Article pubs.acs.org/IECR
Unexpected Polymorphism and Unique Particle Morphologies from Monodisperse Droplet Evaporation Kelly M. Carver and Ryan C. Snyder* Department of Chemical Engineering, Bucknell University, Lewisburg, Pennsylvania 17837, United States ABSTRACT: The particle sizes, morphologies, and structures are presented for succinic acid particles formed from the evaporation of uniform droplets created with a vibrating orifice aerosol generator. Particle sizes are monodisperse, and solvent choice is found to be the dominant factor in determining the final morphology and structure. The external particle morphologies range from round to cap shaped, while the surface roughness ranges from fairly smooth to extremely rough and pitted. Internally, the particles have significant void space and noticeable crystals. X-ray diffraction confirms that the particles are crystalline. Thus, the morphologies of the particles take on a crystal filled structure that is unique in comparison to previous particles formed through droplet evaporation. The structure of the particles contains β succinic acid; however, the particles formed from water also contain α succinic acid. α Succinic acid has not previously been able to be formed from solution at near atmospheric conditions. The unique morphologies and ability to identify unexpected polymorphs provide for a potential tool to not only enhance particle engineering but also to identify metastable polymorphs.
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INTRODUCTION Particle engineering continues to be an important area of research as there is a continual demand for improvements in particle properties for a variety of industries including food, pharmaceutical, and fine chemical producers. Being able to produce particles of controlled characteristics as efficiently as possible is critical for pharmaceutical, food, and chemical producers. Specifically, the size or size distribution, morphology, and structure (crystalline polymorph and degree of crystallinity) are each characteristics of particular interest to these industries. Particle size can affect texture in food products, while a narrow size distribution is often desired for potent pharmaceuticals.1 Particle morphology impacts both processes beyond particle formation such as filtering, washing, or drying, and properties that vary with respect to the exposed crystalline facet, such as hydrophobicity or catalytic activity.2 Finally, the structure can have a dramatic impact on particle properties. Amorphous formulations are becoming increasingly important in pharmaceuticals because such a state provides increased solubility for sparingly soluble drugs;3 while for crystalline forms, different polymorphs often have different physical properties, such as density, solubility, and melting point, which can be especially problematic for the pharmaceutical industry.1,4,5 New methods to control and screen for particle properties, in particular crystallinity and polymorph, are continuously being developed. In the past, methods such as vapor diffusion, solvent recrystallization, antisolvents, crystallization from the melt or by sublimation, and precipitation due to pH changes have been used to achieve different solid structures.6,7 Additional techniques such as self-assembled monolayers, crystallization from colloidal suspensions, and the use of polarized laser light have also been investigated as methods to characterize/induce different polymorphs.8,9 Some techniques are centered on highthroughput screening which utilizes technologies to efficiently carry out simultaneous crystallizations by several of the aforementioned methods.6 The more that is known about a © 2012 American Chemical Society
particular substance and its crystallization tendencies, the easier it is to design a process to produce it, and the lower the probability of unexpected polymorphs being discovered in late stages of development or actual production.10 With this in mind, identifying technologies to not only control polymorphism but also to generate unique morphologies and controlled sizes is desirable. In this work, we investigate the potential for the use of monodisperse droplet generators (MDGs), specifically a vibrating orifice aerosol generator (VOAG), to produce particles with controllable or unique characteristics with regard to size, morphology, and structure. Monodisperse droplet generators resemble small-scale industrial spray driers; however, they provide some unique advantages for studying individual particles. Spray driers are difficult to use for this type of study because they present many challenges with regard to the ability to study and control particle properties. Differences in initial droplet sizes lead to an array of problems including caking on walls and inconsistencies in morphology and moisture content of the resulting particles.11 Monodisperse droplet generators have previously been used to produce a variety of monodisperse particles by using systems such as an inkjet spray drying setup to produce lactose particles12,13 and a monodisperse spray drying setup to produce chitosan particles.14 Many other studies have been carried out on an assortment of compounds using various versions of a monodisperse spray drying setup and have been reviewed elsewhere.15,16 In each of these cases, monodisperse particle sizes were successfully obtained and a variety of particle shapes were noted that depended on air flow rates, drying temperature, and the presence of an additive (additional particle morphology Received: Revised: Accepted: Published: 15720
June 15, 2012 September 27, 2012 October 28, 2012 October 29, 2012 dx.doi.org/10.1021/ie3015439 | Ind. Eng. Chem. Res. 2012, 51, 15720−15728
Industrial & Engineering Chemistry Research
Article
Figure 1. Schematic of the droplet generator assembly; during operation, the drain tube is closed off to produce the liquid jet. Inset shows close-up view of orifice plate and exit of dispersion cap.
droplet size (experiments that utilize the 15-μm orifice explicitly state that change). Solutions are prepared with succinic acid (Alfa Aesar, 99+%) as the solute. Solvents include ultrapure water obtained from a simplicity water purification system (Millipore), isopropanol (VWR International, 99.5%), and acetone (VWR International, ACS Reagent grade). For comparison between solvents, the concentration of each of the solutions is chosen so that, after some solvent evaporation, the droplet diameter at which the droplet reaches the bulk solubility of the solution is identical in each case, 38 μm. This condition provides for a consistent thermodynamic starting point for each of the droplets from which the particles are formed allowing for comparisons among particles formed from different solvents to be justified. The solubility data for water, isopropanol, and acetone at ambient temperature are taken to be 60, 40, and 35 g/L, respectively;26 solubility data for succinic acid in water was based on our own experiments. The resulting initial solution concentrations are then 23, 15, and 13 g/L of solvent for water, isopropanol, and acetone, respectively. Solutions are introduced to the VOAG (flow rates of ∼0.21 mL/min for the 20-μm orifice and ∼0.09 mL/min for the 15μm orifice) using 60-mL disposable syringes (BD) and clarified with 0.45-μm Fluoropore filters (Millipore). A schematic of the droplet generator of the VOAG is shown in Figure 1. A frequency is applied to a piezoelectric ceramic which controls the vibration of the orifice, creating a periodic disturbance of the jet and allowing for monodisperse droplets to be achieved. For all experiments using the 20-μm orifice, the frequency was maintained at 45 kHz, which was experimentally determined to be a desirable operating frequency in order to obtain a single jet without any satellite droplets. For the 15-μm orifice, 50 kHz was experimentally determined to be a desirable operating frequency. Air is introduced into the setup in two distinct methods. First, the dispersion air is introduced under the dispersion cap and acts to disperse the droplets by transforming the liquid jet into a spray cone of droplets as depicted in Figure 1. Second, the dilution air enters through the perforated plate and acts as a carrier gas for the droplet spray. A clean, dry air source at ambient temperature and 30 psi is used for both air flows. The droplet generator is run in an inverted setup (see overall setup in Figure 2). Droplets are generated at the top of the column and mixed with the dilution air to form solid particles
details follow in comparison to our results). Particle structure, either crystallinity or polymorphism, was not strongly considered in these cases since the particles were generally found to be amorphous. However, some work has previously been performed on crystallinity in spray dried particles for sugars, primarily lactose, which showed various degrees of crystallinity.17−20 Furthermore, Beckmann and Otto21 explored spray drying Abecarnil, a pharmaceutical molecule, and found that entirely crystalline powders of form B were produced, regardless of solvent choice. In this work, we specifically look toward producing crystalline particles from a monodisperse droplet generator. Additionally, this work aims to demonstrate the importance of solvent variation since it is one of the most important factors in determining the morphology and structure obtained in a crystallization process.4,22 With regard to solute, succinic acid is chosen because it is commonly used as a model organic molecule and has previously been shown to have a crystal habit easily modified by solvent choice using other crystallization techniques.23 Succinic acid is known to have two stable polymorphs, α and β. The α and β polymorphs of succinic acid have been found to be an enantiotropic system, with the β polymorph being stable at lower temperatures, and the α polymorph being stable at higher temperatures; the transition temperature is reported to occur at approximately 137 °C.24,25 Previously, the β polymorph was obtained in crystallizations close to ambient conditions. The remainder of this paper is organized as follows. First, the materials and methods used to generate and analyze particles are described. Next, the results of solvent variation with respect to particle size, morphology, and structure are presented along with a discussion of the similarities and differences obtained as compared to previous monodisperse droplet generation in general and bulk succinic acid crystallization. Then, results and discussion of variations in initial droplet size and air flow rates are presented. Finally, conclusions about this work are given along with potential areas for future development.
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EXPERIMENTAL SECTION Particle Preparation. Particles are prepared using a modified vibrating orifice aerosol generator (TSI, Inc., model 3450). Most experiments are performed using a 20-μm orifice, while a 15-μm orifice is also used for comparison of initial 15721
dx.doi.org/10.1021/ie3015439 | Ind. Eng. Chem. Res. 2012, 51, 15720−15728
Industrial & Engineering Chemistry Research
Article
Particle Analysis. After particles are collected at the bottom of the chamber, they are analyzed for their key characteristics of interest: size, morphology, and internal structure. Three different analysis techniques are used to examine these properties in the particles produced from the VOAG: scanning electron microscopy (SEM) was used to determine the size and morphology, nanoindentation in combination with SEM was utilized to determine the internal morphology of the particles, and X-ray diffraction was used to evaluate the structure of the particles. Samples are collected on various media depending on the desired analysis technique. Samples collected for structure analysis are analyzed by X-ray diffraction as quickly as possible to mitigate the effects of any solid-state phase transformation. All particles are maintained in a desiccating environment after collection and before analysis to mitigate the effects that any humidity or residual solvent from the experiment would have on the resulting morphology or structure (e.g., a solution-mediated phase transformation). Scanning Electron Microscopy (SEM). For SEM, samples are collected on 12-mm steel disks covered with carbon tape. In most cases, a conductive coating is applied to the samples using a gold sputter system (Denton, Vacuum Desk IV) with argon gas (Airgas). Some particles are viewed without coating to confirm that all morphologies are that of only the particle and not the gold coating. The resulting samples are viewed with a scanning electron microscope (JEOL, JSM-6390LV) to analyze the particle morphology. Nanoindentation. For nanoindentation, particles are collected on 12-mm steel disks and intentionally broken apart using a nanoindenter (Hysitron, TI 950 TriboIndenter) to examine the interior. A 100-μm flat punch tip is used to apply a load force sufficient enough to fracture (but not crush) the particles over select areas of the samples. The broken particles are subsequently gold coated as described above and analyzed using a scanning electron microscope. X-ray Diffraction (XRD). For X-ray diffraction, samples are collected on a zero background sample holder (PANalytical). XRD is performed using an X-ray diffraction system (PANalytical, PW 3040-X’pert Pro) with a copper anode. The generator is operated at 40 kV and 45 mA. Scanning rate, and step size are adjusted based on the sample to maximize the quality of the scan. The scanning range is chosen for the main region of interest for succinic acid.
Figure 2. Schematic of the overall particle production setup.
that are collected at the base of the column. Samples are collected on sample holders which are chosen based on the desired types of analysis as described in the next section. The height of the column (3−6 ft) is chosen so that particles have sufficient time to dry before reaching the bottom of the column. The 6-ft column is typically used for each of the experiments; however, for ease of use, a 3−5-ft column sometimes was used to collect particles for experiments where the volatility of the solvent (e.g., acetone) allowed for drying in a shorter column (provided the particles dried, no differences are seen in any results with respect to change in height). Dispersion air is used in the range of 1000−2000 cc/min and dilution air is introduced in the range of 20−60 L per minute (LPM) for the experiments conducted. The air flows used are described as being “high”, “medium”, or “low” according to the values in Table 1. Note that Figure 2 illustrates one of multiple air flow patterns utilized for experimentation; however, all air flow patterns used to generate any results shown here had identical results with respect to size, morphology, and structure. The air flow pattern shown here is our current best practice.
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RESULTS AND DISCUSSION The primary goal of this work is to determine the importance of solvent in generating particles through small droplet evaporation, thus those results are presented first, followed by the results for varied droplet diameters and air flows. Solvent Variation and Particle SizeMonodispersity. Uniform dry particles are successfully produced using the VOAG. Figure 3 depicts arrays of particles produced from water (a), isopropanol (b), and acetone (c). As can be seen in the images, the particles are all fairly uniform within each sample. Particle diameters (taken as an average of the horizontal and vertical caliper diameters) are measured using Adobe Photoshop CS5 and are provided in Table 2. These measurements show that a very narrow size distribution was obtained for each of the solvents (standard deviations
