Supplementary Information

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1 Supplementary Information Electrospun polymer blend nanofibers for tuneable drug delivery: the role of transformative phase separation on controlling the release rate Pratchaya Tipduangta 1, Peter Belton 2, László Fábián 1, Li Ying Wang 3, Huiru Tang 4, Mark Eddledton 5, Sheng Qi 1 * School of Pharmacy University of East Anglia, Norwich, Norfolk, UK, NR4 7TJ 1 School of Chemistry University of East Anglia, Norwich, Norfolk, UK, NR4 7TJ 2 School of Physics and Technology, Wuhan University, Peoples R China 3 Chinese Academy of Sciences, Key Lab Magnet Resonance Biol Syst, State Key Lab Magnet Resonance & Atom & Molecular Physics, Wuhan Center for Magnet Resonance, Wuhan Institute of Physics & Math, Wuhan , Peoples R China 4 Department of Chemistry, University of Cambridge, Cambridge, UK 5 Corresponding author: Sheng Qi, sheng.qi@uea.ac.uk

2 List of content 1. Fedor s group contribution calculation for estimating solubility parameters of the model drug and polymers used in this study 2. Gordon-Taylor calculation of three-component system for the polymer blends loaded with the model drug 3. Molecular structure of paracetanol (PCM), polyvinyl pyrrolidone (PVP) and hypomellose acetate succinate (HPMCAS). 4. MTDSC data of the pure polymers and binary blend of each polymer with the model drug 5. Power X-ray diffraction data of the pure crystalline drug, physical mixtures of the crystalline drug with the polymer blends and the electrospun polymer blend fibres 6. CPMAS-NMR of the raw materials and electrospun fibres 7. Visual observations of the effect of PVP to HPMCAS ratio on the disintegration and dissolution rate of the electrospun fibres 8. Visual observation of the significant shrinkage of the fibre mats after wetting. 2

3 Fedor s group contribution calculation for estimating solubility parameters of the model drug and polymers used in this study The theoretical miscibilities of PVP and HPMCAS and each of them with the model drug were estimated to provide an indication of the intrinsic mixing behaviour of the polymers and the drug in the absence of any effects induced by processing. The most widely used method for miscibility estimation is comparing the solubility parameter (δ) of the components of interest. In this study, the solubility parameters were calculated by Fedor s group contribution method as described using Equation 1 (1). In Euqation 1, E coh is cohesive energy density and V is molar volume at K. The E coh and V values shown in Table 1 are obtained from Van Kevelen et. al (2). As an example, the solubility of PCM calculated was shown below. The solubility parameters (δ) calculated using this method are 28.2 and 27.2 MPa 1/2 for PVP and PCM, respectively. The solubility parameter of HPMCAS being 22.4 MPa 1/2 is from Mark et.al (3). Table 1. Parameters used for Fedor s group contribution calculation Group Quantity E coh (kj/mol) V (cm 3 /mol) CH OH C=O NH Benzene ring =( ) / [1] ΣE coh = [(4710x1)+(21850x1)+(17370x1)+(8370x1)+(31940x1)] = 84,240 J/mol Σ V = [(33.5x1)+(13x1)+(10.8x1)+(4.5x1)+(52.4x1)] = cm 3 /mol 3

4 Glass transition temperatures of the ternary blend of polymers and the model drug predicted using Gordon-Taylor equation Lu and coworkers adapted the Gordon-Taylor (G-T) equation for calculating the glass transition temperature of ternary blends using the modified version as shown in Equations 2 and 3 (4). In this study, theoretical glass transition temperatures of the ternary blends of PCM, PVP and HPMCAS were estimated using the modified three-component G-T equation. = [2] and [3] Where w 1, w 2 and w 3 are weight fraction of PCM, PVP and HPMCAS, T g1, T g2 and T g3 are T g of PCM, PVP and HPMCAS, and C p1, C p2 and C p3 are heat capacity change of PCM, PVP and HPMCAS respectively. Using this calculation method, the T g values for the ternary systems investigated in this study are 110, 101 and 96ºC for PVP-HPMCAS-PCM systems with PVP-HPMCAS 3:1, 1:1 and 1:2 ratios, respectively. 4

5 Figure 1 Molecular structures of paracetamol (PCM), polyvinyl pyrrolidone (PVP) and hypomellose acetate susccinate (HPMCAS). The average molecular weight of HPMCAS is 18,000 which used size exclusion chromalography with multiangle laser light scattering system (SEG-MALLS) to determine the molecular weight (5). 5

6 As seen in Figure 2, single T g can be observed in both SS-fibres of PVP-PCM and HPMCAS- PCM indicating that 25% PCM is highly miscible with each polymer to form amorphous molecular dispersions. The measured T g of PVP-PCM in excellent agreement with the G-T prediction, whereas the T g of the HPMCAS-PCM dispersion is significantly lower than the G-T predicted value. A melting of crystalline paracetamol is also evident at c.a. 153ºC C(I) A Rev Cp (J/(g C)) C(I) B C D C(I) C(I) Temperature ( C) Universal V4.5A TA Instruments Figure 2. Reversing heat capacity signals of the MTDSC results of (A) PCM-PVP and (B) PCM-HPMCAS beaded fibers containing 25% w/w PCM; and (C) pure PVP K 90 and (D) pure HPMCAS. 6

7 All electrospun polymer blend fibre formulations show halo pattern in Figure 3. This indicates the amorphous nature of all fibre formulations. This was confirmed by the CPMAS- NMR spectra of all formulations shown in Figure 3. It can be seen that within the ppm region of the CPMAS-NMR spectra, which contains characteristic crystalline paracetamol peaks, significant peak broadening can be observed. The twin peak at 135 and 137 in the spectrum of the crystalline paracetamol also merged into a single peak in the spectra of all blend fibre formulations. These results are clear indications of the formation of amorphous dispersion of PCM in PVP-HPMCAS blend fibres. A B C D E F H θ Figure 3. The comparison of PXRD patterns of physical mixtures (PVP, HPMCAS and PCM powder) and PVP-HPMCAS blends electrospun fibres loaded with PCM. PVP/HPMCAS physical mixture ratios (w/w) of 3:1 (A), 1:1 (B), 1:2 (C). The PVP/HPMCAS blends electrospun fibres with polymer ratios of 3:1 (D), 1:1 (E), 1:2 (F) and PCM crystalline form I (H). 7

8 Offset Y values PPM PC M PVP HPMC PC M PC M/PVP/HPMC 1:2 PC M/PVP/HPMC 1:1 PC M/PVP/HPMC 3:1 25% PC M/ HPMC 25 % PC M/PVP C hemical S hift/ppm Figure 4. CPMAS-NMR of the electrospun fibres in comparison to the raw materials 8

9 Figure 5. Visual observations of the effect of PVP to HPMCAS ratio on the disintegration and dissolution rate of the electrospun fibres 9

10 The rapid disintegration and dissolution of the SS polymer blend fiber mats are demonstrated in Figure 5. As seen in Figure 5, PVP-PCM and the blend fibre mat with 3:1 PVP-HPMCAS ratio show ultra fast disintegration and dissolution within 3-5 seconds after in contact with the dissolution media. The disintegration and dissolution rate reduces with increasing the HPMCAS content in the formulations. For the blend fibre mas with 1:1 and 1:2 PVP- HPMCAS ratios, the mats exhibited significant shrinkage on the dimensions upon wetting, as shown in Figure 6. For the CS core-shell fibre mat (with PVP as the shell layer and HPMCAS as the core), the disintegration is significantly slower than the SS fbres. As seen in Figure 4, after 60 seconds immersed in the dissolution media, no significant disintegration of the mat can be observed. Figure 6. Visaul observations of the shrinkage of the SS-electrospun PVP/HPMCAS fibre mats after immersion into ph 1.2 dissolution media for 3 minutes. 10

11 References 1. Fedors RF. A method for estimating both the solubility parameters and molar volumes of liquids. Polymer Engineering & Science. 1974;14(2): Van Krevelen DW, Te Nijenhuis K. Properties of polymers: their correlation with chemical structure; their numerical estimation and prediction from additive group contributions: Elsevier; Marks JA, Wegiel LA, Taylor LS, Edgar KJ. Pairwise Polymer Blends for Oral Drug Delivery. Journal of Pharmaceutical Sciences. 2014;103(9): Lu Q, Zografi G. Phase Behavior of Binary and Ternary Amorphous Mixtures Containing Indomethacin, Citric Acid, and PVP. Pharmaceutical research. 1998;15(8): Fukasawa M, Obara S. Molecular weight determination of hypromellose acetate succinate (HPMCAS) using size exclusion chromatography with a multi-angle laser light scattering detector. Chemical and Pharmaceutical Bulletin. 2004;52(11):