Formation of Crystalline Amino Acid Particles via Spray Drying

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1 Formation of Crystalline Amino Acid Particles via Spray Drying Ruohui Lin 1, Wenjie Liu 1, Meng Wai Woo 1, Cordelia Selomulya 1*, Xiao Dong Chen 1, 2 1 Department of Chemical Engineering, Monash University, Clayton, Victoria 3800 Australia ruohui.lin@monash.edu, wenjie.liu@monash.edu, meng.woo@monash.edu *Corresponding author: cordelia.selomulya@monash.edu 2 College of Chemistry, Chemical Engineering and Material Science, Soochow University Suzhou City, Jiangsu PR China dong.chen@monash.edu, xdchen@suda.edu.cn Abstract- Spray drying is a robust industrial process in food engineering and can be used to manipulate size and shape of amino acid particles. In addition to physicochemical properties of amino acids, more understanding is needed on effects of drying on properties of amino acid particles. The aim here is to investigate the effects of the drying temperature on the morphology and crystallinity of spray dried particles. Glycine solution was spray dried at the temperature of C using a Micro-Fluidic-Jet-Spray-Dryer. Results showed that the drying temperatures had little effect on the particle shrinkage ratio, but had significant effects on the particle morphologies in terms of surface roughness, internal structure and the particle shell formation. XRD results showed the particles were mostly crystalline. Péclet number (Pé) was used to explain the formation of thicker shell dried at 185 C than that at 145 C. The possible limitations of Pé used at predicting shell formation of easycrystallized amino acid during spray drying were also discussed in this paper. Keywords - spray drying; amino acid; glycine; Péclet number; XRD; crystalline I. ITRODUCTIO Apart from the long recognized physiological functions [1], recent reports have shown the other functions of amino acid including improving the aerosolization performance by modifying the surface used in dry powder inhalation [2] and protecting sensitive active agents (peptide or proteins) as cryoprotectants[3]. The morphology of the amino acids particles and the degree of crystallinity are of interest in the areas of drug delivery for inhalation and food engineering. Recently, amino acids have attracted great attentions and shown promising applications in both food and pharmaceutical engineering, as spray drying has been applied in the manufacture processing. Spray drying is applied to transform materials from liquid states (solution/ droplets) into solid state (powder/particles) in one-step process. This robust industrial process is considered a commercially efficient means of drying food materials with large surface area exposed to heating as a result of the initial atomization process [4]. The spray dried or co-spray dried amino acid particles have been produced: to modify the surface of drug (disodium cromoglycate) particles by amino acids early precipitation on the surface of the evaporating droplet to improve the particle de-agglomeration and the deposition profiles of the drug [5]; to reduce the bulk density of drug carrier particles by mixing amino acid as a low density additive [6, 7]; to selectively produce desirable amino acid polymorphic forms [8, 9]. Considering the broadened applications of amino acids, a clear understanding of spray drying amino acids is needed to further develop potential applications of amino acids. However, limited knowledge of spray drying amino acids is available in literatures [5-12], although extensive knowledge exists in either spray drying process or properties of amino acid. It is unclear that whether the existing knowledge of spray drying process can be directly applied in amino acid, since the drying kinetics or crystallization behavior would be material-specific. Unlike spray-dried sugar with large systematic knowledge in terms of drying kinetics and crystallization behavior, there is very limited knowledge on spray dried amino acid in terms of morphology, crystallization behavior or the mechanism of particle formation. Given this fact, we tend to compare the understanding obtained from spray dried amino acids with that of sugars. In contrast of well-known knowledge that spraydried material (sugar, fat, protein) are mainly amorphous due to the fast evaporation [13], it has been reported that spray dried leucine [5] and glycine powder were most crystalline [8] from XRD results, without detailed discussion on how the drying process influences the properties of these amino acids. More understanding specific to spray dried amino acid is desired to capture the particle formation mechanism behind the process and to be extrapolated to other process conditions. Therefore, with this in mind, glycine, the simplest amino acid [14] was chosen as a model amino acid to understand this process. The aim of the first part of work is to investigate the influence of the drying process condition on the structural properties of spray dried glycine particles, in terms of morphology and the degree of crystallinity. In contrast to the typical amorphous sugar particles obtained from spray drying exploiting the rapid evaporation in the process [13], the high crystalline hollow glycine particles with the unique morphology were obtained at the temperature range from C, according to X-ray Diffraction and scanning electron microscopy results. The understanding of the mechanism of 1

2 distinct morphological formation is needed before the manipulation of particle characteristics properties is possible. In second part of work, Péclet number (Pé), a dimensionless number that characterizes the relation between convective and diffusive (conductive) transport [15, 16], was introduced to investigate the possible particle formation. Pé has been reported an effective tool to explain the mechanism of the spray dried particle formation [11, 17-20]. In this paper, the use of Pé was able to explain the increasing thickness of the particle shell but has limitations when Pé is used to interpret the particle formation in terms of shell. Here, to our best knowledge, it is first time that the limitations of using Pé in crystallisable amino acids are pointed out. The main reason for this limitation was attributed to the effect of crystallization on the shell formation, which was not accounted for in the current form of Péclet number, whilst liquid-phase crystallization appears to be the dominant process in the spray drying of glycine. II. EXPERIMETALS A. Monodisperse glycine droplets drying by Micro-Fluidic- Jet-Spray-Dryer (MFJSD) Glycine, aminoethanoic acid ( 99 %, G G, Sigma Aldrich, Australia) was used without further purification. Amino acid solution was prepared by dissolving 8.0 g glycine in 92.0 g de-ionized water (Milli-Q system QGARD00R1, Millipore, Australia) to make up a total solid concentration of 8wt%. To avoid particles of various characteristics in terms of size, morphology, and structure within the same batch, a specially designed microfluidic spray dryer was used to produce particles, since it has been reported that monodisperse microparticles with high reproducibility and comparatively high yield of production of uniformity of the particles could be produced [21-23]. Compared with conventional spray dryer, Micro-Fluidic-Jet-Spray-Dryer (MFJSD) can produce uniform particles by using a special microfluidic aerosol nozzle system with an orifice diameter of 75 μm to generate the monodisperse droplets [14-16]. The droplet formation was monitored by a digital SLR camera (ikon, D90) with a speed light and a microlens and the images taken were also used to measure the diameter of the generated droplets. These monodisperse droplets obtained were then dried at different drying temperatures of 105, 145 and 185 C in MFJSD. The detailed descriptions of MFJSD and associated procedures are given elsewhere [16]. B. Particle characterization Scanning electron microscopy (SEM) and X-ray Diffraction (XRD): The spray dried particles were fixed to an aluminium sample stub using conducting carbon tape and then sputter-coated with ~4 nm gold palladium to produce a conductive surface for SEM observation. Phenom G2 pro desktop Scanning electron microscopy (SEM, Lambdaphoto, UK) with the condition of accelerating voltage of 5kv was also employed in this study. Directly after spray drying, spraydried glycine particles were analysed within 0.5 h with X-ray powder diffractometry. XRD was conducted using a Rigaku Mini Flex 600 diffractometer (Rigaku, Japan) with i-filtered Cu Ka radiation (40 kv, 15 ma). The scanning range was 2 50, the step size was 0.02, and the scanning rate was 2 /min 1. Particle size calculation: The initial droplet size and the final particle size referred in this work was defined as the diameter of the droplet ( d ) and that of the dried particles 0 ( d ), which were analysed using the software Image J based on camera images during droplet generation by a microfluidic aerosol nozzle system mentioned above and the SEM images. As the spray-dried particles were not exactly spherical in shape, Feret diameters, the longest distance between any two points along the boundary of the particles, were thus employed as the equivalent diameter. The average of the diameters was considered as the final particle diameter. Same method was conducted to measure thickness of the particle shell based on the SEM images. In addition, a small systematic error may be also present due to preferential orientation of the particles. The average particle size ( d ) was defined as 1 d1 + d d d = di = i= 1 The standard deviation of the particle size was described as (1) 2 1/2 (2) i SD = (( ( d d ) ) / ( 1)) where d was the diameter of the i th particle and was the i total number of particles counted. To minimize the errors, 40 particles are counted. Shrinkage ratio K sh (%) is defined as K = (1 d / d ) 100 (3) sh C. Péclet number calculation When glycine solution is spray dried, Pé is defined to be the ratio of the evaporation rate of water from the droplet into the air to the diffusion coefficient rate of water in the solution [11]. For analytical solutions, Pé is also given in the dimensionless form as 0 ( dr Pé = r ) / 0 D (4) AB dt where r 0 is equal to the radius of the droplet, dr / dt, the change in radius of the droplet with respect to time [11,17]. D refers to the diffusion coefficient of species water - A in AB species glycine-b. For this classical binary system - the solute is glycine B while the solvent water A, D, the binary AB diffusion coefficient of species water - A in species glycine- B, is equal to D, the binary diffusion coefficient of species BA glycine - B in species water-a [22]. In this part of work, Pé at the wet bulb temperature of droplet at corresponding drying air is of interest, which refers to the moment when glycine droplets are generated. The solution was prepared at the room temperature (20 ± 1 C). However, all the drying temperatures were above 100 C and the ratio of air to feed in the dryer is particularly high, close to 1000:1 (kg s -1 : kg s -1 ) [23]. Hence, the droplet temperature is assumed to reach the wet bulb temperature immediately after the droplet generation. This 2

3 work adopted the diffusivity of glycine solution report by Umecky et al., [24]. However, their experimental data expressed were transformed to the form of temperature with coefficient of determination (R 2 ) of in a range from 10 to 70 C. D T T 2 = (5) where D is the diffusion coefficient of glycine solution in the unit of -10 m 2 /s, T is the droplet temperature in C. III. RESULTS AD DISCUSSIOS A. Effects of drying temperature on glycine morphology and internal structure The experimental results of the spray dried particle were shown in TableⅠand SEM images displayed overall spherical shape of the spray dried glycine (Fig.1). The value of shrinkage ratio in the investigated drying temperatures falls in a range of %. This indicates the changes of drying temperature have little effect on the shrinkage ratio. Meanwhile, Figure S1 in supporting information shows that uniform particles can be produced via MFJSD, which circumvent the differential granulometric effect. By contrast, significant differences in particle morphology and internal structure were clearly noticed. Specifically, particles with sheet-like wrinkled surface and sheet-like shaped crystals inside were clearly noticed at a lower drying temperature of 105 C. The particles dried at higher temperature of 185 C showed donut-like shape with a relatively smooth surface. Hollow structure and large block-shaped crystals constituting the noticeable shell was also found for particles dried at the high temperature of 185 C, in contrast to the denser particles found at the low temperature of 105 C. The morphology obtained from the intermediate temperature (145 C) presented the combined features of these particles dried at a lower and a higher temperature. These particles maintained partial roughness and smoothness on the surface, while internal structure was relatively hollow, containing both blocks and the sheet-like crystals. TABLE I. THE EXPERIMETAL RESULTS OF SPRAY DRYIG 8WT% GLYCIE SOLUTIO AT DRYIG TEMPERATURE OF 105,145 AD 185 C. Drying temperature ( C) Particle properties Droplet size (μm) 190 ± ± ± 36 Particles size (μm) 83.38± ± ±10.59 Shrinkage ratio (%) Shell thickness (μm) -- 4 ± 2 9 ± 2 Particle morphology Sheet-like crystals existing in both surface and the internal structure Combinatio n of sheetlike crystals and block crystals Hollow particle with relative smooth surface constituted by block crystals Figure 1. SEM images of spray dried amino acid particles at various drying temperature: (A) 105 C, (B) 145 C, (C) 185 C. The internal structure and shell formation was identified in the right line. Taking a closer look on the cross section of the particles, shells could be noticed in the samples dried at 145 and 185 C since the hollow structure can be easily identified. By contrast, particles dried at a lower drying temperature of 105 C were dense and thus the shell was indistinguishable (Fig. 1.A1 B2, C2). In addition, the shell became thicker as the temperature increased from 145 to 185 C (Table Ⅰ). The reason to form the thick shell at higher temperature was further discussed in section C. B. Crystallinity of the spray dried particles Following the discussion on the smooth surface observed at high temperature, it is not clear that whether the spray dried glycine particles is crystalline, especially for these samples with relatively smooth surface. Based on published literature, the smooth surface of spray dried sugar-base material has been reported as the contribution of amorphous material presented in the particles [24-26]. In addition, one concern in the spray drying of sugar is the degree of crystallinity, which is a fundamental factor influencing the properties of the final spray dried products [24]. If the spray dried material is mainly amorphous or partially crystalline, solid-phase crystallization would occur during storage or even when the particles still 3

4 maintain in the drying chambers. This solid-phase crystallization, referring to the amorphous solid obtained from spray drying transforming into crystalline, will therefore cause stickiness and aggregation. Highly crystalline material is hence desired to avoid possible phase transitions during storage [27]. Various process improvements, including increasing the inlet temperature and the humidity of the outlet part of the spray dryer, as well as the residence time of the particles, have been extensively studied to obtain higher degree of crystallinity [24,29,30]. In contrast to spray dried sugar-rich material, results in Fig. 2. show that sharp and strong peaks can be easily identified in spray dried glycine particles in various temperatures. These peaks indicated glycine powder were mostly crystalline. In our study, fresh spray-dried glycine particles were shown most crystalline according XRD, which was conducted within 0.5h after spray drying. The possibility of solid-phase crystallization during spray drying or storage would not be our main concern, as the high degree of crystallinity of spray dried glycine. In addition, given the dried particle were formed and collected within approximately 2 s [31], it was considered that the liquid-phase crystallization is the predominate process when spray drying glycine. The finding of most crystalline glycine obtained from spray drying was in a good agreement with previous report on spray drying glycine, although smooth surface was not observed from SEM images in previous report [1]. Analogously, the spray dried leucine particles was also found to be mostly crystalline [5]. However, unlike the reported presence of β-glycine when spray drying glycine solution at the temperature from 90 to 180 C [9], β-glycine, the most unstable polymorphic form of glycine [28], was only found in the sample of 185 C, with the main characteristic peak at 2θ = 18 is present in XRD pattern, while it was not present in the samples dried at 105 and 145 C. This might be possibly due to the rapid water evaporation of the glycine solution to form the unstable polymorphic form at high temperature. Figure 2. XRD patterns of the spray dried glycine particles at different inlet temperatures. The time between spray drying and corresponding XRD analysis was controlled within 0.5 h. (A) 105 C, (B) 145 C, (C) 185 C. It should be noted that there is a possible application of spray dried glycine. Based on the previous discussion, the highly crystalline glycine particles with the unique morphology obtained via spray drying could be applied in drug delivery of inhalation, although the aerodynamic particle size was not taken into consideration. In particular, the highly crystalline particles with rough surfaces obtained at temperature of 105 and 145 C in our work are desirable, since the particles with these features and properties have been reported to improve aerosolization performance by avoiding stickiness and aggregation (Chan et al.[32]). In addition, the hollow structures obtained from spray drying have been reported to have lower particle density and thus improve the dispersibility of particles. The same hollow structure of the particles has been found to improve aerosolization performance in dry powder inhalation (Frijlink et al.[33]). Further research is needed to explore the application in drug delivery by employing the unique features of glycine particles obtained from spray drying. C. Discussions on particles formation by using Péclet number Péclet number was employed to explain the formation of distinct morphologies of glycine particle at various drying temperatures. Pé could be used to interpret the spray dried particle formation in some research, where the materials were sugars with partially crystallinity [11, 17] or polymers with a large molecule [19]. For all drying temperatures, the value of Pé increased as drying temperature increased (Table Ⅱ.). The increasing trend of Pé sheds the light on the mechanism of shell formation. When Pé > 1, one could easily interpret that the evaporation (water) is faster than the diffusion of water from the internal droplet onto the surface of the particle. Larger Pé above the value of 1 further indicates much faster evaporation rate than diffusion rate. Consequently, the contribution from convective flow (convection) would be more significant than the contribution from pure molecular diffusion (conduction) within the droplet. In another word, the water was not able to replenish the particle surface. Therefore, accelerating glycine concentration caused by the evaporation induces the early precipitation of the glycine nuclei on the surface. As the glycine crystals continuously formed in the surface, and the resultant hollow structure of the particle was formed. When drying temperature increases, the increasing Pé indicates the gap between the value of evaporation and diffusion rate became more broadened. This indication then further interprets the thicker shell (Table Ⅰ.) and more hollow structure at higher temperature from 145 to 185 C observed from SEM images. Generally, the value of Pé =1 has been considered as the critical value to determine whether the shell of the solid is formed [11, 19, 20]. Specifically, when Pé <1, the rate at which moisture is removed from the droplet onto the surface is faster than at which moisture is removed from the surface into the bulk air, indicating that there is sufficient time for surface to be replenished with moisture. Under this condition, the droplet shrinkage is known as isotropic or perfect shrinkage where no shell forms during drying, and this type of shrinkage results in a relatively solid particle [19, 20]. By contrast, when Pé >1, the moisture is unable to replenish the surface, causing 4

5 local solutes to accumulate mostly on the surface and form a shell.[20] TABLE II. DIFFUSIO COEFFICIET AD RESULTS AT DIFFERET DRYIG TEMPERATURE OF 105, 145 AD 185 C Drying temperature ( C) Wet bulb temperature ( C) Diffusion coefficient * (10-10 m 2 /s) * Diffusion coefficient from the data of Umecky et al and fitted into equation (5) [24] From this theoretical consideration, one should expect the Pé value of glycine powder dried at lower temperature of 105 C is below 1, since shell was barely observed in these samples. However, Pé of this sample turned out to be 1.5. The reason could be that the lack of consideration given to the effect of crystallization on the shell formation when spray drying amino acids. Spray drying amino acids is complicated since it involves both drying and crystallization processes [34]. These two processes simultaneously progress and are complementary to each other. The driving force of drying is the difference between the vapor concentration of the droplet surface and that of the drying media (dry bulk air) [35], while the driving forces of crystallization from liquid growth medium is the level of supersaturating of the droplet at a certain temperature[36,37]. Drying, which refers to the continuous moisture removal, concentrates glycine solution causing it to reach saturation. The resulting saturation correlates to the tendency of glycine to precipitate. Crystallization, which refers to nucleus formation or the crystal growth, dilutes the local solution in the vicinity of the precipitated crystals. The dilution maintains the concentration gradient within the droplet. Driven by the concentration gradient, the moisture transfers from droplet onto the surface before it eventually evaporates from the droplet surface into the bulk air. Drying is divided into two steps: the moisture diffuses from droplet into the droplet surface and then evaporates from surface into the drying bulk air. By definition, Pé well describes the relationship between the two steps of the drying processes, but the application of Pé in explanation of the shell formation of spray dried amino acids fails to consider the effect of crystallization. In other words, when Pé is applied to explain the shell formation, then the criteria of smaller than a critical value (usually 1) may be not be satisfied[11,19,20], since this process is solely considered from drying viewpoint and could not represent all processes occur with the presence of liquid-phase crystallization during drying. To the best of the authors knowledge, this is the first time that Pé has been used to explain the shell formation of spray dried amino acid and that the limitations of Pé applied to the crystallisable amino acids have been pointed out. However, the reason that Pé can be used to interpret the formation of some spray dried particles, might be that liquid-phase crystallization was not the dominant process during spray drying (because mainly amorphous material was obtained from spray drying) [11,19,20]. This effect of crystallization on the value of Pé can be thus ignored. Therefore, Pé is only valid under condition of negligible liquid-phase Pé crystallization. For better understanding of the mechanism of spray dried particle formation, application of Pé alone may not be sufficient as it cannot represent the whole process involving both the drying and crystallization processes, although how to get the more accurate application of Pé to amino acids is unclear. Whether Pé >1 is suitable to determine the shell formation for amino acids requires further exploration when spray drying these types of materials. IV. COCLUSIOS In the investigated range, various drying temperatures had little effect on the shrinkage ratio of the spray dried glycine particles, but significant effects on the morphologies of the particle in terms of surface roughness, internal structure and the particles shell formation. XRD results showed the spray dried glycine was mainly mostly crystalline. β-glycine, the most unstable polymorph form of glycine, was only found in the sample dried at 185 C possibly due to rapid water evaporation. Meanwhile, the highly crystalline glycine particles with hollow structure and rough surface can potentially be engineered as drug carriers. Pé, defined as the ratio of advective transport rate to the diffusive transport rate, could be correlated to the formation of the increasingly thick shell with hollow structure of the glycine particles dried from 145 to 185 C. However, when crystallisable amino acid is spray dried, the critical value Pé > 1 reported by other researchers might not be suitable to determine the shell formation due to the lack of consideration of liquid-phase crystallization during spray drying. To the best of the authors knowledge, this is the first time that Pé was used to explain the shell formation of spray dried amino acid and the limitations for the use of Pé in crystallisable amino acids are pointed out. Future work is needed to understand the simultaneous crystallization and drying processes to obtain better understanding on the mechanism of the particle formation. V. ACKOWLEDGMET R. Lin thanks Guangzhou Elite Project and Guangzhou Ling an Intel Enterprise Group Co., Ltd for the PhD scholarship. The inputs from Dr Zhangxiong Wu on discussion of XRD and Mr Jiahan Chew on calculation of Pé are greatly appreciated. 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