Stefano Bianco

Frederic Tewes

Lidia Tajber

Vincent Caron

Owen I Corrigan

Anne Marie Healy
email: healyam@tcd.ie

Bulk, surface properties and water uptake mechanisms of salt/acid amorphous composite systems

Developing amorphous pharmaceuticals can be desirable due to advantageous biopharmaceutical properties. Low glass transition temperature (Tg) amorphous drugs can be protected from crystallisation by mixing with high Tg excipients, such as polymers, or with salt forms. However, both polymers and salts can enhance the water uptake. The aim of this study was to formulate physico-chemically stable amorphous materials, by co-processing different proportions of sulfathiazole and its sodium salt to produce an optimum ratio, characterised by the best physical stability and lowest hygroscopicity. Both sulfathiazole and salt amorphised upon spray drying. At room temperature, sulfathiazole crystallised within 1 hour at <5% relative humidity while the salt deliquesced when exposed to ambient humidity conditions. In the case of composite systems, FTIR spectroscopy, thermal and surface analysis suggested interactions with an acid:salt stoichiometry of 1:2. Increasing proportions of salt raised the Tg, enhancing the storage stability, however this was opposed by an enhanced hygroscopicity. The water uptake mechanism within the different amorphous systems, analysed by fitting the water sorption isotherms with the Young and Nelson equation, was dependent on the ratio employed, with the salt and the acid facilitating absorption and adsorption, respectively. Tuning the properties of amorphous salt/acid composites by optimising the ratio appears potentially promising to improve the physical stability of amorphous formulations.

Introduction

The requirement to improve the bioavailability of poorly soluble active pharmaceutical ingredients (API) has resulted in a growing use of processes such as milling and spray drying, which reduce particle dimensions and increase specific surface area. It is well established that partial or full amorphisation of an API can occur as a result of these processes and that changes in the solid state nature can alter the physicochemical and biopharmaceutical properties [START_REF] Caron | A comparison of spray drying and milling in the production of amorphous dispersions of sulfathiazole/polyvinylpyrrolidone and sulfadimidine/ polyvinylpyrrolidone[END_REF][START_REF] Tajber | Physicochemical evaluation of PVP-thiazide diuretic interactions in co-spray-dried composites -Analysis of glass transition composition relationships[END_REF][START_REF] Yu | Amorphous pharmaceutical solids: Preparation, characterization and stabilization[END_REF]. Amorphous materials are structurally disorganised and have different bulk and surface properties compared to the corresponding crystalline materials.

They typically display higher surface free energy (Newell et al., 2001b), higher hygroscopicity [START_REF] Newman | Characterization of the "hygroscopic" properties of active pharmaceutical ingredients[END_REF], greater solubility and a higher dissolution rate [START_REF] Tajber | Physicochemical evaluation of PVP-thiazide diuretic interactions in co-spray-dried composites -Analysis of glass transition composition relationships[END_REF].

Although these properties are relevant from a pharmaceutical development perspective, the full exploitation of amorphous drugs and formulations cannot always be achieved, mainly due to low physical and chemical stability [START_REF] Caron | A comparison of spray drying and milling in the production of amorphous dispersions of sulfathiazole/polyvinylpyrrolidone and sulfadimidine/ polyvinylpyrrolidone[END_REF][START_REF] Yu | Amorphous pharmaceutical solids: Preparation, characterization and stabilization[END_REF]. Therefore a thorough understanding of the properties of the amorphous state is required to develop new strategies to physico-chemically stabilise amorphous compounds.

Previously, we studied several physicochemical properties of sulfathiazole (ST) and sulfathiazole sodium (STNa), which solidify into unstable amorphous materials on spray drying [START_REF] Bianco | Modification of the Solid-State Nature of Sulfathiazole and Sulfathiazole Sodium by Spray Drying[END_REF]. The acid rapidly crystallised regardless of the relative humidity (RH) conditions. The crystallisation of amorphous solids can be promoted by heat and therefore these materials usually require storage at temperatures well below their glass transition temperature (Tg) [START_REF] Caron | A comparison of spray drying and milling in the production of amorphous dispersions of sulfathiazole/polyvinylpyrrolidone and sulfadimidine/ polyvinylpyrrolidone[END_REF][START_REF] Hancock | Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures[END_REF][START_REF] Yu | Amorphous pharmaceutical solids: Preparation, characterization and stabilization[END_REF]. Considerable effort has been made to address this problem, either by co-processing heat labile amorphous drugs with high Tg excipients [START_REF] Caron | A comparison of spray drying and milling in the production of amorphous dispersions of sulfathiazole/polyvinylpyrrolidone and sulfadimidine/ polyvinylpyrrolidone[END_REF] or by using amorphous salt forms of these compounds [START_REF] Tong | Influence of alkali metal counterions on the glass transition temperature of amorphous indomethacin salts[END_REF][START_REF] Tong | Solid-state characteristics of amorphous sodium indomethacin relative to its free acid[END_REF]. In many cases a shift of the Tg to higher temperature has been achieved, which is potentially a good strategy to stabilise amorphous formulations. However this is not always sufficient and other influential factors affecting stability must also be considered. For instance, amorphous STNa was characterised by a 60°C increase in Tg compared to ST and was physically stable when stored under desiccated conditions. Nevertheless, it deliquesced when exposed to ambient RH conditions [START_REF] Bianco | Modification of the Solid-State Nature of Sulfathiazole and Sulfathiazole Sodium by Spray Drying[END_REF].

Deliquescence together with adsorption, capillary condensation, hydrate formation and absorption, is one of the known mechanisms of solid-water interactions [START_REF] Airaksinen | Role of water in the physical stability of solid dosage formulations[END_REF][START_REF] Hiatt | Effects of co-formulation of amorphous maltodextrin and deliquescent sodium ascorbate on moisture sorption and stability[END_REF]. It is a first order phase transition that happens when a water soluble solid generates a saturated solution by dissolving into the water sorbed from the environment at a specific relative humidity (RH0) characteristic for that solid. Due to high void space and enlarged free volume relative to the crystalline state, amorphous substances absorb water below RH0 and undergo deliquescence at a lower RH compared to their crystalline counterparts [START_REF] Mikhailov | Amorphous and crystalline aerosol particles interacting with water vapor: Conceptual framework and experimental evidence for restructuring, phase transitions and kinetic limitations[END_REF]. The amount of water absorbed into amorphous materials is proportional to the volume/weight of the amorphous solid and high absorption and retention of water can enhance chemical reactions which may lead to product degradation [START_REF] Hancock | Water vapour sorption by pharmaceutical sugars[END_REF].

Furthermore, sorbed water as well as heat can promote the crystallisation of amorphous materials [START_REF] Baird | Evaluation of amorphous solid dispersion properties using thermal analysis techniques[END_REF][START_REF] Burnett | Investigating the moisture-induced crystallization kinetics of spray-dried lactose[END_REF].

Therefore strategies to stabilise amorphous materials should aim at both increasing the Tg and protecting the amorphous system from water uptake. Co-formulation of a deliquescent salt form (sodium ascorbate) with excipients (maltodextrins) was seen to reduce the moisture sorption and enhance the physical stability of this salt [START_REF] Hiatt | Effects of co-formulation of amorphous maltodextrin and deliquescent sodium ascorbate on moisture sorption and stability[END_REF]. It was also observed that the production of molecular dispersions of indomethacin and indomethacin sodium via evaporation under vacuum influenced the physicochemical characteristics of each species [START_REF] Tong | A study of amorphous molecular dispersions of indomethacin and its sodium salt[END_REF].

The aim of the current research was to improve the physical stability of amorphous ST/STNa mix in terms of crystallisation and deliquescence by adjusting the salt/acid ratio in the composite systems.

Materials and Methods

Materials

Sulfathiazole (ST) form III and sulfathiazole sodium (STNa) anhydrous were purchased from Sigma Ireland. Ethanol (99.5% v/v) was purchased from Corcoran Chemicals (Ireland) and deionised water produced by a Millipore Elix Advantage water purification system.

Spray drying

Spray dried powders were obtained using a Buchi B-290 Mini Spray dryer (Buchi Laboratoriums-Technik AG, Flawil, Switzerland) operating in an open cycle mode configuration using air as the drying gas. 0.5% w/v feed solutions were prepared by dissolving the APIs (Table 1) in a mixture of ethanol and deionised water at a v/v ratio of 9:1, as previously described [START_REF] Bianco | Modification of the Solid-State Nature of Sulfathiazole and Sulfathiazole Sodium by Spray Drying[END_REF]. Spray drying of ST and ST-STNa systems was performed using the following parameters: gas flow of 40 mm (473 L/hr); aspirator rate of 100% and feed flow rate of 30% (8 ml/min). The inlet temperature for the mixtures was adapted to the amount of salt employed in the system ranging from 85 to 90°C and reported in table 1. The salt alone was instead spray dried with an inlet of 160°C so as to produce a dry powder [START_REF] Bianco | Modification of the Solid-State Nature of Sulfathiazole and Sulfathiazole Sodium by Spray Drying[END_REF].

Samples were transferred to Amebis humidity devices (Amebis Ltd., Ireland) at <5% RH [START_REF] Bianco | Modification of the Solid-State Nature of Sulfathiazole and Sulfathiazole Sodium by Spray Drying[END_REF] and stored in a cold room at 5±1°C immediately after spray drying. (Mettler Toledo Ltd., Greifensee, Switzerland) using nitrogen as a purge gas. Samples (3-7 mg)

were placed in closed aluminium pans with three vent holes and were heated at a scanning rate of 10 °C/min from 25°C to 280°C. The thermograms (n ≥ 2) were analysed by Mettler Toledo STAR e software.

Modulated temperature DSC (MTDSC) scans were recorded on a QA-200 TA instruments (TA instruments, United Kingdom) calorimeter using nitrogen as a purge gas. Weighed samples (1.5-3.5 mg, n ≥ 2) were sealed in closed aluminium pans with one pin-hole. The method selected was similar to that previously reported by [START_REF] Caron | A comparison of spray drying and milling in the production of amorphous dispersions of sulfathiazole/polyvinylpyrrolidone and sulfadimidine/ polyvinylpyrrolidone[END_REF]. A scanning rate of 1°C/min, amplitude of modulation of 1°C and modulation frequency of 1/60 Hz were employed for all the experiments. The temperature range was from 5°C to 200°C.

Powder X-ray diffraction (XRD)

X-ray powder diffraction measurements were conducted using a low background silicon sample holder and a Rigaku Miniflex II desktop X-ray diffractometer (Rigaku, Tokio, Japan) as previously described [START_REF] Caron | A comparison of spray drying and milling in the production of amorphous dispersions of sulfathiazole/polyvinylpyrrolidone and sulfadimidine/ polyvinylpyrrolidone[END_REF][START_REF] Tewes | Steroid/mucokinetic hybrid nanoporous microparticles for pulmonary drug delivery[END_REF]. The samples (n ≥ 2) were scanned over a range of 5-40° in 2θ scale using a step size of 0.05°/s. The X-ray source was a Cu Kα radiation (λ =1.542 Å) and the diffractometer was operated with a voltage of 30 kV and a current of 15 mA.

Attenuated total reflection Fourier transform infra-red spectroscopy (ATR-FTIR)

Infrared spectra were produced using a PerkinElmer Spectrum one FT-IR Spectrometer and evaluated using Spectrum v5.0.1 software as previously described [START_REF] Grossjohann | Characterisation, solubility and intrinsic dissolution behaviour of benzamide: Dibenzyl sulfoxide cocrystal[END_REF][START_REF] Tewes | Evaluation of HPβCD-PEG microparticles for salmon calcitonin administration via pulmonary delivery[END_REF]. An average of 6 scans with a resolution of 4 cm -1 over a wavenumber region of 4000-650 cm -1 was used for each sample. All spectra were baseline corrected. The spectrum of pure STNa was subtracted from the mixture spectra, considering their molar ratio.

Scanning electron microscopy (SEM)

SEM micrographs of samples were taken using a Tescan Mira XMU (Brno, Czech Republic) SEM. The dry powder samples were fixed on aluminium stubs with double-sided adhesive tape and a 10 nm-thick gold film was sputter coated on the samples before visualisation. Primary electrons were accelerated under a voltage of 5 kV. Images were formed from the collection of secondary electrons.

Water sorption analysis

Water sorption behaviour of samples was determined using a DVS Advantage 1 apparatus (DVS Surface Measurement Systems, London, UK), as previously described [START_REF] Tewes | Development and characterisation of soluble polymeric particles for pulmonary peptide delivery[END_REF].

Samples placed in a microbalance were exposed to three cycles of RH (0-90-0 %) at 25°C, with the following steps: 3, 6, 10 and then every 10% RH (n=3). Water sorption isotherms were calculated using the equilibrated mass (dm/dt ≤ 0.002 mg/min for 10 min) recorded at the end of each stage and expressed as a percentage of the dry sample mass. The Young-Nelson equations were used to fit experimental equilibrium sorption and desorption data of the isotherms [START_REF] Tewes | Development and characterisation of soluble polymeric particles for pulmonary peptide delivery[END_REF]:

RH B θ) A(β M s     (1) RH B θ) A(β M d max     (2)
where M s and M d are, respectively, the mass percentage of water contents of the system at equilibrium for each %RH during sorption and desorption. A and B are constants characteristic of each system and defined by the following equations:

) W ( VolM m w A   (3) ) W ( VolA m w B   (4)
where w

 is the density of the water, M Vol and A Vol are respectively the adsorbed and absorbed water volumes and m W is the weight of the dry material.

In this model, θ is the fraction of the surface covered by at least one layer of water molecules. It is defined as follows, with E a constant depending on the material.

)

) 1 ( ( RH E RH RH     (5)
 is defined by the following equation:

  ) 1 ln( ) 1 ( ) 1 ( ln ) 1 ( )) 1 ( ( 2 RH E E E RH E E E E RH E RH E                 (6)
Thus, Aθ is the mass of water in a complete adsorbed monolayer expressed as a percentage of the dry mass of the sample. A(β+θ) is the total amount of adsorbed water, and Aβ is the mass of water which is adsorbed beyond the mass of the monolayer (i.e., in multilayer or cluster adsorption). B is the mass of absorbed water at 100% of RH, and, hence, BθRH is the mass of absorbed water when the water coverage is θ for a given %RH. According to the model characteristics, from the estimated values of A, B, and E, the corresponding profiles of water adsorbed in monolayer (Aθ), multilayer (Aβ) and absorbed (BθRH) were obtained.

Surface free energy measurement

Surface free energy measurements were carried out using inverse gas chromatography (iGC) (SMS Ltd., London, UK), as described previously [START_REF] Tewes | Evaluation of HPβCD-PEG microparticles for salmon calcitonin administration via pulmonary delivery[END_REF]. Powders were packed into silanised glass columns (300mm x 3mm). The columns were pre-treated for 1 h at 30 • C and 0% RH to remove any physisorbed molecules. Then, 250 L of the elution mixture (probe vapour and helium) was injected into the carrier gas (helium) flow. All injections of probe vapours were performed at 0.03% v/v of the saturated probe vapour. A flame ionization detector was used to monitor the elution of probe vapours. Measurements were performed at 0, 10 and 20% of RH and 30 • C, (n = 2). In acid-base theory, the total surface free energy of a solid (γ which are independent and additive, according to Eq. (7).

AB s d s T s      (7)
In order to calculate γ s d of the powders, alkane probes with a known dispersive contribution (γ p d ) and a nil specific contribution (γ p AB ) were used. Methane was used as inert reference to determine the dead volume of the system. At this low % of saturation (0.03% v/v), iGC was used in infinite dilution conditions and γ s d was calculated using the method developed by Schultz et al. [START_REF] Schultz | The role of the interface in carbon-fiber epoxy composites[END_REF]. γ s AB was obtained indirectly via the measurement of the specific free energy of adsoption (∆G SP ) of 2 monopolar probes and by using the acid-base theories developed by Van Oss et al. (vOCG) [START_REF] Van Oss | Additive and nonadditive surface tension components and the interpretation of contact angles[END_REF]. In the vOCG theories, γ s AB is subdivided into two nonadditive parameters γ s + and γ s -related according to Eq. ( 8), representing the electron acceptor (acid) and donor (base) properties, respectively. Additionally the spreading coefficient ( SL S ) was calculated using the dispersive contribution (γ s d )

   S S AB s    . 2 (8)
and the acid-base contribution (γ s + and γ s -) of the total surface free energy of the solid and of the liquid (water) by the following equation.

d L L L L S L S d L d S SL S          2 . 4 . 2 . 2 . 2            (9)
Where γ L d , γ L + and γ L -are respectively the dispersive contribution (γ L d ) and the acid-base contribution (γ L + and γ L -) of the total surface free energy of the of the liquid (water) [START_REF] Zdziennicka | Behavior of cationic surfactants and short-chain alcohols in mixed surface layers at water-air and polymer-water interfaces with regard to polymer wettability. II. Wettability of polymers[END_REF].

Density measurements

The density of spray dried ST and STNa was measured by an Accupyc 1330 Pycnometer (Micromeritics ®) using helium (99.995% purity) to determine the volume of the sample.

Samples were dried prior to measurement for 24 h in a Gallenkamp vacuum oven operating at 600 mbar and 25°C.

Statistical analysis

Data were statistically evaluated by a two-way analysis of variance (ANOVA) test with

Bonferroni test as post-hoc test. Significance level was α <0.05.

Results and discussion

PXRD, DSC and FTIR analysis of spray dried systems

Previous experiments showed that ST and STNa solidified into amorphous materials on spray drying. However, both spray dried substances were physically unstable. Amorphous ST started to crystallise to polymorph I ~30 minutes after the end of the spray drying process regardless of the temperature and RH of storage. In contrast, spray dried STNa remained amorphous when stored for over a year in desiccated conditions at 5±1°C. Nevertheless, amorphous STNa rapidly deliquesced at ambient conditions (18-22°C and 40-80% RH) [START_REF] Bianco | Modification of the Solid-State Nature of Sulfathiazole and Sulfathiazole Sodium by Spray Drying[END_REF].

All ST: STNa spray dried composites presented a diffuse halo pattern, characteristic of XRD amorphous materials (Fig. 1). The ST: STNa ratio employed and the storage conditions influenced the physical stability of the processed powders. For example, in desiccated conditions at 5°C, by using just 10% w/w of the salt form, the resulting composite remained amorphous for ~2 months as observed by PXRD.

Higher amounts of salt in the composites increased the stability by up to 5 months for ST 3:1 and by six months for ST 1:1 and ST 1:3.

SEM images showed that ST: STNa composite samples were homogeneous and consisted of spherical smooth particles with surface indentations for systems comprising up to 50% w/w STNa (Fig. 2a-b-c). In contrast, no discrete particles were detected by SEM for a higher STNa content. Both ST 1:3 (Fig. 2d) and STNa deliquesced, indicating a higher affinity of these two samples for water compared to the other systems. Previously reported thermal analysis of pure spray dried ST showed an exotherm of crystallization at 79±0.5°C followed by an endotherm of melting at 201±0.5°C while the amorphous salt crystallised above 160°C and melted at 268±0.2°C [START_REF] Bianco | Modification of the Solid-State Nature of Sulfathiazole and Sulfathiazole Sodium by Spray Drying[END_REF]. Spray dried ST 9:1, ST 8:2, ST 3:1 and ST 15:85 (Fig. 3) presented one endothermic event of melting.

These composites also showed one exotherm of crystallisation with onset ranging between those of the pure materials. In contrast ST 6:4, ST 1:1, ST 4:6 and ST 1:3 did not show either exothermic or melting peaks on the thermograms. The inhibition of crystallisation upon heating (at 1 or 10°C/min) for these mixtures could be due to the development of molecular interactions between ST: STNa for these specific ST: STNa ratios [START_REF] Tong | A study of amorphous molecular dispersions of indomethacin and its sodium salt[END_REF]. The glass transition temperature (Tg) for pure ST and STNa were previously found to be ~59°C and ~120°C, respectively [START_REF] Bianco | Modification of the Solid-State Nature of Sulfathiazole and Sulfathiazole Sodium by Spray Drying[END_REF]. To determine the Tgs of the various composites and distinguish between thermal events which could happen simultaneously upon heating, MTDSC was employed in this work. All reversing heat flow thermograms recorded for the different spray dried systems showed a single Tg, with values between those of the pure materials and increasing with the STNa content. According to several authors [START_REF] Bosma | Polymer-polymer miscibility and enthalpy relaxations[END_REF][START_REF] Caron | A comparison of spray drying and milling in the production of amorphous dispersions of sulfathiazole/polyvinylpyrrolidone and sulfadimidine/ polyvinylpyrrolidone[END_REF][START_REF] Tong | A study of amorphous molecular dispersions of indomethacin and its sodium salt[END_REF] the detection of a single Tg is indicative of homogeneous amorphous phases (molecular dispersions). Therefore, thermal analysis revealed that the increase of physical stability was due to the introduction of STNa in the mixture which shifted the Tgs to higher temperatures. Measured Tgs and Tg values calculated using the Gordon

Taylor with Simha-Boyer rule (GTequation 10) [START_REF] Caron | A comparison of spray drying and milling in the production of amorphous dispersions of sulfathiazole/polyvinylpyrrolidone and sulfadimidine/ polyvinylpyrrolidone[END_REF][START_REF] Tajber | Physicochemical evaluation of PVP-thiazide diuretic interactions in co-spray-dried composites -Analysis of glass transition composition relationships[END_REF] were plotted versus STNa weight fraction (Fig. 4).

2 1 2 2 1 1 ) ( w K w T w K T w mix T GT g GT g g   
where The true densities for the pure amorphous components of 1.52 g/cm 3 and 1.57 g/cm 3 for ST and STNa respectively, were used in the calculation of theoretical Tg values. The Tgs of the composites were found to deviate positively from the GT predicted values. The Gordon-Taylor equation is widely accepted to predict the Tg of mixtures. The theory affirms that in the ideal mix free volumes are additive and no interaction between the components takes place during mixing [START_REF] Caron | A comparison of spray drying and milling in the production of amorphous dispersions of sulfathiazole/polyvinylpyrrolidone and sulfadimidine/ polyvinylpyrrolidone[END_REF]. However, because of the presence of interacting groups in either species, the ST-STNa mixture could, in theory, result in the formation of intermolecular bonds, such as hydrogen or ion-dipole bonding, which should cause an increase in Tg compared to the predicted values. Tong and Zografi also showed positive deviations of Tg from GT predicted values when indomethacin was co-processed with its corresponding sodium salt, suggesting a stronger acid-salt interaction in the amorphous state than that between acid-acid and salt-salt [START_REF] Tong | A study of amorphous molecular dispersions of indomethacin and its sodium salt[END_REF].

FTIR spectroscopy has been used to investigate molecular interaction between species, included in composites [START_REF] Caron | A comparison of spray drying and milling in the production of amorphous dispersions of sulfathiazole/polyvinylpyrrolidone and sulfadimidine/ polyvinylpyrrolidone[END_REF][START_REF] Tong | A study of amorphous molecular dispersions of indomethacin and its sodium salt[END_REF]. FTIR spectra (1800-1000 cm -1 ) of spray dried ST, STNa and ST mixed in different proportions with STNa are shown in Fig. 5A. Peak shifts of different magnitudes were recorded, depending on the STNa content, indicative of interactions between the two species [START_REF] Caron | A comparison of spray drying and milling in the production of amorphous dispersions of sulfathiazole/polyvinylpyrrolidone and sulfadimidine/ polyvinylpyrrolidone[END_REF][START_REF] Tong | A study of amorphous molecular dispersions of indomethacin and its sodium salt[END_REF]. For example, in the 3000-3500 cm -1 region, the N-H 2 asymmetric stretch peak, which in the spectrum of pure amorphous ST appears at ~3462 cm -1 , shifted to lower wavenumbers (data not shown). The shift to lower wavenumbers can be due to weakening of the N-H bond as a result of a stronger involvement in H-bondings [START_REF] Kaushal | FTIR studies on differential intermolecular association in crystalline and amorphous states of structurally related non-steroidal anti-inflammatory drugs[END_REF][START_REF] Tang | A spectroscopic investigation of hydrogen bond patterns in crystalline and amorphous phases in dihydropyridine calcium channel blockers[END_REF]. The simultaneous shift to higher wavenumbers of the C-NH 2 stretching peak (~ 1417 cm -1 on the spectrum of ST), confirmed the NH2 group being increasingly involved in H-bonds (Fig. 5A). In the 1000-1600 cm -1 region, shifts to lower wavenumbers were seen for the peaks at 1140 and 1084 cm -1 , characteristic of the stretching of both symmetric SO 2 and C-S peaks [START_REF] Hu | Quantitative analysis of sulfathiazole polymorphs in ternary mixtures by attenuated total reflectance infrared, near-infrared and Raman spectroscopy[END_REF]. These shifts to lower wavenumbers suggested the SO 2 group as the H-bond acceptor and the development of N-H . . . O bondings. This type of interaction was previously described to link dimers of ST in polymorph I [START_REF] Parmar | Polymorph selection with morphology control using solvents[END_REF].

The stretching peak shifts of N-H 2 and C-S for the different composites were plotted against the mole fraction of STNa to create a Job plot representation (Fig 5B) in order to determine the stoichiometry of the interaction involving -NH 2 and -SO 2 groups [START_REF] Likussar | Theory of continuous variations plots and a new method for spectrophotometric determination of extraction and formation constants[END_REF]).

This approach using solid ATR-FTIR was adapted from the study of Osmani et al. [START_REF] Osmani | The use of FTIR and NMR spectroscopies to study prepolymerisation interactions in nitrogen heterocycles[END_REF] who generated a Job plot from FTIR C=O band shifting frequency in solution. The STNa molar fraction associated to the maximum of the Job plots, obtained at two wavenumbers, were between 0.6 and 0.7. The ST: STNa molar ratio of 1:2 lies between these two molar fractions. Therefore, from the plot, it appears that one molecule of ST interacted with two molecules of STNa. This interaction between ST and STNa could be responsible for the lack of thermal events observed on the DSC thermograms obtained for the ST 4:6 and ST 1:3, as the ST:

STNa molar ratio of 1:2 falls between these two composites.

iGC and DVS analysis

iGC was used to more fully investigate the surface of the systems and to assess the possibility of interactions between ST and STNa at the surface of the spray dried particles. Several phenomena of pharmaceutical importance start at the surface, and are critically affected by the surface properties of the substances involved [START_REF] Buckton | The importance of surface energetics of powders for drug delivery and the establishment of inverse gas chromatography[END_REF][START_REF] Puri | Wettability and surface chemistry of crystalline and amorphous forms of a poorly water soluble drug[END_REF]. Surface solidliquid interactions for example, besides affecting processes such as dissolution, can have a deep impact on the stability of the solid, powder flow etc., and are, above all, governed by solid surface free energy (γ s T ) [START_REF] Puri | Wettability and surface chemistry of crystalline and amorphous forms of a poorly water soluble drug[END_REF]. Generally a substance in its amorphous form has a higher γ s T than the corresponding crystalline form because of a more random orientation of molecules exposing higher surface energy groups at the particle surface [START_REF] Brum | Quantification of surface amorphous content using dispersive surface energy: The concept of effective amorphous surface area[END_REF]Newell et al., 2001a). This γ s T differences can have a significant impact on the behaviour of the two solid states (amorphous versus crystalline) upon processing. Differences in the γ s T can also be displayed by amorphous samples of the same material obtained with different processing techniques and changes with time due to relaxation can affect the γ s T of amorphous material upon storage [START_REF] Buckton | The importance of surface energetics of powders for drug delivery and the establishment of inverse gas chromatography[END_REF]. As a consequence of the development of interactions between the species included in the processed mixtures, variations of the γ s T among the various systems would be expected. STNa and four different composites were analysed by iGC. The γ s T values measured for ST 9:1 and ST 3:1 were not significantly different, and were found to be the highest among the systems studied, at ~53 mJ/m 2 (Fig. 6). The increase in STNa content to the ST 1:3 system decreased significantly the γ s T values, down to ~41 mJ/m 2 (P<0.001). Then γ s T rose up again for the pure amorphous salt, reaching ~48 mJ/m 2 (Fig. 6). The minimum of γ s T obtained for ST 1:3 could be due to a different organisation and/or to the development of interactions between the molecules at the surface of the particles, decreasing the number of chemical groups available to interact with external molecules such as the probe molecules. Moreover, changes in ST: STNa ratio also influenced the polarity of the powder surfaces as shown by the variation in the polarity index ( ) in Fig. 7A. An increase in salt content from ST 9:1 to ST 3:1 raised the polarity index, reaching a value similar to that obtained for pure amorphous STNa. However, a further increase (in salt content)

to ST 1:1 and ST 1:3 reduced the surface polarity. The ST: STNa molar ratio 1:2 falls between that of these two systems (i.e. ST 1:1 and ST 1:3), which supports the concept of the development of 1:2 interactions, as previously suggested by FTIR spectroscopy. Therefore, ST-STNa interaction should involve polar bonding, decreasing the amount of polar chemical groups available at the surface to interact with the probe molecules.

Water adsorption is strongly influenced by surface polarity [START_REF] Bradley | Dependence of water vapour adsorption on the polarity of the graphene surfaces of multi-wall carbon nanotubes[END_REF]. In particular, water vapor molecules can interact with solids through specific hydrogen-bonding with surface polar groups. Furthermore, when the solid is ionic, water molecules can interact with the components of the solid through ion-dipole interaction. For amorphous solids, the wettability and interaction with water are fundamental aspects to be studied because they can affect both dissolution properties [START_REF] Puri | Wettability and surface chemistry of crystalline and amorphous forms of a poorly water soluble drug[END_REF] and physical stability [START_REF] Hancock | The relationship between the glass transition temperature and the water content of amorphous pharmaceutical solids[END_REF][START_REF] Puri | Wettability and surface chemistry of crystalline and amorphous forms of a poorly water soluble drug[END_REF]. Both STNa and ST 1:3 deliquesced when exposed to ambient humidity conditions.

Hence, the interaction of the composites with water was investigated by calculating the powder wettability and analysing the water vapor sorption isotherms.

The wettability of a powder by water depends on both the work of adhesion of the water onto the powder surface (W A ) and on the water work of cohesion (W C ). Complete spreading of the water over a powder is possible if the work of adhesion onto the surface is equal to or higher than the work of cohesion among the water molecules [START_REF] Zdziennicka | Behavior of cationic surfactants and short-chain alcohols in mixed surface layers at water-air and polymer-water interfaces with regard to polymer wettability. II. Wettability of polymers[END_REF]. This difference equals the spreading coefficient (S SL ). The S SL of water over the composites, for various %RH, is reported in Fig. 7B. For all systems the S SL was negative, indicating that the spreading of water on the powder surface is not favoured and requires work. For each system, S SL was not affected by a change in the %RH from 0% to 20% but changed depending on the ST: STNa ratio. An increase in salt content from ST 3:1 to ST 1:3 decreased the S SL , indicating a decrease in water affinity for the powder surfaces.

The overlayed DVS 1 st sorption isotherm plots of the systems indicated that the whole/entire water uptake increased with the increase of salt content over the entire RH range (Fig. 8). The mass gain recorded at 90% RH was linearly proportional to the STNa content in the composites.

The coefficient of determination (r 2 ) of the linear fit was 0.99. For instance, spray dried STNa mass uptake was 36% w/w of the dry mass and decreased to 3.6% w/w for ST 9:1. As previous studies on the hygroscopicity of ST after spray drying indicated that the API had a maximum water uptake of only 0.5% at 90% RH [START_REF] Bianco | Modification of the Solid-State Nature of Sulfathiazole and Sulfathiazole Sodium by Spray Drying[END_REF], the water uptake for the blends is primarily due to the salt. The kinetic profiles obtained for systems ST 9:1 (Fig. 9A), ST 3:1 and ST 1:1 showed continuous water uptake versus time before reaching equilibrium for each % RH steps up to 40% RH. For these systems during the 50% RH step an initial mass increase was followed by a decrease in mass. A similar behaviour was also seen for ST 1:3 but the decrease in mass was lower, recorded at a lower RH and in two steps at 30% and 40% RH (Fig. 9B). A decrease in mass versus time with increasing RH for amorphous substances corresponds to the crystallisation of the material [START_REF] Burnett | Investigating the moisture-induced crystallization kinetics of spray-dried lactose[END_REF]. The mass loss is attributed to water loss due to the reduced hygroscopicity of a new crystalline phase compared to the amorphous form. Therefore the content of salt in the mixtures influenced the RH at which crystallisation took place by promoting the water uptake which acts as a plasticiser for the mixture. In contrast the kinetics for the pure amorphous STNa did not show any mass loss but a continuous increase in mass with increasing RH (Fig. 9C). Generally, crystalline solids with high solubility such as salts may deliquesce at a RH value lower than 100%, defined as RH 0 , which is characteristic of the material. RH 0 of a compound can be determined from the moisture sorption isotherm as a sharp break due to a sudden change in water uptake which takes place at deliquescence [START_REF] Hiatt | Effects of co-formulation of amorphous maltodextrin and deliquescent sodium ascorbate on moisture sorption and stability[END_REF]. In contrast, when dealing with amorphous solids, deliquescence can be regarded as a non-equilibrium phase transition because water uptake by amorphous substances proceeds in a gradual way and their transformation from solid to liquid state may involve intermediate semi-solid stages [START_REF] Mikhailov | Amorphous and crystalline aerosol particles interacting with water vapor: Conceptual framework and experimental evidence for restructuring, phase transitions and kinetic limitations[END_REF]. It was not possible to determine the RH of deliquescence for amorphous STNa either from the water sorption isotherm (Figure 9C) or the corresponding kinetics (Figure 9C').

Both ST 1:3 and STNa recorded mass uptake of respectively ~4.3% and 7% at the end of the first cycle. The water uptake for amorphous STNa was previously attributed to the crystallisation of the amorphous salt to a sesquihydrate [START_REF] Bianco | Modification of the Solid-State Nature of Sulfathiazole and Sulfathiazole Sodium by Spray Drying[END_REF]. PXRD analysis performed at the end of the water sorption isotherm confirmed that the composites converted to the same sesquihydrate form. Additional mass losses were detected in the kinetics for all composites in the second DVS sorption cycle (Fig. 9). These mass losses were of lower magnitude compared those in the first cycles. These mass losses indicated a not complete (i.e. partial) crystallisation of the amorphous systems at the end of the first sorption cycle. Full crystallisation following exposure to a first full 0-90% RH cycle was not achieved and this may be attributed to water not completely penetrating the bulk of the composites.

If we consider the adsorption process as the only mechanism of interaction between water and the powders, the higher the surface energy, surface polarity and spreading coefficient the greater is the expected water uptake. However, the surface properties measured for the different composites examined did not correlate with the whole water uptake isotherms. The γ s T of ST 9:1 and ST 3:1 were greater than those of STNa, ST 1:1 and ST 1:3, respectively. Nonetheless, ST 9:1 and ST 3:1 were characterised by lower water uptake compared to the other systems. Despite having the lowest γ s T profile (Fig. 6) among all systems examined, the water uptake of ST 1:3 was the second highest, lower only than STNa. However amorphous materials can either adsorb water, or absorb it in the bulk of the material [START_REF] Agrawal | Water distribution studies within microcrystalline cellulose and chitosan using differential scanning calorimetry and dynamic vapor sorption analysis[END_REF][START_REF] Alvarez-Lorenzo | Interactions between hydroxypropylcelluloses and vapour/liquid water[END_REF][START_REF] Bravo-Osuna | Water sorption-desorption behaviour of methyl methacrylate-starch copolymers: effect of hydrophobic graft and drying method[END_REF]. Hence, the distribution of water in the different systems was determined by establishing quantitative correlations between equilibrium moisture content and the %RH using the Young and Nelson equations [START_REF] Agrawal | Water distribution studies within microcrystalline cellulose and chitosan using differential scanning calorimetry and dynamic vapor sorption analysis[END_REF][START_REF] Alvarez-Lorenzo | Interactions between hydroxypropylcelluloses and vapour/liquid water[END_REF][START_REF] Bravo-Osuna | Water sorption-desorption behaviour of methyl methacrylate-starch copolymers: effect of hydrophobic graft and drying method[END_REF][START_REF] Tewes | Development and characterisation of soluble polymeric particles for pulmonary peptide delivery[END_REF]. Fitting DVS data with the Young-Nelson equations indicated that the water distribution within the different systems was dependent on the ST:STNa ratio. For ST 9:1, adsorption was the main process of water uptake, as can be confirmed by the high value of the A parameter, compared to the B parameter of the Young-Nelson equations (Fig. 10). It was found that an increase in STNa content increased the proportion of water absorbed, and water sorption for ST 1:1 and ST 1:3 was mainly by absorption. Fig. 10 shows a comparison of the Young and Nelson distribution patterns of water obtained by fitting DVS results for two systems (A) ST 1:3 and (B) ST 3:1 which are characterised respectively by low and high surface free energy. Most of the water uptake by ST 1:3 was absorbed in the bulk while only a minute amount was adsorbed on the surface. In contrast the water uptake for the higher γ s T system ST 3:1 was due to both adsorption and absorption. The higher amount of water adsorbed by ST 3:1 compared to ST 1:3 is consistent with the surface profiles for the two different systems.

Therefore the ratio ST:STNa influenced not only the total hygroscopicity but also the water distribution in the different systems and this may have an important impact on the physical stability of the powders. Several authors have attributed the water uptake by amorphous materials mainly to absorption processes [START_REF] Alvarez-Lorenzo | Interactions between hydroxypropylcelluloses and vapour/liquid water[END_REF][START_REF] Bravo-Osuna | Water sorption-desorption behaviour of methyl methacrylate-starch copolymers: effect of hydrophobic graft and drying method[END_REF]

Conclusions

This study showed that an extremely unstable amorphous API like sulfathiazole can be protected from crystallisation by co-spray drying it with its corresponding sodium salt form. In particular the addition of just 10% w/w salt was enough to delay the crystallisation of the resulting powder from 1 to 60 days of storage under desiccated conditions. Increasing the proportion of salt in the composite further improved the storage stability; however this was opposed by an increased hygroscopicity. The increased physical stability may be attributed to interactions between the species which cause the shift of Tg to higher temperature. FTIR spectroscopy, iGC and thermal analysis suggested interactions between the species with a stoichiometry of 1 molecule of acid for 2 molecules of salt. For the systems investigated, by analysing the hygroscopic properties it has also emerged that water uptake by an amorphous material could either be mainly by adsorption or by absorption depending on the chemical nature of the material, with the salt facilitating water absorption. Therefore controlling the physico-chemical properties of the composites by varying the ratio of the components can be beneficial to stabilise amorphous formulations. For example among the ST: STNa composites an optimum mixture which provided the best compromise between hygroscopicity and stability was the 1:1 w:w system. In this ratio the amorphous powder was characterised by good physical stability, intermediate water uptake and low surface free energy.

Acknowledgement

This paper is based upon works supported by the Science Foundation Ireland under grant no.

07/SRC/B1158, as part of the Solid State Pharmaceutical Cluster (SSPC) and grant no.

07/SRC/B1154, as part of the Irish Drug Delivery Network (IDDN).

  By using ethyl acetate (γ p -= 475.67, γ p + = 0 mJ/m 2 , at 30 o C) as the base probe and dichloromethane (γ p -= 0, γ p + = 124.58 mJ/m 2 , at 30 o C) as the acid probe with the acid and base component values calculated based on the Della Volpe and Siboni scale (Della Volpe and Siboni, 1997), γ s + and γ s -of the surface of the powders were calculated. Polarity index ( ) was then calculated.

Figure 1 :

 1 Figure 1: PXRD patterns of: (a) unprocessed ST (form III); b) spray dried ST; c) spray dried ST 9:1; d) spray dried ST 3:1; e) spray dried ST 1:1; f) spray dried ST 1:3; g) spray dried STNa; h) unprocessed STNa.

Figure 2 :

 2 Figure 2: SEM micrographs of: a) spray dried ST 9:1; b) spray dried ST 3:1; c) spray dried ST1:1; d) spray dried ST1:3.

Figure 3 :

 3 Figure 3: Heat flow thermograms of: (a) unprocessed ST (form III); b) spray dried ST; c) spray dried ST 9:1; d) spray dried ST 3:1; e) spray dried ST 1:1; f) spray dried ST 1:3; g) spray dried ST 15:85 h) spray dried STNa; i) unprocessed STNa.

  and d are the glass transition temperature in degrees Kelvin, the weight fraction, and density of the subscripts 1 -first component, 2second component, respectively.

Figure 4 :

 4 Figure 4: Glass transition temperatures of ST: STNa systems as a function of STNa content (squared markers). The solid line represents the Tg predictions based on the Gordon-Taylor with Simha-Boyer rule equation.

Figure

  Figure 5A: FTIR spectrum in the 1800-1000 cm -1 range of a) spray dried ST; b) to f) spray dried ST:STNa in the ratios 9:1, 3:1, 1:3, 15:85 and g) FTIR spectrum of spray dried STNa. 5B: Job plot representation

Figure 6 :

 6 Figure 6: Total surface free energy for the different weight ratios (ST: STNa) at different %RH. Statistical analysis compares data obtained at the same RH value. System ST 1:3 was taken as reference of comparison for statistical post-hoc analysis. *** P<0.001

Figure 7 :

 7 Figure 7: Polarity index (A) and spreading coefficient (B) changes for different weight ratios and %RH. Statistical analysis compares data obtained at the same RH value. System ST 1:3 was taken as reference of comparison for statistical post-hoc analysis *** P<0.001, ** P<0.01, * P < 0.05.

Figure 8

 8 Figure 8 Water sorption isotherms for spray dried systems with different ST: STNa weight ratios.

Figure

  Figure 9 DVS kinetics (A, B, C) and isotherms (A', B', C') of: A-A') spray dried ST 9:1; B-B') spray dried ST 1:3; C-C') spray dried STNa.

Figure 10 :

 10 Figure 10: Moisture distribution patterns for 1:3 (A) and 3:1 (B) samples obtained by fitting experimental DVS results with the Young and Nelson equations. Estimated A, B, E Young and Nelson parameters and fit correlation coefficient for all the composites investigated are inserted in the chart (A).

Figure 1 :

 1 Figure 1: PXRD patterns of: (a) unprocessed ST (form III); b) spray dried ST; c) spray dried ST 9:1; d) spray dried ST 3:1; e) spray dried ST 1:1; f) spray dried ST 1:3; g) spray dried STNa; h) unprocessed STNa.

FigureFigure 3 Figure 4 :Figure 5A :Figure 6 :Figure 7 :Figure 8 :Figure 10 :

 345A67810 Figure(s)

Table 1 : Spray drying parameters for ST: STNa systems. (An inlet temperature higher than 85°C for ST 9:1 resulted in partially crystalline materials. For the other systems an inlet temperature lower than 90°C resulted in wet powders).

 1

	ST: STNa
	Weight ratio	Code	Inlet (°C)
	(w/w)
	9:1	ST 9:1	85
	8:2	ST 8:2	90
	3:1	ST 3:1	90
	3:2	ST 6:4	90
	1:1	ST 1:1	90
	4:6	ST 4:6	90
	1:3	ST 1:3	90
	15:85	ST 15:85	90
	2.3 Thermal analysis

Differential scanning calorimetry (DSC) runs were conducted on a Mettler Toledo DSC 821 e


Coincident ion acceleration and electron extraction for space propulsion using the self-bias formed on a set of RF biased grids bounding a plasma source D.V. Rafalskyi, Ane Aanesland

Coincident ion acceleration and electron extraction for space propulsion using

the self-bias formed on a set of RF biased grids bounding a plasma source D. Rafalskyi We propose an alternative method to accelerate ions in classical gridded ion thrusters and ion sources such that co-extracted electrons from the source may provide beam space charge neutralization. In this way there is no need for an additional electron neutralizer. The method consists of applying RF voltage to a two-grid acceleration system via a blocking capacitor. Due to the unequal effective area of the two grids in contact with the plasma, a DC self-bias is formed, rectifying the applied RF voltage. As a result, ions are continuously accelerated within the grid system while electrons are emitted in brief instants within the RF period when the RF space charge sheath collapses. This paper presents the first experimental results and a proof-ofprinciple. Experiments are carried out using the Neptune thruster prototype which is a gridded Inductively Coupled Plasma (ICP) source operated at 4 MHz, attached to a larger beam propagation chamber. The RF power supply is used both for the ICP discharge (plasma generation) and powering the acceleration grids via a capacitor for ion acceleration and electron extraction without any DC power supplies. The ion and electron energies, particle flux and densities are measured using retarding field energy analyzers (RFEA), Langmuir probes and a large beam target. The system is operating in Argon and N 2 . The DC self-bias is found to be generated within the gridded extraction system in all the range of operating conditions. Broad quasi-neutral ion-electron beams are measured in the downstream chamber with energies up to 400 eV. The beams from the RF acceleration method are compared with classical DC acceleration with an additional external electron neutralizer. It is found that the two acceleration techniques provide similar performance, but the ion energy distribution function from RF acceleration is broader while the floating potential of the beam is lower than for the DC accelerated beam.

I. Introduction

Since the early 1990s, broad-beam ion sources (IS) have been used as thrusters for commercial satellites and engines for scientific space missions. Using IS in space thruster applications require neutralization or compensation of both the ion positive space charge and the ion current [START_REF] Goebel | Fundamentals of Electric Propulsion[END_REF]. Commonly, electrons are injected from an external neutralizer into the downstream beam. The neutralizer is a dedicated device based on thermo-electron emission or different kinds of gas discharges that usually needs additional power supplies and gas injection systems. Although much progress on the neutralizer technology has been achieved over the last few years, they are still considered as the part of the thruster with shortest lifetime and they are fragile during launch [START_REF] Goebel | Fundamentals of Electric Propulsion[END_REF][START_REF] Hitoshi | [END_REF][3].

Simultaneous emission of oppositely charged particles from a single source [4][5][6][7][8][START_REF]AIAA-87 -1407 from AIAA 19th Fluid Dynamics, Plasma Dynamics and Lasers Conference[END_REF][START_REF] Chabert | Electronegative plasma motor US[END_REF][START_REF] Aanesland | [END_REF] may provide several advantages in space. The additional neutralizer is then redundant, reducing the corresponding power and efficiency losses in the thruster and subsystems etc. Concepts using magnetic nozzles [8] or double layer structures formed at the plasma source output allow the acceleration of a quasi-neutral plasma [7,[START_REF]AIAA-87 -1407 from AIAA 19th Fluid Dynamics, Plasma Dynamics and Lasers Conference[END_REF]. Though these concepts provide in principle long-life neutralizer-free operation, the achievable performance such as specific impulse and thrust efficiency are generally lower than the performances provided by the traditional electric propulsion concepts (ion-and Hall-thrusters) [7,[START_REF]AIAA-87 -1407 from AIAA 19th Fluid Dynamics, Plasma Dynamics and Lasers Conference[END_REF]12,13]. Concepts based on simultaneous extraction of positive ions and electrons [4][5][6][7][8][START_REF]AIAA-87 -1407 from AIAA 19th Fluid Dynamics, Plasma Dynamics and Lasers Conference[END_REF] or positive and negative ions [START_REF] Chabert | Electronegative plasma motor US[END_REF][START_REF] Aanesland | [END_REF] accelerated via biased grids may also provide a quasi-neutral beam. One advantage of these systems is the similarity with space proven gridded thrusters allowing technology heritage. The PEGASES thruster is a gridded ion-ion thruster that accelerated alternately positive and negative ions for thrust [START_REF] Chabert | Electronegative plasma motor US[END_REF]. Operation of the PEGASES source is possible only with electronegative gases, i.e. halogens, and the best propellant for this thruster is Iodine [START_REF] Aanesland | [END_REF]. Therefore, for operation with Xe or other inert gases is not possible with this concept. Ions and electrons have been co-extracted from a single-grid source where the grid is biased with RF frequency, and this concept was also proposed for electric propulsion [4,14]. In the latter case, a so-called RF plasma self-bias effect is used for acceleration and co-extraction of electrons [START_REF] Lieberman | Principles of Plasma Discharges and Materials Processing[END_REF]. This source provides a separate control of the ion energy and flux of the broad quasi-neutral beam. However, it was shown that the source could not operate with ion energies of more than 200-300 eV and the ion extraction efficiency remained low [START_REF] Dudin | [END_REF]. As a result, this concept was not developed further for space applications.

We propose here an alternative method to accelerate ions using the "RF self-bias" effect. Briefly, the idea is to apply an RF bias voltage to a two-grid acceleration system via a blocking capacitor. In this case the space charge sheath in front of the grids oscillates with the RF frequency. The blocking capacitor charges up as a result of the effective area ratio between the first and second grid being larger than one. This allows rectification of the applied RF voltage by plasma and formation of a DC self-bias. In this system ions are continuously accelerated within the grids while electrons are emitted in brief instants within the RF period when the RF space charge sheath collapses.

This paper presents the first experimental results and proof-of-principle. The paper is organized as follows. In section II, the RF acceleration concept is presented with a detailed discussion on the RF self bias in a gridded system. The experimental setup is presented in section III, results are discussed in section IV and a conclusion is drawn in section V.

II. The Neptune RF acceleration concept

RF powered electrodes in asymmetric capacitive coupled plasma sources are widely used in the semiconductor industry to control independently the ion flux and ion energy impinging on the biased surface [START_REF] Lieberman | Principles of Plasma Discharges and Materials Processing[END_REF]17,18]. The RF voltage drop across the sheath in front of the driven and grounded surfaces is inversely proportional to the sheath capacitance, C=ε 0 A/d, where A and d are the sheath surface and thickness, respectively, and ε 0 is the vacuum permittivity. Hence, the largest voltage drop is across the smaller electrode. When this driven electrode is connected to ground via a blocking capacitor (avoiding DC currents to ground [START_REF] Lieberman | Principles of Plasma Discharges and Materials Processing[END_REF]), a DC bias is formed that rectify the RF voltage drop across the sheath. The self-bias formed across the low pressure sheath is typically V dc ~0.78V rf , where V rf is the amplitude of the RF voltage applied to the electrode [START_REF] Lieberman | Principles of Plasma Discharges and Materials Processing[END_REF]. As a result, the ions are accelerated continuously across the combined DC-RF sheath, while electrons escape during the short RF period where RF voltage approaches the plasma potential and the sheath collapses [4,14,17,18]. The average ion and electron currents to the electrode are equal due to the presence of the blocking capacitor in the circuit. Due to the RF oscillating sheath, the ion energy distribution impinging on the electrode surface tends to be bimodal with an energy spread decreasing with increasing RF frequency [START_REF] Lieberman | Principles of Plasma Discharges and Materials Processing[END_REF]. Replacing the smaller driven electrode by a grid allows the generation of coincident ion-electron flow, as shown in a single-grid system [4]. As mentioned in the introduction, single-grid systems are strongly limited by grid sputtering and low source efficiency [START_REF] Dudin | [END_REF].

In this paper we propose to apply only the RF voltage to a set of grid in a "classical" gridded ion thruster or ion source. In the following we will elaborate how this may accelerate positive ions creating thrust, with co-extracted electrons provide space charge neutrality. Note, that we call this new concept "Neptune" after a dedicated research project acronym [START_REF] Rafalskyi | Dispositif de formation d'un faisceau quasi-neutre de particules de charges opposées French patent application[END_REF].

Figure 1 shows a simplified drawing of the grid system and an equivalent RF electric circuit in line with the one of Coburn and Kay [17]. The RF voltage is applied between the first and second grid. The first grid is directly in contact with the plasma while the second grid is placed downstream and seen by the plasma only through the holes in the first grid. Oscillating space charge sheaths, represented by a capacitor and diode in parallel, are formed between the plasma and first grid, and between the plasma and second grid. The diodes in the circuit appears due to the asymmetry in the time response between the heavy ions and the much lighter electrons to the applied electric field, where the electron motion is controlled by the instantaneous electric field while the ion motion is mainly defined by the average electrical field. The sheath capacitance between the plasma and the first grid C 1 is higher than the sheath capacitance between the plasma and the second gird C 2 since the second grid is partially screened by the first one, i.e. the effective area ratio between the first and second grid is larger than one. As a result, the applied RF voltage V RF mainly drops across the sheath formed in front of each aperture of the second grid. The RF voltage is rectified to a DC self-bias voltage V DC due to the mentioned asymmetry in time response between ions and electrons and due to blocked DC current by blocking capacitor. Thus, in this case the asymmetry or difference in the DC self-bias voltage is formed between the extraction grids (external to the main plasma source).. The DC component then accelerates ions continuously while electrons are expelled in moments when the oscillating plasma potential approaches zero and the inter-grid sheath collapses. Figure 2 shows the expected RF plasma potential waveform with respect to the grounded second grid. A φ cr is the plasma potential corresponding to the sheath collapse, and can be estimated using the Child's law for the given aperture dimensions and ion flux from plasma [START_REF] Lieberman | Principles of Plasma Discharges and Materials Processing[END_REF][START_REF] Dudin | [END_REF].

As for RF biased electrodes, the ion energy distribution depends strongly on the applied RF frequency [START_REF] Gahan | [END_REF]. For the self-bias to form, the applied RF frequency ω must be situated between the ion ω pi and electron plasma frequency ω pe defined as:

here e 0 is the electron charge, n e is the plasma density, ε 0 is the vacuum permittivity and M i is the ion mass. Usually, this range includes RF signals from a few to hundreds of MHz, where the ion energy spread is inversely proportional to the applied frequency [START_REF] Lieberman | Principles of Plasma Discharges and Materials Processing[END_REF]. Fig. 2. The plasma potential waveform during the simultaneous extraction of ions and electrons from the two-grid RF-biased source. The plasma potential is shown with respect to the grounded second grid. φ cr is the plasma potential corresponding to the sheath collapse, and can be estimated using the Child's law for the given aperture dimensions and ion flux from plasma [START_REF] Lieberman | Principles of Plasma Discharges and Materials Processing[END_REF][START_REF] Dudin | [END_REF].

III. Experimental setup

The experiments are carried out using an inductively coupled plasma source attached to a larger beam propagation chamber illustrated in figure 3. This system has been detailed previously [21,22], however the gridded thruster used here is a modification of the PEGASES thruster prototype II [START_REF] Dudin | [END_REF]. We call the modified RF thruster "Neptune". Due to the partly thruster heritage, the first prototype has a rather unconventional geometry compared to classical gridded thrusters. The source is a rectangular parallelepiped with size of 8x12x12 cm. The plasma is generated using an inductively coupled plasma (ICP) discharge (see ref [23] for details) powered by a 4 MHz RF generator. A set of two grids is placed at the source exit. In this particular Neptune source, an RF distribution and matching system (see Fig. 3) is introduced to allow matching of the RF generator with the plasma load and to distribute the RF power between the ICP inductor (b) and extraction grid system. The first grid in contact with the plasma is biased with RF voltages via a blocking capacitor and the applied RF voltage amplitude is controlled using the RF power distribution system in the range 0-600 Vp-p. The second grid is grounded. The DC component of the first grid voltage is measured using both an oscilloscope and a 24 bit ADC board equipped with high RF impedance filters and resistive dividers. Note here, that the grids are called the "first" and "second" grid referring to the position from the plasma source; in the literature they may also be referred to as the "screen" and "acceleration" grids, respectively. Both grids are made of stainless steel and have an optical transparency of 0.6 and an aperture diameter of 2.5 mm; the intergrid distance is 2 mm. The extraction system is a rectangular with dimensions 65x105 mm. The aperture size in the extraction system ensures periodical electron sheath collapse when time-oscillating plasma potential is below approximately 95 V (relative to the grounded second grid), according to estimation using Child's law [START_REF] Lieberman | Principles of Plasma Discharges and Materials Processing[END_REF][START_REF] Dudin | [END_REF]. At this potential space charge sheath thickness becomes equal to the radius of the apertures in the extraction grid allowing plasma expansion through the extraction system. The RF power is continuously measured for both the ICP and extraction channels separately, so it is possible to operate the source with constant ICP power while changing the RF voltage applied to the extraction system. Due to the experimental heritage the design of this prototype has not been optimized in the view of gas utilization and efficiency requirements, and is used in this work only to demonstrate a proof-of-principle.

A Langmuir probe and a planar probe are introduced into the prototype through the grids in order to measure the plasma density and the ion flux to the extraction system. The experiments presented here were performed at a constant ion current density to the extraction system of about 1 mA/cm 2 , which corresponds to approximately 150 W of RF power absorbed by the ICP channel with Ar gas at standard working pressure (see below). At this set of parameters, the ion plasma frequency ω pi /2π is approximately 4 MHz, which is equal to the RF generator frequency and therefore corresponds to the lower frequency limit allowing the DC self-bias to form according to eq. ( 1). The Neptune thruster prototype is connected to a 1m long, 70 cm diameter beam propagation chamber. The chamber is equipped with a 15 cm diameter beam target, a retarding field energy analyzer (RFEA) and an RF-compensated Langmuir probe. The Langmuir probe and the RFEA can be moved perpendicular and parallel to the beam propagation, while the beam target can only be moved in the axial (parallel) direction. The RF compensation of the Langmuir probe is made using a reference electrode connected to the probe tip via a capacitor and inductor chokes connected in series with the probe acquisition system, allowing the probe potential to follow RF fluctuations in the beam-plasma. The reference electrode serves also as a probe tube holder and has a total area of about 5 cm 2 . RF oscillations in the beam are measured using the reference electrode connected to an oscilloscope with a low-impedance line. In order to compare the Neptune beam parameters with parameters of an ion beam generated in a classical way (using DC ion acceleration with an external neutralizer) a hot cathode neutralizer can be introduced into the beam chamber. In this case, the first grid is disconnected from the RF system and connected to a DC voltage source.

The gas is fed into the Neptune prototype via a shower-like injection system. Ar is used as a working gas, unless stated otherwise. The Ar flow rate is 25 sccm. The pressures in the discharge chamber and beam chamber are about 1.5 mTorr and 0.2 mTorr, respectively. The beam chamber is pumped using a turbo pump in connection with a dry pump. In total, the various experiments using the Neptune RF extraction system were running for about 15 hours. The measured currents and fluxes are repeated with a variation less than ±10%, and include heating and cooling effects of the RF system, drift in the mass-flow controller, etc. Fig. 3. Schematic of the experimental setup. The "LP" is the Langmuir probe, the "PP" is the planar probe and the "Ref" is the reference electrode, connected capacitively to the "LP" tip. In the RF mode the neutralizer and DC voltage source (shown in grey on the figure) are not included in the experimental system. The neutralizer and DC source are installed and turned on only in the experiments with DC ion extraction (DC mode).

IV. Experimental results

The first tests of the Neptune prototype operating with Ar is carried out by measuring the RF and DC voltages formed on the first grid as a function of the applied RF voltage. Fig. 4 (a) shows a typical voltage waveform measured on the first grid. The offset of about 200 V DC shows that the RF voltage is rectified and that a DC self-bias is formed. Fig. 4 (b) shows the measured DC component of the grid voltage V DC as a function of the amplitude of the applied RF voltage V RF . It is seen that V DC ≈ 0.8 V RF , which is in agreement with theoretical estimations for the self-bias effect in low-pressure plasmas with asymmetrical electrodes [START_REF] Lieberman | Principles of Plasma Discharges and Materials Processing[END_REF]. The formation of a DC self-bias allows a continuous ion extraction/acceleration from the Neptune prototype. Fig. 5 shows the measured ion beam current as a function of the DC self-bias voltage. It is seen here that the extracted current continuously increases with increasing DC selfbias voltage reaching 16 mA at about 300 V of V DC . To evaluate this result, the RF acceleration technique is compares with the extracted ion current obtained using a traditional gridded thruster configuration, i.e. in this case the neutralizer is switched "on" and only a DC voltage is applied between the extraction grids. Below we will call this the "DC-mode" of operation and the RF extraction without neutralizer the "RF-mode".

The ion beam current measured as a function of the applied DC voltage (from the DCmode) is also plotted on figure 5. Comparing the two results shows that the ion extraction in the RF-mode is about 20%-30% more efficient than in the DC-mode. This is in agreement with previous observations in the single-grid RF sources [4,[START_REF] Dudin | [END_REF]. The reason for this effect may be due to the difference in the effective space charge sheath thickness between a pure DC sheath and a DC+RF sheath due to the oscillating nature of the RF sheath [START_REF] Lieberman | Principles of Plasma Discharges and Materials Processing[END_REF], hence a change in the ion optics. Note however that the extraction system has not yet been optimized for the given acceleration voltage (0 -400 V) and ion current density from the plasma (1 -1.5 mA/cm 2 ). Therefore, the ion beam currents in both the DC and RF modes do not reach the saturation limit given by the optical grid transparency and the space charge limit. We expect that the maximum value of the extracted ion current will be similar for DC and RF ion extraction since this is only a question of optimizing the grids for the given ion flux and acceleration voltage [START_REF] Goebel | Fundamentals of Electric Propulsion[END_REF]. Fig. 5. The ion beam current as a function of the generated DC self-bias (circles) or applied DC voltage (squares) on the extraction system. A downstream electron neutralizer is used in the DC mode. Fig. 6 shows simultaneously measured ion and electron energy distribution functions (IEDF and EEDF, respectively) emitted from the source for two different DC self-bias voltages. The neutralizer is not used here. The ion energy distribution is multi-peaked while electrons have a single peak extracted with low energy of about 10 eV. At RF voltages above about 100 V, the accelerated beam becomes visible (see photo on fig. 7) which may indicate excitation of neutrals and ions in the downstream region by co-extracted electrons emitted from the source. The RFEA measurements show that the total amount of ions and electrons are similar and indicates that the space charge is compensated. This will also be demonstrated from target measurements below.

The IEDF measured in the RF mode is not similar to the case of DC ion acceleration shown in fig. 8. This can be explained as follows. In theory, the IEDF of single mass ions accelerated in an RF+DC electrical field is double-peaked, where the peak separation width is a function of the applied frequency [24]. This happens when the ion transit time across the sheath is comparable to the RF period. Figure 6 show that in our case the IEDFs are multi-peaked, where the main peak roughly corresponds to the self-bias potential. Similar behavior of IEDFs has been observed in relatively high-pressure RF discharges where the space charge sheath becomes collisional with dominating charge-exchange collisions [25]. Our estimations using cross-sections for both ion-neutral collisions and charge-exchange processes Ar + +Ar=Ar+Ar + [26,27] indicates however that the sheaths in the Neptune prototype is collisionless in the pressure range of a few mTorr. We therefore suppose that the multi-peak behavior of the IEDF originates from the non-flat shape of the oscillating RF sheath located between the grids (in contrast to common RF plasma systems), so the ion transit time across the sheath is a function of the initial radial ion position in front of each beamlet. In any case, the ion peak broadening seen on the measured IEDF is expected to be significantly lower at higher RF frequencies, when the ion transit time across the sheath is much longer than the RF period [24]. Fig. 6. Energy distribution functions for the ions (IEDF, solid line) and electrons (EEDF, dashed line) measured simultaneously at the Neptune source output using 200 V (a) and 400 V (b) of peak-to-peak RF voltage applied to the extraction system. The EDFs are plotted in arbitrary units (a.u.). Fig. 5 and Fig. 9 provide the corresponding fluxes. The spatial distribution of the ion flux from the Neptune prototype has been measured using a movable RFEA placed in the beam transport chamber 10 cm from the source output. Fig. 9 shows the ion flux measured in the RF and DC mode. The ion beams are well confined with quantitatively the same beam profile in both cases. Hence, in this system RF powering of the extraction system provides ion beam formation of almost the same quality as with conventional DC-bias and neutralizer. It should be mentioned here that the apparent "focusing" of the beam (i.e the beam envelope being narrower than the grid size) is most likely due to the plasma density distribution is the source rather than an "optical" beam focusing due to the grid optics. While ion and electron extraction from an RF powered extraction system is demonstrated by the results shown above, the space charge compensation in the downstream beam needs to be investigated separately. This is investigated by a big planar probe (beam target) placed 10 cm downstream of the grids. Fig. 10 (a) shows an IV curve measured on this beam target when a 300 eV ion-electron beam propagates in the downstream chamber. The figure shows that both ions and electrons are extracted from the source: when the target is biased positive, with respect to the grounded beam propagation chamber, the emitted electron current is larger than the ion saturation current measured on the target. Equal ion and electron currents are achieved with a target potential of about 10 Volts, i.e. corresponding to the beam floating potential. In the RF mode, the floating potential is around 10-15 V also slightly increasing with the acceleration voltage. The lower floating potential compared to the DC mode may be due to a high directionality of the emitted electrons in this case.

In the RF-mode the electrons are emitted periodically following the 4 MHz RF frequency. Therefore, the measured time-averaged properties of the beam compensation do not show the complete picture as the plume plasma potential may oscillate with a certain amplitude. In order to measure the amplitude of these oscillations, a Langmuir probe is placed on the axis of the i-e beam 10 cm from the source output. Fig. 11 shows the voltage waveform measured on the LP reference electrode ("Ref" at Fig. 3) together with the voltage waveform applied to the extraction system. The floating potential in the beam is non-sinusoidal with sharp local minimums corresponding to the electron injection periods. The peak-to-peak amplitude of the oscillation is however only about 5 Volts, corresponding to less than 1% of the applied RF voltage. The plume potential oscillations are therefore almost negligible. Investigation of thruster plume properties is a difficult task as vacuum facility effects plays an important role [START_REF] Goebel | Fundamentals of Electric Propulsion[END_REF][START_REF] Randolph | Facility Effects on Stationary Plasma Thruster Testing[END_REF]. Also here, the plume potential oscillations are expected to be dependent on the external boundary conditions (in space this is influenced on the various reference potentials between the thruster, spacecraft body, solar panels etc. ) Thus, it is evident that the Neptune thruster should also be tested in larger vacuum facilities.

Fig. 11 Waveforms of the floating probe potential (black) and first grid potential (grey) measured simultaneously for a DC self-bias of 200 V formed on the extraction system, which corresponds to about 220 V of applied RF voltage amplitude (440 V peak-to-peak). Fig. 12. The IEDF and EEDF of the ion-electron beam generated using nitrogen as a working gas.

The possibility to operate the thruster with working gases other than Ar has also been investigated. The IEDF and EEDF of an ion-electron nitrogen beam at an RF voltage of 150 V is shown on Fig. 12. The IEDF of the nitrogen beam is narrower than the one measured in Ar (see fig. 6 above). The beam is also here fully compensated by self-emitted electrons, which was checked by measuring the floating potential in the beam and by comparing fluxes measured by the RFEA. The Neptune thruster acceleration scheme is thus apparently insensitive to the operating gas (propellant). We therefore believe that the Neptune thruster can in principle use propellant from the residual fuel remaining in chemical propellant tanks after spacecraft launches, as well as traditional Xe and other inert gases.

Thought a preliminary comparison between the performance of the Neptune prototype using RF and DC acceleration is present above, further work is required to characterize the thruster efficiency (thrust, power, propellant utilization, etc.) and analyze the various advantages and possible drawbacks of the RF acceleration concept. This should include measurements of the total system efficiency and be compared to standard systems using external neutralizers. However, all of this requires manufacturing of the new Neptune prototype similar to existing ion thruster (by power, thrust and specific impulse values) specially dedicated to such specific measurements.

V. Conclusion

In this paper we experimentally show that a DC self-bias can be formed in a two-gridded system, where only the first biased grid is in direct contact with the plasma and the second grounded grid is in contact with the plasma only via the perforation in the first grid. We propose to use this self-bias formation for ion acceleration accompanied by electron co-extraction. In this case electrons arriving from the plasma to the extraction grids within short time intervals of the RF period (when the RF oscillating sheath potential approaches zero) can be used for beam space charge neutralization.

In this paper we present the first thruster prototype based on this RF acceleration concept. This thruster, called Neptune, is a gridded thruster with strong similarities to space proven thrusters already in operation. The originality lays only in the acceleration technology where the grid system is biased with RF power across a capacitor. This allows a DC self-bias to form charging up the blocking capacitor such that ions are continuously accelerated, while electrons are emitted in a short period in the RF cycle when the plasma-grid sheath collapses.

We have here presented the first proof-of-principles. The first thruster prototype is mounted on a moderate sized vacuum chamber. One single RF generator, at 4 MHz, is used for gas ionization, ion acceleration and electron extraction, without the need for any additional DC supplies. A well-collimated ion-electron beam is formed with independent control of the ion flux and ion energy. The ion beam energy can reach up to 400 eV in the current system, and is limited at the moment by the available experimental equipment. The measured beam current, spatial distribution and plume properties are similar to results achieved using a traditional scheme with DC biased grids and a downstream electron neutralizer. Hence, for an optimized system the propellant and power efficiency are expected to be in the same range as for common gridded thrusters. Our measurements show also that the potentials induced on insulated surfaces in the plume are lower in the RF mode, compared to the traditional DC mode under otherwise similar conditions.

Since the main modification to existing gridded ion thrusters, and in particular the ones driven by RF, is the way the grid system is biased (RF instead of DC), the rest of the thruster implementation can benefit from technology heritage. Hence, facilitating a rather rapid increase in the TRL (Technological Readiness Level) of this technology.

Fig. 1 .

 1 Fig. 1. (a) Schematic view of a two beamlets in the two-grid extraction system when an RF voltage is applied between the grids, t 1 and t 2 corresponds to those on the Fig. 2 below; (b) equivalent circuit of the two extraction grids powered by an RF voltage.

Fig. 4 .

 4 Fig.4. (a) Voltage waveform measured on the RF-powered first grid of the Neptune source; the applied RF voltage amplitude V RF is 200 V. (b) DC self-bias voltage V DC in the extraction system measured as a function of the amplitude of the applied RF voltage V RF .

Fig. 7 A

 7 Fig. 7 A photo of the plume produced by the Neptune source operating in the RF mode with a DC self bias voltage of 200V.

Fig. 8 .

 8 Fig. 8. Ion energy distribution function (IEDF) measured at the Neptune source output using only DC acceleration voltage (200 V) applied to the extraction system. The downstream neutralizer is operating in this experiment.

Fig. 9 .

 9 Fig. 9. The spatial distribution of the ion flux measured 10 cm from the Neptune output using a calibrated RFEA. Circles and squares are measured in RF and DC mode, respectively. The DC component of the acceleration voltage is 200 V in both cases. The center line of the extraction system is located at x = 0 cm, the edge of the extraction system corresponds to -5.2 cm < x < 5.2 cm.

Fig. 10 .

 10 Fig. 10. (a) IV curve of the target affected by the 300 eV ion-electron beam generated by the Neptune source. Positive and negative currents correspond to the current of negatively and positively charged particles, respectively; (b) Floating potential of the target ("Space potential") as a function of the DC component of the grid voltage, measured for DC ion extraction without (squares) and with neutralizer (triangles), and for the RF mode with i-e beam extraction without neutralizer (circles).

  and A. Aanesland

	Laboratoire de Physique des Plasmas (CNRS, Ecole Polytechnique, Sorbonne Universités,
	UPMC Univ Paris 06, Univ Paris-Sud),
	Ecole Polytechnique, 91128 Palaiseau, France

Acknowledgements

This work was supported by a Marie Curie International Incoming Fellowships within the 7th European Community Framework (Neptune PIIF-GA-2012-326054). The authors would like to thank Trevor Lafleur for useful discussions and advices.