http://informahealthcare.com/ddi ISSN: 0363-9045 (print), 1520-5762 (electronic) Drug Dev Ind Pharm, Early Online: 1–6 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2015.1013967
RESEARCH ARTICLE
Micro- and macrostructural characterization of polyvinylpirrolidone rotary-spun fibers 00 Istva´n Sebe1, Barnaba´s Ka´llai-Szabo´2, Krisztia´n Norbert Kova´cs3, Eniko Szabadi2, and Roma´na Zelko´1
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1
University Pharmacy Department of Pharmacy Administration, Semmelweis University, Budapest, Hungary, 2Department of Pharmaceutics, Semmelweis University, Budapest, Hungary, and 3Department of Polymer Engineering, Faculty of Mechanical Engineering, Budapest University of Technology and Economics, Budapest, Hungary Abstract
Keywords
The application of high-speed rotary spinning can offer a useful mean for either preparation of fibrous intermediate for conventional dosage forms or drug delivery systems. Polyvinylpyrrolidone (PVP) and poly(vinylpyrrolidone-vinylacetate) (PVP VA) micro- and nanofibers of different polymer concentrations and solvent ratios were prepared with a highspeed rotary spinning technique. In order to study the influence of parameters that enable successful fiber production from polymeric viscous solutions, a complex micro- and macrostructural screening method was implemented. The obtained fiber mats were subjected to detailed morphological analysis using scanning electron microscope (SEM), and rheological measurements while the microstructural changes of fiber samples, based on the free volume changes, was analyzed by positron annihilation lifetime spectroscopy (PALS) and compared with their mechanical characteristics. The plasticizing effect of water tracked by orthopositronium lifetime changes in relation to the mechanical properties of fibers. A concentration range of polyvinylpyrrolidone solutions was defined for the preparation of fibers of optimum fiber morphology and mechanical properties. The method enabled fiber formulation of advantageous functionality-related properties for further formulation of solid dosage forms.
Electron microscopy, fibres, high-speed rotary spinning, mechamical properties, microstructures
Introduction The increasing proportion of new drug candidates of poor water solubility poses challenge for the pharmaceutical industry. Excipients with excellent functional properties could compensate for the low aqueous solubility and poor mechanical properties of the emerging active ingredients. Different techniques are used to enhance the functional properties of the excipients and reduce the drawbacks1–3. In recent years, nanosponges have gained tremendous impetus in drug delivery due to their small size and porous nature capable of binding poorly soluble drugs within their matrix and improving their bioavailability4. Drug-loaded polymer nanoor microfibers are also intended to enhance the solubility of poorly soluble drugs5,6. Researchers have reported several ways to fabricate porous polymeric fibrous assemblies by using phase separation7, meltblowing8, electrospinning9,10, and selfassembly11 and forcespinning12–14. Among these methods, the most commonly applied technique is the electrospinning which is a promising method for fabricating micro and nanofibers from a variety of materials including polymers, ceramics, and even biomacromolecules. Despite the popularity of the conventional electrospinning, there exist two factors limiting its
Address for correspondence: Romana Zelko, PhD, DSc, University Pharmacy Department of Pharmacy Administration, H-1092 Hogyes E Street 7-9, Budapest, Hungary. Tel/Fax: +36 1 2170927. E-mail: [email protected]
History Received 7 November 2014 Revised 9 January 2015 Accepted 27 January 2015 Published online 18 February 2015
applications: the random orientation of fibrous mats and the relatively high operating voltage of the process. The high-speed rotary spinning technique utilizes centrifugal forces which allow for a host of new materials to be processed into nanofibers (given that electric fields are not required) while also providing a significant increase in yield and ease of production. High-speed rotary spinning, where aqueous solutions of polymers are applied offers a new environment-friendly alternative way of production of polymeric fibers. Fiber formation from polymer solutions in high-speed rotary spinning is induced by the formed centrifugal force and the solvent evaporation15,16. The method enabled the production of fibers with diameters ranging from the micron-scale to nano-scale. The further processing (grinding, micronization) of micro-fibers results in particles of a similar size range than the auxiliary materials of conventional dosage forms (e.g., tablets), while retaining the fiber structure and its known benefits17. The latter enables their application as possible intermediates of different solid dosage forms. Polyvinylpyrrolidone is a watersoluble polymer of excellent biocompatibility with unique amphiphilic structure18. Due to the coexistence of hydrophilic carbonyl group and hydrophobic –CH2CH2CH2– chain, endows PVP with good balance between hydrophilic and hydrophobic interactions when contacting with drugs of poor water-solubility. Drug-loaded PVP fibers could be useful means in the enhancement of the solubility of poorly soluble drugs. Various spinning configurations have been used for the production of polymer fibers16. However, the parameters required for successful spinning
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Figure 1. The scheme of the rotary reservoir. (a) Cross-sectional view. (b) Perspective view. (c) exploded view. (1) Reservoir (polyamide). (2) Nozzle or spinneret (copper). (3) Cover plate (copper). (4) Fixing screw.
of fibers, namely the effect of solution rheology properties, solvent evaporation rate, and centrifugal forces, among others, have yet to be explored which results in poor control over fiber morphology. The purpose of the present work was to implement a complex micro- and macrostructural screening method to study the influence of those parameters which enable successful rotaryspun fiber production from polyvinylpyrrolidone and poly(vinylpyrrolidone-vinylacetate) viscous solutions. Another aim was to establish a correlation between the fiber characteristics of samples and the rheological properties of initial polymer solutions.
Materials and methods Materials Excipients were PVP 25 and PVP 30 (polyvinylpyrrolidone, Kollidon 25, 30, BASF, Ludwigshafen, Germany, approximate molecular weights: 30 000–50 000), PVP VA 64 (poly(vinylpyrrolidone-vinylacetate), Kollidon VA 64, BASF, Ludwigshafen, Germany, weight average: 45 000–70 000), 96% ethanol (Ph.Eur.). The different types of PVPs were kind gifts from BASF Ltd. (Ludwigshafen, Germany). Sample preparation Viscous solutions of different water and alcohol ratios were prepared with polyvinylpyrrolidones (PVP) of different molecular weights and poly(vinylpyrrolidone-vinylacetate). Samples were regularly stirred until the complete homogenization at room temperature. The optimum range of weight percent of the composition was determined by gradual increase of PVP 30 concentration. The extreme values of PVP 30 weight percent necessary for the spinning were also investigated. The values below the optimum correspond to weight percent of PVP 30 solutions, where fiber first formed, while above the optimum can be considered wherein fiber no longer formed. It means ±4%w/w deviation compared with the optimum, and therefore, the samples for this study were prepared based on this experience. Rheological characterization of polymer viscous solutions Rheological measurements were carried out with Kinexus Pro rheometer (Malvern Instruments Ltd, Malvern, UK). Measured data were registered with rSpace for Kinexus Pro 1.3 software (Malvern Instruments Ltd, Malvern, UK). Preparations were measured using a cone and plate geometry. The gap between the cone and the plate of sample placement was 0.15 mm.
The temperature of the samples was controlled with an accuracy of ±0.1 C, by Peltier system of the rheometer (Malvern Instruments Ltd, Malvern, UK). Viscometric properties were determined at 25 C for an hour with a shear rate of 1.0 s1. High-speed rotary spinning technique The fiber formation was carried out with a WSE 602M (AEG, Berlin, Germany) motor based on the high-speed rotary spinning technique. The rotating reservoir was an aluminum–polyamide spinneret with 30 ml internal volume. The various fibers made from the PVP viscous solutions at 411 relative centrifugal force (RCF) with about 1 g/min production rate. The rotating speed was controlled with a toroidal transformator and measured with laser revolution counter (DT-10L, Voltcraft, Hirschau, Germany). The internal diameter of the nozzles was 0.3 mm. In the course of the process, a perforated reservoir rotating at high speeds along its axis of symmetry, which propels a liquid, polymeric jet out of the reservoir orifice that stretches, dries and eventually solidifies to form micro- or nanoscale fibers. The rotary reservoir is own design with unique geometry. The productivity of fiber formation was 15 g/h in average. The type of collector was a rotating metal drum with 5 cm diameter containing grids. Figure 1 represents the scheme of the rotary reservoir of the high-speed rotary spinning device. Modeling of the mechanical load The mechanical stress of the designed spinneret was analyzed by Ansys v12.1 finite element modeling software (ANSYS Germany GmbH, Otterfing, Germany). In the case of the stainless steel, nozzles and the copper cover used the applied materials for the analysis, in the case of polyamide the fragile polyethylene was chosen from the database of the software. For the analysis, the spinneret was composed by 7060 tetrahedron elements and 12 499 nodes. The highest equivalent stress values at the maximal rotation speed (11 000 rpm, 1152 rad/s with 0.2 mm eccentricity) and the yield strengths of different parts of the spinneret are the followings: Aluminum base: 4 MPa and 100–130 MPa Polymer cover: 5.6 MPa and 26–33 MPa Morphology investigation by scanning electron microscopy Morphology of fibers was observed using a scanning electron microscopy (SEM) type JEOL 6380LVa (JEOL, Tokyo, Japan)
DOI: 10.3109/03639045.2015.1013967
after gold coating. The short parts of samples were fixed by conductive carbon adhesive tape. The applied accelerating high voltage and working distance were 10 and 20 kV and 10 mm and 12 mm, respectively. The average diameters of fibers were measured using 50 different randomly selected individual filaments19.
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Positron annihilation lifetime spectroscopy Positron annihilation lifetime spectroscopy (PALS) is a unique method since it is exceptionally sensitive to the free volume. All these measurements are based on the interaction of the free volume holes and the so-called ortho-positronium atom. When a positron meets with its particle counterpart, they annihilate and provide information on the surroundings of the annihilating pair. As the probability of such a meeting depends on the electron density in materials, positrons are exceptionally sensitive to free volumes, i.e., to the variation of electron density. In polymers, a large fraction of the injected positron forms a bound state with electrons before their annihilation. One of the bound states, the ortho-positronium atom or o-Ps, has a ‘‘long’’ lifetime: it lives for 1–10 ns in polymers. This lifetime is long enough for positronium
Figure 2. Scanning electron microscopic morphology of fibers prepared from PVP 30 solution of various concentrations and solvent ratios.
Structural characterization of PVP rotary-spun fibers
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atoms to scan their surroundings and, fortunately, it is long enough to be observed easily20. For positron lifetime measurements, a positron source made of carrier-free 22NaCl was used. Its activity was around 105 Bq and the active material was sealed between two very thin Ti foils. Lifetime spectra were measured with a fast-fast coincidence system based on BaF2/XP2020Q detectors and OrtecÕ electronics (Ro¨hm Pharma, Darmstadt, Germany). Every spectrum was recorded in 4096 channels of an analyzer card for 3600 s and each contained about 1.5 106 coincidence events. Three parallel spectra were measured at each concentration to increase reliability. After summarizing the parallels, spectra were evaluated by the RESOLUTION computer code; the indicated errors are the deviations of the lifetime parameters obtained21. Three lifetime components were found in every spectrum but among these lifetimes the most important was the longest o-Ps. This lifetime is long enough for positronium atoms to scan their surroundings and it can be observed easily. The plasticization effects of water in different PVP polymers were tracked with the o-Ps lifetime changes. All the measurements were performed to room temperature and atmospheric pressure.
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Table 1. Average diameter of PVP 30 fibers of optimum morphology. Optimum Water–ethanol ratio
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1:0 3:1 1:1 1:3 0:1
Average diameter of fibers/mm
Concentration of PVP 30/w/w %
5.5 ± 0.9 10.3 ± 2.3 11.0 ± 3.7 21.4 ± 6.9 23.0 ± 2.8
55 49 45 45 43
Figure 5. Optimum viscosity values of various polymer solutions of different concentrations and water–ethanol ratios.
Figure 3. Average diameter of various fibers as a function of different water–ethanol ratios of polymer solutions.
Figure 4. Changes of the viscosity values of polymer solutions of various water–ethanol ratios and different PVP 30 contents.
Measurement of the tensile strength and the elastic properties of nanofibers The measurements were carried out with Zwick Z005 (Zwick Roell GmbH, Ulm, Germany) universal testing instrument at 5 mm/min test speed and 25 mm clamping length using 15 N upper force limits at room temperature. The tensile strength and Young’s moduli of randomly oriented fiber webs were calculated using the following equation: Fmax ðN Þ ðkg=m3 Þ Pa; N=m2 ¼ TEX ðkg=mÞ
ð1Þ
Figure 6. o-Ps lifetimes values (a) and water contents (b) of different PVP fibers.
Fmax is the maximum force, is the average density of the fibers, TEX is the linear density which equals to W/L where W is the mass of the fibers and L is the length of fiber22. Elongation was determined by maximum force function of displacement curve.
DOI: 10.3109/03639045.2015.1013967
Determination of the residual water content of fiber mats The water content of prepared fibers was determined by Karl Fischer (KF) titration (787KF Titrino, MetrohmAG, Herisau, Switzerland) at 25 ± 1 C. The water equivalency factor of Hydranal was measured using sodium tartarate (Hydranal-water standard, Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany). The solvent was extra dry methanol, which was titrated with Karl Fischer reagent (MetrohmAG, Herisau, Switzerland) (Hydranalcomposite-5) before the method. About 100 mg of fibers were weighed, homogenized (1 min at 15 000 rpm), and titrated with the reagent.
Results and discussion
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Morphological characterization of fibers Figure 2 illustrates that how the polymer concentration and the solvent composition of viscous PVP 30 solutions determine the morphology of the rotary-spun fibers at the predetermined centrifugal force exerted on the solution jet. Ren et al. found similar results by experimentally studying the relationship between the morphology of the polyvinylpyrrolidone (PVP) and poly(L-lactic acid) (PLLA) composite fibers, the obtained spinning product, and the PLLA–PVP ratios and concentrations of polymer solutions23. They stated that the rheological properties of polymer solution determine the product morphologies; whether they are beads, beaded fibers, or fibers after the spinning.
Structural characterization of PVP rotary-spun fibers
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Table 1 summarizes the average diameters of PVP 30 fibers of optimum fiber morphology from the point of visually observed diameter uniformity and the non-fibrous area ratio. The results indicate that along with the increase of the alcohol ratio of the polymer solutions the diameter of fibers also increased. The letter could be explained with the faster solvent evaporation in the course of spinning, causing more dried polymer content of fibers under the predetermined spinning parameters. Figure 3 represents this tendency in each polymeric solution. Rheological characterization of polymer solutions in relation to the fiber formation Figures 4 and 5 demonstrate how the viscosity values changed related to the optimum fiber formation in the case of various polymer viscous solutions. The viscosity of the polymer solution can be interpreted to be a measure of the extent of polymer chain entanglement. With an increasing degree of polymer chain entanglement, the viscosity of the polymer solution increases. When the polymer chain entanglement is deficient in the spinning solution, the low resistance of the jet is not sufficient to prevent the break-up of the solution jet below a certain rotational speed while in the case of the highly entangled polymer chain, the low resistance of the solution stream is too high to be stretched into fiber assemblies under certain centrifugal force. Thus, there exists a critical polymer chain entanglement for the formation of the fiber assembly at various rotational speeds24,25.
Figure 7. Mechanical characteristics of fibers prepared from different polymeric solutions. (a) Disruptive force of alcohol-based fiber samples. (b) Disruptive force of aqueous-based fiber samples. (c) Elongation of fibers as a function of water–ethanol ratio of polymeric solutions. (d) Young’s modules of fibers as a function of water–ethanol ratio of polymeric solutions.
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Microstructural characterization of fibers in relation to their mechanical properties The specific intermolecular interaction tends to align the chain segments to maximize interactions, thus stiffening the segments locally, reducing their convolution and producing a reduction in entanglements between dissimilar chains. Such specific intermolecular interactions were formed in the case of PVP VA 64. The results indicate that the presence of vinylacetate increased the o-Ps lifetime values (Figure 6a), consequently the free volume holes of the fibers and ordered the PVP chains that was showed in the authors’ earlier study by the decreased width of the o-Ps lifetime distribution curves26. The reduced convolution and entanglement between the chains resulted in decreased viscosity (Figure 5). The presence of water in the polymer solution enabled the formation of hydrogen bonds within the polymeric chains in PVPs having free hydrogen binding sites thus increasing the molecular entanglement. The latter can be tracked with the increased viscosity values necessary to the optimum fiber formation and reduced o-Ps lifetime values of the water filled free volume holes of PVPs of different molecular weights (Figure 6a). The amount of remained water also confirmed the polymer–water supramolecular interaction (Figure 6b). One possible reason of the obtained phenomena is that the PVP VA 64 as a copolymer consisting of hydrophilic (vinylpyrrolidone) and hydrophobic (vinylacetate) monomer units that affinity to the water is lower than the other two PVP homopolymers. Figure 7(a) illustrates the deformation versus disruptive force curves of fibers prepared from alcoholic solutions while Figure 7(b) represents those of fibres prepared from aqueous systems. The presence of water acts as a plasticizer thus increased the elongation of fibers (Figure 7c) while the more ordered PVP VA 64 copolymer, due to the reduced molecular mobility, resulted in more rigid fibers of decreased elongation and increased disruptive force (Figure 7a). Furthermore, Figure 7(d) clearly shows that alcohol could not be able to plasticize the PVP 30, therefore, less displacement and disruptive force were needed for the breaking of fibers consequently the strain without permanent deformation (Young’s moduli) became also smaller.
Conclusions High-speed rotary spinning technique was successfully applied for the preparation of polyvinylpyrrolidone and poly(vinylpyrrolidone-vinylacetate) micro- and nanofibers. A concentration and the consequent viscosity ranges were defined for the preparation of fibers of optimum fiber morphology. Positron lifetime distributions revealed the changes of the free volumes of fibers as a function of the composition of the initial viscous solutions. The supramolecular structure of the fibers could be changed by modifying the type of the polymer and the alcohol– water ratios of polymeric solutions which is of impact from the point of their morphological and mechanical characteristics which determine their further formulation processing of solid dosage forms.
Acknowledgements The authors are grateful to Ka´roly Su¨vegh (Laboratory of Nuclear Chemistry, Eo¨tvo¨s Lora´nd University/HAS Chemical Research Center) for the possibility of the use of PALS equipment, to La´szlo´ Zsidai and Istva´n Oldal for the design of the spinneret, to Ma´te´ Petzke for the valuable contribution in the preparation of rotary-spun fibers.
Declaration of interest The authors report that they have no conflicts of interest.
Drug Dev Ind Pharm, Early Online: 1–6
References 1. Rojas J, Kumar V. Coprocessing of cellulose II with amorphous silicon dioxide: effect of silicification on the powder and tableting properties. Drug Dev Ind Pharm 2012;38:209–26. 2. Rojas J, Buckner I, Kumar V. Co-processed excipients with enhanced direct compression functionality for improved tableting performance. Drug Dev Ind Pharm 2012;38:1159–70. 3. Nystro¨m M, Murtomaa M, Roine J, et al. Processing of pharmaceutical materials by electrospraying under reduced pressure. Drug Dev Ind Pharm 2015;41:116–23. 4. Ahmed RZ, Patil G, Zaheer Z. Nanosponges – a completely new nano-horizon: pharmaceutical applications and recent advances. Drug Dev Ind Pharm 2013;39:1263–72. 5. Szabo´ P, Ka´llai-Szabo´ B, Sebe I, Zelko´ R. Preformulation study of fiber formation and formulation of drug-loaded microfiber based orodispersible tablets for in vitro dissolution enhancement. Int J Pharm 2014;477:643–9. 6. Szabo´ P, Ka´llai-Szabo´ B, Ka´llai-Szabo´ N, et al. Preparation of hydroxypropyl cellulose microfibers by high speed rotary spinning and the prediction of fiber forming properties of hydroxypropyl cellulose gels by texture analysis. Cellulose 2014;21:4419–27. 7. Ma PX, Zhang R. Synthetic nano-scale fibrous extracellular matrix. J Biomed Mater Res 1999;46:60–72. 8. Ellison CJ, Phatak A, Giles DW, et al. Melt blown nanofibers: fiber diameter distributions and onset of fiber breakup. Polymer 2007;48: 3306–16. 9. Doshi J, Reneker DH. Electrospinning process and applications of electrospun fibers. J Electrostat 1995;35:151–60. 10. Reneker DH, Yarin AL. Electrospinning jets and polymer nanofibers. Polymer 2008;49:2387–425. 11. Hong Y, Legge RL, Chen P. Effect of amino acid sequence and pH on nanofiber formation of self-assembling peptides EAK16-II and EAK16-IV. Biomacromolecules 2003;4:1433–42. 12. Lozano K, Sarkar K. Methods and apparatuses for making superfine fibers. US Patent 2009/0280325. 13. McEachin Z, Lozano K. Production and characterization of polycaprolactone nanofibers via ForcespinningÔ technology. J Appl Polym Sci 2012;126:473–9. 14. Sarkar K, Gomez C, Zambrano S, et al. Electrospinning to ForcespinningÔ. Mater Today 2010;13:12–14. 15. Padron S, Fuentes A, Caruntu D, et al. Experimental study of nanofiber production through force spinning. J Appl Phys 2013;113: 024318–9. 16. Badrossamay MR, McIlwee HA, Goss JA, et al. Nanofiber assembly by rotary jet-spinning. Nano Lett 2010;10:2257–61. 17. Sebe I, Bodai Zs, Eke Zs, et al. Comparison of directly compressed vitamin B12 tablets prepared from micronized rotary-spun microfibers and cast films. Drug Dev Ind Pharm 2014. [Epub ahead of print]. DOI: 10.3109/03639045.2014.956112. 18. Su¨vegh K, Zelko´ R. Physical aging of poly(vinylpyrrolidone) under different humidity conditions. Macromolecules 2002;35:795–800. 19. Nagy ZK, Balogh A, Wagner I, et al. Nanofibrous drug delivery systems for enhanced dissolution prepared by electrospinning. Eur J Pharm Sci 2011;44:152–3. 20. Szabo´ B, Sebe I, Ka´llai N, et al. Comparison of the micro- and macrostructural characteristics of biopolymer cast films. Eur Polymer J 2013;49:2422–5. 21. Kirkegaard P, Eldrup M, Mogensen OE, et al. Program system for analysing positron lifetime spectra and angular correlation curves. Comput Phys Commun 1981;23:307–35. 22. Andrady AL. Science and technology of polymer nanofibers. Hoboken: John Wiley & Sons, Inc.; 2008. 23. Ren L, Pandit V, Elkin J, et al. Large-scale and highly efficient synthesis of micro- and nano-fibers with controlled fiber morphology by centrifugal jet spinning for tissue regeneration. Nanoscale 2013;5:2337–45. 24. Um IC, Fang D, Hsiao BS, et al. Electro-spinning and electroblowing of hyaluronic acid. Biomacromolecules 2004;5:1428–36. 25. Wu S. Entanglement, friction, and free volume between dissimilar chains in compatible polymer blends. J Polym Sci Pol Phys 1987;25: 2511–29. 26. Sebe I, Szabo´ B, Nagy ZsK, et al. Polymer structure and antimicrobial activity of polyvinylpyrrolidone-based iodine nanofibers prepared with high-speed rotary spinning technique. Int J Pharm 2013;458:99–103.
RESEARCH ARTICLE
Micro- and macrostructural characterization of polyvinylpirrolidone rotary-spun fibers 00 Istva´n Sebe1, Barnaba´s Ka´llai-Szabo´2, Krisztia´n Norbert Kova´cs3, Eniko Szabadi2, and Roma´na Zelko´1
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1
University Pharmacy Department of Pharmacy Administration, Semmelweis University, Budapest, Hungary, 2Department of Pharmaceutics, Semmelweis University, Budapest, Hungary, and 3Department of Polymer Engineering, Faculty of Mechanical Engineering, Budapest University of Technology and Economics, Budapest, Hungary Abstract
Keywords
The application of high-speed rotary spinning can offer a useful mean for either preparation of fibrous intermediate for conventional dosage forms or drug delivery systems. Polyvinylpyrrolidone (PVP) and poly(vinylpyrrolidone-vinylacetate) (PVP VA) micro- and nanofibers of different polymer concentrations and solvent ratios were prepared with a highspeed rotary spinning technique. In order to study the influence of parameters that enable successful fiber production from polymeric viscous solutions, a complex micro- and macrostructural screening method was implemented. The obtained fiber mats were subjected to detailed morphological analysis using scanning electron microscope (SEM), and rheological measurements while the microstructural changes of fiber samples, based on the free volume changes, was analyzed by positron annihilation lifetime spectroscopy (PALS) and compared with their mechanical characteristics. The plasticizing effect of water tracked by orthopositronium lifetime changes in relation to the mechanical properties of fibers. A concentration range of polyvinylpyrrolidone solutions was defined for the preparation of fibers of optimum fiber morphology and mechanical properties. The method enabled fiber formulation of advantageous functionality-related properties for further formulation of solid dosage forms.
Electron microscopy, fibres, high-speed rotary spinning, mechamical properties, microstructures
Introduction The increasing proportion of new drug candidates of poor water solubility poses challenge for the pharmaceutical industry. Excipients with excellent functional properties could compensate for the low aqueous solubility and poor mechanical properties of the emerging active ingredients. Different techniques are used to enhance the functional properties of the excipients and reduce the drawbacks1–3. In recent years, nanosponges have gained tremendous impetus in drug delivery due to their small size and porous nature capable of binding poorly soluble drugs within their matrix and improving their bioavailability4. Drug-loaded polymer nanoor microfibers are also intended to enhance the solubility of poorly soluble drugs5,6. Researchers have reported several ways to fabricate porous polymeric fibrous assemblies by using phase separation7, meltblowing8, electrospinning9,10, and selfassembly11 and forcespinning12–14. Among these methods, the most commonly applied technique is the electrospinning which is a promising method for fabricating micro and nanofibers from a variety of materials including polymers, ceramics, and even biomacromolecules. Despite the popularity of the conventional electrospinning, there exist two factors limiting its
Address for correspondence: Romana Zelko, PhD, DSc, University Pharmacy Department of Pharmacy Administration, H-1092 Hogyes E Street 7-9, Budapest, Hungary. Tel/Fax: +36 1 2170927. E-mail: [email protected]
History Received 7 November 2014 Revised 9 January 2015 Accepted 27 January 2015 Published online 18 February 2015
applications: the random orientation of fibrous mats and the relatively high operating voltage of the process. The high-speed rotary spinning technique utilizes centrifugal forces which allow for a host of new materials to be processed into nanofibers (given that electric fields are not required) while also providing a significant increase in yield and ease of production. High-speed rotary spinning, where aqueous solutions of polymers are applied offers a new environment-friendly alternative way of production of polymeric fibers. Fiber formation from polymer solutions in high-speed rotary spinning is induced by the formed centrifugal force and the solvent evaporation15,16. The method enabled the production of fibers with diameters ranging from the micron-scale to nano-scale. The further processing (grinding, micronization) of micro-fibers results in particles of a similar size range than the auxiliary materials of conventional dosage forms (e.g., tablets), while retaining the fiber structure and its known benefits17. The latter enables their application as possible intermediates of different solid dosage forms. Polyvinylpyrrolidone is a watersoluble polymer of excellent biocompatibility with unique amphiphilic structure18. Due to the coexistence of hydrophilic carbonyl group and hydrophobic –CH2CH2CH2– chain, endows PVP with good balance between hydrophilic and hydrophobic interactions when contacting with drugs of poor water-solubility. Drug-loaded PVP fibers could be useful means in the enhancement of the solubility of poorly soluble drugs. Various spinning configurations have been used for the production of polymer fibers16. However, the parameters required for successful spinning
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Figure 1. The scheme of the rotary reservoir. (a) Cross-sectional view. (b) Perspective view. (c) exploded view. (1) Reservoir (polyamide). (2) Nozzle or spinneret (copper). (3) Cover plate (copper). (4) Fixing screw.
of fibers, namely the effect of solution rheology properties, solvent evaporation rate, and centrifugal forces, among others, have yet to be explored which results in poor control over fiber morphology. The purpose of the present work was to implement a complex micro- and macrostructural screening method to study the influence of those parameters which enable successful rotaryspun fiber production from polyvinylpyrrolidone and poly(vinylpyrrolidone-vinylacetate) viscous solutions. Another aim was to establish a correlation between the fiber characteristics of samples and the rheological properties of initial polymer solutions.
Materials and methods Materials Excipients were PVP 25 and PVP 30 (polyvinylpyrrolidone, Kollidon 25, 30, BASF, Ludwigshafen, Germany, approximate molecular weights: 30 000–50 000), PVP VA 64 (poly(vinylpyrrolidone-vinylacetate), Kollidon VA 64, BASF, Ludwigshafen, Germany, weight average: 45 000–70 000), 96% ethanol (Ph.Eur.). The different types of PVPs were kind gifts from BASF Ltd. (Ludwigshafen, Germany). Sample preparation Viscous solutions of different water and alcohol ratios were prepared with polyvinylpyrrolidones (PVP) of different molecular weights and poly(vinylpyrrolidone-vinylacetate). Samples were regularly stirred until the complete homogenization at room temperature. The optimum range of weight percent of the composition was determined by gradual increase of PVP 30 concentration. The extreme values of PVP 30 weight percent necessary for the spinning were also investigated. The values below the optimum correspond to weight percent of PVP 30 solutions, where fiber first formed, while above the optimum can be considered wherein fiber no longer formed. It means ±4%w/w deviation compared with the optimum, and therefore, the samples for this study were prepared based on this experience. Rheological characterization of polymer viscous solutions Rheological measurements were carried out with Kinexus Pro rheometer (Malvern Instruments Ltd, Malvern, UK). Measured data were registered with rSpace for Kinexus Pro 1.3 software (Malvern Instruments Ltd, Malvern, UK). Preparations were measured using a cone and plate geometry. The gap between the cone and the plate of sample placement was 0.15 mm.
The temperature of the samples was controlled with an accuracy of ±0.1 C, by Peltier system of the rheometer (Malvern Instruments Ltd, Malvern, UK). Viscometric properties were determined at 25 C for an hour with a shear rate of 1.0 s1. High-speed rotary spinning technique The fiber formation was carried out with a WSE 602M (AEG, Berlin, Germany) motor based on the high-speed rotary spinning technique. The rotating reservoir was an aluminum–polyamide spinneret with 30 ml internal volume. The various fibers made from the PVP viscous solutions at 411 relative centrifugal force (RCF) with about 1 g/min production rate. The rotating speed was controlled with a toroidal transformator and measured with laser revolution counter (DT-10L, Voltcraft, Hirschau, Germany). The internal diameter of the nozzles was 0.3 mm. In the course of the process, a perforated reservoir rotating at high speeds along its axis of symmetry, which propels a liquid, polymeric jet out of the reservoir orifice that stretches, dries and eventually solidifies to form micro- or nanoscale fibers. The rotary reservoir is own design with unique geometry. The productivity of fiber formation was 15 g/h in average. The type of collector was a rotating metal drum with 5 cm diameter containing grids. Figure 1 represents the scheme of the rotary reservoir of the high-speed rotary spinning device. Modeling of the mechanical load The mechanical stress of the designed spinneret was analyzed by Ansys v12.1 finite element modeling software (ANSYS Germany GmbH, Otterfing, Germany). In the case of the stainless steel, nozzles and the copper cover used the applied materials for the analysis, in the case of polyamide the fragile polyethylene was chosen from the database of the software. For the analysis, the spinneret was composed by 7060 tetrahedron elements and 12 499 nodes. The highest equivalent stress values at the maximal rotation speed (11 000 rpm, 1152 rad/s with 0.2 mm eccentricity) and the yield strengths of different parts of the spinneret are the followings: Aluminum base: 4 MPa and 100–130 MPa Polymer cover: 5.6 MPa and 26–33 MPa Morphology investigation by scanning electron microscopy Morphology of fibers was observed using a scanning electron microscopy (SEM) type JEOL 6380LVa (JEOL, Tokyo, Japan)
DOI: 10.3109/03639045.2015.1013967
after gold coating. The short parts of samples were fixed by conductive carbon adhesive tape. The applied accelerating high voltage and working distance were 10 and 20 kV and 10 mm and 12 mm, respectively. The average diameters of fibers were measured using 50 different randomly selected individual filaments19.
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Positron annihilation lifetime spectroscopy Positron annihilation lifetime spectroscopy (PALS) is a unique method since it is exceptionally sensitive to the free volume. All these measurements are based on the interaction of the free volume holes and the so-called ortho-positronium atom. When a positron meets with its particle counterpart, they annihilate and provide information on the surroundings of the annihilating pair. As the probability of such a meeting depends on the electron density in materials, positrons are exceptionally sensitive to free volumes, i.e., to the variation of electron density. In polymers, a large fraction of the injected positron forms a bound state with electrons before their annihilation. One of the bound states, the ortho-positronium atom or o-Ps, has a ‘‘long’’ lifetime: it lives for 1–10 ns in polymers. This lifetime is long enough for positronium
Figure 2. Scanning electron microscopic morphology of fibers prepared from PVP 30 solution of various concentrations and solvent ratios.
Structural characterization of PVP rotary-spun fibers
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atoms to scan their surroundings and, fortunately, it is long enough to be observed easily20. For positron lifetime measurements, a positron source made of carrier-free 22NaCl was used. Its activity was around 105 Bq and the active material was sealed between two very thin Ti foils. Lifetime spectra were measured with a fast-fast coincidence system based on BaF2/XP2020Q detectors and OrtecÕ electronics (Ro¨hm Pharma, Darmstadt, Germany). Every spectrum was recorded in 4096 channels of an analyzer card for 3600 s and each contained about 1.5 106 coincidence events. Three parallel spectra were measured at each concentration to increase reliability. After summarizing the parallels, spectra were evaluated by the RESOLUTION computer code; the indicated errors are the deviations of the lifetime parameters obtained21. Three lifetime components were found in every spectrum but among these lifetimes the most important was the longest o-Ps. This lifetime is long enough for positronium atoms to scan their surroundings and it can be observed easily. The plasticization effects of water in different PVP polymers were tracked with the o-Ps lifetime changes. All the measurements were performed to room temperature and atmospheric pressure.
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Table 1. Average diameter of PVP 30 fibers of optimum morphology. Optimum Water–ethanol ratio
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1:0 3:1 1:1 1:3 0:1
Average diameter of fibers/mm
Concentration of PVP 30/w/w %
5.5 ± 0.9 10.3 ± 2.3 11.0 ± 3.7 21.4 ± 6.9 23.0 ± 2.8
55 49 45 45 43
Figure 5. Optimum viscosity values of various polymer solutions of different concentrations and water–ethanol ratios.
Figure 3. Average diameter of various fibers as a function of different water–ethanol ratios of polymer solutions.
Figure 4. Changes of the viscosity values of polymer solutions of various water–ethanol ratios and different PVP 30 contents.
Measurement of the tensile strength and the elastic properties of nanofibers The measurements were carried out with Zwick Z005 (Zwick Roell GmbH, Ulm, Germany) universal testing instrument at 5 mm/min test speed and 25 mm clamping length using 15 N upper force limits at room temperature. The tensile strength and Young’s moduli of randomly oriented fiber webs were calculated using the following equation: Fmax ðN Þ ðkg=m3 Þ Pa; N=m2 ¼ TEX ðkg=mÞ
ð1Þ
Figure 6. o-Ps lifetimes values (a) and water contents (b) of different PVP fibers.
Fmax is the maximum force, is the average density of the fibers, TEX is the linear density which equals to W/L where W is the mass of the fibers and L is the length of fiber22. Elongation was determined by maximum force function of displacement curve.
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Determination of the residual water content of fiber mats The water content of prepared fibers was determined by Karl Fischer (KF) titration (787KF Titrino, MetrohmAG, Herisau, Switzerland) at 25 ± 1 C. The water equivalency factor of Hydranal was measured using sodium tartarate (Hydranal-water standard, Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany). The solvent was extra dry methanol, which was titrated with Karl Fischer reagent (MetrohmAG, Herisau, Switzerland) (Hydranalcomposite-5) before the method. About 100 mg of fibers were weighed, homogenized (1 min at 15 000 rpm), and titrated with the reagent.
Results and discussion
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Morphological characterization of fibers Figure 2 illustrates that how the polymer concentration and the solvent composition of viscous PVP 30 solutions determine the morphology of the rotary-spun fibers at the predetermined centrifugal force exerted on the solution jet. Ren et al. found similar results by experimentally studying the relationship between the morphology of the polyvinylpyrrolidone (PVP) and poly(L-lactic acid) (PLLA) composite fibers, the obtained spinning product, and the PLLA–PVP ratios and concentrations of polymer solutions23. They stated that the rheological properties of polymer solution determine the product morphologies; whether they are beads, beaded fibers, or fibers after the spinning.
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Table 1 summarizes the average diameters of PVP 30 fibers of optimum fiber morphology from the point of visually observed diameter uniformity and the non-fibrous area ratio. The results indicate that along with the increase of the alcohol ratio of the polymer solutions the diameter of fibers also increased. The letter could be explained with the faster solvent evaporation in the course of spinning, causing more dried polymer content of fibers under the predetermined spinning parameters. Figure 3 represents this tendency in each polymeric solution. Rheological characterization of polymer solutions in relation to the fiber formation Figures 4 and 5 demonstrate how the viscosity values changed related to the optimum fiber formation in the case of various polymer viscous solutions. The viscosity of the polymer solution can be interpreted to be a measure of the extent of polymer chain entanglement. With an increasing degree of polymer chain entanglement, the viscosity of the polymer solution increases. When the polymer chain entanglement is deficient in the spinning solution, the low resistance of the jet is not sufficient to prevent the break-up of the solution jet below a certain rotational speed while in the case of the highly entangled polymer chain, the low resistance of the solution stream is too high to be stretched into fiber assemblies under certain centrifugal force. Thus, there exists a critical polymer chain entanglement for the formation of the fiber assembly at various rotational speeds24,25.
Figure 7. Mechanical characteristics of fibers prepared from different polymeric solutions. (a) Disruptive force of alcohol-based fiber samples. (b) Disruptive force of aqueous-based fiber samples. (c) Elongation of fibers as a function of water–ethanol ratio of polymeric solutions. (d) Young’s modules of fibers as a function of water–ethanol ratio of polymeric solutions.
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Microstructural characterization of fibers in relation to their mechanical properties The specific intermolecular interaction tends to align the chain segments to maximize interactions, thus stiffening the segments locally, reducing their convolution and producing a reduction in entanglements between dissimilar chains. Such specific intermolecular interactions were formed in the case of PVP VA 64. The results indicate that the presence of vinylacetate increased the o-Ps lifetime values (Figure 6a), consequently the free volume holes of the fibers and ordered the PVP chains that was showed in the authors’ earlier study by the decreased width of the o-Ps lifetime distribution curves26. The reduced convolution and entanglement between the chains resulted in decreased viscosity (Figure 5). The presence of water in the polymer solution enabled the formation of hydrogen bonds within the polymeric chains in PVPs having free hydrogen binding sites thus increasing the molecular entanglement. The latter can be tracked with the increased viscosity values necessary to the optimum fiber formation and reduced o-Ps lifetime values of the water filled free volume holes of PVPs of different molecular weights (Figure 6a). The amount of remained water also confirmed the polymer–water supramolecular interaction (Figure 6b). One possible reason of the obtained phenomena is that the PVP VA 64 as a copolymer consisting of hydrophilic (vinylpyrrolidone) and hydrophobic (vinylacetate) monomer units that affinity to the water is lower than the other two PVP homopolymers. Figure 7(a) illustrates the deformation versus disruptive force curves of fibers prepared from alcoholic solutions while Figure 7(b) represents those of fibres prepared from aqueous systems. The presence of water acts as a plasticizer thus increased the elongation of fibers (Figure 7c) while the more ordered PVP VA 64 copolymer, due to the reduced molecular mobility, resulted in more rigid fibers of decreased elongation and increased disruptive force (Figure 7a). Furthermore, Figure 7(d) clearly shows that alcohol could not be able to plasticize the PVP 30, therefore, less displacement and disruptive force were needed for the breaking of fibers consequently the strain without permanent deformation (Young’s moduli) became also smaller.
Conclusions High-speed rotary spinning technique was successfully applied for the preparation of polyvinylpyrrolidone and poly(vinylpyrrolidone-vinylacetate) micro- and nanofibers. A concentration and the consequent viscosity ranges were defined for the preparation of fibers of optimum fiber morphology. Positron lifetime distributions revealed the changes of the free volumes of fibers as a function of the composition of the initial viscous solutions. The supramolecular structure of the fibers could be changed by modifying the type of the polymer and the alcohol– water ratios of polymeric solutions which is of impact from the point of their morphological and mechanical characteristics which determine their further formulation processing of solid dosage forms.
Acknowledgements The authors are grateful to Ka´roly Su¨vegh (Laboratory of Nuclear Chemistry, Eo¨tvo¨s Lora´nd University/HAS Chemical Research Center) for the possibility of the use of PALS equipment, to La´szlo´ Zsidai and Istva´n Oldal for the design of the spinneret, to Ma´te´ Petzke for the valuable contribution in the preparation of rotary-spun fibers.
Declaration of interest The authors report that they have no conflicts of interest.
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