1. methods include chemical modifications like change of

1.     Nanotechnology1.1.  Particle size reduction for enhanced drug bioavailability For any solid dosage form when it administrated orally either(tablet or capsule), it needs to be dissolveand then absorbed to the body tissue to exertits action. was found in some oral dosage form when it administrated orally, theabsorption rate is so fast but the dissolution rate is slow it’s called in thiscase dissolution rate limited which mean that the drug to be enter the bloodstream depend on the dissolution rate (Dunneet al., 1999).

Aqueous solubility could be considered as a major challenge facingdrug formulation, especially in optimizing immediate-released oral dosage forms.Most of the new drug entities are poorly water soluble, so increasing drugsolubility can greatly affect their dissolution and consequently their oralabsorption as well as the bioavailability. According to BiopharmaceuticsClassification System (BCS), the limiting factors that govern the rate andextent of oral absorption of a drug are aqueous solubility and permeabilitythrough biological membranes. The aqueous solubility of several drugs have agreater role in determining their permeability and absorption rate, especiallyin the case of class II drugs (high permeability and low solubility) as well asclass IV drugs (low permeability and low solubility) (Dunneet al., 1999; Chen et al., 2011).

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Several approaches were investigatedto enhance aqueous solubility of pharmaceutical active ingredients (APIs), andits bioavailability. These methods include chemical modifications like change of pH, use of buffer, derivatization,complexation, solid dispersion, and salt formationor using physical modifications like particle size reduction(Savjaniet al., 2012; Murtaza, 2012). It has been shown that thesolubility is strongly related the particle size; aswhen the particle size became smaller, the surface area will increase, whichlead to be more interact with thesolvent and consequently increases its solubility (Fig.1).So it is clearly seenthat the particles in nanometer size have higher dissolution than themicronized particles (Savjaniet al.

, 2012).    Figure 1: Relation between particle size and surface area. According to the Noyes–Whitney equation, decreasing drug particlesize to nanometer range will increase the surface area, which is expected toresult in increasing the drug dissolution rate (Szunyoghet al., 2013).   Where: D is the diffusion coefficient of the solute, S the surface area, hthe thickness of the diffusion layer, Cs the solubility of the drug, and C theconcentration of solute or drug in the bulk solution.

 1.2.   Concept of nanotechnologyFormulation of drug substance as nanoparticles by differenttechnique gained a considerable attention as an advanced technology that helpto improve the poorly dissolute drugs (Jia,2005).In the past 20 years are widelyincrease more than before and that lead to increase the pharmaceutical companythat developed product in anonize to  more than 150 companies (Zhanget al., 2008).In in 1994, Oncospar® whicha product manufacture by Enzon was the first nanoparticle that received FDAapproval as nanoparticle formulation for acute lymphocytic leukemia treatment (Duncan,2006). Alsoin 1995, Doxil® ( liposome-encapsulated doxorubicin), which manufacturedby OrthoBiotech, was introduced in the marker as the first FDA-approved liposomeused treatment of HIV-related Kaposi’s sarcoma, and then approved for thetreatment of ovarian cancer and multiple myeloma (Barenholz,2012; Petrosand DeSimone, 2010). In2005, Abraxane® , which was manufactured by Abraxis/AstraZenecawas the approved by FDA as the first protein-based nanoparticle used for thetreatment of metastatic breast cancer (Petrosand DeSimone, 2010).

After that many products wereapproved for the treatment of cancer, pain, and infectious diseases likeFenofibrate tablet as Nanocrystals used for hypercholesterolemia and PaclitaxelPowder for suspension for infusion as nanoparticles used for Breast neoplasma andmany other example that result  toincrease the focus of developing product in nanoparticles (Hafneret al., 2014). 1.3.

   Medicinal  and pharmaceutical applications ofnanoparticles In recent years, applications of nanoparticles are increase in ourlife especially the pharmaceutical and medicinalfields. Pharmaceutical applications include drug delivery, cancer therapy andgene delivery systems, medicinal application like imaging, sensing (Singhet al., 2008).In cancer therapy, nanomaterials can be used in diagnosis and  prevention of different  types of cancer such as bone cancer, coloncancer, prostate cancer, gastric cancer, leukemia, bladder cancer, colorectalcancer and it also can used for treatment by using nanoscale biologicalmarkers, immunotherapy, photodynamic therapy, stem cells, and anticancernanodrugs (Nalwaand Webster, 2007). Breast cancer is one of most cause of death in women, so thereare different normal way to diagnosis it like ultrasound and optical but usingnovel nanomaterials such as using contrast agents as biological imaging, whichcan play a better role in for early breast cancer detection, screening,diagnosis, and prevention because nanomaterials offer significant contrast forbiological imaging that used for breast and also for other types of cancer (Singhand Nalwa, 2011).One of the medicinal application of nanoparticles are the fluorescentnanoparticles that used for biological detection and imaging application thatuses nanoparticles which help tracking and cell-tissue interactions of stemcells which labeled with fluorescent nanoparticles using magnetic resonancetechnique (Chen,2008).On the other side, one of the pharmaceutical application ofnanoparticles is using it as drug delivery systems as lipid nanoparticles,liposomes, genes, polysaccharides, and polymeric nanomicelles which candelivered by oral, pulmonary, ocular, and dermal routes.

Nanoparticles are10?100 nm in dimension can easily cross the blood-brain barrier (BBB) to treat variousbrain disease like cancer, nervous system diseases, and other various types ofcancer (Nalwa,2009). One of the most importance advantagesof successful formation is the delivery of drug in certain place in the bodythat is needed for treatment and minimize reaching other places which minimizesdrug side effects especially in cancertreatment where the tumor may be localizer in certain place in various organsso by using drug delivery leadto increase the amount of drug that reach the desire organ and on the otherhand the amount of drug that reach the undesired organ will be decrease (De Jong and Borm, 2008).Doxil® a liposome-encapsulated doxorubicin, that is usedfor treatment of HIV-related Kaposi’s sarcoma, has advantages over freedoxorubicin are high efficacy and low cardiotoxicity. These advantages are due topassive targeting of tumour due to leaky tumour vasculature that decrease the concentrationsof free doxorubicin in healthy tissue sites (Ninget al., 2007). 1.4.

  Nanonization techniques: 5Recently, nanonization techniques arise to overcome the problem ofpoor aqueous solubility of many new drugs in water by enhancing its dissolutionrates and bioavailability, and it will also help to decrease their systemicside-effects. These techniques despond on decreasing drug particle size tonanometer range which lead to increase in the surface area that results inincreasing the drug dissolution rate, or by changing the crystalline forms, orby preparing nanomaterials that used as carriers for controlled release (Junghannsand Muller, 2008; Marcato and Duran,2008)Nanonization could be prepared by two different techniques,depending on the technology used to achieve the nanonization. One of thetechniques can be prepared by particle size reduction of large crystals whichcalled “top-down techniques” and this can be done by either high-pressurehomogenization or media milling (Van Eerdenbrugh et al., 2008).

The second nanonization technique depend on increasing the particlesize from small to large size by precipitation of dissolved molecules which isreferred as “bottom-up techniques” (Van Eerdenbrugh et al., 2008). 1.4.1.     Top-down nanonization techniquesTop-down techniques are most commonly used for nanonization whichcan be applied using either media milling and/or high-pressure homogenization(HPH) but it often requires a long process time to reduce particle sizes below100 nm (Sinhaet al.

, 2013). High-pressure homogenization (HPH) hasbeen widely used in the pharmaceutical industry since the mid-1990s whenSkyePharma developed Dissocubes® piston-gap homogenizer that is ahigh energy process in which reduction of particles size of drug is achieved byrepeatedly cycling to 200 plus cycles, with the aid of a piston, a drugsuspension through a very thin gap at high velocity, around 500 m/s, andpressure, 1000-1500 bars. (Keckand Muller, 2006; Loh et al., 2015)Recently, HPH is used for preparing drug nanocrystals such asTriglide® (Fenofibrate), which clinically approved for treatment ofhypercholesterolemia or hyperlipidemia .HPH is used also used for preparing drug like “Nanopure”, “Nanocrystal”, “NanomorphTM”and “Nanoedge” (Keckand Muller, 2006; Chen et al., 2011)Nanoedge™ technology which is HPH techniques combined withprecipitation techniques. In this technique, the drug is first dissolved in awater-miscible alcoholic solvent like methanol or ethanol, then cause it toprecipitate by added water.

The particles that precipitated are thenhomogenized. The homogenization is used reduce to the size and sizedistribution of the precipitated particles that help to minimizing the probabilityof crystal growth and improving the stability of the nanosuspension duringstorage (Lohet al., 2015)Ball milling (also called Nanocrystals or Nanosystems) is anotherpopular size reduction technique used top-down conceptwhich was first developed and reported since 1995 by Liversidge co-workers (Liversidgeand Cundy, 1995). For the production of nanoparticles, it is based on mixing the drugpowder with the dispersion media (mostly water) and a suitable stabilizer thathelps to avoid or minimize the particle aggregation after the preparation ofnanoparticles (Chenet al., 2011; Salazar et al., 2014; Lohet al.

, 2015). Themilling media (balls) are available in many types like zirconium dioxide beads,silicium nitride beads and polysterene beads. High shear forces of theballs results in nanonizing will be obtained when vessel jackets rotate at a veryhigh speed. Several parameters can affect the resulting particle size of ballmilling nanonization methods such as the amount of drug, type, and concentrationof stabilizers, the amount and size of the ball, speed, time, and temperature. Manydrugs have been nanonized using this method for the production of drugnanoparticles like fenofibrate, naproxen and ibuprofen (Chenet al., 2011; Loh et al., 2015; Salazaret al., 2014).

Some of these drugs are available in the pharmaceutical markets astablet forms, such as fenofibrate, ibuprofen, and paliperidone palmitate (Lohet al., 2015). 1.4.

2.     Bottom upnanonization techniquesIn the other hand of  top-down techniques, bottom-up techniqueswhich produce nanoparticles from drug molecules in solution by building themand can be done by controlled precipitation (or crystallisation) (Chanand Kwok, 2011). Bottom-up techniques have advantages over the top-down techniquesincluding that they require low energy processes, can  operate using simple instruments, cheaper andcan be operated at a low temperature, that appropriate techniques forthermolabile drugs (Rasenackand Muller, 2004)Usually, precipitation methods are used to prepare the biggerparticle size which is in micro range size but it also can be used to prepare smallparticle size in nanosize range with many method .the researchers in the past twodecade tried to use different methods like precipitation using liquid solvent (antisolventaddition), precipitation in presence of supercritical fluid, precipitation byremoval of solvent and precipitation in presence of high energy processes (Sinhaet al.

, 2013)Precipitation by liquid solvent method (antisolvent addition) dependson dissolving the drug substance in solvent better to be in water misciblesolvent in which the drug has a suitable solubility. Then, the prepared solutionwill be mixed. After that, with an antisolvent addition (water usually) byusing mixing forces, which should be miscible with the solvent phase. Inselection of solvent and antisolvent, the order and volume ratio of solvent–antisolventmixing are one of the critical process parameters of precipitation (Sinhaet al., 2013; Savjani et al., 2012).

NanoMorph® technology (develop by Abbott GmbH & Co.KG,Ludwigshafen, Germany) is an example of precipitation by liquid solvent methodwhich based on preparing a suspension of a drug in organic solvents that formsolution by heating in mixing chamber, then it mixed quickly with a cooledaqueous solution that contain stabilizer that help to nucleation of theparticles leading to form spherical amorphous particle of nanometer size (Shiet al., 2009).Precipitation using supercritical fluids (SCF) are preferred forcommercial use because it is cheap, usually available, neither toxic norflammable, that’s why it is often used in particle engineering, and all drugs notonly the thermolabile drugs. The solvent that generally used as supercriticalsolvents include carbon dioxide, ammonia, fluoroform, ethane and ethylene.

Someof these solvents may limit their uses in pharmaceutical applications becauseof toxicity and flammability. Many different processes to prepare drug nanoparticlesdepend on gas anti-solvent recrystallization (GAS), rapid expansion ofsupercritical solutions (RESS) and supercritical antisolvent (SAS). That ingeneral based on supercritical fluid technologies (deWaard et al., 2011; Sinha et al., 2013). Adami et al. used Supercritical AntiSolvent precipitation (SAS) to micronizedparticles of nalmefene hydrochloride using using EtOH as solvent that result toproduce particles in the range 1–5 ?m (Adamiet al., 2008).

Precipitation by removal of solvent is another method to prepare nanoparticlesby bottom-up technique that is based on the use of either conventional solventremoval techniques like freeze-drying and spray drying or the use of specialfreezing techniques like spray freezing into liquid (SFL) method.(Savjaniet al., 2012).

Precipitation coupled with high energy processes (combinationtechnologies) are one of the process to prepare nanoparticles by bottom-uptechniques which based on use the precipitation method with a high energyprocess such as high pressure homogenization HPH like Nanoedge™ technology (Lohet al., 2015). 1.

5.  Stabilization of nanoparticles Preparing the drug in nanoparticles often lead to increase thesurface area of the nanoparticles compared to microparticles, which is usuallyaccompanied by change in the stability of the particles (Patravaleet al., 2004).

Physical Instability problems like sedimentation, crystal growth,agglomeration, or change of crystallinity state are one of the most commonproblems with nanonization that should be limited or avoided (Wuet al., 2011).  Dry state like solid dosageforms usually have a better stability than suspensions. Therefore, to limit oravoid the stability problem of nanosuspension, nanosuspension should be change topowder form (Patravaleet al., 2004; Abdelwahed et al.,2006).

Agglomeration is one of the physical instability phenomena that affectthe potential of nanonization. It might be accompanied with the preparation ofthe drug in nanoparticles which leads to an increase in the free energy of thesystem resulting in aggregation of the particles to form a large particle (Wanget al., 2013; Verma et al., 2011).Crystal growth or Ostwald ripening is also one of physical instabilityphenomena that happen because the dependence of particles solubility on theirsizes, where large particles have lower saturation solubility than smallparticle size that lead to concentration gradient between large and smallparticle which consequence accumulate to form large particle (Wuet al., 2011). Narrowing particle size distribution can also help to limit the Ostwaldripening, because when the particle size is uniform, the Ostwald ripening willbe at a minimum rate. Mechanical agitation temperature and also affect Ostwaldripening (Rabinow,2004).

Change of crystalline state between amorphous and crystalline stateis also one of the problems that lead to instability of the nanoparticles, wherein top down techniques, the particles tend to form partially amorphous while itform completely amorphous in case of bottom-up techniques (Lindforset al., 2007). Nanoparticlesin amorphous form are usually more soluble and have better dissolution ratethan crystalline form, which make them more stable but the nanoparticles inamorphous form usually thermodynamically unstable and transfer to crystallineform by aging (Wanget al., 2013).

Chemical stability problems like hydrolysis and oxidation canalso affect the stability of nanosuspension (Labilleand Brant, 2010). One of The popular methods to improve the chemical stability is eitherby changing the nanosuspension from liquid state to solid dosage form which a stabilitywill be achieved than nanosuspension. Another method to enhance chemicalstability of drug during nanonization is the increase the of concentration ofthe nanosuspension (Van Eerdenbrugh et al., 2008).Preparing the drug in nanoparticles often result in increasing thesurface area of the nanoparticles compared to microparticles, which may beaccompanied by a change in behavior issue that can affect the stability theparticles like sedimentation, crystal growth, agglomeration, or change ofcrystallinity state which should be limited or avoided (Patravaleet al., 2004; Wu et al., 2011).

One of the important approach to stabilize the nanoparticles  is the addition of suitable stabilizer to theformulation during nanonization process (Peltonenand Hirvonen, 2010). Addition of a stabilizer to the nanosuspension formulation can playan important role to limit agglomeration by reducing the free energy of thesystem during nanosization process. The stabilizer may be used either (i)surfactants such as sodium lauryl sulfate and poloxamer 188, or (ii) polymerssuch as hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP)(Vermaet al., 2011; Wang et al., 2013). The stabilizer that may beused either, surfactants, polymers or mixture of both but the selection of beststabilizer is mainly depend the drug used (Liuet al., 2011).

The first type of stabilizers that popularly used are surfactants, whichcan be either nonionic like tween 80 or ionic like sodium lauryl sulfate anddocusate sodium  (DOSS), but the toxicity of the cationic surfactants limit their application in oral preparation (Kesisoglouet al., 2007).Ionic surfactants can act as stabilizers by creating of surfaces witha charge sufficient enough for nanoparticle stabilization, where the existingof other charged materials can minimize the surface charge of the particles anddecreased electrostatic repulsion which lead to agglomeration (Pallaand Shah, 2000). On the other hand, nonionic stabilizers are most common used butthey do not provide a significant repulsive barrier against agglomeration likeionic surfactants, but these work as a stabilizer based on steric affect thatacts as physical barrier around the nanoparticles that decrease the contactbetween the particles (Pallaand Shah, 2002). Yang et al use tween 80 as nonionic surfactant with fluticasone andbudesonide to evaluate the efficiency of particle size reduction of nanosuspensionusing wet-milling method (used single-sized glass beads with 0.

50–0.75 mmdiameters). Nanosuspension for both compoundsexhibited good physical/chemical properties for pulmonary delivery.

The pharmacokinetic studies after the administration ofnanosuspensions showed deep lung deposition and fast lung absorption, withsolubility playing an important role in lung retention and duration of action (Yanget al., 2008)The other types of stabilizers are polymeric stabilizers like polyvinylpyrrolidone(PVP), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC),and polyvinyl alcohol (PVA) (Van Eerdenbrugh et al., 2008). Polymeric stabilizers act like nonionic stabilizers by steric effects,but with higher adsorption potential than nonionic  surfactant (Pallaand Shah, 2002). Many factors related to stabilizer can affect the optimumefficacy of the nanoparticles stabilizers .

One of the important parameter is theconcentration of stabilizer, where the amount that used to the nanoparticlespreparation should be optimized. For example, in surfactant stabilizers, theamount that should be used at concentrations below the critical micelleconcentration (CMC), while concentration should be enough to give the stericrepulsion between the nanoparticles in suspension. (Peltonenand Hirvonen, 2010; Wang et al., 2013). Verma et al. evaluated variousstabilizers include (SLS, PVP K-30, Pluronic F-68 and F-127, Tween 80 anddifferent (HPMCs)) to study their effects on theformation and stability of ibuprofen nanosuspension using  different top-down and bottom-up approaches.

Thy find higher particle sizes in the case of suspensions made with SLS, Tween80 and Pluronic F-127. The higher increase in particle size suggests thatOstwald ripening may be a key driving force .(Vermaet al.

, 2009)Temperatureof nanonization is also critical parameter that should be controlled duringnanoparticles preparation.