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Quasi-Immiscible Spreading of Aqueous Surfactant Solutions on Entangled Aqueous Polymer Solution Subphases Ramankur Sharma,†,‡ Timothy E. Corcoran,# Stephen Garoff,*,‡,§ Todd M. Przybycien,†,‡,∥ Ellen R. Swanson,‡,⊥,○ and Robert D. Tilton†,‡,∥ †
Department of Chemical Engineering, ‡Center for Complex Fluids Engineering, §Physics Department, ∥Department of Biomedical Engineering, ⊥Department of Mathematical Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States # Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States ○ Department of Mathematics, Centre College, Danville, Kentucky 40422, United States S Supporting Information *
ABSTRACT: Motivated by the possibility of enhancing aerosol drug delivery to mucus-obstructed lungs, the spreading of a drop of aqueous surfactant solution on a physically entangled aqueous poly(acrylamide) solution subphase that mimics lung airway surface liquid was investigated. Sodium dodecyl sulfate was used as the surfactant. To visualize spreading of the drop and mimic the inclusion of a drug substance, fluorescein, a hydrophilic and non-surface-active dye, was added to the surfactant solution. The spreading progresses through a series of events. Marangoni stresses initiate the convective spreading of the drop. Simultaneously, surfactant escapes across the drop’s contact line within a second of deposition and causes a change in subphase surface tension outside the drop on the order of 1 mN/m. Convective spreading of the drop ends within 2−3 s of drop deposition, when a new interfacial tension balance is achieved. Surfactant escape depletes the drop of surfactant, and the residual drop takes the form of a static lens of nonzero contact angle. On longer time scales, the surfactant dissolves into the subphase. The lens formed by the water in the deposited drop persists for as long as 3 min after the convective spreading process ends due to the long diffusional time scales associated with the underlying entangled polymer solution. The persistence of the lens suggests that the drop phase behaves as if it were immiscible with the subphase during this time period. Whereas surfactant escapes the spreading drop and advances on the subphase/vapor interface, hydrophilic dye molecules in the drop do not escape but remain with the drop throughout the convective spreading. The quasiimmiscible nature of the spreading event suggests that the chemical properties of the surfactant and subphase are much less important than their physical properties, consistent with prior qualitative studies of spreading of different types of surfactants on entangled polymer subphases: the selection of surfactant for pulmonary delivery applications may be limited only by physical and toxicological considerations. Further, the escape of surfactant from individual drops may provide an additional spreading mechanism in the lung, as hydrodynamic and/or surface pressure repulsions may drive individual droplets apart after deposition. KEYWORDS: Marangoni flow, surfactant spreading, surfactant transport, pulmonary drug delivery aerosol droplet deposition.6,7 The use of surfactants in the lungs is a relatively long-standing practice in the context of bolus surfactant replacement therapy for neonatal acute respiratory syndrome.8−10 In vitro proof of surfactant-enhanced spreading on complex aqueous subphases that mimic the ASL6,7 and evidence for altered lung clearance patterns after aerosolized surfactant inhalation in humans has been reported.5 Marangoni spreading driven by soluble and insoluble surfactants on liquid subphases has been studied. In some cases, the source of the surfactant is a confined surfactant film which is then released, causing the spreading,11,12 a neat
1. INTRODUCTION A significant problem often encountered when administering aerosolized medications in the treatment of chronic obstructive pulmonary diseases is that the drug does not effectively access all the portions of the lungs,1−3 thereby decreasing efficacy. An important example is the nonuniform deposition of inhaled aerosols in the treatment of bacterial infections of the lungs of cystic fibrosis patients, due to obstructions associated with inflammation and mucus plaques.4−6 Current inhalation therapies rely on aerodynamic mechanisms to disperse and distribute drug inside lungs after inhalation.6 A recently proposed strategy to improve drug penetration downstream of lung obstructions is to add surfactant to the aerosol to harness surface tension gradient driven Marangoni flows which can carry drugs along the airway surface liquid (ASL) after © XXXX American Chemical Society
Received: February 28, 2013 Accepted: May 24, 2013
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dx.doi.org/10.1021/am400762q | ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
ACS Applied Materials & Interfaces
Research Article
surfactant drop,13−19 or a surfactant solution drop.20−25 Several recent reviews detail the existing work on surfactant assisted spreading on liquid subphases.26−29 Since a surfactantcontaining drop has a lower surface tension than the underlying subphase, as it touches the subphase, the capillary imbalance at the three-phase contact line creates the stress that drives the drop to spread. Surface tension gradients develop across the drop/vapor interface and drop/subphase interface and across the subphase surface (i.e., the subphase/vapor interface). The surfactant escapes from the deposited drop’s contact line and moves across the subphase/vapor interface ahead of the drop. The surface Marangoni stress also drives a flow in the subphase, and at the leading edge of the spreading surfactant concentration profile, a capillary ridge forms and moves across the subphase.26,29 The Marangoni or convective spreading of the drop ceases as the three interfacial tensions, drop/vapor, drop/subphase, and subphase/vapor, evolve and the capillary balance is established. Although the dynamics of the drop and surfactant front are fairly well understood at this time, a clear picture of the postspreading fate of each component of the surfactant solution drop on complex liquid subphases is lacking. Knowledge of the latter is the key to designing optimum surfactant formulations. In this work, we study spreading in a system mimicking key characteristics of pulmonary drug delivery, and determine the postspreading fate of formulation components comprising surfactant, water, and a hydrophilic non-surface-active solute that serves as a model drug compound. We have focused on the spreading of individual microliter drops of mock drug formulations rather than aerosols to facilitate experimental interrogation of the system. While we expect that the quantitative aspects of the postdeposition spreading of individual drops will depend on the extent of the system, including both drop size and surfactant inventory, the underlying mechanism determining the qualitative behavior should be independent of drop size. Here, microliter drops of aqueous sodium dodecyl sulfate solutions are deposited on physically entangled aqueous poly(acrylamide) (PA) solution subphases. The entangled polymer solution mimics pulmonary mucus, a 95 wt %/wt aqueous, viscoelastic solution of mucin glycoprotein, DNA, and various other solutes present in different amounts depending on the health of the lungs.30 The principal component of airway mucus is an entangled, randomly coiled network of mucin glycoproteins31 with molecular weights ranging from about 1 to 10 MDa.32 Mucus is heterogeneous and optically opaque at relevant concentrations. To avoid experimental, compositional, and chemical complexities in this study, physically entangled aqueous solutions of high molecular weight PA were used as the liquid subphase. The 5−6 MDa PA used is similar to the molecular weight of porcine gastric mucin which we have used in prior qualitative spreading studies.6,7 The choice of soluble surfactant, sodium dodecyl sulfate, was made for convenience, as our prior work demonstrated that spreading behavior was qualitatively similar for aqueous solutions of anionic, cationic, and nonionic surfactant deposited on both PA and porcine gastric mucin subphases.7 We see a cascade of events and time scales. Upon drop deposition, surfactant crosses the contact line and rapidly moves across the surface ahead of the contact line at speeds on the order of cm/s. Drop spreading ceases after a few seconds, but surfactant that has spread on the subphase outside the drop dissolves into the subphase over time scales of tens of seconds.
Despite the drop content’s complete miscibility with the aqueous subphase, the drop remains as a “lens” (a drop with nonzero contact angle) on the surface for several minutes after both spreading and surfactant dissolution have completed; during this period, the drop and subphase behave as if they were immiscible. The hydrophilic dye stays with the drop rather than convecting across the subphase surface with the surfactant.
2. MATERIALS AND METHODS 2.1. Materials. Subphases were either a 1 wt %/wt aqueous solution of poly(acrylamide) (density 1.0 g/mL) or a 75% v/v glycerol solution in water (density 1.2 g/mL). The poly(acrylamide) (PA; molecular mass 5 000 000−6 000 000 g/mol, CAS# 9003-05-8) was purchased from Polysciences (Cat# 02806). The glycerol (≥99.5%, CAS# 56-81-5) was used as received from Sigma Aldrich (Cat# G7893) and was maintained in a sealed bottle until use. The surfactant was anionic sodium dodecyl sulfate (SDS; Electrophoresis grade, CAS# 151-21-3), purchased from Fisher Scientific (Cat# BP166-100) and used as received. The subphases were buffered to pH 9 using prepackaged buffer salts (Hydrion Buffer Chemvelope pH 9.00) from Micro Essential Laboratory (Cat# 280-9.00); these contain 20−30 wt %/wt sodium carbonate (CAS# 497-19-8) and 70−80 wt %/wt sodium bicarbonate (CAS# 144-55-8). Fluorescein dye (laser grade 99%, CAS# 2321-07-5) was purchased from Fisher Scientific (Cat# AC41062-0010) and used as received. All the glassware used for experiments was cleaned sequentially using ethanol, acetone, and deionized water several times and then dried under a nitrogen stream. The deionized water was obtained from a Milli-Q Academic unit (Millipore Corporation) and had a resistivity of 18 MΩ·cm, pH ∼ 6, a surface tension of 72.7 ± 0.7 mN/m (where the quoted uncertainty here and elsewhere in this article is the standard error of the mean), and a total organic content
