`ß 2004 The Authors
`Received December 11, 2003
`Accepted March 30, 2004
`DOI 10.1211/0022357023691
`ISSN 0022-3573
`
`Pharmaceutical Division,
`University Institute of Chemical
`Technology, Matunga,
`Mumbai-400 019, India
`
`V. B. Patravale
`
`Department of Pharmaceutics,
`Bombay College of Pharmacy,
`Kalina, Santacruz (E.),
`Mumbai-400 098, India
`
`Abhijit A. Date
`
`Department of Cell Biology,
`Neurobiology and Anatomy,
`University of Cincinnati Medical
`Center, Cincinnati,
`OH 45267-0521, USA
`
`R. M. Kulkarni
`
`Correspondence: V. B. Patravale,
`Pharmaceutical Division,
`University Institute of Chemical
`Technology, Matunga,
`Mumbai-400 019, India.
`E-mail: vbp_muict@yahoo.co.in
`
`Review Article
`
`Nanosuspensions: a promising drug delivery strategy
`
`V. B. Patravale, Abhijit A. Date and R. M. Kulkarni
`
`Abstract
`
`Nanosuspensions have emerged as a promising strategy for the efficient delivery of hydrophobic drugs
`because of their versatile features and unique advantages. Techniques such as media milling and high-
`pressure homogenization have been used commercially for producing nanosuspensions. Recently, the
`engineering of nanosuspensions employing emulsions and microemulsions as templates has been
`addressed in the literature. The unique features of nanosuspensions have enabled their use in various
`dosage forms, including specialized delivery systems such as mucoadhesive hydrogels. Rapid strides have
`been made in the delivery of nanosuspensions by parenteral, peroral, ocular and pulmonary routes.
`Currently, efforts are being directed to extending their applications in site-specific drug delivery.
`
`Introduction
`
`The formulation of poorly water-soluble drugs has always been a challenging problem
`faced by pharmaceutical scientists and it is expected to increase because approximately
`40% or more of the new chemical entities being generated through drug discovery
`programmes are poorly water-soluble (Lipinski 2002).
`The problem is even more intense for drugs such as itraconazole and carbamazepine
`(belonging to class III as classified by Washington 1996), as they are poorly soluble in
`both aqueous and organic media, and for drugs having a log P value of 2 (Pouton
`2000). Such drugs often have an erratic absorption profile and highly variable bio-
`availability because their performance is dissolution-rate limited and is affected by the
`fed/fasted state of the patient.
`Traditional strategies, such as micronization, solubilization using co-solvents, the use
`of permeation enhancers (Aungst 1993, 2000), oily solutions (Aungst 1993) and surfact-
`ant dispersions (Aungst et al 1994), which evolved earlier to tackle the formulation
`challenges, have limited use. Although reasonable success has been achieved in formulat-
`ing water-insoluble drugs using liposomes (Schwendener & Schott 1996), emulsions
`(Floyd 1999; Nakano 2000), microemulsions (Lawrence & Rees 2000), solid dispersion
`technology (Serajuddin 1999; Leuner & Dressman 2000; Breitenbach 2002) and inclusion
`complexes employing cyclodextrins (Loftsson & Brewster 1996; Stella & Rajewski 1997;
`Akers 2002), there is no universal approach applicable to all drugs. Hence, there is a
`growing need for a unique strategy that can tackle the formulation-related problems
`associated with the delivery of hydrophobic drugs in order to improve their clinical
`efficacy and optimize their therapy with respect to pharmacoeconomics.
`Nanosuspensions have revealed their potential to tackle the problems associated
`with the delivery of poorly water-soluble and poorly water- and lipid-soluble drugs,
`and are unique because of their simplicity and the advantages they confer over other
`strategies. This review focuses on the various aspects of nanosuspensions and their
`potential as a promising strategy in drug delivery.
`Nanosuspensions can be defined as colloidal dispersions of nano-sized drug parti-
`cles that are produced by a suitable method and stabilized by a suitable stabilizer.
`
`Methods of production
`
`Media milling (NanoCrystals)
`This patent-protected technology was developed by Liversidge et al (1992). Formerly,
`the technology was owned by the company NanoSystems but recently it has been
`acquired by Elan Drug Delivery. In this method the nanosuspensions are produced
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`Coolant
`
`Large
`drug
`crystals
`
`Charged
`with
`drug, water
`and
`stabilizer
`
`Re-
`circubtion
`chamber
`
`Milling
`shaft
`
`Motor
`
`Milling chamber
`
`Screen
`retaining
`milling media
`in chamber
`
`Nanocrystals
`
`Milling media
`
`Figure 1 Schematic representation of the media milling process. The milling chamber charged with polymeric media is the active component
`of the mill. The mill can be operated in a batch or recirculation mode. A crude slurry consisting of drug, water and stabilizer is fed into the
`milling chamber and processed into a nanocrystalline dispersion. The typical residence time generated for a nanometer-sized dispersion with a
`mean diameter of <200 nm is 30–60 min. Reprinted from Merisko-Liversidge et al 2003 with permission from Elsevier Publications.
`
`20
`
`15
`
`10
`
`5
`
`Frequency%
`
`using high-shear media mills or pearl mills. The media mill
`consists of a milling chamber, a milling shaft and a recir-
`culation chamber (Figure 1). The milling chamber is
`charged with the milling media, water, drug and stabilizer,
`as depicted in Figure 1, and the milling media or pearls are
`then rotated at a very high shear rate. The milling process
`is performed under controlled temperatures.
`
`Principle 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 microparticu-
`late drug into nano-sized particles. The milling medium is
`composed of glass, zirconium oxide or highly cross-linked
`polystyrene resin. The process can be performed in either
`batch or recirculation mode. In batch mode, the time
`required to obtain dispersions with unimodal distribution
`profiles and mean diameters <200 nm is 30–60 min. The
`media milling process can successfully process micronized
`and non-micronized drug crystals. Once the formulation
`and the process are optimized, very little batch-to-batch
`variation is observed in the quality of the dispersion.
`
`Advantages
`. Drugs that are poorly soluble in both aqueous and
`organic media can be easily formulated into nanosus-
`pensions.
`. Ease of scale-up and little batch-to-batch variation.
`. Narrow size distribution of the final nano-sized pro-
`duct. A comparison of the size of naproxen crystals
`before and after media milling is given in Figure 2.
`. Flexibility in handling the drug quantity, ranging from
` 1, enabling formulation of very dilute
`1 to 400 mg mL
`as well as highly concentrated nanosuspensions.
`
`0
`
`100
`
`1
`Particle size (µ m)
`Naproxen crystals
`Nanocrystalline
`before media
`naproxen after
`milling
`media milling
`Mean: 24.2 µ m
`Mean: 0.147 µ m
`D90: 47.08 µ m
`D90: 0.205 µ m
`Figure 2 The particle size distribution of naproxen crystals before
`(~) and after (.) milling. Before milling the drug crystals had a mean
`particle size of 24.2 m. After being processed for 30 min in a media
`mill, the mean particle size of the nanocrystalline dispersion was
`0.147 m with D90 ¼ 0.205 m. The particle size measurements were
`generated using laser light diffraction in a Horiba LA-910 using
`polystyrene nanospheres ranging from 0.1 to 10 m as standards.
`Reprinted from Merisko-Liversidge et al 2003 with permission from
`Elsevier Publications.
`
`Disadvantages
`. The major concern is the generation of residues of
`milling media, which may be introduced in the final
`product as a result of erosion (Buchmann et al 1996;
`Mu¨ ller & Bo¨ hm 1998). This could be problematic
`when nanosuspensions are intended to be administered
`
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`829
`
`from being damaged due to the flow (Jahnke 1998). The
`instrument is available in discontinuous and continuous
`versions. The continuous version is suitable for optimizing
`the various parameters of the homogenization process.
`Use of the discontinuous version is sensible if the drug is
`very costly or of limited availability. The instrument can
`be operated at pressures varying from 100 to 1500 bars. In
`some instruments, a maximum pressure of 2000 bars can
`be reached. High-pressure homogenizers are available
`with different capacities ranging from 40 mL (for labora-
`tory purposes) to a few thousand litres (for large-scale
`production). It is advisable to start with the micronized
`drug (particle size < 25 m) for production of nanosus-
`pensions in order to prevent blocking of the homogeniza-
`tion gap. Hence, generally a jet-milled drug is employed as
`the starting material for producing Disso Cubes. Before
`subjecting the drug to the homogenization process, it is
`essential to form a presuspension of the micronized drug
`in a surfactant solution using high-speed stirrers. During
`the homogenization process,
`the drug suspension is
`pressed through the homogenization gap in order to
`achieve nano-sizing of the drug.
`
`Principle During homogenization, the fracture of drug
`particles is brought about by cavitation, high-shear forces
`and the collision of the particles against each other. The
`drug suspension, contained in a cylinder of diameter
`about 3 mm, passes suddenly through a very narrow
`homogenization gap of 25 m, which leads to a high
`streaming velocity.
`In the homogenization gap, according to Bernoulli’s
`equation, the dynamic pressure of the fluid increases
`with the simultaneous decrease in static pressure below
`the boiling point of water at room temperature. In con-
`sequence, water starts boiling at room temperature, lead-
`ing to the formation of gas bubbles, which implode when
`the suspension leaves the gap (called cavitation) and nor-
`mal air pressure is reached again. The implosion forces are
`sufficiently high to break down the drug microparticles
`into nanoparticles. Additionally, the collision of the par-
`ticles at high speed helps to achieve the nano-sizing of the
`drug. To improve the efficiency of nano-sizing, the addi-
`tion of viscosity enhancers is advantageous in certain cases
`as increasing the viscosity increases the powder density
`within the dispersion zone (homogenization gap).
`In order to obtain an optimized formulation, the effect
`of the following process variables should be investigated.
`
`. Effect of homogenization pressure. As the homogenizer
`can handle varying pressures, ranging from 100 to 1500
`bars, the effect of the homogenization pressure on the
`particle size should be investigated in each case in order to
`optimize the process parameters. It is expected that the
`higher the homogenization pressure, the lower the parti-
`cle size obtained. The studies carried out on RMKP 22,
`4-[N-(2-hydroxy-2-methyl-propyl)-ethanolamino]-2,7-bis
`(cis-2,6-dimethylmorpholin-4-yl)-6-phenyl-pteridine, rev-
`ealed that an inverse relationship exists between the
`homogenization pressure and the particle size (Mu¨ ller
`& Bo¨ hm 1998; Mu¨ ller & Peters 1998; Grau et al 2000).
`
`for a chronic therapy. The severity of this problem has
`been reduced to a great extent with the advent of poly-
`styrene resin-based milling medium. For this medium,
`residual monomers are typically 50 ppb and the resi-
`duals generated during the milling processing are not
`more than 0.005% w/w of the final product or the
`resulting solid dosage form.
`
`High-pressure homogenizers (Disso Cubes)
`Disso Cubes technology was developed by R. H. Mu¨ ller
`(Mu¨ ller et al 1998). The patent rights of Disso Cubes were
`initially owned by DDS (Drug Delivery Services) GmbH
`but currently they are owned by SkyePharma plc. Disso
`Cubes are engineered using piston-gap-type high-pressure
`homogenizers. A commonly used homogenizer is the APV
`Micron LAB 40 (APV Deutschland GmbH, Lubeck,
`Germany). However, other piston-gap homogenizers
`from Avestin (Avestin Inc., Ottawa, Canada) and
`Stansted (Stansted Fluid Power Ltd, Stansted, UK) can
`also be used. A high-pressure homogenizer (Figure 3)
`consists of a high-pressure plunger pump with a subse-
`quent relief valve (homogenizing valve). The task of the
`plunger pump is to provide the energy level required for
`the relief. The relief valve consists of a fixed valve seat and
`an adjustable valve. These parts form an adjustable radial
`precision gap. The gap conditions, the resistance and thus
`the homogenizing pressure vary as a function of the force
`acting on the valve. An external impact ring forms a
`defined outlet cross-section and prevents the valve casing
`
`Nanosuspension
`
`Valve
`
`Impact ring
`
`Valve seat
`
`Macrosuspension
`
`Figure 3 Schematic representation of the high-pressure homogeni-
`zation process.
`
`0003
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`V. B. Patravale et al
`
`. Number of homogenization cycles. For many drugs it is
`not possible to obtain the desired particle size in a single
`homogenization cycle. Typically, multiple cycles are
`required. Hence, depending on the hardness of the
`drug, the desired mean particle size and the required
`homogeneity of the product, homogenization can be
`carried out in three, five or 10 cycles. It is anticipated
`that the higher the number of homogenization cycles,
`the smaller the particle size obtained. The optimum
`number of homogenization cycles can be arrived at by
`analysing the particle size and polydispersity index of
`the drug after each cycle.
`
`Advantages
`. Drugs that are poorly soluble in both aqueous and
`organic media can be easily formulated into nanosus-
`pensions.
`. Ease of scale-up and little batch-to-batch variation
`(Grau et al 2000).
`. Narrow size distribution of the nanoparticulate drug
`present in the final product (Mu¨ ller & Bo¨ hm 1998).
`. Allows aseptic production of nanosuspensions for par-
`enteral administration.
`. Flexibility in handling the drug quantity, ranging from
` 1, thus enabling formulation of very
`1 to 400 mg mL
`dilute as well as highly concentrated nanosuspensions
`(Krause & Mu¨ ller 2001).
`
`Disadvantages
`. Prerequisite of micronized drug particles.
`. Prerequisite of suspension formation using high-speed
`mixers before subjecting it to homogenization.
`
`Emulsions as templates
`Apart from the use of emulsions as a drug delivery vehicle,
`they can also be used as templates to produce nanosus-
`pensions. The use of emulsions as templates is applicable
`for those drugs that are soluble in either volatile organic
`solvent or partially water-miscible solvent. Such solvents
`can be used as the dispersed phase of the emulsion. There
`are two ways of fabricating drug nanosuspensions by the
`emulsification method.
`In the first method, an organic solvent or mixture of
`solvents loaded with the drug is dispersed in the aqueous
`phase containing suitable surfactants to form an emulsion.
`The organic phase is then evaporated under reduced pres-
`sure so that the drug particles precipitate instantaneously
`to form a nanosuspension stabilized by surfactants. Since
`one particle is formed in each emulsion droplet,
`it is
`possible to control the particle size of the nanosuspension
`by controlling the size of the emulsion. Optimizing the
`surfactant composition increases the intake of organic
`phase and ultimately the drug loading in the emulsion.
`Originally, organic solvents such as methylene chloride
`and chloroform were used (Bodmeier & McGinity 1998).
`However, environmental hazards and human safety con-
`cerns about residual solvents have limited their use in
`routine manufacturing processes. Relatively safer solvents
`such as ethyl acetate and ethyl formate can still be con-
`sidered for use (Sah 1997, 2000).
`
`Another method makes use of partially water-miscible
`solvents such as butyl lactate, benzyl alcohol and triacetin
`as the dispersed phase instead of hazardous solvents (Trotta
`et al 2001). The emulsion is formed by the conventional
`method and the drug nanosuspension is obtained by just
`diluting the emulsion. Dilution of the emulsion with water
`causes complete diffusion of the internal phase into the
`external phase, leading to instantaneous formation of a
`nanosuspension. The nanosuspension thus formed has to
`be made free of the internal phase and surfactants by means
`of diultrafiltration in order to make it suitable for adminis-
`tration. However, if all the ingredients that are used for the
`production of the nanosuspension are present in a concen-
`tration acceptable for the desired route of administration,
`then simple centrifugation or ultracentrifugation is suffi-
`cient to separate the nanosuspension.
`
`Advantages
`. Use of specialized equipment is not necessary.
`. Particle size can easily be controlled by controlling the
`size of the emulsion droplet.
`. Ease of scale-up if formulation is optimized properly.
`
`Disadvantages
`. Drugs that are poorly soluble in both aqueous and
`organic media cannot be formulated by this technique.
`. Safety concerns because of the use of hazardous sol-
`vents in the process.
`. Need for diultrafiltration for purification of the drug
`nanosuspension, which may render the process costly.
`. High amount of surfactant/stabilizer is required as com-
`pared to the production techniques described earlier.
`
`The production of drug nanosuspensions from emulsion
`templates has been successfully applied to the poorly
`water-soluble and poorly bioavailable anti-cancer drug
`mitotane, where a significant improvement in the dissolu-
`tion rate of the drug (five-fold increase) as compared to
`the commercial product was observed (Trotta et al 2001).
`
`Microemulsions as templates
`Microemulsions are thermodynamically stable and isotro-
`pically clear dispersions of two immiscible liquids, such as
`oil and water, stabilized by an interfacial film of surfactant
`and co-surfactant (Eccleston 1992). Their advantages,
`such as high drug solubilization, long shelf-life and ease
`of manufacture, make them an ideal drug delivery vehicle.
`There are several research papers available that describe
`the use of microemulsions as drug delivery vehicles
`(Constantinides et al 1994, 1995; Kim et al 1998; Park &
`Kim 1999; Kawakami & Yoshikawa 2002). Recently, the
`use of microemulsions as templates for the production of
`solid lipid nanoparticles (Gasco 1997) and polymeric
`nanoparticles (Rades et al 2002) has been described.
`Taking advantage of the microemulsion structure, one
`can use microemulsions even for the production of nano-
`suspensions (Trotta et al 2003). Oil-in-water microemul-
`sions are preferred for this purpose. The internal phase of
`these microemulsions could be either a partially miscible
`liquid or a suitable organic solvent, as described earlier.
`
`0004
`
`
`
`The drug can be either loaded in the internal phase or
`pre-formed microemulsions can be saturated with the drug
`by intimate mixing. The suitable dilution of the microemul-
`sion yields the drug nanosuspension by the mechanism
`described earlier. The influence of the amount and ratio of
`surfactant to co-surfactant on the uptake of internal phase
`and on the globule size of the microemulsion should be
`investigated and optimized in order to achieve the desired
`drug loading. The nanosuspension thus formed has to be
`made free of the internal phase and surfactants by means of
`diultrafiltration in order to make it suitable for administra-
`tion. However, if all the ingredients that are used for the
`production of the nanosuspension are present in a concen-
`tration acceptable for the desired route of administration,
`then simple centrifugation or ultracentrifugation is suffi-
`cient to separate the nanosuspension.
`The advantages and disadvantages are the same as for
`emulsion templates. The only added advantage is the need
`for less energy input for the production of nanosuspen-
`sions by virtue of microemulsions.
`The production of drug nanosuspensions using micro-
`emulsions as templates has been successfully applied to
`the poorly water-soluble and poorly bioavailable anti-
`fungal drug griseofulvin, where a significant improvement
`in the dissolution rate of the drug (three-fold increase) as
`compared to the commercial product was observed. It was
`found that the nature of the co-surfactant affected the
`dissolution rate of the drug nanosuspension, as antici-
`pated (Trotta et al 2003). However, this technique is still
`in its infancy and needs more thorough investigation.
`
`Formulation considerations
`
`Stabilizer
`Stabilizer plays an important role in the formulation of
`nanosuspensions. In the absence of an appropriate stabil-
`izer, the high surface energy of nano-sized particles can
`induce agglomeration or aggregation of the drug crystals.
`The main functions of a stabilizer are to wet the drug
`particles thoroughly, and to prevent Ostwald’s ripening
`(Rawlins 1982; Mu¨ ller & Bo¨ hm 1998) and agglomeration
`of nanosuspensions in order to yield a physically stable
`formulation by providing steric or ionic barriers. The type
`and amount of stabilizer has a pronounced effect on the
`physical stability and in-vivo behaviour of nanosuspen-
`sions. In some cases, a mixture of stabilizers is required to
`obtain a stable nanosuspension.
`The drug-to-stabilizer ratio in the formulation may
`vary from 1:20 to 20:1 and should be investigated for a
`specific case. Stabilizers that have been explored so far
`include cellulosics, poloxamers, polysorbates,
`lecithins
`and povidones (Liversidge et al 1992). Lecithin is the sta-
`bilizer of choice if one intends to develop a parenterally
`acceptable and autoclavable nanosuspension.
`
`Nanosuspensions: a promising drug delivery strategy
`
`831
`
`formulation considerations is not available. The accept-
`ability of the organic solvents in the pharmaceutical arena,
`their toxicity potential and the ease of their removal from
`the formulation need to be considered when formulating
`nanosuspensions using emulsions or microemulsions as
`templates. The pharmaceutically acceptable and less
`hazardous water-miscible solvents, such as ethanol and
`isopropanol, and partially water-miscible solvents, such
`as ethyl acetate, ethyl formate, butyl lactate, triacetin,
`propylene carbonate and benzyl alcohol, are preferred in
`the formulation over the conventional hazardous solvents,
`such as dichloromethane. Additionally, partially water-
`miscible organic solvents can be used as the internal
`phase of the microemulsion when the nanosuspensions
`are to be produced using a microemulsion as a template.
`
`Co-surfactants
`The choice of co-surfactant is critical when using micro-
`emulsions to formulate nanosuspensions. Since co-surfact-
`ants can greatly influence phase behaviour, the effect of
`co-surfactant on uptake of the internal phase for selected
`microemulsion composition and on drug loading should
`be investigated. Although the literature describes the use
`of bile salts and dipotassium glycerrhizinate as co-surfact-
`ants, various solubilizers, such as Transcutol, glycofurol,
`ethanol and isopropanol, can be safely used as co-surfact-
`ants in the formulation of microemulsions.
`
`Other additives
`Nanosuspensions may contain additives such as buffers,
`salts, polyols, osmogent and cryoprotectant, depending on
`either the route of administration or the properties of the
`drug moiety.
`
`Post-production processing
`
`Post-production processing of nanosuspensions becomes
`essential when the drug candidate is highly susceptible to
`hydrolytic cleavage or chemical degradation. Processing
`may also be required when the best possible stabilizer is
`not able to stabilize the nanosuspension for a longer per-
`iod of time or there are acceptability restrictions with
`respect to the desired route. Considering these aspects,
`techniques such as lyophillization or spray drying may
`be employed to produce a dry powder of nano-sized
`drug particles. Rational selection has to be made in these
`unit operations considering the drug properties and eco-
`nomic aspects. Generally, spray drying is more econom-
`ical and convenient than lyophillization. The effect of
`post-production processing on the particle size of the
`nanosuspension and moisture content of dried nano-
`sized drug should be given due consideration.
`
`Organic solvents
`Organic solvents may be required in the formulation of
`nanosuspensions if they are to be prepared using an
`emulsion or microemulsion as a template. As these tech-
`niques are still in their infancy, elaborate information on
`
`Advantages of nanosuspensions
`
`Increase in the dissolution velocity and saturation
`solubility of the drug
`This is an important advantage that makes nanosuspen-
`sions amenable to numerous applications. The reason
`
`0005
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`832
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`V. B. Patravale et al
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`behind the increase in the dissolution velocity and satura-
`tion solubility of the nanosuspensions can be given as
`follows. According to the Nernst–Brunner and Levich
`modification of the Noyes Whitney dissolution model
`equation (Dressman et al 1998; Horter & Dressman
`2001), the dissolution velocity of the nanosuspension
`increases due to a dramatic increase in the surface area
`of the drug particles from microns to particles of nano-
`meter size:
`dX/dt¼ ((D A)/h) (Cs X/V)
`
`where dX/dt is the dissolution velocity, D is the diffusion
`coefficient, A is the surface area of the particle, h is the
`diffusional distance, Cs is the saturation solubility of the
`drug, X is the concentration in the surrounding liquid and
`V is the volume of the dissolution medium.
`In addition, as described by the Prandtl equation, the
`decrease in the diffusional distance with increasing curva-
`ture of ultrafine nano-sized particles contributes to the
`increase in the dissolution velocity. The Prandtl equation
`(Mosharraf & Nystro¨ m 1995) describes the hydrodynamic
`boundary layer thickness or diffusional distance (hH) for
`flow passing a flat surface:
`hH¼ k (L1/2/V1/2)
`where L is the length of the surface in the direction of
`flow, k denotes a constant, V is the relative velocity of the
`flowing liquid against a flat surface and hH is the hydro-
`dynamic boundary layer thickness. Corresponding to the
`Prandtl equation, Nystro¨ m and Bisrat (1988) have shown
`that for solids dispersed in a liquid medium under agita-
`tion, a decrease in particle size results in a thinner hydro-
`dynamic layer around particles and an increase of the
`surface-specific dissolution rate. This phenomenon is
`especially pronounced for materials that have mean par-
`ticle size of less than 2 m.
`The increase in the saturation solubility of the drug
`with a decrease in particle size can be explained by
`Ostwald–Freundlich’s equation:
`log(Cs/C) ¼ 2V/2.303RTr
`
`where Cs is the saturation solubility, C is the solubility of
`the solid consisting of large particles, is the interfacial
`tension of substance, V is the molar volume of the particle
`material, R is the gas constant, T is the absolute tempera-
`ture, is the density of the solid and r is the radius.
`Another possible explanation for the increased satura-
`tion solubility is the creation of high-energy surfaces when
`disrupting the more or less ideal drug microcrystals to
`nanoparticles. Lyophobic surfaces from the inside of the
`crystal are exposed to the aqueous dispersion medium
`during nanosizing. According to Ostwald–Freundlich, Cs
`is dependent on the interfacial tension and subsequently
`on the interfacial energy G (G¼ A). Differences in inter-
`facial energy have a profound effect on the saturation
`solubilities of polymorphic forms of the drug; the same
`explanation might be valid for the nanosuspension (high-
`energy form ¼ polymorph II ¼ higher Cs) compared to
`microparticulate suspensions (low-energy form ¼ stable
`
`polymorph I ¼ lower Cs). Dissolution experiments can be
`performed to quantify the increase in the saturation solu-
`bility of the drug when formulated into a nanosuspension.
`In a study carried out by Mu¨ ller and Peters (1998), an
`increase in the saturation solubility of RMKP 22 with
`decrease in particle size was observed.
`
`Improved biological performance
`An increase in the dissolution velocity and saturation
`solubility of a drug leads to an improvement in the in-
`vivo performance of the drug irrespective of the route
`used. The advantages related to various routes are dis-
`cussed later in detail.
`
`Ease of manufacture and scale-up
`Unlike nanoparticulate carriers such as polymeric nano-
`particles, which were investigated earlier, nanosuspen-
`sions are easy to manufacture. The production processes
`described earlier are easily scaled up for commercial pro-
`duction. The introduction of nanosuspension products
`such as Rapamune and the NanoCrystal colloidal keto-
`profen is sufficient to substantiate this.
`
`Long-term physical stability
`Another special feature of nanosuspensions is the absence
`of Ostwald ripening, which is suggestive of their long-term
`physical stability (Peters & Mu¨ ller 1996). Ostwald ripening
`(Rawlins 1982; Mu¨ ller & Bo¨ hm 1998) has been described
`for ultrafine dispersed systems and is responsible for crystal
`growth and subsequently formation of microparticles.
`Ostwald ripening is caused by the differences in dissolution
`pressure/saturation solubility between small and large par-
`ticles. It is in practice an effect based on the higher satura-
`tion solubility of very small particles as compared to larger
`ones. Molecules diffuse from the higher concentrated area
`around small particles (higher saturation solubility) to areas
`around larger particles possessing a lower drug concentra-
`tion. This leads to the formation of a supersaturated solu-
`tion around the large particles and consequently to drug
`crystallization and growth of the large particles. The diffu-
`sion process of the drug from the small particles to the large
`particles leaves an area around the small particles that is not
`saturated any more, consequently leading to dissolution of
`the drug from the small particles and finally complete dis-
`appearance of the small particles. The lack of Ostwald
`ripening in nanosuspensions 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 the
`different saturation solubilities and concentration gradients
`in the vicinity of differently sized particles, which in turn
`prevents the Ostwald ripening effect.
`
`Versatility
`The flexibility offered in the modification of surface prop-
`erties and particle size, and ease of post-production
`processing of nanosuspensions enables them to be incor-
`porated in various dosage forms, such as tablets, pellets,
`suppositories and hydrogels, for various routes of admin-
`istration, thus proving their versatility.
`
`0006
`
`
`
`Characterization of nanosuspensions
`
`The essential characterization parameters for nanosuspen-
`sions are as follows.
`
`. Mean particle size and particle size distribution. The
`mean particle size and the width of particle size distri-
`bution are important characterization parameters as
`they govern the saturation solubility, dissolution velo-
`city, physical stability and even biological performance
`of nanosuspensions. It has been indicated by Mu¨ ller &
`Peters (1998) that saturation solubility and dissolution
`velocity show considerable variation with the changing
`particle size of the drug.
`Photon correlation spectroscopy (PCS) (Mu¨ ller &
`Mu¨ ller 1984) can be used for rapid and accurate deter-
`mination of the mean particle diameter of nanosuspen-
`sions. Moreover, PCS can even be used for determining
`the width of the particle size distribution (polydispersity
`index, PI). The PI is an important parameter that gov-
`erns the physical stability of nanosuspensions and
`should be as low as possible for the long-term stability
`of nanosuspensions. A PI value of 0.1–0.25 indicates
`a fairly narrow size distribution whereas a PI value
`greater than 0.5 indicates a very broad distribution.
`No logarithmic normal distribution can definitely be
`attributed to such a high PI value. Although PCS is a
`versatile technique, because of its low measuring range
`(3 nm to 3 m) it becomes difficult to determine the
`possibility of contamination of the nanosuspension by
`microparticulate drugs (having particle size greater than
`3 m). Hence, in addition to PCS analysis, laser diffrac-
`tometry (LD) analysis of nanosuspensions should be
`carried out in order to detect as well as quantify the
`drug microparticles that might have been generated
`during the production process. Laser diffractometry
`yields a volume size distribution and can be used to
`measure particles ranging from 0.05–80 m and in
`certain instruments particle sizes up to 2000 m can be
`measured. The typical LD characterization includes
`determination of diameter 50% LD (50) and diameter
`99% LD (99) values, which indicate that either 50 or
`99% of the particles are below the indicated size. The
`LD analysis becomes critical for nanosuspensions that
`are meant for parenteral and pulmon