Double action of HPMCAS as a dry binder and precipitation inhibitor in ASD tablet formulations of nifedipine prepared by hot-melt extrusion

Abstract

Poor tablet hardness and drug re-crystallization are two common challenges of amorphous solid dispersion (ASD) formulations prepared with hot-melt extrusion (HME). In the present study, we investigated the double action of hypromellose acetate succinate (HPMCAS) as a dry binder and precipitation inhibitor when externally added to high ASD load (65 %) tablets of nifedipine (NIF). Binary ASDs of NIF were prepared using either HPMCAS or copovidone (Kollidon® VA 64, PVP-VA64) as carrier polymers. Pre-dissolving HPMCAS (AS-HF) in the dissolution medium inhibited the drug precipitation and prolonged its supersaturation state at 12.5 wt % or 100 wt % relative to NIF content in ASDs prepared with either HPMCAS (1: 2, drug: polymer), or PVP-VA64 (1: 6, drug: polymer), respectively. In contrast, pre-dissolving hydroxypropyl cellulose (Klucel™, HPC-EXF) or PVP-VA64, did not prevent the drug re-crystallization. The external addition of AS-HF (5 % w/w) to the ASD tablets of NIF: HPMCAS (1: 2) improved the tabletability, compressibility and compactibility of the blend, resulting in tablets with good tensile strength (1.9 MPa) vs 1.5 MPa or 0.8 MPa with either HPC-EXF (5 % w/w) or PVP-VA64 (5 % w/w), respectively. The results from this study demonstrate, for the first time, the dual function of HPMCAS (AS-HF) as a dry binder and precipitation inhibitor in high ASD load tablets, independent of the carrier polymer. This can potentially reduce the pill burden and improve the drug bioavailability in ASD tablet formulations.

Introduction

Poor water solubility of active pharmaceutical ingredients (APIs) is a major challenge in pharmaceutical drug development with more than 90 % of APIs belonging to class-II according to the biopharmaceutics classification system (BCS) (Butreddy, 2022). Amorphous solid dispersion (ASD) formulations have been widely used to improve the solubility of poorly soluble drugs. In ASD formulations, the drug is converted from a crystalline into a molecularly dispersed state within a polymer matrix which results in improvement of its solubility as no energy is required to break its crystalline lattice (Bhujbal et al., 2021). ASD formulations can be prepared using solvent-based (e.g. spray drying, spray granulation, co-precipitation) or dry (e.g. hot melt extrusion – HME) methods (Sauer et al., 2021; Mahmah et al., 2014). The drug release from ASD formulations is characterized by two phases, the first phase is where the drug quickly dissolves and reaches supersaturation state (spring effect) and the second phase is where the drug concentration is maintained (parachute effect). To ensure good oral bioavailability of the drug, its concentration must be maintained during the second phase to allow enough time for drug absorption (Butreddy, 2022; Curatolo et al., 2009). The two most used carrier polymers in ASD formulations are either hypromellose acetate succinate (HPMCAS) or polyvinylpyrrolidone vinyl acetate (PVP VA) (Moseson et al., 2024). HPMCAS is a cellulose-based polymer and is characterized by a low hygroscopic nature and an amphiphilic property. Its low hygroscopicity generally prevents water sorption and amorphous phase separation (APS) at high humidity conditions, and its amphiphilic nature results in quick drug release followed by maintenance of its supersaturated state. This results in stable ASD formulations with good oral bioavailability.

Whereas PVP VA and other hydrophilic polymers such as: povidones (PVP), and polyvinyl alcohol (PVA), may result in drug re-crystallization after reaching its supersaturation state (Marsac et al., 2008; de Danda et al., 2019). To prolong the drug supersaturation state, recent studies have evaluated the external addition of HPMCAS to ASD tablets prepared with PVP, PVA, or methacrylate copolymer as carrier polymers. In a study conducted by Monschke and Wagner, the external addition of HPMCAS (AS-LG) prolonged the supersaturation state of celecoxib in PVA-based ASD formulations (Monschke and Wagner, 2020). In another study conducted by Müller and co-workers, the co-administration of HPMCAS (AS-LG) to PVP-based ASDs of regorafenib or applying it as an enteric film to commercially available Strivaga® tablets resulted in maintenance of the drug supersaturation state and provided acid protection in the gastric medium (Müller et al., 2021). Finally, Mudie and co-workers used AS-HF for dry granulation of the rapidly crystallizing drug erolotinib to maintain its supersaturation state in high drug load ASD tablets using Eudragit L100 as carrier polymer (Mudie et al., 2020). These studies demonstrate the precipitation inhibition effect of HPMCAS.

Along with the formulation challenges of ASDs, downstream processing adds further complexity, particularly for those produced by hot-melt extrusion (HME). The process involves sizing, milling, and subsequent compaction of the extrudate powder into tablets or capsules, which is often difficult due to the high viscoelasticity of the extrudates. This leads to large particle sizes after milling and ultimately results in tablets with poor tensile strength (Mishra et al., 2022). Therefore, the addition of a dry binder in these formulations is necessary to ensure adequate compressibility of the powder and tablets with good tensile strength (Sauer et al., 2021). Commonly used dry binders include hydroxypropyl cellulose (Klucel™, HPC-EXF) and copovidones (PVP-VA64), owing to their small particle size. The small particle size of the binder correlates with better binding capacity and improved tablets’ tensile strength (Mangal et al., 2016; Okasha, n.d.). HPCMAS (fine grade) has an average particle size D50 of 6.9 μm, which is smaller than that of PVP-VA64 and HPC-EXF (17 and 49.7 μm, respectively). Thus, in addition to the precipitation inhibition effect of HPMCAS, it could act as a dry binder and improve tablet hardness when externally added to ASD formulations.

The function of HPMCAS as a dry binder when externally added to ASD tablet formulations has not been evaluated before. In the present study, we aimed to study the double function of AS-HF as a dry binder and precipitation inhibitor in high ASD load (65 %) tablets of nifedipine (NIF). NIF is a poorly soluble small-molecule belonging to BCS class-II with a logP value of 2.5 and was selected as the model drug in this study (Van Der Lee et al., 2001). Two ASD carrier polymers were used (HPMCAS and PVP-VA64), and the formulations were prepared using HME. The precipitation inhibition, and binding property of AS-HF were compared to that of HPC-EXF and PVP-VA64 in a series of in vitro dissolution and tablet compaction analysis studies.

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Materials

Nifedipine (NIF) was obtained from Tokyo Chemical industries (TCI CO., LTD, Tokyo, Japan). Hypromellose acetate succinate (HPMCAS, Shin-Etsu AQOAT®: AS-HF, AS-LMP) were supplied from Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). Copovidone (Kollidon® VA 64, standard and fine grades) were obtained from BASF SE (Ludwigshafen, Germany). Hydroxypropyl cellulose (HPC, Klucel™ EXF) was obtained from Ashland Inc. (Wilmington, Delaware). Croscarmellose sodium (Ac-Di-Sol®) was obtained from FMC biopolymer (Newark, Delaware). Microcrystalline cellulose (Avicel® PH-102) was obtained from DuPont chemicals (Wilmington, Delaware). All other chemicals and reagents used, such as acetonitrile, methanol, and water, were of either an analytical or HPLC grade. Throughout the manuscript, HPMCAS is referred to as AS- followed by the substitution grade and particle size specification. Kollidon® VA 64 is referred to as PVP-VA64, standard grade was used as ASD carrier polymer and the fine grade was used as binder/ precipitation inhibitor. Klucel™ EXF is referred to as (HPC-EXF).

David S. Nakhla, Saurabh M Mishra, Christian Lübbert, Luis Mejia, Kess Agatovure, Andreas Sauer, Double action of HPMCAS as a dry binder and precipitation inhibitor in ASD tablet formulations of nifedipine prepared by hot-melt extrusion, International Journal of Pharmaceutics: X, Volume 11, 2026, 100475, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2025.100475.

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