|Title of Invention||
A METHOD FOR MANUFACTURE OF FINE PARTICLES
|Abstract||A method for a manufacture of particles of a desired substance comprising: vibrating a surface (13) at a desired frequency; applying a dispersion having at least a solvent and the desired substance on to or close to the vibrating surface (13) to generate droplets; and applying an antisolvent at near or supercritical conditions to the droplets which results in the desired substance in the form of particles, the solvent being miscible with the antisolvent and desired substance being substantially in the antisolvent.|
METHOD FOR MANUFACTURE OF FINE PARTICLES
BACKGROUND OF THE INVENTION Field of Invention The current invention relates to a method for the production of micro or nanometer size particles by precipitation, wherein dispersion containing the substance of interest is contacted with a supercritical fluid antisolvent under near or supercritical conditions in order to maximize .micro or nanoparticle formation. The invention also provides techniques to control the particle size, particle size distribution and particle morphogy. The invention also includes supercritical fluid coating or composite material particle formation, wherein encapsulation of one substance by amother substance or coprecipitation of more than one substance in the for a of micro or nanoparticles are achieved in the supercritical fluid antisolvent
Background and Prior Art
Nanopartides are of considerable importance in numerous technological applications. Nanopartides of materials in fact exhibit properties significantly different from those of the same material with larger sizes. Some nanostructured material with novel properties indude: fullerenes, zeolites, organic crystals, non-linear optical material, high temperature superconductors, moleular magnetic materials, starbuist deodrimers, piezoelectric materials, shape changing alloys and pharmaceuticals. The novel properties of these nanostruaured materials can be exploited and numerous potential applications can be devdoped by using them in different industries. One such industry where the need for nanopartides is particularly pronounced is the pharmaceutical industry where nanopartides of difffent pharmaceutical materials are used lor designing drug delivery systems' for controlled release and targeting.
Several techniques have been used in the past for the manufcture of nanopartides but tiiese techniques suffer from some inherent limitations, Some of the conventional techniques include: Spray drying, which is one of the well-known techniques for particle formation and can be used to produce particles of 5 μm or less in size. The major disadvantage of this technique is that it requires high temperature in order to evaporate the solvent in use, and this makes it unsuitable for treating blological and pharmaceutical substances. Furthermore, the
final product yield smy be low in case of small-scale applications. Milling can be used to produce particles in the 10 - 50 μm range, but the particles produced by this method have a broad size distribution. Fluid energy grinding can produce particles in the 1-10μm range but this process involve the use of high-velocity compressed air, which leads to electrostatically charged powders. In addition, particle size reduction by this process tends to be more efficient for hard and brittle materials such as salt and minerals, but much less so for soft powders, such as phsomaceuticals and other biological substances. L:yophilization produces partides in the desired range, but with a broad distribution. A main disadvantage of this process is that it employs the use of organic solvents that may be unsuitable for obarmaceutical substances. In addition, control of particle size can also be difficult, and a secondary drying step is required to remove residual solvents. In the case of precipitation of protein particles, not all proteins can be lyophilized to stable products, and the process must be tailored to each protein.
Thus, none of these methods are entirely satisfactory, and it is therefore important to explore alternative methods that will produce particles from 5μm down to as low as 10nm.
Particle Technology Based on Supercritical fluids
One of the first uses of supercritical fluids in particle formation was proposed by Krukonis et al. in 1984 for processing a wide variety of dilficult-to-handle solids. Since then, several experimental studies have been conducted to develop methods for particle formation using this technology. The two primary methods utilizing suercritical fluid technology for particle processing include Supercritical Antisolvent (SAS) Predpitation technique and the Rapid Expansion of Suercritical Solutions (RESS) technique. For many years now, these techniques have been successfully used to produce micropartides of various compounds including difficult to hole explosives (Gallagher et al., 1989), lysozyme, trypsin (Winter et al, 1993), insulin (Yeo et al., 1993; Winfer et al, 1993), prednisolone acetate (US patent 5,803,966), polystyrene HYAFF-11 polymers (Benedetti et d., 1997), dififerent steoids(Larson and King, 1985), and numerous other orgaiuc substances. Other areas of application of supercriticd fluids mclude formation of solvent free, drug loaded polymer micro-spheres for controlled drug release of therapeutic agents (Tom et al, 1992; Mudler and Fischer 1989), production of ultra-fine arid chemicdiy pure ceramic precursors, (Mation et d., 198S a,b, 1987 a,b; Peterson et d. 1985), formation of intimate mixtures of
The Working of the SAS Process
In the SAS process, the supercritcal fluid is used as the antisolvent First the solid of interest is dissolved in a suitable organic solvent Then this solution is introduced into the supercritical fluid using a nozzle. The supercritical fluid dissolves the solvent, precipitating the solid out as fine particles.
The SAS technique can be used to produce particles having a narrow size distribution in the 1-10 μm size range. Unfortunately these techniques cannot produce much smaller particles in the nanometor range. Nanometer size particles are extremely important for many pharmaceutical applications. New applications of nanoparticles of other substances can also
They disclose the use of a commmerical ultrasonic nozzle (Soncnnist, Model 600-1) for the droplet atomization. The sonic waves in this case are created when an energizing gas passes through a resonator cavity at the velocity of sound. The frequency of the sonic waves created is not constant and it is difficult to specify the frequency of the sound waves generated. Trying to vary the sonic energy might interfere with other process conditions and as a result it may not be used as a size control variable.
A major advantage of the present invention over other forms of supercritical fluid particle precipitation techniques is that the sizes of the particles fonned by this technique can be easily controlled by changing the vibraiion intensity of the deflecting surface, which in turn can be controlled by adjusting the input power to the vibrating source. For instance the size control parameters investigate so far in the SAS process are pressure and temperature of the antisolvent, concentration of the dispersion and the flow rate of the dispersion into the supercritical fluid antisolvent. All these parameters axe not robust enough to generate a
pronounces change in particle size. Besides, conflicting results have been obtained by different researchers about the actual effect of these parameters on particle size and distribution and no general trend has been established.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic representation of the apparatus employes for particle production using the SAS-EM technique,
FIG. 2 is a schematic representation of the particle production vessel
FIG. 3 is a resentation of the mechanism for the liquid film disintegration on the horn surface.
FIG. 13 is a representation of average tetracycline particle sizes versus power supply to the horn: (a) number average, and (b) volume average.
FIG. 22 is a representation of volume of long needle shaped Griseofulvin crystals obtained versus power supply.
FIG. 23 is SEM micrographs of spherical shaped polymer encapsulated magnetite nanoparticles obtained from experiments conducted at different input power, using DCM as solvent
FIG- 24 is a TEM micrograph of PLC A encapsulated magnetite particles. The dark and shady regions are due to magnetite particles inside PLGA.
Figure 25. SEM micrographs of tetracycline particles obtained using the SAS-EM technique at 96.S bar, 35oC and at a vibration frequency of 20 kHz.. The nozzle used in this case was a 760 μm stainless steel tube,
DETAILED DESCRIPTION OF THE INVENTION
A particle is a relatively small discrete portion of a given material.
"Desired substance" means
The material comprising of one or more substances of interest.
"Dispersant" means a fluid that helps in dispersing or scattering a material in a medium.
A homogenous or a heterogeneous mixture of the desired substance m one or more suitable solvents with or without dispersants or coreparticles.
A fluid or a combination of fluids, which can dissolve the desired substance in order to form a homogenous solution.
The exterior or the boundary of the horn tip excluding any nozzle surface onto which the dispersion is sprayed.
"Vibrating the surface" means
Moving the surface at a rapid rate by means of an external source.
A material capable of generating vibrations when subjected to applied voltage.
A material capable of generating vibrations when subjected to a change in its state of
"Agglomeration of the particles' means
The particles being clustered together to form a larger mesh or a sphere like structure.
"Collecting the particles in a continuous manner' means
Collection of the produced particles in a manner that does not require stopping the production of particles
"Coreparticles' means particles that are to be coated or surrounded by the desired substance.
"Encapsulated coreparticles' oceans coreparticles being surrounded or coated by the desired substance.
"Medicaments" means substances used in the diagnosis, treatment, or prevention of disease and for restoring, correcting, w modifying organic Actions.
"Morphology of the particle*' means external structural appearance or the form of the particle.
"close to the vibrating surface" means close to the vibrating surface so as to get exposed to atleast one wavelength of vibration Typically one wavelength of vibration with 20Khz frequency in the vessel is about2 cm.
The current from the invention can be practiced either in a batch mode, or in a continuous manner for particle odlectioa Fig. 1 is a schematic of the apparatus used in particle production using SAS-EM Pump I is used to pump CO2 at a constant pressure and at
a desired flow rate. Similarly, pump 4 is used to flow the dispersion at a constant pressure and desired flow rate. Both streams are pumped through individual temperature controlled zones to maintain a desired inlet temperature into the particle production vessel 17. The CO3
biological activity of the protein particles that were exposed to vibration during their formation.
Vibration Intensiiy (Input Power Supply) for Controlling Particle Size
The SAS_EM technique was used to produce Griseofulvin particles of different sizes. The results of the different precipition runs have been summarized in Table 4. Precipitation of GF was carried out using two different solvemts,dichloromethane (DCM) and Tetrahydrofiiran (THF), All SAS-EM particle production experiments were carried out at
When there was no vibration (i,e similar to a SAS experinents) PLGA encapsulated magnetite particles having a mean size of 1.7 μm were obtained as shown in Figure 23a. Figure 24 is a TEM micrograph of the obtained composite particles clearly showing the magnetite particles encapsulated in the polymer matrix. When the power supply to the vibration source was increase to 60 W, there was a reduction in mean particle size to 0.7 μm as shown in Figure 23b. With increase in the power supply there is a further reduction in mean particle size to as much as 0.4 μm as shown in Figure 23c,
1. A method for a manufacture of particles of a desired substance comprising:
(a) vibrating a surface at a desired frequency;
(b) applying a dispersion having at least a solvent and the desired
substance on to or close 10 the vibrating surface to generate droplets,
(c) applying an antisolvent at near or superitical condition to the
droplet which results in the desired substance in the form of particles,
the solvent being miscible with the antisolvent and the desired
substance being substantially insoluble in the antisolvent
2. The method as recited in claim 1 including changing the size of the particles
by changing intensity of vibration of the surface,
3. The method as recited in claim 1 including charging the distribution of the
particles by clanging intensity of vibration of the surface.
4. The method as recited in claim 1 wherein the vibration of the surface is by a
5. The method as recited in claim 1 wherein the vibration of the surface is by a
6. The method at recited in claim 1 including reducing agglomeration of the
particles by changing the intensity of vibrations the surface.
7. The method as recited in claim 1 including collecting the particles in a
8. The method as recited m claim 1 wherein the dispersion containing said
desired substance is applied continuously.
33, The method as recited in claim 30 wherein the vibration of the surface is by a piezoelectric means.
34. The method as recited in claim 30 wherein the vibration of the surface is by a
magneto restrictive means.
35. The method as recited claim 30 including reducing agglomeration of the
particles by changing the intensity of vibrations of the surface.
36. The method as recited in claim 30 including collecting the particles in a
37. The method as recited in claim 30 wherein the antisolvent being selected from
the group consisting of carbon dioxide, propane, butane, isobutene, nitrous
oxide, sulfur hexafluoride and trifluoromethane or a combination thereof
38. The method as recited in claim 30 wherein the desired substance are
39. The method as recited in claim 30 including:
(i) measuring the particle size; and
(ii) changing the particle size by changing the intensity of the vibrations of the surface.
40. The method as recited in claim 30 including changing the morphology of the
particle by changing intensity of vibration of the surface.
|Indian Patent Application Number||932/CHE/2003|
|PG Journal Number||40/2007|
|Date of Filing||14-Nov-2003|
|Name of Patentee||AUBURN UNIVERSITY|
|Applicant Address||309 Samford Hall Auburn University, AL 36849-5176|
|PCT International Classification Number||B01D 11/04|
|PCT International Application Number||PCT/US02/07577|
|PCT International Filing date||2002-03-12|