Materials

Panadol Actifast® tablets (Batch No. HU6S, 500 mg paracetamol/tablet, GlaxoSmithKline Consumer Healthcare, Dublin, Ireland) were purchased from a community Pharmacy in Ireland. Empty HGCs (Quali-G, Size 0, Qualicaps, Spain) were donated by Uni-Pharma S.A., Greece and were filled with 200 mg paracetamol manually. Empty HHCs (Vcaps plus, Size 1, Coni-Snap Standard, Lot # 5,425,007) were donated from Capsugel Belgium N.V and were filled with 100 mg paracetamol manually. Paracetamol micronized powder [purity 99.8%, Batch No. 637521P016 (0064/22) Mallinckrodt Pharmaceuticals, Ireland], was donated by Uni-Pharma S.A., Athens, Greece.

Methocel® K4M Premium Hydroxypropyl methylcellulose (K4M HPMC, Lot No: DTR538299) was donated by Colorcon Co., U.K. Hydrochloric acid, concentrated 37%, was purchased from Sigma-Aldrich (Saint Louis, USA), sodium chloride, analytical grade purity, was purchased from Merck KGaA (Darmstadt, Germany), and sodium hydroxide, ≥ 99.8%, was purchased from Fluka™ Honeywell (Muskegon, USA). Lipofundin MCT/LCT 20% was purchased from B. Braun Melsungen AG (Melsungen, Germany). FEDGAS® Gel was purchased from biorelevant.com Ltd, (London, United Kingdom). Régilait Skimmed Milk Powder [36% proteins, 52% carbohydrates, 0.8% fats, 1.1% salt (w/w), (30)] (Burgundy, France) was purchased locally.

Apparent Viscosity Measurements

Apparent viscosity of disintegration media was measured with a rotational viscometer (RM 100 CP 2000 PLUS, LAMY Rheology, France) equipped with a measuring cone and plate system MK-CP4005. A sample volume of 146 μL was placed on the viscometer’s plate and the measuring cone was lowered in measuring position. The software VISCO-RM Soft was used to control the instrument. As disintegration media were pseudoplastic, measurements were performed under conditions which were identical with those previously applied for measuring the apparent viscosity of pseudoplastic antral contents after a high-calorie, high-fat meal (27, 28). Measurements were performed in triplicate, at 37°C, and sequentially at 50 s−1, at 100 s−1 and at 200 s−1 whereas the duration of each step was 10 s (27, 28).

Disintegration ExperimentsApparatus

Four in vitro setups were evaluated.

1.

The compendial Apparatus II with the USP stationary basket (8-mesh) (31). The stationary basket ensures reproducible hydrodynamics during disintegration (32). Also, based on data collected with a scaled-up version of compendial vessel with a flat bottom, a tablet fixed on a steel wire, and the vessel rotating up to about 50 rpm in viscous medium (about 500 mPa⋅s), gastric relevant surface shear stresses may be generated (22).

2.

The USP stationary basket over the rotating mini-paddle of the Erweka mini-paddle apparatus (Erweka® DT 6, Erweka®, Germany). The Erweka mini-paddle apparatus represents an exact scaled down compendial Apparatus II and all relevant dimensions correspond with those described in pharmacopoeias (33).

3.

The compendial Apparatus II (Erweka® DT 6, Erweka®, Germany). Since IR dose units ingested after a high-calorie, high-fat meal are initially deposited on the top of gastric contents and the region of the stomach where disintegration occurs varies with the disintegration time (3, 8) no sinkers were used.

4.

The compendial Apparatus II (Erweka® DT 6, Erweka®, Germany) with apex vessel [vessel 1 L, apex (former peak), Erweka compatible, Dissolution Accessories, Art No PSGLA0PK-EW] without using sinkers.

Disintegration of Panadol Actifast® Tablets and Paracetamol HGCs in Level II FeSSGF-V2 and the Impact of Apparent Viscosity of the Aqueous Phase

To simulate the volume and composition of gastric contents after a high-calorie, high-fat meal disintegration experiments were performed in 500 mL (24, 26) of Level II fed state simulating gastric fluid version 2 (FeSSGF-V2). Level II FeSSGF-V2 simulates antral pH, buffer capacity, osmolality, and the presence of dietary lipids by using Lipofundin®, a commercially available, standardized product (27). The impact of 0.9% K4M HPMC and of 1% K4M HPMC on disintegration was investigated in triplicate by using:

Panadol Actifast® tablets and the compendial Apparatus II with the USP stationary basket

Panadol Actifast® tablets and the compendial Apparatus II, and

paracetamol HGCs and the compendial Apparatus II.

All experiments were performed at 37°C with the paddle rotating at 75 rpm.

Disintegration of Panadol Actifast® Tablets, Paracetamol HGCs, and Paracetamol HHCs in Level III FeSSGF-V3

Based on published information gastric emptying of paracetamol administered after a high-calorie meal as IR tablet initiates upon completion of disintegration (3), and gastric emptying of amoxicillin administered after a high-calorie, high-fat meal as HGC initiates upon rupture of the capsule (8) implying that most of the disintegration process occurs in the antral region. The volume of antral contents during the first couple hours after administration of a high-calorie, high-fat meal has been estimated to be little more than 300 mL (29). To simulate antral pH, buffer capacity, osmolality, dietary lipid content, and dietary protein content, after a high-calorie, high-fat meal, disintegration was investigated in 330 mL Level III fed state simulating gastric fluid version 3 (FeSSGFF-V3). In Level III FeSSGF-V3, the presence of dietary lipids and proteins is simulated by using commercially available, standardized materials, i.e. FEDGAS gel and Régilait, respectively (25).

Two sets of experiments were performed sequentially. Initially, experiments were performed with Panadol Actifast® tablets by using the USP stationary basket over the rotating mini-paddle of the Erweka mini-paddle apparatus, because the volume of the medium did not allow for using the compendial Apparatus II with the USP stationary basket. As Abrahamson et al. (22) have suggested that about 50 rpm may simulate better the shear stresses during gastric mixing and breakdown of solid food, experiments were performed in triplicate with the mini-paddle rotating at 50 rpm and at 75 rpm.

The second set of experiments was performed with Panadol Actifast® tablets, paracetamol HGCs, and paracetamol HHCs by using:

the compendial Apparatus II with the paddle rotating at 75 rpm, and

the compendial Apparatus II with apex vessel and the paddle rotating at 75 rpm and at 60 rpm.

Each experiment was performed 3 times. However, if, after 3 repetitions, in vitro data variability was high and the difference between the average in vitro disintegration time and the average intragastric disintegration time was small, 3 additional repetitions were performed.

Both sets of experiments were performed at 37°C.

Sampling and Assay Procedures

Samples of 3 mL were collected at various time points after initiation of the experiment using a 5 mL disposable plastic syringe. After each withdrawal, an equivalent volume (3 mL) of fresh disintegration medium (37°C), was added to maintain a constant volume of the disintegration medium during the experiment. Immediately after sample collection, 300 µL were transferred to an Eppendorf tube, and 5% perchloric acid was added in a 1:2 (v/v) ratio (600 μL). The mixture was vortexed for at least 30 s and then centrifuged (10,000 rpm, 10 min, 10°C). The resulting aqueous phase was injected into the HPLC–UV system. Based on a previously published analytical method (34), a reversed-phase Fortis C18 (150 × 3 mm, 5 μm) equipped with a precolumn Hypersil BDS C18 (10 × 4 mm) was used, the mobile phase consisted of aqueous buffer solution of KH2PO4 0.05 M containing 1% glacial acetic acid adjusted to pH 6.5 and acetonitrile (85:15, v/v), the flow rate was 0.5 mL/min, the detection wavelength was 242 nm, the injection volume was 50 μL, and the overall chromatographic run time was 6 min.

Data Treatment

Complete disintegration time, tcomplete, was estimated by the x-axis intercept of the best fitted line to the data in the ascending linear region of individual cumulative % paracetamol in the medium vs. time data sets. Cumulative % paracetamol includes both undissolved and dissolved paracetamol.

Initial disintegration time, tinitial, was estimated after fitting the Weibull function [(35), Eq. 1)] to the individual cumulative % paracetamol in the medium vs. time data sets

where Μ is the cumulative % paracetamol in the medium, Μ0 is the maximum % paracetamol in the medium (theoretically, 100), b is the scale parameter and z is shape parameter. Each fitting aimed at estimating four parameters, i.e. M0, tinitial, b, and z. Fitting was considered successful when the regression was significant, i.e. normality and equal variance tests passed, R > 0.95, and p value in the analysis of variance (ANOVA) table was lower than 0.05. All fittings were performed with Sigmaplot for Windows Version 11.0 (Systat Software, Inc., San Jose, CA, USA).

The impact of apparent viscosity of the aqueous phase of Level II FeSSGF-V2 on the disintegration time was evaluated with one-way ANOVA and the Tukey’s post hoc test. The difference of in vitro estimated disintegration time from the intragastric disintegration time was evaluated by applying the unpaired t-test (Type I error: 0.05), based on the results of the results of the equal variance and normality tests.