Impact of process parameters on particle morphology and filament formation in spray dried Eudragit L100 polymer

Powder Technology 362 (2020) 221–230

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Impact of process parameters on particle morphology and filament formation in spray dried Eudragit L100 polymer Kimberly B. Shepard, Molly S. Adam, Michael M. Morgen ⁎, Deanna M. Mudie, Daniel T. Regan, John M. Baumann, David T. Vodak Global Research and Development, Lonza Pharma and Biotech, Bend, Oregon 97703, USA

a r t i c l e

i n f o

Article history: Received 9 August 2019 Received in revised form 2 December 2019 Accepted 6 December 2019 Available online 10 December 2019

a b s t r a c t Spray drying is one of the most broadly applicable and widely used methods of producing amorphous solid dispersions (ASDs). ASDs can improve the oral absorption of poorly water-soluble active pharmaceutical ingredients. Eudragit L100 is an appealing ASD excipient, due to its favorable impact on ASD physical stability and dissolution performance. However, spray drying Eudragit L100 can lead to high-aspect ratio filaments which reduce flowability, density and yield of the resulting powder. This negatively impacts downstream ASD performance and dosage form manufacturability. This work presents a mechanism for filament formation, which results in a particle engineering design space of key processing parameters, defined by a dimensionless parameter for assessing filament formation risk. Specifically, it was found that solution concentration, spray dryer inlet temperature and solvent volatility had the largest impact on controlling filament formation, based on their influence on the relative time scale to atomize versus droplet skinning during drying. © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction In today's pharmaceutical pipeline, N70% of new therapeutic small molecules have low solubility in water [1,2]. To enable oral delivery of these low-solubility candidates, solubility-enhancing technologies are required. Formulators have embraced delivery approaches based on the use of amorphous forms of active pharmaceutical ingredients (APIs) because these drug forms can exhibit solubilities that are 2 to 100 times higher than those of their corresponding crystalline forms, due to the enhanced free energy present in the disordered amorphous state [3,4].

Abbreviations: ΔHvap, heat of vaporization of the spray solvent; ΔHvap, ref, reference heat of vaporization; τatom, time required for the atomized liquid to break up from sheet to droplet (time to atomization); τgel, time required for the spray solution to form a gelled polymer skin on the droplet surface; %RS, relative saturation; API, active pharmaceutical ingredient; ASD, amorphous solid dispersion; Cskin, experimentally measured polymer concentration (in wt%) at which a gelled skin forms on top of a thin film (for Eudragit L100, it is equal to 15% for acetone or methanol by weight); Csolids, polymer concentration (in wt%) in the spray solution; DSC, differential scanning calorimetry; HPLC, high-performance liquid chromatography; HPMCAS, hydroxypropyl methylcellulose acetate succinate; HPMCP, hydroxypropyl methylcellulose propionate; MAE 100P, methacrylic acid/ethyl acrylate copolymer; RH, relative humidity; RI, refractive index; SDD, spray-dried dispersion; SEC-MALS, size-exclusion chromatography with multiple-angle laser-light scattering; SEM, scanning electron micrography; Tboil, boiling point of the spray solvent; Tg, glass-transition temperature; THF, tetrahydrofuran; Tinlet, temperature of the inlet drying gas. ⁎ Corresponding author at: 64550 Research Road, Bend, Oregon 97703, USA. E-mail address: [email protected] (M.M. Morgen).

However, APIs in their pure amorphous form may have physical stability challenges, since they tend to revert to their more thermodynamically stable crystalline form. To address this issue, drug-product intermediates are formed as amorphous solid dispersions (ASDs) comprising the API and a stabilizing excipient, typically a polymer. These ASDs provide shelf-stable, solid oral dosage forms with rapid dissolution kinetics and improved bioavailability [5–7]. To date, at least 24 ASDs are available as commercial products [8,9]. ASDs are often manufactured using spray drying, a scalable, highthroughput, and robust technique for manufacturing ASDs suitable for a wide range of APIs. In this process, the API and stabilizing polymer are dissolved in a volatile organic solvent, and the solution is then atomized into droplets through a nozzle, providing a significant increase in surface area for evaporation. The droplets are exposed to heated drying gas, causing rapid evaporation of the solvent and formation of solid spray-dried dispersion (SDD) particles [9–11]. SDDs can be formulated in several convenient solid dosage forms (e.g., tablets, capsules and sachets) with a variety of delivery profiles (e.g., immediate or modified release). It has been well-established experimentally and documented in the literature that SDD particle morphology can be engineered via careful design of spray-drying process parameters [12–14]. The ability to tailor the powder and particle properties of the SDD is important because these properties can significantly affect downstream manufacturing [15–19]. Good flowability and density are of particular importance for enabling processes such as blending, granulation and tableting [20–22]. Flowability, density, and particle morphology can also directly

https://doi.org/10.1016/j.powtec.2019.12.013 0032-5910/© 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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affect the yield of product, since poorly flowing or statically-charged powder may remain adhered to the walls of the spray dryer during processing [23]. Many SDD powders exhibit poor flowability. This paper addresses the use of a particularly promising excipient, Eudragit L100 (Evonik, Essen, Germany), a copolymer of methacrylic acid and methyl methacrylate, as a stabilizing polymer in SDDs. The polymer's most desirable attribute is its high glass-transition temperature (Tg), which is 30–70 °C higher than that of many common spraydrying polymers, such as hydroxypropyl methyl cellulose (HPMCAS) and copovidone. This is advantageous because the higher the SDD's Tg, the lower the mobility of the drug in the SDD, promoting good physical stability. Eudragit L100 enables significantly higher API loadings in the SDD than do other polymers, while still maintaining acceptable physical stability of the amorphous state [24]. By increasing the API loading in the SDD, the number of units and overall size of the final tablet can be reduced, helping to improve patient compliance, particularly for highdose medications. The polymer is enteric, resisting dissolution at gastric pH, and retains rapid dissolution kinetics in the intestine. Eudragit L100 is therefore of great interest for SDD formulation development for oral delivery. A key manufacturability challenge limiting widespread use of Eudragit L100 as a spray-drying polymer is that SDDs prepared using this polymer can have undesirable powder properties under common spray-drying conditions. Especially when manufacturing is scaled up to development and clinical-scale spray dryers, Eudragit L100 SDDs form filament particles with high aspect ratios, often resulting in powders that have low density, poor flowability and low yields compared with SDDs manufactured from polymers such as HPMCAS and copovidone. This paper describes fundamental work that examines and explains the formation of these high aspect-ratio filaments. The effects of spraydrying parameters on filament formation are systematically investigated, demonstrating a process design space for manufacturing powder with acceptable properties for high yield and good downstream processing. A dimensionless, scale-independent parameter is proposed that can be used to predict when filament formation will be problematic in spray-drying. The validity of this approach was demonstrated using data from previous studies summarized in the literature. This work demonstrates an approach to SDD particle engineering in which a fundamental understanding of the interplay between process and formulation parameters is successfully used to achieve the desired product attributes.

SDD particle morphology can vary with solution properties and drying conditions, but generally SDDs consist of particles with an aspect ratio of approximately 1. Depending on the kinetics of drying, particles may be nearly spherical or collapsed spheres (see Fig. 2, left). Eudragit L100 SDDs are prone to formation of dried filaments that give rise to poor powder properties. These filaments form tangled agglomerates with spherical particles (see Fig. 2 right). Samples of spray-dried Eudragit L100 with acceptable powder properties do not have appreciable filaments present. This paper hypothesizes that high aspect-ratio filament particles form in Eudragit L100 spray-dried material when the solution dries before the filament-to-droplet breakup has been completed. SEM images of particles with a “bead-on-a-string” morphology support this mechanism, shown in Fig. 3. Two characteristic times are critical in determining particle drying characteristics and resulting morphology: (1) the time required for the atomized liquid to break up from filament to droplet (τatom) and (2) the time required for the solution to form a gelled polymer skin on the droplet surface, effectively fixing its particle geometry, (τgel). In cases where τgel ≤ τatom, spray-dried particles will solidify into the filament geometry rather than the droplet geometry. When τgel N τatom, droplets break up completely prior to solidification and only low aspect-ratio particles form. To design a spray-drying process that minimizes filament formation, it is therefore crucial to understand the impact of process parameters on these characteristic times, as described in detail in Section 4 (Results).

2. Theory

3. Materials and methods

Atomization is a key step during spray-drying and is critical to the prevention of filament formation. Atomization occurs when the liquid spray solution—comprising API, a stabilizing polymer, and solvent—is passed through a spray nozzle, forming droplets that significantly increase the surface area for solvent evaporation. After atomization, heated drying gas rapidly evaporates the solvent, forming SDD particles. The most common nozzle types used to atomize the spray solution are pressure-swirl nozzles and two-fluid nozzles [11]. Although the mechanism of atomization is different between the two nozzle types, both break up liquid filaments into droplets during atomization. Because pressure-swirl nozzles are frequently used in the pharmaceutical industry, particularly at large scale, this discussion is focused on the specific mechanism for droplet formation using this nozzle type. In pressure-swirl atomization, a sheet of liquid is ejected from the nozzle in a hollow-cone geometry. Surface instabilities in the liquid sheet propagate parallel to the direction of liquid flow. The instabilities grow until a critical amplitude is reached. At that point, the sheet breaks up into one-dimensional filaments, which extend perpendicular to the direction of flow. Instabilities then form in the filaments, which eventually break up along the filament axis into spherical droplets [25]. These effects are illustrated schematically in Fig. 1.

3.1. Materials

Fig. 1. Schematic of droplet breakup during atomization, adapted from Ashgriz and Sachami [25].

Eudragit L100 is an enteric random co-polymer of 1:1 methacrylic acid and methyl methacrylate. Eudragit L100 was purchased from Evonik (Essen, Germany). Solvents used for spray-drying (acetone and methanol) were purchased from Sigma-Aldrich (St. Louis, Missouri). 3.2. Methods 3.2.1. Polymer characterization by differential scanning calorimetry (DSC) DSC analysis was used to measure the thermal characteristics of Eudragit L100. Specifically, the Tg of Eudragit L100 was measured on a TA Instruments Q2000 DSC (New Castle, Delaware). For this test, a 2 to 5 mg sample of the polymer was equilibrated for 20 h in a dry box at relative humidity b5% at ambient temperature. The material was hermetically sealed in a Tzero hermetic pan. The sample was scanned in modulated DSC mode from 40 °C to 220 °C at 2.5 °C/min with a modulation amplitude of 1.5 °C and a period of 60 s. Three replicates of the sample were tested, resulting in a midpoint Tg of 187 °C with a standard deviation of 1 °C. It should be noted that the onset of polymer degradation occurs as the material is heated through its glass transition

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Fig. 2. Representative scanning electron micrography (SEM) images of typical, desirable Eudragit L100 SDD particle morphology (a) and Eudragit L100 SDD particles with undesirable filament formation (b).

temperature, typically starting above 170 °C in a nitrogen environment (measured by thermogravimetric analysis, data not shown).

3.2.2. Spray drying In total, 18 spray-drying runs were conducted using two custom spray dryers: (1) a BLD-35 lab-scale dryer with a drying gas throughput of 35 kg/h and (2) a BLD-150 clinical-scale dryer with a drying gas throughput of 150 kg/h. Both dryers were equipped with customized cyclonic systems for powder collection. Spray solutions were prepared by dissolving the Eudragit L100 in the spray solvent (either 97/3 acetone/water by weight, or in 100% methanol) under magnetic stirring at ambient temperature with concentrations ranging from 3 to 11% by weight (all solution compositions in this publication are reported as weight percentage). For the lab-scale dryer, two types of nozzles were used: (1) Schlick pressure-swirl nozzles were used (model 121, size 2.0, 200 μm orifice, Schlick Americas, Bluffton, South Carolina) and (2) Spraying Systems two-fluid nozzles (Model 1/4 J, with a 1650 liquid cap and 70 air cap, Spraying Systems Co., Wheaton, Illinois).

For the clinical-scale dryer, Spraying Systems pressure-swirl nozzles (Models SK-80-16, SK-78-16, and SK-76-16) were used. Specific drying conditions for each set of experiments are given in Table 1, Table 2 and Table 3.

3.2.3. Assessing filaments in spray dried material Early efforts to scale-up Eudragit L100-containing SDDs resulted in unacceptable yield, poor powder flow and low density. Upon examination of the problematic powder using SEM, filament-rich particle morphology was observed. Powder flow was so poor in filament-rich samples that under force of gravity, the powder failed to fall through a 20 mm orifice (such as that used in FloDex testing). Low bulk density of filament-containing samples could not be reliably quantified, as the powder would not pass through a sieve (20-mesh) used for delumping during the analysis. For powders in which material was retained on the 20-mesh sieve, the measurement was rejected as nonuniform. Bulk density of material without filaments typically ranged from 0.10 to 0.15 g/mL. For sprays containing significant filaments, process yields lower than 50% were observed, with significant portions of the spray dried material remaining adhered to the walls of the drying chamber. Due to these complications with quantifying flowability and bulk density directly, a visual assessment of SEM images is used as the primary method of assessing the quality of a spray in this study.

3.2.4. Scanning electron microscopy (SEM) To prepare samples for SEM analysis, a spray-dried sample was placed on adhesive carbon tape, and sputter-coated from a gold/palladium target. Spray dried particle morphology was imaged using a Hitachi SU3500 scanning electron microscope (Hitachi HighTechnologies, Tokyo, Japan) with an acceleration voltage between 5 and 15 kV. Five to ten SEM images of samples at each condition were acquired, and a representative single image is shown here for each result. Table 1 Spray-drying process conditions for Sprays A1-A3 and B1-B3.

Fig. 3. SEM images showing “bead-on-a-string” morphology of Eudragit L100 filaments at two scales.

Process condition

Spray A1

Dryer scale Drying-gas flow rate (kg/h) Spray-solution flow rate (g/min) Polymer concentration in spray solution (wt%) Solvent Inlet temperature (°C) Outlet temperature (°C) Nozzle type

Lab 35 50 7

Atomization pressure (psi)

Spray A2

Spray A3

97/3 acetone/water 117 143 171 35 50 65 Pressure swirl (Schlick 2.0) 200

Spray B1

Spray B2

Spray B3

Clinical 110 160

80 100 35 48 Pressure swirl (SK80-16) 400

110 51

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Table 2 Spray-drying process conditions for Sprays C1-C2 and D1-D4. Process condition

Spray C1

Spray C2

Dryer scale Drying-gas flow rate (kg/h) Spray-solution flow rate (g/min) Polymer concentration in spray solution (wt%) Solvent Inlet temperature (°C) Outlet temperature (°C) Nozzle type Atomization pressure (psi)

Clinical 110 90 190 9

Spray D1 110 142 3

Spray D2

150 5

Spray D3

160 7

Methanol 97/3 acetone/water 150 190 95 35 45 45 44 Pressure swirl (SK80-16) 400

Table 4 Qualitative effect of spray-drying process parameters on droplet τgel and τatom (+ = positive correlation, − = negative correlation, and 0 = negligible effect).

Spray D4

170 9

Spray drying parameter

Droplet τgel correlation

Droplet τatom correlation

Inlet temperature Spray-solution composition Solvent volatility Spray-solution temperature Atomization pressure

− − + − 0

0 + 0 0 −

the Eudragit L100 SDD samples were characterized using qualitative SEM analysis. The effects of each parameter on the droplet τgel and droplet τatom were determined. The results of those tests are summarized in Table 4 and described below.

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3.2.5. Size-exclusion chromatography with multiple-angle laser-light scattering (SEC-MALLS) The molecular-weight distribution of spray-dried Eudragit L100 samples was analyzed using SEC-MALLS. A spray-dried sample containing filaments was passed through a Size 80 sieve (cutoff size 177 μm). The retained material was found to be filament-rich, and the material that passed through the sieve contained few or no filaments, as confirmed using qualitative SEM analysis. The samples were dissolved in 97/3 THF/water by weight at a concentration of 2.5 mg/mL, then passed through a 0.45 μm nylon filter prior to analysis. The molecular-weight distribution was measured on an Agilent HP 1100 high-performance liquid chromatography (HPLC) system (Agilent Technologies, Santa Clara, California) equipped with MALLS and refractive index detectors. The column was a PLgel Mixed-C 5 μm, 300 × 7.5 mm (Agilent), and the guard column a PLgel 5 μm Guard 50 × 7.5 mm (Agilent). Samples were injected into a 97/3 THF/water mobile phase at a flow rate of 0.8 mL/min, using a column and detector temperature of 30 °C.

4. Results To develop and test the hypotheses on the impact of spray-drying process parameters and spray-solution attributes on filament formation, 45 spray-drying runs were conducted, 18 of which are discussed in detail in this work. Placebo SDDs (i.e., polymer only, no API) were prepared using Eudragit L100 dissolved in either 97/3 acetone/water or 100% methanol. The sprays were conducted at two scales of dryer– BLD-35 (lab scale) and BLD-150 (clinical scale)–using two-fluid and pressure-swirl nozzles. Five main spray-drying parameters were evaluated: (1) inlet temperature; (2) spray-solution composition (e.g., polymer concentration and viscosity); (3) solvent volatility; (4) spray-solution temperature; and (5) atomization pressure. These parameters were chosen from extensive experience characterizing and scaling up spray-drying processes. Working from past experience with SDD particle engineering, the authors believed these parameters were most likely to provide the greatest level of control over filament formation and breakup in the spray-drying process for Eudragit L100 SDDs. After spray drying,

4.1. Effect of inlet temperature The goal of these spray-drying experiments was to determine the effect of the inlet temperature of the drying gas on filament formation in spray-dried Eudragit L100 polymer. In the initial stage of atomization and drying, the inlet temperature provides the driving force for solvent evaporation, with higher inlet temperatures resulting in faster solvent removal. It was therefore expected that high inlet temperatures would result in the formation of more filaments. In Sprays A1, A2 and A3, three inlet temperatures were tested: 117 °C, 143 °C, and 171 °C, respectively. Representative SEM images for SDD samples produced at the three inlet conditions are shown in Fig. 4. As Fig. 4 shows, filaments were present in trace quantities for the lowest inlet temperature. Strings increased to moderate levels at the moderate inlet temperature, and to high levels at the highest inlet temperature, at which point decreased yield was observed. These results are consistent with the hypothesis that a high inlet temperature increases the droplet drying kinetics, thus reducing the time to skinning (τgel). These results were replicated on the clinical-scale spray-dryer in Sprays B1, B2, and B3, which tested three inlet temperatures: 80 °C, 100 °C, and 110 °C, respectively. Representative images for SDD samples produced at the three inlet temperatures are shown below in Fig. 5. Similar to the lab-scale samples, filament formation increased as the inlet temperature was increased. Trace amounts of filaments were present in the 80 °C sample, whereas large clusters of entrained filaments and spherical particles were found in the 110 °C sample. Additionally, a large quantity of low-density material remained stuck to the dryer walls for the 110 °C sample. The yield decreased from 85% for the 100 °C inlet temperature to 42% for the 110 °C inlet temperature. The bulk powder consisted of millimeter-to-centimeter sized clusters of filaments with entrained spherical particles. The inhomogeneity made reliable quantification of the bulk density and flowability challenging, as discussed above. For the experiments described above, the inlet temperature was varied and all other spray-drying parameters were held constant except the outlet temperature. This is because when all other parameters are held constant, the inlet and outlet temperature of the dryer are coupled.

Table 3 Spray-drying process conditions for Sprays E1-E2, F1-F2, and G1-G2. Process condition

Spray E1

Dryer scale Drying-gas flow rate (kg/h) Spray-solution flow rate (g/min) Polymer concentration in spray solution (wt%) Solvent Inlet temperature (°C) Outlet temperature (°C) Nozzle type Atomization pressure (psi)

Lab 35 50 7 97/3 acetone/water 152 53 53 Two-fluid (1650/70) 10 30

Spray E2

Spray F1

Spray F2

Clinical 110 180

118 48 Pressure swirl (SK80-16) 500

Spray G1

Spray G2

Lab 35 50

47 Pressure swirl (SK76-16) 200

150 50 50 Pressure swirl (Schlick 2.0) 200

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Fig. 4. SEM images of Eudragit L100 SDDs spray-dried on the lab-scale dryer at inlet temperatures of (a) 117 °C (Spray A1), (b) 143 °C (Run A2), and (c) 171 °C (Spray A3).

To differentiate between the effect of inlet temperature and outlet temperature, a series of sprays was conducted in which the outlet temperature was held constant while the inlet temperature was varied. For a high inlet temperature condition to achieve the same outlet temperature as a low inlet temperature, it is necessary to reduce the drying gas flow rate. This was done for Sprays C1 and C2. It was hypothesized, and then confirmed that the inlet temperature is the key process parameter which controls filament formation, rather than outlet temperature, because the inlet temperature has a larger effect on the initial phase of drying. The outlet temperature sprays were conducted on the clinical-scale dryer, with a constant outlet temperature of 35 °C. Spray C1 was conducted at a low inlet temperature and a high drying gas flow rate. Spray C2 was conducted at a high inlet temperature and a low drying gas flow rate. Although drying gas flowrate was also varied between these two experiments, the drying gas is in such great excess compared to the liquid flow that it is assumed the drying rate in the first second of drying would not be strongly impacted by this change, i.e., the drying rate is limited by diffusion of the solvent through the droplet rather than by convection away from the droplet. Representative images of SDDs from the two sprays are shown in Fig. 6. As the figure shows, when outlet temperature was held constant, the SDD sprayed at the higher inlet temperature spray contained filaments and the SDD sprayed at the lower inlet temperature spray contained negligible filaments. This experiment demonstrates that the inlet temperature, has a larger effect than the outlet temperature on filament formation. 4.2. Effect of spray-solution composition This set of experiments examined two main parameters: (1) the polymer concentration in the spray solution and (2) the solvent system used.

solutions with high polymer concentrations should be more prone to filament formation. This effect was tested on lab-scale and clinical-scale spray dryers using three spray solvents: acetone, methanol, and THF. As anticipated, the number of filaments formed during spray-drying increased as the polymer concentration in the spray solution increased. This trend held across scales and for all solvent systems studied. As a representative example, SEM images demonstrating this effect from Sprays D1 through D4 for acetone/water on the clinical-scale dryer are shown in Fig. 7. At polymer concentrations of 3 wt% and 5 wt%, no filament formation was observed. However, at a 7-wt% polymer concentration, small numbers of filaments were present and, at a 9-wt% polymer concentration, filament formation was prevalent. A similar study was conducted using methanol as the spray solvent on the clinical-scale dryer. SEM results are shown in the supplementary materials. For those spray-drying runs, filament formation was minimal for polymer concentrations of 3-wt%, 5-wt%, 7-wt%, and 9-wt% polymer solutions. Significant filaments were formed at a polymer concentration of 11 wt%. 4.2.2. Effect of solvent system This same dataset can be used to compare solvent effects on filament formation. Comparing the SEM images of 9% polymer solutions spray dried from acetone and methanol, it is clear that use of a lower volatility solvent reduces filament formation. Data are shown in the supplementary material. In this case, it is not clear whether the increased boiling point, higher heat of vaporization of the methanol, or some combination thereof is critical to performance. The solubility of the polymer in the two solvents is similar, further supporting the argument that volatility controls the filament formation. Use of a less-volatile solvent resulted in slower evaporation kinetics during the spray, increasing τgel. Filament formation therefore required a higher polymer concentration for methanol spray solvent than for acetone. 4.3. Effect of atomization conditions

4.2.1. Effect of spray-solution polymer concentration The polymer concentration in the spray solution strongly impacts formation of filaments. Filaments form when solvent evaporates to the point of gelation (τgel) prior to full breakup in atomization (τatom). When the initial spray solution has a high polymer concentration, less evaporation needs to occur before reaching gelation. Therefore,

The previous sections have described parameters that affect the time to τgel. This section examined the effect of atomization pressure on filament formation, specifically the time to atomization, τatom. This effect was investigated using pressure-swirl and two-fluid nozzles. The data presented suggest a common mechanism of filament formation for

Fig. 5. SEM images of Eudragit L100 SDDs spray-dried on the clinical-scale dryer at inlet temperatures of (a) 80 °C (Spray B1), (b) 100 °C (Spray B2), and (c) 110 °C (Spray B3).

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Fig. 6. SEM images of Eudragit L100 SDDs spray-dried on the clinical-scale dryer using a constant outlet temperature and (a) low inlet temperature and high gas-flow rate (Spray C1) and (b) high inlet temperature and low gas-flow rate (Spray C2).

atomizers with different principles of operation (i.e., pressure-swirl versus two-fluid nozzles). For these tests, two atomizing-gas feed pressures were tested— 10 psi (Spray E1) and 30 psi (Spray E2)—using a two-fluid nozzle. All other processing conditions, including the spray-solution flow rate, were held constant. Fig. 8 shows representative SDD images produced under the two conditions. At 10 psi, significant filament formation was observed. At 30 psi, negligible filament formation occurred. Further tests were conducted using pressure-swirl nozzles on the clinical-scale spray dryers. In pressure-swirl nozzles, the atomization pressure and the flow rate are coupled. Therefore, to hold the spraysolution flow rate constant at different atomization pressures, different-sized nozzles must be used. In this experiment, a constant flow rate was achieved by using nozzles with different orifice openings: the SK80–16 nozzle with a 340 μm orifice at 500 psi (Spray F1) versus the SK76–16 nozzle with a 500 μm orifice at 200 psi (Spray F2).

Representative SEM images for the SDDs produced in these processes are shown in Fig. 9. Again, at the low atomization pressure (200 psi), significantly more filaments were observed than at the high atomization pressure (500 psi). This is particularly informative as there are two competing effects in play in this system. The increased atomization pressure decreases the τatom, but at the same time, smaller droplets are formed by the nozzle, decreasing the τgel for the system. These results show that for increased atomization pressure, the decrease in τatom outweighs the decrease in τgel, resulting in fewer filaments. 4.4. Effect of spray-solution temperature During spray-drying, the temperature of the spray solution can vary from well below to well above ambient temperature, depending on the application. For instance, the spray solution may need to be refrigerated to reduce chemical degradation during storage. Conversely, a spray

Fig. 7. SEM images of Eudragit L100 SDDs spray-dried on the clinical-scale dryer from 97/3 acetone/water at four polymer concentrations: (a) 3 wt% (Spray D1), (b) 5 wt% (Spray D2), (c) 7 wt% (Spray D3), and (d) 9 wt% (Spray D4).

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solution may be heated to increase the solubility of the API in the solvent, increasing process throughput [26]. Thus, it is important to understand the effect of solution temperature on filament formation. According to the proposed mechanism of filament formation, a lower solution temperature should result in an increase in τgel, due to the increased time required for heat transfer, plus increased solution viscosity. This effect was tested on the lab-scale dryer for spray solutions stored at two temperatures: −10 °C (cooled, Spray G1) and 20 °C (ambient, Spray G2). Representative images for the SDDs produced in this experiment are shown in Fig. 10. No filament formation was observed for the refrigerated sample, in contrast to the ambient temperature sample, which contained filaments. This demonstrates that filament formation increases with solution temperature, because the particle solidifies more rapidly at higher initial temperatures. This suggests that Eudragit L100 SDDs made from elevated-temperature spray solutions may be at greater risk for filament formation. 4.5. SEC-MALLS analysis to determine molecular weight distribution In addition to qualitative analysis of SEM images, Eudragit L100 SDD samples were analyzed to determine their molecular weight distribution. Because polymeric materials such as Eudragit L100 are polydisperse with respect to their molecular weight, it was initially hypothesized that filament formation might selectively occur for the high-molecular-weight fraction of the spray-dried Eudragit L100. To test this hypothesis, a filament-containing spray-dried sample was physically separated via sieving and then subsequently analyzed using the SEC-MALS protocol described in Section 3.2.5. The molecular weight

Fig. 8. Sprays E1-E2, SEM images of Eudragit L100 SDDs spray-dried from a 7-wt% spray solution using a two-fluid nozzle at two atomization pressures: (a) 10 psi (Spray E1) and (b) 30 psi (Spray E2).

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distributions of filament-rich and filament-poor fractions are shown in Fig. 11. As the figure shows, the molecular weight distributions were similar, indicating that the filament formation is not differentiated by polymer chain length. This result is significant because it demonstrates that filament formation is a property of the bulk material, rather than a high or low molecular-weight fraction of the material.

5. Discussion 5.1. Design spaces for filament formation The results described above support the proposed mechanism for filament formation during droplet breakup in spray-dried polymers. The process and solution parameters investigated all directly affect one or both of two critical characteristic times: τgel or τatom. When τgel b τatom, droplets do not fully break up from the filament stage before they begin to solidify, resulting in formation of high-aspect-ratio filament particles that are deleterious to product flow, density, and yield. A robust process design space is invaluable for manufacturing SDDs, so careful selection of processing parameters is important for commercial viability of the scaled-up process. Using the results of these tests, process design spaces are presented for spray-drying Eudragit L100 SDDs using varying polymer concentrations and inlet temperatures. The results are shown in Figs. 12 and 13 for two solvent systems: 100% methanol and 97/3 acetone/water, respectively. For these process design spaces, the dryer scale, drying-gas flow rate, nozzle size, atomization pressure, and spray solvent were held constant.

Fig. 9. SEM images of Eudragit L100 SDDs spray-dried from a 7-wt% spray solution on a clinical-scale dryer using two different pressure-swirl nozzles at two atomization pressures: (a) an SK80–16 nozzle at 500 psi (Spray F1) and (b) an SK76–16 nozzle at 200 psi (Spray F2).

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Fig. 12. Process design space (shaded area) for Eudragit L100 spray-dried from methanol as a function of spray-solution polymer concentration and inlet temperature. Open circle symbols represent samples where filaments were formed, and solid triangle symbols represent samples where few or no filaments were formed. DSP = dimensionless solvent parameter.

Fig. 10. SEM images of Eudragit L100 SDDs spray-dried on a clinical-scale dryer at two spray-solution temperatures: (a) -10 °C (Spray G1) and (b) 20 °C (Spray G2).

processing space is bounded by the “insufficient drying” limit, where the product is too wet to be acceptable. The exact location of this boundary will vary with the specific solvent and product. The left side of the processing space is bounded by the low throughput limit. At lower polymer contents, the amount of product produced per unit time decreases. The absolute value of this limitation will depend on the product and application. The dotted line represents the boundary between acceptable and unacceptable filament formation. This line corresponds to where the dimensionless solvent parameter, discussed in Section 5.2, is equal to 1. Together, these four limits fully bound the process space. A second process design space, constructed in the same manner, is shown in Fig. 13 for the 97/3 acetone/water solvent system. Due to the increased volatility of acetone, the inlet temperature range of interest is much lower. The polymer degradation processing limit is therefore not restrictive for the solvent system. These maps are useful for process design when avoidance of filaments is critical to product performance, balancing trade-offs such as reduced material throughput and greater residual-solvent content in the SDD product.

In Fig. 12, the process design space for 100% methanol, color-coded triangles, which represent spray-drying experiments where filament formation was evaluated by SEM, are overlaid on the process map. Solid triangles represent product which contained filaments, while open circles represent product that contained few or no filaments. Fig. 12 also illustrates other process considerations based upon the methodology of Dobry et al. [11]. The ideal processing space (shaded) is defined by a set of restrictions. At the top of the plot, the upper boundary is formed by the degradation temperature limit of the polymer, above which, degraded product may be produced. The bottom of the

Using the results described above, which span a range of spray dryers and solvents, an empirical dimensionless solvent parameter was developed to predict the risk of filament formation during spraydrying. Based upon the SEM images, three scale-independent parameters with strong effects on filament formation were identified: (1) the inlet temperature of the drying gas, (2) the polymer concentration of

Fig. 11. Molecular weight distribution of filament-free and filament-rich fractions of spray-dried Eudragit L100 SDD samples.

Fig. 13. Process design space (shaded area) for Eudragit L100 spray-dried from 97/3 acetone/water as a function of solids loading and inlet temperature. Open diamond symbols represent samples where significant filaments were formed, and solid square symbols represent samples where filaments are absent.

5.2. Development of dimensionless solvent parameter to estimate filament formation

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Fig. 14. Correlation of dimensionless solubility parameter with filament formation from this work (internal data) and from the literature, showing excellent agreement.

the spray solution, and (3) the volatility of the spray solvent. To estimate the risk of filament formation when spray-drying Eudragit L100 across different scales and solvents, the following equation was developed: 

ðT inlet −T boil Þ

DSP ¼ 

ðC skin −C solids Þ

.

0:75 

.



T boil

ΔHvap

C skin



1:25

alongside internal data from this work. The results are shown in Fig. 14. Within the 28 data points plotted, spray-drying conditions with and without filament formation are clearly differentiated by the dimensionless solvent parameter value. The DSP is therefore a useful predictor of the risk of filament formation for Eudragit L100 SDDs.

ð1Þ

ΔHvap;ref

where DSP = dimensionless solvent parameter, Tinlet is the temperature of the inlet drying gas in °C; Tboil is the boiling point of the spray solvent in °C (for solvent blends, it is a weighted average of the individual solvent boiling points); Cskin is the experimentally measured polymer concentration (in wt %) at which a gelled skin forms on top of a thin film (for Eudragit L100 it is equal to 15% for acetone or methanol by weight); Csolids is the polymer concentration (in wt%) in the spray solution; ΔHvap is the heat of vaporization of the spray solvent in J/g (for solvent blends, it is a weighted average of the individual solvent heats of vaporization); and. ΔHvap, ref is the reference heat of vaporization (to normalize the dimensionless solvent parameter cutoff to 1, it is taken as 540 J/g). The dimensionless solvent parameter is normalized such that when it is N1, the risk of filament formation during the spray-drying process is high. The dimensionless solvent parameter consists of three normalized contributions to filament formation, which are raised to powers empirically determined to provide the best fit to this experimental dataset. This parameter can be adjusted for use with any volatile solvent system, by simply changing the Hvap and Tboil parameters to match. Filament formation has occurred with other common spray-drying polymers, such as HPMCAS [27], hydroxypropyl methylcellulose propionate (HPMCP) [28], and methacrylic acid/ethyl acrylate copolymer (MAE 100P) [29]. While assessment of the parameter's applicability to other SDD polymer systems is outside the scope of this work, it may prove applicable by simply changing the experimentally measured value of gelled skin formation, Cskin. The utility of the DSP can be demonstrated by plotting results from a range of studies reported in the literature for Eudragit L100. Six literature studies were found where Eudragit L100 polymer was spraydried on a variety of dryers with a variety of spray solvents [30–35]. Using the spray-drying conditions provided in these references, the DSP was calculated for the given process conditions and plotted

6. Conclusions Eudragit L100 is a promising dispersion polymer for the preparation of SDDs to enhance the bioavailability of low-solubility APIs, due to its excellent physical stability and dissolution performance. However, manufacturing SDDs using this polymer can be challenging due to formation of high-aspect-ratio filaments that significantly reduce spraydrying yield, powder flowability, and content uniformity. This work addressed those issues by identifying two characteristic times—τgel and τatom—that control the morphology of particles produced by spray-drying. Three important parameters were also identified that affect these characteristic times and subsequent filament formation: (1) drying-gas inlet temperature, (2) spray-solution polymer concentration, and (3) solvent volatility. Process design spaces for these three parameters demonstrated conditions under which filament formation can be avoided. A dimensionless solvent parameter was developed that accurately describes the risk of filament formation during spray-drying. The dimensionless solvent parameter accurately predicts filament formation, as was successfully demonstrated using existing literature data for spray-dried Eudragit L100. This dimensionless solvent parameter may have additional utility for other polymeric systems, since the phenomenon of filament formation is general and can occur if the drying rate is sufficiently fast and/or atomization and breakup is slow. Overall, this work enables reliable spray-drying particle engineering of a challenging polymeric system, with potential applications both inside and outside of the pharmaceutical formulation space.

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.powtec.2019.12.013.

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