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1876-6196 © 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Peer-review under responsibility of the Organizing Committee of ICCE UNPAR 2013doi: 10.1016/j.proche.2014.05.031

Available online at www.sciencedirect.com

ScienceDirect

International Conference and Workshop on Chemical Engineering UNPAR 2013, ICCE UNPAR 2013

Preparation of fenofibrate microparticles using top-down and bottom-up processes

Stevanus Hiendrawan, Bambang Veriansyah, and Raymond R. Tjandrawinata*

Advanced Technology Development, Dexa Laboratories of Biomolecular Sciences (DLBS), Dexa Medica, Industri Selatan V, Block PP no. 7, Jababeka Industrial Estate II Cikarang, West Java 17550, Indonesia

Abstract

Micronization of fenofibrate using top-down process via jet mill and bottom-up process via rapid expansion of supercritical solution (RESS) was conducted to investigate their effects on the formation of micronized fenofibrate. Processed fenofibrate retained its crystalline structure and have similar chemical structure with unprocessed fenofibrate. The average particle size of fenofibrate was reduced from its original wherein from 68.779±0.146 µm to 3.050±0.085 µm using jet mill process at SFR 2.7 kg/h; and to 3.044±0.056 µm using RESS under the optimum condition. The results revealed that jet mill and RESS processes were applicable for micronization of fenofibrate.

© 2014 Hiendrawan et al. Published by Elsevier B.V. Selection and peer-review under responsibility of the Organizing Committee of ICCE UNPAR 2013.

Keywords: fenofibrate, jet mill, RESS, microparticles, particle size

Nomenclature

ANOVA Analysis of Variance API Active Pharmaceutical Ingredients BCS Biopharmaceutical Classification System CO2 Carbondioxide DSC Differential Scanning Calorimetry

* Corresponding author. Tel.: +62-21-898-41901; fax: +62-21-898-41905. E-mail address:raymond@dexa-medica.com

© 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Peer-review under responsibility of the Organizing Committee of ICCE UNPAR 2013

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EPAS Evaporative Precipitation into Aqueous Solution FP Feeding Pressure FT-IR Fourier Transform Infrared GP Grinding Pressure LD Laser Diffractometer P Extraction pressure PSD Particle Size Distribution RESS Rapid Expansion of Supercritical Solution SCF Supercritical Fluid SEM Scanning Electron Microscope SFR Solid Feeding Rate T Extraction temperature XRD X-Ray Diffraction

1. Introduction

Micronization of active pharmaceutical ingredient (API) becomes the most important process in pharmaceutical industry for improving the dissolution rate and bioavailability of API especially from biopharmaceutical classification system (BCS) class II. Smaller particle size and uniformity in particle distribution through micronization process have several advantages such as bigger surface area that can improve its dissolution rate and lower dosage administration that may reduce adverse effect. Therefore, there is an increase interest in the development of more efficient micronization process1. Generally, micronization can be categorized as top-down and bottom-up processes. Top-down process involves reduction of large API particle size into smaller particle size, using various milling techniques such as wet milling (pearl milling), high pressure homogenization, ball milling, jar milling and jet milling (fluid energy mill). Bottom-up process involves growing the particles from a solution using various techniques such as supercritical fluid (SCF) technology, spray-freezing into liquid process, evaporative precipitation into aqueous solution (EPAS) and liquid solvent change process2-6.

Jet milling is commonly used for reducing particle size of API to low- or sub-micron ranges. The particles to be ground are accelerated in velocity by pressurized gas or steam jets, and the grinding effect is produced by intra- particle or particle-chamber wall collision. Jet milling process offers several advantages that suitable for heat and/or humid sensitive API, such as less contamination because of its dry process, no moving instrument parts, low temperature and no solvent use. In addition, this process has high industrial applicability7-10. As alternatives for the micronization of API, supercritical fluid technology, especially rapid expansion of a supercritical solution (RESS) has gained increasing attention because of particle size controllability11-15. In RESS process, particle size and particle distribution depends on chemical structure of solute and RESS parameters such as extraction pressure, extraction temperature, nozzle diameter and spraying distance16-19. We reported the use of RESS process in the micronization of fenofibrate (isopropyl ester of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid), an anti- hiperlipidemic drug 17. In the previous publication, effects of extraction pressure, extraction temperature and nozzle diameter on particle size were optimized using Taguchi’s orthogonal array. The results showed that particle size decreased as extraction pressure increased, extraction temperature and nozzle diameter decreased. Results from analysis of variance (ANOVA) using MINITAB software showed that the level of extraction pressure, extraction temperature and nozzle diameter had no significant effect on particle size (P > 0.05) with confidence interval 95%.

Herein, micronization of fenofibrate using jet mill process (fluid energy mill), a top down micronization process is examined and is compared to bottom up micronization process using RESS process under the optimum condition. The solid state characterization were characterized by scanning electron microscope (SEM), laser diffraction (LD), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and fourier transform infrared (FT-IR).

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2. Experimental

2.1 Materials

Fenofibrate was purchased from COPRIMA SL (Spain). High purity of carbon dioxide (CO2, purity of 99.95%) was purchased from PT Intergas (Jakarta, Indonesia).

2.2 Jet mill (fluid energy mill) procedure (top down micronization process)

Jet milling process was conducted using 8” sanitary design micronizers (Sturtevant Inc., MA, USA). Solid feeding rate (SFR) was controlled by a volumetric feeder (Schenck Accurate, WI, USA) and was calibrated using fenofibrate raw material before experiment. Fig. 1 shows a schematic illustration of jet mill process. A constant feeding pressure (FP) of 110 psi and grinding pressure (GP) of 90 psi was used. SFR was varied range at 2.7 kg /h and 5 kg/h.

Fig. 1. Schematic illustration of jet mill process [20]

2.3 RESS procedure (bottom up micronization process)

Micronization was conducted using a custom-built rapid expansion of supercritical solution (RESS) apparatus as described in the previous work17. Only a brief description is given here. Fig.2 shows a schematic diagram of the system. Prior to each experiment, 10 grams of fenofibrate was loaded to extraction vessel and then temperature of the extraction vessel was increased to experimental temperature. CO2 was cooled in a precooler and pressurized by a high pressure pump to a desired pressure, heated to a desired extraction temperature by a preheater and allowed to enter the extraction vessel for extraction. After reached the experimental temperature and pressure, the solution was kept in the extraction vessel until supercritical fluid CO2 (scCO2) was saturated with fenofibrate for 1 hour. This mixture was depressurized in a precipitation chamber at atmospheric pressure for 4 min by means of a nozzle to make precipitation of fenofibrate. During the depressurization, the flow of high pressure pump was increased to 50 g/min to ensure the steady state condition of extraction vessel, while the nozzle was also heated to avoid plugging by solid precipitation. The precipitated particles in the frit filter were collected and analyzed.

2.4 Characterization

The morphology of unprocessed and processed fenofibrate from jet mill and RESS processes were analyzed using a JEOL JSM-6510 SEM (JEOL Ltd., Tokyo, Japan). Particle size analysis was determined by LD (Mastersizer 2000, Malvern Instruments, USA) using the dry powder dispersing system Scirocco 2000 at 2 bar pressure. Particle size was characterized by volume-weighted mean diameter. The particle size results represent average values over three measurements performed on each sample. Crystallinity was determined by powder XRD (Ultima IV, Rigaku Co., Tokyo, Japan) analysis with Cu-K radiation. The diffraction patterns was measured with a voltage of 40 kV and a current of 40 mA in the 2 angle range of 2° to 60° with 4°/min scanning rate. Thermal analyzed was performed using a DSC (Q 20, TA Instruments, DE, USA). For the DSC analysis, each sample (3 mg) was placed

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in closed aluminum pan and heated at a rate of 5oC/min from 60oC to 90oC. Fourier transform infrared (FT-IR) spectrophotometer (Jasco 6100, Jasco Inc., MD, USA) in wave number range from 700 to 4000 cm-1 was used to analyze spectrum of unprocessed and processed fenofibrate.

Fig. 2. Schematic diagram of a custom-build RESS apparatus: 1, CO2 cylinder; 2, precooler; 3, high-pressure pump for carbon dioxide; 4, back pressure regulator; 5, preheater; 6, extraction vessel; 7, precipitation chamber; 8, frit filter; 9, cooling bath; 10, heating bath.

3. Result and discussion

3.1 Jet mill process

The effect of solid feeding rate (SFR) on particle size distribution (PSD) is shown in Fig. 3. At a constant feeding pressure and grinding pressure, an increase in SFR from 2.7 kg/h to 5 kg/h leads to an increase in mean particle size from 3.05±0.085 µm to 3.855±0.106 µ m and the PSD becomes broader. This may be attributed to short residence time of particle in the grinding chamber and less specific energy per particle, leading to the formation of larger particles. Similar trend were observed in the micronization of ibuprofen (pre-mixed with 1.0% of silica). The mean particle size increased from 3.7 µm to 9 µm when the SFR increased from 1 g/min to 5 g/min at a constant feeding pressure (FP) of 30 psi and grinding pressure (GP) of 10 psi9. Teng et al.10 also reported mean particle size of potassium chloride increased with the SFR, which can be explained from the energy aspect. This report suggest that larger feed rate leads to short residence time of particle in the grinding chamber, consequently some large particles leaving the grinding chamber sooner.

Fig. 3. Particle size distribution (PSD) profile of of fenofibrate particles. (a) unprocessed; (b) jet mill at SFR 2.7 kg/h.; (c) jet mill at SFR 5 kg/h.

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3.2 RESS process

Micronization of fenofibrate using RESS process was conducted under the optimum condition at extraction pressure 200 bar, extraction temperature 35oC and nozzle diameter at 200 µ m. The average particle size of processed fenofibrate was 3.044±0.056 µ m. Details of experimental results and discussion about micronization process using RESS were described in the previous paper 17.

3.3 Characterization of micronized fenofibrate

Fig. 4 SEM image of fenofibrate particles. (a) unprocessed; (b) jet mill at SFR 2.7 kg/h; (c) RESS at optimum condition

Fig. 4 shows the scanning electron microscopy (SEM) images of unprocessed and processed fenofibrate. Unprocessed fenofibrate has irregular-shape particles with the average particle size 68.779±0.146 µ m as shown in Fig. 4A. The smallest processed fenofibrate was obtained from jet mill at 2.7 kg/h SFR (Fig. 4B) and from RESS method at optimum conditions (Fig. 4C) also has irregular-shape particles. Fig. 5 shows the particle size distribution from laser diffraction analysis. PSD of fenofibrate from jet mill and RESS process shows narrower size distribution compared to unprocessed fenofibrate and there is no difference in the PSD of jet mill process at lower SFR and RESS at optimum condition.

Fig. 5. Particle size distribution (PSD) profile of of fenofibrate particles. (a) unprocessed; (b) jet mill at SFR 2.7 kg/h; (c) RESS at optimum condition

Both processed fenofibrate particles was used for further characterization using XRD, DSC and FT-IR. Fig. 6 and Fig. 7 show DSC and XRD patterns of unprocessed and processed fenofibrate. The melting point of unprocessed fenofibrate is 81.71oC whereas jet mill and RESS processed fenofibrate have melting point 79.98oC and 79.95oC, respectively. Slight lowering of DSC endothermic peak in the processed fenofibrate particles was due to reduce of particle size1. The XRD patterns of processed fenofibrate were similar to the unprocessed fenofibrate which suggests the same crystal structure was obtained after jet mill and RESS processes. The intensity of XRD peak (6.34o, 12.64o, 18.98o, 20.84o, 24.66o and 25.36o) was reduced after jet mill and RESS processed. This is because the reduction in the particle size after jet mill and RESS processes1,1

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Fig. 6. DSC profiles of fenofibrate particles. (a) unprocessed; (b) jet mill at SFR 2.7 kg/h; (c) RESS at optimum condition

Fig. 7. XRD profiles of fenofibrate particles. (a) unprocessed; (b) jet mill at SFR 2.7 kg/h; (c) RESS at optimum condition

Surface of the unprocessed and processed fenofibrate was characterized using FT-IR and results are shown in Fig. 8. FT-IR spectra of processed fenofibrate show similar absorption peak with that of FT-IR spectra of unprocessed fenofibrate, indicating that jet mill and RESS processes did not affect chemical structure and modify the surface of fenofibrate.

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Fig. 8. FT-IR profiles of fenofibrate particles. (a) unprocessed; (b) jet mill at SFR 2.7 kg/h; (c) RESS at optimum condition

4. Conclusion

Micronization of fenofibrate was successfully performed using jet mill and rapid expansion of supercritical solution (RESS) processes. Processed fenofibrate with particle size of 3.050±0.085 µm and 3.044±0.056 µm were obtained from jet mill process at SFR 2.7 kg/h, and RESS under the optimum condition (T at 35oC, P at 200 bar and nozzle diameter at 200 µm), respectively. In the jet mill process, the decrease in SFR leads to reduction of fenofibrate particle size whereas in the RESS process, the size of processed fenofibrate was dependent on the processing conditions. Solid state analysis revealed that the processed fenofibrate particles retained similar crystal and chemical structure. Both processes, jet mill and RESS, were applicable for micronization of fenofibrate.

Acknowledgements

The author(s) thank to Sherly Juliani for critical review on this manuscript.

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