Discussion On The Application Of Low-Temperature Freeze-Drying Technology In The Production Of Powder Injections

Under the conditions of modern society, people begin to pay attention to the production and preparation process of medicines. In order to ensure the stability of drugs, relevant professionals have begun to develop important technologies for processing drugs, including freeze-drying technology. At present, most pharmaceutical companies use comprehensive drying technology, but there are still many problems that need to be solved during the application process. This article briefly introduces the application of low-temperature freeze-drying technology in the production of powder injection drugs, for reference only.

Part 1 Introduction

Under vacuum, the process of sublimating ice in biological products to effectively remove moisture from the substance is called freezing. Vacuum freeze-drying technology has unparalleled advantages over other drying methods, so it is becoming more and more popular among humans. In addition to its wide application in the fields of medicine, biology, food, blood products and active substances, its application scope and scale are still expanding, and vacuum freeze-drying will undoubtedly be an important application technology in the 21st century.

Part 2 Concept And Characteristic Analysis Of Low-Temperature Freeze-Drying Technology

2.1 The Concept Of Low-Temperature Freeze-Drying Technology

Freeze-drying technology has only attracted people’s attention in recent years, and it is considered to be the most advanced drying process in modern society and has been widely used. For example, people will use it to keep food fresh. In modern society, due to the rapid development of science and technology, people pay more and more attention to their health, and with the continuous development of science and technology, people use more science and technology. Low-temperature freeze-drying technology is popular because of its excellent stability. However, precisely because it is susceptible to interference from several other elements, it faces many problems in certain application operations and requires constant strengthening.

2.2 Low-Temperature Freeze-Drying Specifications

This technique has the following characteristics. First, it is usually done in a cryogenic environment. Second, powdered drug products obtained from processing are usually pre-frozen and the weights are accurate. Third, modes such as materialization can be avoided, so that the stability of the product can be properly guaranteed. Fourth, the choice of freeze-drying method contributes to the stability of the drug product. The drug product is dried under freezing, and in this case, the imbalance of freezing forms the drug-related skeleton. After drying, although the volume will shrink and change, but in fact the color, shape and composition of the ingredients will not change, avoiding the phenomenon of concentration. Fifth, in general technical specifications, lyophilized material usually shows a loose and porous morphology, usually in the form of a sponge. Under these conditions, the material has good hydration performance, fast solubility, and more forms of ice crystals, that is, they are easily mixed with inorganic salts and other related substances, thereby avoiding the change of dry inorganic salts with the change of moisture surface and hardened mode.

Part 3 Mechanism Of Action Of Freeze-Drying Protective Agent

3.1 Low Temperature Protection Mechanism During Freezing

The “preferential action” mechanism assumes that the protein solution reacts preferentially with water until a maximum freezing concentration is reached (preferential moisturizing) and generally removes the protectant from the protein domain (preferential repulsion). This is due to the fact that adding protective materials increases the strength of the surface of water molecules and facilitates the interaction between protein molecules and water molecules. In this case, the outer surface of the protein molecule contains relatively more water molecules and relatively few protective molecules, which protect the normal formation of the protein. The “preferential action” mechanism cannot fully explain the phenomenon of protein protection by high concentrations of polymers or the protein itself. Therefore, there should be other safeguards. The surface strength reduction mechanism can be used to explain the protective effect of surfactants in freezing protein solutions. Mechanisms that limit the diffusion of protein molecules believe that many protective substances can increase the viscosity of the solution and prevent the diffusion of active molecules.

3.2 Dry Protection Mechanism

3.2.1 Glass Hypothesis

During drying of the solution containing the protective substance, the mixture of protective material and active ingredient forms a glassy state when the concentration is high enough and the protective material does not crystallize. There are two types of glass conditions: strong glass and weak glass. Weaker glasses increase in viscosity faster than stronger glasses when the temperature drops below the glass transition temperature. As a result, grout forms weak glass that is much better protected than strong glass. Sucrose and trehalose are good protectors because they form weak glasses.

3.2.2 Water Transfer Hypothesis

Since protein molecules contain a large number of hydrogen bonds, bound water binds to protein molecules through hydrogen bonds. When the protein repels moisture during the freeze-drying process, the hydroxyl groups of the protective agent can replace the hydroxyl groups of water on the protein surface, and the formation of a “moisture layer” on the protein surface can protect the hydrogen bonds from direct exposure to the environment. Preserves the integrity of the protein’s native structure and function. When freeze-dried, the protective material can form hydrogen bonds with the dry parts of the biomolecules, rather than preventing the destruction of the bioparticles by freeze-drying.

3.2.3 Storage Protection Mechanism

The time frame that causes protein to break down during drying is hours, while storage time ranges from months or years. In a proper freeze-drying process, the product temperature should be close to the glass transition temperature, and under correct storage conditions, the ambient temperature should be much lower than the glass transition temperature to maintain a long relaxation time.

Part 4 The Principle And Characteristics Of Drug Drying

Freeze-dried drug products are intended for pre-cooling and solid-liquid freezing in solid form. Then, under vacuum, the frozen water from the solid exists in the form of water vapor, and the active ingredient of the drug remains on the ice shelf when frozen, so the volume of the drug does not change after drying, loose and porous. Ice absorbs heat during sublimation, which causes the frozen drug itself to cool down, causing slower sublimation. To increase freezing speed and shorten drying time, medicines must be heated properly. All drying operations are carried out at low temperature. Drug freeze-drying process has the following advantages:

(1) Liquid medicine is easy to process and simplifies the sterilization process. Freeze-drying is performed at low temperatures and is therefore suitable for many heat-sensitive materials. For example, important pharmaceuticals such as active proteins and microorganisms do not change their properties or lose their biological activity during the freeze-drying process. Therefore, freeze-drying technology is widely used in the medical field.

(2) During the low-temperature drying process, there is almost no loss of volatile components in the product.

(3) During the freeze-drying process, the growth of microorganisms and the action of active enzymes cannot continue, thereby retaining their original characteristics and improving the stability of the dry powder.

(4) Since the drying is carried out in a frozen state, the volume of the drug remains practically unchanged, and the original structure is maintained without being concentrated.

(5) The dried material is loose, porous and spongy. After adding water, it dissolves quickly and completely and immediately restores its original properties. The water solubility of the drying lotion is very good.

(6) Vacuum freeze-drying, with little oxygen, therefore, can protect some easily oxidized substances in the drug.

(7) Freeze drying can remove 95% to 100% of the water in the drug, so that the dried drug powder can be stored for a long time without reducing the quality.

Part 5 Low-Temperature Freeze-Drying Production Process Of Powder Injection Medicine

The production process of low-temperature freeze-drying of powder injection drugs generally includes: pretreatment of powder injection drugs → freeze-drying (freezing, freeze-drying, absorbent drying) → packaging → storage.

5.1 Pretreatment Of Medicines For Powder Injection

In order to maintain the effectiveness and good effect of the product, before the powder is freeze-dried from the original, some additives must be added to the powder injection medicine to maintain the effectiveness of the product.

5.2 Initial Freeze

The purpose of pre-freezing the product to be dried is to prepare it for further freeze-drying. Pre-freezing is not only related to the quality of freeze-dried products, but also affects the drying speed of freeze-dried products. In the pre-freezing stage, attention must be paid to controlling the cell structure and active ingredients, freezing method and freezing speed that directly affect powder injection drugs.

5.3 Freeze Drying

During the freeze-drying process of powder injection drugs, it is necessary to maintain continuous vacuum and freezing conditions so that the moisture in the product can be heated quickly. If the temperature increase is too large, the shelf temperature will decrease and the product temperature increase will decrease. Therefore, the shelf temperature should not be too high or too low, but should be controlled within a reasonable temperature range. This depends on three factors: product temperature, refrigeration pressure (e.g. vacuum), and condenser temperature.

5.4 Adsorption Drying

Adsorption drying is the second stage of product drying. At this point, there are no frozen ice crystals in the medicine, but the humidity is about 10%, so more drying is needed. In the analytical drying stage, the temperature of the product will rise rapidly to the highest allowable level and keep it until the end of freeze drying, usually around 25-40°C. If the temperature of the material exceeds a certain threshold, the heat-sensitive components in the powder injection drug will undergo thermal decomposition, effectively separating and reducing the quality. Therefore, the equilibrium moisture content is the ultimate indicator of the end of freezing. The active ingredient in some powdered drug products (such as heat-sensitive materials) can reduce the active ingredient content if the drying time is too long.

5.5 Packaging And Storage

The final step is packaging and storage. If not in contact with oxygen and water vapor in the air, powder injection medicines can be stored for a long time. Packages should be evacuated or purged with nitrogen, argon or carbon dioxide. For some packaged products, rubber stoppers can be pressed in and packaged for storage in a dry room. The storage temperature of freeze-dried medicines is usually 2-8°C.

Part 6 High-Quality Technology in the drying process of cryogenic frozen powder injections

6.1 Good Quality System

The production of any drug must be based on a good quality system, including people, machines, materials, laws, environment, testing, etc. The company must combine all factors to create a system, formulate supporting management procedures and operating standards, and effectively control various quality assurance measures, which can ultimately ensure the consistency of the quality of the products produced.

6.2 Design Of Powder Injection Medicine Production Workshop

According to our research and understanding of the new version of GMP “quality depends on design”, we must control manufacturing risks from the source, and we cannot think “hardware is insufficient, software makes up” at the initial design stage. Before designing, the company must first have a clear design concept, accurately identify the product according to the production diversity characteristics of the product, and consider and evaluate the risk points in each link of the product manufacturing process, including material specifications and characteristics and the parameters of the equipment used. Each aseptic process includes the number of people, time, activities, etc., and develops an appropriate project plan.

Part 7 Conclusion

When the technology was never used in the past, the drugs produced would have deteriorated or failed to maintain their viability. Today, the above-mentioned problems can be largely avoided using this technology. This is common in the pharmaceutical industry. However, in drug production, due to the very complicated process and certain characteristics of the technology itself, the drug will generate a lot of stress during the process, and then deteriorate. In addition, the measure itself has many problems such as not very high speed, time-consuming, requires a lot of energy and requires more equipment. Therefore, in the current situation, the pharmaceutical department should analyze the specific situation on the premise of ensuring quality, study how to save resources, reduce consumption, etc., and further improve dry cooling technology.