Milling of poorly water-soluble drugs in oil via dual centrifugation - A closer look at stabilization and application on orodispersible films

Abstract

In the pediatric patient group, there is a constant need for individualized dosage forms with precise and adjustable drug dosing. Pharmaceutical inkjet printing allows patient-oriented dosage forms, such as orodispersible films, to be individualized. Poorly water-soluble drugs, which make up a large proportion of prescription, present challenges in terms of formulation properties and bioavailability that need to be further investigated. This study investigated an approach to the preparation and application of lipid-based nanosuspensions of the poorly soluble model drugs diclofenac (Dcl), griseofulvin (Gri) and mebendazole (Meb) by milling in medium-chain triglycerides (MCT) with various stabilizing additives. The grinding processes were conducted by dual centrifugation, preparing Gri nanosuspensions of x₅₀ = 520 nm, stabilized with LipoidS20 (LipS20), which also showed storage stability over four weeks. Oily Meb nanosuspensions did not require any stabilizing additives to form stable nanosuspensions (x₅₀ = 130 nm). However, an increased viscosity of the oily formulations was observed, which influences the following 2D printing process of the drug-containing inks. The oily suspensions were therefore further processed and emulsified in water so that the aqueous continuous phase serves as a vehicle for lipid droplets containing the drug nanoparticles. In biphasic in vitro dissolution tests, more than 80 % of the drug was released within 45 min, underlining an improved dissolution behavior of the lipid-formulated nanosuspensions.

Introduction

The vulnerable pediatric patient group includes individuals from neonates to adolescents, which makes the group quite heterogeneous. This group not only exhibits anatomical and physiological differences, but also major differences to adults [1,2]. Therefore, special attention in the treatment focuses on acceptability, safety and capability of the medication [3]. As in adult therapy, the oral administration route is preferred, but the choice of age-appropriate dosage forms, such as liquid formulations and orodispersible films or tablets that meet the above-mentioned requirements, is important [2,4,5]. Despite EU directive EC 1901/2006, which has required a pediatric investigation plan since 2007, a large proportion of pediatric prescriptions in European countries are still off-label [6,7] (different indication, dose, frequency, duration of therapy or different patient group [8]). This shows that there is an urgent need for individualized preparations with precise dosages and possible dose adjustments, which are prepared in hospital or community pharmacies.

A promising way towards individualized dosage forms with highly adjustable doses, also for pediatric therapy, is pharmaceutical inkjet printing (2D printing) of active pharmaceutical ingredients (APIs) on orodispersible film templates [9,10]. Visser et al. evaluated a data set from pediatric prescriptions from the Netherlands regarding suitability for 2D printing and found that the biggest challenge was the poor solubility of the APIs, which led to the use of organic solvents or printing of aqueous nanosuspensions [7]. This reflects the general, recurring challenge faced in pharmaceutical research due to the poor water solubility of APIs, which leads to low bioavailability [11].

Nanosuspensions of poorly water-soluble APIs are generally known to improve the bioavailability of the APIs [12]. Due to their high surface-to-volume ratio, the dissolution rate is increased. They can be prepared by bottom-up or top-down methods, such as high-pressure homogenization or wet media milling. In recent years, dual centrifugation has increasingly become the focus of research for lab-scale preparations of established nanosized drug delivery systems, such as liposomes, solid lipid nanoparticles and nanoemulsions, as well as novel systems like lipodisks [13,14]. The preparation of aqueous nanosuspensions of poorly water-soluble APIs in the dual centrifuge as a form of wet bead milling was also investigated. Key process parameters are the temperature in the vial and process time, the shape of the vial or the addition of different quantities and sizes of grinding beads. In addition, good reproducibility was reported [15,16]. Hagedorn et al. were able to prepare comparable nanosuspensions containing fenofibrate, naproxen and ibuprofen using dual centrifugation and an agitator bead mill, which makes grinding processes by dual centrifugation a powerful predictive tool for upscaling processes [17].

Another beneficial way to further increase bioavailability of poorly soluble APIs is to prepare lipid-based formulations [18]. When administered orally, digestion of the lipids starts in the stomach and, together with the lipid excipients, the drug molecules are solubilized by bile salts and pancreatic fluid, which supports enteric absorption [19]. For molecules with high crystal lattice energies (resulting in high melting points >150 °C) lower solubilities in lipids are expected [20]. For these APIs, a formulation in the form of lipid suspensions could be advantageous and result in a higher possible drug load.

Although there is a lot research on aqueous API nanosuspensions [21] and lipid-based carrier systems, there is less knowledge regarding lipid API nanosuspensions. Lipid suspensions are often formulated as a depot formulation in the context of long-acting injectables [22]. This oil-mediated effect on bioavailability could also be advantageous for oral drug application. The already described preparation methods for oily nanosuspensions can be relatively complex, whereby the API is first nanosized in aqueous medium, freeze-dried and then redispersed in an oily medium [22]. Wang et al. showed the preparation of oily nanosuspensions of dexamethasone and hydrocortisone directly in middle chain triglycerides (MCT) and low viscosity paraffin by dual centrifugation for dermal application. They focused on stabilizer-free oily nanosuspensions, which were stable due to the high viscosity of the samples caused by the oily formulation and high drug loads [23]. In recent studies, inkjet printing of lipid-based systems such as liposomes and lipoplexes has become more relevant [24,25].

Extending this approach to lipid-based formulations containing API particle achieving higher drug loads – such as oily nanosuspensions – provides a promising strategy for overcoming solubility limitations of poorly soluble APIs, enhancing bioavailability and enabling precise and personalized drug delivery through inkjet printing.
This study combines the need for formulation concepts of poorly soluble APIs with enabling high drug loads without the use of organic solvents for individualized oral therapy. For this purpose, emulsified nanodispersions (eND) were developed and printed onto orodispersible film templates. The drug-containing inks consist of an aqueous emulsion in which drug nanoparticles are additionally dispersed in the oily phase. This allows for a higher drug loading, since the saturation solubility is no longer a limiting factor. To prepare these inks, three poorly water-soluble model drugs, griseofulvin (Gri), mebendazole (Meb) and diclofenac acid (Dcl), are first directly ground in MCT using dual centrifugation. All three selected model APIs are classified in class two of the biopharmaceutical classification system (BCS; low solubility and high permeability), whereas for Meb also class four can be found in literature [26]. In the first part of the study, direct milling in oil was examined in detail with regard to stabilizer performance in order to better understand the preparation process of oily nanosuspensions. Afterwards, these oily suspensions were emulsified in water also using dual centrifugation. To enable an individualized oral application of the prepared formulations, structured orodispersible templates (SOFTs) were loaded with lipid-containing nanoparticular formulations and dissolution experiments were carried out. Both formulations (oily nanosuspension and eND) were compared to an unground suspension. In the long term, these lipid-containing eNDs should be used as inks for pharmaceutical 2D printing for individualized patient treatment.

Download the full article as PDF here Milling of poorly water-soluble drugs in oil via dual centrifugation

or continue reading here

Materials

For the preparation of nanosuspensions, three poorly water-soluble APIs were used as model drugs: griseofulvin (Gri) and mebendazole (Meb) from Thermo Fisher scientific Inc. (Waltham, United States) as well as diclofenac (Dcl) acid from Chemodex (St. Gallen, Switzerland). The APIs were mainly selected based on their poor water-solubility, as well as their high melting points (Table 1) and varying Log P values. For stabilization purposes, phospholipids (Lipoid® S20 – LipS20, Phospholipon® 90G – P90G, Lipoid® P75-3 – LipP75-3) were gifted from LIPOID GmbH (Ludwigshafen, Germany). Sorbitan monostearate (Span60; Dehymuls SMS) was purchased from BASF (Ludwigshafen, Germany). Poloxamer 407 (Px407), sodium dodecyl sulfate (SDS) and medium-chain triglycerides (Miglyol® 812 – MCT) from Caesar & Loretz (Hilden, Germany) as well as MCT kindly gifted from Gustav Heess GmbH (Leonberg, Germany) were used.

Lena Mahlberg, Marie Ebenhöch, Denise Steiner, Milling of poorly water-soluble drugs in oil via dual centrifugation – A closer look at stabilization and application on orodispersible films, Journal of Drug Delivery Science and Technology, Volume 126, 2026, 108735, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2026.108735.