Processing of Lipid Nanodispersions into Solid Powders by Spray Drying

Spray drying is a promising technology for drying lipid nanodispersions. These formulations can serve as carrier systems for poorly water-soluble active pharmaceutical ingredients (APIs) that are loaded into the lipid matrix to improve their bioavailability. Once the API-loaded nanocarriers have been further processed into solid dosage forms, they could be administered orally, which is usually preferred by patients. Various solid lipids as well as oils were used in this study to prepare lipid nanodispersions, and it was shown that their nanoparticulate properties could be maintained when lactose in combination with SDS was used as matrix material in the spray-drying process. In addition, for lipid nanoemulsions loaded with fenofibrate, a good redispersibility with particle sizes below 300 nm at a lipid content of 26.8 wt.% in the powders was observed. More detailed investigations on the influence of the drying temperature yielded good results when the inlet temperature of the drying air was set at 110 °C or above, enabling the lactose to form an amorphous matrix around the embedded lipid particles. A tristearin suspension was developed as a probe to measure the temperature exposure of the lipid particles during the drying process. The results with this approach indicate that the actual temperature the particles were exposed to during the drying process could be higher than the outlet temperature.

Introduction

The increasing number of newly developed active pharmaceutical ingredients (APIs) that are poorly water-soluble is a well-known challenge that formulation specialists have been facing in recent years [1]. The high lipophilicity and/or highly stable crystal lattice of these substances often lead to a very low bioavailability [2]. To overcome this drawback, various formulation strategies have been developed. A very promising approach is the loading of these APIs into lipid nanocarriers such as nanosuspensions or -emulsions [3]. These lipid carriers are biocompatible and, therefore, suitable for different routes of administration [4,5]. After preparation, such lipid carrier systems are in the liquid state and can, therefore, be used easily for parenteral and dermal drug delivery, as already done in many applications. For oral use, a solid dosage form is more suitable and enjoys much higher patient acceptance [6]. Studies on the oral bioavailability of poorly water-soluble APIs in lipid nanodispersions revealed a positive effect on the absorption of the APIs due to the presence of the lipid [7,8] and, in addition, a reduction in the so-called food effect [9]. To formulate a solid drug delivery system for the API-containing lipid particles, a further processing of the API-loaded nanodispersions into dry powders is required. These powders could then be administered to the patient directly or serve as an intermediate product for the formulation of granules or tablets [10,11].

One possibility to further process lipid nanodispersions into lipid-containing powders is by spray drying. This drying process is well established and used in various disciplines. The spray-drying behavior of lipid nanoemulsions has already been studied in some detail, with formulations dried with and without the addition of a matrix material. Christensen et al., for example, prepared fractionated coconut oil emulsions (size x₅₀ = 820 nm) with different HPMC (hydroxypropyl methyl cellulose) types and spray-dried these formulations without adding additional matrix material. According to their results, this allowed an embedding of up to 40% lipid in the dry powder mass, with only a slight increase in droplet sizes after redispersion of the powders [12]. In another study of these authors, various matrix materials were added to the emulsion before spray drying to increase the powder density before tableting of lipid-containing but API-free powders. This resulted in solid dosage forms with a lipid content of up to 20% [11]. APIs such as intraconazole [13] or 5-PDTT (5-phenyl-1,2-dithiole-3-thione) [14] have also been incorporated into lipid emulsions and embedded in matrices by spray drying. In vitro and in vivo studies conducted with the resulting API-containing powders showed improved bioavailability of both APIs compared to the unformulated API or a previous dosage form prepared with cyclodextrins.

While the physical state of emulsion droplets is not affected by high temperatures during the spray dying process, drying of solid lipid nanoparticles could be more challenging because they may melt during the process. Foundational studies by Masters on the spray drying of particle-containing formulations indicated that the temperature exposure of the product particles during drying is approx. 15 to 25 °C below the outlet temperature of the drying air (measured between the drying chamber and the process unit for particle separation) [15]. In the course of investigations on the spray-drying behavior of protein solutions, this perception was modified and it is currently assumed that the outlet temperature describes the maximum temperature the formulations are exposed to upon drying [16,17]. The first spray-drying studies with drug-free dispersions of solid lipid particles from different lipid types, such as tristearin and Compritol, indicated that such particles could be embedded in matrices without losing their nanoparticulate properties. The authors of these studies assumed that the temperatures to which the particles were exposed to were well below their melting temperatures and, thus, did not have an effect on the physical state of the lipids during drying [18,19]. In studies dealing with the spray drying of Compritol particles loaded with rapamycin, agglomeration of the particles after redispersion of the powders was observed. This was considered to be a consequence of suboptimal process conditions, although a good reproducibility was shown [20].

The current study started with investigations on tristearin nanodispersions initially focusing on the identification of a suitable matrix material for embedding the lipid particles upon spray drying, as well as an optimized formulation for preparing the nanodispersions by high-pressure homogenization. To evaluate the transferability of the optimized formulation to other lipid nanocarrier systems, various dispersions of oils and solid lipids were spray-dried and the redispersibility of the lipid-containing powders in water was tested. Nanoemulsions loaded with the model API fenofibrate were also included in these investigations. In the last part of this study, the time- and formulation-dependent polymorphic transformation of tristearin nanoparticles was used to further investigate the effect of the drying temperature on the physical state of the particles [21,22]. While triglycerides are known to crystallize first in the metastable α-polymorphic form and then transfer to the more ordered and stable β-modification [23,24], a suspension containing mainly nanoparticles in the β-polymorphic form was spray-dried and the content of particles that had melted during the process was evaluated in dependence on the drying temperature.

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Materials

Various solid lipids as well as oils were used for the preparation of lipid nanodispersions. Solid glycerides: Compritol (mono-, di-, and triesters of behenic acid, Compritol 888; Gattefossé, Saint-Priest Cedex, France), tristearin (Dynasan 118), tripalmitin (Dynasan 116), and trimyristin (Dynasan 114; all from Hüls/Condea, Witten, Germany; all kind gifts from the manufacturer). Oils: Miglyol (medium-chain triglycerides, Miglyol®812; Caesar&Loretz, Hilden, Germany), refined soybean oil (Roth, Karlsruhe, Germany), and refined rapeseed oil (Caelo, Hilden, Germany). Lipid dispersions were stabilized with the polymers PVA (polyvinyl alcohol, Mowiol 3-83; Kuraray Europe, Hattersheim, Germany) or HPMC (hydroxypropyl methyl cellulose, Pharmacoat 606; Shin-Etsu Chemical Eo., Tokyo, Japan; kind gift from Harke Pharma, Mülheim an der Ruhr, Germany) and the surfactant SDS (sodium dodecyl sulphate; Roth, Karlsruhe, Germany). The following matrix materials were used during spray drying: lactose (lactose monohydrate; Meggle, Wasserburg am Inn, Germany; kind gift from the manufacturer), mannitol (D-mannitol; Sigma-Aldrich, Taufkirchen, Germany), and sucrose (D(+)-saccharose; Roth, Karlsruhe, Germany). The poorly water-soluble API fenofibrate (FENO; Novartis Pharma AG, Basel, Switzerland; kind gift) was used as a model substance. Tetrahydrofuran (THF; Sigma-Aldrich, Taufkirchen, Germany) was used for characterization purposes. Bidistilled water was used in all experiments.

Denise Steiner, Leonie V. Schumann, Heike Bunjes, Processing of Lipid Nanodispersions into Solid Powders by Spray Drying, Pharmaceutics 2022, 14(11), 2464; https://doi.org/10.3390/pharmaceutics14112464

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