Effect of Liquid Load Level and Binder Type on the Tabletability of Mesoporous Silica Based Liquisolids

Abstract

Mesoporous silica offers an easy way to transform liquids into solids, due to their high loading capacity for liquid or dissolved active ingredients and the resulting enhanced dissolution properties. However, the compression of both unloaded and loaded mesoporous silica bulk material into tablets is challenging, due to poor/non-existing binding capacity. This becomes critical when high drug loads are to be achieved and the fraction of additional excipients in the final tablet formulation needs to be kept at a minimum. Our study aimed to investigate the mechanism of compression and tabletability dependent on the Liquid Load Level of the silica and type of filler/binder in binary tabletting mixtures. To this end, Vivapur® 101, FlowLac® 90, Pearlitol® 200 SD and tricalcium citrate tetrahydrate were selected and mixed with Syloid® XDP 3050 at various Liquid Load Levels. Compaction characteristics were analysed using the StylOne® Classic 105 ML compaction simulator. Additionally, the Overall Liquid Load (OLL) was defined as a new critical quality attribute for liquisolid tablets. The Overall Liquid Load allows straightforward, formulation-relevant comparisons between various fillers/binders, liquid components, and silica types. Results indicate strong binding capacity and high plasticity of the fillers/binders as key components for successful high liquid load silica tablet formulation. A volumetric combination of 30% Vivapur® 101 and 70% 0.75 mL/g loaded Syloid® XDP 3050 proved to be the most effective mixture, achieving an Overall Liquid Load of 36–41% [v/v] and maintaining a tensile strength of 1.5 N/mm² with various liquid vehicles.

Introduction

Silica is a versatile material extensively used in the pharmaceutical industry for various applications. Primarily, it is used as a glidant, but it can also be utilised as a desiccant or serve as a carrier for actives in solid or liquid form [1, 2]. Silica can be classified into two types, non-porous fumed silica (such as Aerosil® or Carb-O-Sil®) and mesoporous silica, with a pore size ranging from 2–50 nm [3]. Mesoporous silica can be further categorised into ordered and disordered types based on their pore structure [4].

“Liquisolid systems” were developed in the 1990s by Spireas et al., [1, 5] and have shown promising results in increasing the solubility of drugs exhibiting poor aqueous solubility. This is especially important since with the advent of high throughput screening methods, more new chemical entities are poorly water-soluble [6]. In literature, increased in vitro solubility has been described for cannabidiol [7], naproxen [8], furosemide [9], carbamazepine [10], and several other active pharmaceutical ingredients (APIs) [11,12,13]. Additionally, some authors also report successful in vivo trials with both beagle dogs [14] and healthy human volunteers [15].

Liquid components such as hydrophobic vitamins [16], N,N-dimethylacetamide [17], propylene carbonate [18], polyethylene glycol 400 [19], polysorbate 80 [20] or propylene glycol [21] can be successfully incorporated into liquisolid systems. The successful loading of these chemically diverse liquid components shows that, utilising liquisolid technologies, both lipo- and hydrophilic solvents and APIs can successfully be transformed into liquisolid systems.

According to Spireas et al. , [1, 5], “liquisolid systems” are apparently dry, non-adherent and readily compressible powdered forms of liquid medications. Such a liquisolid system is based on a relatively large porous carrier material, such as microcrystalline cellulose, in which pores are filled with a drug solution up to the level, that a thin film forms on the outer surface. The latter drastically reduces the carrier’s flowability. Subsequently, this excess drug solution is absorbed by a very fine (d = 10–5000 nm) coating material, such as various types of fumed silica, which are adsorbed in mono- or multilayers on the surface of the carrier material to bind the excess liquid and thus restore flowability. The carrier-to-coating ratio is recommended to be around 20:1 [1, 5].

In a liquisolid system, maximising total liquid load is crucial, because the maximum achievable dose within a reasonable volume depends on both the solubility of the API in the liquid and the maximum liquid loading into the carrier. This limiting factor has been identified as a major drawback for liquisolid technologies [22], even as the use of newer carrier materials enabled higher liquid loads [16]. However, it is problematic to accurately compare the currently achieved total liquid loads, as the information on loading quantities is usually only given on a mass basis. Due to the different densities of drug solutions and excipients, these values are not accurately comparable. Therefore, further optimisation was needed to enable liquisolids as a viable formulation principle from a key performance indicator as well as a formulation standpoint.

Mesoporous silica generally has a high maximum loading capacity, which can increase the total possible liquid loading [23]. However, mesoporous silica also poses some challenges. It has poor tabletting properties [3], which necessitates the addition of a filler/binder. Certain silica grades such as Syloid® 244FP also exhibit very low bulk density, thus limiting direct tabletting. Others, like Silsol® 6035, are restricted as their maximum loading capacity is below 0.75 mL/g. Syloid® XDP 3050 on the other hand provides a high bulk density and retains excellent flow properties up to its maximum absorption capacity of 1.6 mL/g. Up to this value no coating material to maintain good flow properties is required [23]. Recent debates have arisen regarding the definition of liquisolid systems in literature, particularly concering whether wet, non-flowable forms of liquisolids are nonetheless considered a “liquisolid system” [24, 25]. Due to the lack of coating material, the liquid-loaded Syloid® XDP 3050 presented in this study is technically not a “liquisolid system” by the original patent [5]. However, ever since the original patent had been published, most authors define a “liquisolid” as an apparently dry, non-adherent, free-flowing and compressible powder. Therefore, the blends presented in this study are considered liquisolids by common definition [16, 26].

Our study aimed to investigate the binding properties of Syloid® XDP 3050 at different Liquid Load Levels [v/m]. Our first objective involved finding an optimal filler/binder. Initial investigations revealed that compacts of pure silica violently tare themselves apart upon exiting the die when silica is not loaded, while no bonds are formed at the maximum Liquid Load Level. Our second objective is two-fold: to optimise the maximum liquid loading using patient- and formulation-relevant parameters, while simultaneously achieving a tensile strength of 1.5 ± 0.1 N/mm2 for the resulting tablets.

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Materials

Syloid® XDP 3050 was used as the mesoporous silica, and propylene carbonate as the liquid component for the preparation of liquisolids during the investigation. The silica was provided by Grace GmbH (Germany), and the propylene carbonate was purchased from VWR International S.A.S. (France). The fillers/binders Vivapur® 101, FlowLac® 90, tricalcium citrate tetrahydrate and Pearlitol® 200SD were kindly provided by JRS Pharma GmbH & Co. KG (Germany), Meggle GmbH & Co. KG (Germany), Jungbunzlauer GmbH (Germany) and Roquette Frères S.A. (France), respectively. The die was lubricated using Ligamed MF-2 V magnesium stearate kindly donated by Peter Greven GmbH & Co. KG (Germany). Propylene carbonate was dyed using methylene blue by Merck (Germany). Polyethyleneglycol 400 (PEG400) was purchased from Carl Roth GmbH (Germany), propylene glycol (PG) from Fagron GmbH & Co. KG (Germany) and polysorbate 80 (PS80) from Caesar & Loretz GmbH (Germany).

Appelhaus, J., Steffens, K.E. & Wagner, K.G. Effect of Liquid Load Level and Binder Type on the Tabletability of Mesoporous Silica Based Liquisolids. AAPS PharmSciTech 25, 246 (2024). https://doi.org/10.1208/s12249-024-02958-9

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