Prilling of crystallizable water-in-oil emulsions: Towards co-encapsulation of hydrophilic and lipophilic active ingredients within lipid microparticles

Introduction

Multiparticulate drug delivery systems consist of an assortment of small discrete units, where each unit is composed of the same dose of active substance (Dey et al., 2008). Generally found under various dosage forms such as pellets, beads, granules, micro-granules, spheroids, or micro-tablets, those units are mostly spherical with a diameter between 150 µm and 2 mm (Rajabi-Siahboomi, 2017).

Multiparticulate systems also offer significant advantages in terms of controlled-release (oral route or after implantation), fixed-dose combination, dose flexibility, and personalized dosing, which have a growing interest in the pharmaceutical domain. Indeed, as the dose is distributed equally between the multiple units, a default in one single unit, for example, in the enteric coating or a particle devoid of active substance, does not modify the release behavior of the entire dose. This system improves drug safety and avoids the “dose dumping” phenomenon observed with damaged coated monolithic forms. Moreover, a certain flexibility in drug release can be obtained by mixing particles with different types of coating. Multiparticulates are also convenient for fixed-dose combination (FDC) formulations used to deliver two or more active substances at once. The combination enhances patient compliance by reducing the number of medicines and simplifying their handling. This practicality is a significant advantage over monolithic FDC dosage forms, which have a risk of physicochemical and pharmacodynamic interactions (Fernández-García et al., 2020). Finally, due to its multiple individual units form, the dose administered can be adapted to every individual depending on different parameters such as weight, age, physiological differences, and crossed treatment. This adaptability makes multiparticulates genuinely patient-centric. Compared to the general population, pediatric and geriatric populations have trouble swallowing monolithic solid oral forms such as tablets and capsules due to their size and/or shape. Although it is known for patients with clinically recognized dysphagia, a survey of adults showed that this problem goes beyond the patient population and affects 40 % of the population (FDA, 2013). Besides, this flexibility in dose administration is also relevant in titration treatment, where the dosage is to be taken gradually. Incorporating those microparticles in a medical device should simplify such flexibility and enable personalized dosing.

Amongst other techniques, the prilling process has the advantage of producing spherical and monodisperse particles with a one-step process. The prilling process is an industrial process that consists of extruding a liquid through a vibrating nozzle (several thousand vibrations per second). This enables the laminar jet to break into calibrated droplets, which solidify during the fall.

Initially used in the agri-food industry to microencapsulate aromas, flavors, perfumes, and fertilizers, this technique has been used in the pharmaceutical industry to mask taste, protect active pharmaceutical ingredients (API), or limit interactions with the environment, but most recently in biotechnology to encapsulate recombinant proteins (Zhou et al., 2010) or cells for cell therapies and regenerative medicines (Whelehan & Marison, 2011) (Krishnamurthy & Gimi, 2011).

Microencapsulation using the prilling technique can be differentiated into two underlying processes, depending on the solidification mode of the drops formed at the nozzle outlet: sol–gel prilling and fusion prilling. In sol–gel prilling, the drops are made up of polymer solutions, e.g., alginates, and are collected in a gelling bath, e.g., calcium chloride, to allow their crosslinking before being rinsed and dried. Fusion prilling enables the production of microparticles from molten materials such as lipids. Unlike sol–gel prilling, the droplets solidify by sudden cooling while falling in a cold airstream.

This article will focus on the fusion prilling and the use of lipids as they have numerous benefits in the pharmaceutical industry. Lipids are notably biocompatible and biodegradable materials with low toxicity (Ghasemiyeh & Mohammadi-Samani, 2018). This enables various applications such as controlled and modified drug release of an API, taste masking, drug protection (Preeti et al., 2023) and incorporation of APIs that are slightly or not soluble in water. Those molecules belong to the II and IV BCS classes, which represent 90 % of the molecules in development.
In the pharmaceutical field, the potential of fusion prilling has started to be shown over the last decade. An extensive range of lipidic excipients have successfully been used to produce spherical microparticles such as fatty acids (stearic, behenic, myristic) (Vervaeck et al., 2013, Vervaeck et al., 2015) and mixed glycerides (glyceryl behenate, glyceryl palmitostearate) (Aleksovski et al., 2016, Pivette et al., 2009, Séquier et al., 2014, Séquier et al., 2020). These researchers managed to incorporate highly water-soluble drugs by solubilizing them into the lipidic matrix. Vervaeck et al. explored the controlled release of metoprolol tartrate in fatty acids matrixes (Vervaeck et al., 2013, 2015) and Pivette et al. focused on an antiepileptic drug release from Compritol 888 and paraffin wax (Pivette et al., 2012).

Vervaeck et al. extended their studies to obtain a fixed-dose combination microparticulate system of metoprolol tartrate and hydrochlorothiazide (Vervaeck et al., 2014). However, solubilizing a highly water-soluble drug in molten lipids is not always possible and requires the preparation of a suspension instead of a solution. Unfortunately, because suspension inside lipidic matrices could have high viscosities, a higher risk of clogging, or be non-Newtonian fluids, they can alter the jet breakup and the process feasibility. As defined by De Coninck et al., a suspension processable by prilling should be generated without thermal degradation, nozzle obstruction, or sedimentation during the process (De Coninck et al., 2019). These significant drawbacks, especially nozzle obstruction from API crystals, make choosing this formulation difficult. These authors solved this issue using a 445 µm nozzle and a nozzle/crystals size ratio around 20. However, the microparticles obtained were large in size, around 2 mm, and required to be cooled down in a liquid nitrogen bath (De Coninck et al., 2019).

The present work’s main objective is to deepen the potentialities of prilling for pharmaceutical applications by investigating crystallizable water-in-oil emulsions. Crystallizable emulsion means here that a jet of emulsion will be broken under heat before solidification by crystallization. This would extend the panel of APIs to be processable by prilling and introducing aqueous compartments in the molten lipids, where hydrophilic APIs would be solubilized in water. In the first part of this study, lipidic excipients were evaluated to choose the optimal lipidic emulsion and its processability with the prilling equipment. The second part focused on the characterization of the final microparticles in terms of shape, size, internal structure, drug loading, and stability. Urea and Erythromycin were selected as model molecules, respectively, highly and poorly water-soluble. Urea was solubilized in the aqueous compartment, and Erythromycin was in the lipidic matrix, producing microparticles incorporating two molecules of opposite polarities in a single formulation.

Read more here

Materials

Dynasan® 118 (glyceryl tristearate C18, melting temperature 70–74 °C) was supplied by Sasol (Germany GmbH). Compritol® 888 (mixture of glyceryl mono-, di- and tri-behenate, respectively 20, 52 and 26 %, and a C22 purity of 86 %, melting temperature 67–70 °C) and Precirol® ATO 5 (mixture of C16, C18 glyceryl palmitostearate with a predominant diester fraction, melting temperature 55 °C) were supplied by Gattefossé S.A.S. (Saint −priest, France). Montane® 60 (sorbitan monostearate).

Claire Delmas, Van Hung Nguyen, Jean-Jacques Vachon, David Chapron, Elena Longo, Lucia Mancini, Alexandre Michelet, Marco Meuri, Vincent Faivre, Prilling of crystallizable water-in-oil emulsions: Towards co-encapsulation of hydrophilic and lipophilic active ingredients within lipid microparticles, International Journal of Pharmaceutics, 2025, 125215, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125215.

---

Are you looking for excipients in commercial quantities?