Impact of Hot-Melt Extrusion on Glibenclamide’s Physical and Chemical States and Dissolution Behavior: Case Studies with Three Polymer Blend Matrices

Abstract

This research work dives into the complexity of hot-melt extrusion (HME) and its influence on drug stability, focusing on solid dispersions containing 30% of glibenclamide and three 50:50 polymer blends. The polymers used in the study are Ethocel Standard 10 Premium, Kollidon SR and Affinisol HPMC HME 4M. Glibenclamide solid dispersions are characterized using thermal analyses (thermogravimetric analysis (TGA) and differential scanning calorimetry), X-ray diffraction and scanning electron microscopy. This study reveals the transformation of glibenclamide into impurity A during the HME process using mass spectrometry and TGA. Thus, it enables the quantification of the extent of degradation. Furthermore, this work shows how polymer–polymer blend matrices exert an impact on process parameters, the active pharmaceutical ingredient’s physical state, and drug release behavior. In vitro dissolution studies show that the polymeric matrices investigated provide extended drug release (over 24 h), mainly dictated by the polymer’s chemical nature. This paper highlights how glibenclamide is degraded during HME and how polymer selection crucially affects the sustained release dynamics.

Introduction

Polymers are widely used to formulate oral solid dosage forms with modified drug release. Their physicochemical properties are crucial for assessing their ability to sustain drug release. An appropriate combination of polymers can create matrices that provide the desired sustained release properties and enhance the physical stability of the drug within the polymer–polymer blend matrix [1,2]. The hot-melt extrusion (HME) technique has become a recognized, continuous, solvent-free process in the product development of pharmaceutical dosage forms and innovative new dosage forms, where the active pharmaceutical ingredient (API) is dispersed into polymer (blend) matrices [3,4,5,6]. During the HME process, the API can either remain in a crystalline state or transform into the amorphous form, which shows better bioavailability. However, the amorphous state is thermodynamically unstable and challenging to maintain. Therefore, polymers also play a crucial role as carriers to prevent API recrystallization and stabilize the amorphous form in polymer matrices [7,8]. Besides the possibility of enhancing the drug’s oral bioavailability, HME has been demonstrated as a viable process for the preparation of sustained-release tablets, pellets, granules and injection molding [9,10]. Additionally, the HME process has been used in recent years to produce drug-loaded filaments via HME, enabling three-dimensional printing to create pharmaceutical forms with customized properties such as shape, size, dosage, and release kinetics. This advancement represents a step toward personalized drug therapies for individual patients [11,12]. However, the components of hot-melt extruded formulations must possess thermoplastic properties and exhibit thermal stability [2,13,14].

Indeed, the hot-melt extrusion process represents a challenge to process high-shear energy-dependent or heat-labile drugs [15]. The transformation of the physical state of the drug relies on mechanical and thermal energy inputs [16]. The energy needed for the transformation from the crystalline to amorphous state can cause a degradation of heat-labile drugs. Moreover, poorly stable drugs are susceptible to different degradation processes, including dehydration, isomerization, and, most commonly, hydrolysis and oxidation [9,17]. Chemical degradation can be generated within the HME process by the presence of moisture, oxygen and elevated temperatures [15,18]. Thermally induced degradation is provided by the external heat applied to the barrel [19]. In addition, mechanical energy is induced through the interplay of the screw elements and material within the barrel, which can also be converted to thermal energy. Thus, it becomes challenging to control the energy generated during the process [20]. Our model drug glibenclamide (GLB), also known as glyburide, is an antidiabetic drug rated as a class II compound of the Biopharmaceutics Classification System (BCS) due to its very poor water solubility and high permeability [21,22]. It is a crystalline compound with a melting temperature equal to Tm = 174 °C [23] that can also be amorphized by the classical quench cooling of the melt [22,24,25] or by milling [22,25]. However, according to Patterson et al. [25], with the first amorphization route, heating GLB above its melting point induces thermal degradation. This indicates that GLB is a heat-labile drug that contains two molecular parts susceptible to undergoing thermal degradation under severe conditions: on the one hand, the sulfonylurea part and, on the other hand, the benzamide group [26].

The main objective of the present study was to reach a better understanding of the impact of the hot-melt extrusion technique on the physical state, the chemical changes and the dissolution behavior of glibenclamide when extruded with different polymer blends at a temperature below the melting temperature of GLB. Firstly, the degradation of GLB during the HME process was assessed. Then, the physical state of the processed blends was characterized, and finally, the dissolution behavior of GLB within the different matrices was investigated in a two-stage dissolution set-up with in vitro dissolution media of varying pH.

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Materials

Glibenclamide (CAS number: 10238-21-8) was purchased from Sri Krishna Pharma (99.9% pure, Hyderabad, India). Impurity A of GLB (CAS number: 21165-77-5) was purchased from Merck (99.9% pure, Strasbourg, France). The materials were used as received. Three different polymers were used: ethyl cellulose (EC) under the name Ethocel Standard 10 Premium and hydroxy-propyl methyl cellulose (HPMC) under the trade name Affinisol HPMC HME 4M were kind gifts from Colorcon (Dartford, UK); polyvinyl pyrrolidone/polyvinyl acetate (PVP/PVPAc) branded as Kollidon SR was donated from BASF (Ludwigshafen, Germany). Kollidon SR is composed of 20 wt.% PVP and 80 wt.% PVAc. Phosphoric acid and sodium hydroxide were purchased from Sigma Aldrich (Seelze, Germany). Hydrochloric acid (32%) and monobasic potassium phosphate from Fisher Scientific, UK. Ultra-pure water was obtained from Veolia (Vendin le Vieil, France) and acetonitrile (HPLC grade) from Carlo Erba (Val de Reuil, France.

Zupan, N.; Yous, I.; Danede, F.; Verin, J.; Kouach, M.; Foulon, C.; Dudognon, E.; Florin Muschert, S. Impact of Hot-Melt Extrusion on Glibenclamide’s Physical and Chemical States and Dissolution Behavior: Case Studies with Three Polymer Blend Matrices. Pharmaceutics 2024, 16, 1071. https://doi.org/10.3390/pharmaceutics16081071

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