RESPONSI

PRAKTIKUM TEKNOLOGI SEDIAAN STERIL

REVIEW JURNAL
“Electroblowing and electrospinning of fibrous diclofenac sodium- cyclodextrin complex-
based reconstitution injection”

Oleh:

KETUT MERY VIRGOYANI

18021107
A3D

PROGRAM STUDI FARMASI KLINIS

UNIVERSITAS BALI INTERNASIONAL
DENPASAR
2021
Judul Electroblowing and electrospinning of fibrous diclofenac sodium-
cyclodextrin complex-based reconstitution injection

Jurnal Journal of Drug Delivery Science and Technology

Volume & Halaman Volume 26 & Halaman 26-34

Tahun 2015
Penulis
1. Attila Balogh
2. Timea Horvathova
3. Zoltan Fulo €P
4. Thorsteinn Loftsson
5. Anna Helga Harasztos
6. Gyo €rgy Marosi
7. Zsombor K. Nagy
Riviewer Ketut Mery Virgoyani (18021107)
Tanggal 19 Juli 2021

Tujuan Penelitian Tujuan dari penelitian electroblowing dan freeze-drying ini adalah
untuk menyiapkan kompleks padat berbasis obat berbasis
siklodekstrin yang cepat larut. Injeksi rekonstitusi diuji untuk
mengatasi ketidakstabilan produk berbasis cairan.

Metode Penelitian Menggabungkan luas permukaan besar fitikar brous dengan

kemampuan siklodekstrin untuk menyiapkan injeksi rekonstitusi diuji
untuk mengatasi ketidakstabilan produk berbasis cairan. Natrium
diklofenak digunakan sebagai obat dengan kelarutan air yang terbatas
dan 2-hidroksipropil-β-siklodekstrin (HPβCD) sebagai pembawa dan
pelarut. Komposisi kompleks yang diterapkan ditentukan berdasarkan
pengukuran kelarutan fase. Untuk mengatasi gangguan yang sering
tidak dapat dihindari darifipembentukan ber selama electrospinning
dari HPβCD Solusi, hembusan udara berkecepatan tinggi digabungkan
dengan gaya elektrostatik (electroblowing) untuk menarik HPβCD
bebas polimer fibers terus, apalagi pada laju aliran yang meningkat.
Menurut gambar mikroskop elektron pemindaian, difraksi sinar-X,
 kalorimetri pemindaian diferensial, tidak ada jejak kristalinitas obat
yang terdeteksi difibers sebagai lawan dari produk beku-kering. Tes
rekonstitusi darifimenunjukkan pembubaran cepat memperoleh solusi
yang jelas setara dengan injeksi bolus berbasis cairan yang dipasarkan.

Alat dan Bahan/ 1. Alat yang digunakan yaitu, botol kaca tertutup, deteksi uv,
Formula pengaduk magnet, pemintal elektrostatik, pelat aluminium,
aluminium foil, pompa jarum suntik, penangas ,kompartemen
kondensor, mikroskop elektron, difraktometer sinar-X
PANanalytical X'pert Pro MDP,peralatan setaram, brook-
fiviskometer digital lama model DV-1th dilengkapi dengan
brookfiadaptor UL lama, wadah kedap udara, kamera digital
2. Bahan yang digunakan yaitu, Natrium diklofenak (DCF,
Mw1⁄4318 Da), 2-hidroksipropil-β-siklodekstrin (HPβCD, derajat
substitusi: 0,65, Mw1⁄41400 Da). Metanol, etanol absolut,
dimetilformamida, natrium dihidrogen fosfat dihidrat dan asam
fosfat (85%). Semua larutan dan fase gerak untuk pengukuran
HPLC disiapkan dengan air Milli-Q (Millipore, Billerica, MA,
USA).

Definisi Operasional 1. Siklodekstrin (CD) adalah oligosakarida yang larut dalam air dan
siklik yang terdiri dari 6-8 α-D-unit glukopiranosa. Karakteristik
yang paling penting dari CD adalah bahwa mereka memiliki
rongga pusat yang relatif lipofilik yang dengan mudah membentuk
kompleks inklusi dengan senyawa atau bagian lipofilik. Kompleks
yang terbentuk tetap sangat larut dalam air karena permukaan luar
hidrofilik dari molekul CD hosting.
2. Natrium diklofenak merupakan salah satu obat golongan NSAID
yang paling sering digunakan, dimana NSAID ini sendiri
merupakan salah satu golongan obat yang paling umum digunakan
di seluruh dunia. Natrium diklofenak memiliki efek analgesik,
 antipiretik, dan antiinflamasi dengan potensi tinggi dan toleransi
yang baik. Namun, dibalik keunggulan tersebut, obat ini juga
memiliki potensi efek samping, salah satunya terhadap ginjal.
Karena pengaruhnya terhadap fungsi ginjal yang diukur dengan
kadar serum kreatinin inilah yang mendasari penelitian mengenai
pengaruh natrium diklofenak dosis lazim terhadap kadar serum
kreatinin.
3. Injeksi rekonstitusi adalah sediaan parenteral berbentuk serbuk
yang dilarutkan terlebih dahulu kedalam pelarut yang sesuai ketika
akan digunakan. Injeksi rekonstitusi cocok untuk zat aktif mudah
terhidrolisis. Injeksi rekonstitusi ada dua jenis yaitu injeksi
rekonsrirusi larutan sejati dan injeksi rekonstitusi suspensi.
(Voight, R. 1995)
4. Electrospinning merupakan suatu proses pembuatan serat nano
yang efisien dengan memanfaatkan pengaruh medan listrik dalam
menghasilkan pancaran (jet) larutan atau lelehan polimer
bermuatan listrik. Serat nano polimer terbentuk karena pada proses
tersebut terjadi penguapan pelarut secara simultan
5. Teknik meningkatkan kelarutan obat sangat penting karena ada
semakin banyak bahan aktif farmasi dengan kelarutan air yang
buruk
6. Fase gerak adalah medium angkut dan terdiri atas satu atau
beberapa pelarut. Fase gerak bergerak di dalam fase diam yaitu
suatu lapisan berpori, karena ada gaya kapiler.
7. Rekonstitusi adalah proses penambahan pengencer pada suatu
konsentrat cairan atau serbuk dengan tujuan untuk menghasilkan
konsentrasi tertentu. Rekonstitusi yang baik dapat dicapai jika
sediaan mudah dan cepat terdispersi dengan pembawa.
Cara Kerja / Formulasi 1. Uji kelarutan fase
Larutan berair jenuh natrium diklofenak (DCF) disiapkan dengan
adanya 0-50% (w/v) (0-360 mM) HPβCD. Kelarutan DCF
 ditentukan dengan metode pemanasan yang dijelaskan sebelumnya
di mana jumlah senyawa tamu yang berlebihan ditambahkan ke
HPβCD Solusi dan suspensi yang dihasilkan disonikasi pada 60o C
selama 60 menit dalam botol kaca tertutup. Campuran kemudian
dibiarkan untuk menyeimbangkan pada suhu kamar (22± 1o C)
selama 7 hari dengan pengadukan konstan pada 250 rpm
(pengocok KS 15 A,). Nsfi disaring (0,45 μm) dan sampel yang
diencerkan dianalisis dengan RP-HPLC (Agilent 1100 Series LC
System) untuk menentukan konsentrasi DCF. Elusi isokratik dari
campuran 80% metanol dan 20% larutan asam fosfat (pH1⁄42.5)
dilakukan pada a fltingkat berapa 1,5mL/mnt pada Fenomena Luna
C18 150 4.6mm, 5 Mm, panjang gelombang deteksi UV diatur ke
315 nm.
2. Elektrospining (ES)
2-hidroksipropil-β-siklodekstrin ditambahkan ke dalam etanol
(abs.) dan diaduk dengan pengaduk magnet (600 rpm) pada suhu
kamar sampai benar- benar larut. API dilarutkan dalam HPβCD
Solusi (pengaduk magnetik, 600 rpm), yang dimasukkan ke dalam
pemintal elektrostatik. Pemintal elektrostatik yang digunakan
untuk percobaan dilengkapi dengan suplai DC tegangan tinggi NT-
35. Pelat aluminium yang dilapisi dengan aluminium foil
digunakan sebagai pengumpul. Jarak pemintal dan kolektor adalah
15 cm dan percobaan dilakukan pada suhu kamar. Kecepatan
pemberian dosis adalah 4 mL/jam.
3. Electroblowing (EB)
DCF-HPβCD etanol Solusi disiapkan dengan cara yang sama dan
electroblown menggunakan peralatan makan yang sama (pompa
jarum suntik SEP-10S Plus) dan sumber tegangan tinggi seperti
selama electrospinning. Tabung tengah pemintal adalah jarum G20
stainless steel tumpul, gas tiup (udara) keluar melalui nosel luar
(1,5 mm ID). Kecepatan pemberian dosis adalah 20 mL/jam.
4. Pengeringan beku (FD)
Sampel beku-kering yang digunakan untuk percobaan lebih lanjut
dibuat dari larutan berair yang mengandung 37,5 mg/mL DCF dan
337 mg/mL HPβCD. Solusi (1 mL dalam botol kaca) dengan cepat
dibekukan menggunakan penangas aseton es kering selama 10
menit dan kemudian ditempatkan ke dalam kompartemen
kondensor pengering beku pada 52 C selama 24 jam.
5. Pemindaian mikroskop elektron (SEM)
Morfologi sampel diselidiki oleh mikroskop elektron pemindaian
tipe JEOL 6380Lva. Setiap spesimen adalah direkatkan dengan
pita perekat karbon dua sisi konduktif dan dilapisi sputter dengan
emas sebelum pemeriksaan. Tegangan percepatan dan jarak kerja
yang diterapkan masing- masing adalah 15 kV dan 10 mm.
6. Difraksi sinar-X (XRD)
Pola difraksi sinar-X serbuk direkam oleh difraktometer sinar-X
PAN-analytical X'pert Pro MDP menggunakan Cu-Kα radiasi
(1,542 Ȧ) dan Ni fimenyaring Tegangan yang diberikan adalah 40
kV sedangkan arusnya adalah 30 mA. Bahan baku yang tidak
diolah dan kompleks siklodekstrin yang terbentuk dianalisis untuk
sudut 2θ antara 4o dan 42o.
7. Kalorimetri pemindaian diferensial (DSC)
Pengukuran kalorimetri pemindaian diferensial dilakukan
menggunakan peralatan Setaram DSC 92 (berat sampel: ~10-15
mg, panci terbuka, nitrogen fladuh). Program suhu terdiri dari
periode isotermal, yang berlangsung selama 1 menit pada suhu
kamar dengan pemanasan linier berikutnya dari 25o C ke 325o C
pada tingkat 10o C / menit.
8. Pengukuran viskositas
Sebagai parameter obat berbasis cairan injeksi, viskositas larutan
ditentukan pada 25o C di Brook-fiviskometer digital lama Model
DV-1 dilengkapi dengan Brookfiadaptor UL lama.
 9. Studi kemurnian
Stabilitas kimia DCF selama proses formulasi dan penyimpanan
ditentukan melalui analisis sampel menggunakan RP-HPLC.
Sampel untuk uji penyimpanan ditempatkan ke dalam wadah
kedap udara dan terlindung dari cahaya pada suhu kamar (22± 1 o
C). Untuk pengukuran HPLC pengotor, elusi isokratik dari 66%
metanol dan 34% larutan yang mengandung 0,8 g/L natrium
dihidrogen fosfat yang disesuaikan dengan pH = 2.5 dengan asam
fosfat dilakukan pada a fladuh laju 1,0 mL/menit dan 25o C.
Panjang gelombang deteksi UV diatur ke 254 nm. API
murni,fisampel brous dan beku-kering dilarutkan dalam fase gerak
mendapatkan larutan DCF 1 mg/mL, 20 μl larutan stok ini
disuntikkan ke kolom (Kolom Phenomenex Luna C18 (5 MM; 150
4,6 mm)). Uji kromatografi dilakukan dalam rangkap tiga.
10. Tes disolusi
Uji disolusi volume kecil (rekonstitusi) dilakukan dengan
menimbang sampel tanpa menggiling setara dengan 37,5 mg DCF
ke dalam botol kaca dan menghitung jumlah purifiair ed
ditambahkan untuk mendapatkan filarutan akhir konsentrasi DCF
38,5 mg/mL pada suhu kamar (22 ± 1o C). Untuk mengikuti
pembubaran, gambar diambil pada interval waktu yang telah
ditentukan menggunakan kamera digital yang dikombinasikan
dengan polarizer melingkar untuk menekan silau.
Hasil Penelitian 1. Pembentukan DCF-HPβCD fidengan electrospinning (ES) dan
electroblowing (EB)
 Jumlah HPβCD terlarut dalam larutan etanol secara bertahap
meningkat sejak konsentrasi fiber agen pembentuk dianggap
sebagai parameter teknologi paling kritis selama ES. Konsentrasi
optimal yang ditentukan untuk percobaan selanjutnya adalah 4,5
g HPβCD dilarutkan dalam 10 mL pelarut murni.
Memperkenalkan DCF ke sistem ES diskrit, berbentuk pita bebas
manikfibers dapat diperoleh dengan diameter mulai dari 300 nm
hingga 1-2 μm (Gambar 2.A). Berbeda dengan sampel
electrospun, electroblownfiber sangat berartifilebih pendek,
apalagi, struktur bead-onstring dan partikel yang lebih besar juga
dapat diamati (Gambar 2.B). Selain gaya tarik dari udara yang
bertiup, Taylorcones metastabil juga dapat terbentuk yang
mengarah pada pembentukan bahan electrospun. Selanjutnya,
tetesan yang disemprotkan juga bisa memanjang dan bentuk
fibers ketika listrikfied. Sebagai metode referensi, FD digunakan
untuk menyiapkan DCF-HPβCD padat kompleks dari larutan
berair. Struktur berpori berkualitas tinggi diperoleh: jaringan pori-
pori (1-5 μm) dengan ketebalan dinding submikronik dapat
diamati (Gambar 2.C).

2. Studi fase-kelarutan DCF-HPBSistem air CD

Seperti yang terlihat di Gambar 3, kelarutan DCF meningkat
dengan penambahan HPβCD ke media air. Kemiringanfi Garis
regresi linier tted mendekati satu di HPβCD Konsentrasi hingga
20% (b/v) (~140 mM), yang menunjukkan bahwa rasio
stoikiometri pada DCF-HPβCD yang terbentuk Kompleks juga
merupakan kesatuan. Berdasarkan hasil ini, untuk memastikan
stabilitas fisik yang sesuai untuk DCF dalam fase padat, jumlah
HPβCD yang berlebih harus digunakan di atas rasio stoikiometri
tamu-tuan rumah 1:1. Ketika 375 mg komposisi yang diusulkan
dilarutkan mendapatkan 1 mL larutan 37,5 mg/mL DCF, ~240
 mM HPβCD yang ada akan memastikan untuk melarutkan jumlah
DCF total ~80 mg/mL berdasarkan pro kelarutan fasefisaya
(Gambar 3).

3. Kalorimetri pemindaian diferensial (DSC)

Karakterisasi DCF-HPβCD fibers dan produk beku-kering
dilakukan dengan menggunakan kalorimetri pemindaian
diferensial untuk menyelidiki keadaan fisik DCF (Gambar 4).
Termogram DCF-HPβCD ES dan EB fipengukuran langsung
setelah produksi tidak menunjukkan puncak leleh endotermik dari
DCF kristal yang diharapkan pada sekitar 290o C. Setelah
penyimpanan 6 bulan, perilaku termal sampel yang disiapkan oleh
ES, EB dan FD praktis tidak berubah (Gambar 4). Termogram
yang direkam serupa dengan termogram yang dikeringkan- beku
dari 240 mM (337 mg/
ml, lihat Tabel 1) HPβCD Solusi dan digambarkan dalam Gambar
4. Rekristalisasi DCF mungkin terjadi selama langkah pembekuan
sebelum menempatkan vial ke dalam pengering beku.
4. Difraksi sinar-X (XRD)
Metode konvensional lain untuk menyelidiki kristalinitas dalam
formulasi padat adalah difraksi sinar-X yang hasilnya ditunjukkan
pada Gambar 5. Difraktogram HPβCD dan yang baru disiapkan
serta DCF-HPβCD yang berumur 6 bulan Kompleks yang dibuat
oleh ES, EB dan FD secara praktis serupa, tidak adanya puncak
difraksi yang khas (termasuk sudut paling intens pada 2θ = 6.7o ,
8.6o , 15.2o ) menunjukkan kompleksasi lengkap DCF. Karena
penguapan pelarut yang cepat selama proses electrospinning dan
electroblowing, molekul DCF tetap dikomplekskan dengan
HPβCD hosting bukannya nukleasi DCF kristal dan kompleksasi
stabil melindungi DCF terhadap rekristalisasi.

5. Pengukuran kemurnian
Menganalisis sampel ES, EB dan FD setelah persiapan hanya
sedikit peningkatan yang terdeteksi (di bawah 0,1% total
pengotor) terlepas dari mekanisme produksi yang berbeda. Uji
penyimpanan selama 6 bulan (wadah kedap udara, suhu kamar,
terlindung dari cahaya) menunjukkan peningkatan yang dapat
diabaikan dalam pengotor dalam sampel (masih di bawah 0,1%
total pengotor).
6. Tes disolusi
Dalamfidetik pertama cairan yang terbentuk dari ES fibers relatif
jelas tetapi sampel EB tetap keruh. Dengan demikian, sampel ES
dilarutkan dalam waktu 2 menit, sedangkan produk EB
membutuhkan sekitar 3 menit untuk pembubaran total. Berbeda
denganfibers, kompleks beku-kering larut agak lambat alasan
yang dapat dikaitkan dengan kristal DCF terdeteksi dengan
tingkat disolusi moderat. Padafipertama, piringan berpori naik
dari dasar vial saat air ditambahkan dan dibutuhkan setidaknya 3
menit untuk mendapatkan larutan jernih (dengan pengadukan
manual). Campuran fisik menjadi hampir jernih dengan cepat
karena kelarutan yang baik dari HPβCD tetapi obat kristal yang
 dimikronisasi (ditandai dengan panah di Gambar 6) bertahan lebih
lama. Dalam kasus sampel FD, bagaimanapun, puncak DSC
endotermik terdeteksi sekitar 275o C menunjukkan pembentukan
DCF kristal. Pengukuran pengotor HPLC mengungkapkan bahwa
DCF sangat stabil selama proses formulasi dan penyimpanan. Tes
rekonstitusi darifibers confi Dengan karakteristik disolusi cepat
yang diprediksi, larutan jernih dapat diperoleh dalam waktu dua-
tiga menit melebihi laju disolusi sampel yang disiapkan dengan
pengeringan beku. Berbeda dengan freezedrying, di mana bahan
aktif farmasi rentan terhadap rekristalisasi selama langkah
pembekuan, kemampuan amorfisasi yang sangat baik dari
electrospinning dan electroblowing dikombinasikan dengan fitur
unik dari CD (fi kemampuan pembentukan, pelarutan dan
stabilisasi obat) menawarkan perluasan yang menjanjikan untuk
formulasi obat-obatan parenteral serta bentuk sediaan lainnya
(misalnya, tablet yang larut secara oral atau cepat).

Kekuatan Penelitian 1. Penelitian ini menawarkan kemampuan unik sehubungan dengan

persiapan nano yang dimuat obat fibers dengan cara yang lembut
dari larutan polimer dibawah gaya tarik elektrostatik.
2. Penelitian ini sudah menjelaskan hasil dan menyertakan tabel dan
gambar secara lengkap
3. Jurnal penelitian sudah mencatumkan sumber dukungan yang di
dapatkan untuk penelitian ini
4. Penulisan jurnal penelitian rapi dan menggunakan bahasa yang
mudah untuk dipahami
Kelemahan Penelitian 1. Penelitian ini adalah teknologi intensif energi dengan
memerlukan periode waktu pemrosesan yang lama dan tinggi
biaya investasi
2. Pada abstrak jurnal penelitian tidak mencantumkan secara
lengkap
3. Jurnal penelitian tidak mencantumkan jumlah dana yang
dikeluarkan untuk melakukan penelitian
Accelerat ing t he world's research.

Electroblowing and electrospinning

of fibrous diclofenac sodium-
cyclodextrin complex-based
reconstitution injection
Thorsteinn Loftsson

Journal of Drug Delivery Science and Technology

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 Journal of Drug Delivery Science and Technology 26 (2015) 28e34

Contents lists available at ScienceDirect

Journal of Drug Delivery Science and Technology

journal homepage: www.elsevier.com/locate/jddst

Original research

Electroblowing and electrospinning of fibrous diclofenac sodium-

cyclodextrin complex-based reconstitution injection
Attila Balogh a, Tímea Horva

thova
a, Zolta € p b, Thorsteinn Loftsson b,

n Fülo
Anna Helga Harasztos c, Gyo€ rgy Marosi a, Zsombor K. Nagy a, *
a
Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary
b
University of Iceland, Faculty of Pharmaceutical Sciences, IS-107 Reykjavík, Iceland
c
Budapest University of Technology and Economics, Department of Applied Biotechnology and Food Science, H-1111 Budapest, Hungary

a r t i c l e i n f o a b s t r a c t

Article history: Electrospinning, electroblowing and freeze-drying were investigated to prepare fast dissolving
Received 31 December 2014 cyclodextrin-based drug-loaded solid complexes. Combining the huge surface area of fibrous mats with
Received in revised form the capabilities of cyclodextrins to prepare a reconstitution injection was tested to overcome the
13 February 2015
instability of liquid-based products. Diclofenac sodium was used as drug with limited water solubility
Accepted 26 February 2015
Available online 28 February 2015
and 2-hydroxypropyl-b-cyclodextrin (HPbCD) as carrier and solubilizer. The applied composition of the
complex was determined based on phase solubility measurements. In order to resolve the frequent
unavoidable interruption of the fiber formation during electrospinning from the HPbCD solution, high-
Keywords:
Diclofenac sodium
speed blowing air was coupled with the electrostatic force (electroblowing) to draw polymer-free
Reconstitution injection HPbCD fibers steadily, moreover, at increased flow rates. According to the scanning electron micro-
Enhanced dissolution rate scopic images, X-ray diffraction, differential scanning calorimetry no traces of crystallinity of the drug
Polymer-free electrospinning were detectable in the fibers as opposed to the freeze-dried product. Reconstitution tests of the fibers
Polymer-free electroblowing showed fast dissolution obtaining clear solutions equivalent to a marketed liquid-based bolus injection.
Freeze-drying The results demonstrate the first time the viability of electroblowing for preparing drug delivery systems.
© 2015 Elsevier B.V. All rights reserved.

1. Introduction sulfobutyl ether-bCD) are referred to as FDA approved inactive

Cyclodextrins (CDs) are cyclic, water-soluble oligosaccharides
consisting of 6e8 a-D-glucopyranose units. The most important
characteristic of CDs is that they have a relatively lipophilic central
cavity which readily forms inclusion complex with a lipophilic
compound or moiety. The formed complex remains highly water
soluble due to the hydrophilic outer surface of the hosting CD
molecule.
CDs are used in pharmaceutical formulations mainly to improve
stability and the aqueous solubility of an active substance [1,2].
Nowadays there are over 30 commercially available pharmaceutical
products which contain natural as well as modified CDs as excipient
[3,4]. The pharmaceutical application of CDs is facilitated by their
favorable toxicology and regulatory status [5]. The natural aCD, bCD
and gCD are cited in FDA's generally regarded as safe list, and some
of their more water-soluble derivatives (e.g., 2-hydroxypropil-bCD,
* Corresponding author. 1111 Budapest, Mu} egyetem rakpart 3, Hungary.
E-mail address: zsknagy@oct.bme.hu (Z.K. Nagy).
pharmaceutical ingredients.
Techniques enhancing the apparent solubility of the drug are of
great importance as there are a growing number of active phar-
maceutical ingredients with poor water solubility [6,7]. The benefit
of the increased drug solubility owing to the application of CDs can
be used for formulating both parenteral liquid and oral solid dosage
forms [8]. However, in parenteral solutions and generally in liquids
the drug has a decreased stability due to the higher reactivity in
liquid phase [9]. Reconstitution injections can combine the ad-
vantages of parenteral administration and solid dosage forms, i.e.,
increased stability in the solid phase and efficient, immediate de-
livery into the systemic circulation [10]. Several parenteral products
are available on the market requiring reconstitution prior injection
(Nexium IV, Mefoxin, Protonix IV, Pipracil, Risperdal Consta).
Reconstitutable solids are usually prepared by freeze-drying (FD)
because the fast total water reuptake and dissolution needed for
the subsequent administration can be ensured by the porous
structure generated [11e13]. Nevertheless, FD is an energy inten-
sive technology with long processing time periods and high

http://dx.doi.org/10.1016/j.jddst.2015.02.003
1773-2247/© 2015 Elsevier B.V. All rights reserved.
 A. Balogh et al. / Journal of Drug Delivery Science and Technology 26 (2015) 28e34 29

investment cost [14,15].

In contrast to the disadvantages associated with FD technology,
electrospinning (ES) offers unique capabilities in respect of pre-
paring drug loaded nanofibers in a gentle manner from polymer
solutions (or melts [16,17]) under the drawing force of electrostatic
field [18]. ES has been widely used for preparing fibrous drug de-
livery systems with varied release kinetics adjusted to different
application areas (e.g., enteral formulations [19e24], antibacterial
and tissue engineering scaffolds [25,26], wound dressings [27],
implants [28] and transdermal drug delivery systems [29,30]). The
process can be performed using nonpolymeric compounds, such as
CDs, by formation of polymer-like supramolecular structures via
intramolecular interactions [24,26,31e33]. The effectiveness of ES
on increasing the dissolution rates of poorly water soluble drugs
stems from the huge surface area of the fibers, in accordance with
the NoyeseWhitney equation [34], and the amorphous state of the
drug in the hydrophilic carrier achieved by fast solvent evaporation
(t < 0.1 s [35]).
Although low power consumption and continuous processing
make ES a viable and more cost effective alternative to FD for
formulating pharmaceuticals, the use of volatile solvents can
complicate the laboratory-scale as well as the large-scale produc-
tion of electrospun nanofibers due to the undesired drying of the
solution leading to not optimal conditions, for instance, to Fig. 1. The structure of (a) diclofenac sodium (DCF) and (b) 2-hydroxypropyl-b-
increased viscosity. Um et al. [36] have applied a blowing air stream cyclodextrin (HPbCD).

coupled with electrospinning, i.e., electroblowing (EB), to overcome

difficulties related to processing of highly viscous polymer solu-
2.2. Phase-solubility test
tions, moreover, at increased productivity. Despite the benefits of
EB, only a few articles reported electroblown products, and EB has
Saturated aqueous solutions of diclofenac sodium (DCF) were
not been used yet for preparing drug delivery systems.
prepared in presence of 0e50% (w/v) (0e360 mM) HPbCD. The
Thus, in this work, we investigated the feasibility of polymer-
solubility of DCF was determined by previously described heating
free HPbCD-based solid complexes with high specific surface area
method [38] where an excess amount of the guest compound was
for a fast dissolving diclofenac reconstitution injection. DCF (i.e.,
added to the HPbCD solutions and the resultant suspensions were
diclofenac sodium) is a non-selective cyclooxygenase inhibitor
sonicated at 60  C for 60 min (ColeeParmer Instrument Company
non-steroidal anti-inflammatory drug with limited aqueous solu-
8892, Niles, Illinois) in sealed glass vials. The mixtures were then
bility. The well tolerable HPbCD solubilizer allows for a quick
allowed to equilibrate at room temperature (22 ± 1  C) for 7 days
intravenous bolus injection leading to higher blood levels and, thus,
under constant agitation at 250 rpm (KS 15 A shaker, EB Edmund
to greater efficiency in treatment of postoperative pain than the
Bühler GmbH, Hechingen, Germany). The filtrated (0.45 mm) and
competitors with long infusion times of a more dilute diclofenac
diluted samples were analyzed by RP-HPLC (Agilent 1100 Series LC
sodium solution [37]. As opposed to the natural bCD, HPbCD is
System, Santa Clara, California) to determine the concentration of
readily soluble in water and it is capable to form electrospun fibers,
DCF. An isocratic elution of the mixture of 80% methanol and 20%
while sulfobutyl ether-bCD is not suitable for electrospinning pre-
phosphoric acid solution (pH ¼ 2.5) was performed at a flow rate of
sumably due the ionic repulsion forces of the sulfonyl groups. For
1.5 mL/min on a Phenomenex Luna C18 150  4.6 mm, 5 mm column
the preparation of the solid complexes, besides ES and FD, the
(Phenomenex, UK), the UV detection wavelength was set to 315 nm.
involvement of EB was also necessitated due to technological
problems hampering ES. The interpretation of the performance of
the DCF-cyclodextrin nanofibers and the porous freeze-dried solid 2.3. Electrospinning (ES)
was established on thorough characterization of morphology,
physical state and chemical stability of the DCF incorporated into The 2-hydroxypropyl-b-cyclodextrin was added to ethanol
the carrier, as well as on the investigation of the reconstitution (abs.) and stirred by a magnetic stirrer (600 rpm) at room tem-
process. perature until completely dissolved. The API was dissolved in the
HPbCD solution (magnetic stirrer, 600 rpm), which was introduced
2. Materials and methods into the electrostatic spinner. The electrostatic spinner used for the
experiments was equipped with a NT-35 high voltage DC supply
2.1. Materials (MA2000, Nagykanizsa, Hungary). The electrical potential applied
on the spinneret electrode was 30 kV. A grounded aluminum plate
Diclofenac sodium (DCF, Mw ¼ 318 Da) was purchased from covered with aluminum foil was used as collector. The distance of
SigmaeAldrich (St. Louis, Missouri) and 2-hydroxypropyl-b-cyclo- the spinneret and the collector was 15 cm and the experiments
dextrin (HPbCD, degree of substitution: 0.65, Mw ¼ 1400 Da) was were performed at room temperature. The solution was dosed by a
purchased from Roquette (Lestern, France) (Fig. 1). Methanol, ab- SEP-10S Plus type syringe pump (Aitecs, Vilnius, Lithuania). The
solute ethanol, dimethylformamide, sodium dihydrogen phosphate dosing rate was 4 mL/h.
dihydrate and phosphoric acid (85%) were purchased from Sig-
maeAldrich. All solutions and the mobile phase for HPLC mea- 2.4. Electroblowing (EB)
surements were prepared with Milli-Q water (Millipore, Billerica,
MA, USA). The ethanolic DCF-HPbCD solution was similarly prepared and
30 A. Balogh et al. / Journal of Drug Delivery Science and Technology 26 (2015) 28e34
electroblown using the same feeding equipment (SEP-10S Plus
syringe pump, Aitecs, Vilnius, Lithuania) and high voltage source
(MA2000, Nagykanizsa, Hungary) as during electrospinning.
However, a coaxial type blowing spinneret was built and used as
spinneret. The central tube of the spinneret was a blunt stainless
steel G20 needle, the blowing gas (air) exited through the outer
nozzle (1.5 mm ID). The dosing rate was 20 mL/h. The airflow was
supplied by an oil-free membrane compressor (SF 1 FF, Atlas Copco,
Stockholm, Sweden) and was controlled by manual feedback using
a rotameter at 20 L/min.
2.5. Freeze-drying (FD)
Freeze-dried samples used for further experiments were pre-
pared from an aqueous solution containing 37.5 mg/mL DCF and
337 mg/mL HPbCD. The solutions (1 mL in glass vial) were rapidly
frozen using a dry-ice acetone bath for 10 min and subsequently
placed into the condenser compartment of a Christ Alpha 1e4
(Martin Christ Gefriertrocknungsanlagen GmbH, Osterode, Ger-
many) freeze-dryer at 52  C for 24 h.
2.6. Scanning electron microscopy (SEM)
Morphology of the samples was investigated by a JEOL 6380LVa
(JEOL, Tokyo, Japan) type scanning electron microscope. Each
specimen was fixed by conductive double-sided carbon adhesive
tape and sputter-coated with gold prior to the examination.
Applied accelerating voltage and working distance were 15 kV and
10 mm, respectively.
2.7. X-ray diffraction (XRD)
Powder X-ray diffraction patterns were recorded by a PAN-
analytical X'pert Pro MDP X-ray diffractometer (Almelo, The
Netherlands) using Cu-Ka radiation (1.542 Å) and Ni filter. The
applied voltage was 40 kV while the current was 30 mA. The un-
treated raw materials and the formed cyclodextrin complex were
analyzed for angles 2q between 4 and 42 .
2.8. Differential scanning calorimetry (DSC)
Differential scanning calorimetry measurements were carried
out using a Setaram (Calure, France) DSC 92 apparatus (sample
weight: ~10e15 mg, open pan, nitrogen flush). The temperature
program consisted of an isothermal period, which lasted for 1 min
at room temperature with subsequent linear heating from 25  C to
325  C at a rate of 10  C/min.
2.9. Viscosity measurements
As a parameter of the injectable liquid based pharmaceuticals,
the viscosity of the solutions was determined at 25  C in a Brook-
field digital viscometer Model DV-1þ (Brookfield, Middleboro,
Massachusetts) equipped with a Brookfield UL adapter.
2.10. Purity studies
Chemical stability of DCF during the formulation process and
storage was determined through analyzing the samples using RP-
HPLC (Agilent 1200 series LC System; Santa Clara, California). The
samples for storage tests were placed into airtight containers and
protected from light at room temperature (22 ± 1  C). For impurity
HPLC measurements an isocratic elution of 66% methanol and 34%
of a solution containing 0.8 g/L sodium dihydrogen phosphate
adjusted to pH ¼ 2.5 with phosphoric acid was performed at a flow
rate of 1.0 mL/min and 25  C. The UV detection wavelength was set
to 254 nm. The pure API, the fibrous and freeze-dried samples were
dissolved in the mobile phase obtaining a 1 mg/mL solution of DCF,
20 ml of this stock solution was injected onto the column (Phe-
nomenex Luna C18 column (5 mm; 150  4.6 mm); Torrance, Cali-
fornia). The amount of the degradation products was determined
based on the peak areas according to the European Pharmacopoeia
(Ph. Eur. 8.2, 2014). The chromatography tests were done in
triplicate.
2.11. Dissolution tests
Small volume dissolution tests (reconstitution) were carried out
by weighing samples without grinding equivalent to 37.5 mg DCF
into glass vials and calculated amount of purified water was added
to obtain final solutions of 37.5 mg/mL DCF concentration at room
temperature (22 ± 1  C). In order to follow the dissolution, pictures
were taken at predetermined time intervals using a digital camera
combined with a circular polarizer to suppress glare (Canon Pow-
erShot A490, Tokyo, Japan).
3. Results and discussion
3.1. Formation of DCF-HPbCD fibers by electrospinning (ES) and
electroblowing (EB)
To begin with, a simple optimization process was carried out for
the preparation of electrospun HPbCD-based nanofibers. Ethanol,
being appropriate solvent of HPbCD and diclofenac sodium, was
selected as solvent for ES. The amount of dissolved HPbCD in the
ethanolic solution was gradually increased since the concentration
of the fiber forming agent is considered to be the most critical
technological parameter during ES [18]. The optimal concentration
determined for the further experiments was 4.5 g HPbCD dissolved
in 10 mL pure solvent. Introducing DCF to the ES system discrete,
bead-free ribbon-shaped fibers were obtainable with diameters
ranging from 300 nm to 1e2 mm (Fig. 2A). However, despite the
good quality uniform morphology of the collectable fibers, com-
plications were encountered during the ES. The fiber formation
were maintained only for 1e2 s owing to solvent evaporation at the
droplet surface that resulted in termination of the spinning process
in which case it had to be restarted (e.g., by manual interaction
using an insulator stick or when another droplet grown). Attempts
to decrease the volatility of the liquid by replacing ethanol or
mixing it with a solvent of lower vapor pressure, such as dime-
thylformamide (DMF), resulted in similarly discontinuous electro-
spinning at 1:9 and 2:8 DMF-ethanol ratios. Further increase of the
DMF content and at last leave out ethanol yielded insufficient
morphology (i.e., beads or liquid contamination on the collector),
electrospinning of CDs applying DMF as solvent can be conducted
only from concentrated CD solutions at low flow rate [33] which are
unfavorable in terms of achievable DCF-HPbCD ratio due to the
limited solubility of DCF and productivity, respectively.
Thus, instead of modifying the solvent composition to achieve
continuous formation of fibers, a blow of gas was introduced in
presence of the electrostatic field. This electroblowing (EB) setup
enabled the production of drug-loaded fibrous material. An
elevated flow rate was required to avoid occasional clogging of the
needle tip due to the aforementioned drying of the same ethanolic
solution used for ES. In contrast to the electrospun sample, the
electroblown fibers were significantly shorter, moreover, bead-on-
string structures and larger particles were also observable (Fig. 2B).
Besides the drawing force of the blowing air, metastable Taylor-
cones may be also formed leading to formation of electrospun
material. Furthermore, sprayed droplets are also able to elongate
 A. Balogh et al. / Journal of Drug Delivery Science and Technology 26 (2015) 28e34 31

Fig. 2. Scanning electron microscopic images of HPbCD-based polymer-free (a) electrospun fibers, (b) electroblown fibers, (c) freeze-dried sample containing similarly 10%
diclofenac sodium.

and form fibers when electrified [39]. To our experience, increased

air flow rates had an improved dispersing effect, while small iter-
ations in other important factors, e.g., ±10% HPbCD concentration,
did not affect notably the fiber morphology.
As a reference method, FD was used to prepare solid DCF-HPbCD
complex from an aqueous solution. High quality porous structure
was obtained: a network of pores (1e5 mm) with submicronic wall
thickness could be observed (Fig. 2C). The increased specific surface
area of the ES, EB and FD samples can be advantageous for disso-
lution enhancement according to the NoyeseWhitney equation.

3.2. Phase-solubility study of the DCF-HPbCD aqueous system

A phase-solubility test was carried out in pure aqueous solution

containing up to 50% (w/v) HPbCD to determine the appropriate
drug-HPbCD ratio for preparation of the solid complexes. As it can
Fig. 3. Phase-solubility profile of diclofenac sodium (DCF) in aqueous HPbCD solution.
be seen in Fig. 3, the solubility of DCF increased by addition HPbCD
The error bars indicate the standard deviations (n ¼ 3).
to the aqueous media. The slope of the fitted linear regression line is
near unity at HPbCD concentrations up to 20% (w/v) (~140 mM),
which indicates that the stoichiometric ratio in the formed DCF- solubility of crystalline DCF was determined to be 18 mg/mL
HPbCD complexes is also unity. However, a negative deviation from (~57 mM, 22  C) (the intercept of the phase-solubility diagram).
the linearity was observable at higher HPbCD concentrations, i.e., Based on these results, to ensure appropriate physical stability for
the complexation efficiency decreased indicating that the phase- DCF in the solid phase an excess amount HPbCD should be used
solubility profile is an AN type isotherm according to the classifi- above the 1:1 guest-host stoichiometric ratio. Therefore, HPbCD
cation system composed by Higuchi and Connors [40]. The
32 A. Balogh et al. / Journal of Drug Delivery Science and Technology 26 (2015) 28e34

fibers and freeze-dried samples containing 10% (w/w) DCF were

prepared (1:2 guest-host stoichiometric ratio in the solid phase),
details of preparation are collected in Table 1. To obtain an
increased DCF concentration of 37.5 mg/mL (118 mM, it is the
concentration of DCF in the marketed bolus injection product)
maintaining 1:2 guest-host stoichiometric ratio, ~240 mM HPbCD is
required. When 375 mg of the proposed composition is dissolved
obtaining a 1 mL solution of 37.5 mg/mL DCF, the ~240 mM HPbCD
present would ensure to dissolve a total DCF amount of ~80 mg/mL
based on the phase-solubility profile (Fig. 3).

3.3. Differential scanning calorimetry (DSC)

The characterization of DCF-HPbCD fibers and freeze-dried

products was carried out using differential scanning calorimetry
in order to investigate the physical state of the DCF (Fig. 4).
The thermograms of the DCF-HPbCD ES and EB fibers measured
directly after production did not show the endothermic melting
peak of crystalline DCF which would have been expected at around
290  C. However, in the case of the freeze-dried sample a well-
detectable endothermic peak could be observed with an onset
point of 255  C and minimum at 275  C. After storage of 6 months, Fig. 4. Differential scanning calorimetry thermograms of (a) crystalline diclofenac
the thermal behavior of the samples prepared by ES, EB and FD was sodium, (b) HPbCD, (c) ES, (d) EB and (e) FD HPbCD complex products with 10%
diclofenac sodium directly after production, and (f) ES, (g) EB and (h) FD products after
practically unchanged (Fig. 4 f-h). The appearing endotherm peak
6 months.
of the FD sample, being near to the melting peak of pure DCF, can be
associated with crystalline DCF content. Attempts to eliminate DCF
crystallinity did not succeed in the case of FD. Variations were made
in the concentration of aqueous solutions in the range of
80e320 mM HPbCD (maintaining 1:2 DCF-HPbCD molar ratio) then
the solutions were freeze-dried. The recorded thermograms were
similar to those which were freeze-dried from a 240 mM (337 mg/
mL, see Table 1) HPbCD solution and depicted in Fig. 4. Recrystal-
lization of DCF occurs presumably during the freezing step prior
placing the vial into the freeze-dryer.

3.4. X-ray diffraction (XRD)

Another conventional method to investigate crystallinity in

solid formulations is the X-ray diffraction the result of which is
shown in Fig. 5.
Pure crystalline DCF served as reference. The diffractograms of
HPbCD and the freshly prepared as well as the 6 months old DCF-
HPbCD complexes prepared by ES, EB and FD were practically
similar, the lack of characteristic diffraction peaks (including the
most intense angles at 2q ¼ 6.7, 8.6 , 15.2 ) indicates complete
complexation of DCF. Due to the fast solvent evaporation during the
electrospinning and electroblowing process the DCF molecules
remain complexed with the hosting HPbCD instead of nucleation of Fig. 5. X-ray diffraction patterns of (a) crystalline diclofenac sodium, (b) HPbCD, (c) ES,
crystalline DCF and the stable complexation protected the DCF (d) EB and (e) FD HPbCD complex products with 10% diclofenac sodium directly after
against recrystallization. In the case of FD, the missing diffraction production, and (f) ES, (g) EB and (h) FD products after 6 months.
peaks imply that DCF was not present in crystalline form but do not
explain the ominous DSC peak. However, XRD can be less sensitive
3.5. Purity measurements
compared to DSC, especially when small volume crystallites are
incorporated in an amorphous matrix.
A HPLC-UV method was used to determine the impact of the
formulation processes and storage on the drug substance. ES and
Table 1 especially FD are gentle techniques owing to the low operating
Comparison of the details of manufacturing using different methods. temperatures (room temperature or below) and in the former case
Sample Preparation Applied Dissolved HPbCD-DCF Flow rate due to the very fast solidification of the electrospun fibers. EB is also
method solvent (90:10 m/m%) (mL/h) able to produce solid fibrous material fast but the degradation ef-
ES Electrospinning EtOH 5.0 g þ 10 mL pure solvent 4
fect of the blowing air present has not been evaluated yet. The
EB Electroblowing EtOH 5.0 g þ 10 mL pure solvent 20 European Pharmacopoeia (Ph. Eur. 8.2, 2014) specifies a total im-
FD Freeze-drying purified 3.75 g in 10 mL solution e purity threshold of 0.4% in products containing DCF. According to
water the HPLC measurements, crystalline DCF was very pure (less than
 A. Balogh et al. / Journal of Drug Delivery Science and Technology 26 (2015) 28e34
Fig. 6. Dissolution tests of electrospun (ES), electroblown (EB) and freeze-dried (FD) HPbCD complexes with 10% diclofenac sodium and physical mixture (PM) of the same
composition.
0.1% total impurity). Analyzing the ES, EB and FD samples after
preparation only slight increases were detectable (below 0.1% total
impurity) in spite of the different mechanisms of production. The
storage test of 6 months (airtight container, room temperature,
protected from light) showed negligible increase in impurities in
the samples (still below 0.1% total impurity).
3.6. Dissolution tests
The dissolution properties of the prepared complexes and
physical mixture were compared by adding a small volume of water
obtaining solutions equivalent to a bolus injection solution con-
taining 37.5 mg of DCF per mL (measured density: 1.12 g/mL, vis-
cosity: 6.2 mPa s at room conditions) (Fig. 6).
The huge surface area of the fibrous ES and EB samples collapsed
immediately after addition of water. In the first seconds the formed
liquid from the ES fibers was relatively clear but the EB sample
remained cloudy. Accordingly, the ES sample dissolved within
2 min, while product of EB required about 3 min for total dissolu-
tion. The observed larger particles among the EB fibers can have a
limiting effect on dissolution rates by decreasing the average spe-
cific surface area. A drawback of the fibrous samples is that the
initial volume exceeded that of the final solution, thus, gentle
manual agitation had to be applied to dissolve parts stuck on the
wall of the vial. In contrast to the fibers, the freeze-dried complex
dissolved somewhat slower the reason of which can be related to
the detected DCF crystals with moderate dissolution rate. At first,
the porous disk rose from the bottom of the vial as water was added
and it took at least 3 min to obtain a clear solution (with manual
agitation). The physical mixture became almost clear quickly due to
the good solubility of HPbCD but the micronized crystalline drug
(marked with arrows in Fig. 6) persisted for longer time.
4. Conclusions
Electrospinning (ES), electroblowing (EB) and freeze-drying
(FD) methods for preparation of fast-dissolving DCF-loaded
HPbCD-based solid complexes were compared. Electroblowing was
able to produce fibrous polymer-free HPbCD complexes with large
specific surface area at increased productivity. The new approach of
electrospinning and electroblowing was intended to address the
instability of liquid-based products by a reconstitution injection
formulation with increased solid phase stability. The phase solu-
bility measurement showed that DCF and HPbCD form a 1:1
33
complex. The electrospun and electroblown fibers did not show any
sign of crystallinity according to the differential scanning calorim-
etry and the X-ray diffraction results, even after storage for
6 months at room temperature. In the case of the FD sample,
however, an endothermic DSC peak was detected around 275  C
indicating formation of crystalline DCF. HPLC impurity measure-
ments revealed that DCF was highly stable during the formulation
process and storage. The reconstitution tests of the fibers confirmed
the predicted fast dissolution characteristics, clear solutions were
obtainable within two-three minutes exceeding the dissolution
rate of the sample prepared by freeze-drying. As opposed to freeze-
drying, where the active pharmaceutical ingredient is prone to
recrystallization during the freezing step, the excellent amorph-
ization ability of electrospinning and electroblowing combined
with the unique features of CDs (fiber forming ability, drug solu-
bilization and stabilization) offer a promising extension for the
formulation of parenteral pharmaceuticals as well as other dosage
forms (e.g., orally- or fast-dissolving tablets).
Acknowledgments
We are grateful Sergey Kurkov for his technical support. This
project was supported by the New Sze
chenyi Plan (project ID:


TAMOP-4.2.1/B-09/1/KMR-2010-0002), OTKA grants PD-108975
and 112644, MedInProt Synergy Program and the Ja
nos Bolyai
Research Scholarship of the Hungarian Academy of Sciences.
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