Regulatory Guidelines for API-Excipient Compatibility Studies

Pharmaceutical excipients have important functions such as serving as carriers, improving drug stability, solubilization and slowing down the drug release. They are important ingredients that may affect the quality, safety, and effectiveness of the preparation. Classified by function and purpose, pharmaceutical excipients can be used in different drug forms, including:

Injection, where pharmaceutical excipients are antioxidants, cosolvents, and isotonic regulators, etc.

Oral solid preparations, where pharmaceutical excipients are lubricants, fillers, and adhesives and diluents, etc.

Oral liquid preparations, where pharmaceutical excipients are dispersants, stabilizers and suspending agents, etc.

Besides, pharmaceutical excipients can also serve as anti-adhesives, correctives, and propellants for external use.

However, the various properties of excipients and various external factors may affect the compatibility between APIs and excipients, therefore researchers often start to investigate API-excipient compatibility in the early stage of formulation development. The laws and regulatory agencies have made rigid regulations on the compatibility of APIs and excipients of various dosage forms. Scientists are required to follow these scientific principles and carry out rational experimental designs. Let’s see what regulatory rules are there to guide the API-excipient compatibility studies.

Pharmaceutical Development Q8 (R2) – ICH

Chapter "2.1.1" points out that a compatibility test of APIs and excipients is required at the beginning of formulation development, and the compatibility of the drugs and excipients listed in 3.2.P.1 should be evaluated. For multiple APIs, the compatibility between the APIs should also be assessed.

"Chemistry Review of Question-based Review (QbR) Submissions" issued by the FDA

ATTACHMENT 2: QbR QUESTIONS-DRUG PRODUCT (CHEMISTRY) section, Article 9: 9 points out: What evidence supports excipient-drug substance compatibility and if applicable, excipient-excipient compatibility?

Reasons for incompatibility of API-excipient

The instability of the drug caused by the interaction between API and excipients can be attributed to the following three conditions: 1. caused by the APIs themselves, including their physical and chemical properties, moisture, impurities, specific surface area, crystal form, etc.; 2. caused by the formulation design, including The proportion of API and excipients, mixing method, granulation method, packaging, etc.; 3. caused by the external environment, including temperature, humidity, light, etc. Next, we’ll look into these factors in detail.

Under normal circumstances, while we are studying the compatibility between API and excipients, we mainly consider whether the raw materials and excipients chemically react, however, other factors such as impurities, physical structure and functional properties of the excipients can also cause incompatibility between them. The content of the APIs and impurities can be detected respectively by HPLC.

In fact, when complexes are formed between API and excipients or when APIs are absorbed on the excipients, incompatibility can also occur. For instance, tetracycline can form a poorly soluble complex with calcium carbonate, and phenobarbital can form a poorly soluble complex with PEG-400, all of which lead to a decrease in the solubility and oral bioavailability of the main drug. To cite another example here, the cations of cetylpyridinium chloride can be adsorbed by the stearic acid anions on the surface of magnesium stearate particles, resulting in a decrease in the antibacterial activity of cetylpyridinium chloride. In addition, a variety of external factors may also affect the compatibility of API and excipients, namely, moisture, light, temperature, mechanical stress, and pH value, etc.

To sum up, the significance of the API-excipient compatibility study is to select excipients that can give the active pharmaceutical ingredients better bioavailability and manufacturability without affecting the stability of the APIs. The API-excipient compatibility analysis provided by CD Formulation can provide effective data for the selection and determination of formulation excipients and formulation technology for drug developers. Meanwhile, regulators also need these data in evaluating whether excipients will affect product quality.