Fast Dissolving Paracetamol Caffeine Nanofibers Prepared by Electrospinning

7172019 Fast Dissolving Paracetamol Caffeine Nanofibers Prepared by Electrospinning

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Pharmaceutical nanotechnology

Fast dissolving

paracetamolcaffeine

nano1047297bers prepared byelectrospinning

U Eranka Illangakoon a Hardyal Gill a Gemma C Shearmanb Maryam Parhizkar cSunthar Mahalingam c Nicholas P Chatterton b Gareth R Williams aaUCL School of Pharmacy University College London 29-39 Brunswick Square LondonWC1N 1AX United Kingdomb School of Human Sciences Faculty of Life Sciences and Computing London Metropolitan University 166-220 Holloway Road London N7 8DB United

KingdomcDepartment of Mechanical Engineering University College London Torrington Place London WC1E 7JE United Kingdom

A

R

T

I

C

L

E

I

N

F

O

Article history

Received 7 July 2014Received

in

revised

form

6

October

2014Accepted 11 October 2014Available online 17 October 2014

PubChem classi 1047297cations

Caffeine (PubChem CID 2519)Paracetamol (PubChem CID 1983)Polyvinylpyrrolidone (PubChem CID 6917)

Keywords

ElectrospinningNano1047297ber

ParacetamolCaffeineFast-dissolving drug delivery system

A

B

S

T

R

A

C

T

A seriesof polyvinylpyrrolidone1047297bers loadedwith paracetamol (PCM) and caffeine (CAF)was fabricatedby electrospinning and explored as potential oral fast-dissolving 1047297lms The 1047297bers take the form of uniform cylinders with smooth surfaces and contain the drugs in the amorphous form Drugndashpolymerintermolecular interactions were evidenced by infrared spectroscopy and molecular modeling Theproperties of the1047297bermats were found tobehighlyappropriatefor thepreparation of oral fast dissolving1047297lms their thickness is around 120ndash130mm and the pH after dissolution in deionizedwater lies in therange of 67ndash72 Except at the highest drug loading the folding endurance of the1047297berswas found to begt20 timesA 1047298avoring agent caneasilybe incorporated into the formulation The1047297bermats are all seentodisintegrate completely within 05 s when added to simulated saliva solution They release their drugcargowithin around 150s in a dissolution testand to undergomuchmore rapid dissolution than is seenfor the pure drugs The data reported herein clearly demonstrate that electrospun PCMCAF 1047297berscomprise excellent candidates for oral fast-dissolving 1047297lms which could be particularly useful forchildren and patients with swallowing dif 1047297culties

atilde

2014 Elsevier BV All rights reserved

1 Introduction

Fast-dissolving drug delivery systems (FD-DDSs) were 1047297rstdeveloped in the late 1970s and rapidly gained interest in thepharmaceutical industry (Chaudhary et al 2013 Hoffmann et al2011) These delivery systems either dissolve or disintegrate in themouth very rapidly without requiring any water to aid inswallowing By releasing their drug cargo directly in the mouth

they enhance bioavailability and deliver rapid onset of action(Seager 1998) FD-DDSs are available in the form of tablets (Pathanet al 2013) 1047297lms (Yu et al 2009) wafers (Boateng et al 2010El-Mahrouk et al 2014) and buccal (Dinge and Nagarsenker 2008)or sublingual patches (Vrbata et al 2013) Examples currently in

the market include Zuplenz1 (an oral soluble

1047297lm used for theprevention of chemotherapy-induced radiotherapy-induced andpostoperative nausea and vomiting) and Suboxone1 (a sublingual1047297lm for the treatment of opioid dependence) Various other oraldissolving

1047297lm formulations are in the pipeline for example totreat central nervous system conditions such as Parkinsonrsquosdisease schizophrenia or Alzheimerrsquos disease (Hoffmann et al2011)

Sublingual 1047297lms in particular have many advantages comparedto other dosage forms these include rapid onset of actionavoidance of 1047297rst past metabolism and convenient and non-invasive administration (Dixit and Puthli 2009 Hearnden et al2012) There are however also some limitations The relativelysmall surface area in the sublingual mucosa means that it ispossible for the drug to be washed away with saliva before it canpermeate the mucosal membrane In addition the tendency forinvoluntary swallowing of liquids greater in volume than 200 mL can lead to the dissolved drug entering the gastrointestinal tractrather than being absorbed in the mouth Dislodging of the

Abbreviations CAF caffeine PCM paracetamol Corresponding author Tel +44 207 753 5868 fax +44 207 753 5942 Corresponding author Tel +44 207 133 4373 fax +44 207 133 4682E-mail addresses

nchattertonlondonmetacuk

(NP

Chatterton)gwilliamsuclacuk (GR Williams)

httpdxdoiorg101016jijpharm2014100360378-5173atilde 2014 Elsevier BV All rights reserved

International

Journal

of

Pharmaceutics

477

(2014)

369ndash379

Contents

lists

available

at

ScienceDirect

International Journal of Pharmaceutics

j ourna l homepage wwwelsev ier comlocate i jpharm

Downloaded From httpwwwelearnicair





temperature to obtain homogeneous solutions The conductivitiesof the spinning solutions were recorded using aPRIMO5 conductivity meter (Hanna Instruments WoonsocketRI USA)The spinning solutions were carefully placed into a plastic

syringe (5 mL BD Sunderland UK) with great care taken to avoid

any air bubbles A metal dispensing tip (spinneret gauge 20061 mm inner diameter Nordson EFD Dunstable UK) wasattached to the syringe The positive electrode of a high voltagepower DC supply (HCP35-35000 FuG Elektronik RosenheimGermany) was then connected to the spinneret The groundedelectrode was connected to a metal collector (17

17 cm2)

wrapped with aluminum foil Electrospinning was carried outunder ambient conditions (22

1 C and relative humidity

35

3) An electrical potential of 15 kV was applied across a

1047297xed distance of 12 cm between the spinneret and the collectorThe polymer solution was dispensed from the syringe at a feed rateof 12 mLh using a syringe pump (78-9100C Cole-Parmer LondonUK) Fibers were stored in a vacuum desiccator post-synthesis tofacilitate the removal of residual organic solvents and moisture

23 Characterization

231 Thickness of the 1047297ber mat

2 mL of each spinning solution was spun onto Al foil and threecircular sections of 3 cm diameter cut out using a biopsy punchThe thickness of each section was measured by using a digitalVernier caliper Results are reported as mean

SD

232 Folding endurance

The folding endurance gives a measure of the brittleness of a1047297lm 3 cm diameter circular sections of each mat (produced asdetailed in Section 231) were repeatedly folded by hand at thesame line until they broke or a visible crack was observed The

number

of

times

a

1047297lm

can

be

folded

without

breaking

or

visiblycracking is de1047297ned as the folding endurance (Mundargi et al2007) Experiments were performed in triplicate and datareported as mean SD

233 pH of the 1047297ber solution

A 3 cm diameter section from each formulation was dissolved in10 mL of distilled water and the pH was measured (pH 211 meterHanna Instruments Woonsocket RI USA) Each experiment wascarried out in triplicate and data are reported as mean

SD

234 Morphology

The 1047297ber morphologies were assessed using a scanning electronmicroscope (Quanta 200 FEG ESEM FEI Hillsborough OR USA)

Prior

to

examination

the

samples

were

gold

sputter-coated

under

argon to render them electrically conductive Images were thenrecorded at an excitation voltage of 5 kV The average

1047297ber size wasdetermined by measuring their diameters at over 50 points in SEMimages using the ImageJ software (National Institutes of HealthBethesda MD USA) The porosities of the 1047297ber mats werecalculated using the method of Ghasemi-Mobarakeh et al (2007)

235 X-ray diffraction

X-ray diffraction (XRD) patterns were obtained on a MiniFlex600 diffractometer (RigaKu Tokyo Japan) with Cu Ka radiation(l= 15148Aring) Data were recorded over the 2u range 5ndash45 at40 mV and 15 mA

236

Differential

scanning

calorimetry

Differential scanning calorimetry (DSC) analyses were carriedout using a DSC Q2000 calorimeter (TA Instruments New CastleDE USA) Sealed samples were heated at 10Cmin from 40 C to300 C under a 50 mLmin

1047298ow of nitrogen Recorded data wereanalyzed using the TA Instruments Universal Analysis software

237 Fourier transform infrared spectroscopy

Fourier transform infrared (FTIR) spectroscopy was conductedusing a Spectrum 100 FTIR spectrometer (PerkinElmer Massachu-

setts USA) 1047297tted with an ATR attachment The scanning range was4000ndash600 cm1 and the resolution set at 1 cm1

24

HPLC

analysis

A high-performance liquid chromatography (HPLC) methodwas developed in order to detect PCM and CAF simultaneouslyHPLC was performed using an Agilent 1260 In1047297nity instrument(Agilent Technologies Santa Clara CA USA) The mobile phaseconsisted of 20 vv acetonitrile 08 vv tri1047298uoroacetic acid and792 vv distilled water Analysis was carried out under isocraticconditions using a C18 column (00G-4326-60 PhenomenexMaccles1047297eld UK) The column temperature was set to 40 C andthe

1047298ow rate at 1 mLmin 10 mL of each sample was injected and

chromatograms were recorded at 254 nm for 6 min (to detect PCM)and at 276nm for another 4 min (to detect CAF) The percentagedrug loading was calculated using a pre-determined calibrationcurve prepared using a mixture of PCM and CAF

25 Wetting assays

3 cmdiametercircularsections werecutfromthe1047297bermatsusinga biopsy cutter and placed in a Petri dish containing 15 mL of simulated saliva (NaCl 800 g KH2PO4019 g Na2HPO4238 g in 1 L of distilled water pH 68) at room temperature The disintegration anddissolution of the

1047297ber mats was recorded at 1000 framess using ahigh speed video camera (Fastcam SA3 Photron Tokyo Japan)

26

Dissolution

studies

The standard British Pharmacopoeia dissolution test is per-formed in 900 mL of a dissolution medium However this does notre1047298ect the volume of the oral cavity (Hoffmann et al 2011)Therefore a modi1047297ed dissolution study was performed using a1 cm long magnetic stirrer in a 7 cm diameter glass Petri dish15 mL of simulated saliva pre-warmed to 37 C was placed in the Petridish and stirred at 150 rpm on a multipoint stirrer (CimarecTM iPoly15 ThermoScienti1047297c Loughborough UK) 200 mL of the superna-tant was removed at pre-determined time points and replacedwith 200 mL of pre-warmed simulated saliva to maintain aconstant volume Experiments were carried out in triplicate andresults reported as mean

SD The temperature remained at

37

2

C

throughout

the

experiment

Table 1

The compositions of the composite 1047297bers and the physical mixture (denoted as F5)

Composition Formulation

F0 F1 F2 F3 F4 F5

Spinning solutions PCM (wv) 0 100 250 500 250 ndash

CAF (wv) 0 013 033 065 033

ndash

PVP (wv) 1000 860 860 860 860 Raspberry 1047298avor (vv)

ndash

ndash

ndash

ndash 020

Electrospun 1047297bers

PCM (ww) 0 1028 2187 3509 2187 2187 CAF (ww) 0 134 289 456 289 289

PVP

(ww)

100

8839

7524

6035

7524

7524

UE Illangakoon et al International Journal of Pharmaceutics 477 (2014) 369ndash 379 371



27 Molecular modeling

Molecular mechanics in vacuo calculations were undertakenusing HyperChem version 8010 (a molecular modeling softwarepackage) The structures of each of the compounds (Fig 1) were1047297rst generated with Accelrys Draw 41 A decameric PVP specieswas chosen to represent the polymer Each structure wasindividually imported into HyperChem and a 3-D structure usingpreset bond angles and lengths produced (all hydrogen atoms wereexplicitly included) Initial geometric minimization was nextperformed with the MM+ force

1047297eld followed by a full energeticminimization using the AMBER 3 (Assisted Model Building andEnergy Re1047297nement) force 1047297eld Nonbonded electrostatic inter-actions were calculated using bond dipole interactions in MM+optimization For AMBER 3 minimizations the distance-depen-dent dielectric constant was assigned a scale factor of 1 and the 1ndash4 scale factors (representing the nonbonded interactions betweenatoms separated by three atoms) were electrostatic 05 and vander Waals 05 Both MM+ and AMBER 3 force

1047297elds were computedusing a PolakndashRibiere conjugate gradient method 1047297nishing whenthe root mean square gradient reached 0001 kcal(Aring mol) No cut-offs were applied The energetic contributions to the total stericenergy of the structures by bond stretchingcompressing bond

angle deformations torsional strain van der Waals repulsionshydrogen bonding and electrostatic repulsions were all consideredCombinations of the energetically minimized structures were thenmerged to create drugndashpolymer complexes These complexessubsequently underwent the same minimization procedures

3

Results

and

discussion

31 Electrospinning

The polymeractive pharmaceutical ingredient (API) spinningsolutions used to make the 1047297ber materials F0 F1 F2 and F3 weretransparent and clear For F4 concentrated raspberry 1047298avor (2 mLmL spinning solution) was also added to fabricate

1047298avored

nano1047297bers The raspberry 1047298avor is expected to act as a tastemasking agent hiding the bitter taste of PCM and also as a coloringagent the spinning solution turned slightly pink upon addition of the raspberry

1047298avor Details of the solutions and resultant

1047297bers arepresented in Table 1 The conductivities of the spinning solutionswere measured and found to be approximately the sameregardless of the drug content and the presence or absence of the raspberry

1047298avor (see Table 2)


The mean thicknesses of 3 cm diameter circular sections cutfrom electrospun mats of each formulation lie between

ca 121 mm

and 131 mm (data are given in Table 2) This is entirely appropriate

for

an

oral

fast-dissolving

1047297lm

and

can

be

adjusted

very

easily

byvarying the collection time (ie the volume of solution processed)These values are comparable with those in the literature for

instance Londhe has reported 1047297lms of ca 50 mm (Londhe andUmalkar 2012) while Cilurzo et al have generated

1047297lms of 120ndash131 mm thickness (Cilurzo et al 2010 2011) and systems of 88ndash420 mm were prepared by Ibrahimrsquos team (Sayed et al 2013)


The folding endurance of 3 cm diameter circular sections of each 1047297ber mat was assessed by hand-folding the sections along a1047297xed line and the results are provided in Table 2 The foldingendurance is seen to decease as the drug loading is increasedindicating that the 1047297ber mat becomes more brittle with increasingdrug loading F3 has a folding endurance of only 667 times andhence is very likely to be too brittle for use as an oral

1047297lm Howeverthe other

1047297bers have high folding endurance of gt20 times thusindicating their high potential in this area

34

pH

of

the

1047297ber

solution

Solutions prepared by dissolving a 3 cm diameter circularsection of the 1047297ber mats in 10 mL deionized water were found tohave pH values lying in the range 67ndash72 (see Table 2) Acidic oralkaline pHs may cause damage to the oral mucosa and so the pH

of the dissolved oral fast dissolving 1047297lm should be close to theneutral pH of the mucosa (El-Mahrouk et al 2014) Mucosal pHvalues have been found to vary between 628 (buccal mucosa) and734 (palate) (Aframian et al 2006) The materials fabricated herehence give solutions with pHs close to those observed for the oralmucosa and can be expected not to cause mucosal damage uponadministration

35 Fiber morphology

Scanning electron microscopy (SEM) images of the electrospunproducts are given in Fig 2The SEM data show that the composite1047297bers were cylindrical in shape with smooth surfaces and nosecondary particles visible No bead-on-string morphology can be

observed This indicates that both the PCM and CAF areencapsulated homogeneously in the PVP 1047297ber matrices Thefabricated 1047297bers are oriented in a random manner The mean 1047297berdiameters (Table 3) are F1 443

93 nm F2 750

222 nm F3

1553

435 nm and F4 518

175 nm respectively The

1047297berdiameter thus appears to increase with the drug loading (F1contains PCM 1028CAF 134 (ww) while F3 is PCM 3509CAF456 (ww)) Both F2 and F4 comprise 2187 PCM and 289 CAF(ww) but the latter also incorporates a raspberry

1047298avoring Sincethe F4 1047297bers are somewhat narrower than the F2 material it seemsthat the incorporation of even a small amount of 1047298avoring causes adecrease in

1047297ber diameter The complex nature of the raspberry1047298avor which is not a single chemical entity but rather a mixture of compounds makes it dif 1047297cult to ascertain the precise cause of this

size

variation

The

porosities

of

the

1047297ber

mats

were

calculated

to

liein the range of 818ndash836 being largely invariant with API loadingand the presence or absence of 1047298avor

Table 2

Characterizing data for the spinning solutions and electrospun 1047297bers

Formulation Conductivity of spinning solution (mS) Folding endurancea Thickness (mm) pHb

F0 11 gt30 121

556 677

006

F1 12 gt30 131

305 680

010

F2 12 gt30 127

665 687

006

F3 12 667

15 128

68 697

006

F4 12 2033

26 126

556 717

015

a The number of times a circular section of mat 3 cm in diameter can be folded at the same place without breaking or crackingb The pH of a solution comprising a 3 cm diameter circular section of 1047297ber mat dissolved in 10 mL of distilled water

372 UE Illangakoon et al International Journal of Pharmaceutics 477 (2014) 369ndash 379



Fig 2

SEM

images

and 1047297ber

diameter

distributions

of

the

PCM

and

CAF

loaded

nano1047297bers

(a)

F1

(PCM

1028

CAF

134)

(b)

F2

(PCM

2187

CAF

289)

(c)

F3

(PCM

3509CAF 456) and (d) F4 (PCM 2187 CAF 289 with 1047298avor) The scale bars for the main images are 5 mm in length the white bars in the insets represent 1 mm




The

1047297ber mats were found to be very resilient to cutting andcould be formed into a range of different shapes appropriate for useas oral 1047297lms Photographs of the F4 1047297ber mat cut into differentshapes are shown in Fig 3


X-ray

diffraction

was

undertaken

to

examine

the

physical

stateof the components of the composite nano1047297bers Characteristicre1047298ections (see Fig 4 (a)) of CAF appear at diffraction angles 2u of 1124 2564 and 2625 and for PCM distinct re1047298ections can be

observed at 1718 2266 and 2558 A physical mixture of PVPPCM and CAF in the same ratios as F2 (F5) shows the diffractionfeatures of both PCM and CAF superimposed on a broadbackground from the amorphous PVP polymer The pattern of 1047297bers containing only PVP (F0 Fig 4(b)) was characterized by theabsence of any diffraction peaks with only a broad halo observedthis con1047297rms the PVP to be amorphous after electrospinning In thepatterns of the drug-loaded nano1047297bers the characteristic re1047298ec-tions of PCM or CAF cannot be seen while the characteristic humps

of amorphous materials are observed This suggests that bothactive ingredients were present in amorphous form in the

1047297bers

37 Differential scanning calorimetry

The differential scanning calorimetry (DSC) curves of pure PCMand CAF (see Fig 5(a)) each show a clear melting endothermicpeak The PCM form I melt can be seen at 1694 C For CAF theprincipal feature in the thermogram is the melting of form I of theAPI at 2384 C There is however a small additional endothermicpeak at around 160C attributed to the presence of a small amountof caffeine form II in the material provided (Hubert et al 2011) Thephysical mixture (F5) shows a broad shallow endothermic peakbelow 100C due to the dehydration of PVP followed by a broadpeak believed to correspond to melting of PCM centered at around150C The CAF melting point cannot be observed probablybecause of its low loading in the physical mixtureThe DSC thermograms of the composite nano1047297bers do not show

any melting peaks with F1 F2 and F4 presenting only a broaddehydration endothermic peak ranging from 40 to 110C with apeak at 80ndash83 C (F3 shows this feature and additionally a secondbroad endotherm centered around 150 oC) This suggested thatPCM and CAF were not present as crystalline materials but had

been converted into an amorphous state in the 1047297bers

38

FTIR

spectroscopy

Compatibility between the drug and the polymer is importantfor the formation of nano1047297bers during electrospinning and for thestability of the resultant materials If the drug is not compatiblewith the polymer then solid phase separation will be observedThe interactions between the drug and the polymer can be probedusing IR spectroscopyThe FTIR spectrum of pure PCM is shown in Fig 6(a) The broad

peak between around 3000 and 3700 cm1 is assigned as H-bonded OmdashH and NmdashH stretching vibrations Absorptions at ca

2880 and 2950 cm1 denote CmdashH stretches The peaks at 1644

1560 and 1511 are assigned to the Cfrac14O stretching and NmdashHbending vibrations of the amide group A very sharp peak at835 cm1 is also visible The infrared spectra of CAF (see Fig 6(a))shows an absorbance at 1650 cm1 corresponding to the Cfrac14Ostretch of the amide group There are also peaks at around1435 and 1504 cm1 (Cfrac14C stretching) and between 1330 and1105 cm1 which may be ascribed to the CmdashN amide stretchesSharp bands at 835 807 and 796 cm1 are present in the1047297ngerprint region The spectrum of the pure PVP

1047297bers F0

Table 3

Fiber diameters and mat porosities

Formulation Fiber diameter (nm) Porosity ()

F1

443

93

826

03F2 750 222 836 15F3 1553

435 829

06

F4 518

175 818

10

Fig 4 X-ray diffraction patterns of the electrospun 1047297bers and raw materials (a) PCM CAF and F5 a physical mixture of PVP (7524 ww) PCM (2187) and CAF (289) (b)The 1047297ber formulations F0 (blank PVP 1047297bers) F1 (PCM 1028 CAF 134) F2 (PCM 2187 CAF 289) F3 (PCM 3509 CAF 456) and F4 (PCM 2187 CAF 289 with

raspberry 1047298

avor)

Fig 3 Photographs of the F4 1047297ber mats cut into different shapes




(Fig 6 (b)) shows broad bands at 3650ndash3050 cm1 (H-bonded OmdashHstretches from residual water) and 2840ndash3010 cm1 (CmdashHstretching) as well as peaks at 1643 cm1 (Cfrac14O) and at1290 cm1 (CmdashN stretch) (Borodko et al 2006)The FTIR spectra of the medicated 1047297bers comprise a composite

of

those

from

PVP

and

the

drugs

They

show

two

main

peaks

ataround 1645ndash1650 cm1 and 1290 cm1 due to the Cfrac14O and CmdashNstretch from PVP Peaks can also be seen corresponding to the PCMand CAF for instance at 1550 cm1 (PCM NmdashH bend) 833 cm1

(PCMCAF 1047297ngerprint) and 793 cm1 (CAF 1047297ngerprint) It is hard tounambiguously assign peaks because of the complexity of thespectra but small shifts in peak positions (eg from 1643 in purePVP to 1650 cm1 in the 1047297bers) indicate that there may beintermolecular interactions between the drugs and PVP


Although interactions between the APIs and polymer aresuggested by the IR spectra the complexity of the spectra mean

that

it

is

impossible

to

characterize

these

in

detail

Molecularmodels of PCM CAF PVP and the APIndashpolymer complexes wereconstructed using the Hyperchem software The geometricpreferences for the energetically minimized APIndashpolymer systemsare depicted in Fig 7 The energetic contributions to the overallsteric energy for the drugndashpolymer complexes and the individualAPI molecules and PVP decamer are given in Table 4 Stabilizationof the complexes is indicated by a negative difference (DE )between the total steric energy of the complex and the sum of thetotal steric energies of the individual molecules The DE values forPVPndashPCM and PVPndashCAF and PVPndashPCMndashCAF are

19126 13105

and

30451 kcalmol respectively These negative values clearlycon1047297rm that there are interactions between the PVP polymer andthe APIs The DE value is more negative for PCM than CAFindicating stronger interactions with the former

310 Drug loading

The percentage drug loadings in the 1047297bers were determined byHPLC A bespoke method was devised to permit the observation of both APIs in the same experiment (see Section 24) The resultantdata are given in Fig 8 Solutions of the PCM and CAF were 1047297rst runseparately and PCM observed at an elution time of 487 min andCAF at 792 min Similar results were observed for the mixture of PCM and CAF where elution was noted at 478 min for PCM and at762 min for CAF The dissolved

1047297ber formulations show peaks atthe same retention times as the pure drug materials (see Fig 8)con1047297rming that neither API was degraded during the electro-spinning process Following construction of a calibration curve thedrug loading was determined for the

1047297bers the results are

presented

in

Table

5 It

can

be

seen

that

the

formulations

generallyshow very high (gt90) loading of both drugs with the exception of F3 where the PCM loading is slightly below 90

311

Wetting

assays

and

dissolution

studies

The PCMCAF-loaded 1047297ber mats were found to be wetted and todisintegrate very rapidly insimulated saliva The process wasrecorded using a standard video camera for all formulations All the1047297ber mats appeared to disintegrate within lt3 s when recordedusing the standard camera but it proved impossible to discern the

Fig

6

FTIR

spectra

of

(a)

PCM

CAF

and

the

physical

mixture

F5

(b)

the 1047297

ber

formulations

F0

F1

F2

F3

and

F4

Fig 5

DSC

data

for

(a)

PCM

CAF

and

the

PVPAPI

physical

mixture

F5

(b)

the 1047297ber

formulations

F0

F1

F2

F3

and

F4

To

permit

ease

of

comparison

the

data

in

part

(a)

havebeen normalized




disintegration time more precisely Further observations were thuscarried out using a high-speed camera for the F2 and F4

1047297ber matsBoth were seen to disintegrate within around 320 ms This isclearly visible from the photographs given in Fig 9 (depicting F4)These disintegration times are exceptionally rapid and eminentlysuitable for the preparation of oral fast-dissolving

1047297lms otherresearchers preparing such systems report disintegration times of 10ndash20s (Cilurzo et al 2010 2011 Londhe and Umalkar 2012)Dissolution studies (see Fig 10) demonstrated that with the

physical mixture (F5) 48

56 of the incorporated PCM and

87

25 of the CAF were released within 6 min Within 30 s 1047297bers

F1

F4

and

F5

respectively

released

38

12

66

70

and45

18 of their PCM loading and 52

12 72

11 and

37

57 of the incorporated CAF The poor folding endurance

of the F3 1047297bers indicated that they were not suitable for oral 1047297lmsand thus dissolution studies were not performedThe rapid dissolution observed with the PCMCAF loaded

1047297bermats can be attributed to the amorphous physical state of the APIsin the formulations the high surface area and high porosity of theof the drug loaded 1047297bers and the exceptional hydrophilicity of PVPAPI release from a formulation occurs at its interface with thebuffer solution the high surface area to volume ratio of the 1047297bermats ensures that this contact area is very high thus acceleratingthe release The amorphous nature of the API removes the need toovercome any crystalline lattice enthalpy again facilitating

dissolution

Finally

the

hygroscopicity

of

PVP

also

encourages

the mat to disintegrate dissolve and free its drug loading intosolution Attempts were made to

1047297t various kinetic models to theexperimental data but these were unsuccessful owing to the veryrapid nature of the release processes

Fig 7 Optimized geometric arrangements of a PVP decamer with (a) PMC (b) CAF and (c) PCM and CAF The PVP decamer can be seen at the top of the images and the drugmolecule(s) at the bottom

Table 4

The energetics of the optimized geometries in the PVP-drug molecular models The electrostatic contribution was zero in all cases

Species Minimized energy contributions (kcal mol1)

Bond stretching Bond angle Torsional van der Waals Hydrogen bonding Total

PCM

0632

7718

1301

4669

3679

105 14320CAF 0480 7932 00456 3299 0 11757PVP 4337 82689 46017

12788 0 120255PVPndashPCM

4434

83396

49923

21315

0989

115449PVPndashCAF 4697 89415 46315

21520 0 118907PVPndashPCMndashCAF 4903 92487 48685

29219

0975 115881

Fig 8 HPLC chromatograms of the nano1047297ber formulations STD represents a PCMCAF calibration solution The 1047297ber compositions are F1 PCM 1028 CAF 134 F2PCM 2187 CAF 289 F3 PCM 3509 CAF 456 F4 PCM 2187 CAF 289

with

raspberry 1047298

avor




For all the formulations studied CAF release is seen to be morerapid than PCM dissolution This is consistent with its highersolubility under the dissolution conditions (the respectivesolubilities for CAF and PCM are ca 216 mgmL vs 140 mgmL in water at 25 C (httpwwwdrugbankca)) It is also consistentwith the molecular modeling results (Section 39) which show

stronger interactions between PCM and PVP than between thepolymer and CAF The difference in release rate between PCM andCAF is very much less for the 1047297ber formulations than for thephysical mixture presumably as a result of the amorphous natureof the APIs in the former ameliorating any differences in latticeenthalpy Similar results were recorded by Khan and Craig whenthey performed dissolution studies on solid dispersions of PCMand CAF (Khan and Craig 2003)Overall the systems prepared in this work have great potential

as oral fast dissolving

1047297lms Both PCM and CAF can be successfullyloaded into the

1047297bers in the amorphous physical form and veryrapid disintegration (lt05 s) and release of drug (lt150 s) areobserved The pH of the 1047297ber solution is close to neutral and henceno mucosal irritation is to be expected A

1047298avoring can beincorporated into the

1047297bers to ameliorate issues of bitterness Suchformulations could thus have great utility as pediatric medicines

Table 5

The drug loading and content of uniformity for the composite 1047297bers Loadings areexpressed as a percentage of the theoretical loading

Formulation PCM loading CAF loading

F1 9773 101 9891 415F2 9384

021 9638

159

F3 8820

482 9335

776

F4 9829 514 9509 397

Fig 9 High speed camera images of the disintegration of F4 Images were taken at (a) 0 ms (b) 133 ms(c) 200 ms(d) 243 ms (e) 303 msand (f) 408 msafter the 1047297bers were

added

to

simulated

saliva




The British National Formulary for Children (BNF-C) suggests thatan appropriate dose of paracetamol for the treatment of pain achild of 8 years old is between 240 and 375 mg four times a day(BNF-C 2014-15) The loading in F4 is 2187 ww thus a mass of formulation of between 1100 and 1715 mg would be needed foreach dose For a child of six months to two years in age therequired dose is 120 mg demanding a 1047297ber mass of ca 550 mg Thismass of formulation could easily be prepared and applied bymouth particularly at the lower end of the dosage regimen Inaddition further optimization could increase the drug loading toreduce the formulation mass required

4 Conclusions

In this study we successfully produced fast-dissolving drugdelivery systems for the simultaneous release of paracetamol(PCM) and caffeine (CAF) This was achieved by processing theminto electrospun 1047297bers using polyvinylpyrrolidone (PVP) as the1047297lament forming agent Scanning electron microscopy showedthat the composite nano1047297bers had smooth surfaces and average1047297ber diameters between 400ndash1600 nm IR spectroscopy resultscombined with molecular modeling demonstrated that there wereintermolecular interactions between paracetamol caffeine andPVP X-ray diffraction and differential scanning calorimetry studiesindicated that both the drugs were fully converted into theamorphous form in the 1047297bers Both APIs were observed to remainintact after spinning with drug loadings close to 100 of thetheoretical value In wetting tests the drug loaded 1047297ber mats

disintegrated within 05 s and dissolution studies revealed that allthe embedded drug was freed into solution in less than 150 s asigni1047297cant improvement over the pure APIs and the physicalmixture A 1047298avoring agent can easily be incorporated into the 1047297bersto overcome problems with bitterness These

1047298avored

1047297bers can beused as potential drug delivery systems especially for the pediatricpopulation

Author

contributions

U Eranka Illangakoon prepared and characterized 1047297bersundertook

functional

performance

assays

and

analyzed

theexperimental data Hardyal Gill developed the HPLC protocoland analyzed the resultant data Gemma C Shearman performedmolecular modeling simulations Maryam Parzhizkar and SuntharMahalingam recorded the high-speed camera videos Nicholas PChatterton and Gareth R Williams provided strategic guidance tothe project and support to data analysis All the authorscontributed to the writing of the manuscript

Acknowledgements

The authors gratefully thank David McCarthy (UCL) for SEMimages and London Metropolitan University for provision of a Vice-Chancellorrsquos PhD studentship to UEI The EPSRC is thanked forprovision of the high-speed camera under the EPSRC-UCL Knowledge Exchange Programme

Fig 10 In vitro dissolution pro1047297les Data are given as mean

SD from three independent experiments (a) PCM and (b) CAF release from formulations F1 F4 and F5 are shown

together with the release of both APIs from (c) F1 and (d) F4











17 cm2)



35



23 Characterization



SD



number

of

times

a

1047297lm

can

be

folded

without

breaking

or




SD

234 Morphology


Prior

to

examination

the

samples

were

gold

sputter-coated

under





236

Differential

scanning

calorimetry






24

HPLC

analysis




25 Wetting assays



26

Dissolution

studies



37

2

C

throughout

the

experiment

Table 1



F0 F1 F2 F3 F4 F5


CAF (wv) 0 013 033 065 033

ndash


ndash

ndash

ndash

ndash 020


PCM (ww) 0 1028 2187 3509 2187 2187 CAF (ww) 0 134 289 456 289 289

PVP

(ww)

100

8839

7524

6035

7524

7524









3

Results

and

discussion

31 Electrospinning


1047298avored







ca 121 mm


for

an

oral

fast-dissolving

1047297lm

and

can

be

adjusted

very

easily








34

pH

of

the

1047297ber

solution



35 Fiber morphology



93 nm F2 750

222 nm F3

1553

435 nm and F4 518





size

variation

The

porosities

of

the

1047297ber

mats

were

calculated

to


Table 2



F0 11 gt30 121

556 677

006

F1 12 gt30 131

305 680

010

F2 12 gt30 127

665 687

006

F3 12 667

15 128

68 697

006

F4 12 2033

26 126

556 717

015





Fig 2

SEM

images

and 1047297ber

diameter

distributions

of

the

PCM

and

CAF

loaded

nano1047297bers

(a)

F1

(PCM

1028

CAF

134)

(b)

F2

(PCM

2187

CAF

289)

(c)

F3

(PCM





The



X-ray

diffraction

was

undertaken

to

examine

the

physical




1047297bers





38

FTIR

spectroscopy





1047297bers F0

Table 3



F1

443

93

826

03F2 750 222 836 15F3 1553

435 829

06

F4 518

175 818

10


raspberry 1047298

avor)






of

those

from

PVP

and

the

drugs

They

show

two

main

peaks





that

it

is

impossible

to

characterize

these

in

detail


19126 13105

and


310 Drug loading




presented

in

Table

5 It

can

be

seen

that

the

formulations


311

Wetting

assays

and

dissolution

studies


Fig

6

FTIR

spectra

of

(a)

PCM

CAF

and

the

physical

mixture

F5

(b)

the 1047297

ber

formulations

F0

F1

F2

F3

and

F4

Fig 5

DSC

data

for

(a)

PCM

CAF

and

the

PVPAPI

physical

mixture

F5

(b)

the 1047297ber

formulations

F0

F1

F2

F3

and

F4

To

permit

ease

of

comparison

the

data

in

part

(a)

havebeen normalized









87


F1

F4

and

F5

respectively

released

38

12

66

70

and45


12 72

11 and

37




dissolution

Finally

the

hygroscopicity

of

PVP

also

encourages




Table 4




PCM

0632

7718

1301

4669

3679

105 14320CAF 0480 7932 00456 3299 0 11757PVP 4337 82689 46017


4434

83396

49923

21315

0989

115449PVPndashCAF 4697 89415 46315


29219

0975 115881


with

raspberry 1047298

avor











Table 5



F1 9773 101 9891 415F2 9384

021 9638

159

F3 8820

482 9335

776

F4 9829 514 9509 397


added

to

simulated

saliva





4 Conclusions



1047298avored


Author

contributions


functional

performance

assays

and

analyzed


Acknowledgements















3

Results

and

discussion

31 Electrospinning


1047298avored







ca 121 mm


for

an

oral

fast-dissolving

1047297lm

and

can

be

adjusted

very

easily








34

pH

of

the

1047297ber

solution



35 Fiber morphology



93 nm F2 750

222 nm F3

1553

435 nm and F4 518





size

variation

The

porosities

of

the

1047297ber

mats

were

calculated

to


Table 2



F0 11 gt30 121

556 677

006

F1 12 gt30 131

305 680

010

F2 12 gt30 127

665 687

006

F3 12 667

15 128

68 697

006

F4 12 2033

26 126

556 717

015





Fig 2

SEM

images

and 1047297ber

diameter

distributions

of

the

PCM

and

CAF

loaded

nano1047297bers

(a)

F1

(PCM

1028

CAF

134)

(b)

F2

(PCM

2187

CAF

289)

(c)

F3

(PCM





The



X-ray

diffraction

was

undertaken

to

examine

the

physical




1047297bers





38

FTIR

spectroscopy





1047297bers F0

Table 3



F1

443

93

826

03F2 750 222 836 15F3 1553

435 829

06

F4 518

175 818

10


raspberry 1047298

avor)






of

those

from

PVP

and

the

drugs

They

show

two

main

peaks





that

it

is

impossible

to

characterize

these

in

detail


19126 13105

and


310 Drug loading




presented

in

Table

5 It

can

be

seen

that

the

formulations


311

Wetting

assays

and

dissolution

studies


Fig

6

FTIR

spectra

of

(a)

PCM

CAF

and

the

physical

mixture

F5

(b)

the 1047297

ber

formulations

F0

F1

F2

F3

and

F4

Fig 5

DSC

data

for

(a)

PCM

CAF

and

the

PVPAPI

physical

mixture

F5

(b)

the 1047297ber

formulations

F0

F1

F2

F3

and

F4

To

permit

ease

of

comparison

the

data

in

part

(a)

havebeen normalized









87


F1

F4

and

F5

respectively

released

38

12

66

70

and45


12 72

11 and

37




dissolution

Finally

the

hygroscopicity

of

PVP

also

encourages




Table 4




PCM

0632

7718

1301

4669

3679

105 14320CAF 0480 7932 00456 3299 0 11757PVP 4337 82689 46017


4434

83396

49923

21315

0989

115449PVPndashCAF 4697 89415 46315


29219

0975 115881


with

raspberry 1047298

avor











Table 5



F1 9773 101 9891 415F2 9384

021 9638

159

F3 8820

482 9335

776

F4 9829 514 9509 397


added

to

simulated

saliva





4 Conclusions



1047298avored


Author

contributions


functional

performance

assays

and

analyzed


Acknowledgements










Fig 2

SEM

images

and 1047297ber

diameter

distributions

of

the

PCM

and

CAF

loaded

nano1047297bers

(a)

F1

(PCM

1028

CAF

134)

(b)

F2

(PCM

2187

CAF

289)

(c)

F3

(PCM





The



X-ray

diffraction

was

undertaken

to

examine

the

physical




1047297bers





38

FTIR

spectroscopy





1047297bers F0

Table 3



F1

443

93

826

03F2 750 222 836 15F3 1553

435 829

06

F4 518

175 818

10


raspberry 1047298

avor)






of

those

from

PVP

and

the

drugs

They

show

two

main

peaks





that

it

is

impossible

to

characterize

these

in

detail


19126 13105

and


310 Drug loading




presented

in

Table

5 It

can

be

seen

that

the

formulations


311

Wetting

assays

and

dissolution

studies


Fig

6

FTIR

spectra

of

(a)

PCM

CAF

and

the

physical

mixture

F5

(b)

the 1047297

ber

formulations

F0

F1

F2

F3

and

F4

Fig 5

DSC

data

for

(a)

PCM

CAF

and

the

PVPAPI

physical

mixture

F5

(b)

the 1047297ber

formulations

F0

F1

F2

F3

and

F4

To

permit

ease

of

comparison

the

data

in

part

(a)

havebeen normalized









87


F1

F4

and

F5

respectively

released

38

12

66

70

and45


12 72

11 and

37




dissolution

Finally

the

hygroscopicity

of

PVP

also

encourages




Table 4




PCM

0632

7718

1301

4669

3679

105 14320CAF 0480 7932 00456 3299 0 11757PVP 4337 82689 46017


4434

83396

49923

21315

0989

115449PVPndashCAF 4697 89415 46315


29219

0975 115881


with

raspberry 1047298

avor











Table 5



F1 9773 101 9891 415F2 9384

021 9638

159

F3 8820

482 9335

776

F4 9829 514 9509 397


added

to

simulated

saliva





4 Conclusions



1047298avored


Author

contributions


functional

performance

assays

and

analyzed


Acknowledgements










The



X-ray

diffraction

was

undertaken

to

examine

the

physical




1047297bers





38

FTIR

spectroscopy





1047297bers F0

Table 3



F1

443

93

826

03F2 750 222 836 15F3 1553

435 829

06

F4 518

175 818

10


raspberry 1047298

avor)






of

those

from

PVP

and

the

drugs

They

show

two

main

peaks





that

it

is

impossible

to

characterize

these

in

detail


19126 13105

and


310 Drug loading




presented

in

Table

5 It

can

be

seen

that

the

formulations


311

Wetting

assays

and

dissolution

studies


Fig

6

FTIR

spectra

of

(a)

PCM

CAF

and

the

physical

mixture

F5

(b)

the 1047297

ber

formulations

F0

F1

F2

F3

and

F4

Fig 5

DSC

data

for

(a)

PCM

CAF

and

the

PVPAPI

physical

mixture

F5

(b)

the 1047297ber

formulations

F0

F1

F2

F3

and

F4

To

permit

ease

of

comparison

the

data

in

part

(a)

havebeen normalized









87


F1

F4

and

F5

respectively

released

38

12

66

70

and45


12 72

11 and

37




dissolution

Finally

the

hygroscopicity

of

PVP

also

encourages




Table 4




PCM

0632

7718

1301

4669

3679

105 14320CAF 0480 7932 00456 3299 0 11757PVP 4337 82689 46017


4434

83396

49923

21315

0989

115449PVPndashCAF 4697 89415 46315


29219

0975 115881


with

raspberry 1047298

avor











Table 5



F1 9773 101 9891 415F2 9384

021 9638

159

F3 8820

482 9335

776

F4 9829 514 9509 397


added

to

simulated

saliva





4 Conclusions



1047298avored


Author

contributions


functional

performance

assays

and

analyzed


Acknowledgements











of

those

from

PVP

and

the

drugs

They

show

two

main

peaks





that

it

is

impossible

to

characterize

these

in

detail


19126 13105

and


310 Drug loading




presented

in

Table

5 It

can

be

seen

that

the

formulations


311

Wetting

assays

and

dissolution

studies


Fig

6

FTIR

spectra

of

(a)

PCM

CAF

and

the

physical

mixture

F5

(b)

the 1047297

ber

formulations

F0

F1

F2

F3

and

F4

Fig 5

DSC

data

for

(a)

PCM

CAF

and

the

PVPAPI

physical

mixture

F5

(b)

the 1047297ber

formulations

F0

F1

F2

F3

and

F4

To

permit

ease

of

comparison

the

data

in

part

(a)

havebeen normalized









87


F1

F4

and

F5

respectively

released

38

12

66

70

and45


12 72

11 and

37




dissolution

Finally

the

hygroscopicity

of

PVP

also

encourages




Table 4




PCM

0632

7718

1301

4669

3679

105 14320CAF 0480 7932 00456 3299 0 11757PVP 4337 82689 46017


4434

83396

49923

21315

0989

115449PVPndashCAF 4697 89415 46315


29219

0975 115881


with

raspberry 1047298

avor











Table 5



F1 9773 101 9891 415F2 9384

021 9638

159

F3 8820

482 9335

776

F4 9829 514 9509 397


added

to

simulated

saliva





4 Conclusions



1047298avored


Author

contributions


functional

performance

assays

and

analyzed


Acknowledgements















87


F1

F4

and

F5

respectively

released

38

12

66

70

and45


12 72

11 and

37




dissolution

Finally

the

hygroscopicity

of

PVP

also

encourages




Table 4




PCM

0632

7718

1301

4669

3679

105 14320CAF 0480 7932 00456 3299 0 11757PVP 4337 82689 46017


4434

83396

49923

21315

0989

115449PVPndashCAF 4697 89415 46315


29219

0975 115881


with

raspberry 1047298

avor











Table 5



F1 9773 101 9891 415F2 9384

021 9638

159

F3 8820

482 9335

776

F4 9829 514 9509 397


added

to

simulated

saliva





4 Conclusions



1047298avored


Author

contributions


functional

performance

assays

and

analyzed


Acknowledgements

















Table 5



F1 9773 101 9891 415F2 9384

021 9638

159

F3 8820

482 9335

776

F4 9829 514 9509 397


added

to

simulated

saliva





4 Conclusions



1047298avored


Author

contributions


functional

performance

assays

and

analyzed


Acknowledgements











4 Conclusions



1047298avored


Author

contributions


functional

performance

assays

and

analyzed


Acknowledgements








Fast Dissolving Paracetamol Caffeine Nanofibers Prepared by Electrospinning

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Transcript of Fast Dissolving Paracetamol Caffeine Nanofibers Prepared by Electrospinning