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Nanotechnology will affect our lives tremendously over the next decade in very different fields, including medicine and pharmacy. Transfer of materials into the nanodimension changes their physical properties which were used in pharmaceutics to develop a new innovative formulation principle for poorly soluble drugs: the drug nanocrystals. The drug nanocrystals do not belong to the future; the first products are already on the market. The industrially relevant production technologies, pearl milling and high pressure homogenization, are reviewed.

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Poor water solubility for many drugs and drug candidates remains a major obstacle to their development and clinical application. Conventional formulations to improve solubility suffer from low bioavailability and poor pharmacokinetics, with some carriers rendering systemic toxicities e. Cremophor1 EL. To date, nanoscale systems for drug delivery have gained much interest as a way to improve the solubility problems.

The reduction of drug particles into the sub-micron range leads to a significant increase in the dissolution rate and therefore enhances bioavailability. Nanosizing techniques are important tools for improving the bioavailability of water insoluble drugs. In this review, several major nanonization techniques that seek to overcome these limitations for drug solubilization are presented. Strategies including drug nanocrystals, nanoemulsions, nanosuspension and polymeric micelles are reviewed.

Finally, perspectives on existing challenges and future opportunities are highlighted. Author Guidelines Submit Manuscript. Drug Dev.

This is an open access paper distributed under thecopyright agreement with Serials Publication, whichpermits unrestricted use, distribution, andreproduction in any medium, provided the originalwork is properly cited. Related article at Pubmed , Scholar Google. Key words Poor water soluble drugs, Bioavailability, Drug delivery, Nanosuspension Introduction Poorly water-soluble drugs pose a great challenge in drug formulation development1.

The low saturated solubility and dissolution velocity lead to poor bioavailability. With the increasing number of newly developed lipophilic drug compounds, many techniques have been proposed, such as solid dispersions, cosolvents, emulsions, liposomes and nanoparticles based on lipidic or polymer carriers. However, the use of large amounts of excipients or organic solvents is limited in pharmaceutical formulations due to possible toxicity of the compounds.

A pharmaceutical nanosuspension is defined as very finely dispersed solid drug particles in an aqueous vehicle for either oral and topical use or parenteral and pulmonary administration.

The particle size distribution of the solid particles in nanosuspensions is usually less than one micron with an average particle size ranging between and nm Nanosuspension is a sub-micron colloidal dispersion of drug particles which are stabilized by surfactants, polymers or a mixture of both2 This formulation has a high drug loading, low incidence of side effects by the excipients, and low cost3 Owing to the increased surface-to- volume ratio of the nanocrystals, an increase in saturated solubility and very fast dissolution rate can be seen ,especially below particle sizes of 1?

Nanosuspension technology can also be used for drugs, which are insoluble in both water and organic solvents. Hydrophobic drugs such as naproxen5, bupravaquone6, nimesulide7, amphotericin B8, omeprazole9, nifedipine10 are formulated as nanosuspension.

The stability of the particles obtained in the nanosuspension is attributed to their uniform particle size which is created by various manufacturing processes. The absence of particles with large differences in their size in nanosuspensions prevents the existence of different saturation solubilities and concentration gradients, consequently preventing the ostwald ripening effect.

Ostwald ripening is responsible for crystal growth and subsequently formation of microparticles. Molecules diffuse from the higher concentration area around small particles which have higher saturation solubility to an area around larger particles possessing a lower drug concentration.

This leads to the formation of a supersaturated solution around the large particles and consequently to drug crystallization and growth of the large particles Various approach to produce nanosuspension Nanosuspension preparation can be broadly classified into two categories: i top-down processes and ii bottom-up processes. Top-down processes consist of particle size reduction of large drug particles into smaller particles using various wet milling techniques such as: media milling, microfluidization and high pressure homogenization.

No harsh solvents are used in these techniques. However, all media milling processes involve high energy input and are highly inefficient Considerable amount of heat is generated in these operations making processing of thermolabile materials difficult. In the bottom-up approach the drug is dissolved in an organic solvent and is then precipitated on addition of an antisolvent in the presence of a stabilizer. Various adaptations of this approach include: i solvent—anti-solvent method; ii supercritical fluid processes and iii emulsion— solvent evaporation13, Top Down Process Technology High pressure homogenization Dissocubes : High pressure homogenization has been used to prepare nanosuspension of many poorly water soluble drugs.

In the high pressure homogenization method, the suspension of a drug and surfactant is forced under pressure through a nanosized aperture valve of a high pressure homogenizer. The principle of this method is based on cavitation in the aqueous phase. The particles cavitations forces are sufficiently high to convert the drug microparticles into nanoparticles.

The concern with this method is the need for small sample particles before loading and the fact that many cycles of homogenization are required. Dissocubes technology is an example of this technology developed by R. In this method the nanosusensions are produced using high-shear media mills or pearl mills.

Wet milling is an attrition based process in which the drug suspension is subjected using a pearl mill in the presence of milling media.. The grinding media consists of glass, zirconium oxide stabilized with zirconium silicate or highly cross linked polystyrene resin in a spherical form 0. The high energy and shear forces generated as a result of the impaction of the milling media with the drug provide the energy input to break the microparticulate drug into nano-sized particles.

The media milling procedure can successfully process micronized and non- micronized drug crystals. Once the formulation and the process are optimized, very short batch to batch variation is observed in the quality. A nanosuspension of Naproxen with a mean particle size of nm was prepared using pearl milling technique Nanoedge : This technique is also called opposite stream technology, uses a chamber where a stream of suspension is divided into two or more parts.

Both streams are colloid with each other at high pressure. The high shear force produced during the process results in particle size reduction. Dearns had prepared nanosuspensions of atovaquone using the microfluidization process. The major disadvantage of this technique is the high number of passes through the microfluidizer and that the product obtained contains a relatively larger fraction of microparticles19 Bottom up Process Technology a Solvent — Antisolvent method :.

Precipitation has been applied for years to prepare submicron particles within the last decade 20, especially for the poorly soluble drugs. Typically, the drug is firstly dissolved in a solvent. Then this solution is mixed with a miscible antisolvent in the presence of surfactants. Rapid addition of a drug solution to the antisolvent usually water leads to sudden supersaturation of drug in the mixed solution, and generation of ultrafine crystalline or amorphous drug solids.

This process involves two phases nuclei formation and crystal growth. When preparing a stable suspension with the minimum particle size, a high nucleation rate but low growth rate is necessary.

Both rates are dependent on temperature: the optimum temperature for nucleation might lie below that for crystal growth, which permits temperature optimization Precipitation technique is not applicable to drugs which are poorly soluble in aqueous and non aqueous media.

In this technique, the drug needs to be soluble in at least one solvent which is miscible with nonsolvent. The major challenge is to avoid crystal growth due to ostwald ripening being caused by different saturation solubilities in the vicinity of the differently sized particles.

In RESS technique, drug solution is expanded through a nozzle into supercritical fluid, resulting in precipitation of the drug as fine particles by loss of solvent power of the supercritical fluid. As the removal of solvent occurs, the solution gets supersaturated and finally precipitation occurs.

In supercritical antisolvent process, drug solution is injected into the supercritical fluid and the solvent gets extracted as well as the drug solution becomes supersaturated C Emulsification-solvent evaporation technique: This technique involves preparing a solution of drug followed by its emulsification in another liquid that is a non-solvent for the drug.

Evaporation of the solvent leads to precipitation of the drug. Crystal growth and particle aggregation can be controlled by creating high shear forces using a high-speed stirrer. In this method the drug will be dissolved in the suitable organic solvent and then emulsified in aqueous phase using suitable surfactants.

Then the organic solvent will be slowly evaporated under reduced pressure to form drug particles precipitating in the aqueous phase forming the aqueous suspension of the drug in the required particle size.

Then the suspension formed can be diluted suitably to get nanosuspensions. Moreover, microemulsions as templates can produce nanosuspensions Microemulsions are thermodynamically stable and isotropically clear dispersions of two immiscible liquids such as oil and water stabilized by an interfacial film of surfactant and co-surfactant. The drug can be either loaded into the internal phase or the pre-formed microemulsion can be saturated with the drug by intimate mixing.

Suitable dilution of the microemulsion yields the drug nanosuspension An example of this technique is the griseofulvin nanosuspension which is prepared by the microemulsion The advantages of lipid emulsions as templates for nanosuspension formation are that they easy to produce by controlling the emulsion droplet and easy for scaleup.

However, the use of organic solvents affects the environment and large amounts of surfactant or stabilizer are required. Other techniques Dry Co-Grinding: Stable nanosuspensions using dry-grinding of poorly soluble drugs with soluble polymers and copolymers after dispersing in a liquid media has been reported Physicochemical properties and dissolution of poorly water soluble drugs were improved by co-grinding because of an improvement in the surface polarity and transformation from a crystalline to an amorphous drug The co-grinding technique can reduce particles to the submicron level.

Itoh et al 26 reported the colloidal particles formation of many poorly water soluble drugs; griseofulvin, glibenclamide and nifedipine obtained by grinding with polyvinylpyrrolidone PVP and sodium dodecylsulfate SDS.

Characterization of Nanosuspensions Nanosuspensions are characterized in similar ways as those used for conventional suspensions such as appearance, color, odor, assay, related impurities, etc. Apart from the aforementioned parameters, the nanosuspensions should be evaluated for their particle size, zeta potential, crystalline status, dissolution studies and in vivo studies a Particle size distribution Particle size distribution determines the physiochemical behavior of the formulation, such as saturation solubility, dissolution velocity, physical stability, etc.

The particle size distribution can be determined by photon correlation spectroscopy PCS , laser diffraction LD and coulter counter multisizer. The coulter counter multisizer gives the absolute number of particles, in contrast to the LD method, which gives only a relative size distribution. Nanosuspensions can undergo a change in the crystalline structure, which may be to an amorphous form or to other polymorphic forms because of highpressure homogenization.

Nakarani M. The nanocrystals seem to be more rounded, perhaps because the particles were coated with a surfactant layer. These two parameters should be determined in various physiological solutions.

The assessment of saturation solubility and dissolution velocity helps in determining the in vitro behavior of the formulation. Size reduction leads to an increase in the dissolution pressure.

An increase in solubility that occurs with relatively low particle size reduction may be mainly due to a change in the surface tension leading to increased saturation solubility. Muller explained that the energy introduced during the particle size reduction process leads to an increase in the surface tension and an associated increase in the dissolution pressure Physical stability of nanosuspensions The small particle size of nanosuspensions, which is inherent to their success, is also responsible for their physical instability.

Nanosuspensions consist of hydrophobic particles dispersed in a hydrophilic medium usually water. The enormous surface area associated with the small size of these particles results in high interfacial tension, which in turn results in an increase in the free energy of the system.

Accordingly, nanosuspensions are essentially thermodynamically unstable systems To decrease their free energy nanoparticles tend to reduce interaction with water via flocculation, aggregation or crystal growth. However, these processes adversely affect the central characteristics of nanosuspensions i. Stabilizers are added to reduce the free energy of the system by decreasing interfacial tension, and to prevent nanoparticle aggregation by electrostatic or steric stabilization.

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Nanosuspension: An approach to enhance solubility of drugs

One of the major problems associated with poorly soluble drugs is very low bioavailability. The problem is even more complex for drugs like itraconazole, simvastatin, and carbamazepine which are poorly soluble in both aqueous and nonaqueous media, belonging to BCS class II as classified by biopharmaceutical classification system. Formulation as nanosuspension is an attractive and promising alternative to solve these problems. Nanosuspension consists of the pure poorly water-soluble drug without any matrix material suspended in dispersion. Preparation of nanosuspension is simple and applicable to all drugs which are water insoluble.

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5. Nanosuspension Technology for Solubilizing Poorly Soluble Drugs

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