Quantitative XRD - Detection of low amounts of crystalline impurities for pharmaceutical process control

X’Pert PRO MPD and CubiX FAST diffraction systems equipped with the X’Celerator detector, offer excellent low limits of detection for pharmaceutical polymorphic phases – down to a tenth of a percent. They also offer a significantly shorter measurement time, or can generate greatly improved counting statistics in the same time as a traditional point detector.

X-ray powder diffraction (XRPD) can greatly enhance the manufacturing process control of active pharmaceutical ingredients (APIs) by monitoring phase(s) present, quantifying polymorphic phases, and determining sample crystallinity. In this example application, standard samples of Form I of an API were spiked with low levels of the polymorph Form II. XRPD was used to calibrate an analysis, programmed in PANalytical’s X’Pert Industry software, which could then be used for manufacturing process control to ensure that the right polymorph crystallized in the process steps. 

Introduction

X-ray powder diffraction (XRPD) can greatly enhance the manufacturing process control of active pharmaceutical ingredients (APIs) by monitoring phase(s) present, quantifying polymorphic phases, and determining sample crystallinity. In this example application, standard samples of Form I of an API were spiked with low levels of the polymorph Form II. XRPD was used to calibrate an analysis, programmed in Malvern Panalytical’s X’Pert Industry software, which could then be used for manufacturing process control to ensure that the right polymorph crystallized in the process steps.

Summary

X’Pert PRO MPD and CubiX FAST diffraction systems equipped with the X’Celerator detector, offer excellent low limits of detection for pharmaceutical polymorphic phases – down to a tenth of a percent. They also offer a significantly shorter measurement time, or can generate greatly improved counting statistics in the same time as a traditional point detector.

Polymorph analysis

X-ray powder diffraction (XRPD) is an essential analytical tool for distinguishing pharmaceutical polymorphic - chemically identical but structurally different - active pharmaceutical ingredients (APIs). These structural differences can lead to differences in performance and efficacy. Therefore, XRPD analysis for low limit detection (LLD) of crystalline impurities is an important part of pharmaceutical manufacturing. XRPD knowledge of polymorphs can also strengthen a patent position.

Experimental

Quantitative XRPD analysis of powder sample preparations was performed using an X’Pert PRO MPD diffractometer. By using PANalytical sample holders specially designed for back-loading powders, the effect of preferred crystal orientation was kept to a minimum. These sample holders comprise a common bottom plate together with a large or small top ring, with size dependent on available sample volume. Particle size for quantification is ideally less than 50 micrometer for best particle statistics and precision. However, care should be taken when grinding organic samples to prevent phase changes or loss of crystallinity due to heat and/or pressure.

The achievable detection limit (DL) for a given experiment will be a function of the signal to noise ratio. In case of using a calibration curve derived from peak areas (including the background), the following equation applies [1]:

DL = 3σ/S

where

σ =  standard deviation of the response (approximately the RMS),

S = the slope of the calculation line.

The quantification limit (QL) is the level at which an analyte can be quantified with acceptable precision and accuracy, and can be expressed as follows [1]:

QL = 10 σ/S = 3.3 DL

[1] Validation of Analytical Procedures: Methodology, ICH Steering Committee 6 Nov. 1996, www.ICH.org

Typical instrument setup

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Results

Five calibration standards with known concentrations ranging from 0 to 0.575% Form II were utilized in the construction of a calibration curve (see Fig. 1). The calibration curve (Fig. 2) demonstrates the linear relationship between intensity (peak area) and weight fraction of polymorphic phase II. Goodness of fit is reported as RMS (root mean square) and K value. Both indicate the statistical difference between the calculated and given concentrations, with the K value weighting the fit at the extreme ends of the calibration curve. The calculated DL from the calibration line is 0.1%. Assuming that the DL for shorter measurement times declines mainly due to worse counting statistics (~ t-½), DLs for shorter measurement times were estimated and shown in Table 1.

Figure 1: Five standard samples prepared to calibrate an XRD process control analysis program 

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Table 1: Calculated and estimated DLs under various experimental conditions 

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Figure 2: Calibration curve generated in X’Pert Industry from the measurements of the standard samples 

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X’Pert Industry can be configured to operate in a 21 CFR part 11 compliant environment. 

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Features of X’Pert Industry

  • Automated quantitative analysis of crystalline phases and amorphous content
  • Any calculation involving peak height, area, d-spacing, 2θ angle, or FWHM (e.g. crystallite size, lattice parameter)
  • Statistical Process Control (SPC) charting capability
  • Integrated graphics
  • XML file format
  • Ready for 21 CFR part 11

Conclusions

XRPD is a valuable tool in monitoring the API manufacturing process. It offers great sensitivity to even tenths of a percent of polymorphic phases, together with tools such as SPC charting, and the ability to operate in an environment that supports the requirements of FDA regulation 21 CFR part 11.

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