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

Abstract

Solid dispersions of active pharmaceutical ingredients are of increasing interest due to their versatile use. In the present study polyvinylpyrrolidone (PVP), poly[N-(2-hydroxypropyl)-metacrylamide] (pHPMA), poly(2-ethyl-2-oxazoline) (PEOx), and polyethylene glycol (PEG), each in three Mw, 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 (1)H-(13)C and (1)H-(1)H correlation experiments combined with T1((1)H) and T1ρ((1)H) 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 (13)C and (15)N CP/MAS NMR spectra combined with the measurements of (1)H-(15)N dipolar profiles. Overall potentialities and limitations of individual experimental techniques were thoroughly evaluated.

Biodegradable system for drug delivery of hydrolytically labile azanucleoside drugs

“…% DIC was chosen for further study by solid state NMR spectroscopy. Interpretation of the recorded data is based on previous comprehensive structural ss-NMR analyses of various polymeric solid dispersions of active compounds [19][20] , see Fig. 4 for the chemical structures.…”

Synthesis and Characterization of New 3-(4-Arylpiperazin-1-yl)-2-hydroxypropyl 4-Propoxybenzoates and Their Hydrochloride Salts

“…The calculated changes in 15 N resonance frequencies are in very good qualitative agreement with the experimental data obtained for base form 3e and monohydrochloride form 4e; see Figure 1. However, to verify the protonation of both nitrogen sites and/or to site-specifically locate the position of H + ion, we assessed the strength of 1 H-15 N dipolar couplings for each resolved nitrogen site by using the CPPI experiment [17][18][19] with a variable polarization-inversion (PI) period. As was previously demonstrated, the nitrogen moieties N, NH, NH 2 and NH 3 exhibit characteristic and clearly distinguishable PI profiles.…”

“…The 13 C cross-polarization (CP) magic angle spinning (MAS) NMR spectra were measured at a spinning frequency of 11 kHz, a nutation frequency of B 1 ( 13 C) field of 62.5 kHz and a contact time of 1 ms with a repetition delay of 8-12 s. The number of scans providing acceptable signal-to-noise ratio was 1-2 K. The 15 N-CP/MAS NMR spectra were measured at a MAS frequency of 10 kHz, a nutation frequency of B 1 ( 15 N) field of 42 kHz and a contact time of 2 ms with a repetition delay of 8-12 s. The detection of high-quality 15 N-CP/MAS NMR spectra required the acquisition of 8-20 K scans. As demonstrated previously [17,20], for identification of NH + moiety, the 1 H-15 N dipolar profiles were measured using the cross-polarization/polarization-inversion (CPPI) experiment [18]. The CP period was set to 500 µs, and the PI period was incrementally increased from 0 to 100 µs.…”

Chitosan/Poly(2-ethyl-2-oxazoline) Films with Ciprofloxacin for Application in Vaginal Drug Delivery

“…Poly(2-ethyl-2-oxazoline) is one of the representatives of poly(2-oxazolines) family that is a non-ionic water-soluble polymer available commercially. The application of this material in the design of dosage forms for drug delivery has received a substantial interest in the last few years and it is often viewed as a potential alternative pharmaceutical excipient to well-established water-soluble polymers [25][26][27][28].…”