Formulation Strategies in the Development of Novel Nanostructured Multiparticulate Drug Delivery System for Poorly Water Soluble Antipsychotics: Ziprasidone Hydrochloride Monohydrate and Paliperidone

Abstract

Poor aqueous solubility remains one of the most persistent barriers to successful oral drug development, particularly for crystalline molecules for which dissolution rather than membrane permeability is the dominant rate-limiting step. Lipid-based systems, nanocrystals and nanosuspensions have therefore become important formulation platforms for increasing apparent solubility, dissolution rate and, in selected cases, oral exposure.¹⁻⁸ Ziprasidone hydrochloride monohydrate (ZHM) and paliperidone (PPD) are useful case studies because both are poorly water-soluble antipsychotics for which nanoscale and lipid-based approaches have been investigated, yet the published literature remains fragmented across different nanoarchitectures and evaluation models. This review integrates the formulation principles, mechanisms, material-selection criteria, preparation technologies, process variables, characterization requirements and translational considerations relevant to developing nano-enabled multiparticulate oral dosage forms of ZHM and PPD. Particular emphasis is placed on top-down nanosuspension/nanocrystal production, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), lipid nanoconstructs (LNCs), and nanocrystal– silica–lipid hybrid microparticles. Published ZHM work has demonstrated microfluidization-based nanosuspensions and a nanocrystal–silica–lipid hybrid system, while PPD has been investigated in SLNs, NLCs, LNCs and solvent– antisolvent nanosuspensions.⁹⁻¹⁴ A key formulation-development proposition emerging from the literature is that 'nano' should be treated as an intermediate product attribute rather than the final dosageform concept. For oral products, the nano-intermediate must survive processing, solidification, gastrointestinal dilution and, for lipid systems, digestion without losing the intended performance. Consequently, a robust development program should connect critical material attributes (CMAs) and critical process parameters (CPPs) to critical quality attributes (CQAs) and it must include dissolution studies, permeability and pharmacokinetic testing to establish mechanistic relevance.¹⁵⁻²² This publication proposes a formulation decision tree, stepwise preparation workflows, a CMA–CPP–CQA framework, comparative tables of published ZHM and PPD nanoformulations, and a research-gap agenda for developing dry, stable, scalable multiparticulate products. The intended outcome is a practical development framework for formulation scientists seeking to progress ZHM or PPD from laboratory-scale nanostructuring toward a rational and scalable oral nanomedicine