The control of paracetamol particle size and surface morphology through crystallisation in a spray dryer

Advanced Powder Technology xxx (xxxx) xxx

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Original Research Paper

The control of paracetamol particle size and surface morphology through crystallisation in a spray dryer Alan F. McDonagh, Lidia Tajber ⇑ Synthesis and Solid State Pharmaceutical Centre, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland

a r t i c l e

i n f o

Article history: Received 7 August 2019 Received in revised form 20 October 2019 Accepted 23 October 2019 Available online xxxx Keywords: Paracetamol Spray drying Crystallisation Particle size Evaporation

a b s t r a c t The parameters governing the crystallisation of paracetamol using various conventional techniques has been extensively studied, however the factors influencing the drug crystallisation using spray drying is not as well understood. The aim of this work was to investigate the crystallisation of an active pharmaceutical ingredient through evaporative crystallisation using a spray dryer to study the physicochemical properties of the drug and to use semi-empirical equations to gain insight into the morphology and particle size of the dried powder. Paracetamol solutions were spray dried at various inlet temperatures ranging from 60 °C to 120 °C and also from a series of inlet feed solvent compositions ranging from 50/50% v/v ethanol/water to 100% ethanol and solid-state characterisation was done. The size and morphology of the dried materials were altered with a change in spray drying parameters, with an increase in inlet temperature leading to an increase in particle Sauter mean diameter (from 3.0 to 4.4 mm) and a decrease in the particle size with an increase in ethanol concentration in the feed (from 4.6 to 4.4 mm) as a result of changes in particle density and atomised droplet size. The morphology of the dried particles consisted of agglomerates of individual crystallites bound together into larger semi-spherical agglomerates with a higher tendency for particles having crystalline ridges to form at higher ethanol concentrations of the feed. Ó 2019 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.

Abbreviations: us,mix, Association parameter; P, Atmospheric pressure; ATR, Attenuated total reflectance; Tb, Boiling temperature of solvent; k1, Constant of Thybo equation; k2, Constant of Thybo equation; Pc,g, Critical pressure of drying gas; Pc,s, Critical pressure of solvent; Tc,g, Critical temperature of drying gas; Tc,s, Critical temperature of solvent; qatm, Density of atomising gas; qg, Density of drying gas; qs, mix, Density of solvent; do,i, Diameter on inner liquid orifice; DSC, Differential scanning calorimetry; Ds/g, Diffusion coefficient of solvent in the drying gas; Dc/s, Diffusion coefficient of solute in the solvent; sd, Droplet drying time; DVS, Dynamic vapour sorption; Hm, Enthalpy of fusion; EtOH, Ethanol; FTIR, Fourier transform infra-red spectroscopy; HPLC, High performance liquid chromatography; Tin, Inlet temperature; LD, Laser diffraction; Watm, Mass flow rate of atomising gas; Ws, Mass flow rate of liquid feed; Zs,mix, Mass fraction of solvent at droplet surface; Zs,1, Mass fraction of solvent away from droplet surface; Tp, Melting point peak temperature; Vms,mix, Molar volume of solvent; Ms,mix, Molecular weight of solvent; Mg, Molecular weight of the drying gas; Rc, Paracetamol recrystallised from ethanol; Pe, Peclet number; k, Rate of droplet evaporation; dsm, Sauter Mean Diameter; LD dsm, Sauter Mean Diameter calculated from LD data; SEM, Scanning electron microscopy; Sc, Solvent composition; cs,mix, Solvent surface tension; SD, Spray dried; qtap, Tapped density; TG, Temperature of the outlet drying gas; To, Temperature of onset of melting; Twb, Temperature of the wet bulb; ssat, Time to droplet supersaturation; Ptot, Total drying chamber pressure; qt, True density; Ps,mix, Vapour pressure of the solvent; vatm, Velocity of atomising gas; ls,mix, Viscosity of the solvent; PXRD, Powder X-ray diffraction. ⇑ Corresponding author at: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, College Green, Dublin 2, Ireland. E-mail address: [email protected] (L. Tajber).

1. Introduction Spray drying is a well-established, versatile, scalable and rapid technique used to dry a wide range of mixtures including aqueous and organic solutions, suspensions, slurries and emulsions. By pumping a narrow stream of a solvent inlet feed through an atomiser before encountering an atomising source, usually an inert gas such as nitrogen, the feed becomes atomised by the rapid disintegration of the solvent liquid waves due to their increasing amplitude and eventual shearing brought upon by turbulent aerodynamic stresses caused by the atomisation source [1]. These atomised droplets, usually on the scale of micrometres, then come into contact with the drying gas and rapidly shrink due to the very large surface area for heat transfer associated with their decreased size. In the case of spray drying from solution, this decrease in droplet size, decrease in solvent volume and therefore increase in solute supersaturation allows for the crossing of the barrier to nucleation. The composition of the dried particle, either amorphous or crystalline, primarily depends on the composition of the feed, spray drying parameters and the properties of the material being dried [2–4]. Spray drying, through its ability to quickly

https://doi.org/10.1016/j.apt.2019.10.021 0921-8831/Ó 2019 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.

Please cite this article as: A. F. McDonagh and L. Tajber, The control of paracetamol particle size and surface morphology through crystallisation in a spray dryer, Advanced Powder Technology, https://doi.org/10.1016/j.apt.2019.10.021

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produce dried powders through the rapid evaporation of the carrier solvent, has been increasingly utilised in recent years for the formation of amorphous materials [5–7], however the use of this technique is not as well understood or employed as a method of crystallisation. Paracetamol (acetaminophen, PAR, C8H9NO2) is a common active pharmaceutical ingredient (API) having analgesic and antipyretic properties and used in a wide range of pharmaceutical roles. It has two hydrogen bond accepting functional groups (AOH, @O) and two hydrogen bond donating functional groups (ANH, AOH). It forms NAH  O and OAH  O hydrogen bonds by ANH, AOH, and AC@O groups. To date, three polymorphic forms of PAR have been reported. The crystalline structure of the commercially available and most stable form I (monoclinic) was first described by Haisa et al. [8] and Welton et al. [9], the metastable form II (orthorhombic) was first observed by Haisa et al. in a recrystallisation study using ethanol (EtOH) as a solvent [10], and the unstable form III was observed under fusion experiments obtained in both an orthorhombic and monoclinic form [11–14]. PAR form I is readily soluble in EtOH (0.886 mol/L) and slightly soluble in water (0.101 mol/L) at 25 °C [15]. Its solubility increases with an increase in EtOH concentration up to a maximum of 80% v/v EtOH/water before the solubility of PAR decreases [15]. The morphology of PAR is greatly influenced by the method of crystallisation, solvent used, temperature, pressure and supersaturation rate [16]. The effect of these crystallisation parameters on the crystallisation of PAR is well published. Finne at al. [17] investigated the growth of PAR crystals at various supersaturation levels and found that the degree of supersaturation had a large impact on the growth rate and crystal habit. Shekunov et al. [18] studied the effect of temperature on the properties of PAR crystals and found that the growth of individual faces being prominent at low and high temperatures led to crystals with varying degrees of crystal hardness, elasticity and brittleness. Granberg et al. [19] and Sudha et al. [16] studied the effect of the solvent composition on the crystallisation of PAR and found that if the drug is crystallised from common solvents such as water, EtOH or methanol, the interaction between the solvent and solute had a large effect on the crystal habit as a result of the change in solubility and supersaturation. In any crystallisation process, the internal variations of an idealised supersaturated solution govern the crossing of the barrier to nucleation and therefore crystal growth. To impose this supersaturation, the equilibrium solubility of the solute must reduce below that of the solute concentration. This can be done by various means such as altering the solution pH (reactive precipitation) [20], changing the solvent composition (anti-solvent crystallisation) [21], changing the solution temperature (cooling crystallisation) [22] and evaporating the solvent (evaporative crystallisation) [23]. In relation to crystallising from a spray dryer the latter method is applied. During evaporation crystallisation the most important parameter to control is the solvent evaporation rate [24]. The temperature and solvent composition are therefore two very important factors in this crystallisation process. In spray drying the inlet temperature and nature of the solvent have a combinatorial effect on the outlet temperature [25], and the boiling point of the solvent is governed by its composition [26]. Both parameters are directly proportional to the wet bulb temperature of a droplet [27]. The temperature therefore governs the physical properties of the droplet from the solvent density to the droplet surface tension including kinetic properties such as diffusion coefficients. Parameters such as the diffusion coefficient of the solvent into the drying gas, solvent density, drying gas density and mass fraction of solvent at the droplet surface all contribute to the solvent evaporation rate in an atomised droplet and therefore it is clear that in order to investigate the crystallisation of PAR using a spray dryer, these parameters must first be considered.

The aim of this work was to investigate the evaporative crystallisation of PAR using a spray dryer at various inlet feed hydroalcoholic solvent compositions and inlet temperatures to explore further into the roles and outcomes of varying such parameters on the physical and morphological characteristics of spray dried PAR through the characterisation of the resulting atomised droplets. 2. Materials and methods 2.1. Materials Paracetamol (PAR) was purchased from Sigma-Aldrich (Ireland), while ethanol (EtOH, technical grade) was purchased from T.E Laboratories (Ireland). Deionised water was produced using a Purite Prestige Analyst HP water purification system. HPLC gradient grade water (for DVS) was obtained from Fisher Chemical (UK) and anhydrous EtOH (for DVS, <0.003% H2O) was purchased from VWR Chemicals (Ireland). 2.2. Methods 2.2.1. Spray drying 2.2.1.1. Effect of spray dryer inlet temperature. A series of 5% w/v PAR solutions were made up using 100 mL of EtOH. These solutions were spray dried (n = 3) using a Büchi B-290 mini spray dryer (Büchi, Switzerland) at inlet temperatures (Tin): 60 °C, 70 °C, 80 °C, 90 °C, 100 °C, 110 °C and 120 °C corresponding to outlet temperatures (Tout) of 38 °C ± 2 °C, 46 °C ± 3 °C, 52 °C ± 3 °C, 58 °C ± 3 °C, 66 °C ± 5 °C, 71 °C ± 5 °C and 76 °C ± 4 °C respectively (samples #1-#7, Table 1). A 2-fluid atomising spray nozzle with a 0.7 mm cap was used. The solutions were fed into the spray dryer through an incorporated peristaltic pump at an approximate rate of 9 mL/min (setting: 30%) with an aspirator drying air flow rate of 38 m3/h (setting: 100%) and flow meter spraying flow rate of 475 L/h (height: 40 mm) [28]. The drying gas used was air and the dispersant spraying gas was nitrogen. The dried materials were collected from the collection vessel only (production yields are presented in Table 1) and were thoroughly mixed using a spatula prior to refrigerated storage (4 ± 1 °C) in 15 mL amber powder bottles. 2.2.1.2. Effect of inlet feed solvent composition. A series of 5% w/v solutions were made up at different EtOH/H2O solvent compositions (Sc): 50/50% v/v EtOH/H2O, 60/40% v/v EtOH/H2O, 70/30% v/v EtOH/H2O, 80/20% v/v EtOH/H2O, 90/10% v/v EtOH/H2O and 100% EtOH. These solutions were spray dried (n = 3) using the same instrument settings as above with the exception that the Tin was maintained at 120 °C. The corresponding Tout were 65 °C ± 1 °C, 66 °C ± 1 °C, 71 °C ± 1 °C, 75 °C ± 1 °C, 77 °C ± 1 °C and 77 °C ± 1 °C respectively (samples #13 - #8, Table 1). 2.2.2. Slow crystallisation of paracetamol from EtOH PAR was recrystallised using a slow evaporation technique from EtOH (n = 3). A volume of 100 mL of EtOH was filtered using a Fisherbrand 0.45 lm PTFE hydrophilic membrane syringe filter and used to dissolve 10 g of PAR at 20 °C. Once completely dissolved, 30 mL of this solution was then added to a glass specimen tube and sealed using parafilm. A needle was used to puncture small holes in the parafilm to allow the evaporated EtOH to be removed. The solutions were left in a fume hood until sufficient solvent evaporation had occurred to produce a supersaturated solution (~2 weeks). The precipitated crystals were extracted and allowed to dry in air before being crushed using a mortar and

Please cite this article as: A. F. McDonagh and L. Tajber, The control of paracetamol particle size and surface morphology through crystallisation in a spray dryer, Advanced Powder Technology, https://doi.org/10.1016/j.apt.2019.10.021

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Table 1 Summary of spray dryer experimental parameters. Tin - inlet temperature, Tout – outlet temperature, Twb – wet bulb temperature, Cs1,i – concentration of EtOH used, Cs2,i – concentration of water used, F – spray dryer inlet feed pump setting, G – spray dryer dispersion force setting (gas flow setting), A – spray dryer aspirator setting.

*

Spray dryer condition

Tin (°C)

Tout (°C)

Twb (°C)*

Cs1,i (% v/v)

Cs2,i (% v/v)

F (%)

G (mm)

A (%)

Yield (%)

#1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 #13

120 110 100 90 80 70 60 120 120 120 120 120 120

76 ± 4 71 ± 5 66 ± 5 58 ± 3 52 ± 3 46 ± 3 38 ± 2 77 ± 1 77 ± 1 75 ± 1 71 ± 1 66 ± 1 65 ± 1

16.95 15.81 14.82 13.46 12.25 11.01 9.74 16.79 16.59 16.78 16.93 17.08 17.22

100 100 100 100 100 100 100 100 90 80 70 60 50

0 0 0 0 0 0 0 0 10 20 30 40 50

30 30 30 30 30 30 30 30 30 30 30 30 30

40 40 40 40 40 40 40 40 40 40 40 40 40

100 100 100 100 100 100 100 100 100 100 100 100 100

42 ± 5 51 ± 2 54 ± 1 56 ± 2 50 ± 4 53 ± 3 34 ± 4 42 ± 5 35 ± 3 38 ± 4 37 ± 5 35 ± 6 36 ± 4

Predicted from Eq. (2).

pestle. The resulting powder was then placed in an oven at 60 °C overnight to fully dry the sample. 2.2.3. Thermal analysis Differential scanning calorimetry (DSC) was carried out using a Mettler Toledo DSC 821e (Greifensee, Switzerland). The same heating range and rate was used for both investigations. The range was 25–250 °C at a rate of 10 °C/min. The purge gas flow rate was set to 10 mL/min and the gas used was nitrogen. All samples were accurately weighed (5–7 mg) using a microbalance (Mettler Toledo MT5, Greifensee, Switzerland) and placed into 40 lL aluminium crucibles. Three holes were punctured using a pin to allow any gases produced to be released during the heating process. All measurements were carried out in triplicate. Thermogravimetric analysis was performed using a Mettler TG 50 (Greifensee, Switzerland) module linked to a Mettler MT5 balance in the furnace under nitrogen purge. Sample masses were between 7 and 8 mg and were placed into open aluminium pans. A heating rate of 10 °C/min was implemented in all measurements up to a temperature of 300 °C. The weight loss was evaluated between 25 and 120 °C. 2.2.4. Powder X-Ray diffraction (PXRD) PXRD profiles were taken using an X-ray diffractometer (Rigaku Miniflex II, Japan) operating in the BraggBrentano reflection mode. It was equipped with a Cu Ka radiation X-ray source (1.54 Å) and was operated by placing the samples front-loaded onto a zero-background silicon sample holder. The samples were placed on the holder using a spatula and gently pressed using a glass slide to obtain a uniformity of depth amongst all the samples. The samples were then scanned over a range of 5–40° (2h). All measurements were carried out in triplicate. 2.2.5. Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) A PerkinElmer Spectrum 1 FT-IR (USA) with an ATR and ZnSe crystal accessory was used to record FT-IR spectra of each material tested. Absorbance spectra were obtained over a scanning wavelength range of 4000–650 cm1 using a resolution of 4 cm1. The reported results are presented as an average of 10 scans per each sample. All measurements were carried out in triplicate. 2.2.6. Dynamic vapour sorption A DVS Advantage–1 automated gravimetric sorption analyser (Surface Measurement Systems, UK) was used to measure the vapour sorption capabilities of the spray dried samples. Samples were tested at 25.0 ± 0.1 °C using water and EtOH separately as

the adsorbing vapour. A mass of 15–20 mg of material was placed in the sample basket and allowed to settle until a steady state weight change of 0.0002 mg/min was reached taking between 1 and 2 h at 0% RH (for water)/0 p/p0 (for EtOH). Once stable the sample was exposed to changes in RH / p/p0 from 10% RH/0.1 p/p0 to 90% RH/0.9 p/p0 in 10% RH/0.1 p/p0 increments and in reverse during the desorption process. The samples were analysed using two sorption/desorption cycles and were re-tested using DSC and PXRD post-DVS testing. 2.2.7. Scanning electron microscopy (SEM) SEM analysis was completed using a Carl Zeiss ultra 3 SEM (Oberkochen, Germany). Samples were gently applied to doublesided adhesive pads and excess powder was removed using compressed air before coating. Samples were treated using a Cressington 208HR sputter coater using gold/palladium as a coat for 90 s. An accelerating voltage of 5 kV was used along with a working distance of 12 mm. 2.2.8. Particle size analysis Measurements of particle size and particle size distributions were obtained using a laser diffraction particle sizer Mastersizer 2000 (Malvern Instruments, UK). Particles were dispersed using a Scirocco dry feeder instrument with 3 bar pressure. An obscuration of between 0.5%6% was obtained using a vibration feed rate of 75%. The surface weighted Sauter mean diameter (dsm, D[3,2]) was calculated using the Mastersizer 2000 software. All measurements were carried out in triplicate. 2.2.9. Density and porosity The true density (qt) of the powders (n = 3) was determined using an AccuPyc 1330 pycnometer (Micromeritics, Norcross, GA, USA) using helium (99.995% purity). Tapped density (qtap, n = 3) was measured by adding a known quantity of material to a 5 mL graduated glass cylinder [29] and tapping the cylinder off the table top the required number of times for the compacted powder to reach a constant volume value. Once the volume reading was constant over 100 tap periods, the weight was measured again and the density was calculated. Porosity was calculated using the following equation and expressed as a percentage (Eq. (1)) [30].

e¼

ðqt  qtap Þ

qt

x100

ð1Þ

where e is the porosity presented as a percentage, qt is the true density and qtap is the tapped density.

Please cite this article as: A. F. McDonagh and L. Tajber, The control of paracetamol particle size and surface morphology through crystallisation in a spray dryer, Advanced Powder Technology, https://doi.org/10.1016/j.apt.2019.10.021

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2.3. Statistical analysis Differences between spray dried samples were statistically tested by running a one-way ANOVA model with a two-sided confidence interval with 95% confidence. Tukey comparisons were used to check the significance of individual responses and a p-value of 0.05 was the cut off for significance. Normal probability plots, histograms of residuals and residuals vs. fitted values were also plotted to check for deviations from statistical assumptions 3. Calculation of parameters to characterise atomised droplet The physical characteristics of spray dried droplets were calculated in order to understand the effect of Tin and Sc on spray dried droplets during the process. The first parameter calculated was the droplet’s wet bulb temperature (Twb) (Eq. (2)) [31].


0:68 Tb Twb ¼ 137 log ðTG Þ  45 373:15

ð2Þ

where Tb is boiling temperature of solvent and TG is temperature of the outlet drying gas. One of the assumptions made during the drying process is that the solvent in the droplet is at the wet bulb temperature throughout the drying process [32]. All physical properties such as: solvent density, solvent viscosity, solvent surface tension, drying gas density, atomising gas density, diffusion coefficient of the solute in the solvent, diffusion coefficient of the solvent in the drying gas, solvent saturated vapour pressure as well as the PAR solubility were taken at this temperature. Wilke-Chang proposed an equation to calculate the diffusion coefficient of a solute in a dilute solvent (Dc/s) (Eq. (3)) [14].

Dc=s

   1:173  1016 us;mix 0:5 Ms;mix 0:5 ðT wb Þ   ¼  ls;mix Vms;mix 0:6

ð3Þ

where /s,mix is the association parameter, Ms,mix is molecular weight of solvent, ls,mix is viscosity of solvent and Vms,mix is molar volume of solvent. To estimate the diffusion coefficient of the solvent in the drying gas a correlation was proposed by Slattery et al. The following equation combines kinetic theory and corresponding states arguments to estimate the diffusion coefficient at low gas pressures (Ds/g) (Eq. (4)) [33,34].



Pc;s Pc;g

13 

Tc;s Tc;g

b 1
T wb 1 2 p ffiffiffiffiffiffiffiffiffiffi ffi þ a Ms;mix Mg

125 

Ds=g ¼

1

Tc;s Tc;g

P

ð4Þ

where Pc,s is the critical pressure of the solvent, Pc,g is the critical pressure of the drying gas, Tc,s is the critical temperature of the solvent, Tc,g is the critical temperature of the drying gas, Mg is the molecular weight of the drying gas and P is atmospheric pressure. The evaporation rate of solvent (k) away from the droplet surface was estimated using Eq. (5) proposed by Finlay [35].

k ¼ 8Ds=g

 qg  Z  Zs;1 qs;mix s;mix

ð5Þ

where qg is the density of the drying gas, qs,mix is the density of the solvent, Zs,mix is the mass fraction of solvent at the droplet surface and Zs,1 is the mass fraction of solvent away from the droplet surface. The mass fraction of solvent at the droplet surface (Zs,mix) given by equation (Eq. (6)) [36].

Zs;mix ¼

Ms;mix 

Ms;mix þ Mg

Ptot Ps;mix

1



ð6Þ

where Ptot is the total drying chamber pressure and Ps,mix is the vapour pressure of the solvent. The solvent vapour pressure was calculated using the Antoine equation (Eq. (7)) [37,38]. AT

Ps;mix ¼ 10

B wb þC

ð7Þ

where A, B and C are constants for the solvent/s used. In order to quantify the ratio of solute diffusion rate to solvent evaporation rate the Peclet number (Pe) was calculated (Eq. (8)) [27].

Pe ¼

k 8Dc=s

ð8Þ

The Pe number is a dimensionless number for which a value of Pe < 1 implies that the diffusion of the solute is faster than the rate of solvent evaporation. This would show that there is adequate time for the solute to diffuse away from the drying boundary layer towards the centre of the droplet forming a spherical particle with a solid core. The larger the Pe value is greater than one, the larger the tendency for a particle to form with an outer shell and hollow core. This is due to the diffusion of the solute being slower than the evaporation rate resulting in an increase in surface enrichment of the solute before being caught by the drying boundary layer and forming an outer shell [39]. Droplet size was estimated by calculating the Sauter mean diameter (dsm) using Eq. (9) [40]. Thybo et al. proposed the following correlation with slight modification from Kemp et al. [41] to calculate the size of droplets.

dsm

!k1 pffiffiffiffiffiffiffiffiffiffiffi
 ls;mix cs;mix Ws k2 pffiffiffiffiffiffiffiffiffiffiffiffi ¼ do;i 1 þ Watm qs;mix qatm vatm 2 do;i 1:5

ð9Þ

where do,i is the diameter of the inner liquid orifice, Ws is the mass flow rate of the solvent, Watm is the mass flow rate of the atomising gas, k1 (0.496) and k2 (3.414) are constants, cs,mix is the surface tension of the solvent, qatm is the density of the atomising gas and vatm is the velocity of the atomising gas. Using dsm and the solvent evaporation rate (Eq. (5)), the droplet drying time (sd) can be calculated as per Eq. (10) [42].

sd ¼

dsm k

2

ð10Þ

The equilibrium concentration of the solute in the solvent and the initial concentration of API in solution at the wet bulb temperature were predicted from experimental data available from literature [15]. Using the change in droplet size to calculate the change in droplet volume over time, together with the initial concentration of drug in the droplet, the change in supersaturation could be then determined as a function of droplet drying time. 4. Results and discussion 4.1. Comparison of spray drying to evaporative crystallisation and main hypothesis of this work Whereas the main parameters influencing evaporative crystallisation from solution have been extensively studied [23,24,43], the effects of these parameters are not as well understood for crystallisation using a spray dryer. This work considers the idea that the conventional view of a crystallisation vessel with a stainless-steel wall, temperature control source and impeller for homogeneity can be translated to spray drying by taking each atomised droplet as being an individual crystallising vessel with a permeable wall of varying characteristics according to the physical properties of the solvent of which it is made. The degree of solute mixing is governed by thermal diffusion and the vessel temperature is

Please cite this article as: A. F. McDonagh and L. Tajber, The control of paracetamol particle size and surface morphology through crystallisation in a spray dryer, Advanced Powder Technology, https://doi.org/10.1016/j.apt.2019.10.021

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controlled by the wet bulb temperature of the droplet, which is a product of the solvent boiling temperature and outlet drying gas temperature (Eq. (2)). The aspirator rate would govern the residence time with a higher rate resulting in a shorter time that each vessel is exposed to the relative temperature for evaporation. The atomising gas feed rate and inlet feed mass flow rate would contribute to the size of the crystallising vessel with an increase in gas flow resulting in a reduction in vessel size and therefore the quantity of solvent to be evaporated to induce nucleation, and finally the inlet mass flow rate would influence the quantity of solvent and solute being added to the vessel (Eq. (9)). The above premise was investigated, applying various inlet temperature and solvent compositions due to the influence and importance of these two parameters for evaporative crystallisation, using a model substance, paracetamol (PAR), as its crystallisation from solution has been well understood and described [12,16,19,44].

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4.2. Solid state characterisation 4.2.1. Powder X-Ray diffraction (PXRD) Fig. 1a and 1b shows the PXRD diffractograms of PAR samples spray dried at various Tin and various Sc respectively. PAR processed from various inlet temperatures showed no apparent differences between the samples as the Tin increased from #7 to #1 with similar Bragg peak positions and intensities with a crystalline material being obtained for each condition. Similarly, the solid state of PAR processed at various Sc (from 100% to 50% v/v EtOH/ H2O, samples #8 - #13) was also comparable between samples. Each sample had 2theta (degree) peaks and corresponding hkl planes of 12.1° 2h (1 1 0), 13.8° 2h (0 0 1), 15.5° 2h (2 0 1), 16.8° 2h (0 1 1), 18.2° 2h (2 1 1), 18.9° 2h (0 2 0), 20.4° 2h (1 2 0), 20.8° 2h (1 1 1), 23.5° 2h (0 2 1), 24.4° 2h (2 2 0), 26.6° 2h (1 2 1) and 27.2° 2h (1 1 2).

Fig. 1. Powder X-ray diffractograms of spray dried paracetamol at (a) #1, #2, #3, #4, #5, #6, #7 and (b) #8, #9, #10, #11, #12, #13 spray drying conditions as well as PAR recrystallised by slow evaporation from EtOH (Rc). PAR diffractograms of form I, II and III were calculated from single crystal structures obtained from CCDC: HXACAN01, HXACAN23 and HXACAN29, respectively.

Fig. 2. Attenuated total reflectance Fourier transform infrared second order derivative spectra of spray dried PAR at (a) #1, #2, #3, #4, #5, #6, #7 and (b) #8, #9, #10, #11, #12, #13 spray drying conditions as well as paracetamol recrystallised by slow evaporation from EtOH (Rc). Red arrows indicate parts of spectra where slight changes were detected. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Please cite this article as: A. F. McDonagh and L. Tajber, The control of paracetamol particle size and surface morphology through crystallisation in a spray dryer, Advanced Powder Technology, https://doi.org/10.1016/j.apt.2019.10.021

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The sample of PAR recrystallised by slow evaporation from EtOH (Rc) showed the same diffraction peaks as the spray dried samples with each peak increasing in intensity in comparison to the spray dried samples with the largest relative increase being attributed to the (2 0 1) plane. There was also a slight change in the average Bragg peak intensity for the spray dried samples as the Tin increased. An increase in peak area is an indication of an increase in the materials crystallinity, however such effects can be masked by the crystals tendency for preferred orientation

during testing [45]. Form I of PAR was the prominent polymorph obtained for both investigations. The characteristic peaks of 14.9° 2h (0 2 0), 17.5° 2h (1 1 2), 18.2° 2h (0 2 2), 19.2° 2h (1 2 0), 21.8° 2h (1 2 2) and 24.0° 2h (2 0 0) for PAR form II and 12.7° 2h (1 1 0), 14.1° 2h (1 0 2), 19.1° 2h (2 0 2), 23.9° 2h (0 0 4) and 25.6° 2h (2 1 3) for form III were not observed in any of the SD samples. This trend is explained as PAR has a higher tendency to crystallise in its stable form I after solvent evaporation with PAR form II being metastable at all temperatures at ambient pressure [46].

Fig. 3. Dynamic vapour sorption kinetic plots of PAR samples spray dried at conditions: #7 using (a) EtOH and (b) water as the probe vapour; #8 using (c) EtOH and (d) water as the probe vapour and #13 using (e) EtOH and (f) water as the probe vapour.

Please cite this article as: A. F. McDonagh and L. Tajber, The control of paracetamol particle size and surface morphology through crystallisation in a spray dryer, Advanced Powder Technology, https://doi.org/10.1016/j.apt.2019.10.021

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7

Fig. 4. Particle size distribution of paracetamol spray dried at various inlet temperatures (a) and solvent compositions (b).

Fig. 5. Analysis of predicted droplet Peclet number, predicted droplet Sauter mean diameter, dried particle Sauter mean diameter, dried particle tapped density and dried particle porosity as a function of spray dryer inlet temperature.

4.2.2. Infrared analysis (FTIR) As evidenced by Figure SI.1 and Table SI.1, the characteristic bond vibrations of PAR form I [47]: NAH stretching vibration (3161 cm1), CAH stretching vibration of the phenyl ring (1610 cm1), deformation of the CANH bond mixed with the stretching vibration of the phenyl ring (1565 cm1 and

1516 cm1), deformation of the methyl group mixed with the stretching vibration of the phenyl ring (1442 cm1) and the deformation of the PhAH bond mixed with the stretching of the CAN bond, all matched to those of the SD samples, processed at various Tin and Sc. The bond vibrations associated with those of PAR form II [47] and PAR form III [12] were not observed (Figure SI.1 and

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Fig. 6. SEM imaging of spray dried paracetamol using an inlet temperature of: (a) 120 °C and (b) 60 °C.

Table SI.1). No discernible shifts or other changes were observed in absorption peak locations as the inlet temperature increased or as the concentration of EtOH increased in the spray dryer inlet feed (Figure SI.1). To confirm further that no other polymorphs formed during spray drying, the second order derivative of the FTIR spectra were computed to enhance the analysis (Fig. 2). No new peaks showing the presence of the other crystalline forms were revealed by this procedure, however subtle variations were detected around 1530–1550 cm1, as indicated in Fig. 2 by a red arrow, most likely associated with changes around the phenyl ring and related to differences in crystal lattice of the samples. 4.2.3. Thermal analysis By varying the Tin no observable change was seen between the PAR samples by DSC. Any change in the melting point (onset temperature, To), peak temperature (Tp) or enthalpy of melting (Hm) was not found to be statistically significant (p = 0.10, p = 0.71 and p = 0.24, respectively, Figure SI.2 and Table SI.2). All samples had a To between 168.85 ± 0.06 °C and 169.08 ± 0.10 °C, a Tp between 169.16 ± 0.12 °C and 169.25 ± 0.08 °C and a Hm between 177.68 ± 0.86 J/g and 181.67 ± 1.19 J/g (Figure SI.2). The average Hm of samples processed at condition #7 was slightly lower than the other spray dried samples, which may indicate a slight decrease in sample crystallinity at this inlet temperature in comparison to samples processed at the higher inlet temperatures. All spray dried samples were not statistically different to the Rc sample with To = 169.14 ± 0.08 °C, Tp = 169.57 ± 0.12 °C and Hm = 180.57 ± 0.92 J/g. According to Williams–Landel–Ferry kinetics [48], a higher Tin results in a higher crystallisation rate and this parameter appeared to affect crystallinity of spray dried lactose. However, as PAR has such a high tendency to form a crystalline material, the level of crystallinity amongst the spray dried samples remained unchanged. The residual solvent content in the samples was assessed by thermogravimetry (Figure SI.3). Both, the inlet temperature and solvent content affected the quantity of solvent(s) remaining in the powders with a lower Tin and lower EtOH concentration in the feed resulting in an increased residual solvent content. With exception of the sample processed at condition #7 (Tin = 60 °C), the weight loss recorded by TGA up to 120 °C was <2% (w/w). The weight loss of the Rc sample was 1%. 4.2.4. Dynamic vapour sorption (DVS) DVS analysis on selected samples was performed using water and EtOH as probe vapours to further investigate crystallinity of the samples. The spray dried samples showed a very small % change in mass, not exceeding 0.3% mass change, observed with

an increase in sorbent p/p0 amongst all samples produced, most likely due to surface sorption (Fig. 3). However, for each sample the weight change in the second sorption/desorption cycle was lower compared to the first cycle accounting for a very small reduction in available sites for adsorption after the first cycle. For the sample processed at condition #13 there was a slight lattice rearrangement event seen between 0.6 and 0.8 p/p0 when EtOH was used as the probe vapour, most likely due to residual water liberation (Fig. 3e). Overall, the very small % mass change between the samples as p/p0 of the probe vapour increased was as a result of the highly crystalline nature of the spray dried materials [49], as confirmed by PXRD, FTIR and DSC.

4.3. Particle size analysis and droplet characterisation Laser diffraction particle size analysis showed that the median particle size for the spray dried samples varied between 5 and 16 lm (Table SI.3), with the size distributions (by laser diffraction) shown in Fig. 4. As the inlet temperature increased, so did the particle Sauter mean diameter (Fig. 5 and Table SI.3). Particle size of a spray dried material is a function of the ratio between the droplet evaporation rate and solute diffusivity (characterised by the dimensionless Pe number, Eq. (8)) and the size of the atomised droplet (governing the quantity of dissolved solute per droplet) [50]. As the inlet temperature increased so did the predicted Pe number (Fig. 5). If the drying process has a Pe value <1, then the diffusion of the solute is quicker than the evaporation rate of the solvent resulting in the solute diffusing to the core of the droplet to escape the drying boundary layer and a solid particle will form. If however the Pe value is >1, then the diffusion of the solute is slower than the evaporation rate of the solvent and shell formation will follow due to the surface enrichment of the solute at the surface of the droplet leading to a more porous, less dense material [39]. Fig. 5 shows the changes in predicted Pe number, predicted droplet diameter, particle size (p < 0.001) (Figure SI.4), tapped density (p = 0.009) (Figure SI.5) and porosity as a function of the spray dryer inlet temperature. With an increase in temperature there was an increase in the predicted Pe number [32,39]. This in turn resulted in a decrease in the dried particle density, increase in porosity, and therefore an increase in particle size. Such a decrease in density and increase in size can be seen in Fig. 6 in which particles spray dried at higher inlet temperatures (Fig. 6a) showed a hollow semi-spherical agglomerated particle consisting of individual crystallites. Fig. 6b showed smaller, denser particles consisting of smaller individual entities.

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Fig. 7. Scanning electron microscopy micrographs of paracetamol spray dried at various spray dryer Tin: (a–d) #7 and (e–h) #1.

The predicted initial size of the atomised droplet was found to decrease as the inlet temperature increased, which would have a contradictory effect on the size of the final dried particle (with a smaller initial droplet size, there would be less material in solution per droplet). However, the decrease in droplet size was small with respect to the increase in Pe number and particle density resulting in an overall increase in final particle size. This trend can be seen in the SEM images below in which smaller agglomerated particles were produced at lower temperatures (Fig. 7a–d) compared to materials processed at higher temperatures (Fig. 7e–h). Crystalline spray dried materials have been known to produce structures con-

sisting of large individual crystallites bound together in an agglomerated particle [51]. With an increase in the EtOH concentration in the feed there was a slight decrease in particle size (p < 0.001) (Fig. 8, Table SI.3 and Figure SI.6). The decrease in size was due to a decrease in solvent viscosity and solvent surface tension (Table SI.5a), as well as solvent mass flow rate (Table SI.5c). These parameters are all temperature sensitive and are a result of a decrease in the droplets wet bulb temperature (Table SI.5a). With a decrease in droplet size there was a decrease in the mass of solute per droplet volume. Average solute mass (g/droplet) was predicted to be

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Fig. 8. Analysis of predicted droplet Peclet number, predicted droplet Sauter mean diameter, dried particle Sauter mean diameter, dried particle tapped density and dried particle porosity as a function of spray dryer solvent feed composition.

Fig. 9. Comparison between the evaporation rate (blue) and diffusion coefficient of the solute in the solvent (red) and their relationship to the Peclet number (black filled squares) at each solvent composition spray dryer condition. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

6.12  1010 g per droplet when spray drying condition #13 was used and decreased to 1.57  1010 g per droplet when using condition #8 (Table SI.5d). With a decrease in solute mass fraction, there was a decrease in the overall particle size of the dried powder.

The droplet Pe was found to increase from systems #13 to #11 before beginning to decrease to a minimum value for the system #8. Unlike the almost linear influence with increasing the Tin (Fig. 5), the effect of increasing the EtOH concentration of the inlet feed caused the Pe to first increase, level off then decrease as the

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Fig. 10. Predicted droplet Sauter mean diameter (dsm) and droplet supersaturation for spray dried paracetamol at (a) #1, #2, #3, #4, #5, #6, #7 and (b) #8, #9, #10, #11, #12, #13 spray drying conditions.

Fig. 11. Scanning electron microscopy micrographs of paracetamol spray dried at various spray dryer conditions: #13 (a–b), #10 (c–d) and #8 (e–f).

concentration of EtOH in the feed increased. This was due to the changing ratio of the solvent evaporation rate to solute diffusion which can be seen in Fig. 9. The evaporation rate increased at a

constant rate in comparison to the diffusion coefficient, which increased at a faster rate as the concentration of EtOH increased. This caused the slope of the evaporation rate to the diffusion

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coefficient to be positive at lower EtOH concentrations. As the concentration of EtOH in the inlet feed increased, the slope between the two parameters decreased closer to zero before becoming negative. This change was as a result of the total solvent viscosity being much larger using 100% EtOH compared to at a higher water content concentration. The decrease in droplet size as the spray dryer inlet temperature increased was due to the variation in droplet drying time and solvent evaporation rate as per Eq. (10) [42]. At higher temperatures the evaporation rate was also higher however, the drying time was shorter resulting in an overall decrease in droplet size. Using the same equation (Eq. (10)), in order for the droplet drying time to be longer, the droplet diameter must also be larger. Thybo et al. [40] proposed Eq. (9) with slight modification from Kemp et al. [41] to predict the Sauter mean diameter (dsm) of a droplet. As the temperature increased the solvent density, atomising gas density and atomising gas mass flow rate all decreased which resulted in a decrease in dsm, however there was a larger decrease in the solvent viscosity, surface tension and solvent mass flow rate resulting in an overall decrease in droplet size. Slight differences in the tapped density values of the spray dried powders were seen as the concentration of EtOH in the feed increased (p = 0.020) (Fig. 8 and Figure SI.7). As the % of EtOH increased above 80%, the tap density increased as a result of a decrease in the Pe number resulting in the porosity of the material also decreasing. This manifested in a slight decrease in particle size at higher EtOH concentrations. As the spray dryer Tin increased, so did the predicted supersaturation rate (Fig. 10). This was as expected, with each droplet having the same drug concentration between the various Tin, but at higher temperatures the droplets were smaller, and the evaporation rate of solvent was higher. This means that a supersaturation ratio (C0/Ceq) of 1 (represented as a solid horizontal line in Fig. 10) was reached sooner, which resulted in crystallisation occurring earlier when higher Tin were used. As well as a decrease in initial droplet size (time = 0 s), there was a predicted increase in droplet drying time (sd), predicted using Eq. (10), as the concentration of EtOH decreased. As discussed above, the droplet diameter decreased as the concentration of EtOH increased and at higher concentrations the evaporation rate increased. This was due to an increase in drying gas density, a decrease in solvent density and an increase in the mass fraction of solvent at the droplet surface. The droplet supersaturation rate increased with an increase in EtOH concentration and therefore a supersaturation ratio of 1 was reached sooner. The morphologies of spray dried PAR at various hydroalcoholic solvent compositions can be seen in Fig. 11. SEM images showed irregularly shaped agglomerates consisting of semi-spherical particles. During the crystal growth phase of a droplet drying, crystallites form that diffuse to the centre of the droplet as the drying boundary layer approaches due to droplet shrinkage. An individual crystallite can form within each droplet, however if multiple critical nuclei form within a droplet then several crystallites will grow simultaneously. When diffusion is no longer possible, the crystallites agglomerate together forming an individual particle (Fig. 6a). From the SEM images these agglomerated particles can be seen to vary in size and shape together with the size and shape of the individual crystallites. It is common for droplets to collide under the turbulent conditions of the spray drying process. The angle of impact and kinetic energy of these collisions play key roles in whether the droplets bounce apart after colliding, coalesce into a larger droplet or separate forming smaller secondary droplets [52]. These droplet collisions can lead to an increase in particle size as agglomerates from separate droplets when they bind together after the collision process. Droplet characterisation equations provide a good prediction of the spray dried particle size and morphology. Through the

selection of droplet size and the ratio of solvent evaporation rate to solute diffusion rate, then a greater control of the size of the final dried particles can be achieved. 5. Conclusions PAR spray dried at various spray drier inlet temperatures ranging from 60 °C to 120 °C and solvent compositions from 50/50% v/v EtOH/water to 100% EtOH produced a crystalline material in its form I with a very slight reduction in crystallinity as the concentration of water in the feed increased. Therefore, the robustness of spray drying was shown, which is desirable when a strict control of physicochemical properties of APIs are needed during pharmaceutical processing. The size and morphology of the dried materials were altered with a change in spray drying parameters, with an increase in inlet temperature leading to an increase in particle size (from 3.0 to 4.389 mm), and a decrease in particle size with an increase in EtOH concentration of the feed (from 4.6 to 4.4 mm). Particle density decreased from 0.53 to 0.46 g/cm3 with an increase in spray dryer inlet temperature and the density increased from 0.41 to 0.46 g/cm3 as the concentration of ethanol in the feed increased. The morphology of the dried particles consisted of agglomerates of individual crystallites bound together into larger semi-spherical agglomerates with a higher tendency for particles having crystalline ridges to form at higher EtOH concentrations of the feed. The drying behaviour of the individual atomised droplets was investigated in detail using semi-empirical equations with particular interest given to the prediction of the droplets size and the ratio of solvent evaporation to solute diffusion. This allowed for the prediction of particle size and morphology through changes in particle density and gave a greater understanding of the overall evaporative crystallisation process. In conclusion, spray drying can be a reliable route to extracting an active pharmaceutical ingredient, of desired characteristics, from solution in a highly crystalline form if the physical properties of the atomised droplet are properly evaluated and the correct process parameters are chosen. 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. Acknowledgements Research leading to these results was supported by the Synthesis and Solid-state Pharmaceutical Centre (SSPC), financed by a research grant from Science Foundation Ireland (SFI) and cofunded under the European Regional Development Fund (Grant Number 12/RC/2275). Appendix A. Supplementary material Supplementary data to this article can be found online at https://doi.org/10.1016/j.apt.2019.10.021. References [1] N. Dombrowski, W.R. Johns, The aerodynamic instability and disintegration of viscous liquid sheets, Chem. Eng. Sci. 18 (1963) 203–214. [2] B. Van Eerdenbrugh, J.A. Baird, L.S. Taylor, Crystallization tendency of active pharmaceutical ingredients following rapid solvent evaporation—classification and comparison with crystallization tendency from under cooled melts, J. Pharm. Sci. 99 (2010) 3826–3838.

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