During the past decades, producing micro- and nano-particles of drugs is gaining attention since it is possible to modify the solubility of insoluble drugs in the gastronical fluids significantly. Respect to this fact, in the current investigation, rapid expansion of supercritical carbon dioxide (RESS) for fabricating the micro-particles of cetirizine is investigated. In this way, different operational conditions including extraction pressure (160 - 220 bar), extraction temperature (308 - 328 K), nozzle length (1 - 8 mm), and nozzle diameter (450 - 1700 μm) are examined. The performed experiments revealed that among the examined operational conditions, nozzle diameter and extraction pressure introduce significant effects on the reduction of particle size compared with the other examined parameters. The results revealed that it is possible to reduce the cetirizine particles from 98.52 μm to 0.53 μm using RESS. In addition, scanning electron microscopy (SEM) analysis is performed to investigate the effect of different operational parameters on the morphology of the particles of cetirizine. The results demonstrate that RESS not only is able to reduce the particle size of the cetirizine, but also is able to change the morphology of the cetirizine particles from the irregular shape to spherical form.
In the science of drug and pharmaceutical production, high solubility rate of the drug powders is an essential parameter helping the pharmaceutical developers toward more effective products. Unfortunately, there are many kinds of drugs exhibiting poor solubility in water and gastronical fluids bounding their application. Poorly water-soluble drug candidates often merge from contemporary drug discovery programs, and present formulators with considerable technical challenges [
One of the proposed techniques to overcome this problem is reducing the particle size of the particles. In more details, it has been proven that dissolution rate is a function of the surface area of the particles. On the other hand, solubility, is a direct function of total surface area for a dispersed phase, and is inversely related to particle size according to the expression, Sv = 6/d, where Sv is the specific surface area and d is the average particle diameter [
In the way of reducing particle size, several techniques have been reported that the common technique for the preparation of micron-size drugs is the mechanical comminution (e.g., by crushing, grinding, and milling) of previously formed larger particles. Although, these techniques are successful in some extend, they introduce several drawbacks (e.g. high amount of energy and alteration of drug substance properties and surface properties in a mainly uncontrolled manner) [
In this way, during the past two decades, the researchers were seeking for methods which produce drug particles in micron- or nano-levels (with narrow particle size distribution), and the drug particles experience no changes in their physicochemical properties. One of the successful methods for producing high-quality drug powders with narrow particle size distribution is supercritical fluid (SCF) based technologies [
Although all the parameters are important to obtain the best results, nozzle and its characterization have a critical role in the RESS process. In many studies, capillary nozzles or laser-drilled nozzles were applied to manufacture micron- and submicron-level particles [
Since the production of laser drilled nozzles is costly and needs unique technologies, a new kind of nozzle was designed and constructed by the coauthors whose applicability and functionality were established previously [
In this way, since there is no report about the micronization of the cetirizine particles using RESS methods based on the best knowledge of the authors, in the current investigation cetirizine is selected as the model drug. For this purpose, several operational parameters including extraction pressure (160 - 220 bar), temperature (308 - 328 K), nozzle length (2 - 11 mm) and diameter (450 - 1700 μm) are examined to find if RESS process is feasible to fabricate micron- or submicron-level particles in size. Cetirizine is a non-sedating antihistamine with molecular weight of 388.888 g∙gmol−1 which works similarly to the other second generation antihistamines, loratadine (Claritin), fexofenadine (Allegra) and azelastine (Astelin). Histamine is a chemical that is responsible for many of the signs and symptoms of allergic reactions, for example, swelling of the lining of the nose, sneezing, and itchy eyes.
The RESS experiments were performed using a homemade apparatus rated for maximum operating temperature and pressure of 353 K and 400 bar, respectively (see
The pressurized CO2 then entered into an extraction vessel (180 ml) fulfilled with a basket including the powder of cetirizine packed with glass beads for preventing channeling phenomenon. In more details, a specific amount of cetirizine powder was mixed with glass beads to enhance the contact surface between the cetirizine powder and supercritical carbon dioxide enhances the solubility of cetirizine in supercrtic.al and preventing channeling of high-pressure carbon dioxide through the bed. The temperature of the surge tank and equilibrium vessel were controlled using a hot water jacket surrounded these sections. In addition, the temperature of the system was sensed by a PT-100 thermocouple control the temperature using PID controlling protocol with accuracy of 0.1˚C. The noteworthy point is that the outlet port of the equilibrium cell was covered by glass wool to ensure that during the expansion of the supercritical solution through the nozzle no undissolved drug particles will carry over the SC-CO2 flow. After preparing the basket containing the drug powder and glass bead, it was then placed into an extraction vessel and was held in the desired conditions for about 3 h to ensure that complete equilibrium has been obtained. After that, the equilibrated solution was then expanded by a pre-heated fine needle valve into a nozzle. The fine needle valve was pre-heated to compensate the heat loss because of the Joule Thomson effect and to prevent the nozzle clogging during the expansion. The precipitated particles were collected on the stubs and analyzed by a SEM to monitor the particle size and morphology.
Cetirizine was kindly supplied from Alma Concept Company (France), and used as received. In addition, the CO2 (99.9% < purity) was supplied from Abughadareh Gas Chemical Company, Iran. The mean particle size of the original cetirizine was about 98.52 μm, respectively (see
The morphology and size of the precipitated particles were examined using scanning electron microscopy (SEM) (S360-CAMBRIDGE). In brief, prior to examine the samples by a SEM the precipitated cetirizine particles were collected on the conductive stubs which were then coated by a sputter-coater (SC-7640-Polaron) with Pd-Pt in the presence of argon (99.9% < purity) at room temperature for a period of 100 s under an accelerating voltage of 20 kV. The mean particle size of the precipitated particles was calculated by counting about 100 particles, arbitrarily selected. The mean particle size was calculated by a written program which randomly selected 100 particles of the SEM images.
The structure of the new nozzle is illustrated in
Also the swirled channel enhances the chance of the formation of spherical form particles which could be helpful to improve the morphology of particles. In the entrance of the nozzle, SC-CO2 is introduced through the spiral channel, so the fluids can be swirled out of the nozzle. In this kind of nozzle instead of the usual diameter, the effective nozzle diameter has been defined as follows:
where SEffective = SShell − SInside. The calculated effective diameters for the experiments are given in
In the current investigation, 12 different experiments were performed to find the effect of different operational parameters including extraction pressure (160 - 220 bar), extraction temperature (308 - 328 K), nozzle length (2 - 11 mm) and nozzle diameter (450 - 1700 μm).
Molecular formula | CAS number | Critical pressure (bar) | Critical temperature (K) | Acentric factor | Average molecular weight (g∙gmol−1) | Structure |
---|---|---|---|---|---|---|
C21H25ClN2O5 | 83881-51-0 | 17.50a | 1025.1a | 0.783b | 388.888 |
aThese properties are estimated using Joback method (Ref. [
Constant diameter (mm) | Variable diameter (mm) | Effective diameter (μm) |
---|---|---|
5.4 | 5.38 | 450 |
5.4 | 5.36 | 650 |
5.4 | 5.32 | 900 |
5.4 | 5.30 | 1000 |
5.4 | 5.28 | 1200 |
5.4 | 5.12 | 1700 |
In the first stage of this investigation, the effect of extraction pressure in the range of 160 bar to 220 bar on the size and morphology of the cetirizine particles were investigated while the other operating conditions including extraction temperature (318 K), nozzle length (5 mm) and nozzle diameter (1700 μm) were kept constant. The obtained results revealed that as the pressure increases from 160 bar to 220 bar, the mean particle size of the precipitated cetirizine particles reduces from 12.68 μm to 7.60 μm. This observed trend can be described based on the solubility of cetirizine in the supercritical carbon dioxide (see
been reported that an increase in the operating pressure from 160 to 400 bar at all the isotherms resulted in an increase in cetirizine solubility. This observed trend was related to this fact that as the pressure increases the intermolecular space between the CO2 molecules reduces consequently increases the density of supercritical carbon dioxide and interactions between the cetirizine and CO2 molecules. As results the solubility of cetirizine in the supercritical carbon dioxide enhances consequently results higher super-saturations in the fluid upon expansion. According to classical theory of nucleation, higher super-saturation leads higher nucleation rate and the particle volume is inversely proportional to the nucleation rate; our above results appear to agree with simple theoretical predictions [
In the second stage of this study, the effect of extraction temperature in the intervals of 308, 318 and 328 K was investigated while the other operational conditions including extraction pressure (220 bar), nozzle length (5 mm) and nozzle diameter (1700 μm) were kept constant during the experiments. The obtained results demonstrated that there no clear trend for the effect of extraction temperature on the particle size of precipitated particles was observed. By the way, in the previous study [
In the third series of experiments, the effect of nozzle length on the mean particle size of the precipitated particles was investigated ranging it between 2 - 11 mm while the other operational conditions were held constant as demonstrated in
Similarly, Wang et al. [
No. | Extraction pressure (bar) | Extraction temperature (K) | Nozzle Length (mm) | Effective Nozzle Diameter (mm) | Mean particle diameter (μm) | Standard deviation (μm) | 95% confidence interval (μm) |
---|---|---|---|---|---|---|---|
Effect of extraction pressure | |||||||
1 | 160 | 318 | 5 | 1700 | 12.68 | ±3.31 | 9.37 - 15.99 |
2 | 180 | 318 | 5 | 1700 | 10.98 | ±3.01 | 7.97 - 13.99 |
3 | 200 | 318 | 5 | 1700 | 8.32 | ±2.91 | 5.41 - 11.23 |
4 | 220 | 318 | 5 | 1700 | 7.60 | ±2.50 | 5.10 - 10.10 |
Effect of extraction temperature | |||||||
5 | 220 | 308 | 5 | 1700 | 5.15 | ±2.15 | 3.00 - 7.30 |
6 | 220 | 318 | 5 | 1700 | 7.60 | ±2.50 | 5.10 - 10.10 |
7 | 220 | 328 | 5 | 1700 | 9.42 | ±4.23 | 5.19 - 13.65 |
Effect of nozzle length | |||||||
8 | 220 | 308 | 2 | 1000 | 2.81 | ±1.10 | 1.71 - 3.91 |
9 | 220 | 308 | 5 | 1000 | 3.67 | ±1.56 | 2.11 - 5.23 |
10 | 220 | 308 | 8 | 1000 | 5.15 | ±2.15 | 3.00 - 7.30 |
11 | 220 | 308 | 11 | 1000 | 5.25 | ±2.33 | 2.92 - 7.58 |
Effect of effective nozzle diameter | |||||||
12 | 220 | 308 | 5 | 450 | 0.52 | ±0.21 | 0.31 - 0.73 |
13 | 220 | 308 | 5 | 650 | 0.72 | ±0.33 | 0.39 - 1.05 |
14 | 220 | 308 | 5 | 1000 | 3.67 | ±1.56 | 2.11 - 5.23 |
15 | 220 | 308 | 5 | 1700 | 5.15 | ±2.15 | 3.00 - 7.30 |
precipitated particles of the cetirizine experienced narrow particle size distribution with more spherical shape morphology (see
At the last series of experiments, the effect of nozzle diameter on the size of the cetirizine particles was investigated by ranging this parameter between 450 μm to 1700 μm. The obtained results revealed that increasing the nozzle diameter from 450 μm to 1700 μm leads to an increase in the mean particle size of the precipitated particles from 0.52 μm to 5.15 μm (see
Finally, examining the SEM images not only revealed that particle size distribution of the precipitated cetirizine particles become narrower but also the particles move toward more spherical morphology (see
In the current study, the efficiency and applicability of RESS process for producing micro-size particles of cetirizine were investigated. For this purpose, a systematic series of experiments was performed to find the optimum operational conditions of extraction pressure and temperature, nozzle length and nozzle diameter leading to producing the micron-size particles of cetirizine while carbon dioxide was selected as the supercritical fluid. The obtained results demonstrated that an increase in the extraction pressure leads to a reduction in the particle size, while for other three parameters including nozzle length, extraction temperature and nozzle diameter, an increase leads to an increase in the size of precipitated particles. Also, the obtained results demonstrated that among the examined parameters, extraction pressure and nozzle diameter introduced the highest influence on the reduction of the cetirizine particle diameter. Furthermore, the SEM analysis revealed that the RESS process not only is able to reduce the particle size but also is able to modify the particle morphology from irregular shape to somehow spherical shape. Totally, based on the obtained results it can be concluded that RESS process is an applicable and feasible tool for producing the micron- and submicron-size particles of poorly soluble cetirizine particles.
Ali Zeinolabedini Hezave,Mostafa Lashkarbolooki,Feridun Esmaeilzadeh, (2015) Micronization of Cetirizine Using Rapid Expansion of Supercritical Carbon Dioxide. Open Access Library Journal,02,1-14. doi: 10.4236/oalib.1101277