Characterization of Polymer Adsorption onto Drug Nanoparticles

Article pubs.acs.org/molecularpharmaceutics

Characterization of Polymer Adsorption onto Drug Nanoparticles Using Depletion Measurements and Small-Angle Neutron Scattering Daniel J. Goodwin,†,‡ Shadi Sepassi,† Stephen M. King,§ Simon J. Holland,∥ Luigi G. Martini,† and M. Jayne Lawrence*,† †

Institute of Pharmaceutical Science, King’s College London, Stamford Street, London SE1 9NH, United Kingdom GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, United Kingdom § ISIS Facility, STFC Rutherford Appleton Laboratory, Didcot, OX11 0QX United Kingdom ∥ GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 0DP, United Kingdom ‡

S Supporting Information *

ABSTRACT: Production of polymer and/or surfactant-coated crystalline nanoparticles of water-insoluble drugs (nanosuspensions) using wet bead milling is an important formulation approach to improve the bioavailability of said compounds. Despite the fact that there are a number of nanosuspensions on the market, there is still a deficiency in the characterization of these nanoparticles where further understanding may lead to the rational selection of polymer/ surfactant. To this end small-angle neutron scattering (SANS) measurements were performed on drug nanoparticles milled in the presence of a range of polymers of varying molecular weight. Isotopic substitution of the aqueous solvent to match the scattering length density of the drug nanoparticles (i.e., the technique of contrast matching) meant that neutron scattering resulted only from the adsorbed polymer layer. The layer thickness and amount of hydroxypropylcellulose adsorbed on nabumetone nanoparticles derived from fitting the SANS data to both modelindependent and model dependent volume fraction profiles were insensitive to polymer molecular weight over the range Mv = 47−112 kg/mol, indicating that the adsorbed layer is relatively flat but with tails extending up to approximately 23 nm. The constancy of the absorbed amount is in agreement with the adsorption isotherm determined by measuring polymer depletion from solution in the presence of the nanoparticles. Insensitivity to polymer molecular weight was similarly determined using SANS measurements of nabumetone or halofantrine nanoparticles stabilized with hydroxypropylmethylcellulose or poly(vinylpyrrolidone). Additionally SANS studies revealed the amount adsorbed, and the thickness of the polymer layer was dependent on both the nature of the polymer and drug particle surface. The insensitivity of the adsorbed polymer layer to polymer molecular weight has important implications for the production of nanoparticles, suggesting that lower molecular weight polymers should be used when preparing nanoparticles by wet bead milling since nanoparticle formation is more rapid but with no likely consequence on the resultant physical stability of the nanoparticles. KEYWORDS: Nanoparticle, nanosuspension, wet bead milling, small-angle neutron scattering, adsorption isotherm

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Early work in the field was involved with demonstrating proof of concept by studying the improved bioavailability afforded by nanoparticles.3−6 Only more recently has work concentrated on understanding the formulation and processing aspects of nanoparticles7,8 and attempts at providing a rational selection of stabilization agents based on identifying drug− stabilizer interactions.9−11 Work by our group has paid particular attention to the role of the polymeric stabilizer in the production of sterically stabilized nanoparticles and particularly the influence of the polymer molecular weight on milling time.12 These systems are quite challenging to study,

INTRODUCTION Production of solid crystalline drug nanoparticles stabilized by polymers and/or surfactants (nanosuspensions) using wet bead or media milling has been established as a useful tool to improve the bioavailability of poorly soluble drugs and has resulted in a number of products on the market employing such technology.1 The relative success of this technology compared with other methods of formulating water-insoluble drugs can be considered to be a consequence of the small number of additional excipients required (typically one or two per product) and a simple method of production that can be easily scaled-up to commercial manufacturing.2 Stabilization of nanoparticles can be through steric and/or electrostatic mechanisms to produce a nanosuspension after milling which can be further processed to enable incorporation into solid dosage forms or used as-is. © XXXX American Chemical Society

Received: March 8, 2013 Revised: September 22, 2013 Accepted: September 27, 2013

A

dx.doi.org/10.1021/mp400138e | Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Molecular Pharmaceutics

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quantities can be derived from Φ(z). Furthermore, the form of Φ(z) can be indicative of the type of adsorbed layer (e.g., “brush”-like, or “comb”-like). The behavior of polymeric stabilizers at interfaces is also the subject of an extensive literature over several decades, embracing experiment, theory, and modeling, resulting in a well-developed understanding.19,20 In this paper we use a combination of optical rotatory spectroscopy and, in particular, SANS to characterize the adsorbed layers formed by common pharmaceutical stabilizers on nanoparticles formed by two extremely poorly water-soluble drugs. The majority of polymer adsorption studies using SANS have employed well-characterized, relatively monodisperse, spherical “model” particles typically less than 100 nm in size. The reason for this is simply that a regular geometry permits the subtle features of the polymer layer, and any effect on it, to be more easily determined. Aqueous-based studies of this type have typically focused on the adsorption of poly(vinyl alcohol) or poly(ethylene oxide) polymers to polystyrene latex or silica nanoparticles.19,21−24 However, SANS has been used to study the adsorption of less chemically regular, polydisperse polymers on monodisperse polystyrene latex nanoparticles,25 or of more monodisperse polymers onto nonspherical particles such as Laponite (a synthetic clay).26,27 There are very few examples of SANS being used to investigate the behavior of polymeric stabilizers in pharmaceutically relevant systems. Washington et al.28,29 elucidated the structure of poloxamer block copolymers (of poly(ethylene oxide) and poly(propylene oxide)) adsorbed at the perfluorodecalin−water interface in submicrometer emulsions and found a good correlation between derived estimates of Γ and adsorbed layer dimensions obtained from light scattering. The later work investigated the effect of electrolyte and temperature on the structure of the polymer layer. The novelty of the current work is encompassed (and complicated) by the fact that the system under study is a “real-life” pharmaceutical system. The adsorbent is nanoparticles of a poorly water-soluble drug nabumetone, produced by wet bead milling. The adsorbate is hydroxypropyl cellulose (HPC), a pharmaceutically acceptable cellulose ether which is semisynthetic and hence exhibits a certain degree of polydispersity and has a relatively low molecular weight compared to many of the polymers typically studied using SANS.30 In addition, the drug nanoparticles studied here are large and polydisperse. The adsorption characteristics of HPC on nabumetone have been studied using SANS as a function of polymer molecular weight and concentration. The amount of polymer adsorbed has also been independently assessed using optical rotatory dispersion spectroscopy. For comparison, measurements have also been performed on hydroxypropyl methylcellulose (HPMC, hypromellose) stabilized nabumetone nanoparticles and poly(vinylpyrrolidone) (PVP) and HPMC stabilized halofantrine nanoparticles. This is the first time such a study has been performed on drug nanoparticles.

not least because it is impossible to produce a stable “reference” system (i.e., without stabilizer). The optimum conditions for effective steric stabilization are a high-surface coverage of a strongly bound (either physically or chemically) stabilizer, well-extended into the bulk phase. Different experimental techniques can probe different aspects of these conditions: for example, analytical chemistry or spectroscopy can determine the amount of stabilizer adsorbed to the interface, Γ; NMR relaxation time measurements can determine the fraction of stabilizer molecule “bound” to the interface, ⟨p⟩; while hydrodynamic methods, including dynamic light scattering (DLS), and other scattering measurements can determine various moments of the thickness, σ, or span/extent, l, of the adsorbed layer (Figure 1a).13,14 However one technique, small-angle neutron scattering (SANS), stands out because it is capable of determining the actual time-average distribution of stabilizer density normal to the interface; the volume fraction profile, Φ(z) (Figure 1b).15−18 All of the other

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MATERIALS AND METHODS Materials. Nabumetone and halofantrine were supplied by GlaxoSmithKline (Harlow, UK). Hydroxypropyl cellulose (HPC) molecular weight grades Klucel EF and Klucel JF were obtained from Hercules (Wilmington, USA). Hydroxypropylmethylcellulose (HPMC) molecular weight grade Methocel E3LV was obtained from Colorcon (Dartford, UK), and unbranded hydroxypropylmethylcellulose (grade 11K) was obtained from Sigma-Aldrich UK Ltd. (Gillingham, UK).

Figure 1. Representation of an adsorbed polymer layer comprising loops, tails and trains. The parameters essential for characterization of a polymer-stabilized dispersion are: the adsorbed amount, Γ; the span of the polymer layer, l; the extent of the center-of-mass of the layer, σ; and the bound fraction, ⟨p⟩. (b) Example of a volume fraction profile of an adsorbed polymer which shows how the polymer density (ϕ) varies with distance from the interface (z). Labeled is the bound fraction (shaded dark blue), ⟨p⟩; the center-of-mass of the adsorbed layer, σ; the absorbed amount (shaded blue), Γ; and the span of the polymer layer, l. B



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Table 1. Characteristics of the Polymersa polymer

[η] (mL/g)

Mv (kg/mol)

HPC-EF 112b HPC-EF 82b HPC-EF 79b HPC-EF 64b HPC-EF 55b HPC-EF 47b HPMC 11kc HPMC E3LVc PVP K12c PVP K30c

1.09 ± 0.02 0.84 0.82 ± 0.01 0.69 ± 0.01 0.60 ± 0.01 0.53 ± 0.02 88.9 ± 1.2 61.4 ± 0.2 4.7 ± 0.1 20.8 ± 0.1

112.2 82.2 79.4 64.5 55.2 47.0 7.7 5.0 3.0 46.2

Mw,GPC (kg/mol)

Mn,GPC (kg/mol)

Pd

Mw,LS (kg/mol)

Rg (nm)

110.0

40.3

2.8

138.5

23.9 ± 0.8

74.5

32.2

2.3

80.0

17.8 ± 0.6

55.4 45.6 23.1 3.4 41.0

29.5 5.8 4.2 2.7 16.0

1.9 7.9 5.5 1.2 2.6

57.5

15.5 ± 0.6

± 2.9 ± ± ± ± ± ± ± ±

1.6 0.5 1.3 1.9 0.1 0.0 0.1 0.4

[η] is the intrinsic viscosity at 20 °C (n = 3 ± s.d., except HPC-EF 82 where n = 1). Mv is the viscosity-average molecular weight from capillary viscosity measurements (n = 3 ± s.d.). Mw,GPC and Mn,GPC are the weight- and number-average molecular weight from GPC (n = 2). Polydispersity Pd = Mw,GPC/Mn,GPC. Mw,LS is the weight-average molecular weight from static light scattering, and Rg is the solution radius of gyration from DLS (n = 3 ± s.d). bData taken from refs 12 and 30. cData taken from ref 32. a

Table 2. SANS Data Model-Fitting Parametersa drug nabumetone nabumetone halofantrine halofantrine

polymer HPC HPMC HPMC PVP

polymer density δ (g/cm3)

contrast (ρl − ρm) (cm−2) −3.06 −3.06 −4.79 −4.20

1.29 1.33 1.33 1.18

× × × ×

9

10 109 109 109

particle radius Rpb (nm)

volume fraction ϕp

400 400 300 300

0.05 0.035 0.04 0.04

a

Densities for HPMC and PVP were obtained from Rowe et al.41 The density of HPC is as quoted by the manufacturer.42 bParticle radius determined from laser diffraction measurements.

a Retsch MM200 mixer mill (Glen Creston, Stanmore, UK). These conditions were considered to be the optimum in terms of particle size reduction for production of nabumetone or halofantrine nanoparticles.32 The particle size of the nanoparticles required for determining the amount of polymer adsorbed using SANS and depletion measurements of polymer adsorption was determined at 25 °C using a Malvern 2600 series laser diffractometer (Malvern Instruments, Malvern, UK) where a particle size based on the mass moment mean (D[4,3]) was obtained. In addition, both the size and the morphology of the nanoparticles was determined from scanning electron microscopic (SEM) images taken using a FEI Quanta 200F scanning electron microscope (FEI UK Limited, Cambridge, UK). The microscope was operated in low vacuum mode at a chamber pressure of 1.05 Torr (140 Pa) using an accelerating voltage of 5 kV and a small spot size to minimize specimen damage. The use of a low vacuum was essential,32 as nabumetone nanoparticles were prone to melt (melting point 78−83 °C) under standard vacuum settings. Depletion Measurements of Polymer Adsorption. Nabumetone nanoparticles stabilized by HPC with a viscosity average molecular weight (Mv) of 57, 89, and 107 kg/mol were produced as detailed above by milling in the presence of polymer over the concentration range 0.5−3.0% (w/w). The resulting nanosuspensions were centrifuged, the supernatant harvested and then assayed for HPC content by measuring the optical rotation at 350 nm using a Jasco J600 spectropolarimeter (Jasco UK Ltd., Great Dunmow, UK). This method of analysis was found to be suitable over the molecular weight range of the polymer being studied. By subtracting the amount of (unadsorbed) polymer in the supernatant from the initial amount, it was possible to elucidate the adsorbed amount. Normalization of polymer adsorption per unit surface area of drug was possible based on the particle size of the nanoparticles and the true density of the drug, determined using helium

Poly(vinylpyrrolidone) (PVP) molecular weight grades Kollidon K12 and K30 were supplied by BASF (Cheshire, UK). Yttrium zirconia (YTZ) milling beads of diameter 0.44 mm were obtained from the Nikkato Corp. (Tokyo, Japan). Double-distilled water was used throughout, and D2O (99.9% purity) from Sigma-Aldrich (Gillingham, UK) was used for the preparation of samples for SANS measurements. Characterization of Polymers. The dimension in solution (Rh) of selected molecular weight HPC polymers was characterized using dynamic light scattering (ALV-5000, ALVLaser Vertriebsgeellschaft mbH, Langen, Germany) and analyzed using cumulants analysis (ALV-Correlator software v3.0). The polymer radius of hydration was converted to radius of gyration (Rg) using the relationship Rg = 2.05Rh based on the assumption that the polymer was polydisperse and exhibited a random coil architecture in water.31 The measured characteristics of the polymers are given in Table 1. Production of Drug Nanoparticles. Solid polymerstabilized drug nanoparticles were produced using a wet bead milling method as detailed by Sepassi et al.32 A 20% (w/w) nabumetone or 30% (w/w) halofantrine crude suspension was formed by mixing 10 g of nabumetone in a solution of HPC or HPMC or 15 g of halofantrine in a polymer solution of HPMC or PVP. Polymer solutions of a range of molecular weights and concentrations were prepared by dispersing the dried polymer in distilled water and leaving to dissolve with constant stirring. Since HPC was not commercially available over a suitable molecular weight range of < ∼80 kg/mol (it is not possible to produce nanoparticles using higher molecular weight HPC for this system),12 a 4.0% (w/w) solution was ultrasonically degraded at 2 °C as described by Goodwin et al.30 and diluted to the required polymer concentration. A sample of 10 mL of crude suspension and 10 mL of beads was added to a 25 cm3 milling jar made from food grade nylon (Nylacast, Leicester, UK), and milling was performed for 6 h at 30 vibrations/s using C



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pycnometry (Quanta Chrome Instruments, UK), of 1.19 g/cm3 but under the assumption of spherical drug particles. While it is recognized that this assumption will introduce a source of error into the quantification of the polymer adsorption using this method, leading to an overestimation, it is not considered to be an unreasonable assumption as only 20% less absorption is calculated if cuboid particle morphology is assumed (as observed in the present study for nabumetone nanoparticles milled in the presence of HPC of varying molecular weight).12,32 Preparation of Nanoparticles for Neutron Scattering. After wet bead milling, the beads were removed and the unadsorbed polymer separated from the nanoparticles by centrifugation. The nanoparticles were then resuspended in an equal weight of aqueous solvent containing various % (v/v) D2O and diluted to a solid volume fraction of either 3.5, 4.0, or 5.0% (v/v) (Table 2) to allow the highest possible scattering from the sample while at the same time minimizing interlayer interactions, excluded volume effects and possible multiple scattering effects from the drug particles.17,18 Prior to the SANS experiments the theoretical neutron scattering length density (SLD, ρ) of the drugs and polymers were calculated from a knowledge of their chemical structure and density (Table S1). Such knowledge allowed both the rational selection of a range of D2O and H2O mixtures in which, on resuspending the drug nanoparticles, the theoretical SLD could be optimized using SANS (Figures S1−S3) and confirmed that there would be sufficient contrast between the drug particles and the polymers to allow the SANS experiments to be performed. The experimentally determined SLD for both drugs agreed extremely well with the theoretically calculated value and all other SANS measurements were made with nabumetone or halofantrine nanoparticles dispersed in 31.3 or 33.8% (v/v) D2O solutions, respectively. Small-Angle Neutron Scattering. Neutrons have a number of useful properties,33 but three in particular are of value in the study of adsorbed polymer layers: they are highly penetrating and so do not perturb or destroy the structure of the experimental system; they have a wavelengths of the order 0.1−1 nm, comparable to nanoscale dimensions; and they are scattered differently by different isotopes of an element. In this work we have exploited the last property by selectively employing deuterium for hydrogen isotopic substitution. This allows parts of the system under study to either be “contrast matched” (cf. refractive index matching) or selectively “highlighted”. Here we have contrast matched the drug particles to the dispersion medium by carefully mixing H2O and D2O until the SLD of the mixture equaled that of the drug. Under this condition only the adsorbed polymer layer is “visible” by the neutrons, as illustrated in Figure 2. The drawback with this approach is that the effective concentration of polymer stabilizer is very small, and so the signal-to-noise is generally poor and long measurement times are needed. To circumvent this “off-contrast” procedures have been developed, but these require many more measurements in media of different SLD values (raising issues about the repeatability of sample preparation) and more complex data manipulation.34−36 SANS measurements were performed on the D11 camera at the Institut Laue-Langevin (ILL) (Grenoble, France) using an incident neutron wavelength λ of 0.8 nm. The neutrons scattered from the nanoparticle samples contained in 1 mm path length quartz cuvettes (Hellma GmbH, type 110-QS) were recorded on a 64 cm2 3He position-sensitive detector

Figure 2. Diagrammatic representation of the contrast matching of the continuous phase to the adsorbent of a nanosuspension using a mixture of H2O and D2O as the solvent to obtain the neutron scattering solely from the adsorbed polymer layer.

(LEA CERCA) mounted on a moveable trolley in a vacuum vessel. Sample transmission measurements were performed at a sample−detector distance of 5 m (to improve accuracy and reduce counting times), while scattering measurements were generally performed at two sample−detector distances of 5 and either 10 or 15 m, to give an accessible scattering vector range, Q (= 4π/λ sin θ, where θ is half the scattering angle), of ∼0.04−0.6 nm−1, sufficient to probe length scales in the samples between a few nanometers and a couple of hundred nanometers, as required here. Each sample scattering measurement was performed for between 30 min (short sample− detector distances) and 120 min (long sample−detector distances). We re-emphasize that, as a consequence of the relatively large particle size (giving rise to a locally flat interface in molecular terms) and effectively low concentration of adsorbed stabilizer, the signal measured in excess of the background is quite weak. At the same time the neutron count rate falls off with sample−detector distance as an inverse square law. Measurements of the scattering from B4C (a neutron absorber; to determine the detector electronic background), 1 mm H2O (for detector response corrections), an empty sample cuvette (as a transmission reference sample), and the dispersion media containing the appropriate amount of D2O (as a sample background) were also recorded and used to correct the sample scattering data into absolute units.37 This “reduced” data was then placed on an absolute scale using the known scattering from a partially deuterated polystyrene blend calibration sample.37 Data Analysis. The measured SANS, per unit volume, from a dispersion of sterically stabilized particles may be expressed as:38 I(Q ) = VpϕpP(Q )S(Q ) + B

(1)

where I(Q) is (formally) the coherent differential neutron scattering cross-section, ϕp is the volume fraction of particles, Vp is the volume of one particle, and B is the residual background scattering. The function S(Q) describes positional correlations between the particles and may be ignored in dilute systems (i.e., S(Q) → 1). The function P(Q) is more important. This describes the visibility, shape, and size of those components in the sample contributing to the scattering and in the present case comprises four terms:17,18 D



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P(Q ) = [(ρp − ρm )2 Fp(Q )2 ] + [2(ρp − ρm )(ρl − ρm )Fp(Q )Fl(Q )] 2

Given a knowledge of Φ(z), additional information can be extracted from the integral and moments of the profile, namely:

(2a)

2

+ [(ρl − ρm ) Fl(Q ) ] + Ill̃

(2b)

∫0

(2c)

where eq 2a describes the scattering from the core particle, eq 2b describes the interference scattering between the particle and the adsorbed stabilizer, and eq 2c describes the scattering from just the adsorbed layer, Pll(Q). When the particles are contrast-matched to the dispersion medium, ρp = ρm, and it is seen that P(Q) reduces to Pll(Q). Explicitly, this may be written: ⎡ 1 Pll(Q ) = (ρl − ρs ) 2πA p⎢ 2 × | ⎣Q 2

∫0

t

⟨p⟩ = ⟨z n⟩ =

δ Γ

∫0

δ Γ

(5)

t

∫0

Φ(z) dz t

Φ(z)z n dz ;

(typically for t ∼ 1 nm)

(6)

σrms = ⟨z 2⟩1/2 ; (7)

For both model-fitting procedures the data were weighted by the experimentally determined error, and optimization proceeded until the lowest chi-square or goodness-of-fit (GoF) value was obtained.

2

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RESULTS Adsorption Isotherms. The adsorption isotherms of HPC on nabumetone (Figure 3) appear different to those commonly reported in the polymer adsorption literature42 since the initial (rising) portion of each isotherm is absent. This is due to the fact that nanoparticles can only be produced once the concentration of stabilizer is above a certain threshold to completely coat the surface of the drug particle. For example, at a starting concentration of 1.0% (w/v) HPC-EF (107 kg/mol), the mean polymer concentration remaining in solution after milling was found to be 0.46% (w/v), suggesting that a concentration of at least 0.54% (w/v) is needed to be present to stabilize the nanoparticles. Particle size analysis results confirm this finding since milling nabumetone with a concentration of HPC less than 0.54% (w/v), for example 0.50% (w/v), led to the production of micro- rather than nanoparticles. If the initial portions of the isotherms were measurable, we would expect them to be well-rounded, because of the broad molecular weight distributions of the polymers used.19,43 The remaining portion of the adsorption isotherm is usually found to exhibit a plateau corresponding to saturation of the solid surface with polymer.44 Results for the adsorption of HPC showed a slight decrease with increasing polymer concentration which could be explained by the fact that, with this change in initial polymer concentration, the drug particle morphology tends to change from being mainly spherical (minimum surface area to volume ratio) at low to intermediate concentrations to containing a larger fraction of columnar or cuboidal particles at high polymer concentrations (higher surface area to volume ratio) (Figure S4).12 The assumption that monodisperse, spherical nanoparticles are formed throughout the polymer concentration range therefore slightly overestimates the available surface area in the system with the amount absorbed being 20 and 28% less when particles are assumed to be cuboidal and rodlike, respectively.32 The plateau value of polymer adsorption for the three molecular weight HPC polymers on nabumetone can be averaged to Γ ∼ 3.5 mg/m2 (Figure 3) which is within the range of 1.5−16 mg/m2 as found by Lee45 in a study of HPC (60 kg/mol) adsorption onto ∼10 μm microparticles and ∼150 nm nanoparticles of an undisclosed drug. Notably, typical polymer adsorption isotherms were not obtained by Lee either; adsorption onto the microparticles was similar to that reported here, while adsorption onto the nanoparticles was found to

(3)

where Φ(z) is the volume fraction profile, Ap is the surface area per unit volume of the particles, and Ill̃ describes spatial inhomogeneities in the average structure of the adsorbed layer, the contribution from which is small and generally ignored, allowing Φ(z) to be recovered by Hilbert inversion of eqs 1 and 3.39 Alternatively, mathematical approximations (parametrized in terms of the layer thickness, adsorbed amount, bound fraction, etc.) for Φ(z) can be inserted into eq 3 which is then back-transformed to calculate the expected I(Q) and which can, in turn, be compared with the measured scattering by nonlinear least-squares fitting. It is this latter approach that has been used here (program “Playtime”). Three functional forms for Φ(z) were tested against each data set: a block (i.e., step) profileas would be expected from a dense “brush”-like adsorbed layer of even thickness; an exponential profileas is typical of the ‘train−loop−tail’ conformation adopted by physically adsorbing homopolymers; and a parabolic profileas would be expected from an adsorbed layer formed by terminally attached polymers.15,16,19 As an aside, it is clear from eqs 1−3 that the scattering decreases with increasing Q. Thus experimentally it is only necessary to measure a small range of Q values appropriate to the system under study, even though a SANS camera will often measure a much wider range. Neutron beams are a limited resource and must be utilized efficiently. When the radius of the particles, Rp, is much greater than the maximum extent of the adsorbed polymer layer, the exponential term in eq 3 can be replaced by a series expansion. Recognizing that the integral of Φ(z) is also proportional to the adsorbed amount then results in the following limiting form of the adsorbed layer scattering: ⎡ 6πϕ ⎤ 2 p Γ I(Q ) ≈ (ρl − ρm )2 ⎢ 2 2 exp( −Q 2σ 2)⎥ + B ⎢⎣ Q δ R p ⎥⎦

Φ(z) dz

σ 2 = ⟨z 2⟩ − ⟨z⟩2

Φ(z) exp(iQz) dz|

⎤ + Ill̃ ⎥ ⎦

l

Γ=δ

(4)

where δ is the density of the polymer. Equation 4 is the interfacial analogue of the well-known Guinier approximation in small-angle scattering and was least-squares fit to the measured scattering to obtain estimates of Γ and the average distance of the center-of-mass of the polymer from the interface, σ (program “SANDrA”).40 The input parameters used in the program are given in Table 2. An important feature of eq 4 is that it is independent of the actual functional form of Φ(z). E



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homopolymers (>1000 repeat units) in a good solvent, the absorbed amount can become almost independent of chain length due to saturation of the surface;19,42 however the polymers used in the present study are not long enough for this situation to occur. In fact Figure 3 appears to show something in-between these two extremes, suggesting that the HPC is adsorbing in a relatively compact conformation.44,49 This observation has important implications for the selection of polymer molecular weight when producing nanoparticles by wet bead milling. Layer Structure: Effect of Polymer Molecular Weight and Concentration. An example of the SANS data from HPC-stabilized nabumetone nanoparticles after appropriate data treatment is illustrated in Figure 4. These data were initially fitted to the surface Guinier function (eq 4), which is independent of the functional form of the volume fraction profile, to obtain values for Γ, σ, and the background level. These were then used as initial estimates for the fitting of the data to model volume fraction profiles by the inverse transform method using eq 3 (Figure 5 and Figures S5−S8). Although the resulting profiles of the various models of the adsorbed layer are markedly different (Figure 6), the difference in the quality of the fits of the calculated scattering from these model volume fractions to the experimental data is rather more subtle, due mainly to the poor signal-to-noise in this low Q range. The relative GoF values for the three fits in Figure 5 were 1:1.4:1.8 for the exponential, parabolic, and block profiles, respectively. Typically the best goodness-of-fit and average residual values were found when fitting an exponential profile, the profile form that would be theoretically expectedand which has been repeatedly demonstratedfor a physically adsorbing homopolymer where the adsorbed layer structure comprises a mixture of trains, loops, and tails.19,23 Futhermore, the calculated scattering from the exponential profile is also most similar to the surface Guinier fit. Conversely, the block profile is seen to be a poor description of the polymer distribution at the interface. The exponential profile contrasts with the parabolic profile demonstrated by block copolymers and some terminally attached chains as a result of the formation of a large number of tails of similar length.42 These different profile forms will, of course, also return different measures of the thickness of the adsorbed layer. This fact is discussed shortly. The values of Γ given in Table 3, measured at the same initial solution concentration, are shown to remain fairly constant over the molecular weight (Mv) range of 47−112 kg/mol of HPC. When the data were fit to a parabolic or block volume fraction profile, the actual values of Γ changed only marginally, and the trend with respect to polymer molecular weight seen in Table 3 was unaffected (data not shown). The apparent insensitivity of Γ to polymer molecular weight is in agreement with the trend found from depletion measurements, although the actual values of Γ from SANS (Table 3) are approximately double that found by depletion measurements (Figure 3). A possible reason for this is discussed later. Further assessment of the properties of the adsorbed layer can be made by comparing the dimensions of the polymer in solution with estimates of the adsorbed layer thickness.22 It is apparent from the data in Table 3 (measured at the same solution concentration) that fitting the scattering data assuming an exponential volume fraction profile results in an adsorbed layer thickness that is approximately twice as thick as that estimated using the model independent (surface Guinier) method. This observation suggests that the assumption of an

Figure 3. Adsorption isotherms (closed symbols) and mean particle size (open symbols) of HPC (107 kg/mol (top), 89 kg/mol (middle), and 59 kg/mol (bottom)) stabilized nabumetone nanoparticles wet bead milled for 6 h (n = 3 ± s.d.).

continue to increase with increasing polymer concentration in the milling media up to the maximum studied of 3% (w/v) HPC. Other examples of work studying the adsorption properties of HPC on ibuprofen46 or HPMC on pyrantel pamoate47 have been conducted using drug macroparticles rather than nanoparticles; unfortunately here the authors quote the extent of polymer adsorption as the weight of polymer adsorbed per gram of drug. Expressing polymer adsorption in this way is not helpful for comparing systems, particularly where the drug particle sizes are of different magnitudes, because it neglects the significant difference in surface area. Analysis of the molecular weight dependence of Γ (when expressed in mg/m2) serves as a useful tool to characterize the conformation of polymer molecules at an interface.48 For example, if a polymer adsorbs “end-on” in the form of a “brush” then, provided there is sufficient surface coverage, Γ will be directly proportional to the polymer molecular weight as the chains stretch away from the surface. For very long F



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Figure 4. Example of the combined and fully reduced SANS data from nabumetone nanoparticles stabilized with HPC 47 kg/mol at 1.5% (w/w). Notice the change in error bars between the different sample−detector distances (different count rates) at Q ∼ 0.23 nm−1. The continuous line is a fit to the surface Guinier function (eq 4) for the parameter values in Tables 2 and 4. The dotted line is a calculation using the same parameters but for an adsorbed layer half as thick (50% σ). The dashed line is a calculation using the same parameters but for an adsorbed layer with half as much polymer adsorbed (50% Γ).

Figure 5. Exponential (continuous line), parabolic (dotted line), and block (dashed line) volume fraction profile (inverse transform) fits to the SANS data from nabumetone nanoparticles stabilized with HPC 47 kg/mol at 1.5% (w/w).

exponential like profile, although giving the best fit to the experimental data, is not the optimal description of the volume fraction profile, and some sort of truncated exponential might be a better representation. However due to the nature of the system under study, that is, a physically adsorbing homopolymer, and applying Occam’s Razor, it is the parameters obtained from fitting a simple exponential profile which will be used in the ensuing discussion unless otherwise stated. The thickness of an adsorbed polymer layer (e.g., σ, σRMS) has been noted to extend up to distances of the order of Rg,42

although the data for estimates of the adsorbed layer thickness in Table 3 are generally less than Rg, suggesting that the adsorbed chains adopt conformations which are on the whole flatter than random coils27 particularly, for example, HPC Mv = 112 kg/mol where Rg = 23.9 nm, whereas σrms ∼ 15.4 nm. Despite the fact that the dimensions of the polymer in solution are reduced as the molecular weight of the polymer decreases, like the adsorbed amount, the adsorbed layer thickness also appears to remain relatively constant at ∼11−14 nm (Table 3). This may suggest that the lower molecular weight polymers are G



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Figure 6. Example of volume fraction profiles from HPC adsorbed onto nabumetone nanoparticles stabilized with HPC 47 kg/mol at 1.5% (w/w) derived from the fits to the illustrated SANS data.

Table 3. Comparison of the HPC Dimensions in Solution with Parameters Summarizing the Adsorbed Layer Thickness on Nabumetone Nanoparticles Prepared Using 1.5% (w/v) Polymer Solution over a Range of Polymer Molecular Weights

a

polymer Mv (kg/mol)

HPC-EF 112 112

Rh (nm) Rg (nm)

11.7 ± 0.4 23.9 ± 0.8

Γ (mg/m2) σ (nm) x2 ave. residual

7.9 ± 0.1 4.1 ± 0.3 0.221 0.0034

Γ (mg/m2) σ (nm) σRMS (nm) l (nm) ⟨p⟩ GoFa ave. residual

8.7 11 15.4 24.5 0.09 0.012 0.0106

Sample Parameters HPC-EF 79 HPC-EF 65 79 65 Polymer Dimensions in Solution 8.7 ± 0.3 17.8 ± 0.6 Surface Guinier Model 8.6 ± 0.1 9.2 ± 0.1 8.5 ± 0.1 4.9 ± 0.2 6.5 ± 0.2 5.7 ± 0.2 0.246 0.212 0.224 0.0021 0.0009 0.0001 Fit to Exponential Profile 9.5 9.4 9.2 9.1 8.1 10 12.7 11.2 14 22 20.5 23 0.1 0.12 0.1 0.005 0.002 0.005 0.0048 0.0824 0.0557 HPC-JF 82 82

HPC-EF 55 55

HPC-EF 47 47 7.6 ± 0.3 15.5 ± 0.6

8.6 ± 0.1 5.7 ± 0.2 0.247 0.0005

10.8 ± 0.1 5.5 ± 0.2 0.470 0.0020

9.3 10.1 14.2 23 0.09 0.004 0.0551

11.7 9.9 13.8 23 0.1 0.007 0.0124

GoF = goodness of fit.

adopting a more expanded conformation at the interface compared with their higher molecular weight counterparts. A suggested explanation for this is that the HPC molecule adsorbs to the nabumetone nanoparticle surface at specific points along the polymer chain. As the molecular weight of the polymer is reduced, the number of loops and trains per polymer molecule reduces accordingly, but the distance between the points of attachment remain the same, preserving the average size of the loops (Figure 7) and thus the reported layer thickness as observed from the data in Table 3. Further support for this hypothesis of the conformation of HPC at the interface as illustrated in Figure 7 comes from the consistent values of ⟨p⟩ with changing HPC molecular weight (Table 3), again suggesting that the distance between points of

polymer attachment to the drug particle surface remain consistent with altering polymer chain length. The actual values of ⟨p⟩ ∼ 0.1 (Table 3) (suggesting an adsorbed layer with long loops and tails) are thought to be quite low bearing in mind the fairly compact nature of the polymer layer as suggested by estimates of the layer thickness. However, the values of ⟨p⟩ are reported to vary with the technique used,49 and any conclusion made about the conformation of the adsorbed layer should not be based on this parameter alone.50 A relatively low ⟨p⟩ parameter will also be a consequence of using a homopolymer as a steric stabilizer, since only a small number of sites along the polymer may possess the required properties to adsorb to the nabumetone nanoparticle, compared to a block copolymer, for example, where long H



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Figure 7. Representation of the adsorbed polymer layer showing how the thickness (σ), amount of polymer adsorbed (Γ), and the bound fraction ⟨p⟩ remains constant at both (a) low and (b) high molecular weights.

Figure 8. Comparison of the best-fit exponential polymer volume fraction profiles from nabumetone nanoparticles stabilized with varying molecular weights of HPC at 1.5% (w/w). Mv = 112 kg/mol (dotted line), Mv = 82 kg/mol (chain dashed line), Mv = 79 kg/mol (dashed line), Mv = 65 kg/ mol (double chain dashed line), and Mv = 47 kg/mol (continuous line). The Mv = 55 kg/mol data is omitted for clarity but is similar to the Mv = 65 kg/mol profile.

The parameter l, the span of the adsorbed polymer layer, represents a layer thickness taking into account a greater contribution from the tails (compared to σ or σrms). The results in Table 3 show that by fitting the SANS data to an exponential profile the thickness of l approximates to 23 nm and this is again independent of HPC molecular weight over the range studied. However, the maximum extent of the polymer layer thickness may extend beyond this estimate as SANS will be relatively insensitive to any ultradilute, far-extending, tails.23 For physisorbed homopolymers these can approach an extension normal to the interface of greater than three times that of σ,49 greatly contributing to colloidal stability.51 This is highlighted by comparing the magnitude of the layer thickness of similar polymers found by other workers using viscometry. The hydrodynamic thickness of the polymer layer obtained using viscometric measurements is much more sensitive to the

sections of the polymer have the desired properties to attach to the surface and the remainder of the chain exists in loops or tails. In the present work the picture is further complicated by the generally broad molecular weight distributions of the commercial polymers used. It has been shown that where a polydisperse mixture of chains of the same homopolymer are able to adsorb, the shorter chains adsorb first (because they diffuse to the surface faster), but these are subsequently displaced by the longer chains (because these lose proportionally less configurational entropy per unit mass).19 At the same time, any measured thickness of the adsorbed layer will also depend on the degree of surface coverage (determined by the adsorbed amount) and on the actual measure of layer thickness used. I



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Table 4. Summary of Parameters Describing the Adsorbed Polymer Layer of Nabumetone Nanoparticles Milled in the Presence of HPC over a Range of Concentration 0.5−2.0% (w/w) and Molecular Weight Mv = 47 and 112 kg/mol Sample Parameters

a

Mv (g/mol) concentration (% w/w)

0.5

1


9.3 8 0.172 3 × 10−4

8.5 6.5 0.182 2 × 10−4

Γ (mg/m2) σ (nm) σRMS (nm) l (nm) ⟨p⟩ GoFa ave. residual

10.4 13.1 18.4 27.0 0.07 6.2 × 10−3 0.058

9.5 12 16.9 25.5 0.08 6.8 × 10−3 0.053

112

47 1.5

2 Surface Guinier Model 7.9 8.7 4.1 6.1 0.221 0.282 3.4 × 10−3 1.0 × 10−3 Fit to Exponential Profile 8.7 9.5 11 10.3 15.4 14.5 24.5 23.5 0.09 0.09 1.2 × 10−2 4.8 × 10−3 0.011 0.006

0.5

1

1.5

2

6.9 5.8 0.175 3 × 10−4

8.5 6 0.239 9 × 10−4

10.8 5.5 0.47 2 × 10−3

8.6 5.6 0.29 7 × 10−4

7.4 9.4 13.1 22 0.1 4.0 × 10−3 0.04

8.9 8.6 11.9 21 0.11 4.0 × 10−3 0.003

11.7 9.9 13.8 23 0.1 7.3 × 10−3 0.012

8.9 7.6 10.5 19.5 0.12 3.7 × 10−3 0.004

GoF = goodness of fit.

contribution of the tails.24 For example, Law and Kayes46 report a layer thickness of ∼43 nm for HPC-EF adsorbed onto polystyrene latex, whereas a thickness of ∼134 nm of HPMC adsorbed onto pyrantel pamoate particles was found by Duro et al.47 However, viscometry would not be a suitable technique for studying the current system since it relies upon measurements of particles both with and without adsorbed polymer; due to their high surface energy, it is not possible to isolate and perform measurements on bare nanoparticles. Perhaps a more accurate indication of the extent of the adsorbed layer can be obtained from the distance from the interface at which Φ(z) ∼ 0 (Figure 8), and these values for HPC adsorbed on nabumetone are closer to those quoted by Law and Kayes.46 The adsorbed polymer layer on nabumetone nanoparticles milled in the presence of HPC over a concentration range 0.5− 2.0% (w/w) at low (47 kg/mol) and high (112 kg/mol) polymer molecular weight was also characterized using SANS (Table 4). As with the samples stabilized with varying HPC molecular weight but at the same concentration (Table 3), altering the polymer concentration did not change the fact that the exponential profile typically yielded the best fit to the SANS data. Consideration of how Γ varies with the initial HPC polymer concentration (Table 4) enables adsorption isotherms to be established at low and high polymer molecular weights. Between 1.0 and 2.0% (w/w) HPC, the values of Γ remain fairly constant at approximately 8−9 mg/m2 at both low and high molecular weight although intriguingly the sample prepared with 1.5% (w/w) HPC at 47 kg/mol appears to have a higher polymer adsorption than the other samples at almost 12 mg/m2. Again, at ∼8−9 mg/m2, the adsorbed amounts are double that measured using the depletion method (Figure 3). This difference could (at least partially) be due to the assumption of monodisperse drug particles when calculating the surface area to determine Γ using the depletion method. The value of Γ as determined from SANS data varies as the √Rp and so was less sensitive to particle size. The assumption that is made by the fitting programs is that the interface is “locally flat”, and this is considered to be fulfilled given the large difference in size between the polymer layer and radius of the particle. In contrast to SANS, the measure of Γ determined from depletion measurements of HPC in solution is directly related to the

average particle size used for calculation of the nanoparticle surface area. If there are some larger (>1 μm) particles present in the sample which are not represented by the average particle size obtained using laser diffraction, then the calculated surface area will be overestimated resulting in a value of Γ which is underestimated. There only needs to be a relatively few large particles in a sample to cause this discrepancy because of the much larger volume that these particles occupy. The possibility of multilayer adsorption has been raised for homopolymers52 and may also go part way to explaining the observation of high Γ values (due to chain entanglement occurring at the particle surface giving rise to large, “pseudoadsorbed” amounts of polymer).53 This phenomenon has been used to rationalize the observation of increasing Γ with increasing polymer concentration above the plateau region for cellulose ethers, HPC, HPMC, and hydroxyethylcellulose (HEC), adsorbing on polystyrene latex particles.44 There is a possibility that this effect is occurring in the system currently under study, particularly due to the relatively high concentrations of HPC used. Although, as the estimated thickness of the polymer layer is fairly thin when compared with the Rg of the polymer in solution, and the fact that the SANS data fits reasonably well to an exponential function, the experimental evidence would seem to suggest otherwise. Of particular note is that the aforementioned work based their conclusions on little more than measures of Γ, rather than on any detailed knowledge of the polymer distribution at the interface as obtained in the present work.46 Another possible explanation is that the adsorbed HPC layer is very heavily hydrated, causing an increase in the scattering length density of the adsorbed layer and thereby a reduction in the contrast of the layer, which may in turn lead to an overestimation of the thickness of the adsorbed layer or the adsorbed amount, or both, obtained from the SANS data. Based on the high adsorbed values obtained from the depletion experiments, it is perhaps more likely that HPC forms heavily hydrated, multilayers on the surface of the nabumetone nanoparticles. In summary, the apparent insensitivity of the adsorbed amount and layer thickness to changes in HPC molecular weight remains something of an enigma and in need of further investigation. Theoretically, dependencies of something like ∼M0.4 > Γ > ∼M0.1 and σrms ∼ M0.4 would be predicted for the J



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Table 5. Summary of Parameters Describing the Adsorbed Polymer Layer of Nabumetone and Halofantrone Nanoparticles Milled in the Presence of HPMC and PVP

a

polymer druga Mv (kg/mol) polymer conc. (% w/v)

HPMC E3LV Nab 5 1.25


4.6 9.7 0.002 2.1 × 10−8

Γ (mg/m2) σ (nm) σRMS (nm) l (nm) ⟨p⟩ GoFb ave. residual

5.5 15.4 21.8 29.1 0.06 0.26 × 10−4 2.1 × 10−5

Sample Parameters HPMC 11k HPMC E3LV Nab Halo 7.7 5 1.25 1.43 Surface Guinier Model 7.7 2.4 8.3 3.3 0.011 0.04 1.0 × 10−8 5.2 × 10−8 Fit to Exponential Profile 9.3 2.4 13.3 3.6 18.9 5 27.3 12 0.07 0.24 0.10 × 10−3 0.12 × 10−4 −5 1.1 × 10 9.4 × 10−5

HPMC E3LV Halo 5 2.14

PVP 12 Halo 3 1.43

PVP 30 Halo 46.2 0.71

14 11.2 0.043 3.3 × 10−7

1.9 5.2 0.056 2.2 × 10−8

1.8 5.3 0.076 1.6 × 10−8

25.2 25.1 38.2 37.8 0.07 0.18 × 10−2 3.6 × 10−5

1.8 3 4.1 10.6 0.28 0.21 × 10−4 5.6 × 10−5

1.7 3 4.1 10.5 0.28 0.29 × 10−4 1.4 × 10−4

Nab = nabumetone, Halo = halofantrine. bGoF = goodness of fit.

layer (Table 5). A similar finding of a lower value for Γ was found from depletion measurements for this polymer adsorbed onto halofantrine (range 2.5−3.1 mg/m2).30 The bound fraction from SANS was also much higher than when adsorbing onto nabumetone nanoparticles, and this is thought to indicate that HPMC is adsorbing in a flatter conformation on the nanoparticle surface with more points of attachment. The difference in the adsorption characteristics of HPMC on the two drugs is thought to be due to the different chemical composition of the nanoparticle surface and thus the potential for different strength polymer−surface interactions to occur through either hydrophobic interaction or hydrogen bonding.54 We have no explanation for why a modest increase in initial polymer concentration, from 1.43 to 2.14% (w/v), should give rise to such a significant increase in Γ and σ. These data probably reflect a problem with that particular experimental sample. As an alternative to cellulose-based steric stabilizers, the adsorption properties of PVP on halofantrine were investigated (PVP was not able to stabilize nabumetone nanoparticles). The magnitude of Γ for PVP on halofantrine nanoparticles was much lower than that found for the cellulose ethers and more in-keeping with the range of Γ quoted for adsorption studies on many model systems in the literature. The values of Γ estimated from SANS for PVP 30 (1.7 mg/m2) are also closer to those obtained from depletion measurements by Sepassi et al.30 of 0.9−1.4 mg/m2. The fact that Γ was remained virtually constant, regardless of the molecular weight of the PVP over the average weight range of 3−46 kg/mol indicates that it adsorbs in a flat conformation, and this is corroborated by the fact that both estimates of the layer thickness remain constant and the value of ⟨p⟩ is relatively high (Table 5).

sorts of polymer molecular weights used in this work.19 However, these predictions assume monodisperse homopolymers, and the likelihood is that the significant polydispersity of the polymers used here has resulted in a much more complex adsorption process. Layer Structure: Effect of Polymer or Drug. Table 5 compares the adsorption characteristics of HPC on nabumetone with that of HPMC on nabumetone and HPMC and PVP on another hydrophobic drug, halofantrine. As with the nabumetone−HPC system, the best fit to all drug−polymer combinations was obtained using a model exponential volume fraction profile. Comparison of the adsorption properties of different polymers on drug nanoparticles is complicated by the additional variable of polymer molecular weight, since only a limited range of molecular weight grades are available for each polymer type. Coupled with this fact is the inconsistency of molecular weight determinations between different manufacturers.29 Due to the fact that the production of nanoparticles using wet bead milling requires the lowest molecular weight polymers,30 the molecular weight grade of the alternative polymers studied was typically selected based on their performance in producing nanoparticles by wet bead milling. HPMC appears to adsorb to the nabumetone nanoparticle surface forming a slightly thicker polymer layer (Table 5) compared to HPC (Table 3). The values of Γ for HPMC on nabumetone appear to be more dependent upon the polymer molecular weight than the HPC stabilized nabumetone nanoparticles. However, the limited molecular weight range should be borne in mind along with the fact that the two polymers were obtained from two separate manufacturers, and therefore, in contrast to ultrasonically degraded HPC there is a higher chance of substitution differences.29 Using the depletion method, the amount of HPMC E3LV adsorbed onto nabumetone nanoparticles has been quantified by Sepassi et al.30 and was found to be similar (range 2.6−3.5 mg/m2) to that found for HPC adsorption onto nabumetone (range 2.6− 4.4 mg/m2). The properties of the adsorbed layer of HPMC E3LV adsorbed onto halofantrine nanoparticles revealed the polymer to adsorb to a lesser extent and form a much thinner adsorbed

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CONCLUSION Of the conventional techniques available to ascertain detailed information regarding the structure of adsorbed polymer layers, only SANS has the potential to obtain the greatest level of information by elucidation of the volume fraction profile. Traditional laboratory techniques often only provide information on one property of the adsorbed layer, and results may K



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Notes

vary widely between the different methods used. In addition to this, the basis of many methods involves measurements of a particle both with and without the adsorbed polymer to obtain the information of interest. For the systems in question, however, this is impossible due to the fact that the drug nanoparticles cannot be produced without the presence of a stabilizer. The estimates of the thickness of the polymer layer tend to suggest HPC is adsorbing in a typical loops−trains−tails conformation with the average size of the loops extending to approximately 10−15 nm. The maximum extent of the HPC polymer layer as detected from SANS is at least 23 nm, which is similar to the Rg of the polymer in solution. This may be the result of the polymer adsorbing with relatively short tails, or that longer tails are present but cannot be detected using SANS. Surprisingly, the thickness of the polymer layer was independent of the polymer molecular weight over the range studied despite the Rg of the polymer in solution differing by approximately 45% between the highest and the lowest molecular weight studied. Thus, it is thought that the extent of the loops remained constant with changing polymer molecular weight because HPC was adsorbing to the nabumetone particle surface at specific points along the polymer chain, and this distribution did not vary with the polymer molecular weight. Further support for this was obtained from the fact that the fraction of bound polymer (⟨p⟩) was also independent of the polymer molecular weight. There was little discernible effect in the SANS data concerning the effect of polymer concentration on the thickness of the polymer layer or ⟨p⟩ when considering the parameters obtained from both model-fitting techniques. The insensitivity of polymer molecular weight on the adsorbed layer properties has implications for the formulation of wet bead milled polymer-stabilized nanoparticles. The lower viscosity and faster diffusion of lower molecular weight polymers can result in shorter processing times but does not lead to a decrease in physical stability.12 It appears from the SANS data described herein that this is due to the configuration of the adsorbed polymer layer. By comparing the SANS data from combinations of different drug particles and stabilizing polymers it is revealed that the properties of the adsorbed polymer layer are highly dependent on both the adsorbing polymer and the nature of the drug particle surface.

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS D.G. and S.S. would like to thank the EPSRC, Impact Faraday and GlaxoSmithKline for the award of studentships, and Prof. Terry Cosgrove, University of Bristol, for a copy of the “Playtime” program. The authors would also like to acknowledge the assistance of Dr. Peter Timmins and Dr. Phil Callow at ILL, Grenoble for assistance with SANS measurements and the ILL for the provision of neutron beam time (Experiment INDU-56 and ILL 9-10-713).

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ASSOCIATED CONTENT

S Supporting Information *

Chemical structures of the drugs. Supplementary Table S1 shows the neutron scattering length densities of the drug nanoparticles and polymers used and method of calculation. Figure S1 shows contrast variation SANS data from halofantrine nanoparticles. Figure S2 shows contrast variation SANS data from nabumetone nanoparticles. Figure S3 shows contrast match plot for halofantrine and nabumetone nanoparticles. Figures S4−S7 show surface Guinier and inverse transform fits to the SANS data from HPC and HPMC adsorbed on nabumetone at various concentrations and molecular weights. This material is available free of charge via the Internet at http://pubs.acs.org.

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Characterization of Polymer Adsorption onto Drug Nanoparticles

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