Sneha V Sawant et al.

, IJSID 2011, 1 (3), 1-15

ISSN:2249-5347

IJSID
International Journal of Science Innovations and Discoveries
Review Article
An International peer Review Journal for Science

Available online through www.ijsidonline.info

DRUG NANOCRYSTALS: NOVEL TECHNIQUE FOR DELIVERY OF POORLY SOLUBLE DRUGS

Sneha 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 Mumbai 400614. ABSTRACT During the last two decades, many modern technologies have been
Received: Modified: 16.09.2011 03.10.2011

established in the pharmaceutical research and development area. The automation of the drug discovery process by technologies such as high throughput screening, combinatorial chemistry, and computer- aided drug design is leading to a vast number of drug candidates possessing a very good efficacy. Unfortunately, many of these drug candidates are exhibiting poor aqueous solubility. The use of drug nanocrystals is a universal formulation approach to increase the therapeutic performance of these drugs. Nanocrystal dispersions comprise water, active drug substance and a stabilizer. They are physically stable due to the presence of stabilizers that prevent reagragregation of the active drug substance. Different techniques can be used to prepare nanocrystal formulations of a drug powder such as homogenization, coprecipitation, spray drying and milling. There are several

Published: 29.12.2011 Keywords: Nanocrystal, Dissolution rate, Particle size, Bioavailability, Stabilizers
*Corresponding Author

INTRODUCTION
of nanocrystal

advantages

formulations

such

as,

enhanced

oral

bioavailability, improved dose proportionality, reduced food effects, suitability for administration by all routes and possibility of sterile filtration due to decreased particle size range. Nanocrystal technology is cheap and easy to apply; thus, it appears that this technology will be substantially
Name: Sneha V Sawant Place: Navi Mumbai, Maharashtra, India E-mail: manu2sneha@gmail.com

INTRODUCTION

useful for the manufacture of poorly water-soluble drug products. This review article describes the physicochemical properties of drug

nanocrystals, production methods, potential clinical applications and limitations.

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INTRODUCTION It is estimated that 40% or more of active substances being identified through combinatorial screening programs are poorly soluble in water. Poor solubility is not only a problem for the formulation development and clinical testing; it is also an obstacle at the very beginning when screening new compounds for pharmacological activity. From this, there is a definite need for smart technological formulation approaches to make such poorly soluble drugs bioavailable. Making such drugs bioavailable means that they show sufficiently high absorption after oral administration, or they can alternatively be injected intravenously.
[1]

Since many years the approaches to

increase drug solubility are solubilisation by surfactants, complex formation (e. g. cyclodextrin, macromolecules) self-emulsifying drug delivery systems (SEDDS), microemulsions and especially for oral administration micronisation of drug powders
[2].

Micronization, meaning the transfer of drug powders into the size range

between typically 1-10m. However, nowadays many drugs are so poorly soluble that micronization is not sufficient. The increase in surface area, and thus consequently in dissolution velocity, is not sufficient to overcome the bioavailability problems of very poorly soluble drugs of the biopharmaceutical specification class II. A consequent next step was to move from micronization to nanonization. At the beginning of the 1990s the drug nanocrystals 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 nm up 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 same

result was found for the chemically labile drug omeprazole when formulated as a nanosuspension, the stability was distinctly increased in comparison to the aqueous solution. [4] Increasing Dissolution through Nanonization Most differentiating features of drug nanocrystals are the increased saturation solubility and the accelerated dissolution velocity. A drug specific constant which depends only on the solvent and the temperature is called as the saturation solubility (Cs). As described by the Nernst Brunner/Noyes-Whitney equation [5], the solid API dissolution rate is proportional to the surface area available for dissolution as discussed below

Where, 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 dissolution rate because of increase insurface area. Furthermore, as explained by the Prandtl equation, the diffusion layer thickness will also be reduced, thus resulting in an enhanced dissolution rate.[6] An increase in saturation solubility of the nanosized API has also been explained by the FreundlichOstwald equation:

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Where, S = saturation solubility of the nanosized API, S= saturation solubility of an infinitely largeAPI crystal, = crystal-medium interfacial tension, M = molecular weight of the compound, r = particleradius,

= density, R = gas constant, T =temperature. Finally, surface wetting increment by surfactants in nanosuspension formulations, in comparison to conventional micronized formulations results in further enhancement of dissolution rates. Hence, better therapeutic drug efficacy was obtained. Also, the rejection of new drug entities because of poor solubility can be prevented. Hence novel and patented techniques are mushrooming up in the pharmaceutical sector. [7] Nanocrystal Technology Preparation of drug nanocrystals is basically a nanosizing method, which is utilized to enhance the oral bioavailability of poorly water-soluble drugs. Drug nanocrystals are nanoscopic crystals of the drug with dimensions less than 1000 nm as defined in the first patents in this field.
[8]Nanocrystal

dispersions contain

dispersion media (water, aqueous solutions or nonaqueous media), active drug substances and surface active agents or polymers required for stabilization. [9]If necessary, other substances such as buffers, salts and sugars can be added.There are many advantages of nanocrystal formulations designed for oral administration. Theyare as follows: 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 be administered 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 very small 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 concentration of active drug substances leads to an increased reliability for patients Sustained crystal structure-Nanocrystal technology leads to an increase in dissolution rate depending on the increase in surface area obtained by reduction of the particle size of the active drug substance down to the nano size range preserving the crystal morphology of the drug Improved stability- They are stable systems because of the use of a stabilizer that prevents

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reaggregation of active drug substances during preparation . Suspension of drug nanocrystals in liquid can be stabilized by adding surface active substances or polymers Applicability to all poorly soluble drugs becauseall these drugs could be directly disintegrated into nanometersized particles. [10] Bottom up Technologies There are two basic approaches to produce drug nanocrystals, the bottom up and the top down technologies. In the bottom up processes, one starts from the molecule in solution, the molecules are aggregated to form particles, being crystalline or amorphous. There are various bottom up technologies. [11] 1. Precipitation method A poor water-soluble drug is dissolved in an organic medium, which is water miscible. A pouring of this solution into a non solvent, such as water, will cause a precipitation of finely dispersed drug nanocrystals. A problem associated with this technology is that the formed nanoparticles need tobe stabilized to avoid growth in micrometer crystals. In addition, the drug needs to be soluble at least in one solvent , this creates problems for the newly 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 the precipitated nanocrystals is the use of polymeric growth inhibitors, which are preferably solublein the aqueous phase. The increased viscosity of the aqueous phase can reduce particle growing. [12 ] A basic disadvantage of many precipitation processes is the use of organic solvents, which need to be removed again in most cases, increasing the costs. Especially when large solvent volumes are required, being the case when the drug exhibits low solubility in water and also in organic solvents. Therefore, for pharmaceutical industry, typically the top down technologies are employed for the products introduced to the market. [13] 2. Sonocrystallization Recrystallization of poorly soluble material using liquid solvents and antisolvents has also been employed successfully to reduce particle size. The novel approach for particle size reduction on the basis of crystallization by using ultrasound is sonocrystallization. Sonocrystallization utilizes ultrasound power characterized by a frequency range of 20-100 kHz for inducing crystallization. It not only enhances the nucleation rate but also an effective means of size reduction & controlling size distribution of the active pharmaceutical ingredient (API). Most applications used ultrasound in the range 20 khz -5mhz.Sonocrystallization technique or technology has also been studied to modify the undesirables of NSAIDS I) i.e. poor solubility and dissolution rate and consequently the poor bioavailiability. Flubiprofen was poured in deionized water at 25C and sonicated for 4 minutes at an amplituted of 60% and cycle is 40 sec on and 10 sec off. The particle size of treated flubiprofen was significantly reduced and the increased solubility of treated flurbiprofen was about 35%. The intrinsic dissolution rate of treated flubiprofen increased by 2-fold. The dissolution studies obtained that 90% of the drug was released within 20 minutes for treated flubiprofen as compared to untreated flubiprofen obtained 60% release of the drug.
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3. Gas antisolvent recrystallization-GAS This 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 SCF diffuses 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 pressure required for these processes restrict the utility of this technology in the pharmaceutical industry. [14] Top Down Technologies In the top down technologies, one starts from large crystals in the m range and goes down to the nano dimension by diminuting the crystals.There are several top down technologies which are discussed below.[11] 1. Media milling In this protocol, the milling chamber is charged with milling pearls, dispersion media(e.g. water), drug powders and stabilizers. The pearls are rotated at a very high speed to generate strong shear forces to disintegrate drug powders into nanoparticles. The pearls or balls consist of ceramics, stainless steel, glass, or highly crosslinked polystyrene resin-coated beads.[15] Physical characteristics of the resulting nanocrystals depend on the number of milling pearls, the amount of drug and stabilizer, and milling time, speed and temperature. Drug nanocrystals can be prepared by a wet milling procedure using a rotation/revolution mixer and zirconia balls. The technique showed superior performance compared with the beads mill, enabling drug nanocrystals to be produced in a quick process (approximately 5 min) using a small amount of zirconia balls. The potential shortcomings of media milling are difficulty in the removal of residual milling media fromthe final product and the loss of drug owing to adhesion to the inner surface of the milling chamber.
[16]

A problem associated with the pearl milling

technology is the erosion from the milling material during the milling process. In order to reduce the quantity of impurities caused by an erosion of the milling media, the milling beads were coated with highly cross-linked polystyrene resin.
[17]

Furthermore, the method is not suitable for drug powders with elasticity. Despite these

limitations, the milling method is the most commonly used method in industry because of its low cost and capacity for rapid production. [16] 2. High Pressure Homogenization methods 1. Microfluidization (IDD-P technology) The microfluidizer is a jet stream homogenizer of two fluid streams collided frontally with high velocity (up to1000m/sec) under pressures up to 4000 bar. There is aturbulent flow, high shear forces, particles collied leading to particle diminution to the nanometer range.The high pressure applied and the high streaming velocity of the lipid 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 this process is the required production time. In many cases, 50 to 100 time- consuming passes are necessary for a sufficient particle size reduction. SkyePharma Canada, Inc. (previously RTP, Inc.) applies this principle for its IDDP technology toproduce submicron particles of poorly soluble drugs. [15]
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2. Piston-gap homogenization It is also known as High pressure homogenization in water (Dissocubes).Drug nanocrystals can also be produced by high-pressure homogenization using piston gap homogenizers.Depending on the homogenization temperature and the dispersion media, there is a difference between the Dissocubes technology and the Nanopure technology.Dispersion medium of the suspensions was water. A piston in a large bore cylinder creates pressure up to 2000bar. The suspension is pressed through a very narrow ring gap. The gap width is typically in the range of 3-15 micrometer at pressures between 1500-150 bar. There is a high streaming velocity in the gap according to the Bernouli equation. Due to the reduction in diameter from the large bore cylinder (e.g. 3 cm) to the homogenization gap, the dynamic pressure (streaming velocity) increases and simultaneously decreases the static pressure on the liquid. The liquid starts boiling, and gas bubbles occur which subsequently implode, when the suspension leaves the gap and is again under normal pressure (cavitation). Gas bubble formation and implosion lead to shock waves which cause particle diminution. The patent describes cavitation as the reason for the achieved 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 thermolabile drugs 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 resulting nanosuspension is directly used without modifications, such as drying steps.Many different drugs have been processed by high pressure homogenization to produce DissoCubes. Up to now each drug investigated could be converted into a nanosuspension. Examples include RMKP22, carbamazepin, bupravaquone aphidicolin, cyclosporine, paclitaxel, RMBB98, azodicarbonamide, and prednisolone. [19] 3. Nanopure Technology In Nanopure technology (PharmaSol GmbH, Germany), poorly water-soluble drugs are transferred to drug nanocrystals via a high-pressure homogenization process. The drug powder is dispersed in a surfactant solution and the forces in the high-pressure homogenizer are strong enough to disintegrate the coarse drug powder into drug nanoparticle with a mean diameter, typically between 200600 nm. The drug powder is dispersed in a nonaqueous medium (e.g., PEG 600, Miglyol 812) or a water-reduced mixture (e.g., water-ethanol) and the obtained presuspension is homogenized in a piston-gap homogenizer. A suitable machine for the laboratory scale is the Micron Lab 40 (APV Deutschland GmbH). Nonaqueous dispersion media such as PEG or oils yield suspensions that are suitable for the direct filling of capsules and thus an intermediate step required when using pure aqueous nanosuspension is avoided. With nanopure technology, homogenization can be performed in a nonaqueous phase or phases with reduced water content. And, in contrast to more pronounced cavitation at higher temperatures, homogenization was similar or more efficient at lower temperatures, even below the freezing point of water. [20]

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COMBINATION TECHNOLOGIES 1. Nanoedge Technology Nanoedge technology (Baxter Healthcare Corporation, Deerfield, IL) described the formulation method for poorly water-soluble drugs. It is a useful technology for active ingredients that have high melting points and high octanol-water partition coefficients, logP. It is based on direct homogenization, microprecipitation, and lipid emulsions. 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 to form particles having an average effective particle size of 400 nm to 2 . The energy-addition step involves adding energy through sonication, homogenization, countercurrent flow homogenization, microfluidization, or other methods of providing impact, shear, or cavitation forces. A drug suspension resulting from these processes may be administered directly as an injectable solution, provided water-for-injection is used in the formulation and an appropriate means for solution sterilization is applied. Nanoedge technology facilitates small particle sizes (<1000 nm [volume weighted mean]), high drug loading (10200 mg/mL), long-term stability (up to 2 years at room temperature or temperatures as low as 5 C), the elimination of co solvents, reduced levels of surfactants, and the use of safe, well-tolerated surfactants [21]NANOEDGE process is particularly suitable for drugs that are soluble in non aqueous media possessing low toxicity, such as N-methyl-2-pyrrolidinone. [15] 2. Rapid expansion from a liquefied-gas solution (RESS) This process is applicable to the substances those are soluble in supercritical fluids. This process offers a solvent free final product. In this process, first the solute is dissolved in a supercritical fluid then it is passed through a nozzle at supersonic speed. Pressure reduction of solution in a nozzle leads to a rapid expansion. This RESS leads to super saturation of the solute and subsequent precipitation of solute particles with narrow particle size distributions.
[22]

Pathak et al., 2004 applied SCF processing technique i.e. rapid expansion of super critical

solution in a liquid solvent (RESOLV) for the nanosizing of water insoluble drug particles. The drugs used for nanosizing were anti-inflammatory Ibuprofen and Naproxen for which CO2 and CO2co solvent system were used due to its favorable processing characteristics like its low critical temp (TC=31.1-C) and pressure (PC=73.8 bar). The RESOLVE process produced exclusively nanoscale (less than 100nm) particles.Ibuprofen and Naproxen particles suspended in aqueous solution and the aqueous suspension of the drug nanoparticle are protected from agglomeration and precipitation by using common polymeric and oligomeric stabilizing agents. [23] OTHER METHODS 1. Spray drying One of the preparation methods of nanocrystals is spray drying. This method is usually used for drying of solutions and suspensions. In a conical or cylindrical cyclone, solution droplets are sprayed from top to bottom, dried in the same direction by hot air and spherical particles are obtained. Spraying is made with an atomizer which rapidly rotates and provides scattering of the solution due to centrifugal effect. The solution, at a certain flow rate, is sent to the inner tube with a peristaltic pump, nitrogen or air at a constant pressure is sent to the outer
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tube. Spraying is provided by a nozzle. Droplets of solution become very small due to spraying; therefore, surface area of the drying matter increases leading to fast drying.Concentration, viscosity, temperature and spray rate of the solution can be adjusted and particle size, fluidity and drying speed can be optimized. The dissolution rate and bioavailability of several drugs, including hydrocortisone, COX-2 Inhibitor (BMS-347070) were improved utilizing this method. [24] Selection of Stabilizers for Nanocrystal Preparation Selection of stabilizers is very important in nanocrystal formulations because the type and concentration of stabilizer affect the final size of the particles, and also, stabilizers prevent nanocrystals from aggregating. Polymers or surface active agents exert their effect by covering the surface of drug nanocrystals and providing stabilization by creating a steric barrier. At the nano size, forces between particles due to dispersion or van der Waals forces come into play. Nanosized particles with a high surface area have high surface free energy (G). Thus, particles tend to agglomerate in order to decrease the surface free energy leading to an increase in particle size and reduction in the surface area. Therefore, a stabilizer leads to a decrease in G by decreasing the interfacial tension.
[25]

: interfacial tension between the surface of solid and the surrounding liquid phase (joule/m2) G: change in surface free energy (joule) A: change in the surface area (m2) The concentration of the stabilizer is an important factor that affects the physical stability of the final product.
[26]

Hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), povidone (PVP K30), and

pluronics (F68 and F127) are polymers suitable for use as stabilizers. The chains should be long enough to provide a 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 the wetting, electrostatic stabilization and dispersion of the drug particles, which are usually very hydrophobic. HPMC E3, Povidone, and SLS are some of the stabilizers that have been used in the nanocrystal formulations of drugs that are on the market today. [27] Characterization of Nanocrystals The essential characterization parameters for nanosuspension include evaluation of size and size distribution, zeta potential, crystalline state, dissolution velocity and saturation solubility, surface hydrophilicity/hydrophobicity. Other tests include chemical investigation such as evaluation of possible degradation products and evaluation of moisture of nanocrystals (for lyophilized API).The mean size and size distribution (polydispersity index) are important parameters because they govern properties such as saturation solubility, dissolution velocity,physical stability, and certain biological performances. Photon

correlationspectroscopy (PCS) or dynamic light scattering technique (DLS) are employed, but limited to measuring sizes of 3 nm to 3 m, therefore laser diffractrometry (LD) is used to detect aggregates of drug nanocrystals. LD is
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able to measure particles of0.05 m to 2000 m. Scanning (or transmission) electron microscopy(SEM, TEM) may also be used for size evaluation. The polydispersity index (PDI) is an important index of physical stability of the nanocrystal. 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 important parameter also governing the stability of the nanosuspensions. It is measured by means of electrophoresis and is expressed as electrophoretic mobility or converted to zeta potential. This measurement allows for the prediction of storage stability of the nano-dispersions. Usually the particles with sufficient zeta potential are less likely to aggregate. Literature states that a zeta potential of at least -30 mV for electrostatic and -20 mV for sterically stabilized nanoparticles is desirable for physically stable suspensions.Evaluation of crystalline character is required to ensure that crystallinity of the drug has been retained upon nanonization because fabrication procedures may alter the polymorphic state of the drug. For instance high pressure homogenization may generate nanocrystals 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 be evaluated in comparison to the traditional dosage forms of the drug. The determination of such parameters alsohelps to anticipate the in vivo performance of the nanocrystal formulation. Characterization of surface properties is essential as it provides insight of the in vivo performance of the generated nanocrystals. In the case of intravenous injection, the in vivo behaviour of the drug depends on organ distribution, which in turn depends on its surface properties such as hydrophibicity and interactions with plasma proteins. Hydrophobic interaction chromatography is able to evaluate the surface hydrophobicity of nanocrystals. Two-dimensional gel electrophoresis (2-D) PAGE is a method employed for the qualitative and quantitative measurements of protein adsorption after intravenous injection of nanosuspension. Such analysis is imperative to evaluate the in vivo biological performance of the fabricated nanocrystals and establish in-vitro/in-vivo correlation [28,29] DOSAGE FORMULATION AFTER NANONIZATION After nanonization, drug nanocrystals are frequently formulated in conventional dosage forms such as tablets, capsules, pellets and injectable suspensions. This step requires the removal of suspension solvent and incorporation of drug nanocrystals into the new dosage forms without compromising their physical, chemical and pharmaceutical properties. Numerous techniques such as freeze drying, spray drying, centrifugation and ultrafiltration havebeen employed to dry or concentrate drug nanoparticles. Protectants such as mannitol, sucrose and trehalose are usually added to the nanoparticles to avoid agglomeration. In the freeze drying procedure, the nature and amount of protectants and freezing rate are important factors. For solid dosage forms, the addition of excipients such as fillers, binders, humectants, disintegrating agents and lubricants is crucial in retaining the properties of drug nanoparticles. [16]

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POTENTIAL CLINICAL ADVANTAGES OF NANOCRYSTALS Application for Oral Drug Delivery The oral route is the most important and preferred route of administration. The formulation of drug nanocrystals 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 the conventional suspension to 82.3 10.1% for the nanosuspension.
[30]The

increased dissolution velocity and

saturation 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 in comparison to conventional suspensions. Another important advantage of drug nanocrystals is their adhesiveness and the increased residence time, which canpositively influence the bioavailability. The mucoadhesiveness can be raised by the use of mucoadhesive polymers in the dispersion medium. Additionally the utilized mucoadhesive polymers can prevent the drug from degradation. The reduced particle size can be also exploited for improved drug targeting, as reported for inflammatory tissues. [31] Nanosuspensions enable incorporation of all hydrophobic drugs in well established sustained release technologies. However whole doing so,the effect and interaction of dosage form excipients with the nanocrystalline drug must be critically investigated. Drug nanosuspensions can be incorporated into dosage forms, such as tablets, capsules, and fast melts by means of standard manufacturing technologies. A ketoprofen nanosuspension has been successfully incorporated into pellets to release drug over a period of 24 hrs. [32] Intravenous drug delivery In principle aqueous nanosuspensions are an ideal formulation approach to overcome side effects of i. v. formulations due to not very well tolerated excipients (example: Paclitaxel formulated with Cremophor EL in the product Taxol; Itraconazole formulated with cyclodextrine in the product Sporanox).However, injection of nanosuspensions leads to a different pharmacokinetics compared to injecting the drug solutions. Nanocrystals above 200 nm do not dissolve fast enough; they are taken up by the macrophages of the liver, potentially targeting toxicity to the liver. In case nanosuspensions of very small nanocrystals are injected, they dissolve much faster due to their nanocrystals size well below 100 nm. Therefore they are considered to be better suited to minimize/avoid uptake by the liver and to mimic intravenously injected solutions. [33] Pulmonary drug delivery As an alternative to dry powders for inhalation, nanosuspensions can be used in case of poorly soluble drugs. Application can simply be performed by placing aqueous nanosuspensions in an aqueous nebulizer. The nebulizer generates an aerosol, with a droplet size suitable for pulmonary administration, e.g. 15 m 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 0.51 m are being exhaled. The advantage of nanocrystals is that they show an increased dissolution velocity compared to
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micronsized crystals. When the aerosol droplets deposit in the lung, as fine particles they should spread more evenly on the lung surface, especially when stabilized with surfactants with good spreadability. Budesonide (corticosteroid) nanosuspensions for pulmonary delivery have been successfully formulated. [34] Intensive studies for pulmonary delivery of nanosuspensions were performed
[35]

by comparing different commercial portable

[36]

nebulizers regarding their ability to nebulize nanosuspensions.

All of them were suitable, showing that

nebulisation of well-stabilized nanosuspensions can be performed successfully. Ocular drug delivery Nanosuspensions have not been yet exploited for this route of drug administration. The general problem is that solutions are relatively fast cleared from the eye , adhesive nanoparticulate suspensions can show prolonged release due to their adhesion properties. Polymeric (Eudragit RS 100 and Eudragit RL 100) nanoparticulate suspensions of flurbiprofen and ibuprofen
[37]

revealed superior in vivo performance over the existing marketed

formulations and could sustain drug release for 24 h. Drug nanosuspensions can also be used for drugs that exhibit poor solubility in lachrymal fluids providing advantages of prolonged residence time in a cul-de-sac. Currently there are few studies are investigating NSAIDs in the form of nanocrystals for ophthalmic application.
[38]

An

increased rate and extent of drug absorption and intensity of drug action was reported for ocular nanosuspensions of 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 the nose, from here to the pharynx. That means, the materials used in formulation need to be approved for occular administration. As many polymers are not approved by official authorities. As nanosuspensions do not contain any matrix material, and are purely composed of drug and comparatively small amount of stabilizer. [15] Dermal drug delivery Nanocrystals can increase the penetration of poorly soluble cosmetic and pharmaceutical actives into the skin.The increased saturation solubility leads to an increased concentration gradient, thus promoting passive penetration. Molecules penetrated into the skin are very fast replaced by new molecules dissolving from the nanocrystal 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 a 500 times higher bioactivity (as measured by sun protection factor (SPF) [40] Of course the same principle can be applied to poorly soluble pharmaceutical drugs of interest for dermal application. Targeted Drug Delivery Nanosuspension can be used for targeted delivery as their surface properties & changing of the stabilizer can easily alter in vivo behaviour. Their versatility and ease of scale up and commercial production enables the development of commercially viable nanosuspensions for targeted drug delivery. The natural targeting process could pose obstacles when macrophages are not the desired targets.Hence, in order to bypass the phagocytic uptake of drugs,its surface potential needs to be altered. Kayser developed the formulation of aphidicolin as a nanosuspension to improve the drug targeting effect against Leishmania-infected macrophages. He stated that
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aphidicolin was highly active at a concentration in the microgram range.
[41]

Nanosuspensions afford a means of

administrating poorly soluble drugs to brain with decreased side effects. Significant efficiency has been associated with microparticulate busulfan in mice administered intrathecally .[42] Nanocrystals in nutrition There is an increasing consciousness about nutritional health and an increasing demand to complement the daily nutrition by additives or nutraceuticals. From the philosophy for a healthy population, nutrition plays a very 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 a low 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 nutraceutical products in future [43]. STATUS OF NANOCRYSTALS IN THE MARKET Table.1 [13] Trade name Rapamune (Rapamycin, Sirolimus) Emend (Aprepitant) Triglide (Fenofibrate) Megace ES (Megestrol acetate) Avinza (Morphine sulfate) Focalin XR (DexmethylphenidateHCl) Ritalin LA (Methylphenidate HCl) Antianorexic Therapeutic use Applied technology Pharma company Wyeth Pharmaceuticals Administration route Oral

Immunosuppressive lannanosystems

Antiemetic Hypercholesterolemia

lannanosystems IDD-P technology lannanosystems

Merck & Co. Abbott Laboratories Produced by SkyePharma marketed by Sciele Pharma Inc. (Atlanta, CA, USA). Par Pharmaceutical Companies Inc. (Spring Valley, NY, USA) King Pharmaceuticals Novartis

Oral Oral Oral

Tricor (Fenofibrate) Hypercholesterolemia lannanosystems

Oral

Psychostimulant drug lannanosystems lannanosystems

Oral Oral

lannanosystems

Novartis

Oral

Zanaflex Capsules Muscle relaxant lannanosystems Acorda Oral (TizanidineHCl) Nanocrystals for oral administration were the first products on the pharmaceutical market due to the huge market potential and the easier way of product realization compared to the intravenous route. Various
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products exploited use different features of the nanocrystals, an overview of market products is given in Examples of nanocrystal products on the market in Table1. LIMITATIONS OF DRUG NANOCRYSTAL TECHNOLOGY High cost instruments required for the production of drug nanocrystal that increases the cost of dosage forms.This technique is limited to BCS class II drug only. Formation of nanocrystal and their stability depend on molecular structure of drug so only certain class of compounds will qualify. [44] CONCLUSION Poor aqueous solubility is rapidly becoming the leading hurdle for formulation scientists working on oral delivery of drug compounds and leads to employment of novel formulation technologies. The use of drug nanocrystals is a universal formulation approach to increase the therapeutic performance of these drugs in any route of administration. Almost any drug can be reduced in size to the nanometer range. Owing to their great formulation versatility drug nanocrystals are no longer only the last chance rescue for a few drugs. Many insoluble drug candidates are in clinical trials formulated as drug nanocrystals. Currently, attention is turned to improving the 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 with higher drug loadings, better redispersability at their site of action, and an improved drug targeting. REFERENCES
1. 2. Lipinski C, Poor aqueous solubility an industry wide problem in drug discovery, Am.Pharm. Rev.2002; 5: 8285. Keck C, Kobierski S, Mauludin R, Mller 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 nanosuspensionproduction and chemical stability, Controlled Release Society 31st annual meeting, Honolulu, HI, 2004. 4. Mschwitzer J, Achleitner G, Pomper H, Muller RH, Development of an intravenously injectable chemically stable aqueous omeprazole formulation using nanosuspension technology, European Journal of Pharmaceutics and Biopharmaceutics, 2004; 58(3):615619. 5. 6. Noyes A, Whitney W, The rate of solution of solid substances in their own solutions, J Am Soc,1987;19:930-934. Mosharraf M, Nystrom C, The effect of particle size and shape on the surface specific dissolution rate of micronized practically 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 of Lipophillic 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, WO 666, 539 , March 28,2002. 9. JunghannsJUAH, Muller AH, Nanocrystal technology, drug delivery and clinical Applications, Int J Nanomedicine, 2008; 3(3):295309. 10. Gulsan T, Gursoy RN, Oner L, Nanocrystal Technology For Oral Delivery of Poorly Water-Soluble Drugs, J. Pharm. Sci, 2009; 34: 5565. International Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 2011

13

Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15

11. MllerRH, GohlaS, Keck C, State of the art of nanocrystals Special features, production, nanotoxicology aspects and intracellular delivery, European Journal of Pharmaceutics and Biopharmaceutics, 2011; 78(1): 1-9. 12. Van Eerdenbrugh, B. et al, Top-down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products, Int. J. Pharm, 2008; 364: 6475. 13. Shegokar R, Mller RH, Nanocrystals: Industrially feasible multifunctional formulation technology for poorly soluble actives, International Journal of Pharmaceutics, 2010; 399(1-2): 129-139. 14. Sharma S, Aggarwal G, Novel technologies for oral delivery of poorly soluble drugs, Research Journal of Pharmaceutical, Biological and Chemical Sciences,2010; 1(4):293-295. 15. Katteboinaal S, Chandrasekhar P, Balaji S, Drug nanocrystals: a novel formulation approach for poorly soluble drugs, International Journal of PharmTech Research, 2009; 1(3): 682-694. 16. Chen H, Khemtong C, Yang X, Chang X and Gao J, Nanonization strategies for poorly water soluble drugs, Drug Discovery Today, 2010;00:1-6. 17. Bruno JAD, Brian D. Gustow Evan, Illig, Kathleen J, Rajagopalan, Nats, Sarpotdar, Method of grinding pharmaceutical substances. US 5, 518,187, 1992. 18. Miiller RH, Becker R, Kruss B and Peters K (1994) Pharmazeutische Nanosuspensionen zur Arzneistoffapplikation als Systeme mit erhohter Sattigungsloslichkeit und Losungsgeschwindigkeit. German patent 4440337.2, US Patent 5.858.410 (1999). 19. Rawat N, Kumar MS, Mahadeven N, Solubility: Particle Size Reduction is a Promising Approach to the Bioavailability of Lipophillic Drugs, International Journal of Recent Advances in Pharmaceutical Research, January 2011; 1: 8-18. 20. Radke M, Pure drug nanoparticles for formulation of poorly soluble drug, New drug delivery: www.pharmasol-berlin.de. Kipp JE, Tak Wong JC, Doty MJ, Rebbeck CL. US Pat. application no. 20020168402 A1.2002 21. Trk M, Hils P, Helfgen B, Schaber K, Martin HJ, Wahl MA, Micronization of pharmaceutical substances by Rapid Expansion of Supercritical Solutions (RESS): a promising method to improve the bioavailability of poorly soluble pharmaceutical agents, J Supercrit Fluids,2002:7584. 22. Pathak P, Meziani MJ, Desai T, Sun YP, Nanosizing drug particles in supercritical fluid processing , J Am Chem Soc,2004; 126 (35): 1084210843. 23. Yin SX, Franchini M, Chen J, Hsieh A, JenS, Lee T, Hussain M, Smith R, Bioavailability Enhancement of a COX-2 Inhibitor, BMS-347070, from a Nanocrystalline Dispersion Prepared by Spray-Drying, J Pharm Sci.2005; 94: 15981607. 24. Martin A, Bustamante P, ChunAHC, Interfacial phenomenon, Physical Pharmacy Lippincott Williams & Wilkins, Maryland, 1993: 362392. 25. Merisko-Liversidge E, Liversidge GG, Cooper ER, Nanosizing: A Formulation Approach for Poorly-Water-Soluble Compounds, Eur J PharmSci.2003; 18: 113-120. 26. Kesisoglou F, Panmai S, Wu Y, Nanosizing Oral formulation development and biopharmaceutical evaluation, Adv Drug DelivRev,2007;59: 631644. 27. Gao L., Zhang D. et al, Drug nanocrystals for the formulation of poorly soluble drugs and its application as a potential drug delivery system, J Nanopart Res.2008; 10: 845-862. 28. Mller RH, Jacobs C., et al., Nanosuspensions as particulate drug formulations in therapy rationale for development and what we can expect for the future, Adv. Drug Deliv. Rev, 2001; 47: 3-19. International Journal of Science Innovations and Discoveries, Volume 1, Issue 3, November-Deceber 2011

14

Sneha V Sawant et al., IJSID 2011, 1 (3), 1-15

29. Liversidge GG, Cundy KC, Particle size reduction for improvement of oral bioavailability of hydrophobic drugs, Int J Pharm. 1995; 125:9197. 30. Jacobs C, Kayser O, Mller RH, Production and characterisation of mucoadhesive nanosuspensions for the formulation of bupravaquone, Int J Pharm, 2001; 214(1 2):37. 31. VergoteGJ, An oral controlled release matrix pellet formulation containing nanocrystalline ketoprofen, Int J Pharm, 2001;219(1-2):81-7. 32. Singla AK, Garg A, Aggarwal D, Paclitaxel and its formulations, Int J Pharm, 2002; 235(12):179192. 33. Mller RH and Jacobs C, Buparvaquone mucoadhesive nanosuspension: preparation, optimisation and long-term stability, Int. J. Pharm, 2002; 237: 151161. 34. Hernandez-Trejo N, Development and characterisation of buparvaquone nanosuspensions for pulmonary delivery in the treatment of Pneumocystis pneumonia, Ph.D. Thesis, Freie Universitt, Berlin, Germany, 2006. 35. Hernandez-TrejoN, Kayser O, Steckel H and Mller RH, Characterization of nebulized buparvaquone nanosuspensionseffect of nebulization technology, J. Drug Target, 2005; 13: 499507. 36. Bucolo C, Maltese A, Puglisi G and Pignatello R, Enhanced ocular anti-inflammatory activity of ibuprofen carried by an Eudragit RS100 nanoparticle suspension, Ophthalmic Res,2002; 34 : 319323. 37. Arajo J, Gonzalez E, Egea MA, Garcia ML and Souto EB, Nanomedicines for ocular NSAIDs: safety on drug delivery, Nanomed: Nanotechnol. Biol. Med, 2009; 5: 394401. 38. Kassem MA, Rahman A, Ghorab MM, Ahmed MB and Khalil RM, Nanosuspension as an ophthalmic delivery system for certain glucocorticoid drugs, Int. J. Pharm, 2007;340: 126133. 39. Petersen R, Nanocrystals for use in topical cosmetic formulations and method of production thereof, US Patent 60/8866233. 40. Kayser O, Nanosuspensions for the formulation of aphidicolin to improve drug targeting effects against Leishmania infected macrophages, International Journal of Pharmaceutics, 2000;196(2):253-256. 41. Raval J, Nanosuspensions as particulate drug delivery systems, 2006, Dec 27:

http://www.pharmainfo.net/reviews/nanosuspensionsparticulate-drug-delivery-systems. 42. Mauludin R, Nanosuspensions of poorly soluble drugs for oral administration, Ph.D. Thesis, Freie Universitt Berlin, Germany,2008. 43. Patel AP, PatelJK, Patel KS,A Review on drug nano crystals carrier free drug delivery system,IJRAP;2011,2(2),448-458.

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