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Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15ISSN:2249-5347IJSIDInternational Journal of Science Innovations and DiscoveriesAn International peerReview Journal for ScienceReview ArticleDRUG NANOCRYSTALS: NOVEL TECHNIQUE FOR DELIVERY OF POORLY SOLUBLE DRUGSSneha V. Sawant*, DR. Vilasrao J. Kadam, DR. Kisan R. Jadhav and Shirish V. Sankpal*Department of Pharmaceutics, Bharati Vidyapeeth's College of Pharmacy, Sector-8, CBD Belapur, Navi MumbaiReceived: 16.09.2011Modified: 03.10.2011Published: 29.12.2011Keywords:Nanocrystal,Dissolution rate,Particle size,Bioavailability,Stabilizers*Corresponding AuthorName:Sneha V SawantPlace:Navi Mumbai, Maharashtra, IndiaE-mail:manu2sneha@gmail.com400614.Available online through www.ijsidonline.infoABSTRACTDuring the last two decades, many modern technologies have beenestablished in the pharmaceutical research and development area. Theautomation of the drug discovery process by technologies such as highthroughput screening, combinatorial chemistry, and computer- aided drugdesign is leading to a vast number of drug candidates possessing a very goodefficacy. Unfortunately, many of these drug candidates are exhibiting pooraqueous solubility. The use of drug nanocrystals is a universal formulationapproach to increase the therapeutic performance of these drugs.Nanocrystal dispersions comprise water, active drug substance and astabilizer. They are physically stable due to the presence of stabilizers thatprevent reagragregation of the active drug substance. Different techniquescan be used to prepare nanocrystal formulations of a drug powder such ashomogenization, coprecipitation, spray drying and milling. There are severalINTRODUCTIONadvantages of nanocrystal formulations such as, enhanced oralbioavailability, improved dose proportionality, reduced food effects,suitability for administration by all routes and possibility of sterile filtrationdue to decreased particle size range. Nanocrystal technology is cheap andINTRODUCTIONeasy to apply; thus, it appears that this technology will be substantiallyuseful for the manufacture of poorly water-soluble drug products. Thisreview article describes the physicochemical properties of drugnanocrystals, production methods, potential clinical applications andlimitations.International Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 20111

Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15INTRODUCTIONIt is estimated that 40% or more of active substances being identified through combinatorial screeningprograms are poorly soluble in water. Poor solubility is not only a problem for the formulation development andclinical testing; it is also an obstacle at the very beginning when screening new compounds for pharmacologicalactivity. From this, there is a definite need for smart technological formulation approaches to make such poorlysoluble drugs bioavailable. Making such drugs bioavailable means that they show sufficiently high absorption afteroral administration, or they can alternatively be injected intravenously. [1] Since many years the approaches toincrease drug solubility are solubilisation by surfactants, complex formation (e. g. cyclodextrin, macromolecules)self-emulsifying drug delivery systems (SEDDS), microemulsions and especially for oral administrationmicronisation of drug powders [2] . Micronization, meaning the transfer of drug powders into the size rangebetween typically 1-10μm. However, nowadays many drugs are so poorly soluble that micronization is notsufficient. The increase in surface area, and thus consequently in dissolution velocity, is not sufficient to overcomethe bioavailability problems of very poorly soluble drugs of the biopharmaceutical specification class II. Aconsequent next step was to move from micronization to nanonization. At the beginning of the 1990s the drugnanocrystals were developed as more efficient approach to increase drug solubility and dissolution velocity.Instead of micronising the drug powder, it is nanonised leading to nanocrystals with a typical size of about 200 nmup to approximately 600 nm. Drug nanocrystals can be used for a chemical stabilization of chemically labile drugs.The drug paclitaxel can be preserved from degradation when it is formulated as a nanosuspension. [3] The sameresult was found for the chemically labile drug omeprazole when formulated as a nanosuspension, the stability wasdistinctly increased in comparison to the aqueous solution. [4]Increasing Dissolution through NanonizationMost differentiating features of drug nanocrystals are the increased saturation solubility and theaccelerated dissolution velocity. A drug specific constant which depends only on the solvent and the temperature iscalled as the saturation solubility (Cs). As described by the Nernst Brunner/Noyes-Whitney equation [5] , the solidAPI dissolution rate is proportional to the surface area available for dissolution as discussed belowWhere, dx/dt= dissolution rate, Xd = amount dissolved, A= particle surface area, D = dissolution rate constant,V = volume of fluid available for dissolution, Cs =saturation solubility, h = effective boundary layerthickness.Hence, due to further decrease in the particle size in the sub-micron range will further increase dissolutionrate because of increase insurface area. Furthermore, as explained by the Prandtl equation, the diffusion layerthickness will also be reduced, thus resulting in an enhanced dissolution rate. [6] An increase in saturation solubilityof the nanosized API has also been explained by the Freundlich–Ostwald equation:International Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 20112

Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15Where, S = saturation solubility of the nanosized API, S∞= saturation solubility of an infinitely largeAPIcrystal, = crystal-medium interfacial tension, M = molecular weight of the compound, r = particleradius,ρ = density, R = gas constant, T =temperature.Finally, surface wetting increment by surfactants in nanosuspension formulations, in comparison toconventional micronized formulations results in further enhancement of dissolution rates. Hence, bettertherapeutic drug efficacy was obtained. Also, the rejection of new drug entities because of poor solubility can beprevented. Hence novel and patented techniques are mushrooming up in the pharmaceutical sector. [7]Nanocrystal TechnologyPreparation of drug nanocrystals is basically a nanosizing method, which is utilized to enhance the oralbioavailability of poorly water-soluble drugs. Drug nanocrystals are nanoscopic crystals of the drug withdimensions less than 1000 nm as defined in the first patents in this field. [8] Nanocrystal dispersions containdispersion media (water, aqueous solutions or nonaqueous media), active drug substances and surface activeagents or polymers required for stabilization. [9] If necessary, other substances such as buffers, salts and sugars canbe added.There are many advantages of nanocrystal formulations designed for oral administration. Theyare asfollows:• Increased rate of absorption• Increased oral bioavailability• Rapid effect• Improved dose proportionality• Reduction in required dose• Applicability to all routes of administration inany dosage form. Contrary to micronized drugs, nanocrystals can beadministered via several routes. Oral administration is possible in the form of tablets, capsules, sachets or powder;preferably in the form of a tablet. Nanosuspensions can also be administered via the intravenous route due to verysmall particle size, and in this way, bioavailability can reach 100 %.• Reduction in fed/fasted variability• Rapid, simple and cheap formulation development• Possibility of high amounts (30-40 %) of drug loading• Increased reliability - Usually side effects are proportional to drug concentration, so decreasing the concentrationof active drug substances leads to an increased reliability for patients• Sustained crystal structure-Nanocrystal technology leads to an increase in dissolution rate depending on theincrease in surface area obtained by reduction of the particle size of the active drug substance down to the nanosize range preserving the crystal morphology of the drug•Improved stability- They are stable systems because of the use of a stabilizer that preventsInternational Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 20113

Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15reaggregation of active drug substances during preparation . Suspension of drug nanocrystals in liquid can bestabilized by adding surface active substances or polymers• Applicability to all poorly soluble drugs becauseall these drugs could be directly disintegrated into nanometersizedparticles. [10]Bottom up TechnologiesThere are two basic approaches to produce drug nanocrystals, the bottom up and the top downtechnologies. In the bottom up processes, one starts from the molecule in solution, the molecules are aggregated toform particles, being crystalline or amorphous. There are various bottom up technologies. [11]1. Precipitation methodA poor water-soluble drug is dissolved in an organic medium, which is water miscible. A pouring of thissolution into a non solvent, such as water, will cause a precipitation of finely dispersed drug nanocrystals. Aproblem associated with this technology is that the formed nanoparticles need tobe stabilized to avoid growth inmicrometer crystals. In addition, the drug needs to be soluble at least in one solvent , this creates problems for thenewly synthesized or discovered drugs, being poorly soluble in water and simultaneously in organic media.Lyophilization is recommended to preserve the particle size. Another approach to preserve the size of theprecipitated nanocrystals is the use of polymeric growth inhibitors, which are preferably solublein the aqueousphase. The increased viscosity of the aqueous phase can reduce particle growing. [12 ] A basic disadvantage of manyprecipitation processes is the use of organic solvents, which need to be removed again in most cases, increasing thecosts. Especially when large solvent volumes are required, being the case when the drug exhibits low solubility inwater and also in organic solvents. Therefore, for pharmaceutical industry, typically the top down technologies areemployed for the products introduced to the market. [13]2. SonocrystallizationRecrystallization of poorly soluble material using liquid solvents and antisolvents has also been employedsuccessfully to reduce particle size. The novel approach for particle size reduction on the basis of crystallization byusing ultrasound is sonocrystallization. Sonocrystallization utilizes ultrasound power characterized by a frequencyrange of 20-100 kHz for inducing crystallization. It not only enhances the nucleation rate but also an effectivemeans of size reduction & controlling size distribution of the active pharmaceutical ingredient (API). Mostapplications used ultrasound in the range 20 khz -5mhz.Sonocrystallization technique or technology has also beenstudied to modify the undesirables of NSAID’S I) i.e. poor solubility and dissolution rate and consequently the poorbioavailiability. Flubiprofen was poured in deionized water at 25°C and sonicated for 4 minutes at an amplituted of60% and cycle is 40 sec on and 10 sec off. The particle size of treated flubiprofen was significantly reduced and theincreased solubility of treated flurbiprofen was about 35%. The intrinsic dissolution rate of treated flubiprofenincreased by 2-fold. The dissolution studies obtained that 90% of the drug was released within 20 minutes fortreated flubiprofen as compared to untreated flubiprofen obtained 60% release of the drug.International Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 20114

Sneha V Sawant et al., IJSID 2011, 1 (3), 1-153. Gas antisolvent recrystallization-GASThis processing requires drug polymer mixture be solubilized via conventional means into a solvent i.e.then sprayed into an SCF (supercritical fluid), the drug should be miscible with the organic solvent. The SCFdiffuses into the spray droplets, causing expansion of the solvent present and precipitation of the drug particles.The low solubility of poorly water-soluble drugs and surfactants in supercritical CO2 and the high pressurerequired for these processes restrict the utility of this technology in the pharmaceutical industry. [14]Top Down TechnologiesIn the top down technologies, one starts from large crystals in the μm range and goes down to the nanodimension by diminuting the crystals.There are several top down technologies which are discussed below. [11]1. Media millingIn this protocol, the milling chamber is charged with milling pearls, dispersion media(e.g. water), drugpowders and stabilizers. The pearls are rotated at a very high speed to generate strong shear forces to disintegratedrug powders into nanoparticles. The pearls or balls consist of ceramics, stainless steel, glass, or highly crosslinkedpolystyrene resin-coated beads. [15] Physical characteristics of the resulting nanocrystals depend on thenumber of milling pearls, the amount of drug and stabilizer, and milling time, speed and temperature. Drugnanocrystals can be prepared by a wet milling procedure using a rotation/revolution mixer and zirconia balls. Thetechnique showed superior performance compared with the beads mill, enabling drug nanocrystals to be producedin a quick process (approximately 5 min) using a small amount of zirconia balls. The potential shortcomings ofmedia milling are difficulty in the removal of residual milling media fromthe final product and the loss of drugowing to adhesion to the inner surface of the milling chamber. [16] A problem associated with the pearl millingtechnology is the erosion from the milling material during the milling process. In order to reduce the quantity ofimpurities caused by an erosion of the milling media, the milling beads were coated with highly cross-linkedpolystyrene resin. [17] Furthermore, the method is not suitable for drug powders with elasticity. Despite theselimitations, the milling method is the most commonly used method in industry because of its low cost and capacityfor rapid production. [16]2. High Pressure Homogenization methods1. Microfluidization (IDD-P technology)The microfluidizer is a jet stream homogenizer of two fluid streams collided frontally with high velocity (upto1000m/sec) under pressures up to 4000 bar. There is aturbulent flow, high shear forces, particles collied leadingto particle diminution to the nanometer range.The high pressure applied and the high streaming velocity of thelipid can also lead to cavitation additionally, contributing to size diminution. To preserve the particle size,stabilization with phospholipids or other surfactants and stabilizers is required. A major disadvantage of thisprocess is the required production time. In many cases, 50 to 100 time- consuming passes are necessary for asufficient particle size reduction. SkyePharma Canada, Inc. (previously RTP, Inc.) applies this principle for its IDD-P technology toproduce submicron particles of poorly soluble drugs. [15]International Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 20115

Sneha V Sawant et al., IJSID 2011, 1 (3), 1-152. Piston-gap homogenizationIt is also known as High pressure homogenization in water (Dissocubes®).Drug nanocrystals can also beproduced by high-pressure homogenization using piston gap homogenizers.Depending on the homogenizationtemperature and the dispersion media, there is a difference between the Dissocubes® technology and theNanopure® technology.Dispersion medium of the suspensions was water. A piston in a large bore cylinder createspressure up to 2000bar. The suspension is pressed through a very narrow ring gap. The gap width is typically inthe range of 3-15 micrometer at pressures between 1500-150 bar. There is a high streaming velocity in the gapaccording to the Bernouli equation. Due to the reduction in diameter from the large bore cylinder (e.g. 3 cm) to thehomogenization gap, the dynamic pressure (streaming velocity) increases and simultaneously decreases the staticpressure on the liquid. The liquid starts boiling, and gas bubbles occur which subsequently implode, when thesuspension leaves the gap and is again under normal pressure (cavitation). Gas bubble formation and implosionlead to shock waves which cause particle diminution. The patent describes cavitation as the reason for theachieved size diminution. [18] The use of water as dispersion medium is associated with some disadvantages.Hydrolysis of water-sensitive drugs can occur, as well as problems during drying steps. In cases of thermolabiledrugs or drugs possessing a low melting point, a complete water removal requires relatively expensive techniques,such as lyophilization. For these reasons, the Dissocubes® technology is particularly suitable if the resultingnanosuspension is directly used without modifications, such as drying steps.Many different drugs have beenprocessed by high pressure homogenization to produce DissoCubes. Up to now each drug investigated could beconverted into a nanosuspension. Examples include RMKP22, carbamazepin, bupravaquone aphidicolin,cyclosporine, paclitaxel, RMBB98, azodicarbonamide, and prednisolone. [19]3. Nanopure® TechnologyIn Nanopure technology (PharmaSol GmbH, Germany), poorly water-soluble drugs are transferred to drugnanocrystals via a high-pressure homogenization process. The drug powder is dispersed in a surfactant solutionand the forces in the high-pressure homogenizer are strong enough to disintegrate the coarse drug powder intodrug nanoparticle with a mean diameter, typically between 200–600 nm. The drug powder is dispersed in anonaqueous medium (e.g., PEG 600, Miglyol 812) or a water-reduced mixture (e.g., water-ethanol) and theobtained presuspension is homogenized in a piston-gap homogenizer. A suitable machine for the laboratory scaleis the Micron Lab 40 (APV Deutschland GmbH). Nonaqueous dispersion media such as PEG or oils yieldsuspensions that are suitable for the direct filling of capsules and thus an intermediate step required when usingpure aqueous nanosuspension is avoided. With nanopure technology, homogenization can be performed in anonaqueous phase or phases with reduced water content. And, in contrast to more pronounced cavitation at highertemperatures, homogenization was similar or more efficient at lower temperatures, even below the freezing pointof water. [20]International Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 20116

Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15COMBINATION TECHNOLOGIES1. Nanoedge® TechnologyNanoedge technology (Baxter Healthcare Corporation, Deerfield, IL) described the formulation method forpoorly water-soluble drugs. It is a useful technology for active ingredients that have high melting points and highoctanol-water partition coefficients, logP. It is based on direct homogenization, microprecipitation, and lipidemulsions. In microprecipitation, the drug first is dissolved in a water-miscible solvent to form a solution. Then,the solution is mixed with a second solvent to form a presuspension and energy is added to the presuspension toform particles having an average effective particle size of 400 nm to 2 μ. The energy-addition step involves addingenergy through sonication, homogenization, countercurrent flow homogenization, microfluidization, or othermethods of providing impact, shear, or cavitation forces. A drug suspension resulting from these processes may beadministered directly as an injectable solution, provided water-for-injection is used in the formulation and anappropriate means for solution sterilization is applied. Nanoedge technology facilitates small particle sizes (

Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15tube. Spraying is provided by a nozzle. Droplets of solution become very small due to spraying; therefore, surfacearea of the drying matter increases leading to fast drying.Concentration, viscosity, temperature and spray rate ofthe solution can be adjusted and particle size, fluidity and drying speed can be optimized. The dissolution rate andbioavailability of several drugs, including hydrocortisone, COX-2 Inhibitor (BMS-347070) were improved utilizingthis method. [24]Selection of Stabilizers for Nanocrystal PreparationSelection of stabilizers is very important in nanocrystal formulations because the type and concentration ofstabilizer affect the final size of the particles, and also, stabilizers prevent nanocrystals from aggregating. Polymersor surface active agents exert their effect by covering the surface of drug nanocrystals and providing stabilizationby creating a steric barrier. At the nano size, forces between particles due to dispersion or van der Waals forcescome into play. Nanosized particles with a high surface area have high surface free energy (ΔG). Thus, particlestend to agglomerate in order to decrease the surface free energy leading to an increase in particle size andreduction in the surface area. Therefore, a stabilizer leads to a decrease in ΔG by decreasing the interfacial tension.[25]: interfacial tension between the surface of solid and the surrounding liquid phase (joule/m2)ΔG: change in surface free energy (joule) ΔA: change in the surface area (m2)The concentration of the stabilizer is an important factor that affects the physical stability of the finalproduct. [26] Hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), povidone (PVP K30), andpluronics (F68 and F127) are polymers suitable for use as stabilizers. The chains should be long enough to providea steric layer, but not too big to slow down dissolution. Polysorbate 80 (nonionic), sodium lauryl sulfate anionic)are some examples of suitable surfactant stabilizers for physical stability. Also, surfactants often help in thewetting, electrostatic stabilization and dispersion of the drug particles, which are usually very hydrophobic. HPMCE3, Povidone, and SLS are some of the stabilizers that have been used in the nanocrystal formulations of drugs thatare on the market today. [27]Characterization of NanocrystalsThe essential characterization parameters for nanosuspension include evaluation of size and sizedistribution, zeta potential, crystalline state, dissolution velocity and saturation solubility, surfacehydrophilicity/hydrophobicity. Other tests include chemical investigation such as evaluation of possibledegradation products and evaluation of moisture of nanocrystals (for lyophilized API).The mean size and sizedistribution (polydispersity index) are important parameters because they govern properties such as saturationsolubility, dissolution velocity,physical stability, and certain biological performances. Photoncorrelationspectroscopy (PCS) or dynamic light scattering technique (DLS) are employed, but limited to measuringsizes of 3 nm to 3 µm, therefore laser diffractrometry (LD) is used to detect aggregates of drug nanocrystals. LD isInternational Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 20118

Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15able to measure particles of0.05 µm to 2000 µm. Scanning (or transmission) electron microscopy(SEM, TEM) mayalso be used for size evaluation. The polydispersity index (PDI) is an important index of physical stability of thenanocrystal. PDI values vary between 0 (monodisperse particles) to 1 (broad distribution), however lower values(.0.3) areusually more appreciable for long-term stability of the nanosuspension. Surface charge is an importantparameter also governing the stability of the nanosuspensions. It is measured by means of electrophoresis and isexpressed as electrophoretic mobility or converted to zeta potential. This measurement allows for the prediction ofstorage stability of the nano-dispersions. Usually the particles with sufficient zeta potential are less likely toaggregate. Literature states that a zeta potential of at least -30 mV for electrostatic and -20 mV for stericallystabilized nanoparticles is desirable for physically stable suspensions.Evaluation of crystalline character isrequired to ensure that crystallinity of the drug has been retained upon nanonization because fabricationprocedures may alter the polymorphic state of the drug. For instance high pressure homogenization may generatenanocrystals with amorphous fraction. Differential scanning calorimetry (DSC) and X-ray diffraction analysis(XRD) may be used to evaluate the polymorphic state. Dissolution velocity and saturation solubility need to beevaluated in comparison to the traditional dosage forms of the drug. The determination of such parametersalsohelps to anticipate the in vivo performance of the nanocrystal formulation. Characterization of surfaceproperties is essential as it provides insight of the in vivo performance of the generated nanocrystals. In the case ofintravenous injection, the in vivo behaviour of the drug depends on organ distribution, which in turn depends on itssurface properties such as hydrophibicity and interactions with plasma proteins. Hydrophobic interactionchromatography is able to evaluate the surface hydrophobicity of nanocrystals. Two-dimensional gelelectrophoresis (2-D) PAGE is a method employed for the qualitative and quantitative measurements of proteinadsorption after intravenous injection of nanosuspension. Such analysis is imperative to evaluate the in vivobiological performance of the fabricated nanocrystals and establish in-vitro/in-vivo correlation [28,29]DOSAGE FORMULATION AFTER NANONIZATIONAfter nanonization, drug nanocrystals are frequently formulated in conventional dosage forms such astablets, capsules, pellets and injectable suspensions. This step requires the removal of suspension solvent andincorporation of drug nanocrystals into the new dosage forms without compromising their physical, chemical andpharmaceutical properties. Numerous techniques such as freeze drying, spray drying, centrifugation andultrafiltration havebeen employed to dry or concentrate drug nanoparticles. Protectants such as mannitol, sucroseand trehalose are usually added to the nanoparticles to avoid agglomeration. In the freeze drying procedure, thenature and amount of protectants and freezing rate are important factors. For solid dosage forms, the addition ofexcipients such as fillers, binders, humectants, disintegrating agents and lubricants is crucial in retaining theproperties of drug nanoparticles. [16]International Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 20119

Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15POTENTIAL CLINICAL ADVANTAGES OF NANOCRYSTALSApplication for Oral Drug DeliveryThe oral route is the most important and preferred route of administration. The formulation of drugnanocrystals can impressively improve the bioavailability of perorally administered poorly soluble drugs. In 1995,Liversidge and Cundy reported an increase in bioavailability for the drug Danazol from 5.1 ± 1.9% for theconventional suspension to 82.3 ± 10.1% for the nanosuspension. [30] The increased dissolution velocity andsaturation solubility lead to fast and complete drug dissolution, an important prerequisite for drug absorption.Whenever a rapid onset of a poorly soluble drug is desired, the formulation of drug nanocrystals can be beneficial.If absorption windows limit the drug absorption or by food effects, drug nanocrystals have advantages incomparison to conventional suspensions. Another important advantage of drug nanocrystals is their adhesivenessand the increased residence time, which canpositively influence the bioavailability. The mucoadhesiveness can beraised by the use of mucoadhesive polymers in the dispersion medium. Additionally the utilized mucoadhesivepolymers can prevent the drug from degradation. The reduced particle size can be also exploited for improveddrug targeting, as reported for inflammatory tissues. [31] Nanosuspensions enable incorporation of all hydrophobicdrugs in well established sustained release technologies. However whole doing so,the effect and interaction ofdosage form excipients with the nanocrystalline drug must be critically investigated. Drug nanosuspensions can beincorporated into dosage forms, such as tablets, capsules, and fast melts by means of standard manufacturingtechnologies. A ketoprofen nanosuspension has been successfully incorporated into pellets to release drug over aperiod of 24 hrs. [32]Intravenous drug deliveryIn principle aqueous nanosuspensions are an ideal formulation approach to overcome side effectsof i. v. formulations due to not very well tolerated excipients (example: Paclitaxel formulated with Cremophor EL inthe product Taxol®; Itraconazole formulated with cyclodextrine in the product Sporanox®).However, injection ofnanosuspensions leads to a different pharmacokinetics compared to injecting the drug solutions. Nanocrystalsabove 200 nm do not dissolve fast enough; they are taken up by the macrophages of the liver, potentially targetingtoxicity to the liver. In case nanosuspensions of very small nanocrystals are injected, they dissolve much faster dueto their nanocrystals size well below 100 nm. Therefore they are considered to be better suited to minimize/avoiduptake by the liver and to mimic intravenously injected solutions. [33]Pulmonary drug deliveryAs an alternative to dry powders for inhalation, nanosuspensions can be used in case of poorly solubledrugs. Application can simply be performed by placing aqueous nanosuspensions in an aqueous nebulizer. Thenebulizer generates an aerosol, with a droplet size suitable for pulmonary administration, e.g. 1–5 μm droplets.The nanocrystals are contained inside these droplets. The nanocrystals cannot be inhaled as a powder. First of all,the nanocrystals are highly adhesive with a tendency to agglomerate, and in addition particles below 0.5–1 μm arebeing exhaled. The advantage of nanocrystals is that they show an increased dissolution velocity compared toInternational Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 201110

Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15micronsized crystals. When the aerosol droplets deposit in the lung, as fine particles they should spread moreevenly on the lung surface, especially when stabilized with surfactants with good spreadability. Budesonide(corticosteroid) nanosuspensions for pulmonary delivery have been successfully formulated. [34] Intensive studiesfor pulmonary delivery of nanosuspensions were performed [35] by comparing different commercial portablenebulizers regarding their ability to nebulize nanosuspensions. [36] All of them were suitable, showing thatnebulisation of well-stabilized nanosuspensions can be performed successfully.Ocular drug deliveryNanosuspensions have not been yet exploited for this route of drug administration. The general problem isthat solutions are relatively fast cleared from the eye , adhesive nanoparticulate suspensions can show prolongedrelease due to their adhesion properties. Polymeric (Eudragit RS 100 and Eudragit RL 100) nanoparticulatesuspensions of flurbiprofen and ibuprofen [37] revealed superior in vivo performance over the existing marketedformulations and could sustain drug release for 24 h. Drug nanosuspensions can also be used for drugs that exhibitpoor solubility in lachrymal fluids providing advantages of prolonged residence time in a cul-de-sac. Currentlythere are few studies are investigating NSAIDs in the form of nanocrystals for ophthalmic application. [38] Anincreased rate and extent of drug absorption and intensity of drug action was reported for ocular nanosuspensionsof hydrocortisone, prednisolone and dexamethasone. [39] In contrast to the polymeric nanoparticles,nanosuspensions have a clear regulatory advantage. The particles are drained via the lipophilic channels to thenose, from here to the pharynx. That means, the materials used in formulation need to be approved for occularadministration. As many polymers are not approved by official authorities. As nanosuspensions do not contain anymatrix material, and are purely composed of drug and comparatively small amount of stabilizer. [15]Dermal drug deliveryNanocrystals can increase the penetration of poorly soluble cosmetic and pharmaceutical actives into theskin.The increased saturation solubility leads to an increased concentration gradient, thus promoting passivepenetration. Molecules penetrated into the skin are very fast replaced by new molecules dissolving from thenanocrystal depot in the cream. The first four cosmetic nanocrystal products with rutin were launched by Juvena.Compared to the water-soluble rutinglucoside, the original rutin molecule as nanocrystal formulation possesses a500 times higher bioactivity (as measured by sun protection factor (SPF) [40] Of course the same principle can beapplied to poorly soluble pharmaceutical drugs of interest for dermal application.Targeted Drug DeliveryNanosuspension can be used for targeted delivery as their surface properties & changing of the stabilizercan easily alter in vivo behaviour. Their versatility and ease of scale up and commercial production enables thedevelopment of commercially viable nanosuspensions for targeted drug delivery. The natural targeting processcould pose obstacles when macrophages are not the desired targets.Hence, in order to bypass the phagocyticuptake of drugs,its surface potential needs to be altered. Kayser developed the formulation of aphidicolin as ananosuspension to improve the drug targeting effect against Leishmania-infected macrophages. He stated thatInternational Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 201111

Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15aphidicolin was highly active at a concentration in the microgram range. [41] Nanosuspensions afford a means ofadministrating poorly soluble drugs to brain with decreased side effects. Significant efficiency has been associatedwith microparticulate busulfan in mice administered intrathecally . [42]Nanocrystals in nutritionThere is an increasing consciousness about nutritional health and an increasing demand to complementthe daily nutrition by additives or nutraceuticals. From the philosophy for a healthy population, nutrition plays avery important role. The nutraceutical market is growing, and there are many nutraceutical compounds, e.g.antioxidants, which are poorly soluble. Presently most popular molecules isCoenzyme Q10 capsules, but Q10 has alow oral bioavailability. There are products on the market, claiming to contain “nano Q10” being 100% bioavailable(e.g. containing surfactants for solubilization), requiring only one tenth of the regular dose in normal products.Nanocrystals are also a suitable formulation technology for poorly soluble nutraceuticals like Coenzyme Q10, rutin,hesperidin, apigenin etc. Nanocrystals can be efficiently used to provide effective, bioavailable nutraceuticalproducts in future [43] .STATUS OF NANOCRYSTALS IN THE MARKETTable.1 [13]Trade name Therapeutic use AppliedtechnologyRapamune ®(Rapamycin,Sirolimus)Pharma companyAdministrationrouteImmunosuppressive élannanosystems Wyeth Pharmaceuticals OralEmend ® (Aprepitant) Antiemetic élannanosystems Merck & Co. OralTricor ® (Fenofibrate) Hypercholesterolemia élannanosystems Abbott Laboratories OralTriglide ®(Fenofibrate)Megace ES ®(Megestrol acetate)Avinza ® (Morphinesulfate)Focalin ® XR(DexmethylphenidateHCl)Ritalin ® LA(MethylphenidateHCl)Hypercholesterolemia IDD-P ®technologyProduced by SkyePharmamarketed by Sciele PharmaInc. (Atlanta, CA, USA).Antianorexic élannanosystems Par PharmaceuticalCompanies Inc. (SpringValley, NY, USA)International Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 2011OralOralPsychostimulant drug élannanosystems King Pharmaceuticals Oralélannanosystems Novartis Oralélannanosystems Novartis OralZanaflex Capsules Muscle relaxant élannanosystems Acorda Oral(TizanidineHCl)Nanocrystals for oral administration were the first products on the pharmaceutical market – due to thehuge market potential – and the easier way of product realization compared to the intravenous route. Various12

Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15products exploited use different features of the nanocrystals, an overview of market products is given in Examplesof nanocrystal products on the market in Table1.LIMITATIONS OF DRUG NANOCRYSTAL TECHNOLOGYHigh cost instruments required for the production of drug nanocrystal that increases the cost of dosageforms.This technique is limited to BCS class II drug only. Formation of nanocrystal and their stability depend onmolecular structure of drug so only certain class of compounds will qualify. [44]CONCLUSIONPoor aqueous solubility is rapidly becoming the leading hurdle for formulation scientists workingon oral delivery of drug compounds and leads to employment of novel formulation technologies. The use of drugnanocrystals is a universal formulation approach to increase the therapeutic performance of these drugs in anyroute of administration. Almost any drug can be reduced in size to the nanometer range. Owing to their greatformulation versatility drug nanocrystals are no longer only the last chance rescue for a few drugs. Many insolubledrug candidates are in clinical trials formulated as drug nanocrystals. Currently, attention is turned to improvingthe diminution performance to produce drug nanocrystals well below 100 nm, also incases of very hard drugs.First approaches were already successful. New technologies are in development to produce final dosage forms withhigher drug loadings, better redispersability at their site of action, and an improved drug targeting.REFERENCES1. Lipinski C, Poor aqueous solubility— an industry wide problem in drug discovery, Am.Pharm. Rev.2002; 5: 82–85.2. Keck C, Kobierski S, Mauludin R, Müller RH, Second generation of drug nanocrystals for delivery of poorly soluble drugs:smartcrystals technology,D O S I S,2008; 24(2):125-127.3. Troester F, Cremophor-free aqueous paclitaxel nanosuspension—production and chemical stability, Controlled ReleaseSociety 31st annual meeting, Honolulu, HI, 2004.4. Möschwitzer J, Achleitner G, Pomper H, Muller RH, Development of an intravenously injectable chemically stable aqueousomeprazole formulation using nanosuspension technology, European Journal of Pharmaceutics and Biopharmaceutics,2004; 58(3):615–619.5. Noyes A, Whitney W, The rate of solution of solid substances in their own solutions, J Am Soc,1987;19:930-934.6. Mosharraf M, Nystrom C, The effect of particle size and shape on the surface specific dissolution rate of micronizedpractically insoluble drugs, Int J Pharm, 1995; 122: 35-47.7. Rawat N, Senthil M, Solubility: Particle Size Reduction is a Promising Approach to Improve The Bioavailability ofLipophillic Drugs, International Journal of Recent Advances in Pharmaceutical Research, 2011; 1: 8-18.8. Ruddy SB, Ryde NP, inventors; Elan PharmaInternational Limited, assignee, Solid dose nanoparticulate compositions, WO666, 539 , March 28,2002.9. JunghannsJUAH, Muller AH, Nanocrystal technology, drug delivery and clinical Applications, Int J Nanomedicine, 2008;3(3):295–309.10. Gulsan T, Gursoy RN, Oner L, Nanocrystal Technology For Oral Delivery of Poorly Water-Soluble Drugs, J. Pharm. Sci, 2009;34: 55–65.International Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 201113

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