Solid state thermomechanical engineering of high-quality pharmaceutical salts via solvent free continuous processing

Abstract

Solvent-free, continuous processing of high-quality pharmaceutical salts through via hot-melt extrusion as an alternative to solvent based approaches.

Advanced Methodologies for Pharmaceutical Salt Synthesis

“…These issues highlight the need to develop solvent-free processes for pharmaceutical manufacture. There are currently very few solvent-free methods being used for pharmaceutical salt preparation, such as mechanochemical neat grinding and extrusion . Nevertheless, solvent processing techniques are frequently used due to their ease for salt formation and scale-up, the simplicity of configuration (e.g., equipment), and the possibility to couple with process analytical tools (e.g., NIR, Raman probes).…”

“…The progress of salt formation in different extrusion zones was determined by analyzing the sample collected from different zones. The analyses illustrated that the rate of salt formation depends on the availability of the proton donor and acceptor in the API-salt former mixture, along with other extrusion parameters …”

“…(A) Hydrogen bonds between oxalic acid (OA) dimers and imidazole ring of the ketoconazole (KTZ) moiety, (B) crystal packing projections for KTZ–OA salt (hydrogen bond). Other hydrogen and van der Waals bonds have been omitted for clarity …”

Continuous Manufacture and Scale-Up of Theophylline-Nicotinamide Cocrystals

“…Over the last decade, HME has received renewed attention in the pharmaceutical industry as it offers distinct advantages over other commercially available pharmaceutical processing technique [ 26 ]. Some of these advantages include the fact it is a solvent-free non-ambient process; is economical offering a reduced production time and having fewer processing steps when compared to other techniques; it is a continuous process; extrudes products in a uniform shape; quality assurance can be easily monitored through process analytical technology (PAT) and that HME has been shown to increases the solubility and bioavailability of insoluble compounds when compared to other processing techniques [ 30 , 31 , 32 , 33 ].…”

“…A 1:1 stoichiometric ratio of theophylline (THL), and nicotinamide (NIC) will be utilized as a model API-coformer system, to investigate the effect of these parameters in the scale-up of production via HME. These two materials have been selected because THL-NIC cocrystals have been used in a wide array of publications and there is sufficient information available on THL-NIC crystal structure to reliably use as a model drug to evaluate the purity of our product produced under different conditions [ 32 , 33 , 34 , 35 ]. The main aim of the study is to provide a scale-up paradigm of high-quality cocrystals processed by HME.…”