontaneously heat to increasingly high temperatures. If the boiling point of the mixture is reached, it will boil over and even ignite. Some raw materials will degrade at higher temperatures, and this degradation can self-accelerate, releasing more heat than the reaction itself. When the reaction requires urgent cooling, switching and cooling are not as convenient and rapid as in a pilot test.

Of course, for reactions that are understood and proven safe, adding raw materials all at once is acceptable. However, this should be avoided during the initial scale-up of a process.

The most common method for controlling exothermic reactions is to add a single reagent dropwise. The addition time depends on the heat of the reaction and the heat transfer capacity of the reactor. During addition, avoid accumulation of raw materials that could cause a sudden reaction. Add at an appropriate temperature to ensure immediate reaction, such as in the preparation of Grignard reagents.

3. Avoid heating without stirring. Heat transfer within the reactor in production relies primarily on stirring. In addition to ensuring safety, good stirring reduces temperature differences within the reactor, ensuring more accurate temperature readings. Typically, the reactor wall temperature is higher than the center temperature, which can cause localized overheating, product decomposition or coking, ultimately impacting yield and quality. Stirring should also not be stopped until the reaction is complete and has cooled to a safe temperature.

4. Do not ignore potential degradation reactions.

Do not conduct reactions within 50°C of the known degradation temperature of the reactants to prevent runaway reactions. In addition to calorimetric evaluation of exothermic reactions, self-accelerating degradation reactions should also be investigated. This requires additional testing, such as adiabatic reaction calorimetry (ARC). If analysis indicates that the reaction may produce potentially unstable and easily degradable products, appropriate calorimetric testing should be performed.

Some degradation reactions may proceed very slowly and be undetectable through conventional testing. Even below the initiation temperature, the exotherm will still increase at a very small rate. By the time a significant temperature rise is observed, decomposition has already occurred.

5. Avoid adding solids to the reaction mixture.

Do not add solids to a refluxing or hot reaction mixture. This is a common practice in small-scale experiments but difficult to implement in production. Adding solids in batches is done to control the reaction and is easy to do in small-scale experiments. However, adding solids in production inevitably requires opening a manhole, and the solvent vapors already in the reactor can form an explosive mixture with air. If the materials react quickly, the liquid may spray out of the manhole (a similar incident has occurred during sodium hydrogen dosing).

One improvement is to consider adding the solids first, followed by the solvent. However, changing the order of addition may affect the selectivity of the reaction. Alternatively, the solids can be dissolved and added, or even formed into a slurry before being pressed into the reactor.

If changing the process is not possible, engineering considerations are needed to ensure that the addition is performed under closed conditions. Experiments and improvements are ongoing in this area, such as using vacuum loading, but currently there is no economical, effective, and universally applicable solution, especially for corrosive, highly toxic, or poorly fluid solid raw materials and intermediates.

6. Avoid evaporation to dryness

Using rotary evaporation to concentrate the liquid to dryness is a common practice in small-scale experiments. However, most reactors in the workshop have a minimum stirring volume of approximately 10-20%. When the liquid is concentrated to the final stage, heating without proper stirring is unavoidable. The hazards of heating without stirring have been discussed previously. This can lead to safety and quality issues. When evaporating to dryness is performed to replace solvents, repeated distillation after distilling to a certain volume can avoid the need for concentration to dryness. However, this depends on the relative volatility of the two solvents and whether they coexist azeotropically. A more efficient method is to use "constant volume distillation."

Concentration to dryness is a common process in our production. If the pilot-scale process provides a concentration to dryness procedure, production will follow it accordingly. While this process may be simple, it is uncontrollable and lacks a standard. It is only when yield and quality issues arise later that it is discovered that the previous distillation step was insufficiently dry. Examples include broken stirrer shafts, incomplete solvent replacement leading to yield reductions, and poor stirring after concentration to quench the slug. Therefore, during R&D, it is important to consider alternative process options.

7. Avoid Underestimating Process Time

For those new to process scale-up, the biggest surprise may be how long all operations take. It is crucial to conduct stability assessments for all raw materials, intermediates, and products before scale-up. Avoid reactions that require immediate quenching and isolation.

8. Avoid Overlooking Solvent Usage

In pilot-scale experiments, solvents with good solubility and easy distillation recovery may be used. However, some of these should be avoided during production. This includes all Class I solvents, those with a flash point below -18°C. n-Hexane has a flash point of -23°C and poor conductivity, making its use prohibited in production by international companies, with heptane being used instead. However, due to cost concerns, it is still used in some processes. Dichloromethane is less toxic than other chlorinated hydrocarbon solvents (chloroform, dichloroethane, etc.), but its use should still be avoided. In some processes, methyl tert-butyl ether or toluene can be used as an alternative.

9. Avoid Neglecting Quenching and Extraction

Many scale-up issues arise from post-processing. Therefore, it should receive the same attention as the reaction. Avoid having the upper layer of the demixed liquid as waste. Extraction often involves the largest solvent volume. To increase production capacity per unit volume, the amount of solvent used in extraction should be minimized. Increasing the amount of solvent increases the demixing and discharge time, potentially exacerbating emulsification. In weakly acidic/alkaline environments, prolonged extraction and separation times can lead to hydrolysis of compounds containing easily hydrolyzed functional groups. When scaling up an API intermediate to 80 tons/year, one extraction step requires two extractions with 2,000 L of solvent, for a total of 4,000 L of solvent. The solvent transfer alone takes three to four hours.

Ethyl acetate, a common extraction solvent, readily hydrolyzes in acidic or alkaline environments to produce acetic acid, increasing the acidity of the system. More stable isopropyl acetate or butyl acetate can be used instead. These solvents have lower saturated water content and are easier to recycle.

10. Safety

Safety is paramount. The emphasis here is on not risking the complete reaction of limited raw materials all at once. Be prepared for possible failure, especially with new processes. Split the process into two or smaller batches to avoid project suspensions due to exhaustion of all raw materials. Smaller batches also provide greater heat transfer area per unit, reducing mixing issues and the scale-up factor.

Common Problems and Solutions for Evaporation and Crystallization

1. How can I prevent pipe blockage and scaling in my wastewater evaporator?

Answer: There are generally two causes of pipe blockage: one is the deposition of crystallized salts; the other is scaling caused by calcium and magnesium ions. Therefore, preventing pipe blockage requires addressing these two aspects:

First, choosing the right evaporation method is the first step in preventing pipe blockage. Thin-film evaporators, such as falling film evaporators, are not suitable for applications where crystallization occurs. If these thin-film evaporators are used, pipe blockage is inevitable. For applications prone to crystallization, forced circulation or scraped-surface evaporators should be used. Forced circulation evaporators are highly recommended due to their large evaporation area and ease of operation. The flow rate within the heat exchange tubes should be maintained above 2 m/s. Although this project claims to be a forced circulation type, the pump flow rate is far from sufficient, resulting in salt deposition due to the unspecified flow rate.

Second, the layout of the evaporation pipeline is also crucial for reducing salt buildup. Our pipeline design eliminates dead corners and adheres to the principles of salt flow and deposition, ensuring that all crystallized salt is collected in the salt collector and ultimately discharged through the salt discharger. If scaling is caused by calcium or magnesium ions, the following measures can be taken:

① Soften the wastewater to a certain extent to reduce the concentration of calcium and magnesium ions;

② Use a forced circulation evaporator;

③ Use gypsum seeding to prevent scale or add a small amount of scale inhibitor;

④ Routinely clean the evaporation equipment. Calcium and magnesium scale can generally be removed with dilute acid.

2. Evaporator operating costs and how to reduce them?

Answer:

Method 1: Use a multi-effect evaporation process. Each additional effect reduces operating costs, but the initial investment increases. For wastewater salt distillation, the number of effects is generally limited to three, and at most four.

Method 2: Use a thermal compression evaporator (TVR). This can reduce the energy consumption of one effect. However, system operation will become more complex.

Method 3: Use a mechanical vapor compression evaporator. This reduces operating costs, but due to the immaturity of domestic steam compressors, the equipment is expensive and maintenance is more difficult. Furthermore, mechanical vapor compression evaporators are not suitable for evaporating salts and alkalis with large boiling point rises. When evaporating saline wastewater, careful consideration should be given to the use of mechanical vapor compression evaporators.

Method 4: Ensure proper insulation of the evaporation equipment to minimize heat loss.

Method 5: Utilize the sensible and latent heat of the condensate. Use a preheater to recover the sensible heat of the condenser and raise the feed temperature of the evaporation liquid; use a flash evaporation system to recover the latent heat of the condensate.

3. How is the salt produced by evaporation?

Answer: There are generally two methods for evaporating salt: centrifuge salt extraction. Centrifuge salt extraction has a low moisture content, but increases initial investment and operating costs. This method is suitable for those with high requirements for the quality of the evaporated wastewater.

Another method is to use a salt extractor equipped with a crystallizer. Salt is precipitated as crystals with low external moisture content, resulting in simpler equipment and easier operation. Trace moisture can be returned to the raw liquid tank through the filter and then evaporated.

4. How should the evaporator material be selected?

Answer: The choice of evaporator material is closely related to the composition of the wastewater. Salts can be divided into chloride salts (such as sodium chloride and ammonium chloride) and non-chloride salts (sodium sulfate, ammonium sulfate, sodium carbonate, nitrates, etc.). For chloride salts, the preferred order of corrosion resistance is: titanium, duplex stainless steel, carbon steel, and ordinary stainless steel. For chloride salts, the preferred order of cost-effectiveness is: carbon steel, titanium, duplex stainless steel, and least ordinary stainless steel. For non-heat exchange equipment, carbon steel enamel and PTFE are other options. For low-temperature applications, polypropylene and fiberglass are suitable.

For non-chloride salts, the preferred order of corrosion resistance is: 316L stainless steel, 304 stainless steel, and carbon steel. For non-chloride salts, the preferred order of cost-effectiveness is: 304 or 316L stainless steel, followed by carbon steel. For low-temperature applications, UPVC, PE polypropylene, and fiberglass are suitable.