The application of multiple linear regression to the measurement of the median particle size of drugs and pharmaceutical excipients by near-infrared spectroscopy.

A number of powdered drugs and pharmaceutical excipients were used to demonstrate the ability of near-infrared spectroscopy to measure median particle size (d50). Sieved fractions and bulk samples of aspirin, anhydrous caffeine, paracetamol, lactose monohydrate and microcrystalline cellulose were particle sized by forward angle laser light scattering (FALLS) and scanned by fibre-optic probe FT-NIR spectroscopy. Two-wavenumber multiple linear regression (MLR) calibrations were produced using: NIR reflectance; absorbance and Kubelka-Munk function data with each of median particle size, reciprocal median particle size and the logarithm of median particle size. Best calibrations were obtained using reflectance data versus the logarithm of median particle size (NIR predicted lnd50 versus ln(FALLS d50) for microcrystalline cellulose and lactose monohydrate sieve fraction calibrations: r = 0.99 in each case). Working calibrations for lactose monohydrate (median particle size range: 19.2-183 microns) and microcrystalline cellulose (median particle size range: 24-406 microns) were set-up using combinations of machine sieve-fractions and bulk samples. This approach was found to produce more robust calibrations than just the use of sieved fractions. The method has been compared with single wavenumber quadratic least squares regression using reflectance and mean-corrected reflectance data with median particle size. Correlation between NIR predicted and FALLS values was significantly better using the MLR method.