Assessment of dry powder inhaler carrier targeted design: a

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Assessment of dry powder inhaler carrier targeted design: a comparative case-study of diverse anomeric compositions and physical properties of lactose Joana T. Pinto, Sarah Zellnitz, Tomaso Guidi, Eva Roblegg, and Amrit Paudel Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00333 • Publication Date (Web): 01 Jun 2018 Downloaded from http://pubs.acs.org on June 2, 2018

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Molecular Pharmaceutics

Assessment of dry powder inhaler carrier targeted design: a comparative case-study of diverse anomeric compositions and physical properties of lactose Joana T. Pintoa,b, Sarah Zellnitza, Tomaso Guidic, Eva Roblegga,b, Amrit Paudela,d*

a

Research Center Pharmaceutical Engineering GmbH, Inffeldgasse 13, 8010 Graz, Austria

b

Institute of Pharmaceutical Sciences, Pharmaceutical Technology and Biopharmacy, University of Graz, Universitätsplatz 1, 8010 Graz, Austria c

Chiesi Farmaceutici S.p.A., R&D Department, Largo F. Belloli 11/A - 43122 Parma, Italy

d

Institute of Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13, 8010 Graz, Austria

*Corresponding author: Amrit Paudel Research Center Pharmaceutical Engineering GmbH Inffeldgasse 13/II, 8010 Graz, Austria Email: [email protected] Phone: +43 316 873 30912 Fax: +43 316 873 1030912

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Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract The pulmonary administration landscape has rapidly advanced in recent years. Targeted design of particles by spray-drying for dry powder inhaler development offers an invaluable tool for engineering of new carriers. In this work, different formulation and process aspects of spraydrying were exploited to produce new lactose carriers. Using an integrated approach, lactose was spray-dried in the presence of polyethylene glycol 200 (PEG 200) and the in vitro performance of the resulting particles compared with other grades of lactose with varying anomeric compositions and/or physical properties. Anomeric composition of lactose in lactosePEG 200 feed solutions of variable compositions was analyzed via polarimetry at different temperatures. These results were correlated with the solid-state and anomeric composition of the resulting spray-dried particles using modulated differential scanning calorimetry and wideangle X-ray scattering. The distinct selected grades of lactose were characterized in terms of their micromeritic properties using laser diffraction, helium pycnometry and gas adsorption and their particle surface morphologies evaluated via scanning electron microscopy. Adhesive mixtures of the different lactose carriers with inhalable sized salbutamol sulphate, as a model drug, were prepared in low doses and evaluated for their blend homogeneity and aerodynamic performance using a Next Generation Impactor. Characterization of the spray-dried particles revealed that predominantly crystalline (in an anomeric ratio 0.8:1 of α to β) spherical particles with a mean size of 50.9 ± 0.4 µm could be produced. Finally, it was apparent that micromeritic, in particular shape, and surface properties (inherent to solid-state and anomeric composition) of carrier particles dominantly control DPI delivery. This provided an insight into the relatively inferior performance of the adhesive blends containing the spherical spray-dried lactose-PEG 200 composites. Keywords: Dry Powder Inhaler (DPI), lactose, carrier, particle engineering, particle physical chemistry, anomeric design


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Graphical Abstract

Table of Contents

1

Introduction .......................................................................................................................... 4

2

Materials and methods ......................................................................................................... 6 2.1

Materials ....................................................................................................................... 6

2.2

Production of lactose-PEG 200 composite particles ...................................................... 6

2.3

Polarimetry .................................................................................................................... 6

2.4

Solid-state characterization ........................................................................................... 7

2.4.1

Modulated differential scanning calorimetry (MDSC) .............................................. 7

2.4.2

Wide angle X-ray scattering (WAXS)...................................................................... 7

2.5

2.5.1

Particle size distribution.......................................................................................... 8

2.5.2

True density ........................................................................................................... 8

2.5.3

Specific surface area and porosity analysis ............................................................ 8

2.5.4

Scanning electron microscopy ................................................................................ 9

2.6

3

4

5

Micromeritics and surface characterization .................................................................... 8

Adhesive mixtures ......................................................................................................... 9

2.6.1

Mixing homogeneity ............................................................................................... 9

2.6.2

In vitro aerosolization performance......................................................................... 9

Results ............................................................................................................................... 10 3.1

Anomeric composition of lactose in feed solution, raw materials and particles ............ 10

3.2

Solid-state characterization of raw and spray-dried lactose particles ........................... 11

3.3

Micromeritics and surface characterization of the lactose carriers ............................... 13

3.4

Adhesive mixing and in vitro aerosolization performance ............................................ 14

Discussion .......................................................................................................................... 15 4.1

Engineering of the lactose-PEG 200 composites......................................................... 15

4.2

Performance of lactose particles with diverse properties as DPI carriers ..................... 17

Conclusions........................................................................................................................ 20



1

Introduction

Pulmonary administration has been used, mainly, for the local delivery of drugs used in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). However, there is an emergence of the lungs as a possible route for the systemic delivery of peptides and proteins, anti-viral vaccines and drugs requiring rapid onset of action 1. Dry powder inhalers (DPIs) are formulated as a dry powder of drug and excipient particles; these provide higher stability and ease of processing and are, therefore, often times preferred to other inhaled drug delivery devices 2. DPIs are either formulated in the presence or absence of carrier particles. Considering that the inhalable size of active pharmaceutical ingredient (API) particles is between 1-5 µm, coarser excipient particles – the carrier – are frequently blended with the drug in order to provide bulk and improve flowability, increasing dosing accuracy and minimizing dose variability 3. α-Lactose monohydrate is the excipient (carrier) of choice in DPIs due to its safe toxicological profile, physicochemical stability, compatibility with most small organic molecules and lower cost 4. Various commercially available inhalation grades of lactose are usually obtained via contrasting crystallization methods 5. These often necessitate further tailoring of solid-state, micromeritic and surface properties for targeted loading and delivery of the API. Spray-drying, an established and widely used process in the pharmaceutical industry, is of particular interest in inhalation due to the unique opportunity that it provides in designing particles with precise characteristics 6. Spray-drying involves atomization of a liquid jet into micron-sized droplets from which the solvent rapidly evaporates to form solid particles. Instantaneous evaporation of solvent during spray-drying often leads solutes to form amorphous particles 7. Alternatively, spray-drying can also allow engineering of large crystalline particles with uniform size, shape, morphology and tailored physicochemical properties. This can be a great advantage when designing tailored DPI carrier particles. Previous works in literature revealed that it is, in fact, possible to produce crystalline lactose particles when co-spray-drying it with an additive like polyethylene glycol (PEG). For instance, Chidavaenzi et al.

8

have reported that co-spray-drying of lactose with a low amount of PEG

4000 (1% w/w) produces completely crystalline particles. Contrarily, Corrigan et al. 9 and Mosén et al.

10

reported a mixture of amorphous and crystalline phases of lactose when higher PEG

4000 concentrations (1.5% to 30% w/w) were used. Additionally, Mosén et al., (2006) also showed that lower molecular weight PEGs were better at promoting the formation of crystalline lactose when compared to their larger counterparts. 4 ACS Paragon Plus Environment

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Geometric particle size can be controlled by tailoring droplet size distribution during atomization and feed solution concentration

6,11

. In a bi-fluid nozzle, droplet diameter can be maximized

using a large nozzle orifice and lower liquid to airflow ratios

12

. From a solution chemistry

perspective, feed solution concentration can be increased to supersaturation as long as this is maintained during the period necessary to spray-dry it. Lactose solutions containing predominately the βanomer are known to be able to maintain supersaturation for long periods due to their high viscosity 13. In carrier-based DPI formulations, it is desired that the fine drug particles adhere homogeneously to the surface of the carrier, yielding non-segregating adhesive mixtures

14

.

However, it is also required that during aerosol delivery these fine particles completely detach from the surface of the carrier (via shear and turbulence induced by dispersion mechanism of DPI device and patient´s inspiratory airflow)

15

. Evidently, this necessitates a delicate balance

between cohesion and adhesion forces between drug and carrier particles. Inter-particle interactions can be tailored by target engineering of their physicochemical properties; therefore, an in-depth understanding of

particle solid-state, micromeritics and surface properties is

16

demanded . It was the aim of the present work to utilize an integrated approach, where relevant spray-drying process parameters and feed solution properties were investigated and optimized in order to produce crystalline composite lactose particles in the carrier size range. For this, lactose was chosen as a model carrier molecule and co-spray-dried with PEG 200, a proven crystal phase modifier of the disaccharide. Influence of PEG concentration on the anomeric composition of lactose in the feed solution was determined within a certain temperature range. Furthermore, the spray-dried lactose-PEG composites were characterized concerning their anomeric composition, solid-state and micromeritic properties. A blend of lactose-PEG 200 particles with a model API (salbutamol sulphate) was produced and the role of carrier properties on DPI efficiency was assessed. For this, the aerosolization performance of the composites blend was compared with a series of other adhesive mixtures containing distinct lactose grades with different anomeric compositions and/or physical properties. The outcome of the comprehensive anomeric, solidstate, micromeritic and surface characterization of the different lactose grades provided an insight into the relatively inferior performance of the adhesive blends containing the spray-dried lactose-PEG 200 composites as DPI carriers (in terms of in vitro aerosolization).



2 2.1

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Materials and methods Materials

α-lactose monohydrate (InhaLac® 70, β anomer ≤ 3%, Meggle, Germany) and polyethylene glycol 200 (Sigma-Aldrich, EUA) were used to prepare the feed solution for spray-drying. DuraLac® H (16.5% α anomer and 83.5% β anomer, Meggle, Germany) was selected as a β anomer control for solid-state analysis and inhalation performance comparison (hereby called Lβ). Additionally, two other grades of α-lactose monohydrate, FlowLac® 90 (β anomer ≤ 3%, Meggle, Germany) and Respitose® SV003 (β anomer ≤ 3%, DFE pharma, Germany) were also evaluated. Micronized salbutamol sulphate (Selectchemie, Switzerland) with particle size of Dv0.1=0.53 ± 0.01 µm, Dv0.5= 1.93 ± 0.09 µm, Dv0.9= 4.89 ± 0.69 µm (determined in accordance to

our

previous

work16)

was

chosen

as

a

model

drug.

Purified

water

(TKA

Wasseraufbereitunssysteme GmbH, Germany), 1- Hexanesulfonic acid sodium salt (≥ 98%, Sigma-Aldrich, USA), acetic acid (Emprove®, Merck Millipore, USA) and methanol (HPLC grade, Sigma-Aldrich, USA) were used as solvents. 2.2

Production of lactose-PEG 200 composite particles

α-lactose monohydrate was solubilized in a water-PEG 200 solution to yield a lactose-to-polymer ratio of 4:1 and a final solid content of 30% (w/w). For this lactose was added to a water-PEG 200 mixture and made to solubilize with the aid of stirring and heating to 40ºC. The resulting solution was let cool down to room temperature (22ºC ± 2ºC) and stirred overnight prior to spraydrying. A dry powder was obtained using a 4-M8-TriX spray-dryer (ProCepT, Belgium) and compressed air as the drying gas (open loop set-up). The solution was fed at a rate of 2.0 ± 0.1 g/min using a peristaltic pump into a bi-fluid nozzle (orifice diameter of 1.2 mm) operating at a pressure of 0.11 ± 0.01 bar (corresponding to an airflow rate of 4.28 ± 1.37 l/min). The resulting jet was dispersed into a 0.05 m3 drying tower working at a drying air flow rate of 0.3 m3/min The inlet and outlet temperatures used were 179.5 ± 0.8 ºC and 60.6 ± 0.5 ºC, respectively, and a cyclone pressure drop 14.8 ± 0.2 mbar was selected as appropriate to collect the dried particles. After production the composite particles were stored in closed vials inside a dessicator at room temperature (18.0 ± 2.0% RH and 22.0 ± 2.0ºC). 2.3

Polarimetry

Polarimetry was carried using a modular circular polarimeter MCP 500 (Anton Paar, Austria). For this, about 3 ml of a solution were carefully filled into a stainless steel sample cell and visualized to guarantee that no air bubbles were formed. The optical rotation, α, of the lactose solutions 6 ACS Paragon Plus Environment

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was determined at 589 nm with a precision of ± 0.002º and the specific optical rotationαtλ , at a wavelength λ and a given temperature, t calculated according to Eq. 1 17: αtλ =

100α (1) lc

where l is the path length (1 dm) and c the concentration of the anhydrous analyte in g/100 ml. The optical rotation of the spray-drying feed solution was determined at various temperatures (15-40ºC) and at 20ºC with and in the absence of PEG 200. Consequently, lactose anomeric composition in the solution was calculated according to Eq. 2: α anomer (%) = where, α = 91.1º and β = 33.5º.

αtλ -β (2) α-β

Additionally, anomeric composition of InhaLac 70 and lactose-PEG 200 composite particles was also determined (see Supporting Information Figure A1)

18

. Before measurement, the

polarimeter was calibrated and zeroed using water or a PEG 200 aqueous solution. 2.4

Solid-state characterization

2.4.1

Modulated differential scanning calorimetry (MDSC)

Modulated differential scanning calorimetry experiments were performed in a DSC 204 F1 Phönix equipped with an intracooler (Netzsch, Germany) and calibrated for temperature and enthalpic response using Indium. Analysis was performed using sealed aluminum pans with pierced lids, where an appropriate amount of powder was used to guarantee the full coverage of the base of the pan (5 to 10 mg). The raw materials and spray-dried lactose-PEG samples were heated at rate of 5ºC/min from 0 to 270ºC, using a modulation amplitude of ± 0.53 ºC every 40 s under nitrogen purge at a flow rate of 250 ml/min. In order to try to obtain an insight on the effects of spray-drying temperature on the solid-state of the input materials, Lβ and Lβ/PEG 200 physical mixtures were prepared and analyzed using a slight distinct MDSC methodology. The samples were heated at rate of 5ºC/min from 20 to 270ºC, with an isothermal step of 5 min at 180ºC and using a modulation amplitude of ± 0.53 ºC every 40 s under nitrogen purge at a flow rate of 250 ml/min. All the resulting thermograms were analyzed using NETZSCH Proteus Thermal Analysis software (Netzsch, Germany). 2.4.2

Wide angle X-ray scattering (WAXS)

Raw materials, spray-dried lactose-PEG 200 samples and Lβ/PEG 200 physical mixtures were analyzed using wide angle X-ray scattering. The measurements were performed using a point7 ACS Paragon Plus Environment


focusing camera system S3-MICRO (Bruker AXS GmbH, Germany). The powder samples were filled into 2 mm diameter glass capillaries and to avoid crystallites preferential orientation effects analyzed under constant rotation (9 rpm/min). Data was recorded in an angular range between 17 and 27º 2θ (corresponding to the real space dimensions of 4.9 to 3.3 Å) with a total measuring time of 600 s at 30 counts/s and room temperature (22 ± 2ºC). The same conditions were used to characterize the lactose-PEG physical mixture at room temperature, 80ºC, 90ºC, 100ºC and 180ºC. Finally, in order to complement the obtained WAXS results, an additional sample of the spray-dried lactose-PEG powder was gently milled using mortar and pestle and analyzed at room temperature with the same equipment under identical data recording conditions (see section 3.2). 2.5 2.5.1

Micromeritics and surface characterization Particle size distribution

Particle size distribution was evaluated using laser diffraction (HELOS/KR, Sympatec GmbH, Germany). For this, an R5 (4.5-875 µm) optical mode was chosen and triggered once an optical concentration of 0.5% was achieved. The powder samples were dispensed using a dry dispersing system (RODOS, Sympatec GmbH, Germany) coupled with a vibrating chute (Vibri, Sympatec GmbH, Germany) using a sampling time of 120 s. Before measurement the powders were evaluated using pressure titration (as recommended by ISO 13320) and a dispersion pressure drop of 31.0 ± 1.0 mbar, corresponding to a primary dispersion pressure of 0.5 bar was found fitting to properly disperse the powders. Volumetric particle size distributions were calculated and analyzed using Windox 5 software (Sympatec GmbH, Germany). 2.5.2

True density

The true density of the powders was determined by helium pycnometry (AccuPyc II 1340, Micromeritics, USA). The powder samples were accurately weighted and their volume measured in five consecutive runs, using 20 gas purges at 19.5 psi with an equilibrium rate of 0.005 psi/min. Particle density was calculated as the ratio of the sample mass and volume. 2.5.3

Specific surface area and porosity analysis

Specific surface area of the powders was determined by gas adsorption in a TriStar II 3020 (Micromeretics, USA). The samples were firstly treated under vaccum (VacPrep 061, Micromeritics, USA), overnight at 30ºC and then analyzed. A 7-point analysis was performed using a nitrogen relative pressure (p/p0) between 0.05-0.20 and the Brunauer, Emmmett and Teller (BET) adsorption theory used to calculate the specific surface area. The Barrett-JoynerHalenda method (BJH) was used to determine the macro- and mesopore size distribution. In 8 ACS Paragon Plus Environment

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this, a modification to the Kelvin equation relates the porosity to the amount of adsorbate removed during each pressure lowering step (55 points, in a range 0.01-0.99 p/p0) of the nitrogen adsorption isotherm at 77.350 K. 2.5.4

Scanning electron microscopy

Surface topography of powder samples was evaluated at different magnifications using scanning electron microscopy (SEM). For this, the particles were sputtered with gold-palladium and then observed using a Zeiss Ultra 55 scanning microscope (Zeiss, Germany), operating at 5 kV. 2.6 Adhesive mixtures Adhesive mixtures of each of the carrier materials (lactose-PEG 200 composite particles, DuraLac® H, FlowLac® 90, Respitose® SV003) and 2% (w/w) of micronized salbutamol sulphate were prepared in a Turbula blender TC2 (Willy A. Bachofen Maschinenfabrik, Switzerland). Prior to blending, 9.8 g of carrier and 0.2 g of drug were weighted and placed into a stainless steel vessel using the sandwich method (the salbutamol sulphate was placed between two even layers of the carrier). The powder was then blended for 90 minutes at 62 rpm. 2.6.1 Mixing homogeneity The homogeneity of the produced mixtures was evaluated by randomly sampling 10 samples (40 ± 2 mg) from distinct zones of the powder bed and the salbutamol sulphate content in the samples determined using a validated HPLC method

19

. The relative standard deviation (RSD)

of drug content of the various samples was then analyzed and used to conclude if homogeneous blends were produced (RSD < 5%). Additionally, HPLC analysis was supported by SEM (see section 2.4.4), where it was investigated how the drug distributes itself within the different surfaces of the carriers. 2.6.2 In vitro aerosolization performance The adhesive mixtures were manually filled (40 ± 2 mg) into hard gelatin capsules size 3 (Capsugel, France), previously conditioned in a dessicator containing silica gel. The capsules were loaded, one at a time, into an Aerolizer® (Novartis, Switzerland) and evaluation of their in vitro aersolisation performance carried out using a Next Generation Impactor (NGI, Copley Scientific, UK). Aerolizer® is a low-resistance inhalation device, therefore before adapting it to the induction port with the proper mouthpiece, the NGI flow rate was adjusted to 100 l/min producing a 4 kPa pressure drop over the inhaler20. For each experiment, four capsules were discharged by opening the solenoid valve of the critical flow controller (TPK, Copley Scientific, UK) for 2.4 s, so that 4.0 l of air could be passed through the NGI. The salbutamol sulphate 9 ACS Paragon Plus Environment


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content of each experiment was quantified using a validated HPLC method

19

. The resulting

salbutamol sulphate in vitro deposition profiles were compared using t-test statistical analysis (see Supporting Information Table A1). 3

Results

3.1 Anomeric composition of lactose in feed solution, raw materials and particles Evidence in literature has shown that lactose anomeric composition on the solid form can be impacted by solution properties before crystallization

21

. Thus, polarimetry allowed the

investigation of lactose anomeric composition both in feed solution and in powder, before and after spray-drying, respectively (Table 1). In solution, lactose interacts with water molecules allowing the opening of the glycopyranose ring from which two distinct lactose anomeric configurations – the α and β – can result

22

. The α and β anomers differ in the configuration of

the hydroxyl group at the C1 carbon of the glycopyranose, being able to co-exist in solution and solid

13

. So, when α-lactose is solubilized in water opening of its glycopyranose ring ensues the

formation of its β chiral counterpart, by a process called epimerization. This reaction occurs until a final α/β equilibrium of 37% to 63% is reached 23. Literature indicates that in water at 20ºC, the anomers present different equilibrium solubilities – 7% and 50% (w/w) for α and β, respectively – resulting in a lactose aqueous solubility of 18 to 19% (w/w) 13,24,25. Epimerization (or mutarotation when measured by polarimetry) kinetics has been shown to increase with temperature by a first-order rate process described by the Arrehenius equation (from 0ºC to 60ºC)

22

. This explains the results in Figure 1, where an increase in temperature

led to higher percentages of the β anomer. So, it follows that when 24% (w/w) of α-lactose was added to an aqueous solution and the temperature increased to 40ºC, solubilization of the raw material was made possible due to more β being formed. Once the solution was cooled down overnight, it was expected that an α/β equilibrium (37% to 63%) and a correspondent solubility of 18-19% (w/w) would be found, however, this was not the case (Table 1). Thus, it is hypothesized that the former phenomenon was delayed due to: (1) the kinetic hindrance of epimerization (by increased solution viscosity due to a greater percentage of solids present within it i.e., 24% (w/w) v. 18-19 % (w/w))

13

and (2) the slower rate of β to α transformation

22

.

These providing a possible explanation as to why, even after overnight stirring, the feed solutions with and without PEG 200 still had a β content (above the α/β equilibrium) of 77.84 ± 0.02% (w/w) and 73.78 ± 0.20% (w/w), respectively. Indeed, the differences found in β content agree well with the kinetic hindrance hypothesis, if one considers that the solution with PEG 200 had a higher solid content (30% (w/w) compared to 24% (w/w) when lactose was used alone); 10 ACS Paragon Plus Environment

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that is the solution with the polymer was more viscous, hindering epimerization to a greater extent. For the powder samples, the anomeric content of the α-lactose monohydrate raw material was first determined and it was observed that this had a trace amount of the β anomer (0.17 ± 0.03%) as in accordance with the manufacturer (≤ 3%). However, the lactose-PEG 200 composite powder (hereby called Lαβ-sph) showed a β content of 54.71 ± 0.35% (w/w) when compared to its feed solution wherein the β content was 77.84 ± 0.02% (w/w); thus revealing that drying/crystallization kinetics during spray-drying can have a further impact on mutarotation. 3.2

Solid-state characterization of raw and spray-dried lactose particles

Calorimetric analysis (Figure 2 a) of the lactose that was used for spray-drying substantiated polarimetry analysis showing an endothermic event at 210.3 ± 0.3ºC with an enthalpy of fusion (ΔH) of 155.5 ± 2.7 J/g corresponding to the melting of the α form of lactose

26

. Moreover, the

presence of a dehydration peak at 137.0 ± 0.2ºC revealed that α-lactose crystals are present in their hydrate form, α-lactose monohydrate. Analysis of the β-lactose control (Lβ) revealed a single endotherm at 228.3 ± 0.0ºC with an ΔH of 212.6 ± 4.8 J/g. Melting of β-lactose has been reported to occur at ca. 230ºC with an enthalpy of fusion in the 204 to 222 J/g range

9,26–28

.

Additionally, no dehydration peak could be observed, evidencing that lactose was present in its anhydrous forms. Likewise, the Lαβ-sph showed no dehydration peak, however the onset temperature of the melting event was detected some degrees lower, at 225.1 ± 0.5ºC with an ΔH of 144.4 ± 10.6 J/g . More importantly, thermal events characteristic of amorphous materials, i.e., glass transition (for better visualization see Supporting Information Figure A2) and nonisothermal crystallization exotherm

29

could not be found, revealing that the parameters selected

to produce the composites via spray-drying were appropriate to produce predominately crystalline particles. To investigate the possible impact of PEG 200 on lactose anomeric composition, Lβ was physically mixed with PEG 200 in increasing ratios of 10%, 20% and 40% (w/w) and heated alone and in PEG mixtures from 20 to 270ºC with an additional isothermal step (5 minutes) at 180ºC (inlet temperature). Although solvent evaporation kinetics effect on solid-state could not be accounted for with the former methodology, the latter was still applied in order to obtain an insight on the possible impact of spray-drying temperature on the input materials. Figure 2 b shows that increasing PEG fractions led to a decrease on Lβ melting onset temperature and its respective enthalpy of fusion. A depression in melting point and lower enthalpy of fusion are expected as less Lβ is present in the sample and PEG increases; however the marked 11 ACS Paragon Plus Environment


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systematic decrease observed in both events (melting onset and ΔH) suggested a possible increase of the α anomer in the sample (as this anomer melts at a lower onset temperature with a smaller ΔH)

28,30

. In fact, at 10% and 20% (w/w) ratios melting point depression and decrease

in ΔH were accompanied by the appearance of a subtle second endotherm at ca. 230ºC. The latter became strikingly evident at 40% (w/w) ratios where the characteristic melting events of both α and β-anomers were clearly identified and verified the presence of increasing quantities of the α anomer within the samples 9. Finally, it was interesting to note that the physical mixture of Lβ/PEG 200 (with 20% (w/w) PEG content) showed a similar melting event to the Lαβ-sph composites with an onset temperature of 225.2 ± 0.2ºC and an ΔH of 134.9 ± 5.1 J/g . X-ray scattering analysis (Figure 3 a) of the lactose used for spray-drying further supported its identity as α-lactose monohydrate as shown by the appearance of the characteristic pattern of the pseudo-polymorph with the major reflections occurring at 19.1º, 19.5º and 19.9º 2θ

31

.

Likewise, the Lβ control revealed characteristic Bragg peak patterns of the β anomer (in particular the ones at 20.6º and 20.8º 2θ), together with the characteristic peaks of the α one (shifted to 19.4º and 19.6º 2θ)

31

. This supported MDSC data and manufacturer’s information

that Lβ is indeed a mixture of the β and α anomers. At room temperature the physical mixture of Lβ/PEG 200 (with 20% (w/w) PEG content) showed identical peak patterns to the ones found for the Lβ sample alone. To investigate the effect of increasing temperatures on the solid-state of the physical mixture of Lβ/PEG 200 distinct X-ray scattering patterns were recorded between 22ºC and 180ºC (Figure 3 b). It was confirmed that at 180ºC there was an overall shift in peak patterns, suggesting that PEG can influence the anomeric composition of lactose but only beyond certain temperatures (see section 4.1). Although the patterns were hard to resolve in terms of relative quantification of the α form versus the β, if one considers MDSC results it is reasonable to assume that the observed changes might have resulted from the increased formation of the α anomer. The X-ray pattern of the Lαβ-sph composites showed, predominantly, peaks characteristic of the β anomer, however as seen in Figure 3 a peak intensity was quite low. Considering, that MDSC indicated that the lactose-PEG 200 composites were predominantly crystalline, it was hypothesized that the low intensity of lactose peaks could be due to the structuring of PEG 200 (a low weight semi-crystalline polymer) on the surface of the spray-dried particles. So, a small portion of the powder was ground and analyzed (Figure 3 c). This milled sample showed, in fact, to have sharper peak patterns, indicating that PEG might be covering the surface of the composites, however more appropriate methods to explore particle surface chemistry (e.g., high resolution micro-spectroscopy and X-ray photoelectron spectroscopy) have to be used in order to verify this. Moreover, it was interesting to observe a 12 ACS Paragon Plus Environment

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mixture of peak patterns corresponding to both β and α anomers in the absence of any new Bragg peaks. Although, changes in the solid-state due to milling cannot be excluded, WAXS supports polarimetry and MDSC results indicating that the sample is composed of a mixture of the α and β anomers present as isolated crystals and not in their 1:1 co-crystalline form 32. 3.3 Micromeritics and surface characterization of the lactose carriers As observed in Table 2, the Lαβ-sph composites, showed a similar size as that of other available inhalation lactose grades, for instance the tomawahk α-lactose monohydrate Respitose® SV003 (hereby called LαH-tom). Thus, it was evident that the rational approach used to select both spray- drying parameters and feed solution composition was successful in unveiling the possibility of producing crystalline lactose-PEG 200 composite particles in the inhalation carrier size range. As the aim was also to compare the aerosolization performance of the Lαβ-sph composites with other lactoses, two other additional grades were selected to be tested: the Lβ control and FlowLac® 90, a spherical α-lactose monohydrate (hereby called LαHsph). Considering the significant impact of carrier particle size on DPI performance

33,34

, the

aforementioned grades were sieved to a size similar to the one found for the Lαβ-sph composites and LαH-tom particles. However, it is noteworthy to mention that due to its lower Dv0.1 Lβ showed a boarder particle size distribution (as indicated by its SPAN value) when compared to its counterpart lactose carriers. It appeared that the smaller Dv0.1 found for this carrier was mainly due to the break-up of its particulate aggregates during dry dispersion PSD analysis (see Figure 4 b). As shown in Table 3, the Lαβ-sph composite particles revealed a markedly lower true density when compared to the other carriers. This was attributed to Lαβ-sph being composed of PEG 200, a low density molecule (1.124 g/cm3), that in combination with lactose yields particles formed by layers of shells containing sandwiched voids between them (see Supporting Information Figure A3). In turn, Lβ showed the highest density of all the analyzed samples. Considering the greater density of the β anomer when compared to its α counterpart, this result was not suprising

35

. Additionally, also the specific surface area (SSA) and porosity of the

carriers were evaluated and compared (Table 3). Porosity values of Lβ and LHα-sph were higher than that of the other carriers as revealed by their respective cumulative pore volumes. However, LHα-sph had a pronounced lower SSA when compared to Lβ. Thus, it can be inferred that when compared to the β-lactose carrier, the α-lactose monohydrate one contains a larger pore diameter. When compared to LHα-sph, the Lαβ-sph composites showed a slightly lower SSA as well as notably lower cumulative pore volume. LHα-tom showed to have the smallest pore volume and SSA among all the analyzed carriers indicating a relatively smoother surface. It 13 ACS Paragon Plus Environment


Page 14 of 37

was hypothesized that vacuum degassing might have dehydrated α-lactose monohydrate, impacting BET results and making comparison of the hydrate samples with the anhydrous ones challenging; however, this was not the case as revealed by the identical dehydration peaks found for the LHα-tom sample (via MDSC) before and after degassing (see Supporting Information Figure A4). The surface topography of the carrier particles was examined using SEM and is presented in Figure 4. As it can be observed, spray-drying yielded spherical particles with a corrugated surface composed of small needle/rod like shaped crystals on the surface (for better visualization see Supporting Information Figure A3). Lβ showed to be composed of primary crystals of diverse shapes (rod/needle, plates, tomahawk)

36

present as very rough particulate

aggregates. Also LHα-sph revealed to have a notably rough surface as particles are composed of agglomerated primary crystals formed by spherical crystallization

37

. Finally, LHα-tom

presented particles with the well-known, tomahawk shape of α-lactose monohydrate and relatively regular surface. SEM inspections supported gas adsorption results confirming the identified trends in carrier morphology. 3.4

Adhesive mixing and in vitro aerosolization performance

After blending, all the mixtures were found acceptably homogeneous (RSD < 5%). SEM inspections (Figure 5) of the blends showed the API particles distributing themselves around the surface of the carriers, preferentially in their ridges and clefts. Furthermore, with the exception of the blends containing Lαβ-sph particles (as carriers), no notable API agglomerates could be identified.

The in vitro aerosolization performances of the different blends are summarized

Table 4 and depicted in Figure 6. Considering that the present work aimed, only, to explore potential differences in the in vitro aerosolization behavior of the selected carriers, it was decided to compare their adhesive mixtures performance at a single airflow rate of 100 l/min (corresponding to a pressure drop of 4 kPa over the inhaler). Under these circumstances, Lβ showed to be the best performing carrier, with a significant larger drug FPF (p MMAD) when compared to Lβ and LHα-tom. This was particularly noticeable in the case of the blends containing the Lαβ-sph composites, where the MMAD was nearly two times that of the primary particle size (Dv0.5= 1.93 ± 0.09 µm). SEM images after blending of the Lαβ-sph particles with salbutamol sulphate clearly depict the presence of drug agglomerates supporting in vitro aerosolization results. For instance, Wong and Pilpel


50

defined a shape

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coefficient (SC) to evaluate the impact of particle shape on interactive dry powder mixing. The authors defined SC as (Eq. 4): SC= SSA × ρ× de +N

(4)

where, SSA is specific surface area of the particle, ρ the true density, N the elongation ratio

(defined as the particles length L to breadth ratio B ) and de the Heywood equivalent diameter defined as (Eq. 5): 4×0.77×B×L 2 Heywood equivalent diameter = (5) π 1

So it follows that the value of SC will be higher for denser particles with higher SSAs and elongated shapes (e.g., needles). Using lactose particles, it was reported by the same authors that particles with lower SCs achieved mixing homogeneity faster, but tended to show higher segregation propensity. Considering the lower density, regular shape (spherical) and smoother surface of the Lαβ-sph composites, the aforementioned can partially provide the rationale behind the inferior in vitro aerosolization performance of these carriers. Similar characteristics were found for the LHα-sph particles (with the exception of its true density); however additional qualitative evaluation of these (SEM) showed deep clefts and large pores (seemingly larger than the API) not found in the Lαβ-sph composites. Thus, it is important to address how these structures might also have contributed detrimentally to the in vitro aerosolization performance

51

.

These large spaces might have provided shelter for the API agglomerates (and not single particles), protecting them from dispersion forces52. Literature reports indicate that when using the Aerolizer® the former results in drug detachment being predominately dependent on mechanical forces (instead of dispersion ones) that are minimal when smaller carriers are used33,53. This leads to the drug not being detached from the carrier and a consequent higher emitted dose being found for the LHα-sph adhesive mixtures as well as a greater MMAD (due to the contribution of the API particles that were susceptible to dispersion forces and detach from the clefts/pores of the carrier as agglomerates but for which the mechanical forces generated are not enough to break them up33). The findings by Wong and Pilpel 50 also reasonably explain the superior in vitro aerosolization performance of Lβ (a carrier with elongated shape, higher density and greater SSA) when compared to the other carriers tested in this work. Further work using multiple APIs with diverse physicochemical properties will allow to confirm/extend the knowledge for rational DPI carrier engineering. Finally, it is important to explore powder bed fluidization behavior, when the former is composed of spherical particles vs. more irregular shaped ones. Even though in the present work no 19 ACS Paragon Plus Environment


powder cohesiveness evaluation was done, it is known from literature that due to their higher surface area spherical particles tend to be more cohesive, presenting uniform packing arrangements with higher powder bed tensile strengths

54

. These type of powder beds, contrary

to less cohesive ones, with disordered packing, are difficult to fluidize via airflow, being often lifted as plugs or fractures

55

; this, in turn, results in an inferior and variable lung deposition of

fine drug particles. Attesting to the possible cohesive nature of spherical carriers are the NGI results of the present work where the largest fraction of API particles lost in the pre-separator was found for the Lαβ-sph and LHα-sph blends. 5

Conclusions

The present work offers an insight into how an integrated approach (where feed solution properties and spray-drying parameters are wholly understood) can help generate particles with targeted solid-state, micromeritics and surface properties. In fact, this allowed, for the first time, the production of predominantly crystalline lactose-PEG 200 composite particles of a similar size to other lactose grades used as carriers for inhalation. Moreover, by investigating the contribution of lactose powder properties as a DPI carrier for salbutamol sulphate, it was possible to understand how particle shape can affect aerosolization performance, irrespective of the anomeric composition of the disaccharide. These outcomes help to further expand the knowledge towards the production of fit-for-the purpose DPI lactose carriers via anomeric engineering and particle design. The present findings also support, other various works in the literature using excipients in the same size range, where it was shown that carriers with higher elongation ratios, greater specific surface areas and broader particle size distributions might be advantageous. In case of spray-drying, this can be achieved by manipulating feed solution properties and controlling particle formation during processing. It is well-known, for example, that more elongated particles can be formed during spray-drying by forming collapsed hard shelled particles. So, a systematic workflow of feed solution to particle characterization can be implemented to evaluate different property modifying excipients for lactose particle synthesis via spray-drying. Acknowledgments This work was funded through the Austrian COMET Program by the Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT), the Austrian Federal Ministry of Economy, Family and Youth (BMWFJ) and by the State of Styria (Styrian Funding Agency SFG). The authors would also like to thank: Xedev bvba (Belgium) for their support during the spray-drying experiments, Hartmuth Schroettner and Sabrina Mertschnigg at FELMI-ZFE − Austrian Centre 20 ACS Paragon Plus Environment

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for Electron Microscopy for the scanning electron microscopy measurements, Meggle for kindly providing DuraLac® and FlowLac® and Bruker AXS GmbH (Germany) for allowing the use of their equipment. Supporting Information: • •

Calculation of anomeric composition of lactose in solid samples Modulated differential scanning calorimetry (MDSC) thermograms of β-lactose and the

spray dried composite of lactose-PEG • •

SEM micrographs of the spray dried composites of lactose-PEG Modulated differential scanning calorimetry (MDSC) thermograms α-lactose monohydrate

before and after vacuum treatment overnight at 30°C •

Results of F-test and t-test for the comparison of the aerodynamic performance between

the different carrier particles

Abbreviations API, active pharmaceutical ingredient; BET, Brunauer–Emmett–Teller; COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; ED, mass of emitted dose; EDD, emitted fraction of the nominal dose; FPD, fine particle dose; FPF, fine particle fraction of the emitted dose; Lαβ-sph, lactose-PEG 200 composites; Lβ, DuraLac® H; LHα-sph, FlowLac® 90; LHα-tom, Respitose® SV003; MDSC, modulated differential scanning calorimetry; MMAD, mass median aerodynamic diameter; NGI, next generation impactor; PEG, polyethylene glycol; RSD, relative standard deviation; SC, shape coefficient; SEM, scanning electron microscopy; SSA, specific surface area; WAXS, wide angle X-ray scattering; WLF, Williams-Landel-Ferry.

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Table captions Table 1: Polarimetry results for feed solution and solid material analysis. Table 2: Volume particle size distributions of the different carriers (mean ± SD, n=3). Table 3: True density, specific surface area and porosity of the different carriers (mean ± range, n=2). Table 4: In vitro aerosolisation performance results of salbutamol sulphate adhesive mixtures with the different carriers (mean ± SD, n=3).


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Table 1 Solutions

Specific optical rotation (º)

β anomer concentration (%)

Feed solution with PEG 200

46.26 ± 0.01

77.84 ± 0.02

Feed solution without PEG

48.61 ± 0.11

73.78 ± 0.20

Specific optical rotation (º),

β anomer concentration (%)

(n=3, mean ± SD)

200 Solids

1)

(n=2, mean ± range)

at t=0

α-lactose monohydrate

91.00 ± 0.02

0.17± 0.03

Lαβ-sph

59.59 ± 0.20

54.71 ± 0.35

1)

see calculation in supporting information



Page 28 of 37

Table 2 Raw material

Sample

Dv0.1 (µm)

Dv0.5 (µm)

Dv0.9 (µm)

SPAN1)

Lαβ-sph

26.58 ± 0.23

53.07 ± 0.55

85.89 ± 0.58

1.12 ± 0.01

DuraLac® H

Lβ

6.05 ± 0.16

50.94 ± 0.43

98.74 ± 0.32

1.82 ± 0.02

FlowLac® 90

LHα-sph

37.80 ± 0.05

65.53 ± 0.10

98.66 ± 0.25

0.93 ± 0.01

Respitose® SV003

LHα-tom

34.96 ± 0.75

62.34 ± 0.61

99.01 ± 0.87

1.03 ± 0.01

name Lactose-PEG 200 composites

1)

SPAN=

Dv0.9 -Dv0.1 Dv0.5


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Table 3

Sample name

Density (g/cm3)

Lαβ-sph

Specific surface area

Cumulative pore

(m /g)

volume1) (mm3/g)

1.471 ± 0.001

0.212 ± 0.007

1.09 ± 0.02

Lβ

1.594 ± 0.001

0.509 ± 0.019

1.20 ± 0.06

LHα-sph

1.549 ± 0.003

0.285 ± 0.005

1.33 ± 0.17

LHα-tom

1.534 ± 0.006

0.153 ± 0.039

0.53 ± 0.45

1)

2

Volume of pores between 1.7 and 300 nm diameter



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Table 4 Sample name

ED (µg)

EDD (%)

FPD (µg)

FPF (%)

MMAD (µm)

Lαβ-sph

2829.5 ± 65.0

93.6 ± 0.3

362.0 ± 50.3

13.4 ± 1.6

3.6 ± 0.5

Lβ

2914.4 ± 105.0

93.8 ± 2.1

1642.8 ± 67.6

56.4 ± 1.0

2.1 ± 0.1

LHα-sph

3344.9 ± 165.8

96.9 ± 0.2

420.5 ± 123.0

12.5 ± 3.1

2.7 ± 0.3

LHα-tom

2450.5 ± 152.2

94.8 ± 1.2

765.8 ± 71.6

33.0 ± 2.4

2.1 ± 0.2

ED: mass of emitted dose, EDD: emitted fraction of the nominal dose, FPD: fine particle dose, FPF: fine particle fraction of the emitted dose, MMAD: mass median aerodynamic diameter


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Figure captions Figure 1: Determination of spray-drying feed solution anomeric composition in the 15 to 40ºC range of (n=1). Figure 2: MDSC thermograms (n=2) of (a) the raw and spray-dried materials, (b) the physical mixtures – Lβ and polymer at different ratios (asterisks indicate the appearance of an additional endothermic event). Figure 3: WAXS patterns (n=2) of (a) the raw, spray-dried materials and Lβ/polymer physical mixture, (b) the Lβ/polymer physical at different temperatures, (c) the spray-dried material after milling. Figure 4: SEM images (at a 228.7 µm width and 500 x magnification) of (a) Lαβ-sph composites, (b) Lβ, (c) LHα-sph (d) LHα-tom. Figure 5: SEM images (at a 228.7 µm width and 500 x magnification) of salbutamol sulphate adhesive mixtures with (a) Lαβ-sph composites, (b) Lβ (circles indicate the location of the API), (c) LHα-sph (d) LHα-tom. Figure 6: Stage-by-stage in vitro aerodynamic deposition profiles salbutamol sulphate adhesive mixtures with the different carriers (mean ± SD, n=3).



Figure 1


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Figure 2



Figure 3


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Figure 4



Figure 5


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Figure 6


Assessment of dry powder inhaler carrier targeted design: a

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