New Approach for the Application of USP Apparatus 3 in Dissolution Tests: Case Studies of Three Antihypertensive Immediate-Release Tablets.

The USP Apparatus 3 is a compendial dissolution Apparatus that has been mainly used to assess the performance of modified-release drug products. However, this Apparatus can be applied to dissolution testing of immediate-release tablets as well, with several advantages such as lower consumption of dissolution media, reduced setup time in quality control routine, and minimized hydrodynamic issues. In this work, three immediate-release (IR) tablets containing antihypertensive drugs of different Biopharmaceutic Classification System (BCS) classes were evaluated in order to assess the possible interchangeability between the official dissolution method using typical USP Apparatus 1 or 2 and the proposed methods using USP Apparatus 3. Depending on the selection of the appropriate operational conditions, such as dip rate and sieve mesh size, it was observed that USP Apparatus 3 could provide similar dissolution profiles compared to USP Apparatus 1 or 2 to the drug products tested. In addition, USP Apparatus 3 avoided conning issues related to USP Apparatus 2. The successful application of USP Apparatus 3 in dissolution tests for IR drug products depends on the definition of specific test conditions for each product, considering all the equipment variables, as well as drug and formulation characteristics.

Effect of basket mesh size on the hydrodynamics of a partially filled (500 mL) USP rotating basket dissolution testing Apparatus 1.

The USP Rotating Basket Dissolution Testing Apparatus 1 is listed in the USP as one of the tools to assess dissolution of oral solid dosage forms. Baskets of different mesh sizes can be used to differentiate between dissolution profiles of different formulations. Here, we used Particle Image Velocimetry (PIV) to study the hydrodynamics of the USP Apparatus 1 using baskets with different mesh openings (10-, 20- and 40-mesh) revolving at 100 rpm, when the vessel was filled with 500 mL. The velocity profiles throughout the liquid were found to vary significantly using baskets of different mesh sizes, typically increasing with increased size of the opening of the basket mesh, especially for axial and radial velocities. This, in turn, resulted in a significantly different flow rate through the basket, which can be expected to significantly impact the dissolution rate of the drug product. A comparison between the results of this work with those of a previous study with a 900-mL fill volume (Sirasitthichoke et al., Intern. J. Pharmaceutics, 2021, 607: 120976), shows that although the hydrodynamics in the USP Apparatus 1 changed with fill level in the vessel, the flow rate through the basket was not significantly affected. This implies that tablets dissolving in the two systems would experience similar tablet-liquid medium mass transfer coefficients, and therefore similar initial dissolution rates, but different dissolution profiles because of the difference in volume.

Particle Image Velocimetry (PIV) measurements of USP Apparatus 1 hydrodynamics with 500 mL fill volume.

Changes to hydrodynamics arising from changes within dissolution testing systems, such as the fill volume level, can potentially cause variability in dissolution results. However, the literature on hydrodynamics in Apparatus 1 is quite limited and little information is available for vessels with different liquid volumes. Here, velocities in a USP Apparatus 1 vessel with a liquid fill volume of 500 mL, a common alternative to 900 mL, were experimentally measured using 2D-2C Particle Image Velocimetry (PIV) for different basket rotational speeds. Tangential velocities dominated the flow field, while axial and radial velocities were much lower and varied with location. The velocities distribution increased proportionately with the basket rotational speed almost everywhere in the vessel excepting for underneath the basket. A nearly horizontal radial liquid jet was found to originate close to the basket upper edge. Comparison of these results with those previously reported with 900-mL liquid volume (Sirasitthichoke et al., Intern. J. Pharmaceutics:X; 3 (2021) 100078) showed that the flow rate through the baskets was similar in both systems, implying that, at least initially, the amount of drug in solution would increase linearly with time. In other words, the flow rate through the baskets would be independent of the liquid volume. Velocity profiles were also found to be similar, except in the region above the basket, which was affected by the radial jet with an orientation significantly different between the 500-mL and the 900-mL systems.

Influence of basket mesh size on the hydrodynamics in the USP rotating basket dissolution testing Apparatus 1.

The USP Apparatus 1 (rotating basket), typically used to assess drug product reproducibility and evaluate oral solid dosage forms performance, consists of a cylindrical glass vessel with a hemispherical bottom and a wire basket rotating at constant speed. Baskets with different wire openings can be used in alternative to the standard mesh opening (40-mesh) in order to discriminate between drug formulations during early stage of drug product development. Any changes introduced by different basket geometries can potentially and significantly impact the system hydrodynamics and cause variability of results, thus affecting product quality. In this work, Particle Image Velocimetry (PIV) was used to experimentally quantify the velocity distribution in the USP rotating basket Apparatus 1 using baskets of different mesh sizes (10-, 20-, and 40-mesh size) under the typical operating conditions described in dissolution testing procedures. Similar flow patterns were observed in all cases. However, the radial and axial velocities in the USP Apparatus 1 generally increased with increasingly larger openings of the basket mesh. Increasing the basket agitation speed also resulted in an overall increase in the velocities, especially below in the innermost core region below the basket, where drug fragments typically reside. More importantly, the flow entering and leaving the baskets was quantified from the velocity profiles in the immediate vicinity of the baskets. It was found that the flow increased significantly with increasingly larger mesh openings, which can, in turn, promote faster dissolution of the oral solid dosage forms, thus affecting drug dissolution profiles. Hence, the selection of the basket mesh size must be carefully considered during drug product development.

Experimental determination of the velocity distribution in USP Apparatus 1 (basket apparatus) using Particle Image Velocimetry (PIV).

The USP Apparatus 1 (basket apparatus) is commonly used to evaluate the dissolution performance of oral solid dosage forms. The hydrodynamics generated by the basket contributes, in general, to the dissolution rate and hence the dissolution results. Here, the hydrodynamics of Apparatus 1 was quantified in a vessel filled with 900-mL de-ionized water at room temperature by determining, via Particle Image Velocimetry (PIV), the velocity profiles on a vertical central plane and on 11 horizontal planes at different elevations at three different basket agitation speeds. The flow field was dominated by the tangential velocity component and was approximately symmetrical in all cases. Despite all precautions taken, small flow asymmetries were observed in the axial and radial directions. This appears to be an unavoidable characteristic of the flow in Apparatus 1. The magnitudes of the axial and radial velocity components varied with location but were always low. A small jet was seen emanating radially near the top edge of the basket. Velocities typically scaled well with increasing agitation speed in most regions of the vessel except for a region directly below the basket. The results of this work provide a major insight into the flow field inside the USP Apparatus 1.

Dissolution testing of oral film preparations: Experimental comparison of compendial and non-compendial methods.

In vitro dissolution testing is one of the most frequently used tests in pharmaceutical quality control, since evaluation of the drug release profile and estimation of the dosage form performance is enabled. However, for oral film preparations no standardized compendial dissolution method or specifications are available worldwide. Therefore, four different dissolution methods described in the literature, namely the basket method, the paddle and glass disc (PGD) method, the flow-through cell with adapted film sample holders produced via 3D printing (FTC + FH3D) and the "Punch and Filter" (PAF) method were chosen and their suitability to investigate oral films with different release properties was compared. For this purpose, oral films with immediate (ODFIR) and prolonged theophylline release (ODFPR) as well as double layer films (ODFDL) were produced and investigated. All produced ODFs disintegrated rapidly in 27-46 s and showed content uniformity with acceptance values between 7.3 and 11.3%. The FTC + FH3D and the PGD method showed increased discriminatory power and were suitable to investigate the integrity of the shielding layer of ODFDL as shown by linear prolonged release (mean dissolution time at 80% drug release (MDT80) of 366.8 and 217.1 min for FTC + FH3D and PGD method), which was not possible applying the basket and PAF method. These methods did not allow clear discrimination between ODFIR and ODFDL, since immediate release profiles with MDT80 values of 4.1 and 11.0 min for the basket method and 6.8 and 15.5 min for the PAF method were found for both, ODFIR and ODFDL respectively. The FTC + FH3D method provided high flexibility, which may be used to simulate gastrointestinal transit. The PAF method reflects physiological conditions of the oral cavity and enables mimicking the in vivo film application. These methods are particularly valuable for research and development purposes. Due to the simple and well standardized instrumental setup as well as high robustness, the basket and PGD method are particularly suitable for use in pharmaceutical quality control.