Particle Size and Bulk Powder Flow Control by Supercritical

5302

Ind. Eng. Chem. Res. 2009, 48, 5302–5309

Particle Size and Bulk Powder Flow Control by Supercritical Antisolvent Precipitation Ranjit Thakur,* Auburn E. Hudgins,† Elisabete Goncalves, and Gerhard Muhrer‡ NoVartis Pharma AG, Pharmaceutical and Analytical DeVelopment, 4002 Basel, Switzerland

The purpose of this study was to use silicas for controlling the particle size of a poorly soluble drug in the micrometer to submicrometer range and enhancing the flowability of those particles in a supercritical fluid process. The concept used consists in entrapping a fast precipitated drug into the silica pores and drying the resulting particles fast enough to avoid particle growth and ensure proper size control. Because silica will also enhance the bulk density, it will help in inducing higher flowability to the final product. To prove this concept, a suspension containing a poorly soluble drug and silica was processed using the batch gas antisolvent (GAS) method. Griseofulvin (GF) was used as a model of a poorly water-soluble drug substance, and two types of silica with different pore size and particle size, respectively, were tested. Each experiment was performed at various drug/silica ratios to determine the optimal ratio for particle size control. The products of each experiment were then analyzed using optical microscopy, X-ray powder diffraction (XRPD), and scanning electron microscopy (SEM). In addition, differential scanning calorimetric tests and dissolution rate studies were performed. Increasing the drug/silica ratio results in more pronounced particle size reduction and is accompanied by a change in drug particle morphology. The produced powders with silica showed enhanced flowability by visual inspection with the naked eye when compared to the neat drug. However, the available data shows that the silica has strong affinity with GF particles and affects the dissolution profile even though GF particle size is reduced. Kinetics instead of thermodynamics seems to be the controlling parameter for GF particles. All the experiments in this work were conducted in batch process mode, and further exploration is planned using the continuous supercritical antisolvent (SAS) process. Quantitative analysis of flowability is also part of the future work. 1. Introduction “There is plenty of room at the bottom”, these are the words of famous physicist Robert Feynman which are now becoming more relevant even for the pharmaceutical industry.1 Because more and more drugs coming out of research have poor aqueous solubility and often show limited dissolution rates, special delivery systems are usually sought to achieve adequate in vivo exposure. Particle size reduction to the submicrometer or nanometer range is one of the formulation options for such compounds. “Nanosizing” is particularly useful for compounds that show both poor aqueous solubility and low log P (e.g., griseofulvin (GF)). Two crucial aspects in this direction that are very important from the pharma point of view are the formulation of nanoparticles and the subsequent stabilization of those particles. It is well-known that, as the particle size goes down, cohesive behavior of drug compounds tends to increase agglomeration and also reduce the bulk density, thus causing processability issues downstream. To overcome these issues, various methods have been employed including precipitation with surface active agents.2 Although there are several processes which claim to form stable nanoparticles including Prud’homme’s nanoprecipitation using confined impinging jets,3-5 a precipitation process with additives to control size,6 high gravity precipitation,7 and others, all of them result in nanosuspensions that need a robust drying process to convert the suspension into a powder without affecting particle stability. * To whom correspondence should be addressed. Tel.: +41 61 324 62 54. Fax: +41 61 324 36 96. E-mail: [email protected]. † Current address: Ciba McIntosh, 1379 Ciba road, McIntosh, AL 36553. ‡ Current address: Novartis Pharma AG, Chemical & Analytical Development, 4002 Basel, Switzerland.

Supercritical fluid (SCF) based technology is one of the processes which provides the advantages of mild and inert conditions, practically no residual solvent content, and size and morphology control for dry powder formulations. SCF technology can be divided broadly into two techniquessRESS (rapid expansion of supercritical solution) wherein the SCF is used as a solvent and supersaturation is achieved by changing pressure and PCA (precipitation with a compressed antisolvent) wherein the SCF is employed as an antisolvent to induce supersaturation. All other processes with SCF are based on these two concepts with some modifications and improvements. A plethora of data is available on these two processes with regard to particle formation which have been reviewed extensively.8-11 The RESS process uses the density tunability characteristics of SCF with varying pressure to precipitate the drug particles. The solute is dissolved in SCF above the critical point and then expanded through a micronozzle to either atmospheric or subatmospheric pressure. This sudden pressure drop causes high supersaturation and generally forms uniformly distributed particles. The major limitation of this process is the poor solubility of most drugs and pharmaceutical excipients in supercritical CO2, the SCF of choice. However, researchers have shown that this simple process can be used to form a variety of products ranging from pure drugs to encapsulated compositions.12-15 Also, some modifications were proposed to enhance solubility as well as to control size.16,17 In the PCA process, i.e., precipitation by a compressed antisolvent, the solution is sprayed into the SCF-filled vessel after the vessel has reached the specified temperature and pressure.18-22 The solvent used in this process has higher affinity for SCF than the solute, which leads to supersaturation of the solution and particle formation by homogeneous nucleation. This

10.1021/ie801324q CCC: $40.75  2009 American Chemical Society Published on Web 04/17/2009

Ind. Eng. Chem. Res., Vol. 48, No. 11, 2009

5303

Figure 1. Schematic of the concept.

process is typically a semicontinuous process which can be operated continuously by providing a cyclone separator at the outlet of the high pressure vessel, just as in conventional spray drying where inhalable particles in the micrometer and submicrometer size range are separated using cyclones. The GAS process, which stands for gaseous antisolvent, uses compressed carbon dioxide as the antisolvent in a batch process mode. The solution/suspension is placed in a reactor, which is heated to a desired set temperature, and then, SCF is pumped into the vessel to pressurize to the desired value. As the compressed fluid enters the vessel, it extracts the solvent after reaching significant density (which is a function of pressure), causing supersaturation and leading to precipitation of the drug particles. CO2 is widely used as the compressed antisolvent because it has many desirable properties such as being inert, safe, environmentally friendly, and mild critical temperature and pressure conditions of 31 °C and 7 MPa. It is also nonflammable and inexpensive. Supercritical CO2 can dissolve most of the organic solvents commonly used in the industry. In the present work, Griseofulvin (GF), a derivative of Penicillium griseofulVum, is used as an example of a poorly water-soluble drug.22,23 Poorly soluble drugs cause a dosing dilemma due to the fact that the levels of absorption in the body can fluctuate after the drug is in the intestinal tract. This affects the bioavailability and efficacy of the drug24 and can also be dangerous or life-threatening when using drugs that have a high toxicity. GF is soluble in common organic solvents like acetone and ethanol. The aim of this work is to coprocess GF with two different types of silicas (Aeroperl 300 and RxCipients GL200) using a GAS process in order to not only improve the flowability of the resulting powders and thereby their downstream processability (e.g., tabletting) but also to use silica as a carrier and spacer for precipitated drug particles, thus, allowing a proper particle size control during the precipitation process. Sharma et al.25 were able to adsorb the poorly water-soluble drug Meloxicam on porous calcium silicate as an excipient by an evaporation method. Silicas were used with two objectives: first, as a means to increase the bulk density of the drug and, as a consequence, improve its flowability and downstream processability and, second, to act as a carrier or spacer during the precipitation process such that the extent of particle agglomeration might be decreased, thus allowing size control. Without a spacer, drug particles tend to agglomerate due to interactions caused by their similar surface properties. The goal of using porous silica is to give the drug an area to adhere to, by either becoming entrapped in the pores (ideally) or adsorbed on the surface to avoid particle agglomeration by growth. The schematic of the process is shown in Figure 1. The two silicas used in this study were Aeroperl 300 Pharma and RxCipients GL200. Aeroperl is a porous granulated colloidal silica with a mean particle diameter of 30 µm. RxCipient GL200 is a precipitated silica, with a mean particle size of 20 µm and mean pore diameter of 33 nm. Silica

Figure 2. Schematic of batch gaseous antisolvent (GAS) process.

was chosen as a densification and particle-size-controlling excipient, because it is safe, inert, and a pharmaceutically acceptable inorganic excipient. The precipitation process is started with a suspension of silica and drug in solution. The hypothesis is that, at the end of the precipitation process, if the drug is entrapped completely in the pores, the drug particles should be smaller than the diameter of the silica pores. This hypothesis will be valid if the volume of the available pores is equivalent to the soluble drug mass. One of the goals of this study was to find the optimum ratio of drug to silica needed for proper particle size and flowability control. 2. Materials Griseofulvin (GF) was supplied by Sigma at a purity of 95% HPLC. Aeroperl 300 Pharma (Degussa AG, Germany) is a porous granulated colloidal silica (specifically colloid silicon dioxide) with a surface area of approximately 300 m2/g. RxCipients GL20 (J. M. Huber Corp, Finland) is a precipitated silica with a surface area of approximately 160 m2/g and mean pore size of 33 nm. Acetone was used as the solvent, and it was supplied by Merck at a minimum purity of 99.8%. 3. Methods In the GAS process the temperature was set to 40 °C and the final pressure was set to 100 bar, leaving the different drug to silica ratios as the only variables between the experiments. Figure 2 shows the schematic setup of the GAS process used in the study. The known amount of suspension was sealed in a reactor and slowly pressurized to 100 bar using a high pressure CO2 pump. The system was allowed to equilibrate for less than 1 min, and then, the system was purged, using approximately 150-200 mL of the fresh makeup CO2 for complete removal of solvent from the system. The organic solvent increase in volume as the density of the CO2 increases (nearing that of organic solvent), and at a sufficient supersaturation, particle precipitation is triggered. Different ratios of GF and silica were used for the experiments to determine the optimum amounts of each. The GF was dissolved in acetone (except one experiment which was conducted using ethanol as a solvent) while the silica (which is insoluble) remained suspended in the solution. The ratios tested were the following: drug/silica 100/0, 90/10, 80/20, 70/30, 50/ 50, 10/90, 20/80, and 30/70. Regardless of the ratio tested, the drug was dissolved in 20 mL of solvent and ultrasonicated for approximately 1-2 min.

5304


Figure 3. (a) Optical microscope image of unprocessed pure GF. (b) Optical and SEM image of GAS processed pure GF.

Figure 4. 90/10 GF to silica ratio using RxCipient.

4. Results and Discussion 4.1. Griseofulvin Processed with RxCipients GL200. From the visual inspection of the product, silica seems to have a positive impact on the flowability of the GF particles as compared to pure GF. However, different ratios of silica do not seem to impact flowability. To understand the product quality various analytical methods were employed as described below. 4.2. Image Analysis. Optical microscopy and scanning electron microscopy (SEM) were two methods used to analyze particle morphology as well as the effect of silica on GF. Optical microscopy was the most basic of the analyses we performed on the product. It showed some of the particle details and gave an estimate of the size of the particles we were working with. SEM analysis gave us detailed information about the interaction between the drug and silica along with morphology and qualitative analysis of particle size. Figure 3a shows unprocessed GF particles obtained from the supplier. These particles are micronized with average size of ∼4 µm. The first experiment was performed with pure GF as a control. As shown in Figure 3b, pure GF after GAS processing resulted in long needlelike structures, a few millimeters in length, and 300-400 µm in width, with overlapping wedges. It was also possible to see very small, stringy particles in the pores of the larger structures. It is worth pointing out the fact that the GAS process provides enough time for particles to grow through crystal agglomeration which results in bigger crystalline particles.

When 10% RxCipient GL200 was added to the system, GF morphology changed with silica particles adhering to the GF particles. Although this is not obvious from the optical image (shown in left), it is clearly visible in the SEM picture shown in Figure 4b. Moreover, this picture shows that the pinecone type wedges observed with pure GF have disappeared, and wide particles ∼0.7 mm long and ∼150 µm in width are observed with silica trapped in the small holes. Also, SEM reveals that the silica formed pores on the crystal surface and became entrapped there. This change in width of the particle is controlled due to presence of silica which is restricting sideways growth of the GF particles. Further increasing the amount of silica (RxCipient GL200) in the system up to 20% (Figure 5) yielded particles having a higher aspect ratio than that found at the drug/silica ratio of 90/10. At this drug/silica ratio, there is less wedge formation and GF starts forming regular rodlike particles. The length of the particles also decreases up to ∼300 µm while maintaining almost same width as with 10% silica. Figure 6 shows the result of the GAS processed 70/30 GF to silica ratio using RxCipient GL200. Ethanol and acetone were the two solvents initially selected for this system. However, due to the high solubility of GF in the ScCO2-ethanol system, acetone was selected based on its lower solubility effect. This is the only drug to silica ratio where ethanol was used as a solvent along with acetone.


5305


Figure 6. 70/30 GF to silica ratio using RxCipient with (a) acetone and (b) ethanol as a solvent.



In this system, the particles generated were significantly smaller than at higher drug loadings, with the largest particles reaching approximately 200 µm in length from tip to tip. Also, the morphology of the particles changed to rectangular blocks with few needle shaped particles, but no pinecone wedgelike formation. The silica particles adhere as loose clumps with other silica particles or to the needlelike particles of GF. The change in morphology with solvent can be also seen from Figure 6a and b. But with both solvents it can be clearly seen that size and morphology of GF changed significantly with the presence of higher silica amount. This complies with theory explained in Figure 1.

At a GF/silica ratio of 50/50 GF (Figure 7), needlelike particles were observed with high aspect ratio and are surrounded by silica particles. Although the length of the particles increased when compared with the particles produced at a GF/ silica ratio of 30/70 ratio, the aspect ratio also increased under these conditions. It seems like kinetics is playing the major role in governing the morphology of the GF particles in one direction. This behavior was also observed earlier in an SASEM process by Chattopadhyay and Gupta26 with low power of ultrasound energy. Reducing the drug to silica ratio further yielded long cylindrical needles that were less than 20 µm in diameter which is 20 times smaller than pure GF particles.

5306


Figure 9. GF_AH6 used a 20/80 GF to silica ratio, using RxCipient as the silica.

Figure 10. GAS experiments conducted with Aeroperl silica in 90/10 (a) and 70/30 (b) GF to silica ratio.

Figure 11. 30/70 GF to Aeroperl in GAS process. Table 1. DSC Analysis Values of GAS Processed Product experiment (GF/silica)

onset (°C)

∆H (J/g)

amt tested (mg)

100/0 90/10 80/20 70/30a 70/30b

219.7 219.6 219.5 219.7 219.0

115.7 106.2 67.5 26.3 58.3

2.1680 2.1930 2.9590 2.5760 2.1380

a

Ethanol as solvent. b Acetone as the solvent.

Figure 7b clearly shows the silica particles agglomerating to the long rodlike GF particle. Also, due to the high density, silica particles start segregating from suspension and settle at the bottom of the vessel, which means that less silica is available to act as a spacer to control GF particle growth. At a GF/silica ratio of 30/70, the product could be easily divided into two separate samples at the time of collection. As shown in Figure 8, the silica particles were isolated as small amorphous particles (part a), whereas GF particles were isolated as needlelike particles (part b). The shiny, needlelike particles had collected on the sides of the vessel and on top of the silica particles. At a GF/silica ratio of 20/80, surprisingly long, cylindrical rods of drug were formed (Figure 9). The aspect ratio of the GF particles increased even further at this GF/silica ratio when

compared with the 30/70 GF/silica ratio (Figure 8). Long, thin structures were starting to form, with lengths of around 300-400 µm and diameters of less than 10 µm as shown in Figure 9. This can be explained by above-mentioned theory of settling of silica due to the higher density and not being available for growth control. Studying a wide range of GF to RxCipient ratios showed that silica plays a major role in controlling the size and morphology of the final product. The particles obtained ranged from a few millimeters in length to micrometer size with different aspect ratios along with changes in the morphology relative to drug/ silica ratios. Increasing the drug/silica ratio results in a decrease in drug particle size as clearly seen when comparing Figure 4 (90/10 GF/silica ratio) with Figure 9 (20/80 GF/silica ratio). With regard to results obtained at higher silica amounts, we concluded that the silica was sinking to the bottom of the solution and not properly interacting with the GF. 4.3. Griseofulvin Processed with Aeroperl 300. Another type of silica, Aeroperl 300, was tested to study the effect of surface area of silica on the interaction behavior with the model compound GF. Although this silica is also porous, it has a significantly higher BET surface area when compared with Rxcipients GL200 (300 vs 160 m2/g).


5307

Figure 12. XRD pattern of processed GF with and without silica.

Figure 13. Dissolution profile of processed and physical mixture of GF/ silica.

Figure 10 shows the product obtained at a GF to silica ratio of 90/10 (left image) with Aeroperl 300. Here again the needlelike structures are obtained with approximately 1.0 mm in length. Figure 10b shows the product obtained at a 70/30 DS to silica ratio. It shows particles ranging in length from ∼200-800 µm. It can also be seen that the drug interactions with Aeroperl are very similar to those observed in the experiments using RxCipients GL200. As seen with RxCipients GL200, decreasing the GF/Aeroperl 300 ratio to 30/70 results in longer, thin, rodlike crystalline GF particles that show silica particles adsorbed at their surface (Figure 11). Going by the hypothesis presented earlier (Figure 1), size and morphology of the GF particles can be controlled by using either type of silica. Also, it is clear from all pictures that excess silica adheres to the surface of GF particles which causes higher flowability of the product. Regardless of the type of silica used in the experiments, these studies show that, as the amount of GF decreases and the amount of silica increases, the particles of GF consistently change from short, wide crystals to long, thin, almost cylindrical shaped needlelike structures with high aspect ratios. Similar results have been published by other authors when using the PCA process and a polymer instead of silica21 as excipient. The SEM pictures gave enough detail of the surface morphology of the crystals to show that the silica is actually hindering

the growth of GF particles even though GAS process offers longer growth time for particles. Silica being heavier in the suspension settles down at the bottom of the vessel and therefore has less chance of interacting with the drug. As a consequence, particle growth is not controlled to extent of achieving nanoparticles. However, the PCA process offers less time for growth which will be helpful in controlling sizes in the nanometer range. 4.4. Flow Behavior. The products from all experiments that contained silica, in any amount, demonstrated improved flowability over the pure GF. However, the optimum balance between improved flowability and GF particles seemed to be the experiments that used the 70/30 ratio of DS to silica as it has much less needlelike particles sticking to the surface. There was no quantitative analysis of flowability, but it is based on visual inspection. To quantify the flowability, measurement by rheometer is planned as a next step. 4.5. Thermal Analysis. Differential scanning calorimetry (DSC) is useful in determining the melting point and purity of the sample. While there is no significant change in the melting point for any of the samples, the ∆H values decreased as the silica increased (Table 1). There is also a significant change in the ∆H values of two experiments that had 70/30 ratios, mainly due to the types of solvent used. The experiment using acetone had a ∆H of 58.3 J/g, and the experiment using ethanol was around half-that value, at 26.3 J/g. This is most likely due to the ethanol acting as a cosolvent in the system and causing the majority of the drug to be lost during the purge process and further affecting the impurity (silica in this case). The final product was a wellmixed system, and the exact ratio was calculated based on total mass of silica and final product. As silica is not soluble, it is expected to have same amount of silica in the end of the process and the remaining being GF. 4.6. X-ray Diffraction. A PANalytical XRPD instrument was used to determine the crystallinity of the product with the X’Pert Pro diffractometer system. The measurement was performed under scanning mode with 2θ values of 4-40° in 10 min. Strong, sharp peaks of products indicate that the product obtained has the same crystallinity as of pure processed GF. As shown in Figure 12, peaks of all samples with a GF to silica ratio 100-70% falls at same 2θ values. Even at lower GF to silica ratios, no shift in peaks was observed which can lead to

5308


the conclusion that crystallinity of the GF was intact after processing and that there was no evidence of different polymorphs. 4.7. Dissolution Rate Studies. The dissolution rate (DR) experiments were conducted in a paddle USP 2 apparatus, at 37 °C, 50 rpm, using 900 mL of 0.5% SDS as dissolution rate media. The 50 mg of GF present in the three formulations (physical mixture and two processed GF/silicas) was fully dissolved in the 900 mL of 0.5% sodium dodecyl sulfate (SDS), which means that the experiments were conducted below the saturation solubility of GF in 0.5% SDS. Therefore, any differences in DR behavior can be attributed to different release properties (and not due to the impossibility of completely dissolving the dose use in the DR test). A dissolution rate study was done using the 70/30 GF/ Aeroperl (50 mg GF), the 70/30 GF/RxCipients GL200 (50 mg GF), and a 70/30 physical mixture composed of GF (50 mg) and RxCipients. The dissolution rate study was conducted with UV spectrophotometric analysis at 325 nm. The results show that approximately 21% and 23% of the drug was released from the GF/Aeroperl and GF/RxCipients GAS processed mixtures, respectively, whereas about 100% was released from the physical mixture. In addition, the data show faster dissolution rates for the physical mixture when compared with the GAS processed mixtures. Figure 13 shows the dissolution profile of the processed product and physical mixture. On the basis of the image analysis, we hypothesize that excess silica acts as a coated layer on the top of GF particles and hinders the dissolution. This also shows that affinity between silica and GF is quite high and due to which GF is not able to dissolve even though the particle size of GF was reduced after coprocessing with silica. 5. Conclusions All of the experiments with Griseofulvin used as a model compound yielded a mixture of small, flowable particles and needlelike structures. The flowable particles were very encouraging and proved the concept that various types of silica may be used for this purpose, since the product seemed to be affected more by the ratio used than the type of silica. The optimum ratio for balancing flowability with GF particles appeared to be the 70/30 GF to silica for both types of silica. In addition to controlling particle size and flowability, silica seems also to affect the morphology of the final particles. From the dissolution rate profiles of the product, it can be concluded that silica has a strong affinity with GF particles and provides hindrance in dissolving. Also, excess silica present in the system seems to coat on top of the GF surface. One theory regarding the fibrous and needlelike structures was that they formed due to insufficient contact between the silica and the drug substance while the drug was in solution. During the GAS process, the silica would have time to settle to the bottom of the reactor while the pressure reached the intended 100 bar. The aim of using PCA is to avoid the settling of the silica by spraying the suspension into the vessel and use silica as a spacer between drug particles to control growth. Two problems to overcome in PCA will be selection of the correct nozzle diameter, which may clog if higher diameter silica is used, and finding a suitable pumping system. This batch process showed that particle size reduction, morphology change, and higher flowability can be achieved by coprecipitation of API with a spacer, but due to high growth time in GAS process, product in the nanometer range is hard

to produce. However, nanoparticles can be obtained using a spraying process such as PCA where silica would be in continuous suspension during particle formation giving enough surface to restrict growth of the particle. As part of future work, we plan to use the PCA process to produce submicrometer or nanoparticles in a semicontinuous process. Acknowledgment We thank Kurt Schafflu¨tzel for constructing the high pressure system in a very limited period of time. Miloud Achour from Pharma development helped us a lot with the dissolution studies. We also acknowledge Dierk Ma¨rtin and Kurt Paulus for preparing the SEM images, and Massimo Pignone for XRPD support. Literature Cited (1) Feynman, R. There is plenty of room at bottom. Eng. Sci. 1960, XXIII (5). (2) Rasenack, N.; Hartenhauer, H.; Mu¨ller, B. W. Microcrystals for dissolution rate enhancement of poorly water soluble drugs. Int. J. Pharm. 2003, 254, 137.145. (3) Johnson, B. K.; Prud’homme, R. K. A process and apparatus for preparing nanoparticles compositions with amphiphilic copolymers and their use. WO 02/078674A1, 2002. (4) Johnson, B. K.; Prud’homme, R. K. Chemical processing and micromixing in confined impinging jets. AIChE J. 2003, 49 (9), 2264– 2282. (5) Johnson, B. K.; Prud’homme, R. K. Flash nanoprecipitation of organic actives and block copolymers using a confined impinging jet mixers. Aust. J. Chem. 2003, 56, 1021-1024. (6) Horn, D.; Schmidt, H. W.; Ditter, W.; Hartmann, H.; Lueddecke, E. Verfahren zur Herstellung Von felnVerteilten, pulVerVo¨rmigen Carotinoidbzw. Retinoidpra¨paraten. EP 0065 193 B1, 1985. (7) Chen, J. F.; Zhou, M. Y.; Shao, L.; Wang, Y. Y.; Yun, J.; Chew, N. Y. K.; Chan, H. K. Feasibility of preparing nanodrugs by high-gravity reactive precipitation. Int. J. Pharm. 2004, 269 (1), 267–274. (8) Debenedetti, P. G. Supercritical fluids as particle formation media. Supercrit. Fluids 1994, 719–794. (9) York, P. Strategies for particle design using supercritical fluid technologies. PSTT 1999, 2 (11), 430–440. (10) Pasquali, I.; Bettini, R.; Giordano, F. Supercritical fluid technologies: an innovative approach for manipulating the solid-state of pharmaceuticals. AdV. Drug DeliVery ReV. 2008, 60 (3), 399–410. (11) Chang, C. J.; Randolph, A. D. Precipitation of microsize organic particles from supercritical fluids. AIChE J. 1989, 35 (11), 1876–1882. (12) Tom, J. W.; Debenedetti, P. G. Precipitation of poly (l-lactic acid) and composite poly(l-lactic acid)-pyrene particles by rapid expansion of supercritical solutions. J. Supercrit. Fluids 1994, 7, 9–29. (13) Tu¨rk, M.; Hils, P.; Helfgen, B.; Schaber, K.; Martin, H. J.; Wahl, M. A. Micronization of pharmaceutical substances by the rapid expansion of supercritical solutions (RESS): a promising method to improve bioavailability of poorly soluble pharmaceutical agents. J. Supercrit. Fluids 2002, 22, 75–84. (14) Franklin, R. K.; Edwards, J. R.; Chemyak, Y.; Gould, R. D.; Henon, F.; Carbonell, R. G. Formation of perfluoropolyether coatings by the rapid expansion of supercritical solutions (RESS) process. Part 2: numerical modeling. Ind. Eng. Chem. Res. 2001, 40, 6127–6137. (15) Tu¨rk, M.; Upper, G.; Hils, P. Formation of composite drugpolymer particles by co-precipitation during the rapid expansion of supercritical fluids. J. Supercrit. Fluids 2006, 39 (2), 253–263. (16) Thakur, R.; Gupta, R. B. Formation of Phenytoin nanoparticles using rapid expansion of supercritical solution with solid co-solvent (RESS-SC) process. Int. J. Pharm. 2006, 308, 190–199. (17) Meziani, M. J.; Pathak, P.; Hurezeanu, R.; Thies, M. C. Supercriticl fluid processing technique for nanoscale polymer particles. Angew. Chem., Int. Ed. 2004, 43 (6), 704–707. (18) Dixon, D. J.; Bodmeier, R.; Johnston, K. P. Polymeric materials formed by precipitation with a compressed fluid antisolvent. AIChE J. 1993, 39, 127–139. (19) Thakur, R.; Gupta, R. B. Production of hydrocortisone micro and nano particles using supercritical antisolvent with enhanced mass transfer. Chem. Eng. Commun. 2006, 193 (3), 293–305.

Ind. Eng. Chem. Res., Vol. 48, No. 11, 2009 (20) Muhrer, G.; Meier, U.; Fusaro, F.; Albano, S.; Mazzotti, M. Use of compressed gas precipitation to enhance the dissolution behavior of a poorly water soluble drug: Generation of drug microparticles and drugpolymer solid dispersions. Int. J. Pharm. 2006, 308 (1-2), 69–83. (21) Reverchon, E.; De Marco, I.; Adami, R.; Caputo, G. Expanded micro-particles by supercritical antisolvent precipitation: Interpretation of results. J. Supercrit. Fluids 2008, 44 (1), 98–108. (22) Jarmer, D. J.; Lengsfeld, C. S.; Anseth, K. S.; Randolph, T. W. Supercritical Fluid Crystallization of Griseofulvin: Crystal Habit Modification with a Selective Growth Inhibitor. J. Pharm. Sci. 2005, 94 (12), 2688– 2702. (23) Knoblauch, J.; Zimmermann, I. Thermochemical analysis of the dissolution process of Griseofulvin. Eur. J. Pharm. Biopharm. 2007, 67 (3), 743–751.

5309

(24) Metsugi, Y.; Ogawara, K. I.; Higaki, K.; Kimura, T. Intl. J. Pharm. 2008, 352 (1-2), 36-43. (25) Sharma, S.; Sher, P.; Badve, S.; Pawar, A. P. Adsorption of Meloxicam on porous calcium silicate: Characterization and tablet formulation. AAPS PharmSciTech 2005, 6 (4), article 76. (26) Chattopadhyay, P.; Gupta, R. B. Production of griseofulvin nanoparticles using supercritical CO2 antisolvent with enhanced mass transfer. Int. J. Pharm. 2001, 228, 19–31.

ReceiVed for reView September 2, 2008 ReVised manuscript receiVed January 27, 2009 Accepted April 1, 2009 IE801324Q

Particle Size and Bulk Powder Flow Control by Supercritical

Recommend Documents