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IJP 14536 1–9 International Journal of Pharmaceutics xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
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Pharmaceutical nanotechnology
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Electrospun nanofibers as a potential controlled-release solid dispersion system for poorly water-soluble drugs
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Urve Paaver a, * , Jyrki Heinämäki a , Ivo Laidmäe a , Andres Lust a , Jekaterina Kozlova b , Elen Sillaste a , Kalle Kirsimäe c , Peep Veski a , Karin Kogermann a a b c
Department of Pharmacy, Faculty of Medicine, University of Tartu, Nooruse 1, 50411 Tartu, Estonia Institute of Physics, University of Tartu, Riia 142, 51014 Tartu, Estonia Institute of Ecology and Earth Sciences, University of Tartu, Ravila 14a, 50411 Tartu, Estonia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 September 2014 Received in revised form 12 December 2014 Accepted 13 December 2014 Available online xxx
Electrospinning was introduced as a novel technique for preparing controlled-release (CR) amorphous solid dispersions (SD) and polymeric nanofibers of a poorly water-soluble drug. Piroxicam (PRX) was used as a low-dose poorly-soluble drug and hydroxypropyl methylcellulose (HPMC) as an amorphous-state stabilising carrier polymer in nanofibers. Raman spectroscopy, X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) were used in the physical characterisation of the CR–SD nanofibers. Special attention was paid on the effects of a polymer and solvent system on the solid-state properties and physical stability of nanofibers. The average dry diameter of the electrospun CR–SD nanofibers ranged from 400 to 600 nm (SEM). PRX existed in amorphous form in the nanofibers immediately after fabrication and after a short-term (3-month) aging at low temperature (6–8 C/0% RH) and ambient room temperature (22 C/0% RH). At higher temperature and humidity (30 C/85% RH), however, amorphous PRX in the nanofibers tended to slowly recrystallise to PRX form III. The electrospun CR–SD nanofibers exhibited a short lag-time, the absence of initial burst release and zero-order linear CR dissolution kinetics. In conclusion, electrospinning can be used to fabricate supersaturating CR–SD nanofibers of PRX and HPMC, and to stabilise the amorphous state of PRX. ã 2014 Elsevier B.V. All rights reserved.
Keywords: Electrospinning Polymeric nanofibers Piroxicam Controlled release Solid dispersion Physical stability
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1. Introduction Interest in the development of controlled-release (CR) drug delivery systems for poorly water-soluble drugs has been increasing steadily. One reason for this is the fact that the majority of the promising new drug candidates coming out from the discovery pipeline are poorly water-soluble compounds. Many of these drugs can exist in different polymorphic or solvated crystal forms, and also in the amorphous state the latter having an enhanced dissolution and bioavailability compared to the crystalline state (Hancock and Zografi, 1997). The delivery of high-energy solid forms (such as amorphous forms, co-crystals and the like) may induce the generation of supersaturated solutions, and this
* Corresponding author. Tel.: +372 737 5282; fax: +372 737 5289. E-mail addresses: [email protected] (U. Paaver), [email protected] (J. Heinämäki), [email protected] (I. Laidmäe), [email protected] (A. Lust), [email protected] (J. Kozlova), [email protected] (E. Sillaste), [email protected] (K. Kirsimäe), [email protected] (P. Veski), [email protected] (K. Kogermann).
strategy can be used to enhance oral/topical absorption and also to sustain the drug release by choosing appropriate CR polymers (Brouwers et al., 2009; Tran et al., 2011). A supersaturated drug solution, however, is thermodynamically unstable and has the tendency to return to the equilibrium state by precipitation. The stabilisation of a supersaturated solution can be accomplished by adding polymers (precipitation inhibitors) which may act through a variety of mechanisms (Brouwers et al., 2009). Hydroxypropyl methylcellulose (HPMC) has been reported as the excipient of choice to be included into such formulations as a carrier/stabilizer and precipitation inhibitor (Brouwers et al., 2009; Gao et al., 2009; Q3 Ohara et al., 2005; Raghavan et al., 2001a,b; Tran et al., 2011). A combination of solid dispersion (SD) and CR techniques is a novel dissolution-modulating approach and strategy in designing oral CR drug delivery systems for poorly water-soluble drugs (Tran et al., 2011). The CR–SD systems comprise the advantages and functions of both SD and CR. Piroxicam, PRX is a non-steroidal anti-inflammatory drug widely used in the treatment of rheumatic diseases. It is a poorly water-soluble polymorphic drug which belongs to Class II (high permeability, low solubility) in the
http://dx.doi.org/10.1016/j.ijpharm.2014.12.024 0378-5173/ ã 2014 Elsevier B.V. All rights reserved.
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Biopharmaceutical Classification System (Amidon et al., 1995). To date, PRX has been formulated in oral and topical CR drug delivery systems by using e.g. a solvent evaporation method (Guiziou et al., 1996; Joseph et al., 2002), a spray-drying method (Wagenaar and Muller, 1994), an acoustically modified spraying method (Berkland et al., 2003) and encapsulation of the drug in liposomes (Canto et al., 1999). Since amorphous PRX shows a strong propensity to crystallize (Sheth et al., 2004a), designing and formulating amorphous PRX together with polymers into the CR drug delivery systems could be a beneficial alternative approach. Previously, amorphous PRX has been prepared by melt/quench-cooling and cryogenic ball milling methods but the major limitations associated to these techniques are the chemical degradation of PRX and susceptibility to recrystallize into the respective starting polymorph from which PRX was originally prepared (Redenti et al., 1996; Sheth et al., 2004b; Vre9 cer et al., 1991). According to our recent findings, amorphous state of PRX can be obtained by ballmilling at low temperature but the major limitation of this technique is that amorphous PRX is very unstable (Kogermann et al., 2011). Recently, the production of nanocrystals using a high pressure homogenisation technique was introduced to modify the dissolution and oral absorption of PRX (Lai et al., 2011). Electrospinning is an effective and continuous method to fabricate polymeric nanofibers with diameters ranging from a nanometer level to submicron level and with a large surface area to volume ratio (Agarwal et al., 2008; Lu et al., 2009; Paaver et al., 2014; Pelipenko et al., 2013). In electrospinning, the surface areas of nanofibers can be increased through the formation of much smaller pores in the surface of fibers by controlling e.g. the solution and process parameters of electrospinning (Li and Xia, 2004). Brewster et al. (2004) and more recently Yu et al. (2009) suggested that electrospun ultrafine fibers have the potential to be used as amorphous SDs to improve the solubility and dissolution of poorly water-soluble drugs. The formation of an amorphous SD or solid solution of drug was found when organic-solvent solutions of itraconazole/HPMC mixtures were electrospun resulting in dosage forms with controllable dissolution properties (Verreck et al., 2003). More recently, Huang et al. (2012) introduced a novel time-engineering biphasic CR system for oral delivery of a poorly water-soluble ketoprofen using tri-layered electrospun amorphous nanofibrous mats. Jiang et al. (2012) applied coaxial electrospinning for providing biphasic CR drug release profiles of the nanostructures containing a poorly water-soluble ketoprofen. Consequently, electrospinning could be an interesting alternative for stabilising drugs in an amorphous state in prepared SD, and hence this might lead to improved bioavailability in both oral immediate release and CR drug therapy. For poorly water-soluble drugs, increasing the surface area to volume ratio and/or modification of solid-state form may offer a convenient way to control their dissolution rate and/or stability. The aim of the present study was to combine SD and CR techniques in fabricating supersaturating controlled-release drug delivery systems for poorly water-soluble drugs. Electrospinning was investigated as a new technique in preparing high-energy amorphous SDs of a poorly water-soluble drug PRX, and for fabricating CR–SD nanofibers of PRX and hydrophilic cellulosic carrier polymer. Special attention was paid on the effects of a hydrophilic carrier polymer HPMC and solvent system on solidstate properties, dissolution and physical stability of drug-loaded nanofiber matrices.
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2. Materials and methods
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2.1. Materials
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Piroxicam (anhydrous PRX pure form I, PRXAH I, Letco Medical, Inc., USA) was used as a poorly water-soluble drug in fabricating
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electrospun CR–SD nanofibers. Other crystalline forms of PRX (PRX monohydrate PRXMH and PRX anhydrate form III, PRXAH III) used for comparison were prepared as previously reported (Kogermann et al., 2007a, 2011). Three grades of hydroxypropyl methylcellulose, HPMC were studied as a carrier and stabilising polymers for CR–SD nanofibers: MethocelTM K100M premium CR; MethocelTM K4M premium CR; MethocelTM E5 premium LV (The Dow Chemical Company, USA). The primary solvents applied in the electrospinning studies were methanol (Sigma–Aldrich Chemie GmbH, Germany) and 1,1,1,3,3,3hexa-fluoro-2-propanol (HFIP) (99.0%) (Apollo Scientific Ltd., UK). Applicability of ethanol, acetone, 2-propanol and dichloromethane (Lach-Ner s.r.o., Czech Republic) for electrospinning of nanofibers was also studied. All other reagents and solvents used were of analytical grade.
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2.2. Selection of solvent systems for electrospinning
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Table 1 summarises the results on the solubility/miscibility of the carrier HPMC polymers in different solvent systems. The test was based on visual inspection. Non-aqueous and readily evaporating HFIP was selected as the most suitable solvent system for further electrospinning experiments with PRX and HPMC.
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2.3. Method for fabrication of nanofibers
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A schematic diagram of the electrospinning process is shown in Fig. 1. The automatic syringe pump KdScientific (Model No: KDS250-CE, Geneq Inc., USA) with a pumping speed of 1 ml/h, was used for electrospinning. The high-voltage power supply Gamma High Voltage Research (Model No. ES3OP-10W/DAM, USA) was applied for generating the voltage of 7–22 kV used in the experiments. The distance between the spinneret and the fiber collector was in a range of 8–25 cm. The drug-polymer (PRX/HPMC) ratios (w/w) used in electrospinning experiments were 1:1, 2:1 and 4:1. For preparing the nanofibers containing HPMC K100M premium CR as a carrier polymer and HFIP as a solvent system, the levels for the voltage and distance were 7, 9, 10 kV and 8, 10, 12 cm, respectively. For preparing nanofibers with the other two HPMC grades, the higher operating voltage (22 kV) and different distance (25 cm) were applied. The electrospun nanofibers were investigated immediately after fabrication and within regular time periods during a shortterm (3-month) aging at a low temperature (LT 6–8 C/0% RH) and ambient room temperature (RT 22 C/0% RH). In addition, some samples were also stored for up to 2 months at higher temperature (HT) and humidity conditions (30 C/85% RH).
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2.4. Physicochemical characterisation
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2.4.1. X-ray powder diffraction X-ray powder diffraction (XRPD) patterns of starting materials and electrospun nanofibers (immediately after fabrication and after a short-term aging) were obtained by using a X-ray diffractometer (D8 Advance, Bruker AXS GmbH, Germany). Crystal structures were verified by comparing the experimental results to the theoretical patterns in the Cambridge Structural Database (CSD) or to diffractograms available in the literature (Bordner et al., 1984; Reck et al., 1988; Vre9cer et al., 2003). The XRPD experiments were carried out in a symmetrical reflection mode (Bragg– Brentano geometry) with CuKa radiation (1.54 Å). The scattered intensities were measured with the LynxEye one-dimensional detector with 165 channels. The angular range was from 5 2-theta to 30 2-theta with steps of 0.2 2-theta. The total measuring time was 498 s per step. The operating current and voltage were 40 mA and 40 kV, respectively.
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Table 1 Solubility/miscibility of the three hydroxypropyl methylcellulose (HPMC) carrier polymer grades (Methocel K100M premium CR; K4M premium CR; E5 premium LV) in different solvent systems.
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Exp.
Polymer
Solvent system
Polymer concentration
Remarks
A1 A2 A3 A4 A5 A6 A7 A8
HPMC K100M CR
Acetone:water 1:1 Acetone:water 9:1 Methanol:water 1:1 Ethanol:water 1:1 2-Propanol:water 1:1 Methanol:dichloro methane 1:1 Ethanol:dichloro methane 1:1 HFIP
1% (w/V) 0.5%, 0.75% and 1% (w/V) 1% (w/V) 1% (w/V) 0.75% (w/V) 1% (w/V) 1% (w/V) 0.8% (w/V)
Jelly, sediment Not dissolved (unsuitable solvent system) Viscous, clear solution Jelly, sediment Viscous solution Viscous, cloudy solution Not dissolved (unsuitable solvent system) Viscous, clear solution
B1 B2 B3 B4 B5 B6 B7
HPMC K4M CR
Acetone:water 1:1 Methanol:water 1:1 Ethanol:water 1:1 2-Propanol:water 1:1 Methanol:dichloro methane 1:1 Ethanol:dichloro methane 2:3, 1:2 HFIP
1% (w/V) 1% (w/V) 1% (w/V) 0.375% (m/V) 1% (w/V) 1% (w/V) 0.8% (w/V)
Cloudy, viscous and jelly solution Cloudy, viscous and jelly solution Cloudy, viscous and jelly solution – – Not dissolved (unsuitable solvent system) –
C1 C2 C3 C4 C5 C6 C7
HPMC E5 LV
Acetone:water 1:1 Methanol:water 1:1 Ethanol: water 1:1 2-Propanol:water 1:1 Methanol:dichloro methane 1:1 Ethanol:dichloro methane 2:3, 1:2 HFIP
10%, 15% (w/V) 10%, 15% (w/V) 10%, 15% (w/V) 10%, 15% (w/V) 10%, 15% (w/V) 10%, 15% (w/V) 0.8% (w/V)
Clear, viscous solution Clear, viscous solution Clear, viscous solution Clear, viscous solution Viscous, slightly cloudy solution Viscous, slightly cloudy solution –
2.4.2. Raman spectroscopy Raman spectra of both the starting materials and electrospun nanofibers were collected using a Raman spectrometer equipped with a thermoelectrically cooled CCD detector (1024 64) and a fiber optic probe (B&W TEK Inc., USA). A 300 mW laser source at 785 nm was used (B&W TEK Inc., USA). Spectra were recorded between 200 and 2200 cm 1 with an integration time of 12 s, and were the average of three scans. BWTek software (BWTek-Inc., Newark, USA) was used for the collection of Raman spectra. Raman spectra were normalised and a spectral region from 1000 to 1700 cm 1 was used for analysis. 2.4.3. Differential scanning calorimetry Differential scanning calorimetry (DSC) studies of nanofibers were carried out using a PerkinElmer DSC 4000 differential scanning calorimeter (PerkinElmer Ltd., Shelton, CT, USA). The DSC system was calibrated for temperature and enthalpy using indium as a standard. Samples of 2–3 mg were sealed in an aluminum pan with 2 pinholes in a lid. A nitrogen purge with a flow rate of 20 ml/ min was used in the furnace. The scans were obtained by heating from 30 C to 220 C at a rate of 20 C/min. Each run was performed in triplicate. Temperatures are shown as on-set temperatures of the events unless mentioned otherwise.
2.4.4. Scanning electron microscopy The diameter and surface morphology of nanofibers was investigated with a high-resolution scanning electron microscope (SEM) (Helios NanoLab 600, FEI Company). A measurement function of the microscope driving program xT Microscope Control (FEI) was applied for the dimension measurements. Samples were mounted on aluminum stubs with silver paint and magnetron sputter coated with 3 nm gold layer in argon atmosphere prior to microscopy.
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2.4.5. Dissolution test The in vitro dissolution tests of electrospun nanofiber and pure PRX samples were performed using a USP dissolution apparatus I (basket method). The dissolution experiments were carried out in a semi-automated dissolution system (Termostat-Sotax AT7, Sotax AG, Switzerland). The dissolution studies were carried out both with the nanofibers charged into hard gelatin capsules No. 1 (PosilocTM Elanco) and with the nanofibers freely set into the dissolution baskets. The concentration of PRX in the dissolution medium was measured at 354 nm by using a UV–vis spectrophotometer (Ultrospec III, Biochrom Ltd., UK). The dissolution medium was 900 ml of buffer solution (pH 1.2 or pH 7.2) maintained at 37 0.5 C as described in the USP 28. The basket rotation speed
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Fig. 1. Schematic diagram of an electrospinning equipment. Key: (A) syringe pump; (B) syringe; (C) polymer solution; (D) high-voltage power supply; (E) electrode; (F) grounded collector.
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was set at 50 rpm. Six parallel tests were performed for each sample.
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3. Results and discussion
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3.1. Morphology and diameter of nanofibers
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According to the literature, the morphology and diameter of electrospun nanofibers are dependent on the intrinsic properties of the solution such as the type of polymer, the conformation of polymer chain, viscosity (or concentration), elasticity, electrical conductivity, and the polarity and surface tension of the solvent (Li and Xia, 2004; Lu et al., 2009; Meinel et al., 2012). From the process parameters the most crucial are the applied voltage, the feed rate and the distance to the collector (Rošic et al., 2012). In the present study, the drug loading of CR–SD nanofibers was performed by electrospinning of drug/polymer blends. Different polymer/solvent systems were tested and the best polymer–solvent combination for electrospinning was found to be a 0.8% solution of HPMC (Methocel K100M premium CR) in HFIP (Table 1). The other polymer/solvent systems tested were also electrospinnable, but in this study the lowest concentration of polymer and the solvent with the fastest evaporation were used. Of the process parameters studied, both voltage and distance between the spinneret and the fiber collector were shown to have a significant effect on the formation of nanofibers. Increasing the distance between a nozzle tip and collector resulted in thinner and more uniform nanofibers as the voltage was kept constant. This can be explained by the fact that the distance between the spinneret and collector affects the strength of the electric field, and consequently, governs the stretching of the polymer jet (Rošic et al., 2012). The combination of voltage and distance that yielded the optimal nanofibers in the present electrospinning procedure was found to be 9 kV and 10 cm, respectively. The representative SEM images of the electrospun CR–SD nanofibers of PRX and HPMC, and the reference pure polymer nanofibers (without PRX) are shown in Fig. 2. The nanofibers of PRX and HPMC were slightly larger in diameter (387 125 nm, n = 100) than the reference HPMC polymeric nanofibers 195 143 nm, n = 100) nm (Fig. 2). Both types of electrospun nanofibers (with and without PRX) exhibited very uniform thickness forming a homogeneous non-woven nanomat onto a collector plate. According to Meinel et al. (2012), blending polymer solutions with drugs can affect the geometric properties of electrospun fibers due to the changes in solution viscosity and electrical conductivity. A decrease in the charge density on the surface of the electrospun jet and an increase in solution viscosity result in larger fiber size. In the present study, PRX being capable to be ionized as a zwitter ion, likely influenced the electrical conductivity of the polymer solution. The formation and presence of defects such as beads in the electrospun nanofibers were not
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observed suggesting that the viscosity and surface tension of the polymeric solution was suitable for fabricating the drug-loaded nanofiber matrices. Furthermore, the presence of crystallised PRX on the surface of nanofibers was not observed indicating that the drug was in a non-crystalline state in the electrospun nanofibers. The solid state of PRX in the present nanofibers was investigated further using XRPD and Raman spectroscopy.
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3.2. Physical state of API in the nanofibers
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To date, the behavior and possible solid-state phase transformations of drugs during electrospinning are not very well known and understood. According to Huang et al. (2003), the likely four modes of the drug in the electrospun nanofibers are: (1) The drug is bound on the surface of the carrier polymer that forms nanofibers, (2) Both the drug and carrier polymer form nanofibers, (3) The drug and carrier polymer are integrated into one kind of nanofibers, and (4) The carrier polymer is in a tubular form in which the drug particles are encapsulated. In the present study, amorphisation of PRX was aimed to be facilitated (in line with the mode 3) by fast removal of solvent during electrospinning of a drug/polymer blend into nanofibers. HPMC acts in this electrospun formulation both as a carrier/stabilizer for the amorphisation and stabilizer of the supersaturated state upon the release of drug. Drug solubility and content in the polymer solution have been shown to be important factors affecting the solid-state form and distribution of drug in the electrospun nanofibers (Meinel et al., 2012; Natu et al., 2010).
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3.2.1. XRPD analysis PRX is a polymorphic drug that exists in several X-ray solidstate forms, including the three anhydrate (I–III), monohydrate and amorphous forms (Sheth et al., 2004a; Vre9 cer et al., 2003). In the present study, PRX was originally in PRXAH I as verified by XRPD. As shown in Fig. 3, the characteristic XRPD reflections of PRXAH I were observed at diffraction angles 2u of 8.3 , 11.7, 12.5 , 14.3 , and 17.7. The cellulose ether polymer (HPMC) is an amorphous polymer without any characteristic diffraction reflections in its XRPD pattern. Fig. 3 shows the XRPD patterns of PRX and HPMC nanofibers (Methocel K100M premium CR) immediately after fabrication and after a short-term (3-months) aging at low (LT 6–8 C/0% RH) and ambient room temperature (RT 22 C/0% RH). Amorphous halo in all XRPD patterns indicated the presence of amorphous PRX in the electrospun CR–SD nanofibers (1:1) immediately after fabrication and after a 3-month aging. PRX existed in XRPD amorphous form showing no signs of recrystallisation or polymorphic solid-state changes during the aging. According to Kogermann et al. (2011), the spontaneous recrystallisation of amorphous form of PRXAH I starts within few minutes after the amorphous form preparation. This suggests that the electropinning of PRX with HPMC (Methocel
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Fig. 2. Scanning electron microscopy (SEM) micrographs of electrospun piroxicam (PRX) loaded hydroxypropyl methylcellulose (HPMC) nanofibers (a drug–polymer ratio 1:1) (A, B) and the reference nanofibers of a pure carrier polymer HPMC (MethocelTM K100M premium CR) (C, D).
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Similarly, Naelapää et al. (2012) showed that PRXAH I amorphous samples recrystallised as PRXAH I together with the diffractions of the least stable PRXAH III. Furthermore, the storage conditions have been shown to influence the amorphous state of PRXAH I due to the possible presence of higher residual order in X-ray amorphous PRXAH I samples (Naelapää et al., 2012). Present study reveals that the recrystallisation of amorphous PRX was slowed down by the presence of polymer in nanofibers and also further solid-state changes were inhibited.
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K100M premium CR) in HFIP significantly prevents the solid-state transformation (recrystallisation) of PRX, and consequently, stabilizes the amorphous form of PRX in the solid formulation. HPMC has the ability to form hydrogen bonds between drug molecules and the polymer, and consequently, to increase the activation energy for crystallisation (Brouwers et al., 2009). Furthermore, HPMC can increase the glass transition temperature and sustain supersaturation of the system which makes it a carrier polymer of choice for the present nanofibers. Since the solid-state transformations of drug are dependent on temperature and humidity, a short-term aging of the nanofibers was also carried out at elevated temperature and humidity conditions (30 C/85% RH) (Fig. 4). The appearance of PRXAH III characteristic reflection at a diffraction angle 2u of 8.9 suggested partial recrystallisation of amorphous PRX. Sheth et al. (2004b) reported that by using a cryogenic ball milling some polymorphic memory of PRXAH I could be retained in the respective amorphous form of PRX, which tends to recrystallise predominantly to PRXAH I, although some PRXAH III character may also be present.
3.2.2. Raman spectroscopy analysis Fig. 5 shows the Raman spectra of PRX and HPMC (1:1) nanofibers immediately after fabrication and after 2-months aging at LT and RT. The characteristic Raman spectroscopy peaks of PRXAH I are displayed at 1282, 1338, 1435, and 1525 cm 1 (Fig. 5). These are in a close agreement with previously published ones with only minor differences, and these earlier publications also reported the possible peak assignments (Kogermann et al., 2007a, b; Redenti et al., 1999). Recently, Kogermann et al. (2011) introduced the experimental Raman spectrum of amorphous PRX which allows monitoring the crystalline–amorphous transformations and investigating PRX stability under various conditions. The present nanofibers obtained by electrospinning from PRXAH I showed slightly different Raman spectrum compared to amorphous PRX obtained by ball milling at low temperature (and reported by Kogermann et al., 2011). However, the authors believe that these differences are due to the different equipments used for analysis and their different spectral resolution. The joint characteristic peaks for amorphous PRX are shown at 1159, 1237, 1331, 1365, 1438, 1477, 1531, and 1561 cm 1 (Fig. 5) suggesting the presence of amorphous PRX in the electrospun nanofibers. These characteristic peaks (peak position, intensity and the sharpness of the peaks) differ from all known PRX crystalline forms. This result is also in line with the earlier XRPD analysis. During electrospinning, a large specific surface area is obtained resulting in fast and efficient evaporation of the organic solvent, and consequently, molecules have no time to (re)crystallise and hence they most likely have an amorphous supermolecular structure (Verreck et al., 2003; Zong et al., 2002). In addition, adsorbed HPMC with an ability to form hydrogen bonds can prevent the crystal growth of API by hindering the
Fig. 4. X-ray powder diffraction (XRPD) patterns of electrospun piroxicam (PRX) loaded hydroxypropyl methylcellulose (HPMC) nanofibers (a drug–polymer ratio 1:1) immediately after fabrication and after a three-day aging of the samples at elevated temperature and humidity conditions (30 C/85% RH). Key: PRXAH I = PRX anhydrate form I; PRXAH II = PRX anhydrate form II, PRXAH III = PRX anhydrate form III; and PRXMH = PRX monohydrate.
Fig. 5. Raman spectra of electrospun piroxicam (PRX) loaded hydroxypropyl methylcellulose (HPMC) nanofibers (a drug–polymer ratio 1:1) immediately after fabrication and after a short-term aging of the samples at low (LT 6–8 C/0% RH) and room temperature (RT 22 C/0% RH). Key: PRXAH I = PRX anhydrate form I; PRXAH II = PRX anhydrate form II, PRXAH III = PRX anhydrate form III; and PRXMH = PRX monohydrate.
Fig. 3. X-ray powder diffraction (XRPD) patterns of electrospun piroxicam (PRX) loaded hydroxypropyl methylcellulose (HPMC) nanofibers (a drug–polymer ratio 1:1) immediately after fabrication and after a short-term aging of the samples at low (LT 6–8 C/0% RH) and room temperature (RT 22 C/0% RH). Key: PRXAH I = PRX anhydrate form I; PRXAH II = PRX anhydrate form II, PRXAH III = PRX anhydrate form III; and PRXMH = PRX monohydrate.
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incorporation of drug molecules into the crystal lattice (Brouwers et al., 2009). The Raman spectra of fresh and aged polymeric PRX and HPMC (1:1) nanofibers were identical indicating no solid-state transformations occurred during a short-term aging of nanofibers at LT and RT for 2 months (Fig. 5). The Raman spectroscopy results supported XRPD analysis findings suggesting the presence of amorphous PRX in the nanofibers. However, it is evident that elevated storage conditions readily affect the recrystallisation of amorphous PRX since only three-day aging at 30 C/85% RH led to the formation of PRXAH III. Interestingly, both Raman spectroscopy and XRPD analysis also revealed (data not shown) that the nanofibers with a higher drug–polymer ratio of 2:1 and 4:1 were amorphous immediately after preparation, but after a two-month aging PRX tended to crystallise out from the nanofibers (unlike with the respective 1:1 samples). This suggests that the amount of HPMC is critical and needs to be high enough to prevent the crystallisation of PRX through forming hydrogen bonds in the present electrospun nanofibers. These results highlight the importance of proper storage conditions which remarkably may change the stability of amorphous PRX in the electrospun polymeric nanofibers. It has been shown previously that during RT milling and/or also heating the least stable PRXAH III crystallises first, which then gradually transforms to PRXAH I (Kogermann et al., 2010; Sheth et al., 2004b). The transitions between different crystalline forms of drugs are always directed toward the most stable form at specified conditions thus the transformation of PRXAH I to PRXMH at higher humidity conditions has been reported (Paaver et al., 2012; Sheth et al., 2004a,b). The most likely explanations for the absence of PRXMH form in the nanofibers (immediately after fabrication) are that a non-aqueous solvent (HFIP) was used in electrospinning thereby providing the medium for PRX to exist in the amorphous form obtained from PRXAH I and that the ambient RH of the experiment environment was not high enough to cause instant hydrate formation.
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DSC studies were performed to determine the solid-state form of PRX in the electrospun polymeric CR–SD nanofibers and to confirm the XRPD and Raman spectroscopy results. Fig. 6 shows the DSC thermograms of pure materials (PRXAH I, HPMC),
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Fig. 6. Differential scanning calorimetry (DSC) thermograms. Key: (A) piroxicam (PRX) anhydrate form I (PRXAH I), (B) hydroxypropyl methylcellulose, HPMC (MethocelTM K100M premium CR), (C) electrospun HPMC polymeric nanofibers and (D) electrospun HPMC:PRX nanofibers (a drug–polymer ratio 1:1).
electrospun carrier polymer HPMC nanofibers and electrospun PRX-HPMC nanofibers (1:1). The DSC thermogram of pure PRXAH I exhibited a single melting endotherm at 204.0 C with the enthalpy of melting (DH) 100.8 J/g (Fig. 6A), which is in good agreement with the values reported in the literature (Stulzer et al., 2008; Wu et al., 2009). As seen in Fig. 6B and C, the DSC profiles of pure HPMC and non-drug containing electrospun HPMC nanofibers showed the thermal behavior of amorphous material without any melting endotherms. The only endothermic event was in the range of 40–120 C most likely due to the polymer dehydration. In the case of PRX and HPMC nanofibers (1:1) measured immediately after preparation (Fig. 6D), the thermal parameters of both pure components (PRX, HPMC) were observed in the thermograms (with only a slight shift of thermal parameters), thus suggesting the absence of any solid-state interactions or incompatibility between PRX and HPMC. Furthermore, no thermal events due to the chemical decomposition were found. In addition, the DSC thermograms of electrospun CR–SD nanofibers showed a weak exothermic event at 131.1 C (DH = 25.1 J/g) suggesting partial (minor) crystallisation of amorphous PRX. This observation was confirmed by the second endotherm at about 199.0 C, most likely corresponding to the PRXAH III melting (Fig. 6D). In addition, a concomitant reduction in peak size and enthalpy per unit mass of PRX was evident (DH of PRX decreased from 100.8 to 50.3 J/g). These results also agree with the XRPD and Raman spectroscopy ones. The recrystallisation of PRXAH III from electrospun nanofibers upon heating enlightens the instability of amorphous PRX at higher temperatures.
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According to the recent literature, the drug release from electrospun polymeric nanofibers is dependent on several material and process factors including drug molecular weight, loading and state, carrier polymer(s), fiber crystallinity, fiber diameter and porosity, and drug–polymer–electrospinning solvent interactions (Meinel et al., 2012; Natu et al., 2010). Fig. 7 shows the dissolution profiles of pure PRX powder, physical mixtures and electrospun CR–SD polymeric nanofibers in different dissolution media (pH). The dissolution of pure PRXAH I was dependent on the pH of dissolution media being poorer in the acidic (pH 1.2, Fig. 7A) than in slightly basic (pH 7.2, Fig. 7B) dissolution medium. Interestingly, in case of the PRX and HPMC electrospun nanofibers, the release rate of PRX was less dependent on the pH of dissolution media being only slightly lower at pH 1.2 than pH 7.2. Fig. 8 illustrates the effects of drug–polymer ratio on the release profile of PRX loaded nanofibers. The dissolution of amorphous PRX from the CR–SD nanofibers was a prolonged carrier-polymer controlled process, and the initial dissolution rate of PRX was directly connected with PRX–polymer ratio (Fig. 8). Sustained-release dissolution rate of the CR–SD polymeric nanofibers was attributed to a highmolecular HPMC grade used as a carrier polymer and the formation of a solid matrix inside hard gelatine capsules. As shown in Fig. 7, the present electrospun CR–SD nanofibers loaded in hard gelatine capsules exhibited a short lag-time (10– 15 min), the absence of initial burst release and zero-order linear dissolution kinetics. According to the literature, the drug release profiles from HPMC containing hydrophilic matrices are generally first-order for highly water-soluble drugs or zero-order for insoluble drugs (Tran et al., 2011). It is evident that the amorphous state of PRX and generation of supersaturated solution associated with the present CR–SD nanofibers decreased the lag-time for the drug release in vitro. In addition, it can be expected that CR–SD nanofibers as a kind of supersaturating drug delivery system could enhance the absorption of a poorly water-soluble drug by reducing
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Fig. 7. Release profiles of piroxicam (PRX) loaded hydroxypropyl methylcellulose (HPMC) nanofibers at (A) pH 1.2 and (B) pH 7.2 (n = 6). For clarity purposes, the standard deviation is not shown, but for all dissolution results it was below 5.0%.
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the precipitation of drug and thus generating high free drug concentrations, e.g. in the gastrointestinal tract. According to Brouwers et al. (2009), it is possible that the supersaturation plays a role in the absorption process of various solubilising dosage forms of poorly water-soluble drugs, and thus these dosage forms can be adjusted into supersaturated formulations by using a suitable precipitation inhibitor (e.g. HPMC) in the delivery system. Since our recent study suggests that hard gelatine capsule shells might interact with a carrier polymer (Kogermann et al., 2013), the
dissolution tests with the present nanofibers were performed also without using hard gelatine capsules (i.e. with free nanofibers in the baskets). A slight difference in dissolution was found between the nanofibers that were placed freely in the dissolution baskets or loaded into hard gelatine capsules (Fig. 7; small graphs). The first ones showed an initial burst release and then almost constant difference in prolonged drug release compared to that obtained with the nanofibers loaded in hard gelatine capsules (a drug– polymer ratio 1:1).
Please cite this article in press as: Paaver, U., et al., Electrospun nanofibers as a potential controlled-release solid dispersion system for poorly water-soluble drugs. Int J Pharmaceut (2014), http://dx.doi.org/10.1016/j.ijpharm.2014.12.024
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Fig. 8. Effects of drug–polymer ratio on the dissolution of piroxicam (PRX) loaded hydroxypropyl methylcellulose (HPMC) nanofibers (n = 6). The dissolution behavior of free nanofibers (with a drug–polymer ratio 1:1 and 4:1 w/w) were tested at pH 1.2 and pH 7.2. For clarity purposes, the standard deviation is not shown, but for all dissolution results it was below 5.0%. 485
4. Conclusions
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Electrospinning can be used for the amorphisation of a poorly water-soluble piroxicam (PRX) and for fabricating supersaturated controlled-release solid dispersion (CR–SD) polymeric nanofiber matrices. Binary mixtures of PRX anhydrate form I (PRXAH I) and HPMC in HFIP can be electrospun across relatively low potentials (7–10 kV) generating polymeric nanofibers with uniform diameters ranging from 400 to 600 nm. The properties of CR–SD polymeric nanofibers, such as physical stability and dissolution, are dependent on the grade of the HPMC carrier polymer, initial crystalline form of PRX, solvent system applied, and storage conditions. The recrystallisation of amorphous PRX from CR–SD polymeric nanofibers is less favored at low temperature and humidity. XRPD and Raman spectroscopy complemented with DSC analysis permit thorough solid-state characterisation of PRX forms and its transformations inside electrospun nanofibers. Electrospinning can be a future technology for amorphisation and formulating novel supersaturating CR–SD drug delivery systems of poorly water-soluble drugs.
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Hanhijärvi et al. (2010) and Taepaiboon et al. (2006).
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This research was supported by the European Social Fund’s Doctoral Studies and Internationalisation Programme DoRa. This work is part of the targeted financing project no. SF0180042s09 and ETF grant project no. ETF7980. Estonian Ministry of Education and Research is acknowledged for financial support. The authors are grateful to Prof. Dr. Franc Vre9 cer (Krka, d.d., Novo Mesto, R&D Division, Šmarješka cesta 6, 8501 Novo mesto, Slovenia) for providing the XRPD data of PRXAH III. Dr. Mingshi Yang (University
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of Copenhagen) is thanked for the help with the preparation of PRXAH III. Mr. Jaan Aruväli (X-ray laboratory of Institute of Ecology and Earth Sciences, University of Tartu) and Prof. Väino Sammelselg (Institute of Physics, University of Tartu) are acknowledged for the support in XRPD and SEM experiments, respectively.
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Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
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Pharmaceutical nanotechnology
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Electrospun nanofibers as a potential controlled-release solid dispersion system for poorly water-soluble drugs
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Urve Paaver a, * , Jyrki Heinämäki a , Ivo Laidmäe a , Andres Lust a , Jekaterina Kozlova b , Elen Sillaste a , Kalle Kirsimäe c , Peep Veski a , Karin Kogermann a a b c
Department of Pharmacy, Faculty of Medicine, University of Tartu, Nooruse 1, 50411 Tartu, Estonia Institute of Physics, University of Tartu, Riia 142, 51014 Tartu, Estonia Institute of Ecology and Earth Sciences, University of Tartu, Ravila 14a, 50411 Tartu, Estonia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 September 2014 Received in revised form 12 December 2014 Accepted 13 December 2014 Available online xxx
Electrospinning was introduced as a novel technique for preparing controlled-release (CR) amorphous solid dispersions (SD) and polymeric nanofibers of a poorly water-soluble drug. Piroxicam (PRX) was used as a low-dose poorly-soluble drug and hydroxypropyl methylcellulose (HPMC) as an amorphous-state stabilising carrier polymer in nanofibers. Raman spectroscopy, X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) were used in the physical characterisation of the CR–SD nanofibers. Special attention was paid on the effects of a polymer and solvent system on the solid-state properties and physical stability of nanofibers. The average dry diameter of the electrospun CR–SD nanofibers ranged from 400 to 600 nm (SEM). PRX existed in amorphous form in the nanofibers immediately after fabrication and after a short-term (3-month) aging at low temperature (6–8 C/0% RH) and ambient room temperature (22 C/0% RH). At higher temperature and humidity (30 C/85% RH), however, amorphous PRX in the nanofibers tended to slowly recrystallise to PRX form III. The electrospun CR–SD nanofibers exhibited a short lag-time, the absence of initial burst release and zero-order linear CR dissolution kinetics. In conclusion, electrospinning can be used to fabricate supersaturating CR–SD nanofibers of PRX and HPMC, and to stabilise the amorphous state of PRX. ã 2014 Elsevier B.V. All rights reserved.
Keywords: Electrospinning Polymeric nanofibers Piroxicam Controlled release Solid dispersion Physical stability
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1. Introduction Interest in the development of controlled-release (CR) drug delivery systems for poorly water-soluble drugs has been increasing steadily. One reason for this is the fact that the majority of the promising new drug candidates coming out from the discovery pipeline are poorly water-soluble compounds. Many of these drugs can exist in different polymorphic or solvated crystal forms, and also in the amorphous state the latter having an enhanced dissolution and bioavailability compared to the crystalline state (Hancock and Zografi, 1997). The delivery of high-energy solid forms (such as amorphous forms, co-crystals and the like) may induce the generation of supersaturated solutions, and this
* Corresponding author. Tel.: +372 737 5282; fax: +372 737 5289. E-mail addresses: [email protected] (U. Paaver), [email protected] (J. Heinämäki), [email protected] (I. Laidmäe), [email protected] (A. Lust), [email protected] (J. Kozlova), [email protected] (E. Sillaste), [email protected] (K. Kirsimäe), [email protected] (P. Veski), [email protected] (K. Kogermann).
strategy can be used to enhance oral/topical absorption and also to sustain the drug release by choosing appropriate CR polymers (Brouwers et al., 2009; Tran et al., 2011). A supersaturated drug solution, however, is thermodynamically unstable and has the tendency to return to the equilibrium state by precipitation. The stabilisation of a supersaturated solution can be accomplished by adding polymers (precipitation inhibitors) which may act through a variety of mechanisms (Brouwers et al., 2009). Hydroxypropyl methylcellulose (HPMC) has been reported as the excipient of choice to be included into such formulations as a carrier/stabilizer and precipitation inhibitor (Brouwers et al., 2009; Gao et al., 2009; Q3 Ohara et al., 2005; Raghavan et al., 2001a,b; Tran et al., 2011). A combination of solid dispersion (SD) and CR techniques is a novel dissolution-modulating approach and strategy in designing oral CR drug delivery systems for poorly water-soluble drugs (Tran et al., 2011). The CR–SD systems comprise the advantages and functions of both SD and CR. Piroxicam, PRX is a non-steroidal anti-inflammatory drug widely used in the treatment of rheumatic diseases. It is a poorly water-soluble polymorphic drug which belongs to Class II (high permeability, low solubility) in the
http://dx.doi.org/10.1016/j.ijpharm.2014.12.024 0378-5173/ ã 2014 Elsevier B.V. All rights reserved.
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Biopharmaceutical Classification System (Amidon et al., 1995). To date, PRX has been formulated in oral and topical CR drug delivery systems by using e.g. a solvent evaporation method (Guiziou et al., 1996; Joseph et al., 2002), a spray-drying method (Wagenaar and Muller, 1994), an acoustically modified spraying method (Berkland et al., 2003) and encapsulation of the drug in liposomes (Canto et al., 1999). Since amorphous PRX shows a strong propensity to crystallize (Sheth et al., 2004a), designing and formulating amorphous PRX together with polymers into the CR drug delivery systems could be a beneficial alternative approach. Previously, amorphous PRX has been prepared by melt/quench-cooling and cryogenic ball milling methods but the major limitations associated to these techniques are the chemical degradation of PRX and susceptibility to recrystallize into the respective starting polymorph from which PRX was originally prepared (Redenti et al., 1996; Sheth et al., 2004b; Vre9 cer et al., 1991). According to our recent findings, amorphous state of PRX can be obtained by ballmilling at low temperature but the major limitation of this technique is that amorphous PRX is very unstable (Kogermann et al., 2011). Recently, the production of nanocrystals using a high pressure homogenisation technique was introduced to modify the dissolution and oral absorption of PRX (Lai et al., 2011). Electrospinning is an effective and continuous method to fabricate polymeric nanofibers with diameters ranging from a nanometer level to submicron level and with a large surface area to volume ratio (Agarwal et al., 2008; Lu et al., 2009; Paaver et al., 2014; Pelipenko et al., 2013). In electrospinning, the surface areas of nanofibers can be increased through the formation of much smaller pores in the surface of fibers by controlling e.g. the solution and process parameters of electrospinning (Li and Xia, 2004). Brewster et al. (2004) and more recently Yu et al. (2009) suggested that electrospun ultrafine fibers have the potential to be used as amorphous SDs to improve the solubility and dissolution of poorly water-soluble drugs. The formation of an amorphous SD or solid solution of drug was found when organic-solvent solutions of itraconazole/HPMC mixtures were electrospun resulting in dosage forms with controllable dissolution properties (Verreck et al., 2003). More recently, Huang et al. (2012) introduced a novel time-engineering biphasic CR system for oral delivery of a poorly water-soluble ketoprofen using tri-layered electrospun amorphous nanofibrous mats. Jiang et al. (2012) applied coaxial electrospinning for providing biphasic CR drug release profiles of the nanostructures containing a poorly water-soluble ketoprofen. Consequently, electrospinning could be an interesting alternative for stabilising drugs in an amorphous state in prepared SD, and hence this might lead to improved bioavailability in both oral immediate release and CR drug therapy. For poorly water-soluble drugs, increasing the surface area to volume ratio and/or modification of solid-state form may offer a convenient way to control their dissolution rate and/or stability. The aim of the present study was to combine SD and CR techniques in fabricating supersaturating controlled-release drug delivery systems for poorly water-soluble drugs. Electrospinning was investigated as a new technique in preparing high-energy amorphous SDs of a poorly water-soluble drug PRX, and for fabricating CR–SD nanofibers of PRX and hydrophilic cellulosic carrier polymer. Special attention was paid on the effects of a hydrophilic carrier polymer HPMC and solvent system on solidstate properties, dissolution and physical stability of drug-loaded nanofiber matrices.
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2. Materials and methods
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2.1. Materials
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Piroxicam (anhydrous PRX pure form I, PRXAH I, Letco Medical, Inc., USA) was used as a poorly water-soluble drug in fabricating
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electrospun CR–SD nanofibers. Other crystalline forms of PRX (PRX monohydrate PRXMH and PRX anhydrate form III, PRXAH III) used for comparison were prepared as previously reported (Kogermann et al., 2007a, 2011). Three grades of hydroxypropyl methylcellulose, HPMC were studied as a carrier and stabilising polymers for CR–SD nanofibers: MethocelTM K100M premium CR; MethocelTM K4M premium CR; MethocelTM E5 premium LV (The Dow Chemical Company, USA). The primary solvents applied in the electrospinning studies were methanol (Sigma–Aldrich Chemie GmbH, Germany) and 1,1,1,3,3,3hexa-fluoro-2-propanol (HFIP) (99.0%) (Apollo Scientific Ltd., UK). Applicability of ethanol, acetone, 2-propanol and dichloromethane (Lach-Ner s.r.o., Czech Republic) for electrospinning of nanofibers was also studied. All other reagents and solvents used were of analytical grade.
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2.2. Selection of solvent systems for electrospinning
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Table 1 summarises the results on the solubility/miscibility of the carrier HPMC polymers in different solvent systems. The test was based on visual inspection. Non-aqueous and readily evaporating HFIP was selected as the most suitable solvent system for further electrospinning experiments with PRX and HPMC.
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2.3. Method for fabrication of nanofibers
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A schematic diagram of the electrospinning process is shown in Fig. 1. The automatic syringe pump KdScientific (Model No: KDS250-CE, Geneq Inc., USA) with a pumping speed of 1 ml/h, was used for electrospinning. The high-voltage power supply Gamma High Voltage Research (Model No. ES3OP-10W/DAM, USA) was applied for generating the voltage of 7–22 kV used in the experiments. The distance between the spinneret and the fiber collector was in a range of 8–25 cm. The drug-polymer (PRX/HPMC) ratios (w/w) used in electrospinning experiments were 1:1, 2:1 and 4:1. For preparing the nanofibers containing HPMC K100M premium CR as a carrier polymer and HFIP as a solvent system, the levels for the voltage and distance were 7, 9, 10 kV and 8, 10, 12 cm, respectively. For preparing nanofibers with the other two HPMC grades, the higher operating voltage (22 kV) and different distance (25 cm) were applied. The electrospun nanofibers were investigated immediately after fabrication and within regular time periods during a shortterm (3-month) aging at a low temperature (LT 6–8 C/0% RH) and ambient room temperature (RT 22 C/0% RH). In addition, some samples were also stored for up to 2 months at higher temperature (HT) and humidity conditions (30 C/85% RH).
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2.4. Physicochemical characterisation
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2.4.1. X-ray powder diffraction X-ray powder diffraction (XRPD) patterns of starting materials and electrospun nanofibers (immediately after fabrication and after a short-term aging) were obtained by using a X-ray diffractometer (D8 Advance, Bruker AXS GmbH, Germany). Crystal structures were verified by comparing the experimental results to the theoretical patterns in the Cambridge Structural Database (CSD) or to diffractograms available in the literature (Bordner et al., 1984; Reck et al., 1988; Vre9cer et al., 2003). The XRPD experiments were carried out in a symmetrical reflection mode (Bragg– Brentano geometry) with CuKa radiation (1.54 Å). The scattered intensities were measured with the LynxEye one-dimensional detector with 165 channels. The angular range was from 5 2-theta to 30 2-theta with steps of 0.2 2-theta. The total measuring time was 498 s per step. The operating current and voltage were 40 mA and 40 kV, respectively.
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Table 1 Solubility/miscibility of the three hydroxypropyl methylcellulose (HPMC) carrier polymer grades (Methocel K100M premium CR; K4M premium CR; E5 premium LV) in different solvent systems.
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Exp.
Polymer
Solvent system
Polymer concentration
Remarks
A1 A2 A3 A4 A5 A6 A7 A8
HPMC K100M CR
Acetone:water 1:1 Acetone:water 9:1 Methanol:water 1:1 Ethanol:water 1:1 2-Propanol:water 1:1 Methanol:dichloro methane 1:1 Ethanol:dichloro methane 1:1 HFIP
1% (w/V) 0.5%, 0.75% and 1% (w/V) 1% (w/V) 1% (w/V) 0.75% (w/V) 1% (w/V) 1% (w/V) 0.8% (w/V)
Jelly, sediment Not dissolved (unsuitable solvent system) Viscous, clear solution Jelly, sediment Viscous solution Viscous, cloudy solution Not dissolved (unsuitable solvent system) Viscous, clear solution
B1 B2 B3 B4 B5 B6 B7
HPMC K4M CR
Acetone:water 1:1 Methanol:water 1:1 Ethanol:water 1:1 2-Propanol:water 1:1 Methanol:dichloro methane 1:1 Ethanol:dichloro methane 2:3, 1:2 HFIP
1% (w/V) 1% (w/V) 1% (w/V) 0.375% (m/V) 1% (w/V) 1% (w/V) 0.8% (w/V)
Cloudy, viscous and jelly solution Cloudy, viscous and jelly solution Cloudy, viscous and jelly solution – – Not dissolved (unsuitable solvent system) –
C1 C2 C3 C4 C5 C6 C7
HPMC E5 LV
Acetone:water 1:1 Methanol:water 1:1 Ethanol: water 1:1 2-Propanol:water 1:1 Methanol:dichloro methane 1:1 Ethanol:dichloro methane 2:3, 1:2 HFIP
10%, 15% (w/V) 10%, 15% (w/V) 10%, 15% (w/V) 10%, 15% (w/V) 10%, 15% (w/V) 10%, 15% (w/V) 0.8% (w/V)
Clear, viscous solution Clear, viscous solution Clear, viscous solution Clear, viscous solution Viscous, slightly cloudy solution Viscous, slightly cloudy solution –
2.4.2. Raman spectroscopy Raman spectra of both the starting materials and electrospun nanofibers were collected using a Raman spectrometer equipped with a thermoelectrically cooled CCD detector (1024 64) and a fiber optic probe (B&W TEK Inc., USA). A 300 mW laser source at 785 nm was used (B&W TEK Inc., USA). Spectra were recorded between 200 and 2200 cm 1 with an integration time of 12 s, and were the average of three scans. BWTek software (BWTek-Inc., Newark, USA) was used for the collection of Raman spectra. Raman spectra were normalised and a spectral region from 1000 to 1700 cm 1 was used for analysis. 2.4.3. Differential scanning calorimetry Differential scanning calorimetry (DSC) studies of nanofibers were carried out using a PerkinElmer DSC 4000 differential scanning calorimeter (PerkinElmer Ltd., Shelton, CT, USA). The DSC system was calibrated for temperature and enthalpy using indium as a standard. Samples of 2–3 mg were sealed in an aluminum pan with 2 pinholes in a lid. A nitrogen purge with a flow rate of 20 ml/ min was used in the furnace. The scans were obtained by heating from 30 C to 220 C at a rate of 20 C/min. Each run was performed in triplicate. Temperatures are shown as on-set temperatures of the events unless mentioned otherwise.
2.4.4. Scanning electron microscopy The diameter and surface morphology of nanofibers was investigated with a high-resolution scanning electron microscope (SEM) (Helios NanoLab 600, FEI Company). A measurement function of the microscope driving program xT Microscope Control (FEI) was applied for the dimension measurements. Samples were mounted on aluminum stubs with silver paint and magnetron sputter coated with 3 nm gold layer in argon atmosphere prior to microscopy.
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2.4.5. Dissolution test The in vitro dissolution tests of electrospun nanofiber and pure PRX samples were performed using a USP dissolution apparatus I (basket method). The dissolution experiments were carried out in a semi-automated dissolution system (Termostat-Sotax AT7, Sotax AG, Switzerland). The dissolution studies were carried out both with the nanofibers charged into hard gelatin capsules No. 1 (PosilocTM Elanco) and with the nanofibers freely set into the dissolution baskets. The concentration of PRX in the dissolution medium was measured at 354 nm by using a UV–vis spectrophotometer (Ultrospec III, Biochrom Ltd., UK). The dissolution medium was 900 ml of buffer solution (pH 1.2 or pH 7.2) maintained at 37 0.5 C as described in the USP 28. The basket rotation speed
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Fig. 1. Schematic diagram of an electrospinning equipment. Key: (A) syringe pump; (B) syringe; (C) polymer solution; (D) high-voltage power supply; (E) electrode; (F) grounded collector.
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was set at 50 rpm. Six parallel tests were performed for each sample.
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3. Results and discussion
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3.1. Morphology and diameter of nanofibers
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According to the literature, the morphology and diameter of electrospun nanofibers are dependent on the intrinsic properties of the solution such as the type of polymer, the conformation of polymer chain, viscosity (or concentration), elasticity, electrical conductivity, and the polarity and surface tension of the solvent (Li and Xia, 2004; Lu et al., 2009; Meinel et al., 2012). From the process parameters the most crucial are the applied voltage, the feed rate and the distance to the collector (Rošic et al., 2012). In the present study, the drug loading of CR–SD nanofibers was performed by electrospinning of drug/polymer blends. Different polymer/solvent systems were tested and the best polymer–solvent combination for electrospinning was found to be a 0.8% solution of HPMC (Methocel K100M premium CR) in HFIP (Table 1). The other polymer/solvent systems tested were also electrospinnable, but in this study the lowest concentration of polymer and the solvent with the fastest evaporation were used. Of the process parameters studied, both voltage and distance between the spinneret and the fiber collector were shown to have a significant effect on the formation of nanofibers. Increasing the distance between a nozzle tip and collector resulted in thinner and more uniform nanofibers as the voltage was kept constant. This can be explained by the fact that the distance between the spinneret and collector affects the strength of the electric field, and consequently, governs the stretching of the polymer jet (Rošic et al., 2012). The combination of voltage and distance that yielded the optimal nanofibers in the present electrospinning procedure was found to be 9 kV and 10 cm, respectively. The representative SEM images of the electrospun CR–SD nanofibers of PRX and HPMC, and the reference pure polymer nanofibers (without PRX) are shown in Fig. 2. The nanofibers of PRX and HPMC were slightly larger in diameter (387 125 nm, n = 100) than the reference HPMC polymeric nanofibers 195 143 nm, n = 100) nm (Fig. 2). Both types of electrospun nanofibers (with and without PRX) exhibited very uniform thickness forming a homogeneous non-woven nanomat onto a collector plate. According to Meinel et al. (2012), blending polymer solutions with drugs can affect the geometric properties of electrospun fibers due to the changes in solution viscosity and electrical conductivity. A decrease in the charge density on the surface of the electrospun jet and an increase in solution viscosity result in larger fiber size. In the present study, PRX being capable to be ionized as a zwitter ion, likely influenced the electrical conductivity of the polymer solution. The formation and presence of defects such as beads in the electrospun nanofibers were not
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observed suggesting that the viscosity and surface tension of the polymeric solution was suitable for fabricating the drug-loaded nanofiber matrices. Furthermore, the presence of crystallised PRX on the surface of nanofibers was not observed indicating that the drug was in a non-crystalline state in the electrospun nanofibers. The solid state of PRX in the present nanofibers was investigated further using XRPD and Raman spectroscopy.
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3.2. Physical state of API in the nanofibers
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To date, the behavior and possible solid-state phase transformations of drugs during electrospinning are not very well known and understood. According to Huang et al. (2003), the likely four modes of the drug in the electrospun nanofibers are: (1) The drug is bound on the surface of the carrier polymer that forms nanofibers, (2) Both the drug and carrier polymer form nanofibers, (3) The drug and carrier polymer are integrated into one kind of nanofibers, and (4) The carrier polymer is in a tubular form in which the drug particles are encapsulated. In the present study, amorphisation of PRX was aimed to be facilitated (in line with the mode 3) by fast removal of solvent during electrospinning of a drug/polymer blend into nanofibers. HPMC acts in this electrospun formulation both as a carrier/stabilizer for the amorphisation and stabilizer of the supersaturated state upon the release of drug. Drug solubility and content in the polymer solution have been shown to be important factors affecting the solid-state form and distribution of drug in the electrospun nanofibers (Meinel et al., 2012; Natu et al., 2010).
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3.2.1. XRPD analysis PRX is a polymorphic drug that exists in several X-ray solidstate forms, including the three anhydrate (I–III), monohydrate and amorphous forms (Sheth et al., 2004a; Vre9 cer et al., 2003). In the present study, PRX was originally in PRXAH I as verified by XRPD. As shown in Fig. 3, the characteristic XRPD reflections of PRXAH I were observed at diffraction angles 2u of 8.3 , 11.7, 12.5 , 14.3 , and 17.7. The cellulose ether polymer (HPMC) is an amorphous polymer without any characteristic diffraction reflections in its XRPD pattern. Fig. 3 shows the XRPD patterns of PRX and HPMC nanofibers (Methocel K100M premium CR) immediately after fabrication and after a short-term (3-months) aging at low (LT 6–8 C/0% RH) and ambient room temperature (RT 22 C/0% RH). Amorphous halo in all XRPD patterns indicated the presence of amorphous PRX in the electrospun CR–SD nanofibers (1:1) immediately after fabrication and after a 3-month aging. PRX existed in XRPD amorphous form showing no signs of recrystallisation or polymorphic solid-state changes during the aging. According to Kogermann et al. (2011), the spontaneous recrystallisation of amorphous form of PRXAH I starts within few minutes after the amorphous form preparation. This suggests that the electropinning of PRX with HPMC (Methocel
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Fig. 2. Scanning electron microscopy (SEM) micrographs of electrospun piroxicam (PRX) loaded hydroxypropyl methylcellulose (HPMC) nanofibers (a drug–polymer ratio 1:1) (A, B) and the reference nanofibers of a pure carrier polymer HPMC (MethocelTM K100M premium CR) (C, D).
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Similarly, Naelapää et al. (2012) showed that PRXAH I amorphous samples recrystallised as PRXAH I together with the diffractions of the least stable PRXAH III. Furthermore, the storage conditions have been shown to influence the amorphous state of PRXAH I due to the possible presence of higher residual order in X-ray amorphous PRXAH I samples (Naelapää et al., 2012). Present study reveals that the recrystallisation of amorphous PRX was slowed down by the presence of polymer in nanofibers and also further solid-state changes were inhibited.
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K100M premium CR) in HFIP significantly prevents the solid-state transformation (recrystallisation) of PRX, and consequently, stabilizes the amorphous form of PRX in the solid formulation. HPMC has the ability to form hydrogen bonds between drug molecules and the polymer, and consequently, to increase the activation energy for crystallisation (Brouwers et al., 2009). Furthermore, HPMC can increase the glass transition temperature and sustain supersaturation of the system which makes it a carrier polymer of choice for the present nanofibers. Since the solid-state transformations of drug are dependent on temperature and humidity, a short-term aging of the nanofibers was also carried out at elevated temperature and humidity conditions (30 C/85% RH) (Fig. 4). The appearance of PRXAH III characteristic reflection at a diffraction angle 2u of 8.9 suggested partial recrystallisation of amorphous PRX. Sheth et al. (2004b) reported that by using a cryogenic ball milling some polymorphic memory of PRXAH I could be retained in the respective amorphous form of PRX, which tends to recrystallise predominantly to PRXAH I, although some PRXAH III character may also be present.
3.2.2. Raman spectroscopy analysis Fig. 5 shows the Raman spectra of PRX and HPMC (1:1) nanofibers immediately after fabrication and after 2-months aging at LT and RT. The characteristic Raman spectroscopy peaks of PRXAH I are displayed at 1282, 1338, 1435, and 1525 cm 1 (Fig. 5). These are in a close agreement with previously published ones with only minor differences, and these earlier publications also reported the possible peak assignments (Kogermann et al., 2007a, b; Redenti et al., 1999). Recently, Kogermann et al. (2011) introduced the experimental Raman spectrum of amorphous PRX which allows monitoring the crystalline–amorphous transformations and investigating PRX stability under various conditions. The present nanofibers obtained by electrospinning from PRXAH I showed slightly different Raman spectrum compared to amorphous PRX obtained by ball milling at low temperature (and reported by Kogermann et al., 2011). However, the authors believe that these differences are due to the different equipments used for analysis and their different spectral resolution. The joint characteristic peaks for amorphous PRX are shown at 1159, 1237, 1331, 1365, 1438, 1477, 1531, and 1561 cm 1 (Fig. 5) suggesting the presence of amorphous PRX in the electrospun nanofibers. These characteristic peaks (peak position, intensity and the sharpness of the peaks) differ from all known PRX crystalline forms. This result is also in line with the earlier XRPD analysis. During electrospinning, a large specific surface area is obtained resulting in fast and efficient evaporation of the organic solvent, and consequently, molecules have no time to (re)crystallise and hence they most likely have an amorphous supermolecular structure (Verreck et al., 2003; Zong et al., 2002). In addition, adsorbed HPMC with an ability to form hydrogen bonds can prevent the crystal growth of API by hindering the
Fig. 4. X-ray powder diffraction (XRPD) patterns of electrospun piroxicam (PRX) loaded hydroxypropyl methylcellulose (HPMC) nanofibers (a drug–polymer ratio 1:1) immediately after fabrication and after a three-day aging of the samples at elevated temperature and humidity conditions (30 C/85% RH). Key: PRXAH I = PRX anhydrate form I; PRXAH II = PRX anhydrate form II, PRXAH III = PRX anhydrate form III; and PRXMH = PRX monohydrate.
Fig. 5. Raman spectra of electrospun piroxicam (PRX) loaded hydroxypropyl methylcellulose (HPMC) nanofibers (a drug–polymer ratio 1:1) immediately after fabrication and after a short-term aging of the samples at low (LT 6–8 C/0% RH) and room temperature (RT 22 C/0% RH). Key: PRXAH I = PRX anhydrate form I; PRXAH II = PRX anhydrate form II, PRXAH III = PRX anhydrate form III; and PRXMH = PRX monohydrate.
Fig. 3. X-ray powder diffraction (XRPD) patterns of electrospun piroxicam (PRX) loaded hydroxypropyl methylcellulose (HPMC) nanofibers (a drug–polymer ratio 1:1) immediately after fabrication and after a short-term aging of the samples at low (LT 6–8 C/0% RH) and room temperature (RT 22 C/0% RH). Key: PRXAH I = PRX anhydrate form I; PRXAH II = PRX anhydrate form II, PRXAH III = PRX anhydrate form III; and PRXMH = PRX monohydrate.
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incorporation of drug molecules into the crystal lattice (Brouwers et al., 2009). The Raman spectra of fresh and aged polymeric PRX and HPMC (1:1) nanofibers were identical indicating no solid-state transformations occurred during a short-term aging of nanofibers at LT and RT for 2 months (Fig. 5). The Raman spectroscopy results supported XRPD analysis findings suggesting the presence of amorphous PRX in the nanofibers. However, it is evident that elevated storage conditions readily affect the recrystallisation of amorphous PRX since only three-day aging at 30 C/85% RH led to the formation of PRXAH III. Interestingly, both Raman spectroscopy and XRPD analysis also revealed (data not shown) that the nanofibers with a higher drug–polymer ratio of 2:1 and 4:1 were amorphous immediately after preparation, but after a two-month aging PRX tended to crystallise out from the nanofibers (unlike with the respective 1:1 samples). This suggests that the amount of HPMC is critical and needs to be high enough to prevent the crystallisation of PRX through forming hydrogen bonds in the present electrospun nanofibers. These results highlight the importance of proper storage conditions which remarkably may change the stability of amorphous PRX in the electrospun polymeric nanofibers. It has been shown previously that during RT milling and/or also heating the least stable PRXAH III crystallises first, which then gradually transforms to PRXAH I (Kogermann et al., 2010; Sheth et al., 2004b). The transitions between different crystalline forms of drugs are always directed toward the most stable form at specified conditions thus the transformation of PRXAH I to PRXMH at higher humidity conditions has been reported (Paaver et al., 2012; Sheth et al., 2004a,b). The most likely explanations for the absence of PRXMH form in the nanofibers (immediately after fabrication) are that a non-aqueous solvent (HFIP) was used in electrospinning thereby providing the medium for PRX to exist in the amorphous form obtained from PRXAH I and that the ambient RH of the experiment environment was not high enough to cause instant hydrate formation.
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3.3. Thermal behavior
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DSC studies were performed to determine the solid-state form of PRX in the electrospun polymeric CR–SD nanofibers and to confirm the XRPD and Raman spectroscopy results. Fig. 6 shows the DSC thermograms of pure materials (PRXAH I, HPMC),
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Fig. 6. Differential scanning calorimetry (DSC) thermograms. Key: (A) piroxicam (PRX) anhydrate form I (PRXAH I), (B) hydroxypropyl methylcellulose, HPMC (MethocelTM K100M premium CR), (C) electrospun HPMC polymeric nanofibers and (D) electrospun HPMC:PRX nanofibers (a drug–polymer ratio 1:1).
electrospun carrier polymer HPMC nanofibers and electrospun PRX-HPMC nanofibers (1:1). The DSC thermogram of pure PRXAH I exhibited a single melting endotherm at 204.0 C with the enthalpy of melting (DH) 100.8 J/g (Fig. 6A), which is in good agreement with the values reported in the literature (Stulzer et al., 2008; Wu et al., 2009). As seen in Fig. 6B and C, the DSC profiles of pure HPMC and non-drug containing electrospun HPMC nanofibers showed the thermal behavior of amorphous material without any melting endotherms. The only endothermic event was in the range of 40–120 C most likely due to the polymer dehydration. In the case of PRX and HPMC nanofibers (1:1) measured immediately after preparation (Fig. 6D), the thermal parameters of both pure components (PRX, HPMC) were observed in the thermograms (with only a slight shift of thermal parameters), thus suggesting the absence of any solid-state interactions or incompatibility between PRX and HPMC. Furthermore, no thermal events due to the chemical decomposition were found. In addition, the DSC thermograms of electrospun CR–SD nanofibers showed a weak exothermic event at 131.1 C (DH = 25.1 J/g) suggesting partial (minor) crystallisation of amorphous PRX. This observation was confirmed by the second endotherm at about 199.0 C, most likely corresponding to the PRXAH III melting (Fig. 6D). In addition, a concomitant reduction in peak size and enthalpy per unit mass of PRX was evident (DH of PRX decreased from 100.8 to 50.3 J/g). These results also agree with the XRPD and Raman spectroscopy ones. The recrystallisation of PRXAH III from electrospun nanofibers upon heating enlightens the instability of amorphous PRX at higher temperatures.
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3.4. Dissolution
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According to the recent literature, the drug release from electrospun polymeric nanofibers is dependent on several material and process factors including drug molecular weight, loading and state, carrier polymer(s), fiber crystallinity, fiber diameter and porosity, and drug–polymer–electrospinning solvent interactions (Meinel et al., 2012; Natu et al., 2010). Fig. 7 shows the dissolution profiles of pure PRX powder, physical mixtures and electrospun CR–SD polymeric nanofibers in different dissolution media (pH). The dissolution of pure PRXAH I was dependent on the pH of dissolution media being poorer in the acidic (pH 1.2, Fig. 7A) than in slightly basic (pH 7.2, Fig. 7B) dissolution medium. Interestingly, in case of the PRX and HPMC electrospun nanofibers, the release rate of PRX was less dependent on the pH of dissolution media being only slightly lower at pH 1.2 than pH 7.2. Fig. 8 illustrates the effects of drug–polymer ratio on the release profile of PRX loaded nanofibers. The dissolution of amorphous PRX from the CR–SD nanofibers was a prolonged carrier-polymer controlled process, and the initial dissolution rate of PRX was directly connected with PRX–polymer ratio (Fig. 8). Sustained-release dissolution rate of the CR–SD polymeric nanofibers was attributed to a highmolecular HPMC grade used as a carrier polymer and the formation of a solid matrix inside hard gelatine capsules. As shown in Fig. 7, the present electrospun CR–SD nanofibers loaded in hard gelatine capsules exhibited a short lag-time (10– 15 min), the absence of initial burst release and zero-order linear dissolution kinetics. According to the literature, the drug release profiles from HPMC containing hydrophilic matrices are generally first-order for highly water-soluble drugs or zero-order for insoluble drugs (Tran et al., 2011). It is evident that the amorphous state of PRX and generation of supersaturated solution associated with the present CR–SD nanofibers decreased the lag-time for the drug release in vitro. In addition, it can be expected that CR–SD nanofibers as a kind of supersaturating drug delivery system could enhance the absorption of a poorly water-soluble drug by reducing
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Fig. 7. Release profiles of piroxicam (PRX) loaded hydroxypropyl methylcellulose (HPMC) nanofibers at (A) pH 1.2 and (B) pH 7.2 (n = 6). For clarity purposes, the standard deviation is not shown, but for all dissolution results it was below 5.0%.
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the precipitation of drug and thus generating high free drug concentrations, e.g. in the gastrointestinal tract. According to Brouwers et al. (2009), it is possible that the supersaturation plays a role in the absorption process of various solubilising dosage forms of poorly water-soluble drugs, and thus these dosage forms can be adjusted into supersaturated formulations by using a suitable precipitation inhibitor (e.g. HPMC) in the delivery system. Since our recent study suggests that hard gelatine capsule shells might interact with a carrier polymer (Kogermann et al., 2013), the
dissolution tests with the present nanofibers were performed also without using hard gelatine capsules (i.e. with free nanofibers in the baskets). A slight difference in dissolution was found between the nanofibers that were placed freely in the dissolution baskets or loaded into hard gelatine capsules (Fig. 7; small graphs). The first ones showed an initial burst release and then almost constant difference in prolonged drug release compared to that obtained with the nanofibers loaded in hard gelatine capsules (a drug– polymer ratio 1:1).
Please cite this article in press as: Paaver, U., et al., Electrospun nanofibers as a potential controlled-release solid dispersion system for poorly water-soluble drugs. Int J Pharmaceut (2014), http://dx.doi.org/10.1016/j.ijpharm.2014.12.024
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Fig. 8. Effects of drug–polymer ratio on the dissolution of piroxicam (PRX) loaded hydroxypropyl methylcellulose (HPMC) nanofibers (n = 6). The dissolution behavior of free nanofibers (with a drug–polymer ratio 1:1 and 4:1 w/w) were tested at pH 1.2 and pH 7.2. For clarity purposes, the standard deviation is not shown, but for all dissolution results it was below 5.0%. 485
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Electrospinning can be used for the amorphisation of a poorly water-soluble piroxicam (PRX) and for fabricating supersaturated controlled-release solid dispersion (CR–SD) polymeric nanofiber matrices. Binary mixtures of PRX anhydrate form I (PRXAH I) and HPMC in HFIP can be electrospun across relatively low potentials (7–10 kV) generating polymeric nanofibers with uniform diameters ranging from 400 to 600 nm. The properties of CR–SD polymeric nanofibers, such as physical stability and dissolution, are dependent on the grade of the HPMC carrier polymer, initial crystalline form of PRX, solvent system applied, and storage conditions. The recrystallisation of amorphous PRX from CR–SD polymeric nanofibers is less favored at low temperature and humidity. XRPD and Raman spectroscopy complemented with DSC analysis permit thorough solid-state characterisation of PRX forms and its transformations inside electrospun nanofibers. Electrospinning can be a future technology for amorphisation and formulating novel supersaturating CR–SD drug delivery systems of poorly water-soluble drugs.
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Hanhijärvi et al. (2010) and Taepaiboon et al. (2006).
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This research was supported by the European Social Fund’s Doctoral Studies and Internationalisation Programme DoRa. This work is part of the targeted financing project no. SF0180042s09 and ETF grant project no. ETF7980. Estonian Ministry of Education and Research is acknowledged for financial support. The authors are grateful to Prof. Dr. Franc Vre9 cer (Krka, d.d., Novo Mesto, R&D Division, Šmarješka cesta 6, 8501 Novo mesto, Slovenia) for providing the XRPD data of PRXAH III. Dr. Mingshi Yang (University
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of Copenhagen) is thanked for the help with the preparation of PRXAH III. Mr. Jaan Aruväli (X-ray laboratory of Institute of Ecology and Earth Sciences, University of Tartu) and Prof. Väino Sammelselg (Institute of Physics, University of Tartu) are acknowledged for the support in XRPD and SEM experiments, respectively.
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