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Micronization of p-Aminosalicylic Acid Particles Using High-Gravity Technique Yu-Shao Chen,† Yao-Hsuan Wang,‡ Hwai-Shen Liu,‡ Kuang-Yang Hsu,§ and Clifford Y. Tai*,‡ Department of Chemical Engineering, National Taiwan UniVersity, Taipei 106, Taiwan School of Pharmacy, Taipei Medical UniVersity, Taipei 110, Taiwan Department of Chemical Engineering, Chung Yuan UniVersity, Taoyuan 320, Taiwan
An antisolvent precipitation process was adopted in this study to prepare micrometer-sized p-aminosalicylic acid (PAS) particles using the high-gravity technique. The effects of operating variables on the particle size were investigated. With an increase in the dispersant concentration and disk diameter or a decrease in the drug (PAS) concentration, the particle size of PAS was reduced. In addition, a circular-tube distributor was more effective than a straight-tube distributor for micronization. On the other hand, the effect of the liquid flow rate in the range between 0.25 and 1 L/min was less significant. The high-pressure homogenization following the high-gravity precipitation would effectively reduce the agglomeration of the particles in the suspension to produce drug particles with a mean size of 1 µm. The enhancement of the dissolution rate was significant for the micronized drug particles. The results indicate that the high-gravity process is a promising approach for micronizing drug particles. Introduction In the pharmaceutical industry, a large number of drugs are poorly soluble in water. Roughly 40% of all the investigated compounds failed to develop because of poor bioavailability, which is often associated with low aqueous solubility, thus, a low dissolution rate. There are several methods for enhancing the dissolution rate of poorly water-soluble drugs. Micronization, which reduces the particle size and increases the surface area of particles, is one of the most direct and safest ways to increase the solubility and dissolution rate of these drugs. Common methods for reducing particle size include ball milling, jet milling, and high-pressure homogenization.1-3 There are, however, several drawbacks associated with the “top-down” mechanical comminution processes, such as a broad particlesize distribution due to crushing, physical and chemical instability resulting from disruptions in the crystal lattice, products denatured by exposure to high temperature and pressure, and contamination of the drugs. Viewing the disadvantages of mechanical comminution methods, a “bottom-up” recrystallization method has been developed to generate ultrafine particles and perhaps together with a modification of lattice structure to enhance solubility and dissolution rate. Conventionally, the recrystallization process is performed in a stirred vessel, which would give a broad size distribution and a large mean particle size due to low mixing efficiency. To overcome this problem, several novel techniques have been developed, including the microemulsion technique, supercritical fluid technique, and highgravity technique.4-8 However, disadvantages are associated with each technique. For the microemulsion system, the problems of low yield and contamination by using surfactants and organic solvents have to be solved. The supercritical fluid technique has been widely applied for particle design of pharmaceuticals, cosmetics, and specialty chemicals due to the nontoxicity of CO2 used as a solvent or antisolvent. Nevertheless, the high capital cost and the difficulty in scale-up bound * To whom correspondence should be addressed. Tel.: +886-223620832. Fax: +886-2-23623040. E-mail:
[email protected]. † Chung Yuan University. ‡ National Taiwan University. § Taipei Medical University.
up with a high-pressure system restrict the development and application of this technique. The investigation of the high-gravity technique has become one of the most significant subjects in the field of process intensification. In this technique, gravity force is replaced by a centrifugal force, which is up to several hundred g, to enhance mass-transfer rate and mixing efficiency, leading to a reduction in equipment size and operating cost. Two types of high-gravity equipment, i.e., rotating packed bed (RPB) and spinning disk reactor (SDR), are introduced as novel gas-liquid or liquid-liquid contactors, which have been used in many chemical processes, such as absorption, stripping, distillation, adsorption, and reactive precipitation.9-22 For the liquid-liquid system, studies performed in our laboratory have shown that the micromixing efficiency can be improved considerably by the aid of centrifugal force.23,24 In 1991, Marcant and David25 demonstrated a simplified mixing model for qualitatively predicting the influence of micromixing on precipitation. They found that increasing the mixing intensity would increase the crystallization rate, thus, reducing the particle size in the primary nucleation process. Additionally, in 2002, Cafiero et al.26 estimated the micromixing time and the induction time of BaSO4 precipitation in a spinning disk reactor. They concluded that the micromixing time of reactant streams on the disk surface was shorter than the induction time of nucleation; therefore, small and uniform particles were generated. In our laboratory, nanosized Mg(OH)2 particles were synthesized in an SDR.21 The results indicated that a higher micromixing intensity would reduce the particle size, conforming to the findings of Marcant and David25 and Cafiero et al.26 In addition, silver nanoparticles were successfully synthesized in an SDR via a green chemical process, using environmental-friendly and inexpensive materials of glucose and starch as the reducing agent and protecting agent, respectively.22 Recently, the high-gravity technique has been proven to be useful in the pharmaceutical industry. Oxley et al.6 used an SDR to manufacture pharmaceuticals and found that the particles had a narrow particle size distribution and a mean size of around 3 µm. In addition, the reaction time and the impurity level were significantly reduced when compared with those from a batch process performed in a stirred vessel. In 2004, Chen et al.7 produced nanoparticles of benzoic acid precipitated in an RPB.
10.1021/ie1007932 2010 American Chemical Society Published on Web 08/17/2010
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Figure 2. Particle size distribution of PAS particles prepared at various concentrations of PVP. Other operating variables kept constant are as follows: PAS concentration, 40 g/L; NaOH concentration, 11 g/L; propionic acid concentration, 37 g/L; liquid rate, 0.25 L/min; rotational speed, 2100 rpm.
Figure 1. (a) Schematic diagram of the experimental setup and (b) the circular liquid distributor used in the SDR-L. Table 1. Range of Operating Variables Used in This Study operating variables
range
precipitation in SDR disk diameter (cm) rotational speed (rpm) flow rate of feeding stream (L/min) PAS concentration in the alkaline solution (g/L) PVP concentration in the alkaline solution (g/L) high-pressure homogenization process homogenization pressure (psi) homogenization cycle number
12 and 50 2100 0.25-1.0 40-100 5-20 10000-30000 2-8
The results showed that the particle size decreased with an increase in rotational speed of a packed bed and flow rate of reactants. The particles obtained were as fine as 10 nm in size, and the reduction in size was attributed to the intensified micromixing of reactant streams in an RPB that enhanced nucleation rate while suppressing crystal growth. In 2006, Chen et al.8 prepared cefuroxime axetil particles by an antisolvent precipitation process in an RPB. Amorphous cefuroxime axetil Table 2. Particle Size Distributions of the PAS Particles Precipitated in a SDR at Various PVP Concentrations; Other Fixed Operating Variables Are PAS Concentration (40 g/L), NaOH Concentration (11 g/L), Propionic Acid Concentration (37 g/L), Liquid Rate (0.25 L/min), and Rotational Speed (2100 rpm) particle size (µm) PVP concentration (g/L)
D10
D50
D90
5 10 15 20
3.36 1.80 1.20 1.23
13.6 8.94 6.58 7.18
36.4 19.6 21.5 17.8
Figure 3. SEM micrographs of (a) commercial PAS and (b) micronized PAS produced from the SDR-S operated at PAS concentration of 40 g/L, PVP concentration of 15 g/L, NaOH concentration of 11 g/L, propionic acid concentration of 37 g/L, liquid rate of 0.25 L/min, and rotational speed of 2100 rpm.
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Figure 4. SEM micrographs of the micronized PAS prepared by the SDR-S for the PAS concentrations of (a) 40 g/L, (b) 60 g/L, (c) 80 g/L, and (d) 100 g/L. Other operating variables kept constant are the concentration ratios of NaOH:PVP:PAS (0.275:0.375:1), liquid rate (0.25 L/min), and rotational speed (2100 rpm).
particles of 300 nm with no significant agglomeration were obtained with no dispersant added. The dissolution rate of the recrystallized drug particles was greatly enhanced. Agglomeration of the water-insoluble drug particles, however, is generally observed during a precipitation process because the generated small particles tend to increase the hydrophobic surface. To reduce the agglomeration of particles, dispersants are usually added in a precipitation process.27 In this study, an antisolvent precipitation process proceeded in an SDR, which combined with high-pressure homogenization and freeze-drying, was proposed to generate fine drug particles. The model compound investigated was p-aminosalicylic acid, which is an antibiotic for treatment of tuberculosis. The solubility of PAS is quite low (
