The Role of Raw and Excipient Compatibility Research in Pre-prescription Research

Excipients are an important part of pharmaceutical preparations. The use of inactive and non-toxic excipients can effectively improve the appearance and compliance of the drug, but the active ingredients in the drug are likely to interact with the excipients, which may cause the drug Low availability or interfere with the stability of pharmaceutical preparations. The main purpose of the study on compatibility of raw materials and excipients is to select excipients that can endow the drug substance with good bioavailability and manufacturability without affecting the stability of the drug substance. In pre-prescription research, studying the compatibility of drugs and excipients can provide useful information and references for the selection of excipients in the prescription.

When formulating the formulation, it is necessary to understand the interaction between excipients and excipients, and between excipients and drugs through preliminary investigations to avoid choosing inappropriate excipients. For lack of relevant research data, consider conducting excipient compatibility studies. For the research and development of generic drugs, the composition of the excipients of the prescriptions recorded in the inserts of the marketed drugs is important reference information; for the excipients that are not used in the prescriptions recorded in the inserts of the marketed drugs, it is recommended to conduct an excipient compatibility test. The excipients that need to be investigated and the drugs are separately mixed and then tested for compatibility in order to discover the interaction between the drugs and the excipients.

What are the possible interactions between drugs and excipients?

(1) Adsorption between drugs and excipients

Drug molecules and excipient molecules often adsorb to each other through van der Waals forces or electrostatic interactions, thereby effectively improving the solubility and lubricity of the drug formulation, and improving the quality of the drug. When the reaction is excessive and the adsorption force is too strong, the desorption force is relatively weak, and it is difficult for the drug to enter the body to diffuse, resulting in a decrease in drug utilization and even affecting drug quality.

(2) Embedding between drugs and excipients

In tablets, the small drug molecules and the large molecules on the surface of the excipients are often combined by adding excipients to obtain a uniform and stable formulation. However, there is usually an embedding effect between the drug and the excipient in the tablet. When the embedding effect is excessive, it will affect the release of the drug and reduce the bioavailability of the drug.

When the adsorption and embedding are excessive, the drug is difficult to release, and the drug cannot be fully dissolved in the solvent, resulting in a certain deviation in content determination and quality analysis, which affects quality control.

(3) Chemical effects of excipients and drugs

The pharmaceutical excipients themselves are not completely inert, and their own functional groups or impurities may physically and chemically react with the active ingredients of the drug, thereby affecting the safety, effectiveness and quality controllability of the drug. Hydrogen bonding, precipitation reaction and hydrolysis reaction all affect the effect of the drug. Especially when the precipitation reaction occurs, it is often misunderstood as drug deterioration [1]. In addition, the mixing method and processing method of active ingredients and excipients will also affect the reaction of drugs and excipients to a certain extent.

Generally speaking, the compatibility study of drugs and excipients does not have a uniform regulation. Under normal circumstances, it is determined based on the physical and chemical properties of drugs and excipients. After considering applicability, etc., a corresponding model is established for experimentation. According to some reports, the compatibility studies of raw materials and excipients of the US ANDA usually choose the same conditions as the accelerated stability studies for 0-day and 30-day stakeout. For domestic projects, the conditions of high temperature, high humidity, and light (opening, closed, adding water, and no water) are mostly selected for stakeout of 0 days, 10 days, and 30 days. Both methods have their own shortcomings and need to be adjusted according to product characteristics.

If a researcher passes a stability test to evaluate the rationality of the prescription of the excipients in the eye drops [2]. Methods The orthogonal method was used to investigate the compatibility of different kinds of antibacterial agents and excipients in the prescription through accelerated test. Results The accelerated test after placing it at 60 for 5 days showed that the bacteriostatic thimerosal combined with sodium chloride reduced its content by 50%; combined with the excipient boric acid reduced its content by 15%. The results showed that the bacteriostatic thimerosal had poor compatibility with the excipients boric acid and sodium chloride, and the bacteriostatic benzalkonium bromide and ethyl paraben had better compatibility with the excipients.

It is also important to note when conducting the compatibility study of raw materials and excipients, even if the same excipients, different sources may lead to different impurities. Therefore, in addition to auxiliary materials, the factors affecting the stability of raw materials also need to fully consider the impact of impurities in auxiliary materials. The compatibility of raw materials and excipients is the part of pre-prescription research. Excipients that have obvious effects on the main can be screened out. This experiment uses more stringent conditions to expose the possible contraindications of raw and auxiliary materials as soon as possible, so as to facilitate further Prescription process screening.

[1] Research progress on compatibility of drugs and excipients [J].

[2] Study on prescription compatibility of excipients in eye drops [J].