Downstream processing of spray-dried ASD with hypromellose acetate succinate – Roller compaction and subsequent compression into high ASD load tablets

Despite wide commercial application of hypromellose acetate succinate (HPMCAS) in spray-dried amorphous solid dispersion (ASD) drug products, little information is available in the references on downstream processing of spray-dried dispersions with HPMCAS. Poor flow and high dilution factor are a challenge in formulating spray-dried ASDs into tablets, leaving little space for other excipients facilitating binding and disintegration.

Direct compression is not possible due to the poor powder flow of spray-dried ASDs. Moisture has to be avoided due to the plasticizing properties of water on the ASD, resulting in reduced stability of the amorphous state. Thus, dry granulation by roller compaction and subsequent tablet compression is the preferred downstream process. We report the investigation of downstream processing by roller compaction and tablet compression of a high load formulation with 75% of spray-dried amorphous solid dispersion (Nifedipine:HPMCAS 1:2).

A head to head comparison of microcrystalline cellulose/croscarmellose (MCC/cl-NaCMC) as binder/disintegrant vs. MCC and low-substituted hydroxypropyl cellulose (L-HPC) as excipient for binding and disintegration showed improved re-workability of the formulation with MCC/L-HPC after roller compaction. Upon transfer to the rotary press, a 45% higher tensile strength of tablets is observed after dry granulation with MCC/L-HPC.

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Materials: A spray-dried solid dispersion of Nifedipine and HPMCAS (Shin-Etsu AQOAT® AS-MG), 1:2 ratio, and low-substituted hydroxypropyl cellulose (L-HPC NBD-021) was provided by Shin-Etsu Chemical Co. Ltd. (Japan). Microcrystalline cellulose (MCC, Pharmacel 101) and croscarmellose sodium (cl-NaCMC, Solutab A) were sourced from DFE (Netherlands) and Roquette (France) respectively. Silicon dioxide (Aerosil® 200 Pharma) was sourced from Evonik Industries AG (Germany) and magnesium stearate from Applichem (Germany). All materials were used as received after being stored at ambient condition for minimum two weeks. The powder properties of the Nifedipine:HPMCAS SDD are collated in table SI2 in the supporting information. Two formulation blends were prepared in a plastic bag (Table 2). Formulation 1 (F1) with high amount of solid dispersion was prepared with MCC as binder/filler and an industry typical amount of croscarmellose as disintegrant (Zhao and Augsburger, 2006), similar to the inactive ingredients in commercialized ASDs (Table 1). Formulation 2 was developed with L-HPC replacing part of MCC and all of croscarmellose. A preliminary study revealed that 15% of L-HPC gave a good balance of tablet hardness and low disintegration time (Figs. SI2 and SI3 in the supporting information).

Article information: Andreas Sauer, Shogo Warashina, Saurabh M. Mishra, Ilja Lesser, Katja Kirchhöfer, Downstream processing of spray-dried ASD with hypromellose acetate succinate – Roller compaction and subsequent compression into high ASD load tablets, International Journal of Pharmaceutics: X, 2021. https://doi.org/10.1016/j.ijpx.2021.100099.

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