The comparison of melt technologies based on mesoporous carriers for improved carvedilol dissolution

High-shear (HS) melt granulation and hot melt extrusion (HME) were compared as perspective melt-based technologies for preparation of amorphous solid dispersions (ASDs). ASDs were prepared using mesoporous carriers (Syloid® 244FP or Neusilin® US2), which were loaded with carvedilol dispersed in polymeric matrix (polyethylene glycol 6000 or Soluplus®). Formulations with high carvedilol content were obtained either by HME (11 extrudates with polymer:carrier ratio 1:1) or HS granulation (6 granulates with polymer:carrier ratio 3:1).

Highlights

• HME ASD’s smoother surface contributed to better flowability compared to granules.
• Rough and porous surface of HS granules was beneficial for dissolution properties.
• PEG 6000 was a better alternative to Soluplus® for HS melt granulation purpose.

DSC and XRD analysis confirmed the absence of crystalline carvedilol for the majority of prepared ADSs, thus confirming the stabilizing effect of selected polymers and carriers over amorphous carvedilol. HME produced larger particles compared to HS melt granulation, which was in line with better flow time and Carr index of extrudates. Moreover, SEM images revealed smoother surface of ASDs obtained by HME, contributing to less obstructed flow. The rougher and more porous surface of HS granules was correlated to larger granule specific surface area, manifesting in faster carvedilol release from Syloid® 244FP-based granules, as compared to their HME counterparts. Regarding dissolution, the two HS-formulations performed superior to pure crystalline carvedilol, thereby confirming the suitability of HS melt granulation for developing dosage forms with improved carvedilol dissolution.

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Materials

Carvedilol (CTX Life Sciences Ltd., Gujarat, India) was used as a BCS II model drug.

PEG 6000 (Krka, Novo Mesto, Slovenia) and Soluplus® (BASF, Ludwigshafen, Germany) were used as polymeric binders within the melt technology processes.

Neusilin® US2 (Fuji Chemical Industries Co. Ltd., Japan), the amorphous magnesium aluminometasilicate, and silica Syloid® 244FP (Grace GmbH & Co. KG, Worms, Germany) were used as mesoporous carriers, due to their high liquid adsorbing capacity. These two carriers have the following physical characteristics, where first value is associated with Neusilin® US2 and second value with Syloid® 244FP: specific surface area (m²/g) 300–342 vs 359, median particle size / d₅₀ (µm) 106–108 vs 2.4–3.7, mesopores radius (nm) 8.0–12.7 vs 10.7, oil/water adsorbing capacity (mL/g) 2.4–3.4 vs 1.6–3.0 (Fuji Chemical Industries 2015; Grace 2015; Kostelanská et al. 2022). In shots, both carriers have similar specific surface area, mesopores radius and liquid adsorbing capacity, while they differ a lot in median particle size.

For preparation of dissolution media, KH₂PO₄ (Merck KGaA, Germany), NaOH (Merck KGaA, Germany), HCl (37%, Panreac Quimica S.A.U. Barcelona, Spain) and purified water (reverse osmosis, Faculty of Pharmacy, Ljubljana, Slovenia) were used.

Mila Kovačević, Amrit Paudel, Odon Planinšek, Serena Bertoni, Nadia Passerini, Ožbej Zupančič, Carolina Alva, Ilija German Ilić, Alenka Zvonar Pobirk, The comparison of melt technologies based on mesoporous carriers for improved carvedilol dissolution, European Journal of Pharmaceutical Sciences, 2024, 106880, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2024.106880.

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