Bulk to Nanometer-Scale Infrared Spectroscopy of Pharmaceutical Dry Powder Aerosols

Solid state chemical analysis of pharmaceutical inhalation aerosols at the individual particle level has been an analytical challenge. These particles can range from a few nanometers to micrometers and are a complex mixture of drugs and excipients. Conventional analytical techniques cannot resolve the distribution of excipients and drugs at the submicrometer scale. Understanding the nanochemical composition of individual particles can be critical for pharmaceutical scientists to evaluate drug and excipient stability as well as the drug-drug or drug-excipient interactions that affect the aerosol performance of powders. Herein, we show the novel application of a combination of optical photothermal infrared (O-PTIR) spectroscopy and atomic force microscopy infrared (AFM-IR) spectroscopy to probe nanochemical domains of powders containing the inhaled corticosteroid fluticasone propionate and long-acting β2-agonist salmeterol xinafoate, which are widely used to treat asthma and chronic obstructive pulmonary disease. Three types of powder formulation were analyzed, including the commercial product Seretide, which is a physical mixture of the drugs with crystalline lactose, and two spray-dried powders containing the drugs along with either amorphous or crystalline lactose. We obtained spatially resolved O-PTIR and AFM-IR spectra confirming the presence of peaks related to fluticasone propionate at 1743, 1661, and 1700 cm^-1, salmeterol xinafoate at 1580 cm^-1, and lactose at 1030 and 1160 cm^-1. The location of the drugs and lactose among the particles varied significantly, depending on the formulation type. For the first time, it was possible to map the drug distribution in individual aerosol particles. This is significant as such information has been lacking, and it will open an exciting research direction on how drug distribution affects the aerosol performance of powders and the consistency of dose uniformity. Further, these advanced spectroscopic techniques can be applied to study a wide range of pharmaceutical formulations.