Simultaneous Precipitation And Purification Of Stearic Acid Using Gas Anti Solvent Process

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Simultaneous Precipitation And Purification Of Stearic Acid Using Gas Anti Solvent Process Yap Min Yee Masitah Hasan Department of Chemical Engineering, University of Malaya, 50603 Kuala Lumpur.

1 Simultaneous Precipitation And Purification Of Stearic Acid Using Gas Anti Solvent Process Yap Min Yee Masitah Hasan Department of Chemical Engineering, University of Malaya, Kuala Lumpur. Phone: Fax: ABSTRACT Stearic acid particles were prepared using carbon dioxide in the Gas Anti Solvent (GAS) process where dense carbon dioxide (CO2) was injected into the organic solution containing stearic acid to create supersaturation of the solution and therefore precipitation of stearic acid. The precipitation results show that the particle size was reduced from original 3 mm to 4 mm to about 100 µm using this process. The precipitation results of stearic acid prepared using Gas Anti Solvent process were also compared with stearic acid particles prepared using conventional method. The results show that the particles prepared using this process was much finer than the particles prepared using the conventional method. Besides being able to retain the original crystalline structure, stearic acid particles prepared using this process were also almost solvent-free which is in contrast with stearic acid particles prepared with conventional method where much residual solvents were still retained. The overall results indicate that the Gas Anti Solvent process is a feasible alternative method to produce desired particle size and distribution with high purity in a single-step process. Keywords: Dense Carbon Dioxide, Gas Anti Solvent, Precipitation, Purification 1. Introduction The potential uses of high-pressure gas or dense gas at the vicinity of critical points which exploits the favourable intermediate properties between gas and liquid, have been explored in the downstream processing of chemical industries as new alternatives to conventional energy intensive distillation process since late 1970s and early 1980s, i.e. the Supercritical Fluid Extraction (SFE) process which is already well established to date with several well-known commercial plants such as the decaffeination of coffee beans plant in Germany, extraction of hops plant to date [1]. The dense gas commonly used is carbon dioxide (CO 2 ) since it has mild critical temperature (31.1 C) and pressure (73.8 bar), nonflammable, non-toxic, inexpensive and possess the 'GRAS' (Generally Regarded As Safe) status [2]. The phase diagram of carbon dioxide is shown as in Figure 1. Figure 1: Phase diagram of carbon dioxide Recently, an exciting and new development of dense gas technology has been on particle formation processes which include micronization, crystallization/precipitation of high purity particles, sterilization and coating [3]. Dense gas technology has started to serve as an attractive platform to 1

overcome various limitations encountered by conventional particle formation processes in industry, i.e. wide size distribution, difficulties of residual solvents removal, thermal degradation of

2 overcome various limitations encountered by conventional particle formation processes in industry, i.e. wide size distribution, difficulties of residual solvents removal, thermal degradation of heatsensitive compounds and etc, which are some of the crucial issues in pharmaceutical industry where requirements and specifications of 'smart' particles are becoming more demanding. Gas Anti Solvent (GAS) process, one of the latest dense gas processes developed, is a process which is able to produce micron-sized particles as well as being able to purify the end product in a single-step process. The GAS process involves a minimum of a ternary system, i.e. the solute to be precipitated, a dense gas and an organic solvent. The preferred ternary behaviour in this process is such that the solute of interest is almost insoluble in the dense gas whereas the organic solvent, which dissolves the solute, must have at least partial or complete miscibility with the dense gas. In general, the complexity of conventional processes for particle formation could be greatly reduced by employing the GAS process. The comparison between conventional processes with Gas Anti Solvent process is illustrated as in Figure 2. Figure 2: Comparison of conventional process and GAS process for particle formation [2] The main objective of this work is to explore the capability of GAS process for precipitation of micron-sized particles (micronization) of a longchained fatty acid, stearic acid. Stearic acid has a wide variety of industrial applications ranging from candle manufacturing to coating [4] and recently practical interests has also been directed in the development of drug delivery systems since stearic acid can be considered to be inert, inexpensive and biocompatible as well as being of low toxicity [5]. 2. Materials And Methodology 2.1 Materials Stearic acid (purity >98%) used was a kind supply of Cognis Oleochemicals Malaysia. Ethyl acetate (Merck, HPLC grade, 99.5%) was employed as the organic solvent to dissolve stearic acid. Liquid CO 2 (99.7%) was purchased from Air Products (MJ Sdn. Bhd). All the materials were used as provided without further purification. 2.2 Gas Anti Solvent (GAS) precipitation GAS precipitation was carried out in a 60 cm 3 high pressure view cell (Jerguson, Model 13-R-23) which enabled visual observation of phase behaviour. The base of the precipitation vessel was fitted with a filter frit (pore size: 0.5 /lm), which acted as a sparger during CO 2 addition and as a precipitate trap during washing and drying of the powder with CO 2. CO 2 was supplied by a high pressure syringe pump (ISCO, 260D). The system pressure was monitored by a pressure transducer (Druck, PDCR 4030) and its indicator (Druck, DPI 260). The system temperature was controlled and maintained at desired temperature to within + 0.l o C by immersing the whole system in a water bath heated with an immersion heater circulator (Thermohaake, DCIO). Liquid CO 2 was preheated to the desired temperature through a preheating coil. The apparatus for GAS precipitation is shown schematically as in Figure 3. The GAS precipitation procedures consisted of three stages, i.e. pressurization, precipitate washing and depressurization. A predetermined volume of solution with known concentration was sparged through the frit from the bottom of the high pressure view cell. CO 2 was added in a controlled rate until precipitation was complete. The system was then allowed for thermally equilibration. Washing and drying of the stearic acid precipitate involved flushing fresh CO 2 from the top through the frit mounted on its base. The flushed solution was passed through a solvent trap. The pressure was held constant during the entire washing stage. In this stage, the solvent was continuously removed until the precipitate was dried. In this process, up to 200 g of fresh CO 2 was used to obtain solvent-free product. Finally, depressurization was performed by venting the CO 2 and the total volume of gas CO 2 used was measured by a mass flow meter. 2

with the plot of raw stearic acid without the trace of residual solvents. 3. Results And Discussions Figure 3: Schematic diagram of GAS setup 2.

3 in a KBr plate. The residual solvents in precipitation was then determined qualitatively using the Thermal Gravimetric Analyzer (TGA) based on the comparison between the thermal decomposition plots of the samples with the plot of raw stearic acid without the trace of residual solvents. 3. Results And Discussions Figure 3: Schematic diagram of GAS setup 2.3 Conventional precipitation method Stearic acid solution was prepared under similar conditions (temperature and concentration) with stearic acid solution prepared for GAS process. The experiment was conducted using a hot plate stirrer (Torrey Pines Scientific). The solution was continuously stirred for an hour in a constant temperature water bath to form a clear solution with the temperature controlled and maintained at desired temperature up to + 1 o C by the hot plate temperature probe immersed in the water bath. Finally the solution was filtered and vacuum dried at 40 C. 2.4 Analytical techniques The particles size and morphology of stearic acid were examined using Scanning Electron Miscroscope (SEM). The particle size distribution was determined by using Particle Size Analyzer (Malvern Mastersizer 2000) where deionized water was used as the dispersing medium due to insolubility of stearic acid. The particle size of raw stearic acid was very large, about 3 mm to 4 mm in pellet form as can be seen from the SEM image in Figure 4 (a). After precipitation from GAS process, the stearic acid particle sizes were much reduced down to about 100µm as can been from Figure 4 (b). It was also found that the particles precipitated using this process were mostly aggregates of irregular-shaped crystals. However, the particles precipitated using conventional method were mostly crystalline structures of bipyramidal shape with sharp edges as can been in SEM image in Figure 4 (c). Figure 5 demonstrates the corresponding plot of volume particle size distribution of the particles precipitated from ethyl acetate solution using both GAS process and the conventional method. It can be seen clearly that the GAS-precipitated stearic acid was almost an order of magnitude finer and narrower distribution than the particles precipitated using the conventional method. This is because higher supersaturation ratio could be induced by rapid CO 2 injection causing the formation of mostly nuclei in GAS process whereas only low supersaturation ratio can be induced by conventional method where the subsequent growth of nuclei to larger particles could occur. The relative crystallnity of stearic acid samples was examined using the X-Ray Diffractometry (XRD) with Cu Kαl radiation over the range of 10 o <2θ< 80 o where the crystallinity changes could be observed as the difference in peak height. The crystallinity was also assessed using the Differential Scanning Calorimetry (DSC) by observing the changes of heat of fusion of the samples. The functional groups changes of the stearic acid samples could be detected through the Infra-Red (IR) spectra. The IR spectra of the samples were taken using Fourier Transform Infra-Red (FTIR) (Perkin Elmer Spectrum 1000). Prior to the measurement of IR Spectra, the stearic acid samples were sandwiched (a) 3

precipitated by GAS and conventional method The precipitation results from ethyl acetate solutions using both the GAS process and conventional method are also summarized

Table 1: Precipitation results of stearic acid using GAS process and conventional method a Volumetric particle size distribution, measured with light scattering technique

patterns of raw, conventional-precipitated stearic acid and GAS-precipitated stearic acid are illustrated in Figure 6.

3 which is similar for raw stearic acid and GAS-precipitated stearic acid.

However, the intensity of the XRD peaks of stearic acid processed with GAS process was lower compared to the raw stearic acid, indicating a reduction of crystallinity of

4 precipitated by GAS and conventional method The precipitation results from ethyl acetate solutions using both the GAS process and conventional method are also summarized as in Table 1. Table 1: Precipitation results of stearic acid using GAS process and conventional method a Volumetric particle size distribution, measured with light scattering technique (b) (c) Figure 4: SEM image of (a) raw stearic acid, (b) stearic acid precipitated using the GAS process, (c) stearic acid precipitated using the conventional method XRD patterns of raw, conventional-precipitated stearic acid and GAS-precipitated stearic acid are illustrated in Figure 6. In general, the patterns indicate identical structures with similar peaks reflected from the same plane. Two most distinct peaks can be observed at 21.8 and 24.3 which is similar for raw stearic acid and GAS-precipitated stearic acid. It can be confirmed here that the crystalline structure of stearic acid was still retained after being processed with the GAS process. However, the intensity of the XRD peaks of stearic acid processed with GAS process was lower compared to the raw stearic acid, indicating a reduction of crystallinity of stearic acid after processing with GAS process. On the other hand, it is very interesting to note the most distinct XRD peak of conventional-precipitated stearic acid has shifted to 11.4 although similar peaks were still found to exist at 21.8 and This indicates that the conventional-precipitated stearic acid has slightly modified the preferred crystal orientation of stearic acid compared to raw or unprocessed stearic acid. Figure 5: Volume distribution of particles Figure 6: XRD patterns of (a) raw stearic acid (b) 4

conventionally-produced stearic acid (c) GASproduced stearic acid DSC results of raw, conventional-precipitated and GAS-precipitated stearic acid are shown in Figure 7 in order to confirm the

As can be noted from Figure 7, both treated stearic acid either by conventional method and GAS process shows decrease of enthalpy of fusion ( H m ), indicating the slight decrease of crystallinity of

Figure 8: IR spectra of: (a) raw stearic acid ; (b) GAS-precipitated stearic acid;(c) Conventional precipitated stearic acid Figure 7: DSC results of (a) raw stearic acid (b) conventional-produced

5 conventionally-produced stearic acid (c) GASproduced stearic acid DSC results of raw, conventional-precipitated and GAS-precipitated stearic acid are shown in Figure 7 in order to confirm the crystallinity of stearic acid samples evaluated using the XRD analysis. As can be noted from Figure 7, both treated stearic acid either by conventional method and GAS process shows decrease of enthalpy of fusion ( H m ), indicating the slight decrease of crystallinity of samples as suggested by XRD results. Figure 8: IR spectra of: (a) raw stearic acid ; (b) GAS-precipitated stearic acid;(c) Conventional precipitated stearic acid Figure 7: DSC results of (a) raw stearic acid (b) conventional-produced stearic acid (c) GASproduced stearic acid IR spectra for raw, conventional-precipitated and GAS-precipitated stearic acid is also shown in Figure 8 to detect the functional group or chemical structural changes of processed stearic acid compared to original unprocessed stearic acid. It is noteworthy from Figure 8 that a broad band was detected at wavelength of about cm -l for conventionalprecipitated stearic acid which has been recognized as broad OH stretching bands in literature [6]. This is an evidence of the change of structures of stearic acid after processed with conventional method which could be mostly likely due to the solvent inclusion in the crystals to form solvates. It is not uncommon for compounds precipitated using the conventional method. For example, Mirza et al. [7] also obtained several different solvates of erythromycin as they attempted to recrystallize it from the solution using the conventional method. On the other hand, GASprecipitated stearic acid has demonstrated an advantage over conventional-precipitated stearic acid by ability to retain the original chemical structure of stearic acid as evidenced from the identical bands of the GAS-processed and the raw stearic acid. TG plots in Figure 9 also show that the production of high purity solvent-free stearic acid particles approaching the raw stearic acid could be obtained by using the GAS process. However, the obvious different thermal decomposition of stearic acid particles precipitated using the conventional method indicated that there is possibility of solvent inclusion in the crystal lattice to form solvates as clearly shown in IR results. Figure 9: A comparison plot oftg between: (a) raw stearic acid,' (b) GAS-produced stearic acid (c) conventional-produced stearic acid 4. Conclusions The stearic acid particles were successfully precipitated using the GAS process. The particle size 5

6 was found to be at least an order of magnitude reduction since the particle size was greatly reduced from original 3 mm to 4 mm down to about 100µm which was also found to be much finer and narrower distribution than the particles precipitated using the conventional method. The stearic acid precipitated from GAS process was found to still retain the original crystalline structure although slight reduction of crystallinity was observed. The GAS process has demonstrated many advantages over conventional method where almost solvent-free particles could be cbtained compared to much residual solvents were still retained in stearic acid particles precipitated using the conventional method. Obviously, the GAS process is a feasible process as a new alternative for particle formation process since simultaneous precipitation and purification of particles can be achieved in a single-step process without requiring further post-processing treatments. Acknowledgements The authors would like to express their gratitude to Ministry of Science, Technology and Innovation and University of Malaya for the financial support under IRP A research grant _(No: ). The authors would also like thank Dr. Harcharan Singh and Prof. K.B. Ramachandran for their guidance. Special thanks also extended to Dr. Frank Lucien from University of New South Wales (UNSW), Australia for his useful advice during equipment setup. The authors also thankful to all the members of Supercritical Fluid Research Group, University of Malaya for the useful discussions and meaningful assistance in completing this project. [4]. Markley, K.S. (1960). Historical and General. In Markley, K.S. (ed), Fatty Acids Their Chemistry, Properties, Production, and Uses. New York: Interscience Publishers, Inc.(p. 1-22). [5]. Killen, RD. and Corrigan, 0.1. (2001). Factors influencing drug release from stearic acid based compacts. Int. J Pharm [6]. Si1verstein, R.M., Bassler, C.G. and Morril, T.C. (1997). Spectrometric identification of organic compounds, 3rd edn. New York: John Wiley & Sons Ltd [7]. Mirza, S., Miroshnyk, I., Heinamaki, J., Christiansen, L., Karjalainen, M., and Yliruusi, J. (2003). Influence of solvents on the variety of crystalline forms of erythromycin. AAPS PharmSci. 5(2). Article 12. Retrieved 24 June, 2003,from References [1]. McHugh, M.A. and Krukonis, V.l. (1994). Supercritical Fluid Extraction, 2nd edn. Stoneham: Butterworth- Heinemann. [2]. York, P. (1999). Strategies for particle design using supercritical fluid technologies. Pharm. Sci. Technol. Today [3]. Mammucari, R., Tnadya, A., Ng, A., Meure, L., Bezanehtak, K., Coen, E., Combes, G., Dehghani, F., Regtop, H.L. and Foster, N. (2003). Processing Pharmaceutical Compounds using Dense Gas Technology. Ind. Eng. Chem. Res

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