Article Cite This: Langmuir XXXX, XXX, XXX−XXX
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Toward Improved Understanding of the Interactions between Poorly Soluble Drugs and Cellulose Nanofibers Salvatore Lombardo,§,∥ Pan Chen,†,∥ Per A. Larsson,‡ Wim Thielemans,§ Jakob Wohlert,‡ and Anna J. Svagan*,†,‡ †
Wallenberg Wood Science Center, KTH, Teknikringen 58, SE-100 44 Stockholm, Sweden Fibre and Polymer Technology, KTH Royal Institute of Technology, Teknikringen 56-58, SE-100 44 Stockholm, Sweden § Renewable Materials and Nanotechnology Research Group, Department of Chemical Engineering, KU Leuven, Campus Kulak Kortrijk, Etienne Sabbelaan 53, P.O. Box 7659, 8500 Kortrijk, Belgium ‡
S Supporting Information *
ABSTRACT: Cellulose nanofibers (CNFs) have interesting physicochemical and colloidal properties that have been recently exploited in novel drugdelivery systems for tailored release of poorly soluble drugs. The morphology and release kinetics of such drug-delivery systems heavily relied on the drug−CNF interactions; however, in-depth understanding of the interactions was lacking. Herein, the interactions between a poorly soluble model drug molecule, furosemide, and cationic cellulose nanofibers with two different degrees of substitution are studied by sorption experiments, Fourier transform infrared spectroscopy, and molecular dynamics (MD) simulation. Both MD simulations and experimental results confirmed the spontaneous sorption of drug onto CNF. Simulations further showed that adsorption occurred by the flat aryl ring of furosemide. The spontaneous sorption was commensurate with large entropy gains as a result of release of surface-bound water. Association between furosemide molecules furthermore enabled surface precipitation as indicated by both simulations and experiments. Finally, sorption was also found not to be driven by charge neutralization, between positive CNF surface charges and the furosemide negative charge, so that surface area is the single most important parameter determining the amount of sorbed drug. An optimized CNF− furosemide drug-delivery vehicle thus needs to have a maximized specific surface area irrespective of the surface charge with which it is achieved. The findings also provide important insights into the design principles of CNF-based filters suitable for removal of poorly soluble drugs from wastewater.
1. INTRODUCTION Cellulose and cellulose derivatives are commonly used ingredients in pharmaceutical formulations. However, the advantages of using cellulose in the form of cellulose nanofibers (CNFs) have only recently been investigated and CNFs have been suggested as an attractive new excipient to overcome the shortcomings of poorly soluble drugs.1 Poorly soluble drugs, with poor solubility in aqueous media (Biopharmaceutics Classification System2), represent around 40% of the drugs on the market today and up to 70% of those under development in the pharmaceutical industry.1 Therefore, methods to deliver poorly soluble drugs are expected to become even more important in the future. When given orally, such drugs alone will result in inadequate treatment of patients, thereby proving the necessity of drug-delivery systems. The most common strategies are based on size reduction of drug particles, keeping the drug in its amorphous form, and using lipid-based drugdelivery systems.1 In all of these cases, additional excipients are needed to prevent, e.g., drug nanoparticle aggregation (in the case of drug-delivery systems based on crystalline nanosized © XXXX American Chemical Society
drug particles) or recrystallization of the physically unstable amorphous state of drugs (in the case of amorphous formulations). Valo et al. used CNFs to stabilize and prevent aggregation of crystalline drug nanoparticle.3,4 Bannow et al.5 and Löbmann et al.6 observed favorable interactions between the poorly soluble drug indomethacin and cationic CNFs and consequently an increase in the amorphous fraction of the drug in the final CNF-based materials. Films from such cationic CNFs and indomethacin demonstrated an immediate drug release.1,6 Additionally, recent studies demonstrated that CNFs in combination with poorly soluble drugs, such as furosemide (Furo) and indomethacin, can be used to produce solid foams that offer prolonged drug release. In other words, a fast to prolonged drug release can be achieved by changing the structure (film or foam) and the solid-state form of the material and drug, respectively.6−8 Solid foams could potentially be used Received: February 20, 2018 Revised: April 14, 2018
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DOI: 10.1021/acs.langmuir.8b00531 Langmuir XXXX, XXX, XXX−XXX
Article
Langmuir
Figure 1. (A) Cross section of the cationic model CNF used in the molecular dynamics (MD) simulations. The model CNF has cationic groups (trimethylammonium groups) attached to the outer surface. The crystallographic notations are included in (A). (B) The furosemide molecule.
identifying several new poorly soluble drugs that could benefit from similar molecular interactions with cationic CNFs in pharmaceutical formulations. In particular, it is of interest to find out whether the dominating mechanism for their binding is through direct interactions, such as ionic interactions between charged groups; indirect interactions, such as solvent-mediated hydrophobic association; or a combination thereof. To this end, the drug interaction with CNFs with two different amounts of cationic surface groups is studied using Fourier transform infrared (FTIR) spectroscopy as well as sorption experiments at different temperatures. Additionally, an innovative molecular dynamics (MD) simulation approach provides further insight into the actual adsorption mechanism.
as gastroretentive drug-delivery systems due to positive buoyancy. The prolonged release is a direct consequence of the cellular structure of the foams; the presence of stable and impermeable air-filled cavities in the foams creates a highly tortuous diffusion path through the foam structure for the drug.6−8 The stable cellular structure, on the other hand, is a direct consequence of molecular interactions between the poorly soluble drug and CNFs. The drugs lower the surface energy of the CNFs and facilitate a particle-stabilized pickering foam when air is introduced during processing.5 The number of different drugs that can be sorbed and would benefit from being formulated with CNFs in a similar way is however presently unknown. Improved understanding might also aid in the development of CNF-based filters that are suitable for wastewater management to prevent poorly soluble drugs (such as diclofenac) from ending up in the environment.9,10 The function and the physicochemical properties of cellulose are strongly related to its micro- to nanostructure. In nature, cellulose is found in the form of microfibrils that assemble further into different layers of the elongated cells that make up the trunk of plants.11 These strong microfibril aggregates constitute the basic cohesive units of the wood cell wall. The microfibrils from softwoods are a few nanometers thick and several micrometers long and contain disordered regions as well as a high fraction of crystalline components, where the cellulose Iβ form is prevalent in softwoods. CNFs, i.e., partly or fully liberated microfibrils, can be as thin as 3−4 nm and several micrometers long and are obtained via disintegration of micrometer-thick fibers (top-down processing).11 In microfibrils, the macromolecular cellulose chains will have a parallel alignment extending along the length of the fibril. As a result of the packing and orientation of the hydroxyl groups of cellulose, each microfibril will expose both staggered (crystallographic (110) and (11̅0) planes) and flat faces (crystallographic (200) plane; see Figure 1A), although the structuring of cellulose chains in wood microfibrils is still a matter of debate.12 These two types of surfaces are generally referred to as being the hydrophilic and hydrophobic surfaces of cellulose, respectively, which is a little unfortunate since both surfaces show amphiphilic characteristics. For clarity, however, the notations staggered and flat surfaces were used throughout this article. The aim of the present study is to improve the understanding of the molecular interactions between cationic CNFs and the poorly soluble model drug furosemide (Figure 1) for use in pharmaceutical formulations. Here, furosemide was chosen as a model drug as its bioavailability might potentially be improved when formulated with cationic CNFs.8 Furosemide is used to treat hypertension and edema and has a site-specific absorption in the body.13,14 The exact interaction mechanisms are still poorly understood, and improved understanding might aid in
2. EXPERIMENTAL SECTION 2.1. Materials. Furosemide (>98%) and glycidyltrimethylammonium chloride were purchased from Sigma-Aldrich, and sodium hydroxide (99%, p.a. ISO) was purchased from Carl Roth. The pulp used for making CNFs was a cellulose-rich dissolving-grade acid-sulfite pulp cooked from a softwood mixture (60% Norway spruce and 40% Scots pine). Besides cellulose, the pulp also contained about 4% hemicellulose and
