What is the difference between nanocrystal and nanoparticle

In contrast to high pressure homogenization, it is a low energy milling technique. Smaller or larger milling pearls are used as milling media. The pearls or balls consist of ceramics cerium or yttrium stabilized zirconium dioxide , stainless steel, glass or highly crosslinked polystyrene resin-coated beads. Erosion from the milling material during the milling process is a common problem of this technology.

To reduce the amount of impurities caused by erosion of the milling media, the milling beads are coated Bruno et al Another problem is the adherence of product to the inner surface area of the mill consisting mainly of the surface of the milling pearls and the surface of the mill itself.

There are two basic milling principles. Either the milling medium is moved by an agitator, or the complete container is moved in a complex movement leading consequently to a movement of the milling media.

The milling time depends on many factors such as the surfactant content, hardness of the drug, viscosity, temperature, energy input, size of the milling media.

The milling time can last from about 30 minutes to hours or several days Merisko-Liversidge et al This technology is an important particle size reduction technology which is proven by four FDA-approved drugs using it, which will the subject later in this text.

The Microfluidizer technology can generate small particles by a frontal collision of two fluid streams under pressures up to bar Bruno and McIlwrick This leads to particle collision, shear forces and also cavitation forces Tunick et al The collision chamber can be designed in two shapes, being either Y-type or Z-type.

Surfactants are required to stabilize the desired particle size. Unfortunately, a relatively high number of cycles 50 to passes are necessary for a sufficient particle size reduction. SkyePharma Canada Inc. It is the production of nanoparticle suspensions in water at room temperature.

A drug powder is dispersed in an aqueous surfactant solution and subsequently forced by a piston through the tiny homogenization gap with pressures ranging up to bar, typically to bar Figure 5. The width of the homogenization gap, depending on the viscosity of the suspension and the applied pressure, ranges from approximately. Formation of gas bubbles occurs because the water starts boiling at room temperature. These gas bubbles collapse immediately when the liquid leaves the homogenization gap being again under normal air pressure of 1 bar.

This phenomenon of formation and implosion of the gas bubbles is called cavitation resulting in shockwaves. The drug particles are reduced in size due to high shear forces, turbulent flow and the enormous power of these shockwaves Muller et al Of course, the use of water can have disadvantages, eg, hydrolysis of water-sensitive drugs and problems during subsequent drying steps such as the removal of too much water.

When applied to drugs with a low melting point, the drying process may quire expensive techniques like lyophilization.

Scanning electron microscopic picture of a nanosuspension prepared with high pressure homogenization. The technology uses dispersion media with a low vapor pressure and optionally homogenization at low temperatures. The cavitation in the homogenization gap is very little or nonexistent. The remaining shear forces, particle collisions and turbulences are sufficient to achieve nanoparticles. It is possible to carry out the whole process in nonaqueous media to protect drugs from hydrolysis.

In order to give a complete overview of the available technologies the following methods are also available. Drug nanocrystals with a size of about 50 nm and below are distinctly smaller than the wavelength of the visible light, and so the nanosuspensions are translucent. Among other technologies, the following supercritical fluid methods are mentioned for reasons of completeness only. All nanocrystals in the first four products were produced using the pearl mill technology by Elan Nanosystems.

Prerequisite was the availability of production facilities at sufficiently large scale. SRL is a macrocyclic immunosuppressive drug with a molecular weight of SRL is being used mostly in a combination with cyclosporine or steroids to avoid organ rejection in patients after a kidney transplant.

In cardiology SLR is used because of its antiproliferative effect to avoid a reoccurring constriction restenosis caused by a hyperplasia of the inner vascular after implantation of a stent into the vessels around the heart. The mechanism of action of SLR is different from cyclosporine and tacrolimus. SLR inhibits several cytokine induced signal transduction pathways by complexing the mTOR mammalian Target of Rapamycin protein, which is a kDA phosphatidyl 3 kinase. Therefore the subsequent activation and the protein synthesis of the S6-Kinase p70SK6 is not triggered and the activation of the ribosomal protein S6 does not occur.

The inhibition of mTOR circumvents the activation of the p34cdc2 kinase and thus the complexation with Cyclin E. This results in an inhibition of the T-cell transfer from the G1-phase to the S-phase of the cell-cycle Sehgal It is available in two formulations, as oral suspensions and as a tablet.

The tablet has the advantage of being more user-friendly. The oral single dose of Rapamune is 1 or 2 mg, the total tablet weight being approximately mg for 1 mg formulation and approximately. This means it contains a very low percentage of its total weight as nanocrystals.

An important point is that the drug nanocrystals are released from the tablet as ultra fine nanosuspension. In the event that crystal aggregation takes place to a pronounced extent, the dissolution velocity and subsequently the oral bioavailability of the BSC II drugs will be reduced.

Therefore, there is an upper limit to load tablets with nanocrystals. In case the limit is exceeded and nanocrystals get in contact with each other within the excipient mixture of the tablet, the nanocrystals might fuse to larger crystals under the compression pressure during tablet production.

For drugs with a low oral single dose such as sirolimus in Rapamune, incorporation into tablets causes few or no problems. The main advantages of the nanocrystal technology in this product are the user friendliness and the higher bioavailability in comparison to the oral solution. As discussed previously, a smaller particle size leads to greater solubility and larger surface area, consequently increased dissolution velocity and thus greater bioavailability.

The drug is aprepitant, used for treatment of emesis single dose is either 80 or mg. Aprepitant has little or no affinity for serotonin 5-HT 3 , dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting CINV. Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Aprepitant augments the anti-emetic activity of the 5-HT 3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.

Aprepitant will only be absorbed in the upper gastrointestinal tract Shimizu Bearing this in mind nanoparticles proved to be ideal to ideally exploit this narrow absorption window.

The formulation of a tablet from micronized bulk powder made much higher doses necessary, leading to increased side effects eg, other serotonin receptor induced effects like dizziness Wua et al The drug nanocrystals are contained within a hard gelatin capsule as pellets. Aprepitant was formulated this way in order to make the drug easy to handle by healthcare providers and patients as capsules.

In addition, the pellets can be administered via a stomach tube. Currently studies are being undertaken to evaluate the change in pharmacokinetics if any between the pellets and the capsules. There are special methods and technologies required to produce high nanocrystal-loaded tablets. This example of aprepitant demonstrates once again the importance of an increased bioavailability through nanonization.

In case of a drug with a narrow absorption window which is also poorly soluble it is important to reduce the particle size to a size threshold that will make the drug bio-available by enhancing the solubility.

Tricor is indicated as adjunctive therapy to diet in adult patients with primary hypercholesterolemia or mixed dyslipidemia Fredrickson types IIa and IIb to increase high-density lipoprotein cholesterol HDL-C , reduce triglycerides TG , reduce low-density lipoprotein cholesterol LDL-C , reduce total cholesterol Total-C , and reduce apolipoprotein B Apo B. Fenofibrate increases the lipolyses and the elimination of TH-rich particles from the plasma by activating the lipoprotein lipase and reducing the production of apoprotein C-III, which is an inhibitor of the lipoprotein lipase activity.

The subsequent fall in TG produces an alteration in size and composition of LDL from small dense particles thought to be atherogenic due to their susceptibility to oxidation to large buoyant particle. These particles have a greater affinity for cholesterol receptors and are catabolized rapidly Witztum In general, the uptake from of the gut lumen and thus the bioavailability of fenofibrate is depending on whether the patient is in the fed or nonfed state.

The nanocrystal technology makes the fenofibrate independent of meals. Plasma levels in fed and fasting condition are bioequivalent data on file, Abbott Labs. Fenofibrate is a lipophilic compound and practically insoluble in water. Having no ionizable group, the solubility of fenofibrate was not influenced by changes in pH value through the application of food. The enhanced absorption of fenofibrate in fed patients can be explained with the availability of lipids and other surfactants eg, cholesterol in the food, thus solubilizing the fenofibrate.

By nanonizing the drug, the solubility is enhanced, making it bioequivalent in fed and fasting conditions. Megestrol was synthesized in England in Initially developed as a contraceptive, it was first evaluated in breast cancer treatment in Megestrol is a synthetic progestin and has the same physiologic effects as natural progesterone.

The biochemical mechanism of progestin antitumor activity is not well known but may involve interaction with progester-one and glucocorticoid receptors, and androgenic properties. Megestrol also has direct cytotoxic effects on breast cancer cells in tissue culture and suppresses luteinizing hormone release from the pituitary.

It is mainly used to improve weight gain and appetite in patients undergoing chemotherapy or suffering from an HIV infection.

It can also be used to treat psychologically induced anorexia. Megestrol is well absorbed in the gastrointestinal tract but absorption varies. A bioavailability study comparing the peak plasma concentration and extent of absorption of Megace ES and megestrol acetate oral suspension revealed that in unfed patients, the bioavailability of Megace ES is minimally reduced while there was a substantial food effect for megestrol acetate oral suspension Femia The nanonized drug can be formulated in less volume, so the single dose the patient has to take daily dose mg of megestrol in 5 ml of fluid is reduced by the factor four compared to the oral solution available.

This reduced volume and the improved bioavailability lead to a better patient compliance due to the possibility of flexible dosing in order to provide effective appetite stimulation and weight gain. Another advantage is the reduced viscosity of the Megace ES formulation, which also leads to increased patient compliance. This viscosity reduction is a direct effect of the reduction of the particle size no or little viscosity enhancement necessary to prevent sedimentation Data on file.

Par Pharmaceutical Companies, Inc. Table 3. In general, it can be stated that the advantages of the nanocrystal technology can be applied to many other poorly soluble drugs as well.

There are already several products close to being marketed or in clinical trials. Information about these drugs and products is sparingly available due to high risks for knowledge leaks and fear of competitors in the pharmaceutical industry, but the following examples give an indication of potential future products:.

These signal transduction pathways and proinflammatory molecules are known to be active in various inflammatory and autoimmune diseases. Semapimod may therefore have widespread applications in these diseases. In animal models, Semapimod has shown protective activity against a wide variety of conditions, ranging from stroke to inflammatory bowel disease. A Phase I study in cancer patients demonstrated the safety of the compound and confirmed its activity in preventing the synthesis of TNF-alpha in humans.

Angiotech Pharmaceuticals Inc, Vancouver, BC has developed an intravenous or systemic treatment for rheumatoid arthritis. Treating patients with chronic inflammatory diseases require that side effects of systemic treatments be minimized. This formulation reduces the incidence of hypersensitivity reactions. At this moment there is no information available which nanotechnology was used to produce the resulting nanocrystals.

The company also employs the nanocrystal technology from Elan Nanosystems. Thymectacin is poorly soluble and thus needs to be formulated as nanocrystals to become bioavailable. The Theralux system consists of a photosensitive drug and a device designed to eliminate certain unwanted cells used outside the body. When TH is administered to a stem cell graft, it enters and is retained in the cancerous cells and activated T cells, but not other normal cells such as stem cells, progenitors and precursors.

The process is conducted ex vivo outside the body , thus minimizing side effects and toxicity. With their own nanotechnology, Nucryst Pharmaceuticals Wakefield, MA has developed a way to produce silver nanoparticles which can be used in antimicrobiological coatings for medical use. They are also working on their substance NPI in a cream formulation, which is in clinical development to treat atopic dermatitis Bhol et al ; Bol and Schechter a.

In PLAL method, pure and uncontaminated nanoparticles could be produced by a relatively fast process and it is also a good candidate for mass production at a low cost. Lasers offer a unique ability to directly deposit great amount of energy onto the specified regions of a material to fulfill the response in demand. When the laser energy is delivered onto the material surface, three main cases—reflection, transmission, and absorption—have a significant role in results of the interaction.

In the first two cases, after laser beam hits the material, some amount of the incoming laser energy is reflected due to the real part of the index of refraction and the rest of the laser energy is transmitted through the material.

The reflection from the material also depends on frequency or wavelength of the light source. For example, the reflection from metals varies from 0. This ability can be explained by laser-material interaction, which depends on the internal properties of both lasers and materials.

The effects of linear optical phenomena are taken into account in the approaches mentioned above. These cases for both material and laser are not necessarily the same for all conditions.

For instance, some of the materials have strong nonlinear properties, which affect the refractive index variation for different wavelengths; thus, the whole process will be affected and altered such as self-focusing, defocusing, and soliton propagation [ 3 ]. Also, laser sources could act as an important role for the process.

The laser source could be continuous wave CW or pulsed ps, fs. While continuous wave CW and pulsed laser processing, the single photon absorption is considered; however, in the ps or fs laser processing, nonlinear phenomena could occur such as multi-photon absorption and optical breakdown, which cause a decrease in absorption depths [ 4 ].

These phenomena are very important for the nanomaterial generation, and they will be given in the PLAL. When the material absorbs the laser energy directly, the removal of the material is observed. This phenomenon is called ablation.

Laser ablation is generally considered as a pulsed laser process; however, it is also applicable with CW lasers. The ablation of materials occurs when the laser energy becomes greater than the threshold fluence. Laser and material parameters determine the process characteristics. The main parameters that the laser depends on are wavelength, pulse duration, fluence, and pulse length [ 5 ]. The material properties such as absorption, defects inside the material, and general characteristics of the material are also important for the ablation.

In the PLAL process, laser and material interact in the liquid surrounding and a series of physical phenomenon occur. The plasma plume is created when intense laser beam hits the solid target. The created plasma plume begins to cool and it becomes condensed. Finally, nanoparticles will be generated through this process. Although many synthesis and applications of nanoparticles have been demonstrated by using PLAL method in the past decade, the main physical mechanism behind PLAL method remains a puzzle.

To understand the mechanism, Direct Simulation Monte Carlo DSMC calculations have been performed to simulate the ultra-short, laser-ablated plume dynamics and nanoparticle evolution under realistic experimental conditions [ 6 ].

In this book chapter, a variety of nanomaterial generation through PLAL method will be given in terms of their characterization techniques, properties and applications. Nanoparticles, nanocrystals and nanocomposites synthesis could be successfully achieved since PLAL technique is applicable to a wide range of materials from metals to semi-conductors.

Metal nanoparticles Au, Ag, Ti, etc. Their physical properties such as light absorption, crystal structure, and photoluminescence PL could be used in many applications. Nanodevices such as photodetectors are fabricated successfully due to broadband light absorption of nanomaterials in different regions of spectrum from ultraviolet to infrared.

High-sensitive strain sensor, solar cell, and memory devices have been realized with different nanomaterials synthesized by PLAL technique. Nanomaterial properties and their application areas will be resumed in this part. Moreover, nanoparticles produced by PLAL will be evaluated in terms of their toxicological effects on both the environment and ecosystem and the human health.

PLAL method allows a mass production due to easy and fast process. The chemical-process-free nanoparticle generation provides noncontaminated and pure nanoparticles which contribute to research areas such as biological and chemical sensing, medical applications and strain gauges [ 7 — 9 ].

The conduction property of chemically sensitized Au-NPs is frequently studied [ 10 ]. Chemically obtained Au-NP films tend to show exponential decay dependence due to their chemical ligands over the Au-NPs.

This behavior can be explained by quantum-tunneling effect which depends on the width of the potential barrier. Due to this effect, it is indicated that the Au-NP films can be used for as highly sensitive strain gauges. In principle, the presence of chemical ligands may decrease the performance of the sensitivity. The initial state of the Au-NP-deposited sensor is on the left-hand side where there is no strain and the resistance of the film is denoted as R.

In Figure 1b , the resistance response of the Au-NP films when the strain applied is represented. There would not be any contaminants over the surface of the Au-NPs. Due to this behavior, quantum-tunneling effect becomes stronger and more effective. Nanoparticles exhibit quite different properties compared to their bulk counterparts.

Widespread production and use of nanoparticles in different applications in medical, biological, electronic and industrial fields might lead to unfavorable effects on both humans and a wide range of organisms [ 13 ].

Thus, nanoparticles should be evaluated in terms of ecological and toxicological aspects for a deeper understanding of the impacts on both humans and other organisms. Silver nanoparticles Ag-NPs are one of the commonly used nanoparticles which are utilized in therapeutics, cosmetics, food additives, textiles and antimicrobial coatings on medical implants, catheters, wound dressings and so on [ 14 ]. Ag-NP production is mainly achieved by reducing the Ag salt but there are also other nanoparticle production methods for the synthesis of Ag-NP, such as electrolysis, photoreduction, pyrolysis, and sol-gel methods [ 15 , 16 ].

The major drawback of these Ag-NPs produced by aforementioned methods is that the resulting Ag-NPs are coated either with a by-product due to the chemical reaction or with other molecules on purpose such as polyvinylpyrrolidone PVP , antibodies, and surfactants.

These coatings lead to different surface chemistries which masks the real Ag-NP toxicity. Since pure uncoated Ag-NPs are the commonly found types of Ag-NPs in nature and in industry as products or by-products, it is crucial to reveal their toxicity profile [ 17 ].

Our group studied different aspects of Ag-NP toxicity in two distinctive studies. The Ag-NPs were crystalline in structure and the size distribution of these nanoparticles was determined as 5—50 nm although there were also larger nanoparticles up to micron sizes. The nanoparticles did not show an aggregation pattern as can be observed from both transmission electron microscopy TEM and scanning electron microscope SEM images. Energy-dispersive X-ray EDX analysis revealed that a pure Ag-NP solution was obtained by the nanosecond laser ablation method since the only peak was the silver peak apart from the carbon and copper peaks due to TEM grids.

The characteristic UV—vis absorption peak at approximately nm also confirms the presence of Ag-NP, which is consistent with the previous studies [ 18 ]. These characteristics are present in both the studies mentioned subsequently Figure 2. No precipitation was observed at least for 4 months. Firstly, the toxic effects of Ag-NPs on the environment were evaluated by using an aquatic macrophyte Lemna minor as the model organism.

For this purpose, dose- and time-dependent toxicities were assessed. It was shown that L. When Ag-NP concentrations increase slightly in lower concentrations, there is a remarkable increase in toxicity.

This might be a significant result in ecological perspective since low amounts of Ag-NP, which might be released to the environment accidentally, might affect the ecosystem and aquatic macroflora in a significant manner [ 19 ]. Secondly, as indicated in the aforementioned application fields of Ag-NPs, humans frequently encounter these nanoparticles in daily life.

NPs can reach the brain both by systemic circulation and through the olfactory bulb which leads to serious effects in central nervous system [ 20 ]. It was also demonstrated that Ag-NPs are detected in different brain regions after inhalation [ 21 ].

Our group aimed to determine the effects of Ag-NP on learning and memory, and thus hippocampus was chosen for this study. Furthermore, it was revealed that the size of pure Ag-NPs was crucial for the cellular uptake mechanism of pure Ag-NPs. Phagocytosis was shown as the type of endocytotic pathway that governs the entry of larger Ag-NPs into the hippocampal neurons. This study demonstrated that PLAL is a substantially useful method for studying NP toxicity, since it provides pure NPs mimicking the ones frequently used in the industrial fields.

The generation of the semi-conductor NPs is intensely studied in the past decade because of the physical, chemical, electrical, and optical properties of the nanomaterials [ 22 — 24 ].

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