Factors affecting the stability of pharmaceutical preparations can generally be divided into prescription factors and non-prescription factors. Prescription factors include raw materials and excipients; non-prescription factors include temperature, light, humidity, oxygen, packaging, etc. Understanding these factors in the research and development of generic drugs is of great value to the development of formulations, process selection, packaging material selection, and storage conditions. This article briefly analyzes the above factors to provide reference for R&D personnel.
The chemical structure of the API has a “decisive” effect on the stability of the formulation. For example, if the structure of the drug contains ester bonds and amide bonds, then these drugs will be affected by acid, alkali, humidity, and heat, and may undergo a hydrolysis reaction and produce hydrolysis impurities. In the formulation design, factors such as the compatibility of the drug and the excipients, the contact method, the pH value of the microenvironment surrounding the drug, and the water content in the formulation need to be considered. For example, in the compatibility test of raw materials and excipients, it may be found that certain excipients are likely to cause degradation of the drug. At this time, the use of the excipients should be carefully considered; the acidity and alkalinity of the excipients (such as the acid-base changes caused by the residual acid-base residues on the surface of the excipients, Organic acids in excipients (such as formic acid and acetic acid caused by acid-base changes), the pH value of some tablets should be controlled within the pH range that maintains the stability of the main drug; the control of particle moisture in wet granulation is caused by improper selection of packaging materials The increase in the water content of the formulation in the stability and so on. The evaluation of the sensitive factors of the main drug can be evaluated by means of medicinal chemistry knowledge, literature reports, degradation tests, etc., not only can the sensitive factors be quickly determined, but also the degree of sensitivity to the sensitive factors may be discovered. Sometimes the theoretical analysis based on the structure may be compared with the actual The degradation method is inconsistent. Some import standards stipulate multiple theoretical degradation impurities, which will not be produced at all. They are completely a “smoke bomb”. Therefore, it is necessary to pay attention to the combination of theoretical analysis and specific experimental conclusions to determine the drug. The degradation of impurities, “imitation products are not imitation standards.”
The most common effect of excipients on the stability of the main drug is to react directly with the drug. For example, the USP standard for amlodipine tablets specifies several adduct impurities, which are produced by the interaction between the main drug and the excipient. Surfactants can also affect the stability of drugs. For example, Tween 80 can decrease the stability of vitamin D3. Excipients can evaluate the stability of formulations through influencing factor tests (high temperature, high humidity, light, high temperature and high humidity), accelerated tests, and long-term tests.
Heat (temperature) is a common source of impurities in preparations, because it not only causes the production of impurities, but also accelerates the production of impurities. In preparation production, if the drug is sensitive to temperature, care should be taken not to use high temperature or shorten the drying time in certain processes such as drying of particles. In addition, in the production process of solid preparations, all processes that may generate “heat” should be considered or controlled, such as fluidized bed drying, coating, and tableting. If it is found in the related substance inspection of the finished product that the amount of impurities has increased compared to the bulk drug, then the link of impurity generation should be studied. For example, there is no change in impurities in the total mixed particles, and only the increase in impurities occurs after the tablet is compressed. It may be the heat generated by the pressure of the tableting process. At this time, adjusting the tableting speed, adjusting the pressure, and reducing the action time may reduce the generation of impurities. Similarly, if it is found that the coating process will cause an increase in impurities, then measures such as rapid coating and reducing drying time should be considered.
The photoreaction is caused by the absorption of blue-violet light, purple light and ultraviolet light in the sun by the drug. Among them, ultraviolet light has the greatest impact because of its short wavelength and high energy, which can easily stimulate chemical reactions. Before formula development, light sensitivity should be determined according to literature research. Is the solution sensitive to light or solid? How sensitive is it? If you find that it is very sensitive to light, you should consider adopting corresponding measures. For example, the use of brown packaging materials, double aluminum packaging, coating with sunscreen, etc. form a kind of protection for the preparation. For preparations that require very high lighting conditions, it may be necessary to consider using very weak lights in the production workshop. The degradation mechanism of photoreaction is sometimes very complicated. In the research and development of generic drugs, attention should be paid to the use of foreign patents and foreign documents, and a more scientific mechanism will be discovered.
The moisture in the environment and the moisture in the excipients have an important influence on the stability of the formulation. Generally speaking, the greater the water content and the greater the humidity, the more severe the degradation of the drug. Drugs can be degraded by hydrolysis, so reducing moisture, designing moisture-proof packaging, and choosing appropriate processes are the primary considerations. For example, if the drug is sensitive to moisture, you can choose the powder direct compression process, the dry process, or consider the wet process according to the sensitivity. Then the factors that need to be considered at this time are that the time for wet granulation should be minimized, and the drying process should be used. To control the water content of the particles, it may be necessary to control the upper and lower limits. Some main medicines are very sensitive to humidity, and the humidity in the workshop may need to be controlled within a certain range. The selection of auxiliary materials and the control of water content may also need to be considered.
Oxygen is everywhere, and the oxygen in the air is the main factor that causes the degradation of drugs. There are many ways to control oxygen for easily oxidized drugs. For example, antioxidants such as BHT and BHA can be added to the prescription. When these antioxidants are oxidized, they are first oxidized to prevent the main drug from being oxidized. The choice of antioxidants is related to their antioxidant mechanism, and the content of these antioxidants can be selected according to The consumption of accelerated test is designed. If some antioxidants are found in the prescription of the reference preparation, it can be judged that the drug is sensitive to oxygen. There may be a certain amount of oxygen in the solution (such as water) used in the formulation and in the packaging container, which may be enough to cause the degradation of the drug and produce a large amount of degradation impurities. Sometimes an inert gas, nitrogen, can be used to drive off oxygen. Nitrogen can be passed into the water to reach saturation, which can remove most of the oxygen. The peroxide impurities contained in auxiliary materials should also be paid attention to. For example, peroxide in PVP. In order to avoid these problems, it may be necessary to control the impurities of auxiliary materials and formulate internal control standards.
Drugs are affected by light, humidity, and oxygen, so interference can be eliminated by choosing appropriate packaging. When the prescription and process design cannot fully solve the influence of the above influencing factors, the design of the packaging material can be considered. For example, proper design of the space around the tablet can reduce the presence of oxygen and moisture, such as the size of the bottle and the size of the blister hole. For bottled preparations, it is sometimes necessary to consider adding a desiccant, and the type and weight of the desiccant also need to be considered. For drugs that are sensitive to oxygen, the oxygen permeability of the packaging material needs to be considered, and glass bottles are also an option. For injections, compatibility studies should be conducted in accordance with the packaging material compatibility guidelines. The selection of packaging materials can be rationalized by influencing factors, accelerated, and long-term tests. For relevant test design, refer to the relevant guidelines of ICH, Chinese Pharmacopoeia and CFDA.
Factors such as acid, alkali, heat, light, oxygen, and humidity have important effects on drug stability. A reasonable degradation test design can provide a quick and valuable reference for drug stability evaluation. Therefore, attention should be paid to the design of degradation test (as far as possible). Simulation of actual conditions, using weaker conditions), data analysis and prediction of the formal stability test. There are various prescription and non-prescription factors. When encountering unstable drugs, a large number of literature searches should be carried out to summarize the degradation pathways, degradation mechanisms, and sensitive factors of the drugs, and rational design should be adopted in the development of the prescription process and the selection of packaging materials. avoid risk.
The impurity control strategy should be systematically analyzed and deeply understood based on the characteristics of the source (main drug, auxiliary material), process (production process, production environment) and end point (drug, packaging material) of the preparation. Analysts have transformed from traditional passive research to active thinking, which is also of great significance to R&D team collaboration and personnel growth.
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