A Comparison of Spray-drying and Co-precipitation for the Generation of Amorphous Solid Dispersions (ASDs) of Hydrochlorothiazide and Simvastatin

Co-processing of APIs, the practice of creating multi-component APIs directly in chemical processing facilities used to make drug substance, is gaining increased attention with a view to streamlining manufacturing, improving supply chain robustness and accessing enhanced product attributes in terms of stability and bioavailability. Direct co-precipitation of amorphous solid dispersions (ASDs) at the final step of chemical processing is one such example of co-processing. The purpose of this work was to investigate the application of different advanced solvent-based processing techniques – direct co-precipitation (CP) and the benchmark well-established spray-drying (SD) process – to the production of ASDs comprised of a drug with a high T_g (hydrochlorothiazide, HCTZ) or a low T_g (simvastatin, SIM) molecularly dispersed in a PVP/VA 64 or Soluplus® matrix.

ASDs of the same composition were manufactured by the two different methods and were characterised using powder X-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and scanning electron microscopy (SEM). Both methods produced ASDs that were PXRD amorphous, with some differences, depending on the process used, in glass transition temperature and particle size distribution. Irrespective of manufacturing method used, all ASDs remained PXRD amorphous when subjected to high relative humidity conditions (75% RH, 25°C) for four weeks, although changes in the colour and physical characteristics were observed on storage for spray-dried systems with SIM and PVP/VA 64 copolymer.

The particle morphology differed for co-precipitated compared to spray dried systems, with powder generated by the former process being comprised of more irregularly shaped particles of larger particle size when compared to the equivalent spray-dried systems which may enable more streamlined drug product processes to be used for CP materials. These differences may have implications in downstream drug product processing. A limitation identified when applying the solvent/anti-solvent co-precipitation method to SIM was the high antisolvent to solvent ratios required to effect the precipitation process.

Thus, while similar outcomes may arise for both co-precipitation and spray drying processes in terms of ASD critical quality attributes, practical implications of applying the co-precipitation method and downstream processability of the resulting ASDs should be considered when choosing one solvent-based ASD production process over another.

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Materials

Hydrochlorothiazide (HCTZ) and simvastatin (SIM) were purchased from Glentham Life Sciences Ltd.
(Corsham, UK). Polymers, polyvinyl pyrrolidine/vinyl acetate 60/40 (Kollidon VA64®, PVP/VA) and
polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®) were obtained from BASF (Cork, Ireland). Ethanol (EtOH) was obtained from Corcoran Chemicals (Dublin, Ireland). Liquid nitrogen was purchased from BOC (Dublin, Ireland) while sodium chloride was obtained from Sigma Aldrich (Arklow, Ireland). Dichloromethane (DCM) and hexane were obtained from Sigma-Aldrich (Dorset, UK), deionised water (14.0 MΩ·cm) was obtained using an Elix 3 connected to a Synergy UV system (Millipore, UK).

Monika Myślińska, Michael W. Stocker, Steven Ferguson, Anne Marie Healy, A Comparison of Spray-drying and Co-precipitation for the Generation of Amorphous Solid Dispersions (ASDs) of Hydrochlorothiazide and Simvastatin,
Journal of Pharmaceutical Sciences, 2023, ISSN 0022-3549,
https://doi.org/10.1016/j.xphs.2023.02.012.

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