Atomic force measurements of 16-mercaptohexadecanoic acid and its salt with CH₃, OH, and CONHCH₃ functionalized self-assembled monolayers

Abstract

Chemical and mechanical properties of different compounds can be elucidated by measuring fundamental forces such as adhesion, attraction and repulsion, between modified surfaces by means of atomic force microscopy (AFM) in force mode calibration. This work presents a combination of AFM, self-assembled monolayers (SAMs), and crystallization techniques to study the forces of interaction between excipients and active ingredients used in pharmaceutical formulations.

SAMs of 16-mercaptohexadecanoate, which represent magnesium stereate, were used to modify the probe tip, whereas CH₃-, OH- and CONHCH₃-functional SAMs were formed on a gold-coated mica substrate, and used as examples of the surfaces of lactose and theophylline. The crystals of lactose and theophylline were characterized by scanning electron microscopy (SEM) and X-ray diffraction (XRD). The modification of gold surfaces with 16-mercaptohexadecanoate, 10-mercapto-1-decanol (OH-functional SAM), 1-decanethiol (CH₃-functional) and N-methyl-11-mercaptoundecanamide (CONHCH₃-functional SAM) was studied by X-ray photoelectron spectroscopy (XPS), Auger electron spectroscopy (AES) and Fourier transform-infrared spectroscopy (FT-IR) in specular reflectance mode. XPS and AES results of the modified surfaces showed the presence of sulfur binding, and kinetic energies that correspond to the presence of 10-mercapto-1-decanol, 1-decanethiol, N-methyl-11-mercaptoundecanamide and the salt of 16-mercaptohexadecanoic acid. The absorption bands in the IR spectra further confirm the modification of the gold-coated substrates with these compounds. Force versus distance measurements were performed between the modified tip and the modified gold-coated mica substrates. The mean adhesion forces between the COO⁻Ca²⁺ functionalized tip and the CH₃-, OH-, and CONHCH₃-modified substrates were determined to be 4.5, 8.9 and 6.3 nN, respectively. The magnitude of the adhesion force (ion–dipole) interaction between the modified tip and substrate decreases in the following order: COO⁻Ca²⁺/OH > COO⁻Ca²⁺/CONHCH₃ > COO⁻Ca²⁺/CH₃.

Introduction

Most pharmaceutical industries are dedicated to the manufacture of solid oral dosage products or tablets. The successful optimization and validation of the manufacturing processes require an understanding of how components of these formulations interact. Due to the nature and complexity of the blends, it is a difficult task to understand the interactions of these components using conventional methods [1]. Still drug–excipient and excipient–excipient interactions are not well understood in pharmaceutical processes mainly due to the quantity of excipient functions in the formulation that affects manufacturing processes and the small amount of available information in the corresponding assays.

Based on the fundamental problems and issues that pharmaceutical companies face, it is important to focus on a way to obtain chemical information of the excipients and active drugs that form the blends. The combination of atomic force microscopy (AFM), self-assembled monolayers (SAMs) technique, and crystallization allow us to determine important forces of interactions between excipients and active ingredients. The materials that are represented in this study are: magnesium stearate, the most widely used lubricant in pharmaceutical industries; lactose, one of the most important excipients in tablet formulation, and the drug theophylline. Crystallization data of these compounds was used to reveal the functional ending groups of the crystals, which was crucial to the selection of the representative compounds chosen for the formation of SAMs.

Self-assembled monolayers is based on the spontaneous adsorption of molecules onto the substrate from a homogeneous solution [2]. The organization of monomolecular assemblies at solid interfaces provides a rational approach for fabricating films with a well defined composition, structure and thickness [3]. The relevance of these structure materials has taken a great impetus on adhesion, lubrication, microelectronics, corrosion, protection, wetting, photochemical and electrochemical processes as well as biological interfaces. As a result of the nature and feasibility of SAM technique, there is a variety of works using many metals and nonmetals as substrates including Pt [4], Cu [5], [6], [7], [8], Ag [9], [10], [11], Si and hidroxylated surfaces. SAMs have also been prepared successfully on substrates such as silicon oxide [12], [13], [14], [15], aluminum oxide [16], [17], quartz [18], [19], [20], glass [15], mica [21], [22], zinc selenide [15], [16], germanium oxide [15] and gold [23], [24], [25], [26].

AFM force measurements are very sensitive to tip and sample properties therefore possess a wide range of applications in physical chemistry. Bard and Hu used the modality to study the adsorption process in situ. They studied the deprotonation of mercaptoundecanoic acid on gold in aqueous solution as a function on adsorption time [27]. In addition, Bard and Hu, studied the acid–base properties of carboxylic acid terminated self-assembled monolayers in aqueous solutions of KCl. By varying self-assembled monolayers that terminate in different functional groups, such as (COOH), and (CH₃), on the tip and sample, they studied the adhesion a frictional forces between them [28]. They determined that the interactions are in the order of COOH/COOH > CH₃/CH₃ > COOH/CH₃. van der Vegte and Hadziioannu made a similar study using functional terminal groups in which a single force bond was calculated using the mean adhesion measured from the force distance curve measurements [29]. The last two studies are of great interest for the following reasons: (a) the capacity to modify probe tips with SAMs, they provide a general approach to introduce chemical functionality into probes for the studies of different interactions, (b) physico-chemical parameters can be extracted from the analysis of AFM data under different environments and, (c) mapping of surfaces could be obtained into spatial distribution of a specific interaction including adhesion, elasticity, electrostatic and others.

Several reports of AFM force studies have presented measurements of single-bond contact forces. These have relied upon resolution of the discrete single-bond contact forces. The most used statistical methods to report force measurements raw data are the histogram [28], [29], [30], [32], Poisson [29], [30], [31], [32], and continuum methods [28], [29], [32]. In this work, we used the histogram as the statistical method.