Abstract
The feasibility of upscaling the formulation of co-amorphous indomethacin-lysine from lab-scale to pilot-scale spray drying was investigated. A 22 full factorial design of experiments (DoE) was employed at lab scale. The atomization gas flow rate (Fatom, from 0.5 to 1.4 kg/h) and outlet temperature (Tout, from 55 to 75 °C) were chosen as the critical process parameters. The obtained amorphization, glass transition temperature, bulk density, yield, and particle size distribution were chosen as the critical quality attributes. In general, the model showed low Fatom and high Tout to be beneficial for the desired product characteristics (a co-amorphous formulation with a low bulk density, high yield, and small particle size). In addition, only a low Fatom and high Tout led to the desired complete co-amorphization, while a minor residual crystallinity was observed with the other combinations of Fatom and Tout. Finally, upscaling to a pilot scale spray dryer was carried out based on the DoE results; however, the drying gas flow rate and the feed flow rate were adjusted to account for the different drying chamber geometries. An increased likelihood to achieve complete amorphization, because of the extended drying chamber, and hence an increased residence time of the droplets in the drying gas, was found in the pilot scale, confirming the feasibility of upscaling spray drying as a production technique for co-amorphous systems.
Highlights
It has been estimated that between 80% and 90% of new chemical entities in the research and development pipelines are poorly water-soluble [1], being classified as class II or IV in the Biopharmaceutics Classification System (BCS) [2]
Several studies report on the potential of amino acids (AA) as co-formers for increased physical stability [15,16,17]
Whilst ball milling (BM) is very useful for screening purposes on a laboratory scale, only a few publications delve into the preparation of co-amorphous formulations using larger scalable techniques, so that their potential can be explored industrially
Summary
It has been estimated that between 80% and 90% of new chemical entities in the research and development pipelines are poorly water-soluble [1], being classified as class II or IV in the Biopharmaceutics Classification System (BCS) [2]. Whilst BM is very useful for screening purposes on a laboratory scale, only a few publications delve into the preparation of co-amorphous formulations using larger scalable techniques, so that their potential can be explored industrially. The transfer from a dry technique, such as BM, towards a solvent technique, such as SD, requires the consideration of the influence of the moisture present during production on the obtained product In this respect, previous work by our group reported an interesting drug–AA formulation of indomethacin and lysine (IND–LYS), in which different physical forms of the salt were produced, depending on the presence of moisture during BM [21]. Co-amorphous salt formulations of the acidic drug indomethacin with basic amino acids (arginine, histidine, and lysine) were successfully prepared by lab scale SD, even though the indomethacin–histidine salt could not be prepared by BM [23]. The products were compared with regard to amorphization, and to the glass transition temperature (Tg), yield, bulk density, and particle size distribution
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