Introduction

Neusilin® 's high specific surface area, increased surface adsorption, porosity, anticaking, flow enhancing properties and its ability to keep drugs stable under amorphous state has made Neusilin® the best choice inorganic carrier for development of free flowing powder of solid dispersion and directly compressible tablets. One-step continuous dry granulation via Hot Melt Extrusion (HME) provides one path forward to reduce cost of manufacturing, increase efficiency and allow real time assurance of activity via innovative processing strategies. We previously reported manufacture of Sulindac-Neusilin® amorphous drug complex using HME.¹⁾²⁾ .
In this newsletter, we introduce a collaborative study by Dr. Douroumis research group at University of Greenwich and Fuji Chemical Industries to evaluate the performance of Neusilin® (NEU) as an inorganic carrier in HME processing of indomethacin (INM).³⁾HME was explored as a continuous one-step hot granulation process for the development of solid-state dispersions.

Methods

INM/NEU combinations at 20%, 30% and 40% drug loadings were extruded with a twin screw extruder to produce extruded powder by-passing the downstream processing. The extrudates (EXT) were characterized via differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), SEM, FT-IR and in vitro dissolution studies.

Results and Discussion

During extrusion, a complete dry granulation was performed. Neusilin®'s unique composition (Al₂O₃ MgO: SiO₂) and its ability to interact with INM produced extrudates as free flowing, amorphous granules (Fig.1).

DSC Thermograms

The DSC thermograms of pure INM showed a sharp melting endothermic peak at 161°C.
All drug-excipient physical mixtures (PM) exhibited melting peaks of INM at lower temperatures and reduced ΔH values as the ratio of carrier increased. However, the DSC thermograms for all INM/NEU 20-40% extruded formulations showed no endothermic peaks corresponding to the melting of INM (Fig.2) suggesting that the drug is dispersed in the Neusilin® porous network in amorphous or molecularly dispersed state.

XRPD profile

The physical mixtures of all INM formulations showed identical peaks at lower intensities suggesting that the drug retains its crystallinity at loads of 20-40%. In contrast, no distinct intensity peaks were observed in the diffractograms of the extruded formulations even at high drug loadings. The absence of INM intensity peaks indicates the presence of its amorphous state or molecularly dispersed state into the NEU matrix after extrusion.

FTIR Analysis

INM exists as dimer in crystalline state due to benzoyl carbonyl and carboxylic acid containing structure. The FTIR spectra (Fig.4) of the crystalline INM showed characteristic peaks at 1718 and at 1690 cm-1, corresponding to the dimer carbonyl group and to the benzoyl carbonyl group respectively. As shown in Fig.4, the absorbance peaks of the drug dimer disappeared in all extruded formulations, and a new peak appeared slightly shifted at 1685 cm-1.

Dissolution Profile

Extrudates constituted of 20-30% lNM showed a rapid release (100% in 60 min at pH 7.2) complying with USP monograph for INM while the physical mixture of all INM/NEU ratios, showed relatively slower release compared to that of the extruded formulations, however, slightly faster than the pure INM itself (Fig. 5).

Stability Study

All extruded formulations were investigated for their stability under accelerated conditions (40°C, 40%RH) for over 12 months. The samples were analyzed with XRPD in order to identify any drug recrystallization. The results obtained from the stability study under accelerated conditions showed that the use of Neusilin® as drug carrier retained INM in amorphous state after 6 months storage for all drug loadings (20-40%). In addition no changes were observed in the dissolution profiles. The XRPD data showed that all formulations were amorphous and stable in both open and closed conditions as no INM intensity peaks were observed. The improved physical stability of the extruded solid dispersions could be attributed to their strong H-bonding interactions facilitated during the extrusion which maintain the stability for prolong period of time.

Conclusions

Neusilin® can be successfully used as a carrier to manufacture amorphous solid dispersions, in the form of granules, with enhanced dissolution rates of the poorly water-soluble indomethacin.