Direct Evaluation of Molecular States of Piroxicam/Poloxamer Nanosuspension by Suspended-State NMR and Raman Spectroscopies

Abstract

A nanosuspension of piroxicam (PXC) and poloxamer 407 (poloxamer) prepared by the wet milling method was directly evaluated at the molecular level from the viewpoint of both solution and solid phases. (13)C solution-state NMR measurements revealed a reduction in the concentration of dissolved poloxamer in the nanosuspension. Furthermore, the fraction of dissolved poly(ethylene oxide) (PEO) chain, which is the hydrophilic part of poloxamer, was higher than that of dissolved poly(propylene oxide) (PPO) chain, the hydrophobic part. (13)C suspended-state NMR and Raman spectroscopies detected both solid-state PXC and poloxamer involved in the nanoparticles. Interestingly, the coexistence of crystalline and amorphous PXC in the nanoparticle was demonstrated. The yellow color of the nanosuspension strongly supported the existence of amorphous PXC. Changes in the peak intensity depending on the contact time in the suspended-state NMR spectrum revealed that the PEO chain of poloxamer in the nanoparticle had higher mobility compared with the PPO chain. The PEO chain should project into the water phase and form the outer layer of the nanoparticles, whereas the PPO chain should face the inner side of the nanoparticles. Amorphous PXC could be stabilized by intermolecular interaction with the PPO chain near the surface of the nanoparticles, whereas crystalline PXC could form the inner core.

Characterizing and Exploring the Differences in Dissolution and Stability Between Crystalline Solid Dispersion and Amorphous Solid Dispersion

“…In the topdown method, the drug first forms a suspended state. It has been inferred that this nanosuspension consists of crystalline API core particles surrounded by a semi-solid phase of a drug and a stabilizer (25,26). The semi-solid phase on the surface of the nanoparticles is in equilibrium with the solution and promotes stabilization of the nanoparticles by steric hindrance and electrostatic repulsion (25,26).…”

“…It has been inferred that this nanosuspension consists of crystalline API core particles surrounded by a semi-solid phase of a drug and a stabilizer (25,26). The semi-solid phase on the surface of the nanoparticles is in equilibrium with the solution and promotes stabilization of the nanoparticles by steric hindrance and electrostatic repulsion (25,26). In addition to the top-down approaches described above, there is also a bottom-up approach, whereby prepared ASDs are placed under controlled temperature and humidity to form a CSD (27,28).…”

Combination of NMR Methods To Reveal the Interfacial Structure of a Pharmaceutical Nanocrystal and Nanococrystal in the Suspended State

“…Conventional solution-state NMR and solid-state NMR techniques have been widely used in various fields. , In addition, suspended-state NMR or in situ NMR, a technique in which solid-state NMR is applied to samples containing a mixture of solid and dissolved components, is also often used to investigate a whole suspension sample without preprocessing and has clarified some of the unique features of nanosuspensions. − In a study of nanoparticles in pharmaceutical applications, Zhang et al observed solid–liquid exchange between probucol and the polyvinylpyrrolidone/sodium dodecyl sulfate complex at the surface of the nanoparticle by 13 C solution-state NMR measurement . Hasegawa et al investigated piroxicam/poloxamer nanoparticles using suspended-state NMR and reported that piroxicam nanocrystals formed a core–shell structure with crystalline and amorphous piroxicam surrounded by poloxamer chains . Although these studies successfully determined the interfacial structure of the nanoparticles, directly observing the surface structure of the nanoparticles was difficult.…”

“…23 Hasegawa et al investigated piroxicam/poloxamer nanoparticles using suspended-state NMR and reported that piroxicam nanocrystals formed a core−shell structure with crystalline and amorphous piroxicam surrounded by poloxamer chains. 24 Although these studies successfully determined the interfacial structure of the nanoparticles, directly observing the surface structure of the nanoparticles was difficult. The surface structures of the amorphous drug and polymeric stabilizing agents were thought to be in the intermediate mobility region between solid and solution; hence, neither solid-nor solution-state NMR was able to detect the signals from the surface structure.…”

An Overview on Stability of Extemporaneously Prepared Pharmaceutical Suspension

“…All the suspensions separate on standing. For the formulator, it is one of the main concerns is to permit easy resuspendibilty of settled particulate matter but also to decrease the sedimentation rate [3].…”