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Preparation and Characterisation of Ultra-Rapidly Dissolving Orodispersible Films for Treating and Preventing Iodine Deficiency in the Paediatric Population Cholpon RustemKyzy, Peter Belton, and Sheng Qi J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.5b03953 • Publication Date (Web): 25 Oct 2015 Downloaded from http://pubs.acs.org on October 31, 2015

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Journal of Agricultural and Food Chemistry

Preparation and Characterisation of Ultra-Rapidly Dissolving Orodispersible Films for Treating and Preventing Iodine Deficiency in the Paediatric Population

Cholpon Rustemkyzy1, Peter Belton2, Sheng Qi1*

1. School of Pharmacy, University of East Anglia, Norwich, Norfolk, UK, NR4 7TJ 2. School of Chemistry, University of East Anglia, Norwich, Norfolk, UK, NR4 7TJ

Correspondence: Sheng Qi, [email protected]

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Abstract: 1

Iodine deficiency is a public health problem that is easily prevented in many countries through

2

having a salt iodization programme. However, the World Health Organisation (WHO) recommends

3

that particular population groups including infants and young children have a higher daily iodine

4

dose than adults, whilst also reducing salt consumption in their diet. Whilst many iodine

5

supplements are available, swallowing tablet supplements is physically difficult for young children,

6

thus there is a need for the development of novel iodine delivery systems for paediatric patients. In

7

this study a novel, ultra-rapidly dissolving, nanofiber based orodispersible film formulation

8

containing iodine which is constructed from nanofibers was manufactured using an electrospinning

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technique was developed. The potassium iodate (KIO3) loaded poly (ethylene oxide) (PEO) fibre

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orodispersible films dissolve within seconds on wetting (applying on the tongue) without the need

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for the consumption of water. The electrospinning process and KIO3 loading did not alter the

12

crystallinity and conformation of PEO. With high loading, KIO3 nanocrystals present in the fibers.

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This formulation design allows easy administration of iodine for preventing childhood iodine

14

deficiency. It has also described a novel and easy method for producing and harvesting nanocrystals

15

of inorganic salts that can be potentially adopted for use in other relevant fields.

16

Keywords: iodine deficiency, electrospinning, solid dispersions, nanocrystals, ultra-rapidly

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dissolving orodispersible film

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Introduction

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Iodine deficiency is one of the key factors responsible for mental impairment worldwide and is

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easily preventable by supplementing the population using iodized salt.

1-3

Unfortunately, complete

21

elimination of iodine deficiency in the world has not been achieved.

4, 5

It is still a major health

22

problem in many developing countries and it can easily re-emerge anywhere because of the socio-

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economic situation and/or circulation of iodine in the nature. This has happened in some iodine

24

sufficient countries.

6-11

In an attempt to address this, WHO and UNICEF urged all countries to ACS Paragon Plus Environment

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control and monitor iodine status every three years

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medicaments/supplements for the most vulnerable groups in the population, such as children (90-

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150 µg/d depending on the age group), prenatal, pregnant and lactating women (220-250 µg/d) in

28

order to meet their required daily dose. 13 Existing iodine medicaments and supplements are mostly

29

in tablet form, which often cause serious difficulties in swallowing for paediatric and elderly

30

patients. Although liquid iodine supplement formulations are available, there have a number of

31

drawbacks related with their reduced physical storage stability, increased manufacturing cost, and

32

increased contamination risk for multiple dose formulations.

7

33

developing

for

34

medicaments/supplements to meet paediatric population needs. This study reports the development

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of ultra-rapidly dissolving orodispersible films as an alternative solid form of iodine delivery which

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can meet this urgent need for tackling paediatric iodine deficiency.

37

The orodispersible films are made of an overlapping iodine loaded nanofiber network which

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provides an ultra-rapid disintegration and dissolution once wetted. Additional water as is commonly

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used when taking conventional tablets and capsules and swallowing of bulky solids are not required

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for the administration of this orodispersible film. The child only needs to put the film on the tongue

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and the formulation will dissolve rapidly in saliva and the iodine can be largely absorbed by

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conventional gastrointestinal route. It is anticipated that a small proportion of the saliva-dissolved

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iodine may also be absorbed via buccal mucosa within the oral cavity which has the advantages of

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rapid uptake and by-passing the hepatic metabolism.

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other unfulfilled therapeutic needs such as emergency medications for patients who are unable to

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swallow conventional tablets and capsules, such as geriatric patients with dysphagia and

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unconscious patients who are in seizure.

48

The nanofiber based orodispersible films were produced using electrospinning which has recently

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gained an increased interests in the pharmaceutical, biomedical, food and tissue engineering fields.

50

16-21

countries,

there

is

an

increasing

demand

14, 15

and recommend oral iodine

Therefore and in particular for new

cost-effective

iodine

This delivery concept can also benefit

The main advantages of nanofibers as a delivery system are high surface to volume ratio, ACS Paragon Plus Environment

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enhanced drug loading capacity and relative cost-effectiveness.

However, characterisation of

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the nanofibers can be challenging as a result of their sub-micron dimensions, but this

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characterisation is crucial for understanding and thereby controlling the in vitro and in vivo

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performance and stability of the formulations. In this study, potassium iodate (KIO3), which is the

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most stable form of iodine source under stressed conditions, 25 was used as the active ingredient. In

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order to maximise the stability of KIO3 and to be able to form easy-to-handle films with a uniform

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distribution of a low dose of KIO3, poly (ethylene oxide) (PEO) was used to form a solid dispersion

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with KIO3. PEO is easily processed by electrospinning and is water-soluble. 26, 27

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Despite a rich literature base that have provided insight into solid dispersion based formulations,

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there is a lack of information regarding using them to deliver inorganic molecules. This study

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provides a thorough investigation into the behavior of such a system. The results reveal the

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formation of nanocrystals of KIO3 within the nanofibers at relatively lower loading concentrations

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than is the case with many organic, low molecular weight drugs. This study has demonstrated two

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significant outcomes, 1) the development of a prototype form of a novel solid oral paediatric iodine

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formulation which requires no water and swallowing for administration and 2) a considerable

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contribution to the improving understanding of solid dispersions containing inorganic molecules

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and the production of inorganic nanocrystals using a quick, simple and organic solve-free

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electrospinning method.

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Materials and method:

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Materials

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Poly (ethylene oxide) (Average Mw = 6×105 g/mol) and polydispersity below 1.10 28, KIO3 (ACS

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grade – 99.5 % purity), KI (ACS grade - ≥99 % purity), H2SO4 (ACS grade – 95.0 - 98.0 % purity)

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were all purchased from Sigma Aldrich (Pool, UK).

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Electrospinning ACS Paragon Plus Environment

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PEO and KIO3 were dissolved in water in different w/w ratios in order to produce solid fibers

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containing 0.4 % w/w to 86 % w/w KIO3. Overall, the solid content concentration of the

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electrospun solution was 5-7 % w/v. The electrospinning processing parameters are as follow:

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distance between the collector and the tip of the needle was 150 mm, 200 mm, and 250 mm; flow

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rate was 0.5 ml/h and 0.1 ml/h; applied DC voltage was from 12kV to 25kV, was adjusted

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accordingly during processing until a stable jet was observed. The electrospun PVP fibers

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containing KIO3 or NaCl were prepared using 150mm as the distance between the collector and the

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tip of the needle, 0.5 ml/h flow rate and 30kV DC voltage. PVP and the crystalline salt were

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dissolved in water with solid salt concentration of 4 % to 14 % w/w. All samples were prepared

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under room temperature at 50% relative humidity (RH), with the preparation process being repeated

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at least three times to ensure the reproducibility of the process.

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Scanning Electron Microscopy (SEM)

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The morphology of the fibers was visualized using a JSM5900 LV SEM (JEOL Ltd, Japan). The

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surfaces of the samples were pre-treated with Au/Pd.

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SEM/Energy-dispersive X-ray spectroscopy (EDS)

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The EDS (INCA Energy manufactured by Oxford Instruments) combined with the SEM is capable

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of detecting chemical elements using a “spot mode”

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Resolution: 131eV (Mn K alpha). Acquisition time: 30 to 60 sec. At least 5-10 spots at different

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locations for each samples were examined.

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Transmission Electron Microscopy (TEM)

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The TEM instrument used was a Philips CM30 operating at 300kV. Samples were electrospun

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directly onto TEM grids Support Film of holey-carbon on 300 mesh Cu.

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Wetting, Disintegration and Dissolution testing

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manually chosen in the scanned area.


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The wettability of the films was tested using a moist filter paper method describe previously in

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literature. 30 In summary, a piece of cellulose filter paper (Sigma-Aldrich, Gillingham, Dorset, UK)

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was wetted and saturated with distilled water. The filter paper was then placed in a petri dish and a

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piece of the electrospun film was placed on top of the wetted filter paper. The time taken for the

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film to transform from dry and opaque colour to invisible (indicating complete wetting) was

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recorded. The tests were repeated at least three times.

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The dissolution tests of the fast dissolving oral films were performed simply, because the

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dissolution process was rapid. Placebo and KIO3 loaded films were dissolved in water in a petri dish

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and by gentle stirring and the time taken for the film to dissolve was recorded. In order to see the

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release of KIO3, an iodometric reaction was used. An excess amount of KIO3 and a small drop of

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methylene blue dye were added to water. 1M H2SO4 was added after placing the fiber film in water

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to see the immediate release of iodine to confirm fast release of active ingredient from carrier

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material. Methylene blue dye was used as a colorant indicator to allow the identification of the

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release of active ingredient. This is because that the fiber films were white colour and became

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transparent and difficult to see in water. KIO3 is a good oxidising agent which oxidises iodide to

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iodine in an acidic media and indicates the colour change via the reaction shown below:

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KIO3 + 5KI + 3H2SO4 = 3I2 + 3K2SO4 + 3H2O

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Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR)

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Infrared absorption peaks were measured with the IFS 66/S FT IR spectrometer Bruker Optics Ltd,

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Coventy, UK fitted with a Golden Gate® ATR accessory with heated top plate (Orpington, UK)

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equipped with diamond internal reflection element. The spectral resolution was 2 cm-1 with 64

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scans taken for each measurement. Triplicate measurements for each sample were performed.

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Powder X-Ray Diffraction (PXRD)

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Diffraction peaks were measured with a Thermo-ARL Xtra diffractometer (Therumo scientific, UK)

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with a step size of 0.01°, 0.5 sec time per step, from 3° - 60° 2θ. The wavelength was 1.54 angstrom ACS Paragon Plus Environment

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and the X-Ray source was Cu Kα1 with a power of 45 kV and current 40mA. Samples were

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accurately folded and placed onto the sample holder with zero background and incorporated onto a

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spinner stage.

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Differential scanning calorimetry (DSC)

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DSC measurements were conducted on a DSC Q2000 TA (New Castle, USA) instrument, equipped

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with a RSC 90 cooling unit and which had been calibrated with Indium, Tin and N-Octadacon.

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Samples weights were between 2-3 mg with a heating rate of 10°C/min over the temperature range

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0-120°C. Triplicate measurements for each sample were performed.

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Results and discussion

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Processing optimisation

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SEM images were used to characterise the dimensions and surface morphologies of the nanofiber.

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PEO with molecular weight of 600K yielded smooth placebo nanofibers with a uniform diameter

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range between 50 nm and 1.2 µm, as seen in Figure 1a and b. Addition of KIO3 up to 21% (w/w) led

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to slightly reduced fiber diameter, but no change in the fiber morphology (Figure 1c and d). Using

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the formation of nanofibers films which can be easily peeled off from the collector surface as the

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key measure, the maximum loading of KIO3 was also studied. The optimal loading range to result

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an elastic and easy-to-peel fiber film with smooth and uniform fibers was up to 21 % of KIO3

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loading with a 0.2 ml/h feeding rate. Further increases in KIO3 content to and above 43% led to the

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formation of beaded (formation of small beads on the fibers) nanofibers and brittle films (Figure 1e

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and f). Nonetheless, it is possible to load up to 86 % (w/w) KIO3 into the fiber film, but the

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morphology of the fibers would be beaded. For the fiber films with 13% KIO3 loading, delivering

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0.5mg and 1.1 mg KIO3 require a piece of film with dimensions of approximately 1x1cm2 and 1x2

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cm2, respectively, which meet the WHO recommended daily dose of 90 µg/d for children 0-5 years

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and 200 µg/d for pregnant and lactating women, respectively. This low mass may be difficult to

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handle, but with reducing the drug loading, the weight of oral film administrated can be easily ACS Paragon Plus Environment

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increased into easily manageable size. An alternative delivery method is to put the film on top of an

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edible bulky item, such as conventional children’s snacks, which may also improve patient

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adherence as they are appealing to paediatric population.

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The EDS is able to detect elements with atomic number greater than 5. In combination with SEM, it

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can be used to gain elemental distribution information. 31-33 As seen in Figure 2, the results revealed

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that the KIO3 loaded fibre films consists of K, I, O, C and Au. The presence of Au is due to pre-

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treatment of the SEM sample, C and O are polymer constituents and K, I, O constitutes of KIO3. As

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the electrospun films were highly porous, the quantitative elemental composition assignment of the

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EDS results would have limited reliability. Nevertheless, the atomic ratios between C, O, K and I

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largely align with the molar ratios of these atoms within the formulations examined. The high

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similarity of K and I peak intensities in different areas of the sample using the “spot mode”

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indicates the homogeneity of the distribution of KIO3 in the nanofiber films. Overall the above

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results confirmed that electrospinning is a suitable method for producing easy-to-use oral films for

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delivery of iodine.

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Ultra-rapid wetting, disintegration and dissolution

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With the intention of providing rapid dissolution of these electrospun films on the tongue after

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administration, these films should first demonstrate the ability to be wetted rapidly. The wetted

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filter paper method reported in literature was adopted for simulating the moist surface of tongue. 30

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As seen in Figure 3, the electrospun film wetted rapidly and transformed from an opaque dry film to

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being invisible in less than 20 seconds. As indicated by the disappearance of the opaque films, both

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the placebo and KIO3 loaded films, showed ultra-rapid disintegration and dissolution in the media

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within less than a minute (Figure 4). The rate of dissolution of the KIO3 loaded films was tested

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using sulphuric acid as an indicator. As seen in Figure 4, the dark brown colour of the media after ACS Paragon Plus Environment

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adding sulphuric acid indicates the liberation of I2, which appeared immediately after the fast

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disintegration and dissolution of the nanofiber films. The total dissolution was within less than 30

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seconds.

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Formation of KIO3 nanocrystals in PEO nanofibers

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As discussed earlier, the increases in KIO3 loading affected the mechanical properties of the formed

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fiber films via converting the smooth fibers to beaded fibers as well as reducing the PEO content

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which is responsible for the elasticity of the film. It was also suspected that the physical form of

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KIO3 might be altered with increasing the loading. This assumption was made on the basis of the

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existing literature of polymeric based solid dispersions for delivering organic molecules, in which

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crystalline drug is expected if the loading is significantly exceeds the solubility limit of the organic

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drug in the polymer.

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reduce the mechanical strength of the fibers and result in weak and brittle fiber films. This

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hypothesis was tested using PXRD. PXRD results confirm crystalline and semi-crystalline nature of

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KIO3 and PEO, respectively. All of characteristic diffraction peaks match those ones reported in

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literature.

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KIO3 was formed with loadings at and above 1.2% w/w. This indicates that an inorganic salt such as

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KIO3 has low solubility in solid PEO and instead of the formation of a solid solution or amorphous

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solid dispersion KIO3 is likely to form crystalline solid dispersions with PEO after electrospinning.

36

34, 35

The generation of significant quantities of crystalline KIO3 could also

As seen in Figure 5, it is evident that with increasing the KIO3 loading, crystalline

193

194

However, no crystal or particulate feature were observed using SEM which is an imaging technique

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that examines the surface of the fibers. Therefore TEM was applied to further investigate KIO3

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crystal formation in the PEO fibers. As seen in Figure 6, darker, nano-size particles can be clearly

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seen in the TEM images of the fiber films. These high-density nanoparticles are highly likely to be

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the KIO3 crystals. It is interesting that these nanocrystals are distributed relatively evenly within the


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core of the fibers. This confirms the earlier EDS result, which suggested a uniform distribution of

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KIO3 through the fibers. There appears to be no surface accumulation of the nanocrystals. This

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finding is contrast to the surface and bulk crystallisation behaviour of other inorganic salts in

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electrospun fibers reported in literature.

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hydrophilic polymeric fibers was also observed in electrospun polyvinylpyrrolidone (PVP), a

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widely used pharmaceutical hydrophilic and hygroscopic polymer,

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or KIO3 (Figure 7). This indicates that the phenomenon of inorganic salt crystallisation in the bulk

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of electrospun fibers is not PEO-KIO3 system specific. Although the mechanism of this

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crystallisation behaviour is unclear and further investigation is required, it is noted that both PEO

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and PVP are hydrophilic polymers which exhibit some hygroscopic behaviour. 40 The large surface

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area and the hygroscopic nature of the polymer fibers may lead to a higher moisture content at the

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surface layer of the fibers and this may be sufficient to solubilise the surface salts. The interior core

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of the fibers are likely to be drier than the surface, with the low solubility of the salts in the dry

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polymer interior driving the crystallisation.

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With increasing the iodate loading, beading of the fibers can be seen and agglomeration of KIO3

214

nanocrystals at the beading sites is clearly evident (supplementary information). This indicates that

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there are significantly higher KIO3 local concentrations at the beading sites. It is worth mentioning

216

that as the formation of the nanocrystals occurs at very low loading, it is reasonable to suggest that

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presence of the nanocrystals per se is not the key factor responsible for the mechanical weakness of

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the fiber films. The formation of highly concentrated KIO3 nanocrystal beads at higher iodine

219

loadings in combination with a low PEO content is more likely to be the underlying reason of the

220

poor mechanical properties of those fibers with high KIO3 loadings.

37-39

This interior-specific crystallisation behaviour in

40

fibers containing either NaCl

221

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Effect of processing and KIO3 loading on the crystallisation behaviour of PEO


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PEO is a semi-crystalline polymer and the crystallinity of the polymer can be affected by the

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electrospinning process and the incorporation of KIO3. These could potentially lead to stability

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concerns in the finished product. Therefore the structural conformation and crystallinity of the

226

processed PEO in the fibers were studied in depth. ATR FT-IR spectroscopy was used in the first

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instance to reveal the coexistence of helical (H) and trans (T) structure conformations of PEO. As

228

seen in Figure 8, IR peaks at 1358, 1278, 1235, 1060, 947, 842cm-1 have been specified as

229

indicators for the thermodynamically stable helical structure (H) and 1341, 1240, 961cm-1 for the

230

trans planar (T) conformation. Any changes in these peaks would indicate a change in T or H

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conformation.

232

comparison to the placebo and are independent of KIO3 loading. This implies no significant change

233

in the overall PEO chain conformation occurred after incorporation of KIO3.

41-45

All absorption peaks due to the PEO polymer remained unchanged in

234

235

With 43 % of KIO3 loading, the absorption peak at 745 cm-1 was split into two bands at 756 and

236

738 cm-1. The band splitting at 745 cm-1 may indicate a subtle change of symmetry in the crystal

237

structure.

238

KIO3 crystal symmetry, 48 thus this change was not observed in the PXRD results. Nevertheless for

239

the purpose of this study, such subtle changes in KIO3 nanocrystal are not anticipated to impact the

240

dissolution behaviour of the formulation because of the high solubility of KIO3. The detailed

241

assignments of all detectable FT-IR peaks of the PEO samples can be found in the Supplementary

242

Material.

243

The crystallinity of the PEO after electrospinning and KIO3 incorporation was estimated using

244

DSC. As seen in Figure 9, the DSC results show no significant difference in the melting onset

245

temperature, crystallization onset and offset temperatures and the enthalpies of these transitions of

246

control sample and KIO3 loaded PEO fiber films. This confirms the ATR-FTIR spectroscopic and

247

PXRD results that there was no significant impact on polymer crystallinity after processing and

248

KIO3 loading. However, there are a minimal amount of subtle changes in diffraction peak shape that

46, 47

However, according to literature, PXRD is unable to detect such subtle changes in


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can be seen when comparing the PEO powder as the starting material and the placebo PEO

250

electrospun fibers. There subtle changes may be attributed to an orientation effect of the crystalline

251

PEO chains after electrospinning 16, 49, 50.

252

253

This study was conducted with a clear aim of finding an alternative low-cost and easy-to-use oral

254

iodine supplement formulation for the paediatric population who often have swallowing and

255

adherence difficulties. The formulation developed should fulfil the essential criteria of not requiring

256

swallowing large solids and has the potential to be easy and fun for children to take. The solution

257

proposed in this study is to use electrospinning to produce thin orodispersible films which can

258

instantly dissolve on the tongue for easy administration of nutritional supplements to children. The

259

key outcome reported for this proof-of-concept study is that this is achievable with low

260

requirements for operational optimisation and little effect on the structural conformation of PEO.

261

The formation of KIO3 nanocrystals in nearly all loaded fiber films indicates the low miscibility of

262

PEO with KIO3. This provides new insights into the research area of using polymeric based solid

263

dispersions for inorganic material delivery which is still significantly lacking. The fact that KIO3

264

forms nanocrystals in the PEO fibers and the PEO remains in its original stable conformation is

265

likely to ensure the physical stability of the finished product.

266

Conclusion

267

A novel ultra-rapidly dissolving oral film with high design flexibility was developed to deliver

268

iodine for children. These mas were PEO based electrospun fiber films containing nanofibers of

269

PEO loaded with KIO3 nanocrystals and showed good mechanical properties and fast disintegration

270

and dissolution behaviour in vitro. This novel formulation design allows easy administration of

271

iodine for preventing childhood iodine deficiency. Additionally it has also provided a novel and

272

easy method for producing and harvesting nanocrystals of inorganic salts that can be potentially

273

adopted for other relevant fields.


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Acknowledgement

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Cholpon would like to thank the Islamic Development Bank Merit Scholarship Programme for High

276

Technology [grant number 600014339] to financially support her PhD. The authors would like to

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acknowledge Dr Mark Eddleston, University of Cambridge, for carrying out the some of the TEM

278

experiments on the nanofibers.

279

Reference

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21. Frenot, A.; Chronakis, I. S., Polymer nanofibers assembled by electrospinning. Curr. Opin. Colloid. In. 2003, 8, 64-75. 22. Zamani, M.; Prabhakaran, M. P.; Ramakrishna, S., Advances in drug delivery via electrospun and electrosprayed nanomaterials. Int. J. Nanomedicine 2013, 8, 2997. 23. Bhushani, J. A.; Anandharamakrishnan, C., Electrospinning and electrospraying techniques: Potential food based applications. Trends Food Sci. Techn. 2014, 38, 21-33. 24. Ignatious, F.; Sun, L.; Lee, C.-P.; Baldoni, J., Electrospun nanofibers in oral drug delivery. Pharmaceut. Res. 2010, 27, 576-588. 25. Arroyave, G.; Pineda, O.; Scrimshaw, N. S., The stability of potassium iodate in crude table salt. Bull. World Health Organ. 1956, 14, 183. 26. Son, W. K.; Youk, J. H.; Lee, T. S.; Park, W. H., The effects of solution properties and polyelectrolyte on electrospinning of ultrafine poly (ethylene oxide) fibers. Polymer 2004, 45, 2959-2966. 27. Fong, H.; Chun, I.; Reneker, D. H., Beaded nanofibers formed during electrospinning. Polymer 1999, 40, 4585-4592. 28. Schmitt, A. L.; Mahanthappa, M. K., Polydispersity-driven shift in the lamellar mesophase composition window of PEO-PB-PEO triblock copolymers. Soft Matter 2012, 8, 2294-2303. 29. Kutchko, B. G.; Kim, A. G., Fly ash characterization by SEM–EDS. Fuel 2006, 85, 2537-2544. 30. Yu, D.-G.; Shen, X.-X.; Branford-White, C.; White, K.; Zhu, L.-M.; Bligh, S. W. A., Oral fastdissolving drug delivery membranes prepared from electrospun polyvinylpyrrolidone ultrafine fibers. Nanotechnology 2009, 20, 055104. 31. Piburn, G.; Barron, A. R., An introduction to energy dispersive X-ray spectroscopy. Physical methods in chemistry and nano science. Connexions/Rice University, Houston 2013, 90-98. 32. Wollman, D. A.; Irwin, K. D.; Hilton, G. C.; Dulcie, L. L.; Newbury, D. E.; Martinis, J. M., High‐resolution, energy‐dispersive microcalorimeter spectrometer for X‐ray microanalysis. Journal of Microscopy 1997, 188, 196-223. 33. Chang, H. H.; Cheng, C. L.; Huang, P. J.; Lin, S. Y., Application of scanning electron microscopy and X-ray microanalysis: FE-SEM, ESEM-EDS, and EDS mapping for studying the characteristics of topographical microstructure and elemental mapping of human cardiac calcified deposition. Analytical and bioanalytical chemistry 2014, 406, 359-66. 34. Janssens, S.; Van den Mooter, G., Review: physical chemistry of solid dispersions. J. Pharm. Pharmacol. 2009, 61, 1571-86. 35. Forster, A.; Hempenstall, J.; Tucker, I.; Rades, T., Selection of excipients for melt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis. Int. J. Pharm. 2001, 226, 147-61. 36. Yang, S.; Liu, Z.; Liu, Y.; Jiao, Y., Effect of molecular weight on conformational changes of PEO: an infrared spectroscopic analysis. J. Mater. Sci. 2015, 50, 1544-1552. 37. Zhang, C.; Yuan, X.; Wu, L.; Han, Y.; Sheng, J., Study on morphology of electrospun poly (vinyl alcohol) mats. Eur. Polym. J. 2005, 41, 423-432. 38. Barakat, N. A. M.; Kanjwal, M. A.; Sheikh, F. A.; Kim, H. Y., Spider-net within the N6, PVA and PU electrospun nanofiber mats using salt addition: novel strategy in the electrospinning process. Polymer 2009, 50, 4389-4396. 39. Singhal, R.; Kalra, V., Using common salt to impart pseudocapacitive functionalities to carbon nanofibers. Journal of Materials Chemistry A 2015. 40. Rumondor, A. C. F.; Marsac, P. J.; Stanford, L. A.; Taylor, L. S., Phase behavior of poly (vinylpyrrolidone) containing amorphous solid dispersions in the presence of moisture. Mol. Pharm. 2009, 6, 1492-1505. 41. Takahashi, Y.; Tadokoro, H., Structural studies of polyethers,(-(CH2) mO-) n. X. Crystal structure of poly (ethylene oxide). Macromolecules 1973, 6, 672-675. 42. Kim, G.-M.; Wutzler, A.; Radusch, H.-J.; Michler, G. H.; Simon, P.; Sperling, R. A.; Parak, W. J., One-dimensional arrangement of gold nanoparticles by electrospinning. Chem. Mater. 2005, 17, 4949-4957. 43. Gupta, R. K.; Rhee, H.-W., Plasticizing effect of K+ ions and succinonitrile on electrical conductivity of [poly (ethylene oxide)–succinonitrile]/KI–I2 redox-couple solid polymer electrolyte. J. Phys. Chem. B 2013, 117, 7465-7471. 44. Bergeron, C.; Perrier, E.; Potier, A.; Delmas, G., A study of the deformation, Network, and aging of polyethylene oxide films by infrared spectroscopy and calorimetric measurements. Int. J. Spectrosc 2012, 2012.


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Figure 1. SEM images of (a) the morphology and (b) diameter size distribution of placebo PEO

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nanofibers, (c) the morphology and (d) diameter size distribution of PEO nanofibers loaded with

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21% KIO3, and the beaded morphologies of PEO nanofibers loaded with (e) 43% and (f) 86% KIO3.

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Figure 2. Representative EDS results of PEO nanofibres loaded with 4% (w/w) KIO3 showing the

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detection of K, O and I elements on the fibers.

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Figure 3. Demonstration of the rapid wetting of a piece of KIO3 loaded PEO nanofiber

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orodispersible film. The blue area was used to provide the colour contrast to allow the easy

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observation of the opaque film.

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Figure 4. Ultra-rapid dissolution of KIO3 loaded PEO nanofiber mats. The complete release of

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KIO3 is demonstrated by the colour change of the dissolution medium containing the molecular

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indicator, methylene blue, after adding small amount of H2SO4 solution.

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Figure 5. PXRD diffraction patterns of the starting materials and electrospun nanofibers.

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Figure 6. Representitive TEM image of PEO nanofibers loaded with 43% KIO3. KIO3 nanocrystals

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can be seen as black dots in the fibers.

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Figure 7. Representitive TEM image of PVP nanofibers loaded with (a) 4% NaCl and (b) 14%

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KIO3. Nanocrystals of NaCl and KIO3 (examples highlighted by arrows in the images) can be

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osberved in the core of the fibers with the surfaces of the fibers being largely crystal-free.

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Figure 8. ATR-FTIR spectra of (a) pure PEO powder; (b) electrospun placebo PEO nanofibers and

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PEO nanofibers loaded with (c) 4%, (d) 21% and 43% KIO3. The arrows indicate the position of

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KIO3 signature absorbance peak.

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Figure 9. DSC thermographs of electrospun placebo PEO fibres and KIO3 loaded (4 and 13% w/w)

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PEO fibres.

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TOC Graphic

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Preparation and Characterization of Ultrarapidly Dissolving

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