Dry Amorphization of Itraconazole Using Mesoporous Silica and Twin-Screw Technology

Abstract

Background/Objectives: Amorphization of an active pharmaceutical ingredient (API) can improve its dissolution and enhance bioavailability. Avoiding solvents for drug amorphization is beneficial due to environmental issues and potential solvent residues in the final product.

Methods: Dry amorphization using a twin-screw extruder is presented in this paper. A blend of mesoporous silica particles and crystalline itraconazole was processed using a pharma-grade laboratory scale twin-screw extruder. The influence of different screw configurations and process parameters was tested. Particle size and shape are compared in scanning electron microscopy (SEM) images. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) are used to determine the residual amount of crystalline itraconazole in the final product.

Results: An optimized screw configuration for the process was found which leads to more than 90% amorphous API when processed at room temperature. Full amorphization was reached at 70 °C. The specific mechanic energy (SME) introduced into the material during twin-screw processing is crucial for the dry amorphization. The higher the SME, the lower the residual amount of crystalline API. Two months after processing, however, recrystallization was observed by XRD.

Conclusions: Dry processing using a twin-screw extruder is continuous, free of solvents and can be performed at low temperatures. This study proves the concept of twin-screw processing with mesoporous silica for dry amorphization of itraconazole.

Introduction

The oral administration of drugs requires solubility in the gastrointestinal fluid before its absorption into the bloodstream. However, 90% of new chemical entities and 40% of the top solid oral drugs marketed in the U.S. and Europe are poorly water soluble [1,2]. Generally, crystalline APIs possess high purity and physio-chemical stability, but the crystal lattice energy barrier hinders their dissolution. This results in the low bioavailability of the active pharmaceutical ingredient (API), as it is limited by its solubility and permeability. An API in its amorphous state inheres increased solubility but is thermodynamically unstable and recrystallisation needs to be prevented by excipients or carriers [3]. Typically, these are polymers, e.g., polyvinyl pyrrolidone (PVP) or hydroxypropyl methylcellulose (HPMC) [4]. Recently, inorganic mesoporous carriers possessing high numbers of nano-scale pores, have shown improved stability of the amorphous state of some APIs [5,6,7,8,9,10]. Amorphization can either be achieved by the dissolution of the API crystals in a solvent or by solvent-free methods, i.e., melting or milling [11]. Milling bears the advantages of a solvent-free process with preferentially low temperature impact on the API. The high internal surface area in combination with the intermolecular hydrogen bonding between the API and the carrier results in a stable amorphous single-phase system [5,12]. Solvent-free amorphization of APIs with mesoporous silica in a batchwise ball milling process has shown to improve the API’s dissolution performance [8,12,13,14,15]. However, this processing route requires long milling times (15 min or more) [8,13]. Transferring this batch process into continuous manufacturing promises a reduction in production down-time and costs, faster development times, increased reproducibility, and flexibility of production [16,17]. Twin-screw extruders are used for continuous granulation with controlled throughput, specific mechanical energy introduction, and material temperature. Extruders in twin-screw granulation (TSG) mode allow for the wet and dry processing of pharmaceutical ingredients. In this study, a solvent-free dry granulation process is evaluated for the amorphization of crystalline itraconazole with mesoporous silica powder. The factors with the biggest impact on the process are expected to be the configuration of the screws, the residence time during twin-screw processing, and the specific mechanical energy introduced into the material. However, to our knowledge, this has not been analyzed in detail yet. Therefore, the focus of this study is to evaluate different screw configurations and process settings and their influence in the residual crystallinity of the API in the formulation.

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Materials

Mesoporous silica powder (SYLOID XDP 3050 E551, Grace, Worms, Germany) and the API itraconazole (Sporanox, Janssen Pharmaceutica, Beerse, Belgium) mixed in equal weight fractions (weight fraction itraconazole ωi = 0.5). The blending was performed by manual mixing of a 500 g batch in a container of 2 L size. To homogenize the blend, it was pushed through a sieve with a mesh size of 710 µm.

Richter, M.; Welzmiller, S.; Monsuur, F.; Völp, A.R.; Quadflieg, J. Dry Amorphization of Itraconazole Using Mesoporous Silica and Twin-Screw Technology. Pharmaceutics 2024, 16, 1368. https://doi.org/10.3390/pharmaceutics16111368

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