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Oral modified-release multiparticulate dosage forms, which are also referred to as oral multiple-unit particulate systems, are becoming increasingly popular for oral drug delivery applications. The compaction of polymer-coated multiparticulates into tablets to produce a sustained-release dosage form is preferred over hard gelatin capsules. Moreover, multiparticulate tablets are a promising solution to chronic conditions, patients’ adherence, and swallowing difficulties if incorporated into orodispersible matrices. Nonetheless, the compaction of multiparticulates often damages the functional polymer coat, which results in a rapid release of the drug substance and the subsequent loss of sustained-release properties. This review brings to the forefront key formulation variables that are likely to influence the compaction of coated multiparticulates into sustained-release tablets. It focusses on the tabletting of coated drug-loaded pellets, microparticles, and nanoparticles with a designated section on each. Furthermore, it explores the various approaches that are used to evaluate the compaction behaviour of particulate systems.

The application of pH-sensitive polymers has been widely explored in pharmaceutical industry because of their versatile properties. This work aims to delay the release of indomethacin (IND), a commonly used anti-inflammatory drug, using a pH-dependent polymer within orally disintegrating tablets (ODTs) and to investigate the effect of the polymer particle size on the ODTs. When developing delayed-release formulations for orally disintegrating tablets (ODTs), it's essential to balance the pellet's matrix properties to maintain integrity and delayed release. Different sizes of Eudragit L100 were used to create IND-containing pellets via extrusion spheronization, which were then embedded into the matrix of ODTs. The particle sizes displayed good elastic properties with low Young's modulus (YM) values, and there was no significant difference between the different sizes (45, 60, 93 µm; p  > 0.05). The tensile strength of the pellets was directly proportional to YM ( p  < 0.05), providing enough support to maintain their integrity under compression. Pellets made from 63 µm Eudragit L100 had a suitable balance of mechanical and pharmaceutical properties compared to other sizes. 63 µm pellets had an aspect ratio of 1.49 ± 0.26 and 61% yield, while their ODTs showed a fast disintegration time of 14 ± 0.6 s, while modifying the drug release. Furthermore, IND exhibited modified release in acidic media (pH 1.2) and immediate release in buffer media (pH 6.8). Overall, protecting pellet integrity was crucial to delay release in acidic media and enable immediate release in alkaline media. The newly developed formulation will improve compliance and reduce side effects associated with IND and other irritant drugs particularly in elderly populations. Graphical Abstract Graphical illustration for developing delayed release indomethacin loaded Eudragit L100 pellets embedded in orally disintegrating tablets

Background and Aim: Orally disintegrating tablets (ODTs) combined with multiparticulate formulations of modified-release (MR) properties are considered more efficient medicinal options than traditional immediate-release formulations. ODTs & MR multiparticulates provide ease of medicinal use for dysphagic patients allowing a modified drug release to reduce the undesirable side effects, and the frequent daily dose would be eliminated, thus enhancing patient compliance. Nevertheless, the compaction of multiparticulates is challenging, causing polymeric damage leading to a loss in integrity and a rapid drug release. This project aims to prepare ODTs-MR of indomethacin (IND) and propranolol hydrochloride (PRH) by enhancing mechanical properties and the parameters of ODTs and multiparticulates production. Methods: Two developed and validated HPLC methods (according to ICH guidelines) were utilized to detect and quantify indomethacin (IND) and propranolol hydrochloride (PRH) release from the prepared formulations. The direct compression method was used to prepare ODTs, extrusion spheronization and spray drying to prepare the multiparticulates. The mechanical properties of ODTs and multiparticulates were assessed using texture analysis and hardness testing. Through the project, all formulations were examined using disintegration time, dissolution studies (pH 1.2 and 6.8), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and stereomicroscope. Results and discussion: IND loaded microparticles of Eudragit L100 were successfully delayed IND release in pH 1.2 buffer using acetone as a solvent. The low value of YM, using the appropriate solvent type and setting feed concentration at 5% w/v, was appropriate for modifying IND release. Similarly, Eudragit L100 was used to prepare IND loaded pellets. Lactose and mannitol (63, 125 and 500 µm) ODTs comprised of IND loaded pellets disintegrated in less than 30 seconds with acceptable mechanical properties of less than 1.5 MPa and an adequate elastic profile. Also, ODTs-pellets from lactose and mannitol delayed IND release in acidic media to less than 1.07% at 120 minutes while released more than 93% at 120 minutes in phosphate buffer (pH 6.8). Furthermore, the tensile strength of IND pellets of Eudragit L100 (45, 63 and 90 µm) was directly proportional to YM (p<0.05), offering enough support to maintain their integrity under compression. In addition, the in vitro release study showed a delayed release of IND in the acidic media (pH 1.2) and an immediate release in the buffer media (pH 6.8). On the other hand, the matrix system was unapplicable to delay PRH release from Eudragit RS based pellets despite changing the ratio and type of plasticisers. However, PRH pellets of reservoir system using Eudragit RS, Eudragit RL and combination of Eudragit RS: RL (1:1) w/w showed that the mechanical properties of the coated pellets differ significantly from the uncoated batch (p<0.05). Besides, ODTs reservoir-pellets were able to modify PRH release to ≤ 53.9% in acidic media and ≤ 47.2 % in phosphate buffer for 30 minutes, while the uncoated pellets released > 75% of PRH. Alongside, EDEM® successfully simulated the compaction process and showed that increasing compression force at the beginning of compression strengthens the interparticulate bonds at the surfaces resulting from the low surface roughness. Conclusion: Matrix system to sustain IND release was achieved using Eudragit L100 microparticles and pellets embedded in the ODTs. The lowest percentage of propranolol release was attained from the reservoir system of Eudragit RS and RL pellets embedded in the ODTs. All formulations of ODTs disintegrated in less than 30 seconds. A balance between Young's modulus and tensile strength is essential to enhance the integrity of the multiparticulates and, eventually, drug release.