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

Abstract

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.

Downstream Processing of Itraconazole:HPMCAS Amorphous Solid Dispersion: From Hot-Melt Extrudate to Tablet Using a Quality by Design Approach

“…Rapid disintegration of a tablet into smaller particles is essential for fast release of the drug [ 8 , 12 ]. All tablets prepared in the experimental design disintegrated within one minute ( Table S5, Supplementary Materials ).…”

“…Despite the considerable interest in ASD formulations, downstream processing studies for the development of ASD tablets are limited due to various challenges associated with the properties of ASDs [ 7 ]. In our previous study, we reported on the downstream processing of a spray-dried ASD of nifedipine using hypromellose acetate succinate (HPMCAS) as a carrier polymer [ 8 ]. However, the challenges faced in the downstream processing of ASDs prepared by spray drying are totally different from those encountered in the production of HME-based ASDs.…”

“…However, the challenges faced in the downstream processing of ASDs prepared by spray drying are totally different from those encountered in the production of HME-based ASDs. For instance, spray-dried ASD particles are small and hollow in structure, showing lower bulk density and poor powder flow [ 7 , 8 ]. Thus, densification by dry granulation using roller compaction is usually applied as a downstream process to improve the particle size and flow of spray-dried ASD powders.…”

Impact of Gastric pH Variations on the Release of Amorphous Solid Dispersion Formulations Containing a Weakly Basic Drug and Enteric Polymers

“…6,14,15 Several commercial products are prepared as ASDs with HPMCAS, including telaprevir (Incivek, Vertex, US); ivacaftor (Kalydeco, Vertex, US); vemurafenib (Zelboraf, Roche, Switzerland); posaconazole (Noxafil, Merck, US); and apalutamide (Erleada, Janssen, US). 16−20 In contrast, HPMCP has been used less for commercial ASD formulations, with its use reported only for itraconazole (Lozanoc, Mayne Pharma, Australia) 16,18,21 and delamanid (DLM) (Deltyba, Otsuka, Japan). 22 Importantly, enteric polymers are un-ionized and insoluble in acidic environments, leading to reduced crystal growth inhibition effectiveness at low pH.…”

“…Amphiphilic, ionizable polymers, such as hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), Eudragit L100, and cellulose acetate phthalate, have been found to be effective at maintaining drug supersaturation and enhancing in vivo absorption. ,,− Among these, HPMCP and HPMCAS have been noted to be good crystallization inhibitors for many drugs. ,, Several commercial products are prepared as ASDs with HPMCAS, including telaprevir (Incivek, Vertex, US); ivacaftor (Kalydeco, Vertex, US); vemurafenib (Zelboraf, Roche, Switzerland); posaconazole (Noxafil, Merck, US); and apalutamide (Erleada, Janssen, US). − In contrast, HPMCP has been used less for commercial ASD formulations, with its use reported only for itraconazole (Lozanoc, Mayne Pharma, Australia) ,, and delamanid (DLM) (Deltyba, Otsuka, Japan) . Importantly, enteric polymers are un-ionized and insoluble in acidic environments, leading to reduced crystal growth inhibition effectiveness at low pH. ,− For example, HPMCAS (-LF grade) was found to be less effective at inhibiting the crystal growth of felodipine at a lower pH than at a higher pH .…”