Testing for Reactive Impurities in Excipients

The quantity and type of reactive impurities in excipients can change due to batch and supplier differences, and even trace amounts of reactive impurities can lead to degradation of the drug product, reducing the stability and quality of the product and affecting the final efficacy. Reactive impurities are present in excipients, both for small and large molecule drugs. To ensure the production of reliable clinical and commercial products, the identification and analysis of these impurities is a critical part of the drug formulation development process. At BOC Sciences, combined with our expert knowledge of the potential interactions of common reactive impurities with drug candidates, we offer reactive impurity identification and analysis services that can help pharmaceutical manufacturers screen for optimal excipients in the early formulation development process to ensure robust development of drug products.

Common Reactive Impurities Present in Excipients

• Reducing Sugars

Trace amounts of reducing sugars are present in non-reducing excipients. Reducing sugar impurities react with amines in Maillard Reaction, which will eventually discolor the drug.

Figure 1. Reaction mechanism for the Maillard reaction. (Wu, Y.; et al. 2011）

• Aldehydes
• Hydrogen Peroxide

Many excipients contain trace amounts of hydroperoxide (HPO) impurities, especially polymeric excipients. Hydrogen peroxide is usually produced through free radical reactions.

• Nitrites and Nitrates

Nitrates and nitrites are common nitrosizing impurities in excipients that can interact with APIs, thus affecting the drug efficacy. Moreover, trace amounts of nitrite may also be carcinogenic.

• Organic Acids

Acetic acid, monochloroacetic acid and formic acid and its esters are organic acid impurities that may be present in excipients. Organic acids are further degraded by residual organic solvents during the synthesis of excipients. These trace organic acid impurities may react with the amino and/or hydroxyl groups of the APIs to form a large number of degradates.

Figure 2. Formid acid formation from oxidation and breakdown of expients. (Wu, Y.; et al. 2011）

• Trace Heavy Metals

Heavy metals are commonly found in excipients at very low levels, but can catalyze oxidation reactions of drugs.

Hazards of Reactive Impurities

• Lead to unstable quality of final products
• Loss of pharmaceutical efficacy and decrease of product performance
• Produce toxic degradants

Figure 3. A sample of reactive impurities in excipient. (Wu, Y.; et al. 2011）

Our Methodology

Our experts has established a series of standard methodologies using gas chromatography and liquid chromatography techniques to identify different classes of reactive Impurities in the excipients. Combined with rich experience in the reactive impurities analysis, BOC Sciences is confident to identify, confirm and quantify different types of reactive impurities in common excipients.

Gas Chromatography (GC) - MS Technology

Formaldehyde in pharmaceutical excipients may negatively affect the safety, efficacy, chemical stability and performance of dosage forms, even in trace amounts. It can form adducts with many pharmaceuticals containing nucleophilic functional groups, especially amines and hydroxyl groups. BOC Sciences uses static headspace gas chromatography and flame ionization detection (FID) to determine active impurities such as formaldehyde in excipients. The chemical reaction products of formaldehyde with ethanol are identified using standards and the identity of formaldehyde derivatives are to further confirmed by performing EI mass spectra of the corresponding peaks in the full scan acquired using MS library. Our well-developed method is specific, accurate, and precise in the specified range.

Ultra-high Performance Liquid Chromatography(UHPLC)-MS System

In order to confirm the active impurities in excipients, we add low amounts of reactive impurities in an accurate and precise manner. Finally, these low-molecule weight organic active impurities is determined by employing liquid chromatography method.

High Performance Liquid Chromatography (HPLC) - Charged Aerosol Detector (CAD) System

BOC Sciences has introduced HLPC and CAD methods which allow our experts to efficiently separate and characterize reactive impurities in excipients. We use HPLC columns with different sizes to flexibly and reliably separate complex samples. In addition, CAD detection with higher sensitivity and accuracy is employed for the characterization of reactive impurities. Our HLPC-CAD method can be used to systematically identify structurally diverse reactive compounds, resulting in more efficient and sensitive measurement of intact potentially reactive impurities.

Our Advantages

• Reduce the time of preparing samples and performing analysis
• Characterization of compounds with and without chromophores
• Rapid and accurate identification and analysis of reactive impurities