(W1030-05-30) One Like the Other? A Novel In Vitro Release Method to Ensure Proper Drug Release of Extended-Release Mini-Tablets for Paediatric Use

Purpose: Mini-tablets (MTs) are currently a hot topic in the context of developing age-appropriate paediatric medicines. These dosage forms offer good dose flexibility as it is possible to compress the lowest required single dose of a medicine into a single tablet, while individual dose adjustment can be achieved by varying the number of tablets to be administered. Analytically, MTs present some challenges that are not yet adequately addressed in current pharmacopoeias: Particularly for extended-release (ER) MT formulations, drug release performance represents a critical quality attribute that requires special attention in the development of appropriate analytical assays, as it is crucial that each individual MT meets the specifications. Due to the often very low individual doses, release tests of single MTs using standard pharmacopeial methods such as the paddle or basket method, but also using miniaturised versions thereof, encounter analytical limitations. Therefore, especially for the quality control (QC) of these formulations, there is a need to establish suitable methods for studying drug release of individual MTs. The aim of the present work was to develop a standardised in vitro release method for the QC of ER MTS for paediatric use.

Methods: Sodium valproate (Orfiril^®) MTs with a drug load of 3 mg per MT were used as model drug product. The first series of in vitro release tests was carried out with both individual and multiple mini tablets in a single vessel in USP apparatus 2 (DT 728, Erweka, Germany) in the Mini Paddle mode¹. The agitation speed was 75 rpm and a media volume of 200 mL was applied. The second set of experiments focused on conducting the release experiments in significantly smaller media volumes enabling the reliable quantification of even very small drug concentrations. Experiments were performed with individual MTs using a small volume version of USP apparatus 7 (400-DS, Agilent Technologies, USA). MTs were placed in 50-mesh basket holders agitated at a dip rate of 10 dpm in a media volume of 10 mL. Samples (3.5 mL) were automatically removed at predetermined time points with partial medium substitution of 4.5 mL. All experiments (USP 2 and USP 7) were performed in triplicate (n=3), with both specification-conform and manipulated (out-of-specification - OOS) tablets, the test time was 12 hours, phosphate buffer pH 6.8 at 37 ± 0.5 °C was used as the dissolution medium and all samples were analysed by HPLC (Waters, USA) with UV detection at 210 nm².

Results: In the course of the experiments with the Mini Paddle, it very quickly became clear that if test that have to be carried out with several ER MTs, because otherwise the amount of active ingredient released is not analytically accessible, are not meaningful, as it is not possible to draw conclusions about the release behaviour of individual tablets (Figure 1a). In contrast, the new 400‑DS release method was very good at capturing the release behaviour of individual MTs and revealing differences in quality (Figure 1b). In all experiments, the new release method delivered robust release results that were very reproducible.

Conclusion: A robust and standardised quality control method for paediatric ER MTs was developed based on a small volume version of the USP 7 apparatus. This new in vitro method allows reliable release results to be obtained for individual MTs, even if they have a very low drug load. In the future, the method can be adapted for other MT formulations and will hopefully make a valuable contribution to ensuring the quality of oral paediatric formulations.

References: 1. Klein S., Shah V A Standardized Mini Paddle Apparatus as an Alternative to the Standard Paddle, AAPS PharmSciTech 9 (4) (2008), 1179-1184.
2. Karkossa F et al. Simulating Different Dosing Scenarios for a Child-Appropriate Valproate ER Formulation in a New Pediatric Two-Stage Dissolution Model. AAPS PharmSciTech 18 (2) (2017), 309-316.



Figure 1. Drug release of valproate ER MTs in phosphate buffer pH 6.8, 37 ± 0.5 °C, (a) individual specification-conform (SC) MT and mix of a single SC and two individual manipulated (OOS) MT per vessel in the Mini Paddle apparatus (200 mL, 75 rpm), (b) individual SC and OOS MT in the 400-DS apparatus (10 mL, 10 dpm).