Date of Award
Abu T M Serajuddin
In the present investigation, a continuous, and novel organic solvent-free approach for the synthesis of pharmaceutical salts using the twin screw extruder (TSE) is reported. Although the method offers distinct advantages such as solvent free synthesis and short processing time over the conventional salt synthesis, the produced salts usually require further processing into granules before they can be compressed into tablets or filled into capsules, which makes the final product manufacturing non-continuous. This report, for the first time, describes a process of combining salt synthesis and granulation into a single-step using a TSE. Cinnarizine, a model poorly water-soluble weakly basic drug (pKa 2.55, 7.69) was used with malic acid (pKa 3.25, 4.68) for the salt synthesis using TSE. The formation of cinnarizine-malate salt was confirmed by single crystal X-ray, differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). To establish the feasibility of salt formation by melt extrusion, the mixture of cinnarizine and malic acid was first passed through a TSE and it was compared with the solution crystallized salt. To combine salt synthesis and granulation, physical mixtures of cinnarizine and malic acid (1:1 molar ratio) with binder (2.5-7.5%w/w), disintegrant (2.5%w/w), and glidant (0.1%w/w) were passed through the TSE. To achieve wet granulation, water at various concentrations (7-21%w/w of powder feed rate) was introduced into the extruder barrel. Effect of process parameters like screw speed (150-350 RPM), barrel temperature (65-85°C), powder feed rate (1.5-4.5 g/min), and screw configurations were investigated on the granulation process. Granules were characterized for moisture content granule size distribution, and tablet tensile strength and tablet disintegration time. Raman spectroscopy, DSC and PXRD showed that complete conversion to salt (>99% purity) was obtained during twin-screw granulation. The granules showed less than 12% moisture content and, thus, did not require long drying while tablets showed good tensile strengths (≥1.9 MPa) and disintegration time of <5 min. The process yield, with respect to granule size distribution (F125-1180µm) was more than 85-90%. Thus, present study demonstrated a continuous one-step process of synthesizing and granulating pharmaceutical salts with high crystallinity (>99%) and drug load (>90%w/w) using a twin screw extruder.
Vasoya, Jaydip, "CONTINUOUS SALT SYNTHESIS AND GRANULATION USING SINGLE STEP TWIN SCREW EXTRUSION PROCESS" (2020). Theses and Dissertations. 194.
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