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. 2021 Dec 14;6(51):35433–35441. doi: 10.1021/acsomega.1c04034

Cetylpyridinium Trichlorostannate: Synthesis, Antimicrobial Properties, and Controlled-Release Properties via Electrical Resistance Tomography

Baran Teoman †,‡, Zilma Pereira Muneeswaran †,∥, Gaurav Verma ∇, Dailin Chen §, Tatiana V Brinzari †, Allison Almeda-Ahmadi #, Javiera Norambuena #, Shaopeng Xu §, Shengqian Ma ∇, Jeffrey M Boyd #, Piero M Armenante ‡, Andrei Potanin †, Long Pan †, Tewodros Asefa ∥,⊥,*, Viktor Dubovoy †,*
PMCID: PMC8717397  PMID: 34984275

Abstract

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Cetylpyridinium trichlorostannate (CPC-Sn), comprising cetylpyridinium chloride (CPC) and stannous chloride, was synthesized and characterized via single-crystal X-ray diffraction measurements indicating stoichiometry of C21H38NSnCl3 where the molecules are arranged in a 1:1 ratio with a cetylpyridinium cation and a [SnCl3]− anion. CPC-Sn has shown potential for application as a broad-spectrum antimicrobial agent, to reduce bacteria-generated volatile sulfur compounds and to produce advanced functional materials. In order to investigate its controlled-release properties, electrical resistance tomography was implemented. The results demonstrate that CPC-Sn exhibits extended-release properties in an aqueous environment as opposed to the CPC counterpart.

1. Introduction

Cetylpyridinium chloride (CPC) is a quaternary ammonium compound (QAC), with the stoichiometry C21H38ClN, which is widely used as an antibacterial cationic surfactant.1 Its antimicrobial properties render it useful in a variety of applications including pharmaceuticals, water treatment, and some other industrial applications.2−4 CPC is the active pharmaceutical ingredient (API) at 0.01–1% (w/w) of numerous healthcare products including oral rinses, dentifrices, throat and nasal sprays, dishwashing detergents, and lubricants.1,5−7 It is recognized as a safe and effective active ingredient for dermal and oral applications by the Food and Drug Administration (FDA) in the United States, and it is commonly used in oral care products to prevent and treat dental plaque, gingivitis, halitosis, and calculus.2,8−12

The binding mechanism of CPC to the microbial cell membrane is composed of two simultaneously occurring steps: (1) the positively charged region of CPC binds directly to the polar negatively charged phosphate groups of phospholipids and (2) the nonpolar portion of CPC interacts with non-polar phospholipid tails. These steps result in permeability of the cell membrane, followed by membrane depolarization, leakage of intracellular components, and eventually the death of the microbial cell.8,13 Thus, the interaction between a metal ion (e.g., Zn2+) and CPC in a CPC–metal complex plays a crucial role in the antimicrobial efficacy of CPC.14 Along with CPC, the metal ion should be readily bioavailable in order to quickly and effectively bind to the microbial cell membrane, resulting in the high antimicrobial effect.

The antimicrobial effect of various metal ions (e.g., Cd2+, Co2+, Cu2+, and Zn2+) is thoroughly described elsewhere.15−18 Moreover, the interaction between the metal ions and pyridine analogs has been specifically investigated by many researchers.19−22 However, these studies were not successful in identifying and leveraging an antimicrobial technology that is viable, safe, and effective for widespread healthcare use. Recently, our group reported the synthesis and antimicrobial properties of cetylpyridinium tetrachlorozincate (C42H76Cl4N2Zn = CPC-Zn) against various microbes (i.e., Staphylococcus aureus, Streptococcus mutans, and Salmonella enterica).14 However, this study was limited to Zn that exhibits relatively weak bacteriostatic activity when compared to other divalent metal ions. It was postulated that the rational design of a CPC complex with a stronger bactericidal metal would improve the antimicrobial properties as compared to cetylpyridinium tetrachlorozincate. Thus, other metal ions could potentially be more efficient than Zn.

Among the potential metal ions that could substitute Zn, divalent tin [Sn(II)] is highly relevant, since it is known to exhibit low cytotoxicity and is frequently used in preservation, food packaging, electronics, and in the pharmaceutical industry (e.g., SnF2).23,24 Several attempts have been made to investigate the antimicrobial properties of Sn(II) by dissolving its different forms (i.e., SnF2 and SnCl2) or by forming thin films on the surface of glass that contains Sn(II) ions, all conforming that Sn(II) is a safe and effective antibacterial agent.15,18,25,26

Herein, we report the synthesis and characterization of cetylpyridinium trichlorostannate (CPC-Sn), which was found to have superior antimicrobial activity compared to CPC-Zn. Furthermore, previous work demonstrated that inorganic–organic hybrid advanced functional materials with controlled-release of QACs exhibit efficacious antimicrobial activity.27 Controlled-release antimicrobial agents could be advantageously used in a variety of industrial and consumer product applications. Therefore, in this work, the controlled-release properties of CPC-Sn in an aqueous environment were investigated. To do so, a new methodology was developed based on a novel application of electrical resistance tomography (ERT).

ERT is a methodology that measures the electrical conductivity distribution within a specified region of a liquid by multiple electrode sensors that are directly immersed in the fluid. These electrodes inject electrical current into the liquid, one electrode pair at a time, measure the voltage resulting from the provided current, and construct a conductivity distribution map by deconvoluting the voltage signals.28 Since the conductivity of liquid is directly correlated with the concentration of a polar solute, ERT can be used to quantify the distribution of those materials within the liquid. Due to its fast data acquisition characteristics, capability to conduct real-time process monitoring, and the advantage of providing local data at different locations of the bulk liquid, ERT has become a popular technique in the investigations of phase inversion,29 precipitation,30−32 flow distribution,33,34 and mixing processes.35−38 However, the use of ERT to study dissolution processes has been limited thus far. In fact, to the best of our knowledge, there have only been two reports of implementing ERT to investigate the dissolution process of salts.39,40 In this report, ERT was used to monitor the dissolution of CPC, SnCl2, and CPC-Sn in order to investigate the dissolution characteristics of these materials, as well as the controlled-release properties of CPC-Sn.

The current work reports the synthesis and characterization of cetylpyridinium trichlorostannate (referred to herein as CPC-Sn) that exhibits superior volatile sulfur compound (VSC) reduction properties as compared to CPC-Zn. Additionally, this study demonstrates that ERT is an efficient and reliable methodology to quantify the dissolution process of a wide variety of drug delivery systems (DDS), using CPC-Sn as a model. To the best of our knowledge, this is the first report in which ERT was used to characterize the dissolution of a bioactive compound.

2. Materials and Methods

2.1. Synthesis of Cetylpyridinium Trichlorostannate (CPC-Sn)

Reagent grade SnCl2·2H2O, cetylpyridinium chloride monohydrate, and absolute ethanol were supplied by Sigma-Aldrich (St. Louis, MO, USA) and used as supplied without further purification. Clear solutions of SnCl2·2H2O (10 wt %) and cetylpyridinium chloride monohydrate (25 wt %) were prepared in ethanol. Both samples were sonicated to ensure complete dissolution. It is noteworthy that the samples heated up quite a bit during the sonication (ca. 40–50 °C). A stannous chloride solution was added dropwise to the CPC solution. A crystalline “snowflake” material was formed after several minutes. This material was filtered, washed with copious amounts of water, and characterized via attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and single-crystal X-ray diffraction (SC-XRD), as described below in detail.

2.2. Structural Characterization via ATR-FTIR

The infrared spectra were collected using a Bruker Vertex 70 FTIR spectrometer (Bruker Optics, Billerica, MA) equipped with a GladiATR diamond ATR accessory (Pike technologies, Madison, WI). The spectral range was 80–4000 cm–1, and a resolution of 4 cm–1 was used. All measurements were carried out at room temperature.

2.3. Structural Characterization via SC-XRD

The X-ray diffraction data were collected at −173 °C using aBruker D8 Venture PHOTON 100 CPAD system equipped with a Cu Kα INCOATEC ImuS micro-focus source (λ = 1.54178 Å). Data integration and reduction were performed using SaintPlus 6.01.41 Absorption correction was performed by a multi-scan method implemented in SADABS.42 The space group was determined using XPREP implemented in APEX3.43 The structure was solved using SHELXT (direct methods) and was refined using SHELXL-201944−46 (full-matrix least-squares on F2) through the OLEX2 interface program.47 All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were placed in geometrically calculated positions and were included in the refinement process using a riding model.

2.4. Volatile Sulfur Compound (VSC) Reduction

Methyl mercaptan is a representative ingredient of volatile sulfur compounds (VSCs), which can be used as a marker for the quantitative measurement of mouth odor by gas chromatography-flame photometric detector technology. Sample preparation entailed dissolution of the SnCl2, CPC, and CPC-Sn powders to a final concentration of 0.0075 wt %. Hydroxyapatite (HAP) disks were incubated with whole saliva to develop pellicles followed by the treatment of prepared solutions. After rinsing, the treated disks were transferred to headspace vials and incubated with VSC solution to mimic mouth odor VSC generation. The methyl mercaptan in the headspace was measured through gas chromatography, equipped with a flame photometric detector (GC-FPD). The results would enable the determination of the product’s efficacy in mouth odor reduction.

2.5. Antimicrobial Assays

The bacterial strains, growth conditions, and antimicrobial susceptibility assays were previously described elsewhere.14

2.6. Dissolution Characterization via Electrical Resistance Tomography (ERT)

An ITS P2+ ERT system (Industrial Tomography Systems PLC, Manchester, U.K.), comprising a linear rod probe with 16 electrodes connected to a data acquisition system (DAS) was used for tomographic conductivity measurements. The probe was fixed on the inner wall of a 600 mL beaker that was filled with tap water (40 °C). A magnetic stirrer rod was used to provide a continuous agitation of 600 rpm throughout all the experiments. In the DAS, 15 mA was set as the injection current, and the frequency of the current was 9600 Hz, similar to previous studies.39,40,48 The ERT measurement speed was set to 2 frames/s, where one frame included a matrix with a 10 × 20 = 200 local conductivity value across the ERT probe (i.e., two-dimensional conductivity distribution). Since ERT is a technology that yields relative conductivity, an initial conductivity value of 0.1 mS/cm was set in the DAS for water, a reference frame was taken, and the measurements were started. Three experiments were conducted with 0.1 wt % NaCl solution to confirm the reproducibility.

The materials of interest, CPC + SnCl2 (i.e., physical mixture of CPC and SnCl2·2H2O powders) and CPC-Sn, each having a similar average particle size and a molar concentration of 0.00189 M, were added to the beaker containing water. However, CPC and SnCl2 were pre-mixed in their powder form and then added at the same time to the beaker, whereas CPC-Sn was added by itself. Then, the mean conductivity data for the entire 2D plane were collected and plotted against time. By keeping all DAS settings constant and by following the same experimental procedure described above in all cases, several experiments were also conducted with different amount of CPC-Sn (0.05, 0.1, 0.15, and 0.2 wt %) in order to construct a calibration curve. A linear relationship between the mean conductivity and the concentration of dissolved species was separately obtained. During the actual dissolution experiments, the conductivity evolved over time from its base value to the same final value corresponding to the total dissolution of all species initially in the solids, irrespective of the dissolving species.39

The dissolution process was quantified by the analysis of the time trace of the normalized mean conductivity, χ, at each time t, calculated as

2.6. 1

where σ(t) is the instantaneous mean conductivity at any time t, σo is the reference mean conductivity, prior to the solute addition, and σ( ∞ ) is the value of the conductivity at the end of the experiment when all particles were dissolved (i.e., for t → ∞). The normalized conductivity data were then analyzed using the diffusion-controlled dissolution model for spherical particles under “sink conditions” [referring to a dissolution process in which the solute concentration in the liquid bulk is much smaller than the saturated concentration, i.e., the solubility value]49 suggested by Higuchi et al.(50) and represented by the following equation:

2.6. 2

In this equation, Wo is the initial particle mass, W(t) is the mass of the undissolved particles at time t, and k2/3 is the composite rate constant. This model has two-third dependency functionality on particle mass, and it has been used in previous studies.51,52 To use this equation, we used the linear relationship between conductivity and solid concentration, representing a linear calibration curve described by

2.6. 3

where C(t) is the molar solute concentration at a generic time t, Co and C∞ are, respectively, the initial and final molar concentrations, χ(t) is the mean conductivity at a generic time t, and χo and χ∞ are the initial and final mean conductivity, respectively. Since the mass balance of the dissolving species must be Wo – W(t) = V · C(t), where V is the volume of the media, eq 2 can be rewritten as

2.6. 4

Therefore, a plot of the left-hand side of the equation against time yields the value of the composite rate constant, k2/3. Here, the initial and the final portions of the dissolution curves (indicating, respectively, that the dissolution has not fully started and that the sink condition assumption was no longer valid) were not considered in the analysis. Therefore, from a regression of the left-hand side of eq 4 vs time, using as input the experimental data, the value of the k2/3 constant could be obtained as the slope. For both cases (dissolution of the CPC + SnCl2 mixture and dissolution of CPC-Sn), k2/3 was used to quantify the dissolution performances of the tested materials.

3. Results and Discussion

3.1. Structural and Compositional Characterization

The ATR-FTIR spectra of CPC·H2O, SnCl2·2H2O, as-synthesized CPC-Sn, and previously synthesized cetylpyridinium tetrachlorozincate (CPC-Zn)14 are shown in Figure 1. The spectrum of the CPC-Sn sample clearly shows the fingerprint of the cetylpyridinium confirming its presence in the sample. A close inspection of the spectrum demonstrates that the bands of cetylpyridinium in CPC-Sn do not match those of the CPC·H2O (i.e., the precursor). The majority of the bands related to CH2, C=C, C=N, and C–H stretching and cetylpyridinium bending vibrations display shifted peak positions compared to those of CPC·H2O. The ν(OH) stretching band near 3370 cm–1 seen in the CPC·H2O starting compound also disappears in the presence of Sn. Furthermore, a new cluster of bands below 340 cm–1 (e.g., strong bands at 289, 260, and 237 cm–1) is evident in the spectrum of the CPC-Sn sample, likely originating from the Sn-related vibrations. A comparison to the spectrum of SnCl2·2H2O does not reveal the presence of residual SnCl2·2H2O in the CPC-Sn sample. Finally, it is noteworthy that the spectra of CPC-Sn and CPC-Zn samples are overall similar in the behavior of the cetylpyridinium vibrational bands in the presence of metal. Taken together, the FTIR data indicate the formation of a new compound occurred as a result of the reaction between CPC and SnCl2.

Figure 1.

Figure 1

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Comparison of the infrared absorption spectra for cetylpyridinium chloride monohydrate (CPC·H2O), stannous chloride dihydrate (SnCl2·2H2O), CPC-Sn, and CPC-Zn.

After the initial discovery of the new compound formation from FTIR data, the sample was further analyzed by single-crystal X-ray diffraction. It is evident that the compounds are arranged in a 1:1 ratio with a cetylpyridinium cation and a [SnCl3]− anion. The alkyl chains of CPC align with one another with the polar head groups facing in opposite directions for consecutive molecules. The pyridyl rings show a parallel stacking, and as a result of the packing arrangement, there is a non-polar region consisting of the stacked alkyl chains and a polar region consisting of the pyridinium rings and SnCl3– anions.

The SC-XRD analysis reveals that the CPC-Sn crystallizes in the monoclinic P21/c space group with the unit cell parameters a = 27.68(8) Å; b = 9.62(3) Å; c = 9.14(3) Å; and β = 92.95(10)°. The structural formula can be described as [(C21H38N)][SnCl3] or (CP)SnCl3 with the asymmetric unit consisting of a cetylpyridinium cation and one SnCl3– anion in distorted triangular pyramidal geometry (Figure 2). The positively charged pyridyl head is present in close contact with the negatively charged SnCl3– unit via aromatic C–H–––Cl hydrogen bonding interactions (dCl––H = 2.7 Å). The average Sn–Cl bond length is 2.48(7) Å, which is similar to other SnCl3–-based structures reported in the literature.53,54 It is, however, worth noting that such kinds of hybrid organic–inorganic structures based on Sn(II) featuring independent SnCl3– units are very rare in the literature.55−58

Figure 2.

Figure 2

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Asymmetric unit of CPC-Sn showing the CPC cation and the SnCl3– anion.

The packing of the compounds illustrated in Figure 3 shows stacked layers of interdigitated cetylpyridinium chains with the layers of SnCl3– units present in between them. This gives rise to alternating cationic and anionic regions in the overall framework. This type of packing behavior is similar to other reported CPC structures,59−64 albeit with a different packing arrangement.

Figure 3.

Figure 3

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Packing along (a) the (010) plane and (b) the (001) plane of CPC-Sn.

The adjacent SnCl3– units are aligned in opposite directions possibly due to repulsion between the Cl groups (Figure 4) with a Sn–Sn distance of 4.63 Å. The framework is stabilized by the hydrogen bonding interactions between the Cl from the anion and the aromatic as well as aliphatic C–H hydrogens on the CPC cation (−CH2 attached to the pyridyl nitrogen, d = 2.77 Å). The π–π interactions between the stacked phenyl rings are negligible as the distance between the centroids is greater than 4 Å. The selected bond lengths and angles for the structure are provided in the Supporting Information.

Figure 4.

Figure 4

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(a) Sphere packing diagram of the adjacent SnCl3– units oriented in opposite directions and (b) hydrogen bonding interactions between the Cl from SnCl3 and the aliphatic/aromatic C–H hydrogens.

3.2. Volatile Sulfur Compound (VSC) Reduction

The effects of ZnCl2, SnCl2, CPC-Sn, CPC-Zn, and CPC on in vitro bacteria-generated volatile sulfur compounds (VSC), conducted by measuring the amount of methyl merceptan in the headspace with gas chromatography (GC), are illustrated in Figure 5a. Statistical grouping, calculated using the Tukey method and a 95.0% confidence interval, indicates that CPC and CPC-Sn outperformed the other tested materials for malodor-causing VSCs with CPC and CPC-Sn exhibiting parity efficacy. Both CPC and CPC-Sn exhibited enhanced efficacy as compared to CPC-Zn. At the measured concentrations, ZnCl2 and SnCl2 exhibit a weak VSC reduction effect as compared to CPC, CPC-Zn, and CPC-Sn.

Figure 5.

Figure 5

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Inhibition of (a) methyl mercaptan by SnCl2, ZnCl2, CPC-Zn, CPC-Sn, and CPC and (b) S. aureus, (c) S. enterica, and (d) S. mutans with CPC and CPC-Sn.

3.3. Results of Antimicrobial Assays

The antimicrobial activities of CPC, CPC-Sn, and SnCl2 were investigated against three human bacterial pathogens. A Staphylococcus aureus Los Angeles County clone (LAC) is a community-acquired methicillin-resistant S. aureus (MRSA) strain and a representative of the USA300 epidemic strain in the USA.65Salmonella enterica serovar Typhimurium is a leading cause of salmonellosis worldwide.66Streptococcus mutans is a leading cause of dental caries.67 We individually cultured these bacterial strains with and without CPC, CPC-Sn, and SnCl2 for 24 h and measured the cultures’ optical densities. The amount of SnCl2 required to inhibit growth with >100 μg mL–1 (data not shown) was above its solubility limit in water. It was difficult to determine an exact minimum inhibitory concentration (MIC) for SnCl2 because of Sn(II) precipitation obfuscating the culture optical density readings. There was not a statistically significant difference in minimal inhibitory concentration (MIC) values between CPC-Sn and CPC in any of the three organisms examined (Figure 5b–d). The MIC values were approximately 13, 75, and 3 μg mL–1 for S. aureus, S. enterica, and S. mutans, respectively.

3.4. Results of Dissolution Experiments Using ERT

As previously mentioned, ERT was implemented to quantify the dissolution of the solute concentration as a function of time by measuring the corresponding normalized conductivity (eq 3). In all experiments, the initial conductivity of water was set to 0.1 mS/cm. Although stirring was incorporated, the conductivity remained constant over time (Figure 6a), indicating that the corresponding solute concentration in the solution was zero. In a typical experiment, the same amount (0.00113 mol) of either CPC + SnCl2 powder mixture or CPC-Sn was added to the water while stirring. Upon complete dissolution of the solute, the final solute concentration was 0.00189 M in both cases since the ionic concentrations of the dissolved species were the same. Figure 6a shows the typical mean concentration profiles for both solutes. One can clearly see that the dissolution curves converged toward the same asymptotic value for t →∞ irrespective of the type of compound added initially.

Figure 6.

Figure 6

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Dissolution curves obtained by ERT: (a) mean conductivity profiles for the CPC + SnCl2 physical mixture, CPC-Sn, and tap water; and (b) concentration profiles for the CPC + SnCl2 mixture and CPC-Sn.

Figure 6b shows the corresponding mean conductivity profiles for the CPC + SnCl2 mixture and for CPC-Sn. Here, it is evident that the dissolution of the CPC + SnCl2 mixture was essentially complete for t ≅ 20 s, when the final concentration was reached (0.00189 M). However, the time for the complete dissolution of CPC-Sn was about 10 min.

While it is possible to visually distinguish between the dissolution rates of CPC-Sn and CPC + SnCl2 by simple inspection of the dissolution curves, a more precise analysis can be conducted by quantifying the slope of the initial linearly increasing portions of the same curves. To do so, we applied the dissolution model of Higuchi and Hiestand (eq 2) to the dissolution profiles of the CPC + SnCl2 mixture and CPC-Sn since this model accurately represents the dissolution profiles under sink conditions (Figure 7).51,52 Here, the slopes of the linear portions of these curves yielded composite rate constants of k2/3 = 0.0025 mol2/3/s and k2/3 = 0.0001 mol2/3/s for the CPC + SnCl2 mixture and CPC-Sn, respectively. These results clearly show that the initial dissolution rate of CPC-Sn was about 25 times less than that of the CPC + SnCl2 mixture, although the final concentration of all dissolved species was the same in both cases, thus clearly showing the extended-release characteristics of CPC-Sn in an aqueous environment.

Figure 7.

Figure 7

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Application of the Higuchi and Hiestand (eq 2) dissolution model to the dissolution profiles of the CPC + SnCl2 mixture and CPC-Sn under sink conditions, obtained from ERT.

4. Conclusions

In this study, a novel CPC complex, cetylpyridinium trichlorostannate (CPC-Sn), was synthesized and unambiguously characterized via single-crystal X-ray diffraction indicating a stoichiometry of C21H38NSnCl3 where the molecules are arranged in a 1:1 ratio with a cetylpyridinium cation and [SnCl3]− anion. CPC-Sn exhibited superior antibacterial efficacy as compared to previously reported CPC analogs, especially evident in volatile sulfur compound (VSC) reduction experiments. Its dissolution characteristics, obtained from ERT, showed that CPC-Sn exhibits extended dissolution as opposed to CPC in an aqueous environment. This work suggests that CPC-Sn is a viable and effective antimicrobial agent to combat the global healthcare issues associated with oral and dermal diseases, such as hospital infections, medical device biofilms, and antibiotic resistance. Furthermore, the novel application of ERT to investigate dissolution characteristics of bioactive molecules was demonstrated, which can be applied to a wide range of solutes.

Acknowledgments

The authors would like to thank the X-ray Diffraction Facility and Solid-State Characterization Core Lab at the University of South Florida (USF) for the SC-XRD studies.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.1c04034.

  • Crystallographic data of CPC-Sn (CIF)

  • Experimental details and supporting results for the synthesis, structural characterization, and dissolution characteristics of CPC-Sn (PDF)

Author Contributions

The manuscript was written through contributions of all authors.

The Boyd lab is funded by NIAID award 1R01AI139100-01.

The authors declare no competing financial interest.

This paper was published ASAP on December 14, 2021, with two erroneous phrases in the Abstract. The corrected version was posted on December 28, 2021.

Supplementary Material

ao1c04034_si_001.cif (1.1MB, cif)
ao1c04034_si_002.pdf (342.5KB, pdf)

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