Evaluation of Process Parameters in the Development of Ternary Ketoprofen Amorphous Solid Dispersions via Hot Melt Extrusion

Abstract

Background/Objectives: Poor aqueous solubility of active pharmaceutical ingredients (APIs) remains a critical barrier to effective oral formulation. This study investigated the production of ketoprofen amorphous solid dispersions (ASDs) via hot melt extrusion (HME) using hydrophilic carriers and surfactants to enhance solubility and dissolution.

Methods: ASDs were prepared by the fusion method employing mannitol or polyethylene glycol (PEG) 4000 hydrophilic carriers and further modified by addition of poloxamer 188 or poloxamer 407 as surfactants. Solubility was evaluated, and the best performing formulations were selected for HME to assess the effect of extrusion parameters (temperature, screw speed and re-extrusion) on API solubility and dissolution. Selected ASD extrudates were formulated into tablets and capsules and further tested.

Results: Ternary ASDs exhibited higher solubility than their binary counterparts. The combinations of high-concentration hydrophilic carrier (mannitol or PEG 4000) and poloxamer 407 proved the most effective. The HME-produced ASDs showed superior solubility compared to the simple fusion method, with temperature being the most critical processing parameter, while screw speed and re-extrusion were carrier dependent, enhancing solubility for mannitol-based ASDs but not for PEG 4000; re-extrusion also led to mild color changes and technological issues preventing further processing. The selected ASD extrudates were successfully formulated into tablets and capsules with good physical characteristics and dissolution profiles.

Conclusions: These findings demonstrate the need to further investigate the potential of re-extrusion strategies and surfactant-enhanced ASD systems for improving the oral delivery of poorly soluble drugs.

Introduction

The solubility of an active pharmaceutical ingredient (API) significantly influences the absorption process, bioavailability and the desired therapeutic effect of the medicinal product. Poor solubility presents a challenge for approximately 40% of marketed APIs and up to 90% of new drug candidates [1,2], while low bioavailability resulting from poor solubility is one of the leading causes of failure in the early stages of clinical trials [1,3]. For these reasons, considerable efforts are being directed toward the development of various techniques aimed at enhancing the solubility of poorly soluble APIs, among which the use of amorphous solid dispersions (ASDs) has emerged as a promising strategy due to its efficiency and applicability in the pharmaceutical industry [1,4].

ASDs involve mixing or dispersion in the solid state of poorly soluble, hydrophobic API within a hydrophilic inert carrier or matrix [1,4,5]. Various crystalline carriers (such as urea, sucrose, dextrose, mannitol, etc.) and polymers (including polyvinylpyrrolidone, polyethylene glycol (PEG), hydroxypropyl methylcellulose, etc.) have been employed and investigated for the preparation of ASDs [1,2,4]. Additionally, surfactants are often incorporated into these systems to produce ternary ASDs with improved characteristics and performance [1,4,6,7].

The exact mechanism of action of ASDs is not fully understood. However, it is generally believed that the increased solubility results from the transformation of the API from a crystalline to an amorphous state and its dispersion within the carrier which leads to a reduction in particle size and an increase in the surface area in contact with the dissolution medium [1,4]. The stability of ASDs and the efficiency of solubility and dissolution enhancement largely depend on the structure and physicochemical properties of the system components, as well as on the type and intensity of the interactions established between them [1,8].

Reaggregation and recrystallization of the active substance from the hydrophilic carrier upon contact with the dissolution medium or during storage have been observed. This poses a challenge, as it can significantly slow down the dissolution process [1,4]. To mitigate these issues, ternary amorphous solid dispersions (ASDs) have been investigated, as the addition of a surfactant can enhance the wetting and solubilization of the API, reducing the likelihood of reaggregation or recrystallization [1,4,6,7]. These ternary systems have been shown to significantly improve stability and/or dissolution rate of some ASDs of poorly soluble APIs such as ketoprofen, domperidone and lansoprazole [9,10,11].

A variety of methods exist for the preparation of ASDs, but they are most commonly produced using either the fusion method or the solvent-based method [1,4]. Hot melt extrusion (HME) is a contemporary fusion-based technique in which a powder blend is conveyed through an extruder by rotating screws under elevated temperature and pressure resulting in melting and intense mixing of the components [4,12]. HME offers numerous advantages, as it represents a continuous, efficient, simple and cost-effective approach for producing ASDs, with applicability in the pharmaceutical industry [1,4,12]. However, careful consideration must be given to the potential impact of various processing parameters on the properties of the resulting ASD extrudates [12]. In addition to these considerations, the application of ASDs in the development of final dosage forms is further limited by potential technological issues such as poor powder flowability and compressibility, phase separation during processing or phase separation and slow disintegration due to polymer gelling [13,14].

Ketoprofen belongs to class II of the Biopharmaceutics Classification System (BCS). It is characterized by high permeability (readily crossing biological membranes) and low, pH-dependent solubility, which negatively affects the dissolution rate from pharmaceutical dosage forms and leads to prolonged absorption time and delayed onset of therapeutic effect [5,6,15]. For APIs such as ketoprofen, improving solubility is one of the key strategies for enhancing dissolution and accelerating absorption and onset of action. Owing to its poor aqueous solubility, well-defined physicochemical profile and relatively low therapeutic dose, ketoprofen represents a suitable model API for investigating ASD systems.

Since the stability of ASDs and their effect on solubility enhancement largely depend on the structure and physicochemical properties of the API, the hydrophilic carrier and the surfactant, as well as on their proportions and the conditions under which the ASDs are prepared, investigating the influence of these factors is essential for formulating ternary ASDs with optimal characteristics [1,4,5,6,7]. In this work, we aimed to formulate and prepare binary and ternary ASDs, initially using the fusion method to optimize composition and component ratios and subsequently applying the HME method. This study evaluated the influence of formulation composition and HME processing parameters on the solubility enhancement and dissolution rate of the API. Most suitable ASD extrudates were formulated into powder blends for tablet and capsule preparation, which were evaluated in terms of physical characteristics and dissolution rate to further assess ASD processability and performance.

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Materials

The following chemicals were used in the experiment: ketoprofen (Farmalabor, Canosa di Puglia, Italy, meets USP requirements), mannitol (Farmalabor, Canosa di Puglia, Italy), PEG 4000 (Alfa Aesar, Ward Hill, MA, USA), poloxamer 188 (BASF Chemtrade GmbH, Burgbernheim, Germany), poloxamer 407 (BASF Chemtrade GmbH, Burgbernheim, Germany). Size 0 hard gelatin capsules (Farmalabor, Canosa di Puglia, Italy; composition: indigo FD&C Blue 2 (E132), titanium dioxide, yellow iron oxide (E172), gelatin) were used for the purpose of ASD extrudates dissolution rate testing and preparation of final capsule dosage form. Tablets were prepared using anhydrous lactose (Super Tab 21AN, DFE Pharma, Goch, Germany, donated by Galenika AD, Belgrade, Serbia), magnesium stearate (Mosselman, Ghlin, Belgium), sodium starch glycolate (Primojel®, DFE Pharma, Goch, Germany; donated by Galenika AD, Belgrade, Serbia). Lactose (Capsulac®, Meggle, Wasserburg am Inn, Germany) was used as a filler in the capsule formulations. Methanol (Lachner, Neratovice, Czech Republic) was used for ketoprofen content determination. Purified water for the experiments was obtained by distillation (AC-L8, Optic Ivymen System, J.P. Selecta, Cham, Switzerland) at the Department of Pharmacy of the Faculty of Medicine Novi Sad.

Stjepanović, A.; Todorović, N.; Poša, M.; Marinković, I.; Ristić, I.; Farkaš Agatić, Z.; Lalić-Popović, M. Evaluation of Process Parameters in the Development of Ternary Ketoprofen Amorphous Solid Dispersions via Hot Melt Extrusion. Pharmaceutics 2026, 18, 241. https://doi.org/10.3390/pharmaceutics18020241

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