Incorporation of surface-modified dry micronized poorly water-soluble drug powders into polymer strip films

International Journal of Pharmaceutics 535 (2018) 462–472

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International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

Research Paper

Incorporation of surface-modified dry micronized poorly water-soluble drug powders into polymer strip films Lu Zhang, Yidong Li, Manal Abed, Rajesh N. Davé

T

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New Jersey Center for Engineered Particulates, New Jersey Institute of Technology, Newark, NJ, USA

A R T I C L E I N F O

A B S T R A C T

Keywords: Polymeric film Poorly water-soluble drug Micronized drug powders Surface modification Critical quality attributes

Recent work has established polymer strip films as a robust platform for delivery of poorly water-soluble drugs via slurry casting, in particular using stable drug nanosuspensions. Here, a simpler, robust method to directly incorporate dry micronized poorly water-soluble drug, fenofibrate (FNB), is introduced. As a major novelty, simultaneous surface modification using hydrophilic silica along with micronization was done using fluid energy mill (FEM) in order to reduce FNB hydrophobicity and powder agglomeration. It is hypothesized that silica coating promotes easy, uniform dispersion of micronized and coated FNB (MC-FNB) during direct mixing with aqueous hydroxypropyl methylcellulose (HPMC-E15LV) and glycerin solutions. Uniform dispersion leads to improved film critical quality attributes (CQAs) such as appearance, drug content uniformity and drug dissolution. The impact of polymer solution viscosity (low and high), mixer type (low versus high shear), and FNB surface modification on film CQAs were also assessed. Films with as-received FNB (AR-FNB) and micronized uncoated FNB (MU-FNB) were prepared as control. When MC-FNB powders were used, films exhibited improved appearance (thickness uniformity, visible lumps/agglomerates), better drug content uniformity (expressed as relative standard deviation), fast and immediate drug release, and enhanced mechanical properties (tensile strength, elongation percentage), regardless of the polymer solution viscosity or mixer type. These results compare favorably with those reported using nanosuspensions of FNB, establishing the feasibility of directly incorporating surface modified-micronized poorly water-soluble drug powders in film manufacturing.

1. Introduction Orodispersible drug dosage forms are gaining popularity, particularly for pediatric and geriatric patients as well as patients suffering from dysphagia, due to the ease of handling and convenient application leading to high patient compliance (Averineni et al., 2009; Brniak et al., 2015; Dixit and Puthli, 2009; Hoffmann et al., 2011). Amongst those, orodispersible films (European Pharmacopoeia, 2013) present a relatively new dosage form having advantages such as larger available surface area and capability for precision dosing as compared to drops or syrups (Borges et al., 2015; Brniak et al., 2015). Additionally, film formulation can be readily adjusted to allow for customized disintegration and dissolution rate allowing for creating immediate or extended drug release dosages that may also be used for applications such as patches and implants (Dixit and Puthli, 2009). In that context, terms “thin strip films” or “polymeric films” are used in this paper instead of orodispersible films to maintain generality. The traditional approaches for preparing films with poorly watersoluble drugs are solvent casting and hot melt extrusion (HME) (Dixit

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and Puthli, 2009; Hoffmann et al., 2011). The major weakness of solvent casting is that drug recrystallization may occur during drying, leading to drug loading limitations, poor drug particle size control and the instability of APIs in the products, along with the presence of residual solvents. HME, on the other hand, has been proposed as a solvent-free manufacturing process for films, in particular for poorly water-soluble drugs (Aitken-Nichol et al., 1996). HME method has several advantages, including ability to create amorphous forms. However, the method may pose a few limitations such as the need to carefully consider compatibility of the drug and polymer, their miscibility, melting temperatures, potential for degradation due to high temperatures, etc. Further, most extruders cannot produce films thin enough (less than 100 μm) required for fast disintegration; their minimum thickness being 254–305 μm (Repka et al., 2005; Repka and McGinity, 2000). More recent work reveals that films formed via aqueous slurry casting that include drug nano-particles may have advantages over solvent and HME cast films for poorly water-soluble drugs (SievensFigueroa et al., 2012a). In this process, stable aqueous drug

Corresponding author. E-mail addresses: [email protected], [email protected] (R.N. Davé).

https://doi.org/10.1016/j.ijpharm.2017.11.040 Received 31 August 2017; Received in revised form 9 November 2017; Accepted 19 November 2017 Available online 21 November 2017 0378-5173/ © 2017 Elsevier B.V. All rights reserved.

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drug powders into film formulations was considered. Fenofibrate, a BCS Class II drug, was used as the model drug and micronization was carried out in the FEM with or without surface modification with hydrophilic silica, M5P. Two additional factors, the mixer type (a high-shear planetary mixer and a low-shear impeller mixer) and the viscosity of polymer solution (9000 cP and 15000 cP) were also investigated due to their potential impact on film CQAs (Kulshreshtha et al., 2010; Susarla et al., 2013). Overall, a systematic investigation was performed to test the hypothesis that surface modified micronized powders may be directly incorporated to manufacture films with enhanced CQAs such as drug content uniformity, dissolution and mechanical properties. As will be discussed later, much smaller film sample size is selected in order to better discriminate various outcomes, and hence drug content uniformity is evaluated as the relative standard distribution (RSD) of a number of film samples in each case. In addition, the impact of the viscosity of polymer solution as well as the type of mixer were evaluated. The results are compared to those previously reported using stable drug nanosuspensions (Krull et al., 2015b).

nanosuspensions are mixed with aqueous solution of polymer and plasticizer, preferably having high viscosity to prepare film precursors that are then cast and dried (Krull et al., 2015b; Susarla et al., 2013). Based on such slurry casting, it has been demonstrated that film is a promising, robust platform for the delivery of crystalline nanoparticles of poorly water-soluble drugs (Krull et al., 2015b). It has been shown that this approach can be used to prepare thin films with enhanced film critical quality attributes (CQAs) such as drug content uniformity (expressed through relative standard deviation, RSD), high drug load, smooth film appearance, dissolution control, desired mechanical properties, stability of drug form and overall film performance, etc. (Krull et al., 2017a, b; Krull et al., 2016a, b; Krull et al., 2015a, b; Sievens-Figueroa et al., 2012a; Susarla et al., 2013). However, all of these studies concerned use of stable drug nanosuspensions to prepare films via mixing, casting and drying. In the film literature using drug nanosuspensions cited above, media milling is used, which requires high energy and long processing times and may pose manufacturing limitations, including high cost at production scales. In addition, surfactants and other additives are required during milling to achieve smaller size and to ensure drug nanosuspension stability (Azad et al., 2015). Other than the potential for toxicity arising from the use of surfactants, there is also the risk of product contamination due to milling media wear (Juhnke et al., 2012). Considering these factors, one could question if nanomilling down to 200 nm is necessary to achieve good film CQAs. In fact, particles larger than 500 nm or low-micron sizes have been used before (Beck et al., 2013; Bhakay et al., 2016). Using liquid-antisolvent precipitation (Beck et al., 2013), films prepared with low-micron sizes of griseofulvin, a poorly water soluble drug, were shown to achieve immediate release profiles and low RSD, although at low drug loading (5 wt%). In another paper, an interesting particle formation approach based on meltemulsion of fenofibrate was used to prepare stable ∼600 nm particle suspensions that led to the immediate release of fenofibrate at acceptable drug RSD, again at about 6 wt% drug loading (Bhakay et al., 2016). Interestingly, a less stable formulation in the same paper achieved similar CQAs even when the drug particles were agglomerated to several microns in size. Such results, both requiring use of surfactants, suggest that some but not all of the desired film CQAs may be achieved without using drug nanosuspensions. The main objective of this paper is to examine a simpler route based on dry milling to achieve very fine drug powders as an alternate to wet milling in the film formation process without negatively affecting film CQAs. However, typical micronization leads to downstream problems attributed to their high cohesion, causing poor flow, severe agglomeration and poor dispersion, hence, failing to achieve expected dissolution rate enhancements (de Villiers, 1996; Kendall and Stainton, 2001; Perrut et al., 2005). Poor flow and agglomeration are expected to lead not only to difficulties in handling, but also in mixing of dry agglomerated hydrophobic drug particles with aqueous solution of polymer and plasticizer. Preparing slurries using such powders may not provide films with desirable CQAs. Fortunately, severe agglomeration may be tackled using a novel simultaneous micronization and surface modification method, where additives such as hydrophilic silica may be dry coated onto micronized drug particles using the fluid energy mill (FEM) (Han et al., 2013, 2011; Young et al., 2012). It was shown that ibuprofen powders might be micronized down to 5 or 10 μm and simultaneously dry coated with hydrophilic silica to greatly enhance flow, packing, dispersion and most importantly, dissolution of micronized powders (Han et al., 2011). It was also shown that micronized and surface modified ibuprofen powders provide excellent flow properties for 60% drug loaded blends and very fast dissolution from their tablets (Han et al., 2013). However, to best of our knowledge, the effectiveness of hydrophilic silica on dry coated, micronized hydrophobic drug particles for their direct mixing with aqueous polymer solution and subsequently forming films has not been previously reported. Consequently, the incorporation of micronized and surface modified

2. Materials and methods 2.1. Materials Fenofibrate (FNB; Jai Radhe Sales, Ahmedabad, India) was selected as a model BCS Class II poorly water-soluble drug. Pharmaceutical grade amorphous hydrophilic silica (M5P, Cabot Corporation, MA) with primary particle size of 16 nm was used as the coating material for dry FNB particles. Low molecular weight hydroxypropyl methylcellulose (HPMC; Methocel E15 Premium LV, Mw ∼ 40,000, The Dow Chemical Company, Midland, MI) and glycerin (Sigma-Aldrich, Saint Louis, MO) were used as the film former and the film plasticizer respectively. Sodium dodecyl sulfate (SDS) (Sigma-Aldrich, Saint Louis, MO) was used as the surfactant in the dissolution media. The FNB particles, with or without M5P, processed via FEM (qualification model, Sturtevant Inc., Hanover, MA) were referred to as MC-FNB and MU-FNB particles respectively. All other materials were used as received. 2.2. Preparation of micronized uncoated and micronized coated FNB powders The procedure for pre-mixing of powders via Laboratory Resonant Acoustic Mixer (LabRAM; Resodyn Acoustic Mixers, Inc., Butte, MT), a high-intensity vibrational mixer, and preparation of micronized uncoated and micronized coated dry powders using FEM were followed based on previously established protocols (Davé et al., 2011; Han et al., 2011). As-received FNB powders did not require any secondary pre-milling. Pre-mixing of FNB powder (97 g) and silica (3 g) was performed in the LabRAM by placing powders in a plastic cylindrical jar. LabRAM during pre-mixing process was operated at a frequency of 61 Hz with an acceleration of 70 G for 5 min to ensure that the silica particles were well distributed and attached to FNB particles. The MU-FNB particles were prepared without the pre-mixing step, and the FNB powders were fed directly into FEM. Simultaneous micronization and surface modification of pre-mixed FNB powders was achieved through FEM process as follows. Powder feeding rate was controlled by a volumetric feeder (Model 102M, Schenck Accurate, WI, USA) at a rate of 1 g/min. A constant feeding pressure (FP) of 45 psi and a constant grinding pressure (GP) of 40 psi were maintained. Processed powders were stored in a vacuum desiccator at room temperature for subsequent scanning electron microscopy (SEM) and particle size tests. 2.3. Preparation of FNB microparticle-laden films The method for incorporation of nano drug particles into HPMC 463

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films by slurry casting has been discussed in previous work (SievensFigueroa et al., 2012a). Slurry casting involves the preparation of a polymer solution followed by an addition of drug substances, and the resulting film precursor is passed through a Doctor Blade (3700, Elcometer, MI, USA) for film casting. The novelty of the present work is that the drug substance was used in dry powder form in contrast to stable aqueous nanosuspension form, which was required in previous work (Sievens-Figueroa et al., 2012a). This major departure, necessitates examination of the effect of the viscosity of polymer solution and the type of mixers, since they are expected to impact aggregation and settling of drug particles (Kulshreshtha et al., 2010; Susarla et al., 2013). The viscosity was controlled through two different levels of polymer concentrations. The low viscosity aqueous formulation contained 12% HPMC-E15LV (wt%) and 4% glycerin (wt%), and the high viscosity aqueous formulation contained 17% HPMC-E15LV (wt%) and 5% glycerin (wt%). As for the examination of the effect of mixing intensity, two different types of mixers were used. Lower intensity mixer was the standard impeller mixer (RW16, IKA, NC, USA), used for 3 h at a mixing speed in range 100–120 rpm. The higher intensity mixer was a Thinky planetary mixer (ARE-310, THINKY, CA, USA) which can provide planetary and rotary force simultaneously, and was used for 5 min at 2100 rpm. Polymer solutions were prepared by adding corresponding amounts of HPMC-E15LV and glycerin into deionized water at 90 °C and then cooled down to room temperature while being continuously stirred. The polymer solutions were mixed with either AR-FNB, MU-FNB or MC-FNB particles in the standard impeller mixer. For comparison, another set of polymer solutions were mixed with drug substances using the Thinky mixer. Fig. 1 shows the schematic of the preparation of MC-FNB loaded films and Table 1 shows the composition of polymer formulations with two different mixer types. In each case, the film precursor was cast on a plastic substrate (ScotchpakTM 9744, 3M, MN, USA) using a Doctor Blade (3700, Elcometer, MI, USA). The casting thickness was set in the range 900–1000 μm. The cast film was then dried at 50 °C in a batch mode for 40–60 min in the tape casting equipment (TC-71LC, HED International, NJ, USA) capable of providing simultaneous conductive and convective drying.

times to characterize their particle sizes. The size distribution of re-dispersed drug particles from dry films was assessed by a laser diffraction particle size analyzer (Coulter LS 13320, Beckman Coulter, FL, USA). To assess the redispersibility of drug particles, samples of films using circular punches of 0.72 cm2 in area were mixed with 3–5 ml deionized water by a digital vortex mixer (Fisher Scientific, USA) at 1500 rpm for 5–10 min. The resulting suspension was then analyzed as per previously established protocols (Krull et al., 2015b). 2.4.2. Viscosity The apparent shear viscosity values of polymer solutions and film precursors were measured with a rheometer (R/S-CC + , Brookfield Engineering, MA, USA) equipped with a shear rate-controlled coaxial cylinder (CC25) and a temperature controlled water jacket (Lauda Eco, Lauda-Brinkmann LP, NJ, USA). Both were recorded at a low shear rate (2.2 s−1) and 25 ± 0.5 °C, representing the low-shear rate imparted during film casting at room temperature. 2.4.3. Determination of drug content and uniformity in films Previously established protocols for determining the drug content and uniformity were followed (Krull et al., 2015b). Ten circular samples ∼0.72 cm2 in area were punched randomly from film sample of 8 cm X 15 cm size and dissolved in 100 ml of 7.2 mg/ml SDS solution with continuous stirring for a minimum of 3 h. Despite being roughly 1/10th the size of a traditional film dosage, this smaller size was used to help elucidate differences in drug content uniformity between drug particle size, surface modification, polymer solution viscosity and film precursor mixing process conditions. A Thermo Scientific Evolution 300 UV–vis spectrophotometer (Thermo Fisher Scientific Inc., MA) was used to measure the UV absorbance at a wavelength of 290 nm of each dissolved sample and then the concentration was calculated according to the previously constructed calibration curve. The thickness of ten random punches was measured using a digital micrometer (Mitutoyo Corporation, Kanagawa, Japan). The average and relative standard deviation (RSD) of drug dose per unit area, weight percentage of the drug in the film (wt% drug), and thickness were calculated for each set of ten samples.

2.4. Characterization methods 2.4.4. Mechanical properties of the films A Texture Analyzer (TA-XT Plus, Stable Microsystems, UK) was used to ascertain the effect of surface modification of drug particles, type of mixers and viscosity levels of polymer solution on the mechanical properties of films. Tensile strength (TS), Young’s modulus (YM) and elongation percentage (E%) were calculated from the stress-strain data. For such testing, 3–5 rectangular strips of dimensions 5 cm X 1.5 cm

2.4.1. Particle size distribution of dry FNB particles before and after redispersion from dried films Particle size distribution of dry powders was measured via laser diffraction technique (Rodos/Helos system, Sympatec, NJ, USA) where the d10, d50 and the d90 size statistics are reported at 0.5 bar dispersion pressure. AR-FNB, MU-FNB and MC-FNB particles were tested three

Fig. 1. Graphical representation of the preparation of film loaded with MC-FNB dry powder.

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Table 1 Experimental conditions including the types of mixer and polymer solution composition. Run No.

Drug sample

Viscosity level

Mixing method

HPMC E-15LV (g)

Glycerin (g)

DI water (g)

1 2 3 4 5 6 7 8 9 10 11 12

AR-FNB MU-FNB MC-FNB AR-FNB MU-FNB MC-FNB AR-FNB MU-FNB MC-FNB AR-FNB MU-FNB MC-FNB

Low Low Low Low Low Low High High High High High High

Impeller Impeller Impeller Planetary Planetary Planetary Impeller Impeller Impeller Planetary Planetary Planetary

12 12 12 12 12 12 17 17 17 17 17 17

4 4 4 4 4 4 5 5 5 5 5 5

84 84 84 84 84 84 78 78 78 78 78 78

AR-as-received; MU-micronized uncoated; MC-micronized coated. Fixed drug loading of dry film-20% (wt% to dry film). Polymer solutions: Low viscosity level∼9000 cP; High viscosity level∼15000 cP.

particles in the films. Diffraction patterns were acquired for analysis of amorphous/crystalline behavior of these samples using Philips X’Pert (Almelo, Netherlands), scanning a 2θ angle in the range 5–35° (0.01° step).

were cut from a single film sample. The test strips were held between two clamps positioned at a distance of 3 cm and elongated at a constant speed of 1 mm/s until the breaking point (i.e., tensile failure). The average and standard deviation of TS, YM, and E% were computed over three tests.

2.4.10. Dissolution Dissolution experiments of films laden with AR-FNB, MU-FNB and MC-FNB were performed using a flow-through cell dissolution apparatus (USP IV, Sotax, Switzerland) with cells of an internal diameter of 22.6 mm and 0.2 μm Pall HT Tuffryn membrane disc filters (SievensFigueroa et al., 2012b). Punched circular samples from each film with an area of 0.72 cm2 were horizontally positioned in the cells with 3 g of glass beads at the bottom and 2 g of glass beads on the top. Either 100 ml or 250 ml dissolution media (7.2 mg/ml SDS aqueous solution) was circulated through cells at a flow rate of 16 ml/min with a constant temperature 37 ± 0.5 °C. Six (6) circular samples were used, and the average drug dissolved percentage was plotted as a function of time.

2.4.5. Digital optical microscopy The optical imaging of the dry films laden with AR-FNB, MU-FNB or MC-FNB were captured using a digital optical microscope (VHX-100K, Keyence, Japan). In the test, sample films were cut into strips with dimensions 2 cm X 3 cm, a common commercial strip film size and imaged with 50× resolution. 2.4.6. Scanning electron microscopy (SEM) A field emission scanning electron microscope (FESEM) (LEO1530VP GEMINI, Carl Zeiss Inc., MA, USA) was used to examine the morphology of AR-FNB, MU-FNB, and MC-FNB particles, as well as the film loaded with MC-FNB. The drug particles were placed on carbon tape and were coated with carbon by sputter coater (Bal-Tec MED 020 h, Leica Microsystems, Germany) to enhance the conductivity while under the FESEM. The images of AR-FNB, MU-FNB, and MC-FNB particles were recorded. In order to analyze film structure and the drug particles within the film, a small piece of film laden with MC-FNB was placed on an aluminum stub via carbon tape and carbon coated using a sputter coater prior to imaging. The cross-sectional images of the select film were recorded.

2.4.11. Statistical analysis All calculations were performed using Microsoft Excel (Microsoft Office 2010, USA). Results for mechanical properties are expressed as mean ± SD (standard deviation) while content uniformity results are expressed as mean with RSD % (relative standard deviation). Dissolution profiles were contrasted using similarity and difference factors f1 and f2, as per previously reported protocols (Costa et al., 2003; Costa, 2001).

2.4.7. Thermo-gravimetric analysis (TGA) Thermo-gravimetric analysis (TGA) of placebo film and films with AR-FNB, MU-FNB or MC-FNB were performed using a TGA/DSC1/SF STARe system (Mettler Toledo Inc., OH, USA). In a standard ceramic crucible, 5–8 mg of film sample was heated in a nitrogen atmosphere from 25 °C to 150 °C at a constant rate of 10 °C/min, maintained at 150 °C for 15 min, heated to 250 °C at a rate of 10 °C/min, and finally cooled back to 25 °C at a rate of 10 °C/min.

3. Results and discussion 3.1. Characterization of AR-FNB, MU-FNB and MC-FNB dry particles Physically stable MC-FNB particles were produced using hydrophilic silica as the coating material via FEM. The particle size was reduced from a d50 of 9.43 μm for AR-FNB to d50 of 4.34 μm for MC-FNB, and to d50 of 4.86 μm for MU-FNB. The d90 and d10 values are also measured and reported in Table 2. As an indication of the extent of agglomeration, it may be seen that the d90 of AR-FNB was 16.04 μm, the d90 of MC-FNB was 7.46 μm, and the d90 of MU-FNB was 9.05 μm, illustrating that surface modification helps reduce dry powder agglomeration. SEM images of AR-FNB, MU-FNB, and MC-FNB particles are shown in Fig. 2a–c, respectively. After processing in the FEM, the MC-FNB particles were covered by hydrophilic silica (M5P) (Fig. 2c) and did not exhibit agglomeration. However, both as-received FNB (AR-FNB) and micronized uncoated FNB (MU-FNB) particles exhibited agglomerations (Fig. 2a and b). It has been previously shown that the well dispersed hydrophilic silica particles on the surface of micronized FNB particles result in a significant reduction in cohesion and hence their tendency to

2.4.8. Differential scanning calorimetry (DSC) A differential scanning calorimeter (DSC, Mettler Toledo, Inc., OH, USA) was used to determine the melting degree of AR-FNB and MCFNB, and MC-FNB particles in the film. In a standard aluminum pan, a sample of 5–8 mg of films was heated under a nitrogen flow from 25 °C to 150 °C at a constant rate of 10 °C/min, and then cooled back to 25 °C at a rate of 10 °C/min. 2.4.9. X-ray diffraction (XRD) X-ray diffraction was performed to determine the crystallinity of AR-FNB, MU-FNB and MC-FNB particles, placebo film and drug 465

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Table 2 Particle size distribution of dry drug powders prior to mixing with polymer solution and after re-dispersion from films. Drug sample

AR-FNB MU-FNB MC-FNB

Mixing method

Impeller Planetary Impeller Planetary Impeller Planetary

d10 (μm)

d50 (μm)

d90 (μm)

Dry powder

Re-dispersion

Dry powder

Re-dispersion

Dry powder

Re-dispersion

2.63 2.63 1.48 1.48 0.99 0.99

3.44 3.39 3.11 3.11 2.48 2.43

9.43 9.43 4.86 4.86 4.34 4.34

8.31 8.10 7.01 6.99 4.53 4.33

16.04 ± 0.47 16.04 ± 0.47 9.05 ± 0.24 9.05 ± 0.24 7.46 ± 0.18 7.46 ± 0.18

20.20 ± 0.22 18.40 ± 0.34 14.07 ± 0.01 14.06 ± 0.02 7.55 ± 0.18 7.60 ± 0.06

± ± ± ± ± ±

0.19 0.19 0.02 0.02 0.09 0.09

± ± ± ± ± ±

0.02 0.00 0.00 0.00 0.01 0.00

± ± ± ± ± ±

0.07 0.07 0.00 0.00 0.03 0.03

± ± ± ± ± ±

0.04 0.04 0.00 0.00 0.06 0.04

AR-as-received; MU-micronized uncoated; MC-micronized coated.

mixing with polymer solution and the re-dispersion from films were compared; see Table 2. This comparison allows for testing the hypothesis that silica coating promotes easy, uniform dispersion of MCFNB during film precursor mixing as well as in dried films since it reduces agglomeration and increases wettability (please refer to the wettability profiles in the supplementary material, Fig. S1, and photographs of film precursors, Fig. S2). The d50 of MC-FNB dry powder is 4.34 μm which is comparable to the d50 of 4.53 μm and the d50 of 4.33 μm for the re-dispersion from films processed via the impeller mixer and the planetary mixer, respectively; demonstrating MC-FNB particles are stable and well-dispersed within the films. In contrast, the d50 for MU-FNB increased from 4.86 μm to 6.99 μm and 7.01 μm after re-dispersion from films, processed via the impeller mixer and the planetary mixer, respectively. In addition, similar trend for d90 was observed for MU-FNB and MC-FNB, except that uncoated micronized drug powders get further agglomerated during film processing. The results also indicate that drug particles without surface modification led to particle aggregates regardless of which mixer was used. The d50 of AR-FNB after re-dispersion from films is comparable to that of AR-FNB dry powder. However, there was agglomeration, which may be assessed from d90 sizes after film re-dispersion, as those sizes are increased by 20–40%. With regard to the effect of viscosity, the particle sizes of redispersion from low and high viscosity films are identical. These results indicate that surface modification of micronized drug particles leads to full redispersibility as was the case when stable nanosuspensions were used (Krull et al., 2015b). Such results suggest that surface modification

form agglomerates (Ghoroi et al., 2013; Han et al., 2011). Cohesion reduction due to silica coating also leads to improved flow and dispersion of these fine powders and could facilitate easier dispersion in the film precursors and films. This will be further examined in the next section. 3.2. Characterization of films and drug particles in films 3.2.1. Polymer solution and film precursor suspension viscosities As expected, an increase in HPMC concentration leads to an increase in viscosity. Accordingly, 12% and 17% HPMC concentration corresponded to 9018 cP and 15643 cP for “low level” and “high level” viscosity polymer solutions, respectively. As discussed in Section 2.3, reasonable levels of viscosity were necessary to ensure film precursors could be cast easily, neither spreading too easily at low viscosities nor too viscous to cast at very high viscosities. The viscosities of film precursor increased to 11500–13000 cP and 17000–18500 cP respectively after adding dry FNB particles. No significant difference was found between film precursors with AR-FNB, MU-FNB, and MC-FNB with regard to viscosity. In contrast to an increase in viscosity observed here with the addition of dry powders, viscosity decrease was observed after the addition of nanosuspension, which has the effect of further diluting the polymer solution (Krull et al., 2017a; Susarla et al., 2015). 3.2.2. Drug particle size after re-dispersion from dry films Particle sizes of AR-FNB, MU-FNB and MC-FNB dry powders prior to

Fig. 2. SEM images: (a) AR-FNB, (b) MU-FNB and (c) MCFNB.

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Fig. 3. Digital microscopy morphology images of dry films produced by impeller mixer. Low viscosity precursor: (a) Film with AR-FNB; (b) Film with MU-FNB; (c) Film with MC-FNB; High viscosity precursor: (d) Film with AR-FNB; (e) Film with MU-FNB; (f) Film with MC-FNB.

helps avoid drug agglomeration during mixing, film casting and drying.

results indicate that it is advisable to use surface modified drug particles for improved dispersion of drug particles and achieving better film CQAs. For comparison, when the planetary mixer was used, no drug aggregates were observed on the film surface due to its high shear rate during mixing. For the sake of brevity, those results are not included here but are made available in the supplementary material (Fig. S3). Next, further evaluation of drug dispersion is considered using SEM imaging.

3.2.3. Visual characterization using digital microscopy Digital microscopy images were taken to qualitatively confirm the size of drug aggregates and the surface morphology of dry films. Surface images of films processed via impeller mixer laden with AR-FNB, MUFNB and MC-FNB are shown in Fig. 3. All shown images are typical cases selected from many observations. Images (a)–(c) were films produced using low viscosity polymer solution and images (d)–(f) were films produced using high viscosity polymer solution. Images (a) and (b) show that the ranges of aggregate sizes in the films with AR-FNB and MU-FNB are 283–715 μm and 395–1792 μm, respectively. Larger aggregates in the film with MU-FNB may be due to the high cohesion of micronized powders resulting in larger aggregation that could not be reduced in low viscosity polymer solution (de Villiers, 1996; Perrut et al., 2005). On the other hand, high viscosity polymer solution may result in higher shear forces during the mixing process to break up agglomeration. As a result, the range of aggregate sizes are 364–599 μm for AR-FNB (Fig. 3d), and 433–917 μm for MU-FNB (Fig. 3e), which are both much smaller than those found in films formed by low viscosity polymer solution. In contrast, regardless of the precursor viscosity, smooth surface and no visible signs of drug aggregates can be observed in the images of films loaded with MC-FNB (Fig. 3c and f), indicating surface modification of particles by hydrophilic silica reduces agglomeration and improves dispersion of the micro particles in the films. These visual observations indicate that films have desirable appearance similar to those produced using stable nanosuspensions (Krull et al., 2015b). Since impeller mixing is commonly used in industry, these

3.2.4. SEM imaging In order to assess the morphology of the polymer matrix of the dry films, cross-sectional images of film loaded with MC-FNB are presented in Fig. 4. Well-mixed, uniform matrix of particle and polymer may be observed within the film cross-section (Fig. 4a). In Fig. 4b, higher resolution image from cross-sectional view is shown depicting the surface morphology of what appears to be a single silica coated drug particle (see red arrow). This morphology may be comparable to a high-resolution image of dry coated FNB particle in Fig. 2c. This indicates that it is highly likely that silica coating on the FNB particles was retained after mixing with polymer solution, followed by casting and drying. 3.2.5. Thermo-gravimetric analysis (TGA) Generally, there are free and bound interfacial water molecules in the gel matrix (Ford and Mitchell, 1995). TGA analysis was carried out and the results are shown in Fig. 5 where the curves were plotted to account for varying free or bound water content of various film samples. Films from low viscosity formulations exhibited a weight loss between 0.8% and 2.6% at 100 °C, which is comparable to the 1% loss 467

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Fig. 4. SEM image of the cross section of film containing MCFNB. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 5. TGA curves for films containing AR-FNB, MU-FNB and MC-FNB of low and high viscosity formulations.

Fig. 6. DSC of AR-FNB, MC-FNB dry powders and film laden with MC-FNB.

for FNB film that utilized stable drug nanosuspensions (Krull et al., 2015b). In contrast, the weight loss of films prepared using high viscosity formulations was higher at about 3.5–4.9%. This was most likely due to an increase in bound water associated with larger amounts of hydrophilic polymer as well as the difficulty of water molecular movement in the high viscosity film precursor. The additional weight loss of 10–15% for all films at 150 °C was mainly attributed to the loss of glycerin (Susarla et al., 2013). Overall, the convective-conductive drying process employed is effective in keeping the moisture content under 5%, which is important because high water content can lead to tacky films. Low moisture content is also expected to result in flexible films with increased long term stability (Dixit and Puthli, 2009; Krull et al., 2016b). Fig. 7. XRD patterns of pure FNB and processed FNB powders, placebo film and stripfilm containing FNB particles.

3.2.6. Drug crystallinity The differential scanning calorimetry (DSC) analysis of AR-FNB and MC-FNB particles as well as the film loaded with MC-FNB showed (Fig. 6) a thermal event around 80.0–82.0 ºC, which corresponds to the melting endotherm for FNB, and the sharp endothermic peaks indicating the crystalline property of FNB. As evident from the DSC profiles (Fig. 6), the crystalline state of FNB particles has been preserved after particle coating and film processing. This outcome is also comparable to the films made using drug nanosuspensions where the crystallinity of FNB was maintained throughout the manufacturing process (Krull et al., 2015b). In addition, XRD analysis was performed to study the crystal structure of drug particles and the drug particles incorporated in films. Fig. 7 shows the XRD patterns of AR-FNB, MU-FNB, and MC-FNB particles, placebo film and films laden with these drug particles. AR-FNB, MU-FNB and MC-FNB particles presented sharp, high intensity peaks at the main diffraction angles (2θ) 10.0°–25.0°, indicating the crystalline form of the FNB. Placebo film did not show any peak due to amorphous nature of HPMC. For the films loaded with drug particles, the peaks were attributed to FNB, confirming that HPMC had no effect on the

crystalline structure of the drug. The spectra obtained also demonstrate that the drug in film had crystalline structure that was preserved during the milling, mixing and drying. These results agree well with the DSC results that all processed dry powder and films consisted of crystalline FNB. This is significant in the context of maintaining the drug form stability and release characteristics of the product over time (Vogt et al., 2008). 3.2.7. Mechanical properties of films In the tensile strength testing, the tensile force that a film can withstand is measured while being stretched before breaking (Nair et al., 2013). An ideal film should possess suitable tensile strength and elongation percentage implying film is strong and ductile enough to resist handling and packaging without being damaged (Brniak et al., 2015), and it should have a low Young’s modulus to impart the pleasant sensation in the buccal cavity by the patient. It is noted that currently there are no standards for acceptable values of these parameters. 468

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Table 3 Mechanical properties of films embedded with different dry powders. Run No.

Drug sample

Viscosity level

Mixing method

Tensile strength (MPa)

Young’s modulus (GPa)

Elongation percentage (%)

1 2 3 4 5 6 7 8 9 10 11 12

AR-FNB MU-FNB MC-FNB AR-FNB MU-FNB MC-FNB AR-FNB MU-FNB MC-FNB AR-FNB MU-FNB MC-FNB

Low Low Low Low Low Low High High High High High High

Impeller Impeller Impeller Planetary Planetary Planetary Impeller Impeller Impeller Planetary Planetary Planetary

25.62 21.11 35.88 29.18 31.88 35.49 17.71 18.70 21.70 21.81 20.96 22.30

1.88 1.47 2.08 2.12 1.83 2.18 1.52 1.64 1.69 1.65 1.64 1.77

6.26 4.56 7.66 5.33 6.38 7.78 4.21 5.43 6.87 6.11 5.10 8.25

± ± ± ± ± ± ± ± ± ± ± ±

1.39 1.02 3.22 2.22 3.37 0.84 0.41 2.10 0.52 0.44 1.40 1.44

± ± ± ± ± ± ± ± ± ± ± ±

0.08 0.08 0.11 0.24 0.18 0.11 0.04 0.13 0.10 0.11 0.17 0.02

± ± ± ± ± ± ± ± ± ± ± ±

0.78 0.91 1.24 0.67 2.06 2.38 0.43 2.31 1.86 0.05 1.38 0.91

AR-as-received; MU-micronized uncoated; MC-micronized coated. Polymer solutions: Low viscosity level-9000 cP; High viscosity level-15000 cP.

plasticizer/polymer ratio and higher plasticizer/dry powder ratio. Even though the YM values of all films are in a very small range between 1.47– 2.12 gPa, the YM of low viscosity formulation was 50% higher than YM of high viscosity formulation. Interestingly, these films have lower TS, E% and YM as compared to the films with nanoparticles (Krull et al., 2015b). This is likely due to lower surface area of microparticles as compared to nanoparticles. These mechanical tests showed that mechanical properties, TS and E %, are dependent on how uniformly the drug particles are dispersed in the films. It was found that surface modification or higher shear mixing are beneficial for the dispersion of drug particles, resulting in an increase in tensile strength and elongation percentage.

However, there is a general consensus regarding the properties that should be tested; namely, tensile strength (TS), Young’s modulus (YM) and elongation percentage (E%) (Preis et al., 2014). Tensile strength is calculated by dividing the force (N), at which the film breaks, with the cross-sectional area (mm2) of the film. Young’s modulus serves as a measure of stiffness of the film. Elongation is a measure of the extent of stretching and deformation. Generally, the mechanical properties of film vary significantly depending on the polymer matrix and to a certain extent on the process parameters by which the film is fabricated (Nair et al., 2013). It is has been reported that the types and amounts of polymer, plasticizer, surfactant and drug have a profound effect on the mechanical properties of films (Brniak et al., 2015; Cilurzo et al., 2008; Krull et al., 2017a,b; Krull et al., 2016b, 2015b). The mechanical properties; tensile strength (TS), Young’s modulus (YM) and elongation percentage (E%), of the films loaded with AR-FNB, MU-FNB or MC-FNB are shown in Table 3 and were obtained from stress-strain curves from texture analyzer testing. Films containing ARFNB or MU-FNB exhibited TS in range 17.71–25.62 MPa, and E% in range 4.21–6.26%. Interestingly, films containing MC-FNB exhibited significantly higher TS (21.70–35.88 MPa) and higher E% (6.87–7.66%), suggesting mechanical strength enhancement due to the uniform distribution of micro-particles within the films. These results provide additional evidence that surface modification by hydrophilic silica promotes more uniform drug particles dispersion in the film. Likewise, films processed by planetary mixer exhibited higher TS and E % than films processed by impeller mixer. These results corroborate the previous observations of aggregates in films mixed via impeller mixer, because the films with aggregates tend to break more readily. With regard to the effect of viscosity, the higher TS of films produced by low viscosity formulations can be mainly attributed to their higher

3.2.8. Drug content and uniformity of films Films containing uniformly dispersed BCS class II drug nanoparticles have been shown to have very low RSD values of weight percentage of APIs or very low drug content variation (Krull et al., 2015b; Sievens-Figueroa et al., 2012a; Susarla et al., 2015). Additionally, higher viscosity polymer solution was shown to lead to more uniformly distributed drug nanoparticles in dry films, hence potentially better CU (Susarla et al., 2015, 2013). However, the effect of the type of the mixer, mixing intensity and the effect of using much larger, microsized particles as compared to nanoparticles have not been investigated. Consequently, the effect of the surface modification, the viscosity of the polymer solution and the mixer type on the drug content uniformity measured through sample RSD of films were examined. The results are presented in Table 4, which includes average of film thickness, drug dose per unit area and weight percentage of drug in the film. It is noted that in order to better elucidate possible differences in uniformity between films, smaller sample sizes (∼0.72 cm2) than the conventional

Table 4 Average values of film thickness, drug dose per unit area and drug loading (weight percent) for all formulations. Run No.

Drug sample

Viscosity level

Mixing method

Thickness (μm)

Drug dose per unit area (mg/cm2)

Wt% drug

1 2 3 4 5 6 7 8 9 10 11 12

AR-FNB MU-FNB MC-FNB AR-FNB MU-FNB MC-FNB AR-FNB MU-FNB MC-FNB AR-FNB MU-FNB MC-FNB

Low Low Low Low Low Low High High High High High High

Impeller Impeller Impeller Planetary Planetary Planetary Impeller Impeller Impeller Planetary Planetary Planetary

148 147 126 114 109 110 125 124 115 115 113 113

3.04 2.82 3.27 2.64 2.83 2.48 2.98 3.04 3.18 2.96 2.96 2.97

20.69 18.43 21.20 19.31 20.30 18.00 21.90 22.70 21.86 22.60 22.80 22.28

AR-as-received; MU-micronized uncoated; MC-micronized coated. Polymer solutions: Low viscosity level∼9000 cP; High viscosity level∼15000 cP.

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Fig. 8. Relative standard deviation values of film thickness and drug dose per unit area for all formulations.

difference of dissolution profiles of film loaded with AR-FNB or MUFNB are no more than 10% at the sample time points, implying that the particle reduction from 9.43 μm to 4.86 μm does not have a dramatic effect on dissolution rate. This is most likely due to the dissolution being controlled by the presence of HPMC and the film matrix format, which greatly impact the drug release rate based on the rate of polymer dissolution. In addition, the poor wettability of the hydrophobic surface of fenofibrate may reduce the effective surface area available for dissolution (Buch et al., 2011; Lippold and Ohm, 1986). The effective surface area depends on the wettability of the drug particles for a given dissolution medium (Lippold and Ohm, 1986), and the importance of wettability on dissolution rate have been reported in several studies (Brown et al., 1998; Buch et al., 2011; Lippold and Ohm, 1986; Tian et al., 2007). Another effect could be from drug particle agglomeration after micronization (de Villiers, 1996; Kendall and Stainton, 2001; Perrut et al., 2005). Interestingly, although drug aggregates in the films were larger for films processed via impeller mixer, according to similarity and difference factors (f1 = 0–5; f2 = 60–80) between films produced by impeller mixer and planetary mixer, the effective size of agglomerates did not have a significant effect on the release of FNB. These results are in line with previously reported work for poorly water soluble drugs (Beck et al., 2013; Bhakay et al., 2016; Krull et al., 2015b). For example, the films prepared using FNB nanosuspensions (Krull et al., 2015b) exhibited similar release pattern even when the drug particles were significantly smaller in size. More specifically, for those films (Krull et al., 2015b) having thickness 92–102 μm versus 110–113 μm in this work, the time for 80% drug release was 18–23 min, which is comparable to 20–25 min in this work. Surface modification of FNB with hydrophilic silica is expected to improve wettability and reduce agglomeration and the dissolution results support this hypothesis. When the dry FNB powders were tested for dissolution (see dissolution profiles in supplementary material, Fig. S4), it was found that there was little difference in dissolution rate between as-received (AR-FNB) and micronized uncoated (MU-FNB) powders, and both were slow with less than 50% drug release in 100 min. In contrast, surface coated micronized (MC-FNB) powder exhibited over 80% release in under 20 min. Further, adding HPMC (in physical mixtures of drug and film ingredients) to AR-FNB and MU-FNB only led to a minor increase in the dissolution rate. On the other hand, presence of HPMC slightly slowed down the release of MC-FNB (see dissolution profiles in Supplementary material, Fig. S5). It is interesting to note that MC-FNB embedded films exhibit slower initial release, which can be attributed to the film matrix format, but on the other hand achieved overall fastest release. Regardless of the precursor viscosity or mixing device, films loaded with MC-FNB exhibited faster release rates compared to films loaded with AR-FNB or MU-FNB. Remarkably, improved wettability due to surface modification with hydrophilic silica may also have contributed to complete drug release, since films loaded with MC-FNB exhibited 100% API release while films loaded with AR-

film dosage (4-6 cm2) were used. Fig. 8 shows relative standard deviation (RSD) values for film thickness and drug dose per unit area, since these two quantities are expected to be correlated (Nair et al., 2013). The results in Fig. 8 are also provided in a table form in the supplementary material (Table S1). It is observed from Fig. 8 that films with MC-FNB have improved, lower RSD values compared to films with AR-FB or MU-FNB, for both low and high viscosity formulations processed by impeller mixer. Large thickness variability of films with AR-FNB or MU-FNB is attributed to the formation of drug aggregates in the films. This leads to higher RSD values of drug dose per unit area for AR-FNB and MU-FNB films, which is consistent with the results from digital optical imaging. The results for films with MC-FNB in comparison with those from AR-FNB and MUFNB offer strong evidence that, even under low shear rate mixing conditions that are common in the industry, surface modification of drug particles by hydrophilic silica leads to very low RSD values suggesting that since the sample sizes are very small, such conditions may lead to excellent drug content uniformity once the manufacturing process is fully developed. When impeller mixer was used, the results suggest that high viscosity polymer solution should be used, since it leads to lower RSD values. This is attributed to higher shear due to higher viscosity of the polymer solution that leads to smaller drug agglomerate size and improved mixing. Overall, better mixing and smaller drug agglomerate sizes promote lower RSD values, and those are achieved by use of high-shear mixing as in a planetary mixer, or higher viscosity polymer solution or better yet, surface modification of FNB. Overall, the results suggest that FNB surface modification is highly effective in achieving best RSD values hence it is recommended for industrial applications using impeller type mixers. These results are favorable as compared to the RSD values reported using stable drug nanosuspensions (Krull et al., 2015b), considering the fact that the size of drug micro-particles in the present work is at least an order of magnitude larger than the nanoparticles.

3.2.9. Dissolution For BCS class II drugs, drug absorption is dissolution-rate limited hence in vitro dissolution testing is important (Jamzad and Fassihi, 2006). Therefore, the impact of viscosity of the formulation, mixer type, and type of drug particles (AR-FNB, MU-FNB, and MC-FNB) on dissolution was examined. The results using 7.2 mg/ml SDS as the dissolution media are shown in Fig. 9. It is noted that since dry film thickness can significantly affect the release rate of API (Krull et al., 2016b), they were kept similar (100–110 μm). Fig. 9a and b present low viscosity formulations and Fig. 9c and d present high viscosity formulations; with left panel employing the impeller mixer and right panel employing the planetary mixers. Results show that micronization of FNB promotes slightly faster dissolution since MU-FNB films dissolve faster than corresponding films with AR-FNB. However, according to similarity and difference factors (f1 = 7–13; f2 = 50–70), the average 470

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Fig. 9. Film dissolution profiles of films loaded with AR-FNB, MU-FNB and MC-FNB in 100 ml dissolution medium. Low viscosity: (a) impeller mixer; (b) planetary mixer; High viscosity: (c) impeller mixer; (d) planetary mixer.

Fig. 10. Comparison of dissolution profiles of films in 100 ml and 250 ml dissolution medium: (a) Film loaded with ARFNB; (b) Film loaded with MU-FNB.

FNB or MU-FNB exhibited incomplete release (80%–90% in 100 ml dissolution medium). To verify this effect, the amount of dissolution medium was increased to 250 ml, for which films with AR-FNB or MUFNB achieved full dissolution (Fig. 10). Overall, these results demonstrate that surface modification is necessary for robust dissolution performance.

micronized FNB powders compare favorably with films produced using stable drug nanosuspensions (Krull et al., 2015b), suggesting that the proposed approach presents simpler, more economical route to film product manufacturing without compromising key film CQAs.

4. Conclusions

The authors are thankful for the financial support from National Science Foundation under grant EEC-0540855. The authors are also thankful to Dr. Bhavesh Kevadia and Dr. Scott Krull for their assistance during the manuscript preparation.

Acknowledgements

A simpler method of incorporating dry micronized powders of hydrophobic poorly water-soluble drug in to films is demonstrated. It is found that the surface modification with hydrophilic silica leads to reduced agglomeration and improved dispersion of micronized FNB drug particles in the polymer solution as well as in dried films, independent of the type of mixer or the viscosity of the film precursor. Uniform dispersion of drug microparticles leads to improved film critical quality attributes (CQAs) such as appearance, drug distribution uniformity and drug dissolution. These results demonstrate that surface modification of drug particles with hydrophilic silica leads to more robust film CQAs, including full recovery of drug particles upon redispersion as well as faster and more complete drug release of poorly water-soluble drug FNB. Further, dry coating process does not have any adverse impact on drug form and crystallinity, which are preserved throughout processing. Although high shear mixing and high viscosity film precursors also help improve film CQAs, they are not necessary when the micronized FNB was surface modified. This is an important outcome that demonstrates that proper surface treatment eliminates requirement for specialized mixers and higher viscosity film precursors. These positive outcomes for film produced using surface modified

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