Feasibility of Hot Melt Extrusion in Converting Water-Based Nanosuspensions into Solid Dosage Forms

Abstract

Aim: In addition to numerous benefits provided by nanosuspensions (NSs) (e.g., enhanced saturation solubility, increased area for interaction with fluids), they suffer from major stability, handling and compliance issues. To overcome these challenges, we evaluated the feasibility of hot melt extrusion (HME) in transforming a cinnarizine-based NS, selected as a case study, into granules for oral intake.

Methods: Thermoplastic polymers, in principle compatible with the thermal behavior of the selected drug and characterized by different interaction mechanisms with aqueous fluids, were used as carriers to absorb the NS and were processed by HME.

Results: The extruded granules pointed out good physio-technological characteristics, a drug content > 85% with coefficient of variation (CV) < 5% and tunable in vitro performance coherent with the polymeric carriers they were composed of. Particle size as well as the solid state of cinnarizine was checked using several analytical techniques in combination (e.g., DSC, SEM, FT-IR, Raman). Depending on the composition of the granules, and specifically for formulations processed below 85 °C, the drug was found to remain crystalline and in the desired nanoscale.

Conclusions: HME turned out to be a versatile process to transform, in a single-step, NSs into multi-particulate solid products for oral administration showing a variety of release profiles.

Introduction

In recent years, the advent of digital technologies, such as artificial intelligence, machine learning and high-throughput screening methods, has led to the development of numerous new chemical entities (NCEs) having a high affinity for the biological target and enhanced pharmacological activity [1,2,3]. In this field, major efforts were devoted to the development of solid products for oral administration, like tablets and capsules, containing such NCEs, to ensure high patient compliance and low manufacturing costs, thus facilitating their spread in the pharmaceutical market [4,5].

However, due to their relatively large molecular weight as well as chemical structures, many NCEs present permeability issues through the gastrointestinal (GI) membranes and poor solubility in the GI fluids, which could affect absorption and bioavailability upon oral intake [6,7].

To counteract solubility constraints, nano-sizing poorly soluble drugs, resulting in the attainment of NSs, has been widely investigated [8,9,10].

NSs are submicron colloidal, heterogeneous, aqueous dispersions of practically insoluble active ingredients with a particle size in the 1–1000 nm range, which are stabilized in their crystalline state by different excipients, such as surfactants and thickening agents [11]. They can be attained through top-down or bottom-up methods, the former relying on the application of mechanical stress, while the latter on a controlled condensation/aggregation of particles from a molecular dispersion [12]. Overall, NSs are characterized by many advantages such as (i) enhanced specific surface area of the drug bulk and improved saturation solubility [13], which would result in a faster dissolution rate according to the Noyes–Whitney dissolution model [14], (ii) greater surface of interaction of drug particles with the solvent [15] and (iii) enhanced mucoadhesion, increasing their GI residence and thus the time available to complete the dissolution process [1]. However, they are ale characterized by physical and chemical stability issues, resulting, for instance, in sedimentation, aggregation, solid-state transformation, dimensional alteration and crystal growth [10,16,17].

To reduce these phenomena, removing water and transforming NSs into more convenient solid products, without losing the advantages related to the presence of the drug at the nano-scale, would be fundamental. As a first stage, researchers tested well-established spray-drying and freeze-drying technologies on NSs, improving their stability and handling [18,19,20,21,22,23]. However, such traditional drying methods suffer from high energy consumption and long processing times, representing only the preliminary step in the manufacturing of a solid dosage form. On the other hand, attaining the final medicinal products taking advantage of the so-called continuous manufacturing approach has recently raised a lot of interest [24,25,26,27,28]. Indeed, it was demonstrated a suitable way to increase manufacturing efficiency as well as production rate while reducing expenses per unit, especially if coupled with real-time quality controls. In this respect, hot melt extrusion (HME) using Soluplus™ as the polymeric carrier was tested as an alternative and single-step process to transform NSs into solid products and was named nano-extrusion [29,30,31]. Indeed, hot-processing and particularly HME has recently emerged as a promising and versatile technology [31,32,33,34,35,36], not only towards the manufacturing of solid dispersions, but also to attain a variety of delivery systems (e.g., granules, capsules, pellets, tablets, rings, implants, inserts), ranging from immediate to modified release, and intended for diverse administration routes.

Based on the above-mentioned considerations, in this work we intended to widen the range of formulations undergoing HME to directly transform a water-based NS into solid dosage forms for oral intake. More in detail, HME was carried out to manufacture, in a one-step process, multi-particulate systems (i.e., granules) starting from a cinnarizine-containing NS (CN NS), which was employed as a noteworthy case study. Indeed, CN not only has a challenge of thermal behavior (i.e., relatively low melting temperature, Tm) but could also represent a model compound for the class II of the Biopharmaceutical Classification Systems (BCSs), in which many NCEs fall [37]. For the sake of versatility, polymeric formulations in a diverse range of release performances (i.e., immediate and prolonged release, targeted release to specific sites of the GI tract) were evaluated.

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Materials

In this study, we used polyethylene oxides (PEOs) with different molecular weights (Sentry POLYOXTM WSR N10 LEO NF, PEO N10; Sentry POLYOXTM 303 LEO NF, PEO 303; Iff, Milan, Italy); polymethacrylates (Eudragit® RL PO, Eu RL; Eudragit® RS PO, Eu RS; Eudragit® E PO, Eu E; Evonik, Essen, Germany); glycerol (GLY; A.C.E.F., Milan, Italy); polyethylene glycol 8000 (PEG; Clariant Masterbatches, Milan, Italy); triethyl citrate (TEC; Sigma Aldrich, Milan, Italy); sodium starch glycolate (EXPLOTAB® CLV, EXP; JRS PHARMA, Rosenberg, Germany); hydrated dextrates (EMDEX®, EMD; JRS PHARMA, Rosenberg, Germany); glycerol (GLY; Pharmagel, Lodi, Italy); hydroxypropyl methylcellulose (Pharmacoat® 603; Shin-Etsu Chemical Co., Tokyo, Japan); copovidone (Kollidon® VA 64, BASF SE, Ludwigshafen, Germany); dioctyl sulfosuccinate sodium salt (Sigma Aldrich, Darmstadt, Germany); sodium lauryl sulphate (Carl Roth, Karlsruhe, Germay); potassium dihydrogen phosphate (KH2PO4) (VWR, Milan, Italy); potassium monohydrogen phosphate (K2HPO4) (VWR, Milan, Italy); methanol (VWR, Milan, Italy); HCl (VWR, Milan, Italy); sodium cloride (NaCl) (VWR, Milan, Italy); epoxy resin (Araldite®, Velcro Brand, Deinze, Belgium).

CN NS was kindly supplied by Novartis Pharma AG (Basel, Switzerland) and contained d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), Sigma-Aldrich, Basel, Switzerland) as a steric stabilizer [38]. CN is a highly lipophilic BCS Class II drug, having a highly pH dependent solubility (0.29 mg/mL at pH 2, 0.017 mg/mL at pH 5, and 0.002 mg/mL at pH > 6.5) and Tm of 118–122 °C [39,40]. CN NS was manufactured by Novartis Pharma AG, according to previous studies [32].

Ragucci, E.; Uboldi, M.; Sobczuk, A.; Facchetti, G.; Melocchi, A.; Serratoni, M.; Zema, L. Feasibility of Hot Melt Extrusion in Converting Water-Based Nanosuspensions into Solid Dosage Forms. Pharmaceutics 2025, 17, 662. https://doi.org/10.3390/pharmaceutics17050662