Qualitative and Quantitative Characterization of Composition

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Qualitative and quantitative characterization of composition heterogeneity on the surface of spray dried amorphous solid dispersion particles by an advanced surface analysis platform with high surface-sensitivity and superior spatial resolution Sonal V Bhujbal, Dmitry Zemlyanov, Alex-Anthony Cavallaro, sharad mangal, Lynne S. Taylor, and Qi Tony Zhou Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00122 • Publication Date (Web): 11 Apr 2018 Downloaded from http://pubs.acs.org on April 16, 2018

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Molecular Pharmaceutics

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Qualitative and quantitative characterization of composition heterogeneity on the surface

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of spray dried amorphous solid dispersion particles by an advanced surface analysis

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platform with high surface-sensitivity and superior spatial resolution

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Sonal V. Bhujbal1, Dmitry Y. Zemlyanov2, Alex Cavallaro3, Sharad Mangal1, Lynne S. Taylor1,

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Qi (Tony) Zhou1*

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1

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Stadium Mall Drive, West Lafayette, IN 47907, USA

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2

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47907, USA

Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575

Birck Nanotechnology Center, Purdue University, 1205 West State Street, West Lafayette, IN

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*Corresponding Author: Qi (Tony) Zhou, Tel.: +1 765 496 0707, Fax: +1 765 494 6545, E-

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mail: [email protected]

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Keywords: Amorphous solid dispersions, spray drying, surface composition heterogeneity,

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surface characterization, XPS, ToF-SIMS

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Short title: Surface analysis platform for spray dried ASD

Future Industries Institute, University of South Australia, Mawson Lakes, SA 5095, Australia

ACS Paragon Plus Environment

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Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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ABSTRACT

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Surface composition critically impacts stability (e.g. crystallization) and performance (e.g.

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dissolution) of spray dried amorphous solid dispersion (ASD) formulations; however traditional

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characterization techniques such as Raman and infrared spectroscopies may not provide useful

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information of surface composition on the spray dried ASD particles due to low spatial

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resolution, high probing depth and lack of quantitative information. This study presents an

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advanced surface characterization platform consisting of two complementary techniques: X-ray

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photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-

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SIMS). Such a platform enables qualitative and quantitative measurements of surface

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composition for the fine spray dried ASD particles with ultra-surface-sensitivity (less than 10 nm

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from the surface) and superior spatial resolution (approximately 250 nm for ToF-SIMS). Both

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XPS and ToF-SIMS demonstrated that the polymer (PVPVA) was dominantly enriched on the

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surface of our spray dried naproxen-PVPVA ASD particles. Of a particular note was that XPS

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could differentiate two batches of spray dried ASD particles with a subtle difference in surface

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composition produced by varying feed solution solvents. This advanced surface characterization

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platform will provide essential surface information to understand the mechanisms underlying the

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impact of surface composition on stability (e.g. crystallization) and functionality (e.g.

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dissolution)

in

future


studies.

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Graphic abstract

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INTRODUCTION

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Oral dosage forms are the most popular dosage administration route for pharmaceutical

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products because of lower manufacturing cost, easier administration and higher patient

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compliance as compared with parenteral administrations.1,2 For orally administered medications

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to be absorbed systemically with sufficient bioavailability, drug solubilization and dissolution are

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essential steps, and can be limiting factors for drugs with low aqueous solubility and high

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permeability. Based on the aqueous solubility and membrane permeability of drugs, the

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Biopharmaceutics Classification System (BCS) categorizes drugs into four classes, viz. Class I

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(highly soluble and highly permeable), Class II (low soluble and highly permeable), Class III

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(highly soluble and low permeable) and Class IV (low soluble and low permeable).3

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Unfortunately, a high percentage (> 60%) of drugs in the development pipeline are in the BCS

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Class II category.4,5 Several formulation strategies have been applied to increase the solubility

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and/or dissolution rate of this class of drugs, such as salt formation, amorphous solid dispersions

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(ASDs),

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Formulating BCS Class II drugs into amorphous solid dispersions (ASDs) is one of the more

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widely used strategies for enhancing drug solubility and dissolution.7,8

nanoparticles,

cyclodextrin

complexation,

microemulsions,

and

co-crystals.6

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In an amorphous dispersion formulation, the active pharmaceutical ingredient (API) is

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dispersed in a matrix,9 which is typically a polymer and may contain other components. When

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the drug is in the amorphous state, no energy is needed to break the crystal lattice during

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solubilization.10 Hence, compared to the crystalline form, amorphous drugs generally can

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achieve higher apparent solubility and faster dissolution.11 Dispersion in a hydrophilic polymer

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matrix can further enhance the dissolution rate, particularly at low drug loadings. Several

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techniques can be used to produce ASD formulations including spray drying, hot melt extrusion,


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quench cooling from the melt, solvent evaporation, and electrospinning/spraying. Over the past

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decade, spray drying has increasingly been used to manufacture ASD particles, particularly for

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the thermo-labile molecules that are not suitable for hot melt extrusion.12,13 In spray drying to

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produce an ASD, the feed solution containing the drug and polymer is atomized into fine

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droplets and rapidly dried into particles where the drug is typically trapped in the amorphous

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form.14 Spray drying is used for the commercial manufacture of several ASD formulations15 and

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is a continuous process with a scale-up capability.16

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As ASDs typically contain drug in a high energy state, there is a risk for the drug to

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convert to a more stable crystalline state. Such unwanted crystallization can compromise the

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solubility/dissolution/bioavailability advantages of ASDs.17 The polymers used to formulate

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ASDs typically confer some protection against crystallization by decreasing drug nucleation and

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growth rates, through effects such as reducing the drug chemical potential, forming specific

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interactions such as hydrogen bonds with the drug, decreasing matrix mobility, and increasing

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the glass transition temperature (Tg).18,19 Studies have shown that phase separation of the drug

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and polymer in the dispersion can promote the crystallization of the drug.20,21 Thus, it is

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considered crucial to characterize and maintain a homogenous dispersion of drug and polymer in

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the formulation in order to ensure physical stability.22 However, the spray drying process can

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produce particles with a heterogonous dispersion of components with differentiated physical and

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chemical properties. Zhou et al., showed that the poorly water-soluble compounds, rifampicin23

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or azithromycin,24 were enriched on particle surfaces when they were co-spray dried with the

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water-soluble drug, colistin, from a co-solvent system of water and ethanol. For ASDs, if the

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drug is enriched on the surface of the spray dried particles, crystallization is likely to be

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facilitated, particularly when the particle surfaces are exposed to moisture.25,26 Teerakapibal et


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al., demonstrated that surface coatings with gelatin could inhibit surface crystallization of

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amorphous films of indomethacin or nifedipine.27 Hence, there is a need to characterize and

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understand the heterogeneous distribution of various components in spray dried ASD particles,

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especially at particle surfaces, with an aim of optimizing the formulation and processing

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conditions to achieve a homogeneous distribution and ensure the physical stability.28

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Although there are some reports of macroscopic phase separation in the bulk of

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ASDs,26,29 studies on spray dried particle surfaces are scarce. Characterization of the composition

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of the first few molecular layers of the surface of fine spray dried particles is extremely

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challenging because of the relatively small particle size (ranging from a few microns to tens of

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microns).30,31 To provide meaningful surface information on such fine particles, measurement

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techniques with both high surface-sensitivity and superior spatial resolution are required.

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Unfortunately, many of the common characterization techniques such as Raman or infrared (IR)

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spectroscopies typically have a low spatial resolution, a high probing depth of a few microns,32,33

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and hence, for spray dried particles, provide bulk-level information with low surface sensitivity.

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Therefore, there is a need to develop advanced characterization tools with high surface-

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sensitivity and superior spatial resolution to better understand the properties of spray dried

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particles.

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The surface characterization platform developed in this study consists of two

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complementary measurements:

X-ray photoelectron spectroscopy (XPS) and time-of-flight

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secondary ion mass spectrometry (ToF-SIMS) for fine spray dried ASD particles. This platform

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enables qualitative and quantitative measurements of chemical species on the surface of spray

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dried ASD particles with both ultra-high surface sensitivity (top 10 nm) and nanometer-scale

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spatial resolution (approximately 250 nm for ToF-SIMS). Naproxen, a weakly acidic drug (pKa


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108

of 4.15, logP of 3.18, melting point 153°C and aqueous absolute solubility of 15.9 mg/L at

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25°C)34 was used as the model drug. Kollidon® VA 64 (PVPVA), a copolymer of 1-vinyl-2-

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pyrrolidone and vinyl acetate in a ratio of 6:4 by mass, was used as the model polymer. The

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surface composition information obtained by this advanced platform will be critical to

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understand and optimize the stability of spray dried ASD formulations.

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Supplement Figure 1: Chemical structures of: (A) Naproxen and (B) PVPVA (1-vinyl-2-

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pyrrolidone and vinyl acetate in a ratio of 6:4 by mass).

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EXPERIMENTAL SECTION

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Materials

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Naproxen was purchased from Attix Pharmaceuticals (Toronto, Ontario, Canada).

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Kollidon® VA 64 (PVPVA) was supplied by BASF Corporation (Florham Park, New Jersey,

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USA). Methanol and acetone (HPLC grade) were purchased from Sigma–Aldrich (St. Louis,

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Missouri, USA).

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Spray Drying

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A Büchi 290 spray dryer (Büchi Labortechnik AG, Falwil, Switzerland) was used to


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prepare spray dried ASDs. For Batch 1, equal amounts (500 mg each) of naproxen and PVPVA

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were weighed and dissolved in co-solvent containing equal volumes of methanol and acetone to

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obtain a total solids concentration of 50 mg/mL. The key operating parameters during spray

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drying were slightly modified from the literature35: inlet temperature 50 ± 2°C; outlet

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temperature 30 ± 2°C; aspirator 35 m3/h; atomizer setting 700 L/h; feed rate 12 mL/min. The

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spray dried samples were kept in a desiccator with silica gel until analysis. For Batch 2, equal

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amounts (500 mg each) of naproxen and PVPVA were dissolved in a co-solvent containing

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methanol and acetone in a 1:9 volumetric ratio. The spray drying processing parameters for

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Batch 2 were the same to those for Batch 1. The composition of the co-solvent was changed with

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an expectation to generate different surface compositions of drug and polymer on the spray dried

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particle surfaces. This was because naproxen has a higher solubility in acetone than in methanol,

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while PVPVA has similar solubility in acetone and methanol. It was hypothesized that the

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advanced surface characterization platform developed here can differentiate the subtle change on

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surface composition caused by different co-solvent systems.

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Powder x-ray diffraction (P-XRD)

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P-XRD (Rigaku Smartlab™ diffractometer, Rigaku Americas, Texas, USA) with Cu-Kα

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radiation source and a D/tex ultra-detector was used to determine drug crystallinity. The samples

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were spread uniformly on a glass slide and placed in the measurement chamber. The samples

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were scanned over 2θ range of 5° to 40° with a voltage of 40 kV and a current of 44 mA.

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Scanning electron microscopy (SEM)

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A field emission scanning electron microscope (NOVA nanoSEM, FEI Company,

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Hillsboro, Oregon, USA) was used to evaluate the morphology of spray-dried ASD particles. A

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small amount of sample was spread on an adhesive carbon tape attached to a stainless-steel stub.


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Pressurized air was used to remove excessive powders. These samples were then coated with

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platinum by a sputter coater (208 HR, Cressington Sputter Coater, Watford, UK). An inbuilt

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software was used to capture the images.

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Particle size distribution

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Scanning electron microscopy images were used to determine the particle size of the

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samples.36 Three different SEM images were evaluated using the ImageJ software (National

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Institute of Health, Rockville, Maryland, USA) and the Martin’s diameter of approximately 150

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randomly-selected particles was measured for each sample. D10, D50 and D90 were calculated.

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Time-of-flight secondary ion mass spectrometry (ToF-SIMS)

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Time-of-flight secondary ion mass spectrometry (nanoToF instrument, Physical

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Electronics Inc., Chanhassen, Minnesota, USA) was used to analyze the surface composition of

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the particle surface. In ToF-SIMS analysis, the surface of a solid sample is bombarded with a

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beam of primary ions. This results in the extraction and emission of atomic and molecular

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secondary ions from the outer layers of solid surface (sputtering).37,38 The mass of these

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secondary ions is measured by co-relating it with their time of flight to the detector. Such an

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analysis cycle can be repeated at higher frequencies to obtain a comprehensive mass spectrum.

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The high transmission, high mass resolution of time-of-flight mass spectrometer along with the

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ability to detect ions of different masses simultaneously makes it suitable for secondary ion

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analysis.37,38 The process described by Zhou et al.39 was used in the current study with a few

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minor modifications. The instrument was operated at 30 kV energy and equipped with a pulsed

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liquid metal 79+Au primary ion gun. Electron flood gun and 10 eV Ar+ ions provided dual charge

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neutralization. An “unbunched” Au1 instrument setting was used to optimize spatial resolution

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while performing surface analysis. A positive SIMS mode was used to collect raw data from


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several locations typically using a 100 × 100 µm2 raster area, with 2 min acquisitions. Five

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randomly selected areas of interest were imaged per sample to collect a representative data set

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for purposes of statistical interrogation.

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WincadenceN software (Physical Electronics Inc., Chanhassen, Minnesota, USA) was

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used to generate high-resolution surface composition overlays. Region-of-interest analyses were

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performed on the collected raw image. Mass spectra were extracted specifically from within the

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boundaries of the particles of interest which allowed the surface chemistry of the particle to be

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extracted from the background signals. Characteristic peak fragments for naproxen and PVPVA

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were selected to be [C14H15O3+] [~231 atomic mass unit (amu)] and [C6H9NO+] (~112 amu),

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respectively (Figure 1). These characteristic fragments formed the basis of calibration and peak

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selection from the resulting spectra of samples. The surface chemistry of the particles was semi-

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quantitatively compared by normalizing the integrated peak values of the selected symbol ions to

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the total secondary ion intensity.


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Figure 1: ToF-SIMS spectra of (A) naproxen and (B) PVPVA.

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X-ray photoelectron spectroscopy (XPS)

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X-ray photoelectron spectroscopy (XPS) (AXIS Ultra DLD spectrometer, Kratos

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Analytical Inc., Manchester, UK) with monochromic Al Kα radiation (1486.6 eV) was used for

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quantitative surface composition study of the ASDs. In XPS analysis, the surface of the sample is

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irradiated with an X-ray beam. The photons cause core-level electrons to be emitted with a

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specific kinetic energy, which is measured by an energy analyzer. Such generated photoelectron

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spectrum contains the photoemission peaks of all elements (but H and He). The shift of the core-

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level peaks due a chemical bond with another atom(s), which is often referred to as a chemical

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shift, helps to identify the chemical state of an element. The inelastic mean free path of the

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photoelectrons in a solid is in the range of a few nanometers, and therefore, the XPS information

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depth is limited to approximately 10 nm (for Al Kα radiation of 1486.6 eV). XPS has been used

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for characterization of complex organic material such as peptides40 and drugs.41

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The XPS spectra were collected at constant pass energy (PE) mode using PE of 20 and 160 eV

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for high-resolution and survey spectra, respectively. To avoid non-homogeneous electric charge

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of non-conducting powder and achieve better resolution, a commercial Kratos charge neutralizer

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was employed. Typical full width at half maximum of the photoemission peak from a metal (Au

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7f or Ag 3d) is ~0.35 eV at PE of 20 eV. Binding energy (BE) values refer to the Fermi

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edge. The binding energy scale was calibrated using Au 4f7/2 at 84.0 eV and Cu 2p3/2 at 932.67

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eV. A double-sided sticking Cu tape was used to place powder samples on stainless steel sample

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holder. XPS data was processed using a CasaXPS software. Curve-fitting of the O 1s, N 1s and C

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1s regions was performed to determine the relative fractions of PVPVA and naproxen in ASD

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formulations.26,42–44 The model O 1s, N 1s and C 1s peaks obtained from the pure materials,


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PVPVA and naproxen, were used for curve fitting. The fractional area of the components

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corresponds to the number of atoms of interest (PVPVA and naproxen) in the near-surface

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region. Figure 2 shows the example of the C 1s peak curve fitting by the PVPVA and naproxen

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components for the sample of Batch 1. Atomic concentrations of the elements in near-surface

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region was calculated following a Shirley background subtraction and by considering

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corresponding Scofield atomic sensitivity factors and inelastic mean free path (IMFP) of

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photoelectrons using standard procedures in the CasaXPS software.39 Supplement Figure 2

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shows the reference spectra and curve-fit using O1s. At least five replicates were measured and

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results

were

averaged.

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Figure 2: Example of the C 1s peak curve-fit for the sample of Batch 1.


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Supplement Figure 2: Example of the O 1s peak curve-fit: (a) PVPVA (reference spectrum); (b)

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NAP (reference spectrum); (c) Batch 1 (PVPVA component is blue, NAP component is red), (d)

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Batch 2 (PVPVA component is blue, NAP component is red).

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Statistical analysis

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Data are presented as mean ± standard deviation (SD). The statistical analysis was

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conducted by an independent t-test using SPSS™ software (SPSS Inc. IBM Corporation, New

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York, NY, USA).


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RESULTS AND DISCUSSION

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Two batches of naproxen-PVPVA ASD solids were prepared by spray drying. The

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purpose of preparing two batches was to generate spray dried particles with subtle difference in

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surface composition by adjusting the components of the co-solvents. The hypothesis was that the

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advanced surface characterization platform would be able to measure subtle differences in the

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surface composition of the spray dried ASD particles.

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Crystallinity of the samples was evaluated using P-XRD (Supplement Figure 3). As-

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supplied naproxen showed sharp peaks indicating its crystalline nature. In contrast, solid

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dispersions of naproxen-PVPVA did not exhibit any crystalline peaks, which demonstrated both

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batches of spray dried particles were amorphous.

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Naproxen Batch 1 Batch 2

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Supplement Figure 3: Power X-ray diffraction patterns of supplied naproxen, Batch 1 ASD

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(Naproxen _PVPVA spray dried from methanol and acetone in volumetric ratio of 1:1) and


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Batch 2 ASD (Naproxen _PVPVA spray dried from methanol and acetone in volumetric ratio of

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1:9).

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SEM images of the spray-dried ASD samples are shown in Supplement Figure 4. The

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spray dried particles from both batches had very similar particle shape, size and surface texture.

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SEM images are not capable of providing any information on surface composition.

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Supplement Figure 4: Representative scanning electron microscopy images of: (A) Batch 1:

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Naproxen _PVPVA spray dried from methanol and acetone in volumetric ratio of 1:1; (B) Batch

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2: Naproxen _PVPVA spray dried from methanol and acetone in volumetric ratio of 1:9.

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Table 1 shows the particle size information of the formulations. The values indicate two

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spray dried batches had similar particle sizes. For industrial manufacturing, a larger size for

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spray dried particles is preferable rather than the fine particles generated herein. However, in the

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present study, very small sizes were intentionally generated for the spray dried particles to test


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1 2 3 255 the capability of the surface characterization platform for extremely fine particles. 4 5 6 256 7 8 257 Table 1: Particle sizes (n = 150) and surface compositions as measured by XPS (n = 5) and ToF9 10 11 258 SIMS (n = 5) of Batch 1 ASD (Naproxen _PVPVA spray dried from methanol and acetone in 12 13 259 volumetric ratio of 1:1) and Batch 2 ASD (Naproxen _PVPVA spray dried from methanol and 14 15 260 acetone in volumetric ratio of 1:9). 16 17 18 261 19 20 21 Formulation Particle size (µm) XPS (C 1s spectra) ToF-SIMS (% normalized counts) 22 % Surface % Surface 23 Composition Composition m/z 231 m/z 112 (Theoretical) (Measured) 24 D10 D50 D90 (Naproxen) (PVPVA) 25 Naproxen PVPVA Naproxen PVPVA 26 0.5 ± 0.2 Batch 1 0.1 ± 0.0 1.1 ± 0.1 54 46 12 ± 2 88 ± 2 0.008 ± 0.002 0.025 ± 0.002 27 28 Batch 2 0.1 ± 0.1 0.5 ± 0.1 1.0 ± 0.1 54 46 9 ± 2* 91 ± 2* 0.003 ± 0.001** 0.025 ± 0.001 29 30 31 262 * p < 0.05, ** p < 0.01, significantly different to Batch 1 32 33 263 ToF-SIMS images are shown in Figure 3. The focusing capability of the ion beams used 34 35 36 264 in ToF-SIMS along with the nature of energy transfer from the primary ion beam to the particle 37 38 surface results in a controlled removal of the fragment only from the uppermost surface.37,38 For 265 39 40 266 solid surfaces, about 95% of the sputtering occurs from the top one or two molecular monolayers 41 42 43 267 (approximately 1 nm). This enables characterization of the solid surface chemistry with ultra44 45 268 high surface-sensitivity, a wide mass range, high mass resolution, and a lateral resolution in 46 47 nanometer range (approximately 250 nm in this study).37,38 269 48 49 50 270 In Figure 3, the green signals represent exclusive mass fragment of naproxen, and the red 51 52 271 signals represent exclusive mass fragment of PVPVA. Qualitative image analysis of both 53 54 55 272 formulations indicated a heterogeneous surface composition on the surface of spray dried 56 57 58 59 17 ACS Paragon Plus Environment 60


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particles with an abundance of PVPVA. Table 1 shows the % normalized counts as measured by

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ToF-SIMS. Normalized counts can be defined here as the count of the selected secondary ions of

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each component divided by the total count of ions recorded. Integrated peak values of the

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selected ions have been normalized to the total secondary ion intensities. Since, these values are

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percentages over the total ion signals of all species, percentage normalized counts do not give a

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measure of absolute surface coverage of the component. However, these can be considered as a

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useful tool for studying relative changes as they enabled a semi-quantitative comparison of

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surface compositions between two batches wherein naproxen content was found significantly

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higher (p < 0.01) on the particle surfaces of Batch 1; while no difference was measured in

282

PVPVA between two batches (Table 1). To confirm the observed dominant distribution of

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PVPVA on the particle surfaces and the difference in surface composition between two

284

formulations as measured by ToF-SIMS, the surface composition was further evaluated by XPS.

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A

B

C

D

286 287

Figure 3: Distributions of naproxen (green) and PVPVA (red) measured by ToF-SIMS on the

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particles surfaces of: (A) Naproxen; (B) PVPVA; (C) Batch 1: Naproxen _PVPVA spray dried

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from methanol and acetone in volumetric ratio of 1:1; and (D) Batch 2: Naproxen _PVPVA

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spray dried from methanol and acetone in volumetric ratio of 1:9 (scale bar represents 10 µm).

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XPS provides quantitative information regarding chemical composition of the top

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approximately 10 nm of a particle surface. The XPS data (Table 1) demonstrated that PVPVA is

293

considerably enriched on the particle surface for both formulations, indicating heterogeneity in


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component distribution within the spray dried particles. For example, for the Batch 1, the

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theoretical concentration of PVPVA was approximately 45% (calculated by normalizing the

296

relative carbon atom proportion in the formulation); while the measured surface concentration

297

was 88 ± 2% (as determined by curve-fits of the C 1s). XPS data also clearly differentiated the

298

varying surface compositions between two batches (p< 0.05), even though the difference was

299

subtle (e.g. naproxen 12 ± 2% for Batch 1 and 9 ± 2% for Batch 2). We further confirmed these

300

subtle differences and surface enrichment of PVPVA using O1s (94 ± 3% surface is PVPVA for

301

Batch 1 and 98 ± 2% for Batch 2, p = 0.029). To verify the quantitation by XPS, physical

302

mixtures of spray dried pure drug and pure PVPVA were prepared at ratios of 25:75, 50:50, and

303

75:25. The differences in XPS data for physical mixtures between theoretical and measured

304

values for each ratio is less than 10%, showing the measurement accuracy. In addition, the XPS

305

data were in good agreement with the ToF-SIMS results, which enabled qualitative and

306

quantitative measurements in surface composition for the spray dried ASD particles.

307

Solvent choice is an important factor which is known to impact the surface composition

308

of spray dried particles45 and thus an underlying cause of different surface composition of the

309

two batches could have been the varying solubilities of naproxen and PVPVA in the varying

310

ratios of co-solvents used for the two batches. When a droplet of a solution is being spray dried,

311

the solvent from the outer layers of the droplet is evaporated first. When such a solvent system

312

contains two or more components, the substance with higher solubility in the solvent may have a

313

higher diffusion as the solute molecules tend to diffuse towards the particle core.46 In contrast,

314

the substances with relatively less solubility reach supersaturation rapidly and precipitate,

315

whereby precipitated material has a much lower rate of diffusion, and thus tends to concentrate

316

on the particle surface as the solvent is being evaporated.47 Similarly, in this case, a higher


20

Page 21 of 29 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


317

solubility of naproxen in co-solvent system used for Batch 2 could have led to a lower

318

concentration on the particle surface.

319

Vehring et al. have discussed the correlation of Peclet number for a component of interest

320

on its surface enrichment.47 Peclet number (Pei) given by the following equation, depends on the

321

processes of diffusion and solvent evaporation.

322 323

(1)

324 325

Here k is the solvent evaporation rate and Di is the diffusivity of the component of interest in

326

the solvent system. Simulations by Vehring et al. suggested that higher Peclet number would be

327

associated with higher surface enrichment. When the drying kinetics are faster than the

328

component diffusivity, the component tends to concentrate on the outer surface. The higher

329

molecular weight of the PVPVA relative to the naproxen, is likely to lead to low polymer

330

diffusivity its subsequent surface enrichment. The difference in the formulation surface

331

composition observed in this study could have been a combination of one or more of these

332

factors. Chen et al. showed surface tension may also impact surface composition of spray dried

333

ASD particles because solutes with lower surface tension may concentrate on the air-liquid

334

interface when droplets are formed so as to assemble a surface with low free energy.48 Thus, it is

335

important to note that the process of spray drying is complex with several material properties and

336

processing conditions affecting the particle surface composition. Hence, further systematic

337

studies are warranted to unveil the true mechanisms of such heterogeneity surfaces of spray dried

338

ASD particles.


21


Page 22 of 29

339

In future studies, exposure of the inner surface of these particles by cryo-SEM, as

340

discussed in the work of Gamble et al. may provide a complete picture of drug-polymer

341

distribution in the particle.49 This method involves freezing the samples with liquid nitrogen and

342

subsequently fracturing them to expose the inner surface of the particles. In addition, mass

343

balance of these analysis methods could be investigated to test their ability to detect and quantify

344

the degradation products generated by the sample.

345

CONCLUSION

346

In the present study, an advanced surface composition analysis platform consisting of

347

ToF-SIMS and XPS measurements was developed. This platform had superior surface sensitivity

348

(top 10 nm of the surface) and high spatial resolution (approximately 250 nm for ToF-SIMS),

349

enabling both qualitative and quantitative measurements of compositions on the uppermost

350

surface of spray dried ASD fine particles. It is noteworthy that even a subtle change in surface

351

composition could be differentiated by the developed surface characterization platform between

352

two batches of ASD particles spray dried with a difference feed solvent composition. The

353

advanced surface characterization platform developed in this study will be very useful to

354

understand mechanisms by which process parameters affect surface composition and study the

355

underlying impacts of surface composition on the stability (e.g. crystallization) and functionality

356

(e.g. dissolution) of ASDs in future studies.

357

ACKNOWLEDGEMENTS

358

Qi (Tony) Zhou is supported by the National Institute of Allergy and Infectious Diseases

359

of the National Institutes of Health under Award Number R01AI132681. The content is solely

360

the responsibility of the authors and does not necessarily represent the official views of the

361

National Institutes of Health. Qi (Tony) Zhou is a recipient of the Ralph W. and Grace M.


22

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362

Showalter Research Trust Award. The authors are grateful for the scientific and technical

363

assistance of the Australian Microscopy & Microanalysis Research Facility at the Future

364

Industries Institute, University of South Australia.

365

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Qualitative and Quantitative Characterization of Composition

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