Purpose: The aim of the current investigation was to develop milled extrudates of Theophylline particles via Hot Melt Extrusion processing to investigate the feasibility to produce dry powder inhaler (DPI) formulations with a sustained-release property.
Methods: A highly soluble, anti-asthmatic drug, Theophylline (TH), was selected as the model active pharmaceutical ingredient (API). The thermal stability of TH, mannitol (MAN) and other excipients was studied by differential scanning calorimetry (DSC, DSC 2500, TA Instrument).
The API at different drug loads of 20%-30% was mixed with Eudragit® RL PO (EURL) (0%-30%), Sodium Bicarbonate SB (0-5%), and MAN (40-80%) 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 TH, EURL, and SB, were extruded at 160°C and 200rpm using a co-rotating twin-screw extruder (11 mm Process 11™ ). The extrudates obtained were milled by ball milling and air-jet milling techniques and studied for particle size distribution analysis. An eight-stage nonviable Andersen cascade impactor with a pre-separator was also utilized. Scanning Electron Microscopy (SEM, JEOL JSM-5600; JEOL) was used to study the surface morphology of milled and un-milled extrudates. The X-ray diffraction studies and Fourier Transform Infrared Spectroscopy (FT-IR) were performed to determine crystallinity and molecular interactions of TH in the presence of SB, MAN and EURL in formulations.
Results: The DSC results revealed that TH, MAN and other excipients showed thermal stability over the extrusion temperature (160°C) indicating suitability of the extrusion process parameters. The degradation peak of EURL was observed in the physical mixtures and all extrudates were
studied above 235°C, which is well above the extrusion temperature. Increasing concentrations of MAN in the formulations showed improved processing conditions due to its good flow properties (Figure 1). The crystalline nature of TH in the milled extrudates was decreased
compared to pure TH which was confirmed by XRD studies. The particle size of the formulations was varied based on the milling technique. Ball milling provided particles with different shapes as seen on the SEM data and their size range were non-uniform, which led to a poor aerodynamic performance upon cascade impaction analysis (Figure 2). Air-jet milling improved the desired particle size (≤ 5 μm) for DPIs by more than 4-folds as compared to the ball milling.
Conclusion: The targeted sustained release, milled particles of TH were developed via hot melt extrusion processing using EURL as a polymer and MAN as a milling aid agent. The developed milled particles may be useful for delivery of TH using the inhalation route of administration. However, the performance of the developed product for pulmonary delivery is to be optimized by further studies.
Bjad Almutairy– The University of Mississippi, Mississippi
Mashan Almutairi– Grad Student, University of Mississippi, Oxford
Sandeep Sarabu– University of Mississippi, oxford, Mississippi
Bhavani Prasad Vinjamuri– Ph.D. Student, Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, Mississippi
Craig Herman– University of Texas at Austin
Suresh Bandari– Post-doc, University of Mississippi, OXFORD, Mississippi
Mahavir Bhupal Chougule– Associate Professor, University of Mississippi, Mississippi
Hugh Smyth– University of Texas at Austin, Texas
Michael. A Repka– Professor, University of Mississippi, Mississippi