Enhancing Pharma Processes

Webinar summary

This webinar, part of a series on enhancing pharmaceutical processes, focused on the use of energy dispersive X-ray fluorescence (EDXRF) in the context of pharmaceutical formulation development. The presentation introduced the fundamentals of EDXRF and illustrated how it can complement other analytical methods.

EDXRF is a nondestructive technique that determines the elemental composition of materials by measuring the fluorescent X-rays emitted from a sample when it is exposed to an X-ray source. Each element emits characteristic X-rays, allowing precise identification and quantification. The method is valued for its minimal sample preparation, rapid measurement times, and versatility in handling a variety of sample types, including powders, liquids, tablets, and filters. The instrumentation is compact, benchtop-sized, and requires little maintenance or consumables, making it an economical addition to a laboratory.

In the pharmaceutical setting, EDXRF is particularly useful for monitoring catalyst residues such as palladium, screening for heavy metals like cadmium, and assessing content uniformity in tablets. These applications are vital for process optimization, product safety, and meeting regulatory requirements. For example, the method demonstrated reliable detection of palladium down to levels below two parts per million, and cadmium at sub-ppm concentrations—sensitive enough to meet FDA guidelines. In uniformity testing, EDXRF was shown to provide accurate measurements across multiple tablets without destroying the samples.

The webinar also discussed the differences between direct and indirect excitation systems. Direct excitation units are more compact and cost-effective but may produce more background signal, whereas indirect systems, which use secondary targets, offer superior sensitivity and cleaner spectra, especially for light elements. Calibration approaches range from fully empirical (using known concentration standards) to theoretical modeling using fundamental parameters, with hybrid approaches available that combine both.

In summary, EDXRF offers a fast, reliable, and nondestructive method for elemental analysis in pharmaceutical formulation work. It provides high-quality data suitable for routine screening, process control, and regulatory compliance. The technique’s simplicity, speed, and low operational cost make it a practical and valuable addition to the pharmaceutical analytical toolkit.

Here are some key questions answered in the webinar:

What is Energy Dispersive X-ray Fluorescence (EDXRF) and how does it work?

EDXRF is a non-destructive analytical technique used to determine the elemental composition of a sample. When an X-ray beam hits an atom in the sample, it can eject an inner-shell electron. An electron from a higher energy shell then drops down to fill the resulting hole. This transition releases a fluorescent X-ray with a specific energy characteristic of that element. An EDXRF detector measures the energies and intensities of these fluorescent X-rays. The energy identifies the element, and the intensity is related to its concentration in the sample. The process does not damage or change the sample, allowing for multiple analyses on the same material.

How does EDXRF fit into the pharmaceutical formulation development process?

EDXRF is a valuable tool in formulation development for various applications. It can be used for optimizing reaction processes, particularly for monitoring catalyst residues (such as palladium), which is a significant use case. It also assists in increasing yield by monitoring elemental content. Furthermore, EDXRF can be used for screening heavy metals to ensure product safety and meet regulatory requirements. Its ability to provide relatively quick, non-destructive measurements with minimal sample preparation makes it practical for daily process chemistry work.

What are the different types of EDXRF excitation and their respective advantages and considerations?

There are two main types of EDXRF excitation: direct and indirect. Direct excitation involves the source X-rays beaming directly onto the sample, potentially including some background X-rays. Its strengths include a lower price point and a smaller, more compact bench footprint. However, it may have more background noise, slightly lower sensitivity, and higher detection limits for lighter elements (sodium through chlorine). Indirect excitation, on the other hand, beams source X-rays onto a secondary target, which then fluoresces to excite the sample. This results in essentially no background in the spectrum, providing higher sensitivity and lower detection limits, especially for light elements. Considerations for indirect excitation include a slightly higher price point and a larger bench footprint compared to direct excitation.

What are matrix effects in XRF and how are they handled?

Matrix effects refer to the influence of the sample's composition (the "matrix") on the interaction and detection of X-rays. As X-rays travel through the material, they can be absorbed or enhanced by other atoms. For example, an X-ray from one element might be absorbed by another before it reaches the detector, or it might excite another element, enhancing its signal. The escape depth, which is the distance an X-ray can travel through the material and still be detected, also varies by atomic number. To account for these effects, XRF methodologies use mathematical corrections, often called alpha corrections, influence coefficients, or absorption-enhancement corrections. It's also important for the sample to be homogeneous to minimize variations in measurements due to matrix effects.

How can EDXRF be calibrated for quantitative analysis?

XRF can be calibrated in a couple of ways. One method is empirical calibration using a series of calibration standards with known concentrations of the elements of interest. These standards should ideally be matrix-matched to the actual sample material. By measuring these standards, the analyzer learns the relationship between X-ray intensity and concentration. Another method utilizes fundamental parameters (FP), a theoretical approach that compares the measured X-ray signal to theoretical calculations without requiring reference materials. While FP alone can provide good estimations for screening, its accuracy can be improved by using a matching library, which involves an empirical adjustment based on one or a few known standards to tune the theoretical model to the specific material and referee values (like ICP results). FP is particularly useful for analyzing multiple formulations.

What are some examples of real-world applications of EDXRF in pharmaceutical analysis?

EDXRF has several practical applications in pharmaceuticals. One key example is monitoring catalyst residues, such as palladium, which can be detected down to very low parts per million levels. It is also effective for heavy metal screening, ensuring product safety by detecting elements like cadmium below regulatory limits. Content uniformity testing across multiple tablets is another application, providing valuable, real-time feedback on the consistency of the active ingredient and excipients. EDXRF's versatility allows for the analysis of various sample types, including powders, tablets, and liquids.

What are the key benefits of using EDXRF in a process chemistry lab?

Key benefits of EDXRF include its non-destructive nature, which allows for multiple analyses on the same sample without altering it. It requires minimal sample preparation compared to some other analytical techniques. Measurements are relatively quick, providing faster feedback for decision-making. EDXRF methodologies can be made traceable to other techniques like ICP if needed. This combination of features makes EDXRF a valuable tool for optimizing yield, reliably monitoring catalyst residues, ensuring product safety by screening for heavy metals, and meeting regulatory requirements, including support for 21 CFR Part 11 compliance with appropriate software configurations. It is also often a compact and cost-effective option with low running costs.