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Application of hydroxypropyl methylcellulose as a protective agent against magnesium stearate induced crystallization of amorphous itraconazole
European Journal of Pharmaceutical Sciences 121 (2018) 301–308
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European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps
Application of hydroxypropyl methylcellulose as a protective agent against magnesium stearate induced crystallization of amorphous itraconazole
T
B. Démutha,1, D.L. Galataa,1, A. Balogha, E. Szabóa, B. Nagya, A. Farkasa, E. Hirscha, H. Patakia, ⁎ T. Vighb, J. Menschb, G. Verreckb, Z.K. Nagya, , G. Marosia a b
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1111 Budapest, Műegyetem rkp. 3, Hungary Janssen Research and Development, 2340 Beerse, Turnhoutseweg 30, Belgium
A R T I C LE I N FO
A B S T R A C T
Keywords: Amorphous solid dispersion Hydroxypropyl methylcellulose Dissolution Downstream processing Roller compaction Hydrogen bonding
Itraconazole is a fungicide drug which has low bioavailability due to its poor water solubility. Amorphous solid dispersion (ASD) is a tool that has the potential to greatly increase the dissolution rate and extent of compounds. In this work, the dissolution of tablets containing the ASD of itraconazole with either hydroxypropyl methylcellulose (HPMC) or vinylpyrrolidone-vinyl acetate copolymer (PVPVA) was compared in order to find a formulation which can prevent the drug from the precipitation caused by magnesium stearate. Formulations containing the PVPVA-based ASD with HPMC included in various forms could reach 90% dissolution in 2 h, while HPMC-based ASDs could release 100% of the drug. However, HPMC-based ASD had remarkably poor grindability and low bulk density, which limited its processability and applicability. The latter issue could be resolved by roller compacting the ASD, which significantly increases the bulk density and the flowability of the powder blends used for tableting. This roller compaction step might be a base for the industrial application of HPMC-based, electrospun ASDs.
1. Introduction One of the most important challenges of the pharmaceutical industry is the poor water solubility of recently discovered drugs. Amorphous solid dispersion (ASD) has proved to be a useful tool for enhancing dissolution, and as a result, the bioavailability of these active pharmaceutical ingredients (APIs) (Chuah et al., 2014; Engers et al., 2010; Leuner and Dressman, 2000; Vasconcelos et al., 2007). Electrostatic spinning, which is a thoroughly discussed process, is a potent way of producing ASDs (Agarwal et al., 2013; Ghorani and Tucker, 2015; Nagy et al., 2012; Reneker et al., 2007; Reneker and Yarin, 2008; Yu et al., 2010; Yu et al., 2009a). Electrospun nanofibers gain their enhanced dissolution from the high specific area generated during the process (Balogh et al., 2014; Balogh et al., 2015a; Balogh et al., 2015b; Yu et al., 2009a; Yu et al., 2009b). A promising scaled-up electrospinning technology (high-speed electrospinning, HSES) has been recently developed (Nagy et al., 2015b), which can potentially produce several kilograms of ASDs in a day. HSES has been used to prepare ASDs for different formulations such as tablets (Démuth et al., 2016a) or drugloaded straws (Farkas et al., 2018). Itraconazole (ITR) is an orally active antifungal drug and its ability
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1
Corresponding author. E-mail address: [email protected] (Z.K. Nagy). Authors contributed equally to this work.
https://doi.org/10.1016/j.ejps.2018.06.008 Received 22 February 2018; Received in revised form 16 April 2018; Accepted 11 June 2018 Available online 15 June 2018 0928-0987/ © 2018 Elsevier B.V. All rights reserved.
to bind to fungal cytochrome P-450 isozymes results in the inhibition of ergostherol synthesis, the perturbation of membrane-bound enzyme action, and membrane permeability (Grant and Clissold, 1989). ITR is a drug with remarkably weak aqueous solubility; therefore, it is a good candidate for the research of ASDs. Several articles have discussed that electrostatic spinning was a feasible way of preparing ASDs containing ITR and vinylpyrrolidone-vinyl acetate copolymer (PVPVA) or hydroxypropyl methylcellulose (HPMC) (Démuth et al., 2016b; Nagy et al., 2015a; Verreck et al., 2003a). However, the stability of the amorphous API can be obviously different in different polymer matrices; therefore, it is vital to choose the appropriate polymer to avoid suboptimal results (Ewing et al., 2014; Konno et al., 2008). One of the most important factors which determine the behavior of API-polymer systems is the presence of the various interactions (hydrophobic and hydrophilic interactions, hydrogen bond) between the API molecule and the polymer chains of the matrix (Huang and Dai, 2014; Meng et al., 2015; Ohara et al., 2005; Van Ngo et al., 2016). Polymers that can form hydrogen bonds with the API can protect the drug from crystallization during storage more effectively than those which cannot do so (Wegiel et al., 2013). The possibility of hydrogen bond formation does not only affect the physical stability but the dissolution behavior as well. For instance,
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ranging from 0.125 g/mL to 0.25 g/mL, while ratios of the two solvents (dichloromethane and ethanol) and the two polymers (PVPVA and HPMC) were examined (1:1 or 2:1). The small amounts of the samples were prepared by the commonly used single needle electrospinning apparatus. The applied voltage was 30 kV, the solution was injected at a flow rate of 15 ml/h and the collector-nozzle distance was 300 mm.
HPMC can prevent the drug from precipitation, and thus better bioavailability can be realized than from dispersions without hydrogen bonds (Six et al., 2005). This cellulose derivative is able to form hydrogen bonds with ITR (oxo moiety of the drug and hydroxyl groups of the polymer), and therefore it is a promising choice as the polymer matrix of ASDs containing ITR. It has been found that HPMC can ensure good stability for ITR (keeping it perfectly amorphous for the investigated period of time, i.e. a year) due to the formation of strong secondary interaction with the drug. The crystallization of the API could be prevented for up to 12 months in electrospun nanofibers, even under harsh conditions e.g. 40 °C/75% relative humidity (Démuth et al., 2016b; Verreck et al., 2003b). Our recent research showed that an interaction between ITR and stearic acid (SA) can lead to the precipitation of the API during in vitro dissolution (Démuth et al., 2017b). However, it was also found that HPMC has the ability to prevent this phenomenon if it is applied as matrix in the ASD. To summarize, it can be stated that HPMC displays very beneficial properties with regards to the maintenance of the physical stability and good dissolution of amorphous drugs. Conversion of nanofibers into conventional tablets is rarely discussed in the literature. There are only a few articles about the tableting of the materials produced by electrostatic spinning (Démuth et al., 2016a; Démuth et al., 2017a). In spite of their obviously advantageous behavior with respect to stability and dissolution, no study can be found discussing the downstream processing of HPMC-based, electrospun ASDs. In order to produce tablets, the challenging steps of fiber grinding and increase of the bulk density must be done. The goal of our work was two-fold. Firstly, the protective effect of HPMC was intended to be evaluated by comparing the in vitro dissolution profiles of different tablets containing PVPVA- and/or HPMC-based ASDs or PVPVA-based ASD and various forms of HPMC (tableting excipient or coating material). Furthermore, downstream processing of HPMC-based nanofibers with ITR was investigated to generate tablets.
2.3. Milling of the ASD Two different methods were applied for grinding the fibers: hammer milling on an IKA MF10 equipment (rotational speed was set to 4000 rpm, and a sieve with 1 mm opening diameter was used), and pushing through a sieve with a hole size of 0.8 mm (according to our experience, this method gives very similar product as oscillational milling). 2.4. Modulated Differential Scanning Calorimetry (mDSC) The DSC thermogram was recorded on a DSC Q2000 instrument (TA Instruments, Crawley, UK) by “Heat only” modulation mode, with a heating rate of 2 °C/min, an amplitude of 0.318 °C and a period of 60 s. Standard aluminum pans (TA instruments) were applied with crimping. 2.5. Scanning electron microscopy Samples prepared by SNES and HSES were investigated with a JEOL 6380LVa (JEOL, Tokyo, Japan) type scanning electron microscope. Each specimen was fixed with conductive double-sided carbon adhesive tape and sputter-coated with gold alloy prior to examination. The applied accelerating voltage was set to 15 kV. 2.6. Particle size distribution measurement
2. Materials and methods The particle size distribution of the HSES fibers was examined on a Malvern Mastersizer 2000 (Malvern Instruments Ltd., Worcestershire, UK) laser diffraction particle size analyzer (dynamic light scattering in solid state, i.e. without any solvent). About 1 g material was weighed, and a basket equipped with metal balls was placed after the sample tray to facilitate the disaggregation of particles.
2.1. Materials Itraconazole was given by Janssen Pharmaceutica N. V. (Beerse, Belgium). Hydroxypropyl-methylcellulose 2910 (HPMC) was supplied by Aqualon, Hercules (Zwijndrecht, the Netherlands). Mannitol (Pearlitol® 400DC) was a kind gift from Roquette Pharma (Lestrem, France). MgSt was obtained from Hungaropharma Ltd. (Budapest, Hungary). Aerosil® 200 was received from Evonik Industries (HanauWolfgang, Germany). Microcrystalline cellulose (MCC, Vivapur® 200) was provided by JRS pharma (Rosenberg, Germany). PVPVA and Kollidon® CL were supported by BASF (Ludwigshafen, Germany). Organic solvents and the concentrated HCl solution were ordered from Merck Ltd. (Budapest, Hungary). Opadry OY-S-29019 was given by Colorcon (Chalfont, USA).
2.7. Fourier-transform infrared (FTIR) spectroscopy The FTIR spectra were recorded on a Bruker Tensor 37 type spectrometer (Ettlingen, Germany) equipped with deuterated triglycine sulfate detector. The samples were pressed into pastilles with KBr on a Camille OL95 type press (Manfredi, Turin, Italy). The region of 400 to 4000 cm−1 was investigated with 4 cm−1 resolution, while 16 scans were accumulated. Spectra were baseline corrected and normalized. Samples for FTIR examination were prepared as following: the two substances (HPMC and SA or HPMC and PVPVA) were dissolved in dichloromethane and a droplet of 0.1 N HCl solution was added to the mixture. Solutions were heated until complete dissolution while stirring and poured into a crystallizing dish. The solvent evaporated, and the sample was dried on air for a day.
2.2. Preparation of ASD by electrospinning ASDs were prepared by the HSES method as described in (Nagy et al., 2015a). The solution of ITR and the matrix polymers was loaded into the spinneret using a peristaltic pump at a rate of 91 mL/h. The rotational speed of the spinneret was 16,000 rpm. The electric tension between the spinneret and the collector (earthed aluminum sheet) was 30 kV. The collector-nozzle distance was set to 300 mm. In the case of ASD_HPMC, the solution used for HSES had a concentration of 0.125 g/ mL (40% ITR, 60% HPMC), and the solvent was a 1:1 mixture of ethanol and dichloromethane. As for ASD_PVPVA, the concentration was 0.375 g/mL (40% ITR, 60% PVPVA), and the solvent was a 2:1 mixture of dichloromethane and ethanol. In the case of ASD_PVPVA_HPMC, the composition had to be optimized. The investigated concentration of the solid materials was
2.8. Roller compaction of ASD ASD was compacted on a QuickCompactor (Quick2000 Ltd., Tiszavasvári, Hungary). Feeder screw speed was set to 97 rpm, roll speed was 6 rpm, pressure was set to 80 bar, rotational speed of the granulator was 110 rpm, and a sieve with 1.2 mm size was used. The ASD with HPMC was compacted twice to generate satisfying enhancement of flowability and bulk density. 302
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temperature of the inlet air was 50 °C, the outlet air was 40 °C. The suspension was dosed with a peristaltic pump at a speed of 45.5 mL/h. The rotation speed of the drum was set to 12 rpm. The flow of the inlet air was set to 50 m3/h, the outlet air was set to 55 m3/h in order to provide mild vacuum in the drum. The process was continued until a weight increase of 15 mg weight gain of the tablets was achieved (2.5% increase). 2.12. In vitro dissolution tests Dissolution of ITR from tablets was measured on a Pharmatest PTWS600 dissolution tester (Pharma Test Apparatebau AG, Hainburg, Germany) using the Unites States Pharmacopoeia (USP) II method (paddle method). The rotational speed was 100 rpm. Dissolution tests were carried out in 900 mL of 0.1 N HCl at 37 ± 0.5 °C. Absorbance of the medium at 254 nm was measured with an on-line coupled Agilent 8453 UV–Vis spectrophotometer (Hewlett-Packard, Palo Alto, USA). Concentration of ITR and percentage of dissolution could be calculated from the absorbance data. Flow through cuvettes of 10 mm were used. 3. Results and discussion
Fig. 1. Heat flows of the ASD_PVPVA milled on an oscillatory mill.
3.1. Comparison of ASD_HPMC and ASD_PVPVA
2.9. Characterization of blends
Complete dissolution of amorphous drugs is necessary to ensure as high bioavailability as possible. In our previous study, we found that not entirely 100% of totally amorphous ITR (ASD matrix: PVPVA) could be released from a tablet formulation with MgSt due to the formation of an insoluble adduct (Démuth et al., 2017b). Production of PVPVA-based fibers could be accomplished with a rather concentrated solution (0.375 g/mL concentration for API and polymer), which obviously portends high productivity. Direct tablet compression of the obtained PVPVA-based ASDs was attempted. Hammer milling was not possible since the fibers heated up and melted together into bigger balls. Oscillatory milling, however, worked perfectly fine as a blendable powder was obtained. The amorphous phases did not separate during this process (the lone glass transition temperature was around 90 °C), and ITR did not crystallize as proven by the mDSC investigation (Fig. 1). Electrospinning with PVPVA resulted in fragile fibers. The grinding is visible on the SEM image (Fig. 2a), and it resulted in a powder with particle sizes mainly between 0.5 and 100 μm (d(0.5) = 19.7 μm) (Fig. 2b). These values represent the size of clusters of multiple fiber fragments as diameter of most fibers is around 1 μm (Fig. 2a). HPMC was proved to be able to hamper the precipitation phenomenon (Démuth et al., 2017b). However, productivity of this ASD is considerably lower than that with PVPVA (concentration: 0.125 g/mL). In addition, downstream processing poses a larger challenge in this case. Hammer milling was effective, probably due to the higher glass transition temperature of the ASD. This kind of grinding seemed superior to oscillatory milling since the latter was cumbersome and
The bulk density of the blends was determined by measuring the volume of 100 g of powder. The tapped density of the various mixtures was measured using an Erweka SVM12 tapping volumeter (Erweka, Heusenstamm, Germany) after 1250 taps. The Carr's index of the blends was calculated using the following formula (Carr, 1965):
Carr ′s index (%) =
ρT − ρt × 100 ρT
where ρT is the freely settled bulk density and ρt is the tapped bulk density of the powder. 2.10. Preparation and characterization of tablets ASDs were blended with the excipients except MgSt by manual shaking in a bottle (MgSt was mixed separately after the first mixing). Tablets were compressed on a Dott. Bonapace CPR-6 eccentric tablet press (Limbiate, Italy) equipped with 14 mm concave punches. 2.11. Coating of tablets Tablets were coated using a Glatt film coating device (Pratteln, Switzerland). ASD_PVPVA containing tablets were placed among approximately 800 g of placebo tablets of identical dimension. The tablets were coated with HPMC-based Opadry OS-Y-29019. The coating suspension consisted of 30 g Opadry OS-Y-29019 and 400 mL water. The
Fig. 2. SEM image (a) and particle size distribution (b) of ground ASD_PVPVA. 303
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Fig. 3. SEM image (a) and particle size distribution (b) of ground ASD_HPMC.
precipitating interaction with ITR. According to our presumption, the precipitation induced by magnesium stearate is occurring along with the dissolution process. During the first several minutes of the dissolution test, the tablet is disintegrating and ITR molecules become accessible for dissolution or forming the interaction with stearic acid. Presumably, after ITR molecules are dissolved or the interaction (Hbond) is formed with stearic acid, no change can take place (either from dissolved state to precipitation, or from precipitated state to dissolving). HPMC could protect ITR when it was preliminarily dissolved in the medium, but, interestingly, not to the same extent as when it was incorporated in the nanofibers (even though the same amount, 75 mg was dissolved, these tablets are denoted as ‘ASD_PVPVA_preHPMC’). However, significantly improved dissolution could be achieved in comparison with the pure PVPVA-based formulation not containing HPMC (~89% dissolution extent, faster release). These results suggest that by using ASD_HPMC, we can entirely avoid the precipitation induced by SA. However, downstream processing of this ASD might pose some challenges (such as poor grindability) discussed in Section 3.3. Therefore it might be very difficult to produce applicable tablets from this ASD. As a consequence, we decided to test some PVPVA-based formulations which contain HPMC in different forms. As PVPVA-based ASDs have good grindability, these formulations might be able to combine the protective effect of HPMC with acceptable processability.
Table 1 Composition of tablets with ASD_HPMC and ASD_PVPVA. Material
Tablets
ASD MCC Mannitol Crospovidone Coll. sil. dioxide MgSt Tablet weight
20.8% 33.6% 33.6% 10% 1% 1% 600 mg
worked rather slowly. However, HPMC-based fibers are less fragile than those with PVPVA. This was apparent on the particle size distribution since the mean particle size shifted beyond 200 μm (d(0.5) = 207.3 μm) (Fig. 3). After grinding, both fibrous materials were blended with excipients and compressed into tablets. The composition of the tablets is shown in Table 1. The dissolution results of these tablets are depicted in Fig. 4. Based on the results, it seems obvious that the cellulose-based matrix ensures more advantageous dissolution profile for ITR in tablet formulation. While ASD_HPMC tablets released almost 99% of ITR after 120 min, ASD_PVPVA tablets reached only 72%. This difference is caused by the precipitation (induced by SA derived from MgSt) inhibition by HPMC (Démuth et al., 2017b). However, concentration of ITR does not decrease to the solubility level of the drug (no crystalline ITR can be found). The extent of precipitation is mainly driven by the amount of magnesium stearate (as a matter of fact, the stearate anion) (Démuth et al., 2016a) as the deriving stearic acid forms the
3.2. PVPVA-based formulations with HPMC in different forms The first possible solution of including HPMC in PVPVA-based formulations is simply adding it as an excipient in the directly compressed tablets (‘ASD_PVPVA_excHPMC’). These tablets are similar to those with ASD_PVPVA, but they contain the same amount of HPMC as in ASD_HPMC (75 mg). Another possible way of including HPMC is coating the tablets with a HPMC-based coating material (‘ASD_PVPVA_coaHPMC’). This seems to be an elegant solution as industrially tablets are mainly coated, and HPMC-based suspension can be applied easily. In this case, tablets were coated up to 2.5% weight gain (15 mg, thus tablets contained significantly less HPMC as earlier formulations). Lastly, it is also possible to develop an ASD that contains both HPMC and PVPVA as matrix polymers (ASD_PVPVA_HPMC tablets). An optimization of the solution composition was carried out for this ASD with single needle electrospinning. The optimal concentration of the solution was higher than with HPMC (0.188 g/mL; 40% ITR, 20% HPMC, 40% PVPVA), the solvent was a 2:1 mixture of dichloromethane and ethanol. This composition was used for HSES experiment, too. The so-obtained electrospun material was pressed through a sieve with 800 μm pore size as well. ITR is homogeneously distributed in the dual matrix (solid solution) as a lone glass transition can be found in the thermogram. Unexpectedly, the Tg of the ASD was around 90 °C in this case as well in spite of the relatively high Tg of HPMC (164 °C). The addition of HPMC to PVPVA generated a similar morphology to that of ASD_HPMC based on the SEM image (Fig. 5). Fibers had various
Fig. 4. Dissolution profiles of tablets containing ASDs and physical mixtures of ITR. Parameters: 900 mL of 0.1 N HCl, 100 rpm, 37 ± 0.5 °C, 50 mg dose. PM = physical mixture. 304
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Fig. 5. Modulated DSC heat flows (a) and SEM image (b) of ground ASD_PVPVA_HPMC. Table 2 Composition of ASD_PVPVA_excHPMC, ASD_PVPVA_coaHPMC and ASD_PVPVA64_HPMC tablets. Material
ASD_PVPVA_excHPMC
ASD_PVPVA_coaHPMC
ASD_PVPVA_HPMC
ASD MCC Mannitol Crospov. Coll. sil. diox. Mg-stearate HPMC Film coating Tablet weight
18.5% 29.86% 29.86% 8.88% 0.89% 0.89% 11.11% – 675 mg
20.3% 32.8% 32.8% 9.75% 0.96% 0.96% – 2.44% 615 mg
20.8% 33.6% 33.6% 10% 1% 1% – – 600 mg
It can be observed that after a certain amount, further increase in the amount of HPMC does not yield much better results. ASD_PVPVA_coaHPMC tablets contain less than 10 mg HPMC, ASD_PVPVA_HPMC tablets contain 25 mg and ASD_PVPVA_excHPMC tablets contain 75 mg, yet the difference between the best and worst dissolution results is only ~5%. As it was shown earlier by the authors, carboxyl function of SA (deriving from MgSt) can bind to the triazole group of ITR causing precipitation from the dissolution medium (Démuth et al., 2017b). It is a well-known fact that HPMC can establish H-bonds with the oxo moiety of ITR stabilizing it in solid state (Démuth et al., 2016b) and during dissolution (Van Speybroeck et al., 2010). This H-bond evidenced by FTIR spectroscopy (Démuth et al., 2017b) has an effect on this studied phenomenon. HPMC can compensate the drawback of SA keeping ITR in a soluble state while avoiding the precipitation. However, looking at their structures, HPMC might be able to form H-bonds with SA blocking its binding site (Fig. 7b). The shift of the OHpeak to a smaller wavenumber is relatively small (13 cm−1, from 3479 cm−1 to 3466 cm−1, Fig. 7a). Presumably, due to its apolarity, SA cannot be entangled so much among the hydrophilic HPMC chains. However, this can also have a role in the precipitation phenomenon. This leads us to the conclusion that H-bonding among the excipients and the drug is really important and shaping the dissolution profile. Obviously, when HPMC is applied as the only ASD-matrix, ITR molecules are tightly bound to the polymer via hydrogen bonding. As a solid solution, the matrix and the drug are dissolving together, there is no chance for precipitation. When HPMC is not originating from the same place as the API, from the ASD (i.e. when it is placed in the medium beforehand, applied in the coating or added as a tableting excipient), it is not dissolving together with ITR, so there is smaller probability for binding. Interestingly, complete dissolution cannot be achieved if HPMC is incorporated in the ASD as a second matrix. Presumably, not every ITR molecule can be bound to the HPMC chains. The drug
diameters, but grindability was significantly better (pressing through the sieve was easy to carry out unlike in the case of ASD_HPMC). The composition of the three kinds of tablets can be viewed in Table 2. The dissolution profiles of the three formulations are shown in Fig. 6. ASD_PVPVA_excHPMC tablets and ASD_PVPVA_HPMC tablets yield similar results to ASD_PVPVA_preHPMC tablets, however, unlike the latter these formulations are more favorable from industrial standpoints. ASD_PVPVA_coaHPMC tablets have a surprisingly good result, considering that they contain significantly less HPMC than all other tested formulations.
Fig. 6. Dissolution profiles of tablets with different compositions and physical mixtures of ITR. Parameters: 900 mL of 0.1 N HCl, 100 rpm, 37 ± 0.5 °C, 50 mg dose. 305
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molecules from the PVPVA-rich parts of the ASD are quickly dissolving due to the better solubility of this polymer and are going to be exposed for precipitation. One might think that PVPVA can bind to HPMC, that the oxo moieties can occupy hydroxyl groups of the cellulose derivative. However, no shift can be observed on the FTIR spectra (Fig. 8). Presumably, the chains of the two polymers cannot entangle with each other, and no hydrogen bonds can be formed. ASD_PVPVA_coaHPMC, ASD_PVPVA_excHPMC or ASD_PVPVA_HPMC tablets might be a reasonable compromise of dissolution and processability, since they can reach 90% dissolution, while the grindability of ASD_PVPVA is significantly better than HPMC-based one. However, if a formulation that can reach 100% dissolution is required, then a way must be found to improve the flowability of HPMC-based ASDs. 3.3. Downstream processing of HPMC-based nanofibers Roller compaction is a dry granulation process during which the material passes between two counter-rotating rolls, the material is compacted by the pressure applied by the rolls, and leaves as a ribbon or briquette. ASD_HPMC is extremely fluffy, and its bulk density is really small (0.08 g/mL). Our goal was to evaluate the effectiveness of roller compaction to increase the bulk density of such material. As it was mentioned earlier, ASD_HPMC was ground on a hammer mill. Three different blends were compared: milled ASD_HPMC with excipients (‘ASD_HPMC_milled’), an ASD_HPMC compacted twice as described in Materials and Methods (‘ASD_HPMC_comp’), and a blend containing ASD_HPMC_comp and additional excipients (‘ASD_HPMC_comp_exc’) (same composition as ASD_HPMC_milled blend). The composition of the blends is shown in Table 3. All three blends contained a 40% ITR-60% ASD_HPMC. In the case of ASD_HPMC_milled, the neat ASD was milled on a hammer mill, then mixed with the excipients. As for ASD_HPMC_comp, the ASD was mixed with MCC and Aerosil® 200 followed by roller compaction. Blend of ASD_HPMC_comp_exc contains the same roller compacted material as ASD_HPMC_comp, but it was mixed with additional excipients before tablet compression. In order to compare their processability, the bulk and tapped density of the blends was measured and they were tableted on a single punch tablet press using automatic filling. The measured bulk and tapped density values are shown in Table 4. Blends of ASD_HPMC_milled and ASD_HPMC_comp were not able to produce acceptable tablets with automatic filling. However, ASD_HPMC_comp_exc powder appeared to be more promising, it was possible to produce normal tablets using this blend. It should be noted that blend of ASD_HPMC_comp has a higher density than ASD_HPMC_milled, even though it was not mixed with the high-density excipients (especially mannitol). These results show that roller compaction is able to increase the density of a HPMC-based ASD, blend of ASD_HPMC_comp_exc might be to produce tablets by direct compression on an industrial tablet press equipped with appropriate screw feeding. An in vitro dissolution measurement was carried out using tablets containing ASD_HPMC_comp_exc, the result is shown in Fig. 9. The result shows that this formulation is capable of releasing 100% of the drug. Furthermore, such tablets showed faster and significantly more uniform release compared to directly compressed tablets. Therefore, besides improved processability, dissolution
Fig. 7. FTIR spectra of HPMC, SA, and their common sample (a) and the possible hydrogen bond between HPMC and SA (b). Shift of OH-peak around 3500 cm−1 is observable.
Fig. 8. FTIR spectra of PVPVA, HPMC, and their common sample.
Table 3 Composition of blends with ASD_HPMC. Material
ASD_HPMC_milled
ASD_HPMC_comp
ASD_HPMC_comp_exc
ASD MCC Mannitol Crospovidone Coll. sil. dioxide Mg-stearate
17% 51.17% 20% 10% 0.83% 1%
24.7% 74.1%
17% 51.17% 20% 10% 0.83% 1%
1.2%
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Table 4 Bulk and tapped density values of the blends of ASD_HPMC_milled, ASD_HPMC_comp, and ASD_HPMC_comp_exc (the neat, milled ASD has a bulk density of 0.08 g/mL and is not inclined to be tapped). Density
ASD_HPMC_milled
ASD_HPMC_comp
ASD_HPMC_comp_exc
Bulk density (g/mL) Tapped density (g/mL) Carr's index
0.22 0.31 0.29
0.23 0.32 0.28
0.31 0.43 0.29
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Development and tableting of directly compressible powder from electrospun nanofibrous amorphous solid dispersion. Adv. Powder Technol. 28, 1554–1563. Démuth, B., Galata, D.L., Szabó, E., Nagy, B., Farkas, A., Balogh, A., Hirsch, E., Pataki, H., Rapi, Z., Bezúr, L., Vigh, T., Verreck, G., Szalay, Z., Demeter, Á., Marosi, G., Nagy, Z.K., 2017b. Investigation of deteriorated dissolution of amorphous itraconazole: description of incompatibility with magnesium stearate and possible solutions. Mol. Pharm. 14, 3927–3934. Engers, D., Teng, J., Jimenez-Novoa, J., Gent, P., Hossack, S., Campbell, C., Thomson, J., Ivanisevic, I., Templeton, A., Byrn, S., 2010. A solid-state approach to enable early development compounds: selection and animal bioavailability studies of an itraconazole amorphous solid dispersion. J. Pharm. Sci. 99, 3901–3922. Ewing, A.V., Clarke, G.S., Kazarian, S.G., 2014. Stability of indomethacin with relevance to the release from amorphous solid dispersions studied with ATR-FTIR spectroscopic imaging. Eur. J. Pharm. Sci. 60, 64–71. Farkas, B., Balogh, A., Farkas, A., Domokos, A., Borbás, E., Marosi, G., Nagy, Z.K., 2018. Medicated straws based on electrospun solid dispersions. Period. Polytech. Chem. Eng. 62, 310–316. Ghorani, B., Tucker, N., 2015. Fundamentals of electrospinning as a novel delivery vehicle for bioactive compounds in food nanotechnology. Food Hydrocoll. 51, 227–240. Grant, S.M., Clissold, S.P., 1989. Itraconazole. Drugs 37, 310–344. Huang, Y., Dai, W.-G., 2014. Fundamental aspects of solid dispersion technology for poorly soluble drugs. Acta Pharm. Sin. B 4, 18–25. Konno, H., Handa, T., Alonzo, D.E., Taylor, L.S., 2008. Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur. J. Pharm. Biopharm. 70, 493–499. Leuner, C., Dressman, J., 2000. Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm. 50, 47–60. Meng, F., Trivino, A., Prasad, D., Chauhan, H., 2015. Investigation and correlation of drug polymer miscibility and molecular interactions by various approaches for the preparation of amorphous solid dispersions. Eur. J. Pharm. Sci. 71, 12–24. Nagy, Z.K., Balogh, A., Vajna, B., Farkas, A., Patyi, G., Kramarics, Á., Marosi, G., 2012. Comparison of electrospun and extruded Soluplus®-based solid dosage forms of improved dissolution. J. Pharm. Sci. 101, 322–332. Nagy, Z.K., Balogh, A., Démuth, B., Pataki, H., Vigh, T., Szabó, B., Molnár, K., Schmidt, B.T., Horák, P., Marosi, G., 2015a. High speed electrospinning for scaled-up production of amorphous solid dispersion of itraconazole. Int. J. Pharm. 480, 137–142. Nagy, Z.K., Balogh, A., Démuth, B., Pataki, H., Vigh, T., Szabó, B., Molnár, K., Schmidt, B.T., Horák, P., Marosi, G., Verreck, G., Van Assche, I., Brewster, M.E., 2015b. High speed electrospinning for scaled-up production of amorphous solid dispersion of itraconazole. Int. J. Pharm. 480, 137–142. Ohara, T., Kitamura, S., Kitagawa, T., Terada, K., 2005. Dissolution mechanism of poorly water-soluble drug from extended release solid dispersion system with ethylcellulose and hydroxypropylmethylcellulose. Int. J. Pharm. 302, 95–102. Reneker, D.H., Yarin, A.L., 2008. Electrospinning j`ets and polymer nanofibers. Polymer 49, 2387–2425. Reneker, D., Yarin, A., Zussman, E., Xu, H., 2007. Electrospinning of nanofibers from polymer solutions and melts. Adv. Appl. Mech. 41, 43–346. Six, K., Daems, T., de Hoon, J., Van Hecken, A., Depre, M., Bouche, M.-P., Prinsen, P.,
Fig. 9. Dissolution profile of tablets containing ASD_HPMC_comp_exc. Parameters: 900 mL of 0.1 N HCl, 100 rpm, 37 ± 0.5 °C, 50 mg dose.
characteristics could be ameliorated as well. 4. Conclusions Electrospun ASDs of ITR were evaluated in this work. As opposed to HPMC, electrospinning with PVPVA holds the advantages of larger productivity and obtaining fragile fibers resulting in easy-to-handle powder for tableting. However, ASD_PVPVA cannot resist the precipitating effect of SA (deriving from MgSt), which is causing a release of only ~72%. This impaired dissolution can be improved up to ~90% by smuggling HPMC into the formulation e.g. adding it as an excipient, coating tablets with HPMC-based suspension or applying it as a second matrix in the ASD. Tablets containing ASD_HPMC (HPMC as the only polymer) showed complete dissolution of ITR after 45 min. It is challenging to produce tablets containing ASD_HPMC, however it is possible to improve the processability of these blends with roller compaction enabling us to obtain a formulation that can achieve 100% dissolution of ITR. Acknowledgements This project was supported by OTKA (grant numbers: KH 124541, PD 121051, PD 128241), GINOP-2.1.1-15-2015-00541, New National Excellence Program of the Ministry of Human Capacities (ÚNKP-17-4II), and the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. This work was also supported by the National Research, Development and Innovation Fund of Hungary in the frame of FIEK_16-1-2016-0007 (Higher Education and Industrial Cooperation Center) project. References Agarwal, S., Greiner, A., Wendorff, J.H., 2013. Functional materials by electrospinning of polymers. Prog. Polym. Sci. 38, 963–991.
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Verreck, G., Six, K., Van den Mooter, G., Baert, L., Peeters, J., Brewster, M.E., 2003b. Characterization of solid dispersions of itraconazole and hydroxypropylmethylcellulose prepared by melt extrusion—part I. Int. J. Pharm. 251, 165–174. Wegiel, L.A., Mauer, L.J., Edgar, K.J., Taylor, L.S., 2013. Crystallization of amorphous solid dispersions of resveratrol during preparation and storage—impact of different polymers. J. Pharm. Sci. 102, 171–184. Yu, D.-G., Zhu, L.-M., White, K., Branford-White, C., 2009a. Electrospun nanofiber-based drug delivery systems. Health 1, 67. Yu, D.G., Zhang, X.F., Shen, X.X., Brandford-White, C., Zhu, L.M., 2009b. Ultrafine ibuprofen-loaded polyvinylpyrrolidone fiber mats using electrospinning. Polym. Int. 58, 1010–1013. Yu, D.-G., Yang, J.-M., Branford-White, C., Lu, P., Zhang, L., Zhu, L.-M., 2010. Third generation solid dispersions of ferulic acid in electrospun composite nanofibers. Int. J. Pharm. 400, 158–164.
Verreck, G., Peeters, J., Brewster, M.E., Van den Mooter, G., 2005. Clinical study of solid dispersions of itraconazole prepared by hot-stage extrusion. Eur. J. Pharm. Sci. 24, 179–186. Van Ngo, H., Nguyen, P.K., Van Vo, T., Duan, W., Tran, V.-T., Tran, P.H.-L., Tran, T.T.-D., 2016. Hydrophilic-hydrophobic polymer blend for modulation of crystalline changes and molecular interactions in solid dispersion. Int. J. Pharm. 513, 148–152. Van Speybroeck, M., Mols, R., Mellaerts, R., Thi, T.D., Martens, J.A., Humbeeck, J.V., Annaert, P., Mooter, G.V.d., Augustijns, P., 2010. Combined use of ordered mesoporous silica and precipitation inhibitors for improved oral absorption of the poorly soluble weak base itraconazole. Eur. J. Pharm. Biopharm. 75, 354–365. Vasconcelos, T., Sarmento, B., Costa, P., 2007. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discov. Today 12, 1068–1075. Verreck, G., Chun, I., Peeters, J., Rosenblatt, J., Brewster, M.E., 2003a. Preparation and characterization of nanofibers containing amorphous drug dispersions generated by electrostatic spinning. Pharm. Res. 20, 810–817.
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Contents lists available at ScienceDirect
European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps
Application of hydroxypropyl methylcellulose as a protective agent against magnesium stearate induced crystallization of amorphous itraconazole
T
B. Démutha,1, D.L. Galataa,1, A. Balogha, E. Szabóa, B. Nagya, A. Farkasa, E. Hirscha, H. Patakia, ⁎ T. Vighb, J. Menschb, G. Verreckb, Z.K. Nagya, , G. Marosia a b
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1111 Budapest, Műegyetem rkp. 3, Hungary Janssen Research and Development, 2340 Beerse, Turnhoutseweg 30, Belgium
A R T I C LE I N FO
A B S T R A C T
Keywords: Amorphous solid dispersion Hydroxypropyl methylcellulose Dissolution Downstream processing Roller compaction Hydrogen bonding
Itraconazole is a fungicide drug which has low bioavailability due to its poor water solubility. Amorphous solid dispersion (ASD) is a tool that has the potential to greatly increase the dissolution rate and extent of compounds. In this work, the dissolution of tablets containing the ASD of itraconazole with either hydroxypropyl methylcellulose (HPMC) or vinylpyrrolidone-vinyl acetate copolymer (PVPVA) was compared in order to find a formulation which can prevent the drug from the precipitation caused by magnesium stearate. Formulations containing the PVPVA-based ASD with HPMC included in various forms could reach 90% dissolution in 2 h, while HPMC-based ASDs could release 100% of the drug. However, HPMC-based ASD had remarkably poor grindability and low bulk density, which limited its processability and applicability. The latter issue could be resolved by roller compacting the ASD, which significantly increases the bulk density and the flowability of the powder blends used for tableting. This roller compaction step might be a base for the industrial application of HPMC-based, electrospun ASDs.
1. Introduction One of the most important challenges of the pharmaceutical industry is the poor water solubility of recently discovered drugs. Amorphous solid dispersion (ASD) has proved to be a useful tool for enhancing dissolution, and as a result, the bioavailability of these active pharmaceutical ingredients (APIs) (Chuah et al., 2014; Engers et al., 2010; Leuner and Dressman, 2000; Vasconcelos et al., 2007). Electrostatic spinning, which is a thoroughly discussed process, is a potent way of producing ASDs (Agarwal et al., 2013; Ghorani and Tucker, 2015; Nagy et al., 2012; Reneker et al., 2007; Reneker and Yarin, 2008; Yu et al., 2010; Yu et al., 2009a). Electrospun nanofibers gain their enhanced dissolution from the high specific area generated during the process (Balogh et al., 2014; Balogh et al., 2015a; Balogh et al., 2015b; Yu et al., 2009a; Yu et al., 2009b). A promising scaled-up electrospinning technology (high-speed electrospinning, HSES) has been recently developed (Nagy et al., 2015b), which can potentially produce several kilograms of ASDs in a day. HSES has been used to prepare ASDs for different formulations such as tablets (Démuth et al., 2016a) or drugloaded straws (Farkas et al., 2018). Itraconazole (ITR) is an orally active antifungal drug and its ability
⁎
1
Corresponding author. E-mail address: [email protected] (Z.K. Nagy). Authors contributed equally to this work.
https://doi.org/10.1016/j.ejps.2018.06.008 Received 22 February 2018; Received in revised form 16 April 2018; Accepted 11 June 2018 Available online 15 June 2018 0928-0987/ © 2018 Elsevier B.V. All rights reserved.
to bind to fungal cytochrome P-450 isozymes results in the inhibition of ergostherol synthesis, the perturbation of membrane-bound enzyme action, and membrane permeability (Grant and Clissold, 1989). ITR is a drug with remarkably weak aqueous solubility; therefore, it is a good candidate for the research of ASDs. Several articles have discussed that electrostatic spinning was a feasible way of preparing ASDs containing ITR and vinylpyrrolidone-vinyl acetate copolymer (PVPVA) or hydroxypropyl methylcellulose (HPMC) (Démuth et al., 2016b; Nagy et al., 2015a; Verreck et al., 2003a). However, the stability of the amorphous API can be obviously different in different polymer matrices; therefore, it is vital to choose the appropriate polymer to avoid suboptimal results (Ewing et al., 2014; Konno et al., 2008). One of the most important factors which determine the behavior of API-polymer systems is the presence of the various interactions (hydrophobic and hydrophilic interactions, hydrogen bond) between the API molecule and the polymer chains of the matrix (Huang and Dai, 2014; Meng et al., 2015; Ohara et al., 2005; Van Ngo et al., 2016). Polymers that can form hydrogen bonds with the API can protect the drug from crystallization during storage more effectively than those which cannot do so (Wegiel et al., 2013). The possibility of hydrogen bond formation does not only affect the physical stability but the dissolution behavior as well. For instance,
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ranging from 0.125 g/mL to 0.25 g/mL, while ratios of the two solvents (dichloromethane and ethanol) and the two polymers (PVPVA and HPMC) were examined (1:1 or 2:1). The small amounts of the samples were prepared by the commonly used single needle electrospinning apparatus. The applied voltage was 30 kV, the solution was injected at a flow rate of 15 ml/h and the collector-nozzle distance was 300 mm.
HPMC can prevent the drug from precipitation, and thus better bioavailability can be realized than from dispersions without hydrogen bonds (Six et al., 2005). This cellulose derivative is able to form hydrogen bonds with ITR (oxo moiety of the drug and hydroxyl groups of the polymer), and therefore it is a promising choice as the polymer matrix of ASDs containing ITR. It has been found that HPMC can ensure good stability for ITR (keeping it perfectly amorphous for the investigated period of time, i.e. a year) due to the formation of strong secondary interaction with the drug. The crystallization of the API could be prevented for up to 12 months in electrospun nanofibers, even under harsh conditions e.g. 40 °C/75% relative humidity (Démuth et al., 2016b; Verreck et al., 2003b). Our recent research showed that an interaction between ITR and stearic acid (SA) can lead to the precipitation of the API during in vitro dissolution (Démuth et al., 2017b). However, it was also found that HPMC has the ability to prevent this phenomenon if it is applied as matrix in the ASD. To summarize, it can be stated that HPMC displays very beneficial properties with regards to the maintenance of the physical stability and good dissolution of amorphous drugs. Conversion of nanofibers into conventional tablets is rarely discussed in the literature. There are only a few articles about the tableting of the materials produced by electrostatic spinning (Démuth et al., 2016a; Démuth et al., 2017a). In spite of their obviously advantageous behavior with respect to stability and dissolution, no study can be found discussing the downstream processing of HPMC-based, electrospun ASDs. In order to produce tablets, the challenging steps of fiber grinding and increase of the bulk density must be done. The goal of our work was two-fold. Firstly, the protective effect of HPMC was intended to be evaluated by comparing the in vitro dissolution profiles of different tablets containing PVPVA- and/or HPMC-based ASDs or PVPVA-based ASD and various forms of HPMC (tableting excipient or coating material). Furthermore, downstream processing of HPMC-based nanofibers with ITR was investigated to generate tablets.
2.3. Milling of the ASD Two different methods were applied for grinding the fibers: hammer milling on an IKA MF10 equipment (rotational speed was set to 4000 rpm, and a sieve with 1 mm opening diameter was used), and pushing through a sieve with a hole size of 0.8 mm (according to our experience, this method gives very similar product as oscillational milling). 2.4. Modulated Differential Scanning Calorimetry (mDSC) The DSC thermogram was recorded on a DSC Q2000 instrument (TA Instruments, Crawley, UK) by “Heat only” modulation mode, with a heating rate of 2 °C/min, an amplitude of 0.318 °C and a period of 60 s. Standard aluminum pans (TA instruments) were applied with crimping. 2.5. Scanning electron microscopy Samples prepared by SNES and HSES were investigated with a JEOL 6380LVa (JEOL, Tokyo, Japan) type scanning electron microscope. Each specimen was fixed with conductive double-sided carbon adhesive tape and sputter-coated with gold alloy prior to examination. The applied accelerating voltage was set to 15 kV. 2.6. Particle size distribution measurement
2. Materials and methods The particle size distribution of the HSES fibers was examined on a Malvern Mastersizer 2000 (Malvern Instruments Ltd., Worcestershire, UK) laser diffraction particle size analyzer (dynamic light scattering in solid state, i.e. without any solvent). About 1 g material was weighed, and a basket equipped with metal balls was placed after the sample tray to facilitate the disaggregation of particles.
2.1. Materials Itraconazole was given by Janssen Pharmaceutica N. V. (Beerse, Belgium). Hydroxypropyl-methylcellulose 2910 (HPMC) was supplied by Aqualon, Hercules (Zwijndrecht, the Netherlands). Mannitol (Pearlitol® 400DC) was a kind gift from Roquette Pharma (Lestrem, France). MgSt was obtained from Hungaropharma Ltd. (Budapest, Hungary). Aerosil® 200 was received from Evonik Industries (HanauWolfgang, Germany). Microcrystalline cellulose (MCC, Vivapur® 200) was provided by JRS pharma (Rosenberg, Germany). PVPVA and Kollidon® CL were supported by BASF (Ludwigshafen, Germany). Organic solvents and the concentrated HCl solution were ordered from Merck Ltd. (Budapest, Hungary). Opadry OY-S-29019 was given by Colorcon (Chalfont, USA).
2.7. Fourier-transform infrared (FTIR) spectroscopy The FTIR spectra were recorded on a Bruker Tensor 37 type spectrometer (Ettlingen, Germany) equipped with deuterated triglycine sulfate detector. The samples were pressed into pastilles with KBr on a Camille OL95 type press (Manfredi, Turin, Italy). The region of 400 to 4000 cm−1 was investigated with 4 cm−1 resolution, while 16 scans were accumulated. Spectra were baseline corrected and normalized. Samples for FTIR examination were prepared as following: the two substances (HPMC and SA or HPMC and PVPVA) were dissolved in dichloromethane and a droplet of 0.1 N HCl solution was added to the mixture. Solutions were heated until complete dissolution while stirring and poured into a crystallizing dish. The solvent evaporated, and the sample was dried on air for a day.
2.2. Preparation of ASD by electrospinning ASDs were prepared by the HSES method as described in (Nagy et al., 2015a). The solution of ITR and the matrix polymers was loaded into the spinneret using a peristaltic pump at a rate of 91 mL/h. The rotational speed of the spinneret was 16,000 rpm. The electric tension between the spinneret and the collector (earthed aluminum sheet) was 30 kV. The collector-nozzle distance was set to 300 mm. In the case of ASD_HPMC, the solution used for HSES had a concentration of 0.125 g/ mL (40% ITR, 60% HPMC), and the solvent was a 1:1 mixture of ethanol and dichloromethane. As for ASD_PVPVA, the concentration was 0.375 g/mL (40% ITR, 60% PVPVA), and the solvent was a 2:1 mixture of dichloromethane and ethanol. In the case of ASD_PVPVA_HPMC, the composition had to be optimized. The investigated concentration of the solid materials was
2.8. Roller compaction of ASD ASD was compacted on a QuickCompactor (Quick2000 Ltd., Tiszavasvári, Hungary). Feeder screw speed was set to 97 rpm, roll speed was 6 rpm, pressure was set to 80 bar, rotational speed of the granulator was 110 rpm, and a sieve with 1.2 mm size was used. The ASD with HPMC was compacted twice to generate satisfying enhancement of flowability and bulk density. 302
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temperature of the inlet air was 50 °C, the outlet air was 40 °C. The suspension was dosed with a peristaltic pump at a speed of 45.5 mL/h. The rotation speed of the drum was set to 12 rpm. The flow of the inlet air was set to 50 m3/h, the outlet air was set to 55 m3/h in order to provide mild vacuum in the drum. The process was continued until a weight increase of 15 mg weight gain of the tablets was achieved (2.5% increase). 2.12. In vitro dissolution tests Dissolution of ITR from tablets was measured on a Pharmatest PTWS600 dissolution tester (Pharma Test Apparatebau AG, Hainburg, Germany) using the Unites States Pharmacopoeia (USP) II method (paddle method). The rotational speed was 100 rpm. Dissolution tests were carried out in 900 mL of 0.1 N HCl at 37 ± 0.5 °C. Absorbance of the medium at 254 nm was measured with an on-line coupled Agilent 8453 UV–Vis spectrophotometer (Hewlett-Packard, Palo Alto, USA). Concentration of ITR and percentage of dissolution could be calculated from the absorbance data. Flow through cuvettes of 10 mm were used. 3. Results and discussion
Fig. 1. Heat flows of the ASD_PVPVA milled on an oscillatory mill.
3.1. Comparison of ASD_HPMC and ASD_PVPVA
2.9. Characterization of blends
Complete dissolution of amorphous drugs is necessary to ensure as high bioavailability as possible. In our previous study, we found that not entirely 100% of totally amorphous ITR (ASD matrix: PVPVA) could be released from a tablet formulation with MgSt due to the formation of an insoluble adduct (Démuth et al., 2017b). Production of PVPVA-based fibers could be accomplished with a rather concentrated solution (0.375 g/mL concentration for API and polymer), which obviously portends high productivity. Direct tablet compression of the obtained PVPVA-based ASDs was attempted. Hammer milling was not possible since the fibers heated up and melted together into bigger balls. Oscillatory milling, however, worked perfectly fine as a blendable powder was obtained. The amorphous phases did not separate during this process (the lone glass transition temperature was around 90 °C), and ITR did not crystallize as proven by the mDSC investigation (Fig. 1). Electrospinning with PVPVA resulted in fragile fibers. The grinding is visible on the SEM image (Fig. 2a), and it resulted in a powder with particle sizes mainly between 0.5 and 100 μm (d(0.5) = 19.7 μm) (Fig. 2b). These values represent the size of clusters of multiple fiber fragments as diameter of most fibers is around 1 μm (Fig. 2a). HPMC was proved to be able to hamper the precipitation phenomenon (Démuth et al., 2017b). However, productivity of this ASD is considerably lower than that with PVPVA (concentration: 0.125 g/mL). In addition, downstream processing poses a larger challenge in this case. Hammer milling was effective, probably due to the higher glass transition temperature of the ASD. This kind of grinding seemed superior to oscillatory milling since the latter was cumbersome and
The bulk density of the blends was determined by measuring the volume of 100 g of powder. The tapped density of the various mixtures was measured using an Erweka SVM12 tapping volumeter (Erweka, Heusenstamm, Germany) after 1250 taps. The Carr's index of the blends was calculated using the following formula (Carr, 1965):
Carr ′s index (%) =
ρT − ρt × 100 ρT
where ρT is the freely settled bulk density and ρt is the tapped bulk density of the powder. 2.10. Preparation and characterization of tablets ASDs were blended with the excipients except MgSt by manual shaking in a bottle (MgSt was mixed separately after the first mixing). Tablets were compressed on a Dott. Bonapace CPR-6 eccentric tablet press (Limbiate, Italy) equipped with 14 mm concave punches. 2.11. Coating of tablets Tablets were coated using a Glatt film coating device (Pratteln, Switzerland). ASD_PVPVA containing tablets were placed among approximately 800 g of placebo tablets of identical dimension. The tablets were coated with HPMC-based Opadry OS-Y-29019. The coating suspension consisted of 30 g Opadry OS-Y-29019 and 400 mL water. The
Fig. 2. SEM image (a) and particle size distribution (b) of ground ASD_PVPVA. 303
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Fig. 3. SEM image (a) and particle size distribution (b) of ground ASD_HPMC.
precipitating interaction with ITR. According to our presumption, the precipitation induced by magnesium stearate is occurring along with the dissolution process. During the first several minutes of the dissolution test, the tablet is disintegrating and ITR molecules become accessible for dissolution or forming the interaction with stearic acid. Presumably, after ITR molecules are dissolved or the interaction (Hbond) is formed with stearic acid, no change can take place (either from dissolved state to precipitation, or from precipitated state to dissolving). HPMC could protect ITR when it was preliminarily dissolved in the medium, but, interestingly, not to the same extent as when it was incorporated in the nanofibers (even though the same amount, 75 mg was dissolved, these tablets are denoted as ‘ASD_PVPVA_preHPMC’). However, significantly improved dissolution could be achieved in comparison with the pure PVPVA-based formulation not containing HPMC (~89% dissolution extent, faster release). These results suggest that by using ASD_HPMC, we can entirely avoid the precipitation induced by SA. However, downstream processing of this ASD might pose some challenges (such as poor grindability) discussed in Section 3.3. Therefore it might be very difficult to produce applicable tablets from this ASD. As a consequence, we decided to test some PVPVA-based formulations which contain HPMC in different forms. As PVPVA-based ASDs have good grindability, these formulations might be able to combine the protective effect of HPMC with acceptable processability.
Table 1 Composition of tablets with ASD_HPMC and ASD_PVPVA. Material
Tablets
ASD MCC Mannitol Crospovidone Coll. sil. dioxide MgSt Tablet weight
20.8% 33.6% 33.6% 10% 1% 1% 600 mg
worked rather slowly. However, HPMC-based fibers are less fragile than those with PVPVA. This was apparent on the particle size distribution since the mean particle size shifted beyond 200 μm (d(0.5) = 207.3 μm) (Fig. 3). After grinding, both fibrous materials were blended with excipients and compressed into tablets. The composition of the tablets is shown in Table 1. The dissolution results of these tablets are depicted in Fig. 4. Based on the results, it seems obvious that the cellulose-based matrix ensures more advantageous dissolution profile for ITR in tablet formulation. While ASD_HPMC tablets released almost 99% of ITR after 120 min, ASD_PVPVA tablets reached only 72%. This difference is caused by the precipitation (induced by SA derived from MgSt) inhibition by HPMC (Démuth et al., 2017b). However, concentration of ITR does not decrease to the solubility level of the drug (no crystalline ITR can be found). The extent of precipitation is mainly driven by the amount of magnesium stearate (as a matter of fact, the stearate anion) (Démuth et al., 2016a) as the deriving stearic acid forms the
3.2. PVPVA-based formulations with HPMC in different forms The first possible solution of including HPMC in PVPVA-based formulations is simply adding it as an excipient in the directly compressed tablets (‘ASD_PVPVA_excHPMC’). These tablets are similar to those with ASD_PVPVA, but they contain the same amount of HPMC as in ASD_HPMC (75 mg). Another possible way of including HPMC is coating the tablets with a HPMC-based coating material (‘ASD_PVPVA_coaHPMC’). This seems to be an elegant solution as industrially tablets are mainly coated, and HPMC-based suspension can be applied easily. In this case, tablets were coated up to 2.5% weight gain (15 mg, thus tablets contained significantly less HPMC as earlier formulations). Lastly, it is also possible to develop an ASD that contains both HPMC and PVPVA as matrix polymers (ASD_PVPVA_HPMC tablets). An optimization of the solution composition was carried out for this ASD with single needle electrospinning. The optimal concentration of the solution was higher than with HPMC (0.188 g/mL; 40% ITR, 20% HPMC, 40% PVPVA), the solvent was a 2:1 mixture of dichloromethane and ethanol. This composition was used for HSES experiment, too. The so-obtained electrospun material was pressed through a sieve with 800 μm pore size as well. ITR is homogeneously distributed in the dual matrix (solid solution) as a lone glass transition can be found in the thermogram. Unexpectedly, the Tg of the ASD was around 90 °C in this case as well in spite of the relatively high Tg of HPMC (164 °C). The addition of HPMC to PVPVA generated a similar morphology to that of ASD_HPMC based on the SEM image (Fig. 5). Fibers had various
Fig. 4. Dissolution profiles of tablets containing ASDs and physical mixtures of ITR. Parameters: 900 mL of 0.1 N HCl, 100 rpm, 37 ± 0.5 °C, 50 mg dose. PM = physical mixture. 304
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Fig. 5. Modulated DSC heat flows (a) and SEM image (b) of ground ASD_PVPVA_HPMC. Table 2 Composition of ASD_PVPVA_excHPMC, ASD_PVPVA_coaHPMC and ASD_PVPVA64_HPMC tablets. Material
ASD_PVPVA_excHPMC
ASD_PVPVA_coaHPMC
ASD_PVPVA_HPMC
ASD MCC Mannitol Crospov. Coll. sil. diox. Mg-stearate HPMC Film coating Tablet weight
18.5% 29.86% 29.86% 8.88% 0.89% 0.89% 11.11% – 675 mg
20.3% 32.8% 32.8% 9.75% 0.96% 0.96% – 2.44% 615 mg
20.8% 33.6% 33.6% 10% 1% 1% – – 600 mg
It can be observed that after a certain amount, further increase in the amount of HPMC does not yield much better results. ASD_PVPVA_coaHPMC tablets contain less than 10 mg HPMC, ASD_PVPVA_HPMC tablets contain 25 mg and ASD_PVPVA_excHPMC tablets contain 75 mg, yet the difference between the best and worst dissolution results is only ~5%. As it was shown earlier by the authors, carboxyl function of SA (deriving from MgSt) can bind to the triazole group of ITR causing precipitation from the dissolution medium (Démuth et al., 2017b). It is a well-known fact that HPMC can establish H-bonds with the oxo moiety of ITR stabilizing it in solid state (Démuth et al., 2016b) and during dissolution (Van Speybroeck et al., 2010). This H-bond evidenced by FTIR spectroscopy (Démuth et al., 2017b) has an effect on this studied phenomenon. HPMC can compensate the drawback of SA keeping ITR in a soluble state while avoiding the precipitation. However, looking at their structures, HPMC might be able to form H-bonds with SA blocking its binding site (Fig. 7b). The shift of the OHpeak to a smaller wavenumber is relatively small (13 cm−1, from 3479 cm−1 to 3466 cm−1, Fig. 7a). Presumably, due to its apolarity, SA cannot be entangled so much among the hydrophilic HPMC chains. However, this can also have a role in the precipitation phenomenon. This leads us to the conclusion that H-bonding among the excipients and the drug is really important and shaping the dissolution profile. Obviously, when HPMC is applied as the only ASD-matrix, ITR molecules are tightly bound to the polymer via hydrogen bonding. As a solid solution, the matrix and the drug are dissolving together, there is no chance for precipitation. When HPMC is not originating from the same place as the API, from the ASD (i.e. when it is placed in the medium beforehand, applied in the coating or added as a tableting excipient), it is not dissolving together with ITR, so there is smaller probability for binding. Interestingly, complete dissolution cannot be achieved if HPMC is incorporated in the ASD as a second matrix. Presumably, not every ITR molecule can be bound to the HPMC chains. The drug
diameters, but grindability was significantly better (pressing through the sieve was easy to carry out unlike in the case of ASD_HPMC). The composition of the three kinds of tablets can be viewed in Table 2. The dissolution profiles of the three formulations are shown in Fig. 6. ASD_PVPVA_excHPMC tablets and ASD_PVPVA_HPMC tablets yield similar results to ASD_PVPVA_preHPMC tablets, however, unlike the latter these formulations are more favorable from industrial standpoints. ASD_PVPVA_coaHPMC tablets have a surprisingly good result, considering that they contain significantly less HPMC than all other tested formulations.
Fig. 6. Dissolution profiles of tablets with different compositions and physical mixtures of ITR. Parameters: 900 mL of 0.1 N HCl, 100 rpm, 37 ± 0.5 °C, 50 mg dose. 305
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molecules from the PVPVA-rich parts of the ASD are quickly dissolving due to the better solubility of this polymer and are going to be exposed for precipitation. One might think that PVPVA can bind to HPMC, that the oxo moieties can occupy hydroxyl groups of the cellulose derivative. However, no shift can be observed on the FTIR spectra (Fig. 8). Presumably, the chains of the two polymers cannot entangle with each other, and no hydrogen bonds can be formed. ASD_PVPVA_coaHPMC, ASD_PVPVA_excHPMC or ASD_PVPVA_HPMC tablets might be a reasonable compromise of dissolution and processability, since they can reach 90% dissolution, while the grindability of ASD_PVPVA is significantly better than HPMC-based one. However, if a formulation that can reach 100% dissolution is required, then a way must be found to improve the flowability of HPMC-based ASDs. 3.3. Downstream processing of HPMC-based nanofibers Roller compaction is a dry granulation process during which the material passes between two counter-rotating rolls, the material is compacted by the pressure applied by the rolls, and leaves as a ribbon or briquette. ASD_HPMC is extremely fluffy, and its bulk density is really small (0.08 g/mL). Our goal was to evaluate the effectiveness of roller compaction to increase the bulk density of such material. As it was mentioned earlier, ASD_HPMC was ground on a hammer mill. Three different blends were compared: milled ASD_HPMC with excipients (‘ASD_HPMC_milled’), an ASD_HPMC compacted twice as described in Materials and Methods (‘ASD_HPMC_comp’), and a blend containing ASD_HPMC_comp and additional excipients (‘ASD_HPMC_comp_exc’) (same composition as ASD_HPMC_milled blend). The composition of the blends is shown in Table 3. All three blends contained a 40% ITR-60% ASD_HPMC. In the case of ASD_HPMC_milled, the neat ASD was milled on a hammer mill, then mixed with the excipients. As for ASD_HPMC_comp, the ASD was mixed with MCC and Aerosil® 200 followed by roller compaction. Blend of ASD_HPMC_comp_exc contains the same roller compacted material as ASD_HPMC_comp, but it was mixed with additional excipients before tablet compression. In order to compare their processability, the bulk and tapped density of the blends was measured and they were tableted on a single punch tablet press using automatic filling. The measured bulk and tapped density values are shown in Table 4. Blends of ASD_HPMC_milled and ASD_HPMC_comp were not able to produce acceptable tablets with automatic filling. However, ASD_HPMC_comp_exc powder appeared to be more promising, it was possible to produce normal tablets using this blend. It should be noted that blend of ASD_HPMC_comp has a higher density than ASD_HPMC_milled, even though it was not mixed with the high-density excipients (especially mannitol). These results show that roller compaction is able to increase the density of a HPMC-based ASD, blend of ASD_HPMC_comp_exc might be to produce tablets by direct compression on an industrial tablet press equipped with appropriate screw feeding. An in vitro dissolution measurement was carried out using tablets containing ASD_HPMC_comp_exc, the result is shown in Fig. 9. The result shows that this formulation is capable of releasing 100% of the drug. Furthermore, such tablets showed faster and significantly more uniform release compared to directly compressed tablets. Therefore, besides improved processability, dissolution
Fig. 7. FTIR spectra of HPMC, SA, and their common sample (a) and the possible hydrogen bond between HPMC and SA (b). Shift of OH-peak around 3500 cm−1 is observable.
Fig. 8. FTIR spectra of PVPVA, HPMC, and their common sample.
Table 3 Composition of blends with ASD_HPMC. Material
ASD_HPMC_milled
ASD_HPMC_comp
ASD_HPMC_comp_exc
ASD MCC Mannitol Crospovidone Coll. sil. dioxide Mg-stearate
17% 51.17% 20% 10% 0.83% 1%
24.7% 74.1%
17% 51.17% 20% 10% 0.83% 1%
1.2%
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Table 4 Bulk and tapped density values of the blends of ASD_HPMC_milled, ASD_HPMC_comp, and ASD_HPMC_comp_exc (the neat, milled ASD has a bulk density of 0.08 g/mL and is not inclined to be tapped). Density
ASD_HPMC_milled
ASD_HPMC_comp
ASD_HPMC_comp_exc
Bulk density (g/mL) Tapped density (g/mL) Carr's index
0.22 0.31 0.29
0.23 0.32 0.28
0.31 0.43 0.29
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Fig. 9. Dissolution profile of tablets containing ASD_HPMC_comp_exc. Parameters: 900 mL of 0.1 N HCl, 100 rpm, 37 ± 0.5 °C, 50 mg dose.
characteristics could be ameliorated as well. 4. Conclusions Electrospun ASDs of ITR were evaluated in this work. As opposed to HPMC, electrospinning with PVPVA holds the advantages of larger productivity and obtaining fragile fibers resulting in easy-to-handle powder for tableting. However, ASD_PVPVA cannot resist the precipitating effect of SA (deriving from MgSt), which is causing a release of only ~72%. This impaired dissolution can be improved up to ~90% by smuggling HPMC into the formulation e.g. adding it as an excipient, coating tablets with HPMC-based suspension or applying it as a second matrix in the ASD. Tablets containing ASD_HPMC (HPMC as the only polymer) showed complete dissolution of ITR after 45 min. It is challenging to produce tablets containing ASD_HPMC, however it is possible to improve the processability of these blends with roller compaction enabling us to obtain a formulation that can achieve 100% dissolution of ITR. Acknowledgements This project was supported by OTKA (grant numbers: KH 124541, PD 121051, PD 128241), GINOP-2.1.1-15-2015-00541, New National Excellence Program of the Ministry of Human Capacities (ÚNKP-17-4II), and the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. This work was also supported by the National Research, Development and Innovation Fund of Hungary in the frame of FIEK_16-1-2016-0007 (Higher Education and Industrial Cooperation Center) project. References Agarwal, S., Greiner, A., Wendorff, J.H., 2013. Functional materials by electrospinning of polymers. Prog. Polym. Sci. 38, 963–991.
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