Effect of diluent and binder type on the acetaminophen release from tablets under simulated fasted and fed conditions

This poster has been presented at the 15th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, which took place in Prague, Czech Republic.

Effect of diluent and binder type on the acetaminophen release from tablets under simulated fasted and fed conditions

Introduction

• Immediate-release (IR) solid dosage forms dominate the market due to their manufacturing cost-efficiency, easiness of administration, good adherence and fast therapeutic effect. However, IR tablets containing Biopharmaceutical classification system (BCS) Class III drugs, being characterised by high aqueous solubility and low permeability (Fig. 1), can pose some formulation difficulties, namely prolonged disintegration and dissolution in fed state. In turn, that can result in reduced bioavailability. [1,2,3]
•  Tablet excipients such as diluents and binders affect disintegration and dissolution in fasted and fed conditions. Acetaminophen (AMP), a widely used and well-known analgesic and antipyretic, proves a great model drug, as it belongs to BCS Class III at most clinically relevant doses and is not ionised in gastric pH (Fig. 2). [4]
• This study aimed to study the effect of 2 binder types and 3 diluent types on the disintegration and in vitro release of AMP from IR tablets under simulated fasted and fed conditions.

Materials & Methods

• AMP (Caesar&Loretz GmbH), microcrystalline cellulose (MCC; Ceolus PH-101), and isomalt (galenIQ 801) or Polyvinylpyrrolidone (PVP; Kollidon® 25; BASF) were mixed and granulated with water in a high-shear mixer (TMG; Glatt GmbH, Binzen, Germany). Granules were dried at room conditions, calibrated (2 mm), mixed with isomalt, lactose or mannitol (galenIQ 721; Tabletose®80; or Pearlitol®200SD) and lubricated with MgSt (Magnesia 4264). Then 6 formulations were obtained (Table 1), using STYL’One Nano compaction simulator. [5]
• Particle size distribution (PSD) was determined by a laser diffraction particle size analyser using an ‘Aero S’ module for dry dispersions (Mastersizer 3000, Malvern Instruments, UK). The mean yield pressure (Py) under slow (1 mm/s) and fast (90 mm/s) compression was determined using in-die Heckel plot analysis (Alix software ver. 20220711; Medelpharm, France). [6,7]
• Dissolution (USP II, 75 rpm) and disintegration test were performed in fasted state medium (pH 1.2; according with EP) and fed state medium (acetate buffer solution pH 4.5 (EP) with addition of HPMC E4M (1.4 wt.%)). [8]
• For water uptake weight loss (WUWL) test, fed state media was colored using 0.1% methylene blue solution in pH 4.5 acetate buffer (2% v/v). Tablets were weighed prior and after disintegration test (2 min), then dried to constant mass in the vacuum chamber (105°C).

Results

• AMP is white crystals with irregular shape and rough surface (D50 – 59.1 μm; span – 6.08; Fig. 3 & 5).
• Granules with an isomalt binder (Fig. 4 A) and PVP binder (Fig. 4 B) are close to spherical shape and visually similar in structure.
• Resulted PVP granules are bigger than isomalt granules (mode 916 vs. 484 μm; Fig. 5).
• For AMP, Py comprised 95.6 MPa, while for isomalt and PVP granules, 111.3 and 59.7 MPa (Fig. 6).
• Strain rate sensitivity (SRS) for isomalt granules was low, while PVP granules were more sensitive to tableting speed, indicating higher elasticity of granules (Fig. 7).
• Tablets were prepared with a comparable porosity of 11.98±0.65%.
• In both media, disintegration time was faster for isomalt-binder formulations compared to PVP (Fig. 8).
• On average, in both media, lactose-diluent tablets showed the fastest disintegration time, followed by mannitol and isomalt.
• Interestingly, PVP-mannitol tablets (the longest disint. in the fed state) showed the highest water uptake (Fig. 9).
• Weight loss was mostly inversely proportional to the disintegration time in the fed state (Fig. 10).
• Dissolution in the fed state medium was longer and incomplete (Fig. 11 and Fig. 12).
• Regardless of the media, isomalt-binder tablets, on average, showed faster results compared to PVP.
• On average, lactose-diluent formulations showed the fastest results, followed by mannitol and isomalt (Fig. 12).

Conclusion

• Disintegration time and dissolution time were slower in fed state medium than in fasted state medium.
• Used as an intra-granular binder, independent of the type of soluble diluent used, isomalt binder showed faster disintegration and dissolution time in comparison with the intragranular PVP binder.
• Among diluents, lactose containing formulations showed the fastest results.
• Isomalt binder containing tablets showed the highest weight loss after 2 min of disintegration test in fed state medium.

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Source: Frolova AJ, Gurkina K, Kukuls K, Mohylyuk V. Effect of diluent and binder type on the acetaminophen release from tablets under simulated fasted and fed conditions. 15th PBP; Prague, Czech Republic, 2026.03.23-26; DOI: 10.13140/RG.2.2.26253.09441.

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