Category: Formulation and Quality
Purpose: The aim of the current study was to improve the telmisartan solubility via Hot Melt Extrusion processing and investigate the feasibility to produce pH-modified, solid dispersion formulations with an immediate-release property.
Methods: A low soluble, anti-hypertensive drug, Telmisartan (TEL), was selected as the model active pharmaceutical ingredient (API). The thermal stability of TEL, Meglumine (MEG) and sodium carbonate (SC) were studied by differential scanning calorimetry (DSC, DSC 2500, TA Instrument). The designed formulations were chosen by using a 23 full factorial design of experiments (DoE). The API at different drug loads of 10% and 20% was mixed with AquasolveTM HPMC AS L grade (HPMC AS L) (60%-90%), SC (0-10%), and MEG (0-10%) using a V-shell blender (MaxiBlendTM, GlobePharma, North Brunswick, NJ, USA) at 25 rpm for 15 min. The physical mixtures, which contain different ratios of TEL, HPMC AS L, MEG, and SC were extruded at 180C and 50 rpm using a co-rotating twin-screw extruder (11 mm Process 11™, ThermoFischer Scientific, Karlsruhe, Germany). The obtained extrudates were milled and sieved then kept in a desiccator until further analysis. The milled formulations were studied for drug content and dissolution characteristics using USP type II apparatus (SR8-plus, Hanson) in a pH 6.8 phosphate buffer and a discriminative pH 6.8 phosphate buffer using 0.05% sodium lauryl sulfate (SLS). The X-ray diffraction studies and Fourier Transform Infrared Spectroscopy (FT-IR, Cary 660, Agilent, Santa Clara, CA) were performed to determine crystallinity and molecular interactions of TEL in the presence of SC, MEG, and HPMC AS L in formulations.
Results: The DSC results revealed that TEL, MEG and other excipients showed thermal stability over the extrusion temperature (180C) indicating suitability of the extrusion process parameters. The degradation peak of MEG was observed in the physical mixtures and all extrudates at above 240C, which is well above the extrusion temperature (Figure 1). Increasing concentrations of MEG in the formulations showed improved processing conditions due to its plasticizing property. The crystalline nature of TEL in the milled extrudates was decreased compared to pure TEL which
was confirmed by DSC and XRD studies. The dissolution studies revealed that pure TEL has extremely poor dissolution in pH 6.8 phosphate buffer and other extruded formulations relatively improved its dissolution rate. Formulations that have SC improved the dissolution rate of TEL compared to MEG’s formulations even though both MEG and SC have a high affinity to increase the TEL aqueous solubility. HPMC AS L plays a major role in improving the drug release, so decreasing its concentrations in high drug loaded formulations lead to decreasing TEL dissolution rate (Figure 2).
Conclusion: The solid dispersion formulations of TEL were developed via hot melt extrusion processing using HPMC AS L as a polymer and SC, MEG as pH-modifiers. The developed particles improved the solubility of TEL in pH 6.8 phosphate buffer. However, the stability of the developed product is to be investigated in future studies.
Mashan Almutairi– Grad Student, University of Mississippi, Oxford, Mississippi
Eman Ashour– Oxford, Mississippi
Mohammed Alyahya– Oxford, Mississippi
Abdulmajeed Althobaiti– University of Mississippi, Oxford, Mississippi
Muteb Alharbi– Oxford, Mississippi
Suresh Bandari– Post-doc, University of Mississippi, Oxford, Mississippi
Michael Repka– Professor, University of Mississippi, Oxford, Mississippi