Nano particle engineering processes and applications

Kirupakar.B.R

Nanotechnology is considered to be one of the most important emerging technologies worldwide. It is an innovation driver for many sectors of industry.

Nanotechnological applications for product manufacture involve the addition of substances with a particle size of between 0.1 and 100 nanometres (10^-9 metres). The prefix "nano" (Greek for dwarf) describes a spatial dimension. One nanometer is equivalent to a billionth of a meter. This is about the length of five to ten atoms in a row. A nanometer is to a meter what a football is to the entire earth. Through the controlled manufacture and structuring of materials, it allows the creation of completely new properties in product development. The term nanotechnology is used to describe materials, structures and technologies involving the creation or presence of a spatial dimension smaller than a hundred nanometers. Various engineering processes like High pressure homogeneiser, Wet milling, Super critical fluid technology, precipitation with compressed fluid antisolvent, Rapid expansion from liquefied gas solution and homogenization, cryogenic spray process, spray freezing into liquid process were employed, based on the drug properties and requirement of nanoparticles characters.

Why nanoparticle?

High-throughput screening technologies in drug discovery present an efficient way to find new powerful substances. But in recent years it has become evident that the development of new drugs alone is not sufficient to ensure progress in drug therapy. Poor water solubility of drug molecules, insufficient bioavailability, fluctuating plasma levels or high food dependency are the main and common problems. Major efforts have been spent for the development of customized drug carriers to overcome the disappointing in vivo fates of the drug. For carriers non-toxicity (acute and chronic), sufficient drug loading capacity, possibility of drug targeting, controlled release characteristics, chemical and physical storage stability (for both drug and carrier) and feasibility of scaling up production with reasonable overall costs are required.^1,2.3. Colloidal carriers have attracted the main interest because they are promising systems to fulfill the requirements mentioned above. But in the first place, nanosized carriers are treated as hopeful means to increase the solubility and therefore the bioavailability of poorly water-soluble active ingredients belonging to the classes II and IV in the biopharmaceutical classification system (BCS)

The common characteristic of all colloidal carriers is the sub micron particle size. Nanometric carriers might differ in materials, composition, drug loading and application Spectrum. Corresponding to the broad diversity of colloidal carriers, the possible administration routes vary. Solid particular systems are limited to either the subcutaneous or intramuscular routes of administration, intravenous administration may result in vaso-occlusion As upper limit for intravenous administration to avoid embolism in blood vessels no particles above five micrometers and only few particles between one and five micrometers are accepted. Dermal, peroral, parenteral, ocular and pulmonary applications are known for nanocarriers.

Engineering processes:

High Pressure Homogenization ⁴

High pressure homogenization is mechanical process to prepare nanometer size particle in suspension containing poorly water soluble drugs. The principle of forming nanosuspensions is the cavitation forces created in high pressure homogenizer like piston-gap homogenizer.The particle size of nanosuspension depends on the hardness of the drug substance, processing pressure and number of cycles applied.

Wet Milling⁴

Wet milling is an attrition process in which large micron size drug crystals are wet milled in the presence of grinding media and a surface modifier.⁵ The rigid grinding media is typically spherical in form, having an average size less than about 3 mm. The grinding media used in the process include zirconium oxide, such as 95% ZrO stabilized with magnesia, zirconium silicate, and other media, such as glass grinding media stainless steel, titania, alumina, and 95% ZrO stabilized with yttrium⁵. The surface modifies include various polymers, low molecular weight oligomers, natural products and surfactants, such as polyvinyl pyrrolidone, pluronic F68, pluronic F108, and lecithin. The particle size of the starting materials is typically less than 100 µm and was micronized by a jet milling process. The particle size of the final products is less than 400 nm

High-energy-generated shear forces and the forces generated during impaction of the milling media with the solid drug provide the energy to fracture drug crystals into nanometer-sized particles. Milling efficiency is dependent on the properties of the poorly water-soluble drug, medium and stabilizer. Poorly water-soluble drugs in the nanoparticle suspension are reported to be in a crystalline state due to a low energy used in the milling process.

Supercritical fluid technology ⁴

A single-step supercritical fluid process would be an excellent method, where microparticles and nanoparticles can be formed directly from drug solution. Two processes that use supercritical fluids for particle formation have been developed to improve solubility and dissolution of poorly water soluble drugs. They are rapid expansion of supercritical solutions (RESS) and precipitation with a compressed antisolvent (PCA), which is also referred to as the supercritical antisolvent (SAS) method or the solution enhanced dispersion by the supercritical fluids (SEDS) process.

In thePCA process, the COB2B expands the solvent and the solvent dissolves in COB2B, thus lowering the solvent strength, resulting in precipitation of poorly water soluble drug into a micronized powder. In the RESS process, the solubility of the solute in the COB2B must be sufficient at a given temperature and pressure to produce adequate yields of the micronized powder. The drug solubility in supercritical COB2B can be altered by manipulating the temperature and pressure, and hence, the density of the compressed gas or by adding a co-solvent.

Precipitation with Compressed Fluid Antisolvent (PCA)⁴

 In the PCA process, COB2B is used as an antisolvent. Poorly water-soluble drug and/or polymer solutions are atomized into a chamber containing compressed COB2B. As the two liquids collide, intense atomization into micronized droplets occurs. Because the solvent(s) must be miscible with the compressed fluid COB2B, subsequent drying of the micro droplets occurs as the solvent(s) and COB2B    mix. Microparticles and nanoparticles are formed after drug precipitation caused by two way mass transfers: extraction of the organic solvent into COB2B and COB2B diffusion into the droplets. The mass transfer is dependent upon atomization efficiency and the dispersing and mixing phenomena between the solution droplet and the compressed fluid COB2B.

Rapid Expansion from Liquefied-Gas Solution and Homogenization

(RELGS/RELGS-H/RESAS)⁴

A process based on supercritical fluid, rapid expansion from supercritical to aqueous solution (RESAS), which produces stable nanosuspensions of poorly water-soluble drugs. The principle of this process is to induce rapid nucleation of the supercritical fluid dissolved drugs in the presence of surface modifying agents resulting in particle formation with a desirable size distribution in a very short time. Phospholipids or other suitable surfactants are integrated into the process as a solution or dispersion in the supercritical fluid . The surface modifying agents serve to stabilize the newly formed small particles and suppress any tendency of particle agglomeration or particle growth while they are being formed. While very rapid precipitation is a characteristic of precipitation of solutes from supercritical fluids, the rapid intimate contact with the surface modifier is achieved by having the surface modifiers dissolved in the supercritical fluid containing the dissolved drug. A rapid intimate contact between the surface modifier and the newly formed particle substantially inhibits the crystal growth of the newly formed particle.

Cryogenic spray Process⁴

The cryogenic spray process is an attractive alternative to form microparticles and nanoparticles of poorly water-soluble drugs. Spray-freezing into vapor processes have been developed. Both halocarbon refrigerants and liquid nitrogen have been used as cryogenic media in conventional spray-freezing into vapor processes. In these procedures, the feed solution is atomized through a nozzle positioned at a distance above the boiling refrigerant. The droplets gradually solidify while passing through the cold halocarbon vapor, and freeze completely as contact is made with the boiling refrigerant liquid.

Gombotz et al and Gusman and Johnson have developed spray-freezing into nitrogen vapor processes for the purpose of using an inert cryogen to capture frozen drug particles following atomization . Because atomization occurs in the nitrogen vapor above the liquid gas, the solution droplets gradually agglomerate and solidify while passing through the vapor phase then settle onto the surface of the cryogenic liquid. As a result of droplet agglomeration, broad particle size distributions and non-micronized dry powders may result. Recently, a new cryogenic spray process, spray freezing into liquid (SFL) process was developed to overcome such problem

Spray Freezing into Liquid (SFL) Process⁴

SFL is a cryogenic atomization process in which either an aqueous, organic or aqueous-organic co-solvent solution, aqueous-organic emulsion, or suspension containing an drug and pharmaceutical excipient(s) is atomized directly into a compressed liquid, such as compressed fluid COB2B, helium, propane, ethane, or the cryogenic liquids including nitrogen, argon, or hydrofluoroethers. The SFL process utilizes the atomization of a feed solution drugs and/or excipient(s) directly into a cryogenic liquid to produce frozen nanostructured particles. The frozen particles are then lyophilized to obtain dry, free flowing micronized powders. Because liquid-liquid impingement occurs between the pressurized feed solution exiting the nozzle and cryogenic liquid, a high degree of atomization is achieved by spraying directly into the cryogenic liquid as opposed to spraying into the vapor phase above the cryogenic liquid. Ultra-rapid freezing rates are achieved because of the low temperature of liquid nitrogen and the formation of high-surface area droplets. The ultra-rapid freezing rates prevent the phase separation of solutes within the feed solution and induce formation of amorphous structures. The high degree of atomization and ultra rapid freezing rate led to amorphous nanostructured particles with high surface areas, enhanced wetting and significantly enhanced dissolution rates.

SFL processed frozen powders can be dried by the atmospheric freeze-drying (ATMFD) technique, which uses cryogenic air to fluidize the powder and facilitating mass transfer rates in solvent sublimation. ATMFD is a scalable freeze-drying process that does not require the use of vacuum to sublime solvents. Thus, scalability issues due to vacuum limitation in lyophilization are eliminated with ATMFD. Therefore, large micronized SFL powder batches can be produced. The engineered SFL micronized powders can be used for different delivery systems. If the dissolution enhancement of poorly water soluble drug is desired, the poorly water soluble drug could be engineered within an excipient matrix for immediate release. SFL micronized powders have been compressed into a tablet for oral delivery The ability to stabilize nanostructured high surface area drug powders in high glass transition temperature (TBgB) formulations and to maintain rapid dissolution rate of SFL micronized powders in the tablet formulation offers great promise for pharmaceutical development and manufacturing to improve dissolution rates of poorly water soluble drugs.

Solvent evaporation process-Evapoartive precipitation into aqueous solution (EPAS) process ⁴

Another new nanoparticle formation process, evaporative precipitation into aqueous solution (EPAS) is developed.  EPAS process utilizes rapid phase separation to nucleate and grow nanoparticles and microparticles of poorly water-soluble drugs. Poorly water soluble drug is first dissolved in a low boiling liquid organic solvent. This solution is pumped through a tube where it is heated under pressure to a temperature above the solvent’s normal boiling point and then sprayed through a fine atomizing nozzle into a heated aqueous solution. A stabilizing surfactant is added to the organic solution, the aqueous solution, or both to optimize the particle formation and stabilization. The nozzle is immersed into the aqueous solution to ensure that the nucleating drug particles contact the hydrophilic stabilizing surfactant rapidly, inhibiting crystallization and growth of the drug particles. The stable aqueous drug suspension is dried by a variety of techniques including ultra rapid freezing in conjunction with lyophilization, or spray drying. The stabilization of the drug particles with water soluble stabilizers in the aqueous suspensions facilitates dissolution rates of the final powder after drying. The rapid evaporation of the heated organic solution in EPAS results in fast nucleation leading to amorphous nanoparticle suspensions. A variety of hydrophilic stabilizers were found to diffuse to the surface of the growing particles rapidly enough to prevent growth of the nanoparticles.

Nanoparticle characterization:

The crystallinity greatly impacts the solubility and dissolution rate of poorly water soluble APIs. Powder X-ray diffraction (XRD) can be conducted using the X-ray diffractometer to study crystallinity of the particle. The powders produced by nano technique exhibited very little crystallinity, in contrast with the significant crystallinity for powders made by the conventional lyophilization process.

A field emission scanning electron microscope is used to examine the surface morphology of each sample powder and surface area analyzer is used to determine surface area per unit powder mass. The particle size distribution of the sample powders can be studied by laser light diffraction using a Malvern Mastersizer

The contact angle can determined by measuring the tangent to the curve of the droplet on the surface of the compact using a Goniometer Residual organic solvent content in the SFL powders can be determined using a gas chromatograph. As an estimate for the size of the particles can be determined by photon correlation spectroscopy, laser diffraction  ⁶

Nanotechnology - Applications, Trends and Risks

Despite the widespread use of this technology, there are still unanswered questions from the risk assessment angle. Many people already see nanotechnology as the key technology of the 21^st century. However, the question is increasingly being raised whether the promised benefits of new products with nanotechnology might not also be linked to unknown risks. The behavior of nano particles applied to the skin has been well investigated in the case of titanium dioxide and zinc oxide. All the findings presented at the expert meeting showed that the nano particles do not penetrate healthy skin cells. They are mainly distributed over the skin surface. They reach deeper layers via the hair follicles (root sheaths) where they remain for some time. Hair growth then transports the nano particles back to the surface. It was observed that nano pigments penetrate more deeply when the skin has micro injuries. On the risk issue the experts came to the conclusion that, at the present time, there are no indications of a specific "nano toxicology". In some consumer products nano-sized particles are used because of their physical and chemical properties. In the case of packaging their ability to act as barriers to oxygen, carbon dioxide and water is important or they are utilised as sunscreens or to improve mechanical and thermal properties. For instance, specific nano compounds are used in the plastic polyamide. The probability that these particles migrate to the packaged food is deemed to be very low as these coatings are on the outside. Other packagings are vacuum-coated with nano layers of aluminium or silicon oxide. It is not yet clear whether particles are released from inorganic coatings of this kind.

Nanotechnology has already been used for several decades in varnishes. The small particles are bound there in a mechanically active form. Other application areas are antimicrobial coatings for kitchen appliances and textiles modified with nano particles.  Antimicrobial silver nano particles are used in shoe soles and in some clothing items. For the investigation and detection of nano particles, the parallel use of several analytical methods is recommended at present. There are many open questions from the risk assessment angle. The next challenge is to establish the suitable test strategies for identifying health risks. ⁷

Nano-products with high surface area-to-volume ratios are more sensitive to impurities and micro contamination during processing than larger geometry products. New manufacturing methods, materials and processes generally have the same concerns that previously existed for advanced technologies (e.g. cleanliness, contamination, yield, reliability etc.) However, there are additional concerns regarding health and the environment, including nanoparticle exposure during manufacturing, shipment, and product use.  surface analysis can make towards problem solving during the manufacture and reliability characterization of new materials. These techniques include: SEM, AFM, XPS, SIMS, TOF-SIMS and Auger electron spectroscopy along with their relative strengths and weaknesses with regards to sensitivity, information depth and analytical dimensions.

The continuous improvement of analytical methods is providing increasingly detailed insights into the world of such miniscule structures and is improving our understanding ⁸

Infrastructure Requirements

A wide range of production capabilities, training and facilities are required as part of the creation of an infrastructure that will nurture nanotechnology and provide the basis for industrial development. For example, mathematics, computer modelling and simulation skills will be essential as well as an understanding of tools and standards. Frontier research requires advanced instrumentation to be available across the board; from the level of individual laboratories to national facilities. There is also a need for research on state-of-the-art instruments and their deployment

Key issues are:

i)The production of, or access to specialist materials

ii)The adoption of advanced manufacturing processes

iii)Access to specialist tools needed for manufacturing, test, assembly and inspection

iv)The installation of ultra-clean manufacturing facilities

v)The provision of adequate training facilities for the development of skilled manpower

It is worth noting that business opportunities will exist at all stages of development of the new technology, including the provision of the basic requirements⁹.

Conclusion:

The use of nano particles is by no means as new as some of the spectacular products on the market would have us believe. Nanotechnology already arrived on the scene in consumer products, even if it wasn’t explicitly labelled as such, decades ago in varnishes and medicinal products. Nano particles from titanium dioxide or zinc oxide have also been used in cosmetics for some time as UV filters.

In addition, an amorphous structure, high surface area and increased wettability of the flowable technology is an effective particle engineering process for pharmaceutical development and manufacturing to improve dissolution rates of poorly water soluble APIs for oral delivery systems.

References:

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2.  G. M. Barratt. Therapeutic applications of colloidal drug carriers. Pharm. Science and Technol. Today 3:163-169 (2000).

3. P. Couvreur, C. Dubernet, and F. Puisieux. Controlled drug delivery with nanoparticles: current possibilities and future trends. Eur. J. Biopharm. 41:2-13 (1995).

 4. A nanoparticle engineering process: spray-freezing into liquid to enhance the dissolution of poorly water soluble drugs by Jiahui Hu, B.S. (Pharm.) The University of Texas at Austin August, 2003

5.  Bakatselou, V., Oppenheim, R.C., and Dressman, J.B., 1991. Solubilization and wetting effects of bile salts on the dissolution of steroids. Pharm. Res. 8,1461-1469.

6.  Lipid nanodispersions as drug carrier systems -a physicochemical characterization Dissertation zur Erlangung des akademischen Grades doctor rerum naturalium (Dr. rer. nat.)

7. An expert meeting at the Federal Institute for Risk Assessment (BfR) on 28 March 2006 examined current questions on products containing nano particles and the risks for consumers

8. Analytical Methods for Nanotechnology.A. Mowat, J. Moskito, I Ward and A. Hartzell Evans Analytical Group, US

9. Opportunities for Industry in the Application of Nanotechnology by Kai Wu accessed in internet on April 25 2007.

About Author:

Mr.Kirupakar .B.R earned his master degree on Pharmaceutics in 2000 from The Ramakrishna institute of paramedical sciences affiliated to The Tamilnadu Dr.MGR Medical university.( India ) . He is working for Strides arcolab limited as Senior Executive. He have great interest in Nanotechnology.