Structural Diversity of Solid Dispersions of Acetylsalicylic Acid As Seen by Solid-State NMR

Solid dispersions of active pharmaceutical ingredients are of increasing interest due to their versatile use. In the present study polyvinylpyrrolidone (PVP), poly­[<i>N</i>-(2-hydroxypropyl)-metacrylamide] (pHPMA), poly­(2-ethyl-2-oxazoline) (PEOx), and polyethylene glycol (PEG), each in three <i>M</i>_w, were used to demonstrate structural diversity of solid dispersions. Acetylsalicylic acid (ASA) was used as a model drug. Four distinct types of the solid dispersions of ASA were created using a freeze-drying method: (i) crystalline solid dispersions containing nanocrystalline ASA in a crystalline PEG matrix; (ii) amorphous glass suspensions with large ASA crystallites embedded in amorphous pHPMA; (iii) solid solutions with molecularly dispersed ASA in rigid amorphous PVP; and (iv) nanoheterogeneous solid solutions/suspensions containing nanosized ASA clusters dispersed in a semiflexible matrix of PEOx. The obtained structural data confirmed that the type of solid dispersion can be primarily controlled by the chemical constitutions of the applied polymers, while the molecular weight of the polymers had no detectable impact. The molecular structure of the prepared dispersions was characterized using solid-state NMR, wide-angle X-ray scattering (WAXS), and differential scanning calorimetry (DSC). By applying various ¹H–¹³C and ¹H–¹H correlation experiments combined with <i>T</i>₁(¹H) and <i>T</i>_1ρ(¹H) relaxation data, the extent of the molecular mixing was determined over a wide range of distances, from intimate intermolecular contacts (0.1–0.5 nm) up to the phase-separated nanodomains reaching ca. 500 nm. Hydrogen-bond interactions between ASA and polymers were probed by the analysis of ¹³C and ¹⁵N CP/MAS NMR spectra combined with the measurements of ¹H–¹⁵N dipolar profiles. Overall potentialities and limitations of individual experimental techniques were thoroughly evaluated