Taste-Masked Microparticles of Sodium Warfarin Prepared by Hot Melt Extrusion and Thermal Postprocessing

Abstract

Background/Objectives. Warfarin possesses a bitter taste and requires a personalized dose in the range of 4.5 to 77 mg per week. This study investigated the potential for personalizing warfarin dosing by developing taste-masked matrix pellets. Pellets, supposedly, can be counted and orally administered in the required quantity to obtain the required dose.

Methods. The study evaluated the effects of drug load (10, 20, and 30 wt.%) on the duration of thermal postprocessing (to achieve the desired aspect ratio) and drug release. The warfarin sodium clathrate was characterized by determining its pKa value and dissolution kinetics in water, stomach-simulated media (0.1 M HCl, pH 1.2), and mouth-simulated media (phosphate-buffered solution (PBS), pH 6.8). A solid dispersion of warfarin sodium clathrate with Kollicoat^® Smartseal 100 P or Eudragit^® E PO was prepared using hot melt extrusion (HME). The mechanical properties of extruded filaments were characterized by measuring their elastic modulus. The microparticles (1–4 mm in length) prepared with filament cut pelletizing were thermally treated to produce ‘smoothened’ particles, which were analyzed with optical microscopy and drug release testing.

Conclusions. Microparticles with smoothened edges and an aspect ratio close to one are expected to improve mouthfeel and potentially patient compliance. No drug release was observed in mouth-simulated media, which indicated applicability to the taste masking of the microparticles. The proposed thermal treatment of HME microparticles, exemplified in this study, is a novel concept with underexplored potential in preparing taste-masked matrix pellets and dose personalization.

Introduction

Warfarin, a coumarin derivative and indirect-acting anticoagulant, is a vitamin K antagonist. The use of warfarin is primarily for the prophylaxis and treatment of deep venous thrombosis (DVT) and is commonly prescribed to manage conditions associated with recurrent thromboembolic events and related complications [1,2,3].

Warfarin is classified as a class II drug in the BCS system [4], with the experimentally estimated pKa in the range from 4.85 to 5.15 [5]. Due to warfarin’s poor solubility in aqueous solutions, commercially available dosage forms use the crystalline sodium clathrate form, consisting of warfarin sodium salt and isopropyl alcohol in a 2:1 molar ratio [6] (Figure 1), possessing a monoclinic space lattice [7].

The primary challenges and limitations in warfarin therapy are associated with hy-percoagulable conditions [8] or increased bleeding risk due to improper dosing related to genetic polymorphisms and warfarin’s very narrow therapeutic window [2,5]. Patients with these genetic variants typically require lower doses, associated with an increased risk of bleeding if standard doses are used [2]. The dose for each patient for anticoagulation varies in the range between 4.5 and 77 mg per week. To achieve the desired single dose, patients may need to combine multiple tablets or split tablets, which reduces compliance and increases the risk of side effects [9]. Frequent dose adjustments are often required, leading to the need for dose personalization [2].

Warfarin is available in specific, limited, commercially available dosage forms. Pri-marily, warfarin is commercially available in the form of oral tablets, with dosage ranging from 1 mg to 10 mg (Coumadin®) [10]. However, it is also available as an oral suspension and can be administered intravenously [2], as well as in lyophilized powder for injection. Tablets are the most common dosage form; however, liquid formulations are available for patients who have difficulty swallowing, such as children or the elderly, as oral admin-istration in such cases can lower compliance [10,11].

Splitting tablets or taking multiple tablets is a method of personalized dosing. How-ever, this approach may lack precision [9]. As an alternative approach, multi-unit systems such as mini-tablets or pellets can be considered [12]. Depending on the required dose, the number of mini-tablets or pellets can be adjusted accordingly [13].

Another limitation of oral formulations is warfarin’s bitter taste [14,15]. Attempts to prepare oral liquid taste-masking formulations were previously undertaken [14]. However, one of the most effective ways to prevent a bitter taste is to prevent bitter drug dissolution in the oral cavity. Various polymers with pH-dependent solubility can be used for this purpose, like acrylate-based copolymers [16]. Examples involve aminoalkyl methacrylate copolymer (Eudragit® E) [17] or methyl methacrylate and diethylaminoethyl methacrylate copolymer (Kollicoat® Smartseal 100 P) [12,18]. Another option is polyvinylacetal diethylaminoacetate (AEA) [19]. Effectively reducing bitterness, these polymers exhibit low solubility at the pH of the oral cavity (pH 5.8–7.4), but they are soluble at the pH of the stomach (pH 1–3.5) [16].

For taste masking, dosage forms can be implemented in the coated form [4] or matrix system using a polymer with pH-dependent solubility [16]. In the case of a matrix system, solid dispersion can be obtained by hot melt extrusion (HME), and taste-masked microparticles can be obtained by HME filament cut pelletizing [20].

Taste masking of bitter drugs using functional polymers and HME is currently under development [21]. For example, the effect of taste-masking polymer type (Kollicoat® Smartseal 100 P, Eudragit® EPO, and Kollicoat® MAE 100-55) on the properties of theophylline-containing (10–30 wt.%) pellets was investigated in the context of face-cut pelletized matrix pellets for pediatric application [22]. But cutting the filament typically results in microparticles with sharp edges, which poses discomfort and risk of oral soft tissue damage [23]. There are a significant number of scientific references on using taste-masking polymers (such as Eudragit® E PO or Kollicoat® Smartseal 100 P) for the preparation of taste-masked matrix pellets by HME and face-cut pelletization. Nevertheless, to the best of our knowledge, there is only one literature source reporting smoothening Eudragit® E PO-based particle sharp edges by thermal postprocessing [24]. Microscopic images of pelletized filament particles before and after treatment (at 85–95 °C) in the aqueous media showed the ability of the thermal treatment to change the aspect ratio and to smooth the cut side surfaces. The effect of temperature and the aqueous heat treatment duration on initial pelletized filament particles showed an increase in their aspect ratio difference (ΔAR) with an increase in temperature and treatment duration. The treatment-induced ΔAR was more pronounced for particles with an initial diameter of 1.01 ± 0.06 mm and initial length of 2.34 ± 0.20 mm than for particles with an initial diameter of 1.51 ± 0.09 mm and initial length of 2.93 ± 0.18 mm (Av. ± SD; n = 10). In addition, the thermal treatment with hot air showed the same tendency of ΔAR change as the aqueous thermal treatment [24]. It is known that applying thermal treatment near the polymer’s glass transition temperature enables elastic deformation of the polymer macromolecules [25]. By experimentally optimizing the duration of thermal treatment, microparticles with an aspect ratio close to one can be produced, resulting in shapes that more closely resemble spheroids or mini-tablets [24,26,27]. Thus, the applicability of other polymers for this purpose was not investigated.

This study aimed to investigate the potential for warfarin dose personalization through the preparation of taste-masking Kollicoat® Smartseal 100 P and Eudragit® E PO matrix pellets via hot melt extrusion and thermal postprocessing. During the study, the effects of drug load (10, 20, and 30 wt.%) on the duration of postprocessing thermal treatment (to achieve the desired aspect ratio) and on drug release were examined.

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Materials

The following were obtained: warfarin sodium clathrate (batch # WA22003; Alchymars Icm SM Private Ltd., Tamil Nadu, India) with a warfarin and isopropyl alcohol molar ratio of 2:1 [4]; methyl methacrylate (MMA) and diethylaminoethyl methacrylate (DEAEMA) copolymer (Kollicoat® Smartseal 100 P; BASF SE, Ludwigshafen, Germany); dimethylaminoethyl methacrylate (DEAEMA), butyl methacrylate (BMA), and methyl methacrylate (MMA) copolymer (Eudragit® E PO; Evonik Operations GmbH, Darmstadt, Germany); microcrystalline cellulose spheroids (Celphere™ CP-507 (500–710 μm); Asahi Kasei Co., Tokyo, Japan); glass beads (60 mesh/250 μm; BDH Laboratory Supplies, Poole, UK); and hydrochloric acid (HCl), sodium hydroxide pellets (NaOH), phosphoric acid (H3PO4), and potassium phosphate monobasic (KH2PO4; Merck KGaA, Darmstadt, Germany).

Kaufelde, P.; Aniskevich, A.; Sevcenko, J.; Žogota, M.; Horváth, Z.M.; Mohylyuk, V. Taste-Masked Microparticles of Sodium Warfarin Prepared by Hot Melt Extrusion and Thermal Postprocessing. Pharmaceutics 2026, 18, 582. https://doi.org/10.3390/pharmaceutics18050582

Read also our introduction article on Taste Masking Challenges here: