What is the difference and connection between small trials and scaled-up experiments and pilot production?

Industrial crystallisation process development and equipment design points of analysis

Small test, scale-up experiment and pilot production are three parts that are very closely related to each other. The reaction of the three are the same reaction, that is to say, their reaction principle is the same. However, there are always more or less differences between the three in terms of subtle operations. Many reactions are prone to this and that problem when they are slightly enlarged. In fact, it is not that their reaction process has any problem, but in the treatment of the reaction of the two should have subtle differences. Many teachers or engineers in the enlargement from 200ml reaction bottle to 500ml reaction bottle, always appear reaction yield drop or the reaction temperature range and the original range is slightly different. In fact, these differences are not really differences, just in different spaces, the reaction of the mass and heat transfer space is different. Because the space has a slight difference, resulting in meticulous operation, the same operation actually has a slight difference, and this difference leads to our common yield drop and temperature interval change problem. As long as we can analyse this problem carefully, this problem is not a problem.

 

Scale-up experiments and pilot production are slightly different, because the basis of both is the scale-up of the small test, but due to the magnification of the scale-up and the interval is different, resulting in the two show something different. This is the same integral element in different integral interval integration out of different results. As long as we understand the different characteristics of this integral element in different integration intervals, we will be able to derive the trend of the integral, so as to adjust the various factors to make the integral in the direction we need to transform.

 

In short, the link between the three is the same integral element in different integral interval integration results.

The same thread running through all three is the main reaction process.

 

When the reaction is amplified, due to the increase in space, resulting in the increase in the transmission space of the material, that is, the reactant molecules of the activity of the space has become larger, resulting in the reaction once the start of the reaction, the molecules participating in the reaction of the collision of the chances of the beginning of the smaller, which is a probabilistic problem, and thus amplify the reaction in the same time as the laboratory is the reaction can not react to the same rate of conversion, we need to extend the reaction time to make the reaction more thorough. Therefore, we need to extend the reaction time to make the reaction more complete, but when the reaction is controlled by the kinetics, we can easily encounter that even if the reaction is very long, it can not make the reaction go further, so we need to take some means to make our material concentration become bigger to make the reaction go further, such as refluxing or evaporating part of the solvent and other operations. At the same time, due to the increase in space, resulting in the transmission of heat began to slow down, because in the laboratory, the amount of material is relatively small, and the contact with the outside heating facilities is more compact, and thus the transmission of heat is faster, as long as the control is appropriate, basically does not appear in the material temperature spike or plunge, which affects product quality and even product yield are greatly affected by the situation. In this case, the production, pilot and laboratory are not the same treatment techniques, so when we use the same operation in the production and laboratory, it is easy to appear this or that situation, which is due to the respective heat transfer is not the same. Such as exothermic reaction is more intense, in the laboratory we can take ice water bath and other means to maintain the temperature balance, but to the pilot production, we generally take the way to add inert solvents as a carrier of heat to slow down the sharp rise in temperature. Or we can take the way of adding drops to control the heat release per unit time to keep the temperature stable.

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Pilot test is the preliminary amplification of the laboratory trial, is the initial attempt of small-scale production. It is the most important part of the process from R&D to production, and many very valuable projects fall on this step. The purpose of the pilot test for further production to provide reliable experimental data, and in the process of further amendments to the process, will not be suitable for the industrial part of the elimination, and then develop a suitable process for production. Therefore, a large part of the population is under the impression, based on experience, that pilot testing means researching and developing new process parameters according to the new (production) conditions. This view is slightly biased, the purpose of our pilot test is actually to study the means to achieve or approach the same conditions in the laboratory under the new conditions, rather than to seek new conditions directly. Laboratory, pilot and production of the three pursued reaction conditions should be the same, or almost the same, because most of the reaction conditions are still relatively wide, as long as the reaction interval, the reaction will basically get almost the same result. So the conditions pursued by the three are in fact the same, but due to the slightly different environments of the three, and therefore the means of implementation to achieve the results are slightly different.

 

Small pilot and medium pilot not only lies in the amount of feed, as well as the size of the equipment used, both are to complete different tasks at different times. Small test is mainly engaged in exploring, developmental work, chemical small test to solve the problem of the reaction, separation process and the analysis of the materials involved in the determination, come up with qualified samples, and yields and other economic and technical indicators to meet the expected requirements, can be brought to an end, into the pilot stage. The problem to be solved in the pilot process is: how to use industrial means and equipment to complete the whole process of the pilot, and basically achieve the economic and technical indicators of the pilot, of course, the scale has also been expanded. The process is not lacking in innovation and invention. Such as: a small test will be a material from a container quantitatively moved into another vessel, often a small test with the distinction between the test is a matter of hands, but in the test will have to solve the choice of what type, what specifications, what kind of material pumps, what kind of metering, as well as a series of issues related to safety, environmental protection, corrosion and so on, it is not simple to zoom out, and sometimes to solve such problems is also quite hurtful, and even It is difficult to achieve satisfactory results, the pilot test is to solve such industrial devices and means to adopt the process of the problems encountered; not only contains a small test of great attention to the material accounting, including a small test is not concerned about the heat, momentum of the accounting problem …… for further expansion, to achieve the real industrial significance of the economic scale of the production of reliable process means and data. Production to provide a reliable process means and data basis.

 

How much does the crystalline form of a drug affect it? Hate to know earlier!

 

Summary of Experiences in Intermediate Scale-Up

The intermediate experimental stage is to further study the changing law of the chemical reaction conditions of each step in a certain scale device, and to solve the problems that cannot be solved or found in the laboratory. Although the nature of the chemical reaction will not change due to the different experimental production, but the best reaction process conditions of each step of the chemical reaction, may change with the different experimental scale and equipment and other external conditions. Therefore, pilot scale-up is important.

 

At what stage of the experiment should the pilot test be carried out? At least the following conditions should be available:

 

1. The yield of the small test is stable and the product quality is reliable;

 

2. Operating conditions have been determined, products, intermediates and raw materials have been determined analytical test methods;

 

3. Some equipment, piping material corrosion resistance test has been carried out, and have the necessary general equipment;

 

4. Material accounting has been carried out. Three waste problems have been preliminary treatment methods;

 

5. Raw material specifications and unit consumption quantities have been proposed;

 

6. The requirements of safe production have been put forward.

 

Pilot amplification methods

 

Empirical amplification method: mainly by virtue of experience through the step-by-step amplification (small pilot device – intermediate device – medium-sized device – large device) to feel the characteristics of the reactor.

 

Similar amplification method: the main application of similar principles for amplification. This method has certain limitations, only applicable to physical process amplification. It is not applicable to the amplification of chemical processes.

 

Mathematical simulation amplification method: is the application of computer technology amplification method, it is the direction of future development.

 

In addition, the development of miniature intermediate device is also very rapid, that is, the use of miniature intermediate device instead of large-scale intermediate device, for the industrial device to provide accurate design data. Its advantages are low cost and fast construction.

 

The tasks of the pilot scale-up stage

 

There are mainly the following ten points, according to different situations in practice, can be divided into main and secondary, planned and organised.

 

1. The final determination of the process route and unit reaction operation method. Especially when the original selected route and unit reaction method in the pilot scale-up stage reveals a major problem that is difficult to solve, other routes should be re-selected, and then according to the new route for the pilot scale-up.

 

2. Selection of equipment materials and models. For contact with corrosive materials, the choice of equipment materials should be particularly careful.

 

3. Stirrer type and stirring speed of the investigation. Many of the reaction is non-homogeneous, and the reaction thermal effect is large. In the small test due to the small size of the material, stirring effect is good, heat and mass transfer problems are not obvious, but in the pilot amplification must be based on the nature of the material and the characteristics of the reaction, pay attention to the stirring type and stirring speed of the reaction of the influence of the law, in order to select the requirements of the stirrer and to determine the applicable stirring speed.

 

4. Further study of reaction conditions. Laboratory stage to obtain the best reaction conditions may not be fully in line with the requirements of the pilot scale-up, for this reason, should be one of the main influencing factors, such as charging speed, stirring effect, reactor heat transfer area and heat transfer coefficient as well as refrigerant and other factors, in-depth research, in order to grasp the rule of change of the intermediate device. Get more applicable reaction conditions.

 

5. Determination of process and operation methods. To consider the reaction and post-processing operation methods applicable to industrial production requirements. Pay special attention to shorten the process, simplify the operation, improve labour productivity. So as to finally determine the production process and operating methods.

 

6. Material accounting. When the reaction conditions and operating methods to determine the step, it should be on some low yield, by-products and more three waste reaction for material accounting. The sum of the weight of the reaction products and other products is equal to the sum of the amount of each material input before the reaction is the degree of accuracy that must be achieved by the material balance. In order to solve the weak links. Tapping energy saving, improve efficiency, recovery of by-products and comprehensive use and prevention of three wastes to provide data. No analytical methods of chemical composition should be analytical methods of research.

 

7. Determination of physical properties and chemical constants of raw materials and intermediates. In order to solve the production process and safety measures in the problem, it is necessary to determine the nature of certain materials and chemical constants, such as specific heat, viscosity, explosion limit and so on.

 

8. The development of quality standards for raw materials and intermediates. Small test in the quality standards are not perfect to be revised and improved according to the pilot experiment.

 

9. Consumption quotas, raw material costs, operating hours and production cycle and other determinations. In the pilot study on the basis of the summary report, you can carry out infrastructure design, develop models of equipment purchase plan. Design and manufacture of non-stereotyped equipment, according to the construction plans for the production plant building and equipment installation. In all production equipment and auxiliary equipment installation is completed. If the trial production is qualified and short-term trial production is stable, we can formulate the process procedures and deliver the production.

 

10. From laboratory research to pilot production.

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Selection of the preferred crystal/salt type: starting with marketed drugs

 

The study determines an optimal synthetic process route: 1.

1. A compound can often be synthesised by different routes and methods. The route and method initially adopted in the laboratory may not necessarily be the best, as there is not much examination of the reaction conditions, instrumentation, raw material sources, etc., and there is no excessive demand for yield, but these are very important for industrial production, and the synthetic steps and methods that do not meet the requirements for industrial production should be changed through small pilot studies. A more mature synthetic process route should be: short synthesis steps, high total yield, equipment and technology conditions and process flow is simple, abundant and cheap raw materials.

 

2. Use industrial grade raw materials instead of chemical reagents. Laboratory synthesis of small quantities, commonly used reagent specifications of raw materials and solvents, not only expensive, but also unlikely to have a large supply. Large-scale production should try to use chemical raw materials and industrial-grade solvents. Small pilot stage should be explored, the use of industrial-grade raw materials and solvents on the reaction with or without interference, on the yield and quality of the product has no effect. Through the pilot study to find out the best reaction conditions and processing methods suitable for the production of industrial-grade raw materials, to achieve low cost, high quality and high yield.

 

3. Recycling of raw materials and solvents. Synthetic reactions generally use a large number of solvents, in most cases before and after the reaction of the solvent has no significant changes, can be directly recycled for use. Sometimes the solvent may contain reaction by-products, incomplete reaction of the remaining raw materials, volatile impurities, or the concentration of solvent change, should be studied through the small test to find out the recycling process, and data to show that the use of recycled raw materials and solvents do not affect the quality of the product. Recycling of raw materials and solvents, not only to reduce costs, but also conducive to the three waste disposal and environmental health.

 

4. Safe production and environmental health. Safety is crucial to industrial production, should be studied through the pilot to try to remove toxic substances and harmful gases to participate in the synthetic reaction; to avoid the use of flammable, explosive hazardous operations, it is necessary, and can not be resolved, we should find the appropriate protective measures. Try not to use toxic organic solvents, looking for similar properties and less toxic solvents instead.

 

Pilot production stage: pilot production is an important part of the transition from the laboratory to industrial production is essential, is the bridge between the two. Pilot production is the expansion of the pilot, is the epitome of industrial production, should be carried out in the factory or a special pilot workshop. The main tasks of pilot production are:

 

1. to assess whether the synthetic process route provided by the small test, in terms of process conditions, equipment, raw materials and other aspects of special requirements, is suitable for industrial production;

 

2. Verify whether the synthetic process route provided by the small test is mature and reasonable, and whether the main economic and technical indicators are close to the production requirements;

 

3. In the process of amplifying the pilot study, further assessment and improvement of the process route, for each reaction step and unit operation, should obtain the basic stability of the data;

 

4. Formulate or revise the quality standards of intermediates and finished products, as well as the analysis and identification methods according to the results of the pilot study;

 

5. Preparation of intermediates and finished products of the batch is generally not less than 3-5 batches, in order to accumulate data and improve the pilot production data;

 

6. According to the raw materials, power consumption and man-hours, etc., preliminary accounting of economic and technical indicators, proposed production costs;

 

7. Step planning for each step of the material, and propose measures for recycling and disposal of three wastes;

 

8. Propose the process flow of the whole synthesis route, the process procedure of each unit operation, safety operation requirements and systems.

 

Equipment selection and process piping modification

 

1. according to the results of the small test, in the multi-functional, pilot plant, the selection of equipment, first of all, should consider whether the capacity of the equipment is appropriate, equipment materials, piping materials and process media adaptability, whether corrosion-resistant, whether the heating, cooling and stirring speed to meet the requirements.

 

2. The method of material conveying (feeding, discharging, flow between steps), how to prevent running, solidification and blockage.

 

3. Measurement of materials and charging methods, such as drip how to effectively control?

 

4. Is there any gas generation in the reaction? Will it flush the material? If necessary, gas-liquid separator should be added and reflux pipe should be installed.

 

5. Whether the separation conditions such as centrifugation and press filtration are satisfied?

 

According to the above conditions and other process requirements, make adaptive modification to the equipment and pipeline.

 

Preparation before feeding:

 

1. to the equipment, especially the newly installed and changed equipment or long time not used equipment to test pressure, test leakage work, combined with cleaning work for the linkage test, to ensure that the material after the fire, in the absence of leakage under the condition of the equipment pipeline heat preservation.

 

2. Do a good job of cleaning and clearing equipment to ensure that no debris into the reaction system to prevent cross-contamination and ensure orderly work.

 

3. Approve the feeding coefficient according to the process requirements and test needs, calculate the feeding amount to make the raw materials supporting the use of qualified quality, clearly marked, classified and placed in a fixed position.

 

4. Plan and prepare the intermediates’ containers and stacking places.

 

5. Check the production conditions: steam, oil bath, cooling water and brine is smooth (can be tried by hand to open the valve before and after the temperature difference), the valve switch is in line with the requirements.

 

6. Whether the materials are homogeneous, whether the mixing is enough to make them mix evenly, whether the solids are deposited in the bottom valve concave, especially the solid catalyst or insoluble raw material deposition, how to take measures to avoid the deposition.

 

7. Are the various instruments normal? Estimate the whole process (material shallow full of changes and feed less when) whether the thermometer can be inserted into the material.

 

8. Write good operating procedures and safety regulations.

 

9. Training for employees, process training (especially to make clear the control indicators and points, the hazards of violating the operating procedures and pipeline direction, the control of the valve in and out of the implementation of the control indicators beyond the emergency measures and emergencies). Safety training and labour protection training.

 

10. Define the responsible person of the project, organise the shifts, backbone forces to arrange for good follow up, clear communication and liaison methods between the workers and the backbone and the higher leadership at night.

 

11. Make plans for emergency measures and necessary preparations.

 

Research and development of drug crystal form

 

Pilot scale-up and production process protocols:

The purpose of pilot scale-up is to verify, review and perfect the reaction conditions determined by the laboratory process study, and the study of selected industrial production equipment structure, material, installation and workshop layout, etc., to provide data for the formal production, as well as the quality of the material and consumption, etc..

(I) Research contents of pilot scale-up

 

1. Overview

 

Process: In the production process where directly related to the chemical synthesis reaction or biosynthetic pathway order, conditions (dosage ratio, temperature, reaction time, mixing, post-treatment methods and refining conditions, etc.) collectively referred to as process conditions. Other processes become auxiliary processes.

 

2. Importance of pilot scale-up

 

Determine the process route, each step of the chemical synthesis reaction or biosynthesis reaction will not be due to the small test, pilot scale-up and large-scale production of different conditions and significant changes, but the best process conditions, with the scale of the test and the equipment and other external conditions may need to be adjusted.

 

3. Pilot scale-up study

 

(1) Review of the production process route

 

In general, the method of unit reaction and the production process route should be basically selected at the laboratory stage. At the stage of pilot scale-up, it is only to determine the specific process operation and conditions to adapt to industrial production. However, the selected process route and process, in the pilot scale-up revealed insurmountable major problems, it is necessary to review the laboratory process route, amend its process.

 

(2) the choice of material and type of equipment

 

The beginning of the pilot scale-up should be considered when the material and type of the various equipment required, and examine whether it is appropriate, in particular, attention should be paid to contact with corrosive materials, the choice of equipment materials.

 

(3) stirrer type and stirring speed of the test

 

In the laboratory due to the small size of the material, stirring efficiency is good, heat transfer, mass transfer problems are not obvious, but in the pilot scale-up, due to the impact of stirring efficiency, heat transfer, mass transfer problems are prominently exposed. Therefore, the pilot scale-up must be based on the nature of the material and reaction characteristics of attention to the study of the stirrer type, to examine the impact of the stirring speed on the reaction law, especially in the solid-liquid non-homogeneous reaction, to select the reaction requirements of the stirrer type and appropriate stirring speed.

 

(4) Further study of reaction conditions

 

The best reaction conditions obtained in the laboratory stage may not necessarily meet the requirements of pilot scale-up. Should be one of the main influencing factors, such as exothermic reaction in the charging rate, the reaction tank heat transfer area and heat transfer coefficient, as well as refrigerant and other factors to carry out in-depth experimental research, to master them in the pilot device in the law of change, in order to get a more suitable reaction conditions.

 

(5) the process and the determination of operating methods

 

In the pilot stage of amplification due to an increase in the handling of materials, it is necessary to consider how to make the reaction and post-treatment of the operating method to adapt to the requirements of industrial production, in particular, pay attention to shorten the process, simplify the operation.

 

6）Quality control of raw and auxiliary materials and intermediates

 

① raw and auxiliary materials, intermediates, physical properties and determination of chemical parameters.

 

② raw and auxiliary materials, intermediates, the development of quality standards.

 

Polycrystalline drug quality control guidelines overview

 

(ii) Material Accounting

Material accountancy is the most basic chemical calculation, but also one of the most important content. It is also the basis of energy accounting. Through the material accounting, in-depth analysis of the production process, the production process has a quantitative understanding, you can know the raw material consumption quota, revealing the use of materials; to understand whether the product yield to reach the optimal value, the equipment production capacity and how much potential; the production capacity of the equipment to match, and so on.

 

(1) The theoretical basis of material accountancy

 

Material accounting: is the study of a system of incoming and outgoing materials and changes in composition, that is, material balance. The so-called system is the scope of material accounting, can be a device or multiple devices, can be a unit operation or the entire chemical process.

 

The theoretical basis of material accounting is the law of conservation of mass: the amount of material entering the reactor – the amount of material flowing out of the reactor – the amount of conversion in the reactor = the amount of accumulation in the reactor

 

In the chemical reaction system, the transformation of material obeys the law of chemical reaction, and the quantitative relationship of material transformation can be found according to the chemical reaction equation.

 

(2) Determine the basis for calculation of material accountancy and the annual operating time of the equipment.

 

(1) The basis of material accountancy

 

Usually used benchmarks are: ① to each batch of operation as a benchmark for intermittent operation of equipment, standard or stereotypes of equipment material accounting. ② to the unit time as the basis for continuous operation of the material balance of equipment. ③ to each kilogram of product as the basis for determining the consumption of raw and auxiliary materials quota.

 

(2) Annual equipment operation time: the workshop each year, the number of days of normal production of equipment to start generally 330 days, of which the remaining 36 days as the workshop overhaul time.

 

(3) Collect relevant calculation data and material accounting steps

 

(1) Collecting relevant calculation data: dosage ratio of reactants, concentration, purity or composition of raw and auxiliary materials, semi-finished products, finished products and by-products, etc., total production rate of the workshop, production rate of the stage, conversion rate.

 

(2) Conversion rate: for a component, the ratio of the amount of material consumed by the reactants to the amount of material put into the reactants is referred to as the conversion rate of the component. Generally expressed as a percentage.

 

(3) Selectivity: various main and by-products, the main product of the percentage.

 

(4) Total workshop yield: total workshop yield is the product of the yield of each process.

 

(5) Material calculation steps

 

(1) Collect the basic data necessary for the calculation.

 

(2) List the chemical reaction equation, including the main reaction and side reaction; according to the given conditions to draw a flow sketch.

 

(3) Select the benchmark for material calculation.

 

(4) Carry out the material balance.

 

(5) List of material balance: ① input and output material balance; ② three waste discharge table; ③ calculate the consumption of raw and auxiliary materials quota (kg).

 

(C) production process regulations

 

A product can be used in several different production processes, but there must be one of the most reasonable under certain conditions, the most economical and most able to ensure that the weight of the product. People write the contents of this production process into a document form that is the production process regulations.

 

Production process regulations are important documents to guide production, but also the basic basis for the organisation and management of production; it is the core secrets of the factory. Advanced production process is the collective creation of engineers and technicians, post workers and business managers, belonging to the scope of intellectual property rights, to actively organise the declaration of patents to protect the legitimate interests of inventors and enterprises.

 

(1) the main role of the production process regulations: ① production process regulations is the organisation of industrial production of guiding documents, production planning, scheduling only according to the production process regulations, in order to maintain the coordination between the various aspects of production, in order to complete the task according to plan. ② production process regulations are also the basis for the production of preparatory work. (3) the production process is the basic technical conditions for the construction and expansion of production plants or factories.

 

(2) the development of production process regulations and the basic content of the original information

 

Development of production process regulations, the need for the following original information and include the basic content:

 

(1) product introduction: description of product specifications, pharmacological effects, including name (trade name, chemical name, English name); chemical structure formula, molecular formula, molecular weight; properties (physical and chemical properties); quality standards and testing methods (identification methods, accurate quantitative analysis methods, impurity inspection methods and impurity maximum limit test methods, etc.); pharmacological effects, toxicity and side effects (adverse reactions), use (indications.); packaging and storage, Usage); packaging and storage.

 

(2) chemical reaction process: according to chemical synthesis or biosynthesis, the main reaction, side reaction, auxiliary reaction (such as catalyst preparation, by-products, recycling, etc.) and its reaction principle. Also include the end point of the reaction control methods and rapid laboratory methods.

 

(3) production process: the chemical reaction in the production process as the centre, with a graphic form of cooling, heating, filtration, distillation, extraction and separation, neutralization, refining and other physicochemical processes to be described.

 

(4) equipment list: job title, equipment name, specifications, quantity (volume, performance), material, motor capacity, etc..

 

(5) equipment flow and equipment maintenance: equipment flow chart is in the form of equipment schematic diagrams to indicate the production process of the equipment connection relationship.

 

(6) Operating hours and production cycle: Record the name of the process in each position, the operating time.

 

7）Quality standard of raw and auxiliary materials and intermediates: list by post name, raw material name, molecular formula, molecular weight, specification items, etc.

 

(8) Production process: dosage ratio; process operation; main process conditions and their description; intermediates in the production process, their physical and chemical properties and reaction endpoint control; post-treatment methods and yields.

 

(9) Production technical and economic indicators: production capacity (year, month); intermediates, finished product yield, step-by-step yield and total product yield, yield calculation method; labour productivity and cost; raw and auxiliary materials and intermediates consumption quota.

 

10）Technical safety and fire and explosion prevention.

 

(11) The use of major equipment and safety precautions.

 

(12) Inspection methods for finished products, intermediates and raw materials.

 

(13) Comprehensive utilisation of resources and three-waste treatment

 

(14) Appendix (relevant constants and formulae, etc.)

 

Crystallisation process control and product property regulation

 

Precautions for the production process:

1. Strictly according to the operating procedures, safety regulations, can not be changed at will. If you find new problems need to change, there must be sufficient small test as a basis.

 

2. Strictly control the reaction conditions, such as temperature, pH value, etc., in case of exceeding the standard should be promptly dealt with (the small test should be taken into account, the small test should be done destructive test, to find out how to deal with the problem).

 

3. Pay attention to the pilot, test production thermometer heat transfer sensitivity is not the same as the pilot, the temperature change there is a hysteresis, should be expected in advance to this point for the operation.

 

4. vacuum system leakage how to check and emergency treatment, especially at high temperatures, emergency measures should be taken in a timely manner.

 

5. Sudden power outage, steam outage, water outage, frozen brine outage should be immediately taken necessary emergency measures (equipped with and activated when necessary backup power supply, nitrogen protection, etc.).

 

6. Pay attention to the amplification effect in the production, generally should be gradually amplified, can not only consider the progress, otherwise “want to speed but not achieve”, we must progress step by step.

 

7. Due to the existence of unpredictable factors and amplification, the amount of single batch feeding must be controlled, the implementation of graded approval system.

 

8. The phenomenon of the reaction process is carefully observed, recorded in a timely manner, and timely analysis of the phenomenon, to do a good job of the pilot or tracking the validation of the small test. All relevant personnel must have a high degree of responsibility, pay close attention to the entire production process, and take timely measures to solve the problems that arise.

 

9. How to judge the end point of each step should have clear indicators and methods, each step for strict control, can be combined with the phenomena occurring in the reaction to judge.

 

10. Correctly select the post-treatment method. Extraction, crystallisation and recrystallisation unit operation, in the selection of extractant and solvent, the correct use of “similar solubility” principle to consider the solubility of impurities, products. Selection of solvents must be in consideration of the applicability of the process at the same time, to consider the economy and feasibility, such as price, toxicity, and whether the recovery and easy recovery. These aspects should be taken into account when post-treatment is carried out in small trials.

 

Safety issues

 

1. Adequate small test is the success of the pilot and pilot production to ensure that the small test more effort, more to envisage the implementation of the various aspects of the pilot, the production of methods and operability, the more carefully considered, the more thoughtful, the pilot production will be the more smooth, there will be no production accidents and safety accidents.

 

2. The safety of technical reform fire is the key to safety, due to a number of projects in the same workshop, the project in the technical reform, other projects in production, or the same system before the production of a product, now change the production of another product, or due to a problem that is not taken into account in advance to the middle of the technical reform. In any case, all can be moved to the workshop outside the fire must be removed out of the fire, try to avoid fire in the workshop, must have to fire in the workshop, must do a good job of cleaning and isolation work (including equipment, containers, pipelines), can not leave a dead end, to strictly fire system.

 

3. Staff training and strict compliance with regulations and operating procedures is the focus of safety.

 

4. The division of labour should be clear, before feeding should fill in the “list of production items in the trial” to make clear the responsible person, communicate with each other in time, have a strict system and a high degree of responsibility, the backbone of the force should follow the shift, and in case of any situation should be taken in a timely manner to respond to the measures.

 

5. Possible safety, environmental protection and labour protection problems should be anticipated in advance and corresponding measures should be taken.

 

(I) examine more data conditions and their laws

A; first of all, safety first, in the pilot or production equipment can meet the process conditions under the premise of more small trials of different process control conditions, to determine the programme of several pilot, every process of production can not be negligent, otherwise the problem can not be found!

B; small test must be good, the problem try to consider thoroughly. Safety is the first priority, the other can be boldly tried.

C; in the laboratory, before the pilot test should be done before the time, temperature and other elements of the reaction of the edge of the experiment and destructive experiments, these work if you do the collapse, then in the pilot test in case of unfortunate anomalies, but also should be you have encountered!

D; when doing the small test, you should imitate the process of the pilot test and consider how to industrialise. Imagine how to achieve each step in the pilot, which may require more experience

E; after the small test process is mature, the process report must be completed. Pilot is not only a simple amplification of the pilot, pilot mixing, heat transfer, concentration, filtration, drying process are different from the pilot, the pilot try to simulate the conditions of the pilot to do, in addition, remember to do destructive testing of each step. Figure out the equipment for the pilot test, the physical and chemical properties of the material. Safety first. Before the pilot test small test tracking QUOTE] process tracking, sometimes the amplification process will be inexplicable problems, how you can not imagine out of thin air, so be careful and serious tracking of every detail of the process, especially the anomalies do not let go, otherwise it is very troublesome.

F; small test and test is sometimes two different things, sometimes far apart in any case, before the test should be all the factors as far as possible to take all factors into account, so that the production will also be unexpected always appear so more small test to verify the test including some destructive validation, it is also very important Oh.

G; amplification and the difference between the small test is the amplification effect, do a small test to consider the full range of conditions, do some more tests, to obtain stable data

H; I do production experience, generally from the small test to enlargement will certainly appear some problems, mainly small test time did not take into account the factors of production. Now there are a lot of researchers undeniably in the small test on the high attainments, but in the production on the know-how, really need to improve!

I; sum up personal experience, process design space to be reasonable, process to have durability, must: small test to do the conditions casually, more problems, much summary. In the put to be careful to engage in, a step a stop, small test synchronisation.

 

J; do small test just start not to pursue the yield, but to ensure that the first thing to be able to make qualified things, to target more destructive tests, more problems and solve problems, to amplification will be less problematic!

 

Comment; do chemical research and development to obtain a variety of data as well as the relationship between the various data, the law of the pilot production is crucial to the amplification, at least when the equipment does not meet your optimal process conditions, you still have measures to deal with.

 

(ii) Preparation for pilot production

A; counting from the beginning of work to date, I have done about 6 products or intermediates in the release. All the brothers upstairs are right and very eloquent. Here I will only mention the pre-preparation of the intermediate release. It is very important to think and prepare for the pre-release work, which is related to whether the whole release can be carried out smoothly and completed successfully. In the small test before the release, we must fully consider and imitate the operation of the scene, and the small test should not only make good conditions, but also make bad conditions. Fully look for the possible problems in the release, find solutions, more enquiries, more consultants, many can be done in advance to do the work in front, for the release work or follow-up work to be carried out smoothly to leave time and space. When encountering unexpected situations in the process of release, it is important to be calm and collected, but also to find ways to solve problems in a timely and reasonable manner, and not to be chaotic in case of trouble – not to be chaotic in thinking and not to be chaotic in behaviour! This is my little experience, I hope it can be a little useful to you!

 

B; small test test can be done for the pilot to lay a successful foundation, in the small test process to the key process parameters for detailed examination, the key raw materials and intermediates of the quality standard should be reasonable, and at the same time to make more destructive tests. Before the pilot test to confirm the use of raw materials and your small trial of raw material standards are consistent, equipment modification to meet the process requirements.

 

Whether the equipment modification meets the process requirements, whether the SOP is detailed and accurate, whether the operators are trained in SOP and key operation points and the physical and chemical properties of raw materials and other safety training. At the same time, special attention should be paid to the cleanliness of the equipment, which is the key to ensure quality, and special attention should be paid to the cleaning of valves and pipelines at the dead ends. Production process technicians should be a full range of tracking guidance, the production of problems is normal, first of all, we must deal with calmly, analyse the causes of the problem, while in the laboratory to prove the cause, and then training, in the production of adjusting the parameters and then verify!

 

C; small test process must be considered in the middle of the production process may produce what the situation, whether the amplification of the anomaly, which is mainly to consider the selection of the reactor, stirrer selection, the effect of heat transfer, as well as the effect of the means of post-treatment and so on.

 

The nature of all the chemicals used must be fully informed of the participants, more to strengthen the safety precautions, hanging blackboards in the workshop, some of the key announcements to strengthen safety awareness.

 

Once an accident occurs, on the one hand, we should calmly and promptly deal with it, and at the same time report it to the security department of the enterprise, the direct leader….

 

D; they still need to be in the trial production site! Pay close attention to several or more batches, pay attention to the workshop production conditions and your small trial of the differences and problems

 

E; 1; small test to consider the feasibility of the pilot;

2; pilot test preparation should be carried out on all raw materials to test the small test certificate

3; material transfer, energy conversion, etc. to consider clearly

4; small test more tests of various conditions

5. Problems, to be resolved, the problem is not resolved, do not easily carry out the next step

 

F; 1 individual preferably have practical production experience, fully understand the structure of the device performance.

2. Comprehensive consideration of the impact of uncertainty in the production of the test

3. In the pilot, timely tracking and analysis, solution, will not go out of the principle of the problem

 

The most complete recrystallisation experience and method in history

 

(C) tracking test in the pilot test

A; raw material intermediates must be tested, or die do not know how to die. The first two batches should make a good failure plan, do not do it too fast.

 

Stay calm when encountering problems and never do anything rash. My experience is that the more complex the problem on the surface the more likely it is to be a simple problem, sometimes a valve can mess you up for a day!

 

B; I’ve benefited from seeing so many messages, I’ll mention one more:

Before the pilot test, it is best to all the raw materials are again the laboratory a small test, even so, in the addition of material or go to see, I have done a borohydride Na reduction reaction, when the laboratory with borohydride Na is powdered, made a very good effect, the pilot test feeding I did not go, which did not work well, the reason is that they are taking borohydride Na, even into blocks are used, are failing! Fortunately, finally added some more to react completely, otherwise, millions of things can be gone! In addition, it is very important to do destructive experiments in the small test, including the stability of the product, the stability of the reaction and so on.

 

Comments:The experiment must use industrial materials, reagents and industrial products are different. But even if the use of industrial products before the pilot test must be used to prove a small test, some manufacturers give you a sample and the actual supply is not the same. For example, there are two manufacturing methods for toluene, and the impurities contained in the different manufacturing processes are also different. In the petrochemical plant catalysts in the use of small trials before the evaluation (that is, with a small test to prove it), the ordinary analysis can not fully explain the problem.

 

(D) Examination data in the pilot test

A. As long as there is no safety problem in the pilot test, the more other problems appear, the better it will be for your future production. If the pilot is very smooth, and wait for the production of problems, then it is really annoying!

 

B. First, consider the safety issue. Secondly, consider the equipment, and thirdly, consider the process control points

 

C. Temperature is also a problem that can not be ignored, winter and summer are different.

 

D, have to be familiar with the chemical unit operation of the coefficients, because the purpose of the pilot is large-scale production, so the pilot should be the end of the large-scale production, the pilot as a step, should not be a small test of a simple repetition and amplification.

 

E, during the pilot production stage, but also to do a combination of small test can avoid big problems, if some problems or analysis! Mainly to consider all the possible places where the problem may arise, do the test to pay attention to the emergence of the law of how the problem, small test followed by the test to go, so there should not be too much doubt. Of course, safety is the first thing to consider, other situations have the opportunity to turn the tables, but the accident is not.

 

F, the test must not be in a hurry to rush the sample, we must see the results, stable three batches. Problems are normal, the pilot summary is very important.

 

G, do a small test should take into account the large production or pilot capacity is not easy, such as anhydrous and oxygen-free operation, the impact of metal ions on the reaction. Selected reagents in the dosing process is easy to operate, whether due to the dosing order, fast or slow, etc. will affect the safety, and strive to a high safety factor. Doing synthesis, synthesising something, as long as the conditions are good, if time is not tight, it is not difficult, what is difficult is the amplification, maybe this is the bottleneck.

 

Comments: Pilot is the laboratory technology into the middle of large-scale production, mainly to obtain the process of thermal effects, mass transfer effects and other aspects of the data.

 

(E) post-processing

A, the pilot and the pilot is still different, the pilot should pay attention to your post-treatment can be carried out in the pilot, can not just make things to do, to consider the feasibility of the operation, let’s say that the treatment of oil, in a small bottle in a small bottle is good to get a big jar how to do? Generally, we hope that the pilot test is only solid or liquid transfer, reprocessing methods to try to meet this requirement.

 

B, the key is to do a good job in the small test material constant calculation, especially in the post-processing problems, there must be economic, cost of mind, in the pilot, large-scale production, the work should be planned as well as foresight, prevention in advance! If the method is right, then the rest is a matter of ability! Problems, not solved, resignation

 

Comments: Pilot, production in the post-processing is different from the chemical reaction is unable to experiment in the small test, so the researchers must have pilot experience, understanding of the production equipment. In the experiment should be considered in the pilot may encounter problems, envisage the feasibility of post-treatment.

 

(F) amplification effect, equipment effect

A; pilot and small test is a world of difference, small test can do qualified test is not necessarily. Therefore, the pilot and production problems on the small test is not necessarily a solution. I think we should first find the reasons from the pilot, and then simulate the pilot production on the basis of the small test

 

B; everyone’s analysis is very reasonable, but also very useful practical programme. We should also pay attention to: in the production of a good before to consider what differences exist between the laboratory and production, one by one to list, and then carry out experimental research. Which will have an impact: such as equipment materials, reaction thermometer latency, stirring and dispersion effect of the difference between

 

C; the biggest difference between the small test and the pilot test is that: the small test is easy to control, while there are a lot of unexpected situations in the process of large degree! Some are even fatal

 

D; 1. Each step of the material should not be easily enlarged according to the quality of the original small test, we must pay attention to the mol amount. When the quality changes, the mol amount will also increase, ignored may be unfavourable to the production, but also not easy to detect the place.

2. Make sure the equipment meets the process requirements, otherwise don’t produce.

3. Workers’ attitude must be well trained.

 

E; combined with their own many years of pilot test of some of the problems, summed up the following points of attention, see the joke:

1, the amplification effect, that is, the three passes the problem and the time difference, heat transfer cooling and stirring especially pay attention to the three passes the rate and the difference in the vial is too large, there are special requirements to use special equipment.

2, the amount of difference, the small test is not enough to worry about the amount of problems may become a big problem, so we must repeatedly check and consider the entire process of possible abnormalities, early preparedness, otherwise it is not a question of pouring out to start again.

3, the process of tracking, sometimes the amplification process will appear inexplicable problems, how you can not imagine out of thin air, so be careful and serious tracking of every detail of the process, especially the anomalies do not let go, otherwise very troublesome.

4, careful operation, which is beneficial to the yield of energy consumption and cost estimates, the most important thing is that the life of a small matter, a lapse may be OVER, especially when there are dangerous operations and hazardous materials.

5, detailed records, do not have preconceived ideas, the objective data to the small test of the data closer to the two differences are certain, the pilot test to deliver data closer to the production.

6, careful analysis, including the detection of each intermediate and the entire process can be coherent and simplified analysis, in front of a large kettle you are more likely to think of these issues, because you can not make up the operation!

 

F; each species has its own key points, such as temperature conditions, the possible generation of toxic gases, reaction time, the reaction material state, the material of the equipment required, the reaction process is exothermic or absorptive, the reaction degree of difficulty, whether a large number of gases will be generated. There are a lot of different places to pay attention to in the pilot process!

 

G; test equipment selection is very critical, for heat-sensitive materials heating or solid-liquid reaction stirring requirements fast, solid-liquid reaction is best to use propulsion mixing, to avoid dead ends—.

 

H; If the small test is done better, the test if there is an inexplicable problem, first of all, it is best to consider the problem of equipment and raw materials

 

Industrial crystallisation process development and equipment design points to be analysed

I; everyone year’s view are very clever!!!!

In my humble opinion, we should also consider a lot of conditions in the pilot test can not be achieved in the pilot test, and the pilot test in contact with the conditions such as iron and other pilot test is not possible to contact for some of the fear of metal ions in the production of the production should be more considerations before you do it again!

 

J; or the old saying “safety first”, the test in particular to pay attention to safety, and the laboratory is not the same: hit a bottle may not be a problem. The small test follows the medium test, probably because the small test did not know too much about the medium test equipment, did not consider the medium test of the production process.

 

Small test should pay special attention to the exothermic reaction (the amount of special instruments – calorimeters, not necessarily needed, but can feel the exothermic intensity, according to the degree of exothermic cooling medium can be determined), reflect the speed, the feeding order (a good feeding method can sometimes avoid the generation of by-products) and so on. In the production of homogeneous reaction is easier.

 

Pilot reaction (in addition to harsh high-pressure, strong heat, etc.) to start relatively easy to control, but the post-processing should pay special attention to: washing and separation of liquid attention to the calculation of liquid level, the volume of the reactor; recrystallisation attention to the control of stirring speed, cooling speed temperature difference, etc.; drying, pay attention to the melting point of the material, the beginning of the vacuum after the heating (but if the solvent is volatile, do not only vacuum but solvent icing, you can low-temperature). (But if the solvent is volatile, don’t only vacuum but solvent freezing, can low temperature heating).

 

L; for the vacuum degree, stirring speed, and whether the heat is uniform, should be considered. There is also the problem of discharge. The system is best to facilitate the transfer

 

Comments; amplification effect is actually because your industrial equipment can not reach the level of control of your pilot apparatus, the pilot is prone to problems in the main focus on the “three passes”, it is necessary to do everything personally, so that you have a sensory impression. In the test of the ability to perceive is very important, industrial equipment is not transparent only according to the thermometer, pressure gauge to judge the reaction to the situation. The equipment must be very familiar with and made to the man-machine integration, at any time to determine whether the equipment is running abnormally. In addition to pay attention to your equipment to meet the requirements of your process, I once did Grignard reaction is always a problem, and finally found that the problem in the mixing, although before the pilot test we have paid attention to this problem and the mixing will be put on the very low, (because Grignard reaction to activate the magnesium powder, the mixing of the pilot test can be put on the very low, but in the pilot test is very difficult.) Finally we put the stirring to the bottom of the kettle only 1cm when the reaction is normal.

 

(VII) Personnel cooperation, worker training

A; What we all said is more reasonable, and we also have our own opinions. I would also like to say one more thing, for the same type of different types, such as the difference is not, the courage can be bigger (such as most of the resin reaction, the reaction mechanism is the same, just different raw materials). But for different types of especially newly developed different mechanisms, or more complex, must have the experience of large-scale production, or relevant personnel counselling, otherwise even if you can pass the pilot, often in large-scale production to hit the wall, by the remaining large-scale production of large-scale investment, so the failure is catastrophic. Therefore, before this, to take into account various factors, a variety of indicators are within control. That is to say, to have foresight and possible means.

 

B; In fact, there is nothing, to do a good job in the pilot, the first important thing is to have excellent skilled workers, because the new process is very high requirements for the operation of the staff

 

C; and equipment, technology, safety and other technical personnel and operators to work closely with their own production of this process regardless of theory, or practical operation to have a good idea

 

D; to add, that is, when doing the amplification, must let your boss understand what you do is difficult, let them understand the difference between the pilot and the small test, and not only our own, so they will understand to create a good external environment for us the importance of.

E;

1. each step of the feed do not easily according to the mass of the original small test enlargement, must pay attention to the mol amount. When the quality change is large, mol amount will also increase, ignored may be unfavourable to the production, but also is not easy to notice the place.

2. The equipment must meet the requirements of the process, otherwise do not produce.

3. Worker’s attitude must be well trained.

4. The person in charge must be present for the control of key points.

5. like reflux, condenser is up to standard, here will hide many hidden dangers, especially the product colour requirements are more stringent

 

F; I’m not talented also made a few days in the test, the feeling is not shallow ah!

Three pass < very very very > important, but also pay attention to the exhaust gas pollution and the production capacity of the equipment, that is, the staff’s working environment and work intensity, after all, the work is people to do, automation is not very popular?

 

G; after so many years, after a lot of things, understand a project and a project is not the same can not be used to the fixed thinking to think about the problem.

Other people’s experience can only listen to a little, to absorb the things called their own!

No matter what kind of people say, even if it is a temporary worker must listen to his insights, perhaps you and I have not thought.

Be sure to bring your glasses, gloves. Special tip!!!

 

H; Firstly, we should fully understand the mechanism of the reaction as well as the nature of each chemical material, and we should gradually amplify it in the production in order to avoid the side effects brought by direct amplification, and we should consider the amplification effect. Secondly, in the production process to communicate with the superiors and workshop direct production personnel at any time, to do the whole process of production in mind, so as not to pilot and production problems.

 

I; personnel is still a very important part. Many times, not successful, not because of a man-made details, such as the valve is not tightened, found when, has been too late to regret!

 

J; R & D personnel, of course, to have the courage, the most important thing is not to hesitate in front of the workers, they can not get the idea, not in front of the workers in front of the current colour!

 

To private laboratory to ponder or consult the supervisor, especially the workshop supervisor, do not look at them not much expertise, but their experience is enough, if you are a rookie, to the workshop production, it is best to communicate with the workshop supervisor more in advance.

 

Most of the workers do not know the reason why, so the workers will treat you as an expert, are trusting you, so your wavering, will directly make people doubt your ability.

 

The data of the small test must be complete, anything can happen in the workshop, it is better to do some more destructive experiments, and check the workshop production conditions and workshop equipment. Many times what is easy to do in the lab may not be good in the workshop. Don’t forget that your process will be constrained by the equipment. When you are working on a pilot test or a project, make sure to do a safety assessment. Before operation, be sure to pay attention to the place where the danger may occur.

 

On the basis of the mature process of the pilot, first of all, familiarise yourself with the equipment in the workshop and a series of problems that may occur in the equipment, such as leakage of water, leakage of brine, failure to meet the requirements of no water, the mixing speed of the equipment, and the degree of cleanliness of the equipment. A series of problems before the start of work are properly considered, there must not be a hint of negligence, a pot of bad material may be the pot is not clean or left residue caused by side reactions.

 

Our past problems in the pilot process is usually the cause of the equipment, give full consideration to the effect of amplification of the experiment, such as whether the temperature is as fast as the small test to achieve uniformity, uniformity of the concentration of the reaction, the speed of stirring, the size of the exothermic, and the production of gas, but also pay attention to the amount of gas.