Quantifying Low Amorphous or Crystalline Amounts of Alpha‐Lactose‐Monohydrate Using X‐Ray Powder Diffraction, Near‐Infrared Spectroscopy, and Differential Scanning Calorimetry

Abstract

Efficient and accurate quantification of low amorphous and crystalline contents within pharmaceutical materials still remains a challenging task in the pharmaceutical industry. Since X‐ray powder diffraction (XRPD) equipment has improved in recent years, our aim was 1) to investigate the possibility of substantially lowering the detection limits of amorphous or crystalline material to about 1% or 0.5% w/w respectively by applying conventional Bragg Brentano optics, combined with a fast and simple evaluation technique; 2) to perform these measurements within a short time to make it suitable for routine analysis; and 3) to subject the same data sets to a partial least squares regression (PLSR) in order to investigate whether it is possible to improve accuracy and precision compared to the standard integration method. Near‐infrared spectroscopy (NIRS) and differential scanning calorimetry (DSC) were chosen as reference method. As model substance, alpha lactose monohydrate was chosen to create calibration curves based on predetermined mixtures of highly crystalline and amorphous substance. In contrast to DSC, XRPD and NIRS revealed an excellent linearity, precision, and accuracy with the percent of crystalline amount and a detectability down to about 0.5% w/w. Chemometric evaluation (partial least squares regression) applied to the XRPD data further improved the quality of our calibration.

Key Words:

• X‐ray powder diffraction
• Near‐infrared spectroscopy
• Differential scanning calorimetry
• Amorphous
• Crystalline
• Lactose
• Quantification
• PLS regression