Automated extrusion-based dispensing: Personalized dosing and quality control of clopidogrel tablets for pediatric care
Farnaz Shokraneh, Anne M. Filppula, Aleksi Tornio, Jaan Aruväli, Urve Paaver, Niklas Sandler Topelius
Abstract
The exploration of three-dimensional (3D) printing inspired technologies in pharmaceutical compounding reveals a promising frontier in personalized medicine manufacture. This study focuses on the development of clopidogrel bisulphate tablets, with doses ranging from 2 mg to 20 mg per tablet, suitable for pediatric use. The study explored a semi-solid extrusion-based deposition technology already being used in compounding pharmacies across several European locations. The investigation explored various properties of two formulations of 1 % and 2 % clopidogrel gel tablets, with a specific focus on mass variation, drug content uniformity, in vitro drug release profiles, disintegration time, and stability. The mean weights of the smallest printed 200 mg tablets with 1 % and 2 % clopidogrel concentrations were 199.1 ± 4.6 mg and 201.0 ± 3.2 mg, respectively. For the largest printed 500 mg tablets with 1 % and 2 % concentrations, the mean weights were 499.3 ± 7.7 mg and 501.7 ± 6.5 mg, respectively. The mean clopidogrel content uniformity for 1 % clopidogrel 200 mg and 500 mg tablets were 102.0 ± 1.8 %and 96.6 ± 2.6 %, respectively, and for 2 % clopidogrel 200 mg and 500 mg were 102.6 ± 3.9 % and 101.2 ± 1.6 %, respectively, well within the acceptable acceptance value (AV) range of 3 to 12. Both 1 % and 2 % formulations of clopidogrel tablets exhibited rapid drug release, meeting the USP pharmacopeial target of 85 % release in 15 min. All tablet sizes formulated at 1 % and 2 % concentrations met specified disintegration specifications. The stability assessment over three months revealed consistent pH values and assay results within target specifications for both clopidogrel formulations (93.5 % for 1 % formulation and 93.6 % for 2 % formulation). At three months, X-ray Diffraction (XRD) and Fourier Transform Infrared Spectroscopy (FTIR) results demonstrated stability in clopidogrel tablets. In conclusion, a comprehensive evaluation of our developed clopidogrel tablets demonstrate their suitability for clinical use in an extemporaneous setting using the presented semi-solid extrusion-based automation technology. The graphical abstract titled "Development Phases of Clopidogrel Pharmaceutical Ink" presents a concise overview of the stages involved in creating the ink. It is structured into four main phases: 1. Formulation Preparation: Involves preparing 1 % and 2 % clopidogrel formulations. 2. 3D Printing and In-Process Control: Focuses on the printing process and includes checks for accuracy and tablet appearance, along with a mass variation test. 3. Quality Control: Ensures tablet quality through assay, content uniformity, dissolution, and disintegration tests, as well as primary packaging. 4. Stability Study: Conducts comprehensive tests to assess the long-term stability of the ink, including assay, dissolution, pH, XRD, and FTIR.