Investigating the Correlation between Miscibility and Physical Stability of Amorphous Solid Dispersions Using Fluorescence-Based Techniques

Abstract

The purpose of this study was to investigate the feasibility of using a fluorescence-based technique to evaluate drug-polymer miscibility and to probe the correlation between miscibility and physical stability of amorphous solid dispersions (ASDs). Indomethacin-hydroxypropyl methylcellulose (IDM-HPMC), indomethacin-hydroxypropyl methylcellulose acetate succinate, and indomethacin-polyvinylpyrrolidone (IDM-PVP) were used as model systems. The miscibility of the IDM-polymer systems was evaluated by fluorescence spectroscopy, fluorescence imaging, differential scanning calorimetry (DSC), and infrared (IR) spectroscopy. The physical stability of IDM-polymer ASDs stored at 40 °C was evaluated using fluorescence imaging and X-ray diffraction (XRD). The experimentally determined miscibility limit of IDM with the polymers was 50-60%, 20-30%, and 70-80% drug loading for HPMC, HPMCAS, and PVP, respectively. The X-ray results showed that for IDM-HPMC ASDs, samples with a drug loading of less than 50% were maintained in amorphous form during the study period, while samples with drug loadings higher than 50% crystallized within 15 days. For IDM-HPMCAS ASDs, samples with drug loading less than 30% remained amorphous, while samples with drug loadings higher than 30% crystallized within 10 days. IDM-PVP ASDs were found to be resistant to crystallization for all compositions. Thus, a good correlation was observed between phase separation and reduced physical stability, suggesting that miscibility is indeed an important ASDs characteristic. In addition, fluorescence-based techniques show promise in the evaluation of drug-polymer miscibility.

Advances in coamorphous drug delivery systems

“…A negative or slightly positive value of χ indicates a good miscibility, while a large positive value points to immiscibility 71 . In recent years, several emerging techniques such as fluorescence-based techniques 72 , Raman mapping 73 and solid-state nuclear magnetic resonance (NMR) techniques 74 have been introduced to investigate the miscibility of the various components in the amorphous formulations.…”

Effects of Molecular Interactions on Miscibility and Mobility of Ibuprofen in Amorphous Solid Dispersions With Various Polymers

“…2 Amorphous dispersions are metastable, high-energy glasses that may exhibit physical instability (e.g., drug crystallization or phase separation into drug-rich and polymer-rich phases), 3 ultimately resulting in poor and unreliable bioavailability on administration. 4 The likelihood for occurrence of phase changes is closely related to the miscibility of the drug and polymer. [4][5][6] It is therefore imperative to understand those molecular mechanisms responsible for drug-polymer miscibility based on the structural features of the drug and polymer to select excipients that provide the best miscibility characteristics with the drug of interest.…”

“…4 The likelihood for occurrence of phase changes is closely related to the miscibility of the drug and polymer. [4][5][6] It is therefore imperative to understand those molecular mechanisms responsible for drug-polymer miscibility based on the structural features of the drug and polymer to select excipients that provide the best miscibility characteristics with the drug of interest. Furthermore, formation of ASDs could also inhibit drug crystallization by reducing drug mobility in the matrix, [7][8][9] although this may not always be the case.…”

Superiority of amino-modified chiral mesoporous silica nanoparticles in delivering indometacin

“…Poorly water-soluble indometacin (IMC), the acidic nonsteroidal anti-inflammatory drug that can cause irritation of the gastrointestinal mucosa [36], was chosen as guest molecules to construct drug delivery systems. Many formulation techniques, including cyclodextrins [38], microcapsules [39], microemuslsions [25] and solid dispersions [40][41][42][43], have been widely used to establish IMC drug delivery systems. In the current stage, IMC delivery systems constructed by nanotechnology, such as PLGA nanoparticles [44] and nano-solid dispersions [45], have been reported.…”