Nanocrystals: Current Strategies and Trends - International Journal ...

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701 

_________________________________________Research Paper 

Nanocrystals: Current Strategies and Trends 

Sanjay Bansal 1 *, Meena Bansal 1 and Rachna Kumria 2 

1 M.C.P. College, Jalandhar, Punjab, India. 

2 MMCP, MMU, Mullana, Ambala, Haryana, India. 

___________________________________________________________________________ 

ABSTRACT 

With the advent of modern technologies, a large number of drugs have been discovered which have a better 

efficiency but their clinical application is restricted due to poor water solubility. Nearly 40% of the drugs in the 

pipeline and around 60% of compounds coming directly from synthesis have poor solubility. Poor water 

solubility has become a leading challenge for the formulation of these compounds. Poor solubility is generally 

associated with poor bioavailability. Nanocrystals have the potential to overcome this issue. Change of 

materials into the nanodimension dramatically changes its physical properties. Drug nanocrystals are crystals 

with a size in the nanometer range (mean diameter < 1000nm). This review article outlines the various 

pharmaceutical advantages of nanosization, industrially relevant production technologies available currently 

with advantages and disadvantages of each and the various dosage forms developed using nanocrystals. The 

nanocrystal products in the market/pipeline will be briefly reviewed and the advantages of these as compared 

to traditional products would be highlighted. 

Key Words: Nanocrystals, high pressure homogenization, pearl milling, drug nanocrystals, dissocubes. 

1. INTRODUCTION 

With progress in high throughput screening 

methods and also with 60% of the drugs coming 

directly from synthesis the number of poorly 

soluble drugs is increasing 1 . Research efforts are 

being focused on the approaches to increase drug 

solubility e.g. solubilisation using surfactants, 

formation of micro emulsions , complex formation, 

formation of self emulsifying drug delivery system 

(SEDDS), solid dispersions, etc. Micronization of 

drug powders to size between 1-10 μm, in order to 

increase surface area and dissolution rate is not 

sufficient to overcome bioavailability of BCS Class 

II drugs. The next step towards solubilization is 

nanonization. Nanocrystals are crystals having size 

less than 1μm . As the particle size of a crystal is 

decreased to about 100 nm there is a drastic change 

in the properties of the material. The decreased size 

increases the surface area and solubility of drug 

manifolds and there is proportionate increase in the 

bioavailability of poorly soluble drugs. 

Nanonization has an additional effect when 

compared to micronisation. It increases not only 

the surface area, but also simultaneously the 

saturation solubility. The solubility of normally 

sized powders is a compound specific constant, 

depending only on the temperature and the solvent. 

However, when the particle size of a crystal is less 

than 1-2 μm, the saturation solubility is also a 

function of particle size. The dissolution pressure 

increases due to the strong curvature of the 

particles leading to an increase in saturation 

solubility. The theoretical background is provided 

by the Ostwald–Freundlich and the Kelvin 

equations 2 . 

The increase in saturation solubility has two 

effects: 

a) An increase in saturation solubility leading to an 

increase in dissolution rate. 

b) Formation of a supersaturated solution which 

in-turn increases the concentration gradient 

between the lumen of the gut and the blood. This 

would hasten drug diffusion promoting absorption. 

Nanocrystals offer a quick action onset due to 

faster dissolution and rapid absorption. This is 

advantageous particularly for drugs where a quick 

action is desired e.g. naproxen for relief of 

headache. The bio-availability of various drugs has 

been found to increase significantly when 

administered in the form of nanocrystals. A study 

was conducted by Liversidge and Conzentino 

(1995) 3 on the bioavailability of naproxen, when 

naproxen was administered as a conventional 

tablet, a suspension and as a nanosuspension. It 

was found that the area under the curve (AUC) of 

blood levels for analgesic naproxen was 32.7 mgh/l 

for conventional tablet, 44.7 mgh/l as Naprosyn ® 

suspension and the AUC increased to 79.5 mgh/l 

when naproxen was administered as 

nanosuspensions. Another study was conducted on 

the gonadotropin inhibitor danazol when 

administered as macrosuspension and as a 

Vol. 3 (1) Jan – Mar 2012 www.ijrpbsonline.com 406


nanosuspension. The relative bio-availability was 

found to be 5.1% when danazol was administration 

as a microemulsion. Bioavailability of Danazol 

nanosuspension on the other side was found to be 

82.3% 4 . Due to their small size, nanosuspension 

can be injected intravenously leading to a 100% 

bio-availability. Thus any drug can be made 100% 

bio-available using the nanocrystal technology. 

Nanocrystals can show a strong adhesion because 

of the increased contact area for van der Waals 

attraction. The adhesiveness of the nanoparticles to 

the gut wall after oral administration enhances 

absorption and thereby increases the 

bioavailability. Lamprecht (2001) 5 observed 

differential uptake/ adhesion of polystyrene particle 

to inflamed colonic mucosa, with the deposition 

5.2%, 9.1%, and 14.5% for 10-mm, 1000-nm, and 

100-nm particles, respectively. The behavior of 

polymeric nanoparticles in GIT is influenced by 

their bio-adhesive properties. Therefore, lectins 

have been shown to improve muco-adhesion of the 

drug 6 . 

Nanocrystals may be able to reduce the dose to be 

administered, provide a sustained drug release and 

increase patient compliance. de Waard et al. 

(2010) 7 prepared nanocrystals of ibuprofen and 

fenofibrate. He claimed that shape of the crystals 

increases the drug absorption to a great extent. So, 

Waard claims that doses of poorly soluble drugs 

such as ibuprofen and cholesterol reducing 

fenofibrate can be reduced if they are administered 

in nanocrystal form. The increased bio-availability 

leads to reduction in dosing frequency which may 

improve patient compliance. Pandey et al. (2003) 8 

demonstrated that the nanoparticles provided 

sustained release of the anti-tubercular drugs 

(rifampin, isoniazid and pyrazinamide) and 

considerably enhanced their efficacy after oral 

administration. This solves the problem of patient 

non-compliance and thus reduces the incidence of 

relapse of the disease. Shegokar et al. (2010) 9 

prepared prolonged release formulation for dermal 

use incorporating nanocrystals of poorly water 

soluble lidocaine. Nanocrystals can be incorporated 

in various dosage forms which make administration 

by various routes feasible. Due to better solubility 

and bioavailability, nanocrystals can be supplied in 

patient friendly oral solid dosage forms such as 

tablets and capsules. Nanocrystals of poorly soluble 

drugs can also be incorporated in cosmetic products 

where they provide high penetration power through 

dermal application. A very small size of 

nanoparticles (200-400 nm) even smaller than the 

size of the smallest blood capillaries allows the 

nanosuspensions to be injected intravenously. This 

provides 100% bio-availability and simultaneously 

avoids the use of toxic surfactants or co solvents to 

dissolve the drug. Pulmonary and ophthalmic drug 

delivery of nanocrystals has also been achieved 

with better efficiency. Nanosuspensions can be 

used for targeted delivery because their surface 

properties and changing of the stabilizer can easily 

alter in-vivo behavior. Nanosuspensions afford a 

means of administering poorly soluble drugs to 

brain with decreased side effects. Different 

approaches can be used to target drugs to the site of 

action. One method is direct injection of 

nanoparticles at the target site e.g. injection into 

cancer tissue. 

The drug nanocrystals are a smart delivery system, 

a universal principle, which can be applied to any 

drug because any drug can be diminuted to 

nanocrystals. Furthermore, both lipophilic and 

hydrophilic drugs can be incorporated as 

nanocrystals. Another essential prerequisite for 

entry to the pharmaceutical market is the 

availability of large scale production methods at 

sufficiently low cost and simultaneously meeting 

the regulatory requirements. The nanocrystals 

technology fulfills this criterion also. The pearl 

milling and high pressure homogenization can be 

extended for commercial production of 

nanocrystals and are accepted by the regulatory 

authorities. 

2. Nanocrystal technology 

Drug nanocrystals can be produced by bottom up 

techniques (precipitation methods) or top down 

techniques (size reduction by milling or high 

pressure homogenization). In case of bottom-up 

technologies, one starts with molecules in the 

solution and moves via association of these 

molecules to form solid particles, i.e. it is a 

classical precipitation process. The top down 

techniques are based on size reduction of relatively 

large particles into smaller particles by mechanical 

attrition. For industrial production, all products are 

prepared by top down technique. The basic 

techniques currently used by different companies 

are: 

2.1.Bottom-up technique (Precipitation method) 

2.2 Top down techniques 

2.2.1. Pearl/Ball milling (Nanosystems /Élan 

technology) 

Vol. 3 (1) Jan – Mar 2012 www.ijrpbsonline.com 407 

4, 10 

2.2.2 High Pressure Homogenization (HPH) 

2.2.2.1 Micro fluidizer technology (IDD-P TM 

technology) 

2.2.2.2 Piston gap homogenization in water 

(Dissocubes® technology) 


mixtures or in non-aqueous medium 

(Nanopure® technology) 11-15 

2.2.3 Combination technology 

2.2.3.1. NANOEDGE® Technology 

2.2.3.2. SmartCrystal® Technology 

2.1 Bottom-up technique (Precipitation 

method): This is also known as hydrosol 

technology. This was developed by Sucker and the 

intellectual property is owned by Sandoz


(nowadays Novartis) 16, 17 . In this technique the drug 

is dissolved in a solvent and then this solution is 

added to a non solvent leading to the precipitation 

of the finely dispersed drug nanocrystals. The 

precipitation technique is simple and requires low 

cost equipments. For example, the solvent can be 

poured into the non-solvent with a constant 

velocity in the presence of a high-speed stirrer. 

Main approaches include the use of static mixers or 

micro-mixers, which simulate the precipitation 

conditions in a small volume (i.e., simulating labscale 

conditions). In the case of micro-mixers, 

scaling up can be performed in a simple way by 

arranging many micro-mixers in parallel. This 

equipment is relatively simple and of relatively low 

cost (this is not necessarily valid for the micromixers). 

The drawbacks of this technique are that the drug 

needs to be soluble in at least one solvent. This 

however, is problematic for newly developed drugs 

which are generally insoluble in both aqueous and 

organic media. Secondly, this solvent needs to be 

miscible with at least one non solvent. Solvent 

residues need to be removed, thus increasing 

production costs. 

In case of nanocrystals, care needs to be exercised 

to ensure that the crystals do not grow in size and 

remain stabilized at the nanosize. Spray drying and 

lyophilization are the techniques recommended to 

preserve the particle size in nano range 18 . Another 

alternative to preserve the size of nanocrystals is 

the use of polymeric growth inhibitors. Various 

stabilizers like sodium dodecyl sulfate (SDS), 

polyvinyl alcohol (PVA), tween® 80 and 

polyxamer® 188 have been employed to prepare 

nanocrystals 19 . 

Nanomorphs: Another precipitation method has 

been developed by Soliqs/Abbott, to enhance 

dissolution rate and solubility. Carotene 

nanoparticles were developed for food industry 

e.g., Leucarotin® or Lucantin® (BASF) 20 . For 

preparation of these, a solution of the Carotenoid 

and surfactant in digestible oil was mixed with a 

suitable aqueous solvent. To this a protective 

colloid was added. Carotenoid was stabilized and 

localized in the oily phase of this o/w emulsion. 

This emulsion was then lyophilized. X-ray analysis 

of the lyophilized product revealed that about 90% 

of the carotenoid was in the amorphous state. These 

particles were called nanomorphs (Nanomorph®). 

These were found to have higher saturation 

solubility when compared to crystalline material. 

At present, there is no pharmaceutical product in 

the market based on this technology. 

2.2 Top-down techniques 

2.2.1 Pearl/Ball milling: In this technique, the 

drug along with the milling media, dispersion 

media (generally water) and the stabilizer is fed 

into the milling chamber. Milling balls or small 

pearls are used as milling media. The movement of 

milling media generates high shear forces and 

forces of impact which leads to particle size 

reduction. This technology was developed by 

Merisko-Liversidge et al. (2003) 21 . The pearls or 

balls comprise of ceramic (cerium or yttrium 

stabilized zirconium dioxide), glass, stainless steel 

or highly cross-linked polystyrene resin coated 

beads. The two basic principles of milling are 

employed. Either the milling material can be 

moved by an agitator or the complete container 

may be moved in a complex movement. In the 

latter method large batches are difficult to process, 

so mills using agitators are generally preferred for 

large batches. Milling time, however, depends upon 

various factors such as hardness of the drugs, 

surfactant contents, viscosity, temperature, energy 

input and size of the milling media. The milling 

time can last from 30 minutes to several hours 21 . 

Advantages of Pearl milling include low cost, 

simple technology and ability for large scale 

production. The disadvantages associated with this 

process are erosion from the milling material 

leading to product contamination, adherence of the 

product to the inner surface of the mill and to the 

surface of the milling pearls, long milling times(in 

case of hard drugs), potential growth of germs in 

the water phase (when milling for a longtime), time 

and costs associated with the separation procedure 

of the milling material from the drug nanoparticle 

suspension, especially when producing parenteral 

sterile products. 

Buchmann et al (1996) 22 reported the formation of 

glass micro particles when using glass beads as the 

milling media. The erosion from the glass beads 

could be reduced when these were coated with 

highly cross linked polystyrene resin 23 . The 

wastage of the drug due to adherence to milling 

surface is of significance in case of very expensive 

drugs, particularly when very small quantities are 

processed. 

The first four marketed products containing 

nanocrystals such as Rapamune®, Emend®, 

Tricor®, Megace ES® were prepared by Pearl mill 

technology by Elan nanosystems. 

2.2.2 High Pressure Homogenization Technique 

This Technique has been applied for many years 

for the production of emulsions and suspensions. A 

distinct advantage of this technology is its ease for 

scale up. 

There are three important technologies for 

producing nanocrystals using homogenization 

methods:- 

2.2.2.1. Microfluidizer technology (IDD-P TM 

technology) 

2.2.2.2. Piston gap homogenization in water 

(Dissocubes® technology) 

2.2.2.3. Piston gap homogenization in water 

mixtures or in non-aqueous medium 

(Nanopure® technology) 



2.2.2.1 Microfluidizer technology: 

(Microfluidics TM Inc. USA) This technology is 

based on the jet-stream principle. Two streams of 

liquid with high velocity (upto 1000 m/sec) collide 

frontally under high pressures (upto 1700 bars) 24 . 

The particle size is reduced due to high shear force 

particle collision and cavitation 25 . The same can be 

achieved using jet stream homogenizers such as 

micro-fluidizer (Microfluidizer® Microfluidics 

Inc.). The collision chamber can be either Y-type 

or Z-type in shape. Surfactants or phospholipids are 

required to stabilize the desired particle size 26, 27 . 

Microfluidizer can be used for the production of 

drug nanosuspensions for soft drugs. However, this 

technique is not very convenient for large scale 

production as a large number of cycles (50 to 100 

passes) are required for sufficient particle size 

reduction 28, 29 . This technique is being utilized by 

SkyePharma Canada Inc. for production of 

submicron particles of poorly soluble drugs and 

named it IDD-P TM (Insoluble Drug Delivery- 

Particle technology). 


(Dissocubes® technology). Piston gap 

homogenization technology was developed by 

Müller et al., and acquired by SkyePharma in 

1999 14,30 . In this technique, powdered drug is 

dispersed in an aqueous surfactant solution which 

is then forced by a piston through tiny 

homogenization gap under high pressure. The gap 

width is adjusted according to the viscosity of the 

suspension and the applied pressure and is 

generally in the size range of 5 to 20 μm 31 . 

According to Bernoulli equation the resulting high 

streaming velocity of the suspension causes an 

increase in the dynamic pressure which is 

compensated by a reduction in the static pressure. 

The static pressure in the gap falls below the 

vapour pressure of water at room temperature 32 . So 

water starts boiling in the gap at room temperature 

leading to the formation of gas bubbles. The 

formation of gas bubbles leads to pressure waves 

disintegrating the crystals. When the liquid leaves 

the homogenization gap, the static pressure 

increases to normal air pressure and gas bubbles 

collapse. This process of formation and implosion 

of gas bubbles is called cavitation. There is particle 

size diminution due to high shear forces, turbulent 

flow and the enormous power of these shock 

waves 33 . This technique has been used for 

production of nanosuspension of artemisinin and 

quercetin using Tween 80 as a stabilizer (0.5- 2.5 

% w/w) 34, 35 . 

The use of water as dispersion medium has certain 

disadvantages such as hydrolysis of water sensitive 

drugs and problems during drying step. In case of 

thermolabile drugs or drugs having low melting 

point, removal of water necessitates the use of 

techniques such as lyophilization which are quite 

expensive. Dissocubes® technology therefore is 

most suitable when aqueous suspensions of 

nanocrystals are to be formulated for drugs that are 

poorly soluble in both aqueous and organic 

media 14 . Another advantage of this method is that it 

allows aseptic production of nanosuspensions for 

parenteral use 36 . Nanocrystal suspensions of 

cyclosporine, paclitaxel, amphidicolin, 

bupravaquone, azodyecarbonamide and 

prednisolone have been prepared using this 

technique. 

The two main drawbacks associated with this 

method are high installation and maintenance cost 

of equipments and requirement of preprocessing of 

the drugs (e.g. micronization). 

2.2.2.3 Piston-gap homogenization in water 

reduced mixtures or non-aqueous medium 

(Nanopure® technology): Another approach using 

piston-gap homogenizer is the Nanopure® 

technology which is owned and developed by 

Pharmasol GmbH in Berlin. This technology uses 

non-aqueous phase or phases with reduced water 

content as dispersion media. Use of non aqueous 

media is advantageous for drugs which undergo 

hydrolysis in water. The different media used for 

homogenization include oils, water-glycerol 

mixtures, polyethylene glycols, water- alcohol 

mixture etc. These dispersion media have low 

vapor pressure. The static pressure in the 

homogenization gap does not fall below the vapor 

pressure of the liquid, so the liquid does not boil 

and cavitation does not occur. Even without 

cavitation, sufficient size reduction to nano range 

takes place 11, 12, 37 . The forces responsible for size 

diminution are particle collision and shear forces 

occurring in highly turbulent fluid in the gap 38 . 

Homogenization using Nanopure® technology is 

similar or more efficient at lower temperature, i.e. 

temperature below the freezing point of water. 

Melted non aqueous matrices such as PEG 6000 

that are solid at room temperature can also be used 

as a medium for homogenization. This leads to 

fixation of drug nanocrystals in the solid matrix 

and minimizes crystal contact and subsequent 

crystal growth. Drug nanocrystals dispersed in 

liquid PEG’s (such as Miglyol 812 or 829) or oils 

can be directly filled as drug nanosuspension into 

gelatin or HPMC capsules 39 . Nanocrystals have 

been used as powder for the production of solid 

dosage forms such as tablets and pellets. 

Preparation of solid oral dosage forms from the 

nanocrystal suspension requires the removal of 

dispersion media from the nanocrystals. Dispersion 

medium is removed by either freeze drying or 

spray drying. Nanopure Technology offers 

advantage in this case since evaporation is faster 

and takes place at lower temperature due to the use 

of non aqueous medium or water reduced mixtures. 

This is useful for thermolabile drugs. 



Isotonic drug nanosuspensions for parenteral 

administration can be obtained by homogenization 

in water-glycerol mixtures (2.25 % of water free 

glycerol). Amphotericin-B powder was dispersed 

in liquid PEG-400 and in melted PEG 1000 

respectively and homogenized at 1500 bar up to 25 

homogenization cycles 38 . 

Thus, High Pressure Homogenization has a number 

of advantages to offer (a) it is a continuous process, 

(b) there is a limited contamination from the 

production equipment (e.g. contamination with iron 

was found to be less than 1 ppm ), (c) its ability for 

scaling up, even up to production level (d) 

possibility of production even without water. 

A comparative study on the performance of two 

different techniques of nanonization namely, HPH 

and milling was carried out on Ibuprofen by 

Mauludin et al. 19 . Particle size distribution of the 

nanocrystals formed was compared. It was found 

that the performance of the nanonization technique 

depends strongly on the drug properties. In case of 

Ibuprofen, which consists of hard crystals, HPH 

was superior to the ball milling technology. 

Increasing the milling time could not further reduce 

the particle size distribution. 

Advantages and disadvantages of different 

nanonization techniques have been listed in Table 

1. 

2.3. Combination Technologies 

The term combination technology has been used 

for technologies which combine a pre-treatment 

step followed by a high energy homogenization. 

2.3.1. NANOEDGE® Technology- 

(Microprecipitation and Homogenization). 

NANOEDGE® Technology was introduced by 

Baxter, and this involves a combination of 

precipitation followed by annealing process. 

Annealing process is carried out using high energy 

such as high shear forces and/or thermal energy 40 . 

When drug nanoparticles are produced by 

precipitation method alone, the precipitated 

nanoparticles have a tendency to grow. Also, the 

precipitated particles may be amorphous or 

partially amorphous. Upon keeping, the amorphous 

particles may re-crystallize and this may lead to a 

decreased bioavailability of the drug. Combination 

technology on the other hand has the potential to 

overcome these problems, firstly, by prevention of 

crystal growth and secondly by reducing the 

uncertainty of formation of either crystalline or 

amorphous state as the annealing process converts 

all precipitated particles to crystalline state. 

Nanoedge TM technology is particularly suitable for 

drugs that are soluble in non-aqueous media 

possessing low toxicity, such as N-methyl-2pyrrolidinone. 

But the drawback of this method is 

its cost especially in case of preparation of sterile 

parenteral products. 

2.3.2. SmartCrystal® technology This technology 

was first developed by PharmaSol GmbH and was 

later acquired by Abbott. It is a tool-box of 

different combination processes in which process 

variations can be chosen depending upon the 

physical characteristics of the drug (such as 

hardness). The process H42 involves a combination 

of spray-drying and HPH. Drug nanocrystals can 

be produced much faster in one to a few 

homogenization cycles. Process H69 (Precipitation 

and HPH) and H96 (lyophilization and HPH) yield 

nanocrystals of amphotericin B within a size range 

of about 50 nm 41 . 

S. Kobierski et al. (2008) 42 produced nanocrystals 

in a two-step process i.e. pre- milling followed by 

high pressure homogenization (HPH). 

Nanosuspensions of cosmetic active hesperidin 

were produced by ball-milling process and with 

combination process. Both the prepared 

nanosuspensions were kept for storage. 

Nanosuspension prepared using SmartCrystal® 

technology was found to be of a smaller size 

indicating better physical stability. Also 

combination technique is faster and more 

economical as compared to HPH alone. 

Möschwitzer and Müller 43 (2005) prepared spraydried 

hydrocortisone acetate powder from 

nanosuspension produced by HPH with a micron 

LAB 40 and planetary monomill “pulverisette 6”. 

The number of cycles required could be distinctly 

reduced. Additionally, a smaller particle size and 

better particle size distribution could be obtained. 

Another finding of the study was that the 

application of different homogenization pressures 

(e.g. 300 and 500 bar) was equally efficient. 

Therefore, during large scale production, low 

homogenization pressures (300 bars) may be 

preferred to reduce wearing of the machine 44 . 

3. Processing of nanosuspension to form 

nanocrystals 

The nanonization of drugs by various techniques 

generally results in a liquid product called 

nanosuspension. But these nanosuspensions are 

directly used as a final product only in some special 

cases e.g. as pediatric or geriatric dosage forms. In 

most of the cases, a dry dosage form (particularly 

for oral administration) is preferred, may be a) for 

convenience, b) to achieve a controlled drug 

delivery, c) to prevent drug degradation, d) to 

enable better drug targeting, e) to increase the 

physical stability for long term storage and f) to 

obtain a fine non-aggregated suspension in the 

gastro-intestinal tract after oral administration. In 

such cases, the nanosuspension needs to be 

transformed into solid forms, which may be 

crystalline (Nanocrystals) or amorphous 

(Nanomorphs). Various techniques are used for this 

purpose like spray drying, freeze drying, 

pelletization or granulation. 



3.1 Spray Drying: Spray drying is a simple and 

inexpensive method and is therefore suitable for 

industrial production. This method is used for drug 

nanosuspension produced by high pressure 

homogenization and is an aqueous solution of 

water-soluble matrix materials e.g. polymers (PVP, 

long chained PEG’s or polyvinyl alcohol), sugars 

(saccharose, lactose) or sugar alcohols like 

mannitol and sorbitol. In the subsequent step, the 

aqueous drug nanosuspension can be spray dried 

under adequate conditions. The resulting dry 

powder consists of drug nanocrystals embedded in 

a water- soluble matrix. The loading capacity of the 

solid powder with drug nanocrystals can be 

adjusted by varying the concentrations of 

surfactants in the original aqueous nanosuspension. 

Advantages of this method are that drug 

nanocrystals remain fixed within the matrix. Their 

physical contact is avoided so the chances of longterm 

physical instabilities like aggregation and 

Ostwald ripening are minimized. Exceeding a 

certain maximum loading capacity of the matrix 

with drug nanocrystals has an increasing negative 

effect on crystal growth and release as fine 

dispersion. The spray dried nano sized powder can 

be filled into hard gelatin capsules or sachets or can 

used for making tablets. Drug nanoparticles 

produced in PEG 600 or Miglyol can directly be 

filled into soft gelatin capsules. 

3.2. Freeze drying: Another method for removing 

water from formulation is freeze drying. This 

however, is a complex and expensive process and 

the product obtained is highly sensitive to process 

parameters. This method is not suitable for 

industrial production. 

A new technique based upon freeze drying was 

developed by de Waard (2010) [7] . In this technique 

a mixture of the drug, solvent, and mannitol is 

cooled rapidly, resulting in separation of drug in a 

nanocrystal form encased by a matrix of mannitol. 

This matrix increases the stability of the 

nanocrstallized drug without which the crystals 

may stick together and form one large crystal. de 

Waard also developed a spray-freeze-drying 

method which enables the process to be applied on 

an industrial scale. Another method developed by 

the same author was a spray-freeze-drying method 

which could make industrial application of this 

process simpler. 

Lyophilization of drug nanoparticles produced in 

water-reduced media can be used to produce FDDS 

(Fast Dissolving Drug Delivery Systems). For 

parenteral application Nanopure can be lyophilized 

and reconstituted prior to injection with isotonic 

media (e.g. water with glycerol). 

3.3. Pelletization: A number of pelletization 

techniques are known, but the most commonly 

used techniques are a) extrusion-spheronization and 

b) drug coating onto sugar spheres. The 

pelletization technique is selected on the basis of 

the required drug content, properties of the drug 

and the available equipment. A multi-particulate 

dosage form such as coated pellet system is 

obtained irrespective of the pelletization technique 

applied. These multi-particulate dosage forms show 

distinct advantages over single unit dosage forms 

such as faster and more predictable gastric 

emptying and more uniform drug distribution in 

GIT within different individuals. 

3.3.1. Production of pellets containing drug 

nanocrystal-loaded matrix cores: The drug 

nanosuspension obtained by high-pressure 

homogenization is mixed with matrix material 

(fillers such as MCC, Lactose or Starch). Pellets 

are produced by extrusion-spheronization and can 

be subsequently coated with polymers to modify 

the drug release properties. 

Mucoadhesive budenoside nanocrystals were 

prepared using extrusion-spheronization. The 

obtained pellets were coated with Eudragit L 30 D- 

55 to obtain enteric coating and delayed drug 

release [44] . Another type of modified release pellets 

were prepared by Mauludin et al. [45] (2005). These 

effervescent pellet formulations containing 

ibuprofen drug nanocrystals were produced by 

HPH. These ibuprofen containing pellets loaded 

with nanocrystals of the drug dissolved completely 

within 30 minutes from both formulations. 

Spray coated pellets of hydrocortisone acetate were 

prepared (enteric coated) from mucoadhesive 

nanosuspension of this poorly soluble drug. The invitro 

dissolution tests showed an accelerated 

dissolution rate and an increased drug release for 

the pellets containing drug nanocrystals [46] . 

3.3.2. Production of pellets by Nanosuspension 

layering onto sugar cores: The drug 

nanosuspension obtained by HPH is directly 

layered onto sugar beads and subsequently coated 

with polymers using the same equipment to modify 

the drug release properties. 

4. Advanced Techniques for Production of Solid 

Nanocrystals 

There are many alternative technologies that are 

industrially less relevant. These are discussed 

below. 

4.1. Solution Enhanced Dispersion by the 

Supercritical fluids (SEDS): The SEDS method 

was developed and patented by the University of 

Bradford [47] . This technique uses an antisolventbased 

recrystallization process. CO2 is used as 

antisolvent. The substances are atomized into a 

chamber containing compressed CO2. As two 

liquids collide, intense atomization into micronized 

droplets occurs, subsequently drying of micro 



droplets occur as the solvent(s) and CO2 mix. 

Nanoparticles are formed because the two way 

mass transfer ie extraction of organic solvent and 

CO2 diffusion into the droplets occurs [48] . 

It is important to enhance the mass transfer rate 

between the droplets and the anti solvent before the 

droplets coalesce to form large size drops. 

This technique has produced a new polymorph of 

flucticasone propionate. It also enabled control 

over the particle size and shape of formed particles. 

This polymorph exhibited improved drug delivery 

characteristics in a metered dose inhaler (MDI) 

formulation compared to conventional and 

micronized drugs [49] . 

4.2. Spray Freezing into Liquid (SFL): The 

University of Texas (Austin) was the first to 

develop and patent the SFL method in 2003.This 

technique was first commercialized by Dow 

Chemical Company (Midland, MI).The drug 

present in an aqueous /organic /aqueous organic cosolvent 

solution, aqueous organic emulsion or 

suspension is atomized directly into either a 

cryogenic liquid (e.g. argon, nitrogen or halocarbon 

refrigerants) or a compressed gas (e.g. CO2, ethane, 

propane or helium). 

The fed solution is atomized through a nozzle 

positioned at a distance above the boiling 

refrigerant. The droplets gradually solidify while 

passing through the cold halocarbon vapor, and 

freeze completely as contact is made with the 

boiling refrigerant liquid. These frozen particles are 

then lyophilized to obtain free-flowing and dry 

micronized powder [50] . The SFL powder showed 

better results such as highly effective wettability, 

high surface area and enhanced dissolution rates. 

Unfortunately, this process may result in broad 

particle size distributions and non-micronized 

particles because agglomerates of the solution 

droplets are solidified while passing through the 

vapor phase and settle onto the surface of the 

cryogenic liquid [49] . 

4.3. Rapid Expansion of Supercritical Solution 

(RESS): The principle of the RESS process is to 

induce a fast nucleation of the supercritical fluid of 

dissolved drugs in the presence of surfactants. This 

results in particle formation with a desirable size 

distribution in a very short time. The surfactants 

serve to stabilize the formed small particles and 

suppress any tendency towards particle 

agglomeration or particle growth while they are 

being formed. The rapid intimate contact with the 

surface modifier is achieved by having the surface 

modifiers dissolved in the supercritical fluid 

containing the dissolved drugs. A rapid intimate 

contact between the surfactant and the newly 

formed particles inhibits the crystal growth of the 

newly formed particle [49,51] . 

This technique successfully produced cyclosporine 

nanocrystals with a size of 500–700 nm. 

Cyclosporine could be stabilized at drug 

concentrations as high as 6.2 and 37.5 mg/mL in 

1.0% and 5.0% (w/w) Tween 80 solution, 

respectively [49,52] . The dissolution of griseofulvin 

was two times higher than conventional micronized 

preparation [53] . 

Combination of RESS technique followed by highpressure 

homogenization was used by Pace (2001) 

[51] 

to prepare stable nanosuspensions of poorly 

soluble drugs. 

Young (1999) [54] developed a process based on 

supercritical fluids, rapid expansion from the 

supercritical to the aqueous solution (RESAS). 

4.4. Rapid Expansion of Supercritical Solution 

into Aqueous Solution (RESSAS): In contrast to 

RESAS, the RESSAS process utilizes a 

supercritical fluid which is expanded into an 

aqueous solution containing a stabilizer. This 

technique was used by Turk et al. to produce 

phytosterol particles with a diameter less than 500 

nm. The surfactants or stabilizers are dissolved in 

the aqueous phase, not in the supercritical fluid [55] . 

4.5. Evaporative Precipitation into Aqueous 

Solution Process (EPAS): The evaporative 

precipitation into aqueous solution (EPAS) applies 

rapid phase separation to nucleate and grow 

nanoparticles and micro particles of poorly watersoluble 

drugs. The EPAS was developed and 

patented by the University of Texas at Austin in 

2001 and commercialized by the Dow Chemical 

Company [49] . The drug is dissolved in a low 

boiling point organic solvent. 

The drug solution is pumped through a tube where 

it is heated under pressure at a temperature above 

the solvent’s boiling point. It is then sprayed 

through a fine atomizing nozzle into heated 

aqueous solution. This process results in an 

amorphous suspension. Surfactants are added for 

efficient particle formation and stabilization. The 

stable aqueous drug suspension is dried by 

lyophilization or spray drying. A variety of 

hydrophilic surfactants are added to the solution to 

diffuse to surface of the growing particles rapidly 

enough to prevent growth of particles. The EPAS 

technique has produced cyclosporine-A 

nanosuspension with particle size ranging from 130 

to 460 nm [56] . 

5. Applications of Nanocrystals by various 

routes of administration:- 

5.1 Oral administration: - Enhancement in 

bioavailability of poorly soluble drugs after oral 

administration is well documented in the literature 

[3, 10, 21 ] . Besides it has also been proved by various 

drug nanocrystal products placed in the market. A 

faster onset of action and decreased gastric 



irritancy has been reported when naproxen was 

formulated as nanosuspension [3, 57] . Due to fast 

dissolution of nanocrystals, the drug solubility is 

enhanced, making it bioequivalent in fed and 

fasting conditions. The bioadhesive nature of 

nanocrystals offers additional advantage of 

increased stay in the gastro-intestinal tract which 

enhances bioavailability [58, 59] . The nano size can 

be exploited for better drug targeting as reported 

for lymphatic drug uptake [60] or for inflammatory 

tissues [5] . Nanosuspensions can be formulated as 

more concentrated and less viscous. Patient has to 

take lesser dose of easily swallowed formulation 

(e.g. Megace ES). Nanoparticles provided 

sustained release of anti-tubercular drugs – 

rifampin, isoniazid and pyrazinamide and 

considerably improved their efficacy after oral 

administration [8] . Amphotericin B administered 

orally as a nanosuspension showed dramatically 

improved bioavailability as compared to its 

conventional oral commercial products such as 

Fungizone, AmBisome and micronized 

Amphotericin B [33, 62] . Aqueous nanosuspensions 

can be used directly in a liquid dosage form or 

incorporated in a dry dosage form such as tablets, 

capsules and fast melts by means of standard 

manufacturing technologies. Ketoprofen 

nanosuspensions have been successfully 

incorporated into pellets to release the drug over a 

period of 24 hrs. 

[63] . Oral Fenofibrate 

nanosuspensions showed better bioavailability as 

compared to conventional micronized drug 

suspensions [64] . 

5.2 Parenteral administration:- The conventional 

parenteral preparations (particularly for intravenous 

administration) of poorly soluble drugs are 

formulated by dissolving the drug with the help of 

cosolvents, surfactants, liposomes or cyclodextrins 

which is often associated with toxic effects and 

large injection volumes. Aqueous nanosuspensions 

are an ideal formulation to overcome these 

problems e.g. Paclitaxel nanosuspensions cause 

less toxicity as compared to Taxol with 

Chremophor EL [65] . The parenteral administration 

of Clofazimine, an anti-tubercular drug was 

restricted due to its poor solubility. Clofazimine 

nanosuspension consisting only of the drug and a 

minimum amount of surfactant was injected 

intravenously, which showed better stability and 

efficacy over liposomal Clofazimine in M. avium 

infected mice [66] . An intravenous nanosuspension 

of Itraconazole was reported to enhance the anti 

fungal effect in comparison to its solution dosage 

form in rats [67] . Due to higher loading capacity 

with nanosuspensions, the injectable dose can be 

distinctly reduced, compared to solutions [36] . Drug 

nanosuspensions can be sterilized by autoclaving, 

using gamma radiations or by sterile filtration using 

0.22 mm filter [68, 69] . Nanocrystals above 200nm 

dissolve slowly and are taken up by macrophages 

of the liver. This causes potentially targeted 

toxicity to the liver. Nanocrystals with size well 

below 100 nm dissolve much faster. The injection 

of nanosuspensions containing smaller particles 

resembles the intravenous injection of solutions 

and reduces the uptake by the liver. The targeting 

of clofazimine nanosuspension to the lung, liver, 

spleen and reticulo-endothelial system was 

comparable to the liposomal formulation [66] . 

Intravenous administration of nanosuspensions has 

further advantage of passive drug delivery to 

inflammatory sites where endothelium becomes 

permeable due to pathological processes. The 

passive accumulation in such sites with leaky 

vasculature was found to be more effective with 

long circulating nanoparticles [70] . Flexibility of 

nanosuspensions was further demonstrated by 

effective subcutaneous treatment of mice infected 

with M. tuberculosis [71] . 

5.3 Pulmonary drug delivery: - Poorly soluble 

drugs can be delivered directly to the lungs by 

nebulizing the aqueous nanosuspensions using 

mechanical or ultrasonic nebulizers. Using 

nanoparticles, drug is more evenly distributed in 

droplets. All aerosol droplets are likely to contain 

drug nanocrystals. Budenoside, poorly water 

soluble corticosteroid, has been successfully 

prepared as a nanosuspension for pulmonary 

delivery. It showed long term stability. No particle 

growth and aggregates formed over a period of one 

year [72] . In addition, Buparvaquone 

nanosuspension was formulated for an alternative 

treatment of lung infection (pneumonia) to deliver 

the drug at the site of lung infection using 

nebulization [73] . Administration to infected guinea 

pigs of nebulized rifampin, isoniazid and 

pyrazinamide encapsulated in wheat germ 

agglutinin-functionalized PLG nanoparticles was 

much more effective. Three doses administered 

fortnightly for 45 days were sufficient to produce a 

sterilizing effect in lungs and spleen [74] . Drug 

nanocrystals showed an increased mucoadhesiveness 

leading to a prolonged residence time 

at the lung mucosa [73] . 

5.4 Dermal application: - Dermal 

nanosuspensions are mainly of interest if 

conventional approaches fail. Nanocrystals can 

increase the penetration of poorly soluble cosmetic 

and pharmaceutical substances into skin. This 

happens because increased saturation solubility 

increases the concentration gradient. Juvena 

launched first four Nanocrystal cosmetic products 

with rutin. Petersen (2006) [75] reported that rutin 

Nanocrystal formulation possesses 500 times 

higher bioactivity (measured as Sun Protection 

Factor,SPF) compared to water-soluble rutin- 



glycoside . Dermal application of nanocrystals is 

protected by a US and PCT patent application. 

Shegokar et al. (2011) [76] reported that both rutin 

and hesperidin nanocrystals increased the SPF by 

36% and 59% respectively. This proves that 

nanocrystals increase the penetration into the skin. 

Shaal et al. (2010) [77] prepared apigenin 

nanocrystals and reported that UV skin protective 

potential can be significantly increased by 

decreasing the particle size from micrometer to the 

nanometer range. 

5.5. Ophthalmic drug delivery: - 

Nanosuspensions can prove beneficial for drugs 

that have poor solubility in lachrymal fluids. 

Nanosuspensions offer advantage of prolonged 

retention time in the eye, most likely due to their 

adhesive properties. Another advantage of 

nanosuspensions is high drug loading which avoids 

high tonicity created by water soluble drugs. 

Pignatello (2002) [78] developed a polymeric 

nanosuspension of ibuprofen for ophthalmic drug 

delivery. Ophthalmic nanosuspensions of glucocorticoid 

drugs; hydrocortisone, prednisolone and 

dexamethasone show increased rate and extent of 

drug absorption and also prolonged duration [79] . 

5.6 Targeted drug delivery: - Nanocrystals can 

have deep excess to the human body because of 

particle size and control of surface properties. So 

they can also be used for targeted drug delivery. 

Kayser (2000) [80] developed a nanosuspention of 

aphidicolin to improve drug targeting against 

Leishmania-infected macrophages. He 

demonstrated that aphidicolin was highly active at 

a concentration in the microgram range. Similarly 

peptide dalargin was successfully targeted to the 

brain by employing surface modified poly(butyl ) 

cyanoacrylate nanoparticles [81] . 

Nanoparticles offer a promising new cancer 

treatment that may one day replace radiation and 

chemotherapy. Kangius RF therapy attaches 

microscopic nanoparticles to cancer cells and then 

cooks tumors inside the body with radio waves that 

heat only the nanoparticles and the adjacent 

cancerous cells. 

Muco-adhesive pellets or nanoparticles have been 

used as specific carrier systems for oral 

administration [82-84] . Cevc et al. (1998) [85] used 

transferosomes for targeted topical delivery. 

Bupravaquone nanosuspension was successfully 

used for targeting of Cryptosporidium parvum, (the 

organism responsible for cryptosporidium) by 

altering the mucoadhesive properties [86] . 

Amphoterecin B as pulmonary nanosuspension was 

used to target conditions such as pulmonary 

asperigillosis [87] . 

6. Marketed products and products in the 

pipeline 

The first four marketed products containing 

nanocrystals were prepared by Pearl mill 

technology by Elan nanosystems. Rapamune® was 

the first marketed product containing sirolimus 

nanocrystals introduced in 2000 by Wyeth. The 

main advantages of nanocrystal technology in the 

coated tablets of Rapamune® nanocrystals are 

more convenient dosage form and a 21% higher 

bioavailability as compared to the Rapamune 

solution. A smaller particle size leads to greater 

solubility and larger surface area consequently 

increased dissolution velocity and thus greater 

bioavailability 

Emend®, the second product incorporating 

nanocrystal technology was introduced in 2003 by 

Merck. Emend® is a capsule containing pellets of 

Aprepitant, drug used for the treatment of emesis. 

Aprepitant shows a narrow absorption window i.e. 

absorbed in the upper gastrointestinal tract only. In 

this case, large increase in surface area due to 

nanonisation leads to rapid in-vivo dissolution, fast 

absorption and increased bioavailability. 

Tricor® was launched in December 2004 by 

Abbott Laboratory. The active ingredient is 

fenofibrate. The normal size fenofibrate is absorbed 

when taken with a meal. The nanocrystal 

technology makes the bioavailability of fenofibrate 

independent of meals. 

Megace ES® (Megestrol acetate) (ES stands for 

Enhanced Stability). 

Megace ES® was introduced by Par 

Pharmaceutical companies, Inc. The nanocrystal 

technology leads to several advantages. The 

Nanocrystals offer enhanced bioavailability which 

reduces the amount of single dose. The patient has 

to take less volume. Another advantage is that there 

is no need of increasing viscosity to prevent 

sedimentation. Decreased dose and reduced 

viscosity lead to better patient compliance. 

Products already in the market or in the pipeline are 

listed in table 2 and table 3 respectively. 

7. Limitations of drug nanocrystal technology:- 

Many nanoparticulate delivery systems are under 

academic investigation. But only few made it to the 

market. This may be due to missing nanotoxicity 

and cytotoxicity data, lack of regulatory accepted 

status of the excipients, lack of large scale 

production lines which can be validated and 

acceptable by the regulatory authorities. 

Nanotoxicity may be attributed to the small size 

(below about 150 nm) of nanocrystals, due to 

which they can have access to any cell of the body 

via pinocytosis. This increases the risk of 

cytotoxicity. 

Moreover, this technology requires expensive 

equipments which increase the cost of the final 

product. The use of this technique is restricted to 



BCS class II drugs only. Furthermore, the 

production of nanocrystals and their stability is 

dependent on the molecular structure of the drug. 

Due to this, only certain categories of drugs will be 

suitable candidates for this technique. 

8. Conclusion 

Nanocrystal technology seems to be a promising 

tool for the formulation of poorly soluble drugs. 

The nanocrystals despite being poorly soluble just 

dissolve and disappear in the presence of large 

amount of water. They have been successfully 

employed to improve the bioavailability, better 

drug targeting with minimum side effects, reduced 

drug dosage and hence better patient compliance. 

They can be incorporated in solid dosage forms 

like tablets and capsules which are more patient 

friendly. Nevertheless their nanotoxicity needs to 

be assessed and more authenticated therapeutic 

data is awaited. 

However, nanocrystals hold promise to appear in 

many future products, not only pharmaceutical but 

also cosmetic. They can be seen as a ray of hope in 

the targeted treatment of cancer. 

Declaration of interest 

The authors state no conflict of interests and have 

received no payment in the preparation of this 

manuscript. 

Acknowledgement 

The authors are thankful to Dr. R.H. Müller for 

providing the requisite reference material. 

Table 1: Advantages and disadvantages of different methods for the production of nanocrystals 

Technology Advantages Disadvantages 

Precipitation a. Finely dispersed drug 

b. Better control of desired size 

c. Low-energy technique 

Milling a. Low-energy technique 

b. Proven by first four marketed 

products 

High Pressure 

Homogenization 

a. Universally applicable 

b. Large scale production possible 

c. Fast method (several minutes 

possibly 

d. Continuous process 

a. Particle growth on keeping 

b. Organic solvent residue 

c. Not universally applicable, only drugs with 

certain properties are possible (e.g., soluble in at least one 

solvent) 

d. Needs to be stabilized 

a. Impurity due to erosion from milling material 

b. Can be a slow process (several days) 

c. Wastage of the drug due to adherence to the 

pearls 

d. Large scale production difficult due to size of 

milling chamber 

a. High-energy technique 

b. Great experience required 

Table 2: List of marketed products containing nanocrystals 

Trade name Drug Company Applied technology 

Rapamune® Rapamycin Wyeth Ball milling 

Emend® Aprepitant Merck Ball milling 

Tricor® Fenofibrate Abbott Ball milling 

Megace ES® Megestrol Par Pharmaceutical Companies Ball milling 

Avinza® Morphine sulfate King Pharmaceutical Ball milling 

Focalin® XR Dexmethylphenidate hydrochloride Novartis Ball milling 

Zanaflex CapsulesTM Tizanidine hydrochloride Acorda Ball milling 

Triglide® Fenofibrate Sciele Pharma Inc. HPH (Microfluidizer) 

Ritalin® LA Methylphenidate hydrochloride Accorda Ball milling 

Table 3: Products under clinical trial 

Trade name Drug Company 

Semapimod® Guanylhydrazone 

Cytokine Pharma 

sciences 

Paxceed® Paclitaxel 

Angiotech 

Pharmaceuticals Inc 

Theralux® Thymectacin Celmed BioSciences Inc 

Nucryst® Silver Nucryst Pharmaceuticals 



REFERENCES 

1. Merisko-Liversidge E. 2002. Nanocrystals: 

resolving pharmaceutical formulation issues 

associated with poorly water-soluble 

compounds. Particles; April 20–23; Orlando, 

Florida, USA. 

2. Grant, D.J.W., Brittian, H.G., 1995. In: 

Brittian, H.G. (Ed.), Physical Characterisation 

of Pharmaceutical Solids. Marcel Dekker, New 

York. 

3. Liversidge, G.G., Conzentino, P. 1995. Drug 

particle size reduction for decreasing gastric 

irritancy and enhancing absorption of 

naproxen in rats. Int. J. Pharm. 125,309–313. 

4. Liversidge G.G., Cundy K.C.1995. Particle 

size reduction for improvement of oral 

bioavailability of hydrophobic drugs: Absolute 

oral bioavailabilty of nanocrystalline danazol 

in beagle dogs. Int. J. Pharm. 125, 91-97. 

5. Lamprecht, A., Ubrich, N., Yamamoto, H., et 

al. 2001. Biodegradable nanoparticles for 

targeted drug delivery in treatment of 

inflammatory bowel disease. J. Pharmacol. 

Exp. Ther. 299 (2), 775–781. 

6. Gabor, F., Bogner, E., Weissenboeck, A., 

Wirth, M. 2004. The lectin-cell interaction and 

its implications to intestinal lectin- mediated 

drug delivery. Adv. Drug. Deliv. Rev. 56, 459– 

480. 

7. de Waard, H., De Beer, T., Hinrichs, W.L.J., 

Vervaet, C., Remon, J.P.,Frijlink, H.W., 2010. 

Controlled crystallization of the lipophilic drug 

Fenofibrate during freeze-drying: Elucidation 

of the mechanism by in- line Raman 

spectroscopy. The AAPS Journal 12(4), 569- 

575. 

8. Pandey R., Zahoor A., Sharma S., Khuller 

G.K. 2003. Nanoparticle encapsulated 

antitubercular drugs as a potential oral drug 

delivery system against murine tuberculosis. 

Tuberculosis (Edinb); 83, 373–378. 

9. Shegokar,R., Al Shaal,L., Müller, R.H., 2010. 

Local Anaesthetic nanocrystals as prolonged 

release formulation. First Combined Annual 

Meeting of International Pharmaceutical 

Federation, PSWC and AAPS New Orleans 

Louisiana. USA. Abstract no. 2203. 

10. Liversidge G.G., Cundy K.C., Bishop J.F., 

Czekai D.A. 1992. NANOSYSTEMS LLC. 

Surface modified drug nanoparticles. US Pat.: 

5,145,684. 

11. Müller, R.H., Mäder K., Krause K., 2002. 

PharmaSol GmbH, Dispersions for 

formulation slightly or poorly soluble active 

ingredients. Pat.: CA0002388550A1, Feb. 7. 

12. Radtke, M., 2001. Nanopure TM: pure drug 

nanoparticles for the formulation of poorly 

soluble drugs. New Drugs 3,62-68 

13. Müller, R.H. 2002. Nanopure technology for 

the production of drug nanocrystals and 

polymeric particles. 4 th World Meeting 

ADRITELF/APV/APGI. Florence 

14. Müller, R.H., Jacobs, C., Kayser, O. 2003. 

DissoCubes - a novel formulation for poorly 

soluble and poorly bioavailable drugs, in 

Modified-Release Drug Delivery Systems, 

M.J. Rathbone, Hadgraft, J., Roberts, M. S., 

Editor. Marcel Dekker. 135-149 

15. Akkar, A., Müller, R. H. 2003. Nanocrystals 

of Itraconazole and amphotericin B produced 

by high pressure homogenisation. Annual 

Meeting of the American Association of 

Pharmaceutical Scientists, Salt Lake City. 

16. Gassmann, P., List, M., Schweitzer, A. et al. 

1994. Hydrosols – alternatives for the 

parenteral application of poorly water soluble 

drugs. Eur. J. Pharm. Biopharm. 40, 64–72. 

17. List, M.A., Sucker, H. 1988. Pat No. GB 

2200048. Great Britian. 

18. Speiser, P.P. 1998. Poorly soluble drugs, a 

challenge in drug delivery, In Müller, R.H., 

Benita, S., Bohm, B. (eds.), Emulsions and 

Nanosuspensions for the Formulation of 

Poorly Soluble Drugs, Medpharm Stuttgart. 

Scientific Publishers: 15-28 

19. Mauludin, R., Möschwitzer, J., Müller, R. H. 

2005. Comparison of Ibuprofen Drug 

Nanocrystals Produced by High Pressure 

Homogenization (HPH) versus Ball Milling, 

AAPS Annual Meeting, Nashville, T2217. 

20. Shackleford, D.M., Faassen, W.A., Houwing, 

N., et al.2003. Contribution of lymphatically 

transported testosterone undecanoate to the 

systemic exposure of testosterone after oral 

administration of two andriol formulations in 

conscious lymph duct-cannulated dogs. J. 

Pharmacol. Exp. Ther. 3063, 925–33. 

21. Merisko-Liversidge, E., Liversidge, G.G., 

Copper, E.R. 2003. Nanosizing: a formulation 

approach for poorly-water-soluble compounds. 

Eur. J. Pharma. Sci. 18, 113–20. 

22. Buchmann, S., Fischli, W., Thiel, F.P., Alex, 

R. 1996. Aqueous microsuspension, an 

alternative intravenous formulation for animal 

studies. In: 42nd annual congress of the 

International Association for Pharmaceutical 

Technology (APV), Mainz. 

23. Bruno, J.A.D., Brian, D., Gustow, Evan, Illig, 

Kathleen J, Rajagopalan, Nats, Sarpotdar. 

1992. Method of grinding pharmaceutical 

substances. US 5,518,187. 

24. Bruno, R.P., McIlwrick, R.1999. 

Microfluidizer processor technology for high 

performance particle size reduction, mixing 

and dispersion. Eur. J. Pharm. Biopharm. 56, 

29–36. 

25. Tunick, M.H., Van Hecken, D.L., Cooke, P.H., 

et al. 2002 Transmission electron microscopy 

of mozzarella cheeses made from 



microfluidized milk. J. Agric. Food Chem. 50, 

99–103. 

26. Sunstrom, J.E. IV.,William, R., Marshik- 

Guerts, B. 1996. General Route to 

Nanocrystalline Oxides by Hydrodynamic 

Cavitation. Chem. Mater. 8(8), 2061-2067. 

27. Gruverman, I.J., Thum, J.R., Production of 

Nanostructures Under Turbulent Collision 

Reaction Conditions - Application to Catalysts, 

Superconductors, CMP Abrasives, Ceramics 

and other Nanoparticles. Microfluidics 

Research. 

28. Parikh, I.S., Ulagaraj.1997. Composition and 

method of preparing microparticles of water 

insoluble substances 93969997. 

29. Dearn, A.R. 2000. Atovaquone 

pharmaceutical compositions. US, 08/974248, 

6018080. 

30. Rainbow, B.E. 2004. Nanosuspensions in 

Drug Delivery. Nat. Rev. 3, 785-796. 

31. Möschwitzer, J., Müller, R.H. 2005. 

Application. Germany: 2005. Method for the 

production of ultrafine submicron 

nanosuspensions. DE 10 2005 011 786.4. 

32. Müller, R.H., Peters, K., Becker, R., et al. 

1995. Nanosuspensions – a novel formulation 

for the IV administration of poorly soluble 

drugs. 1st World Meeting of the International 

Meeting on Pharmaceutics, Biopharmaceutics 

and Pharmaceutical Technology; Budapest. 


Nanosuspensions as particulate drug 

formulations in therapy: Rationale for 

development and what we can expect for the 

future. Adv. Drug Deliv. Rev. 471, 3–19. 

34. Sahoo, N. G., Al Shaal, L., Kakran, M., Li, L., 

Müller, R. H. 2010a. Artimisinin nanocrystals 

for improved oral bioavailability in malaria 

treatment, AAPS Annual Meeting, T2154, 

New Orleans. 

35. Sahoo, N. G., Al Shaal, L., Kakran, M., Li, L., 

Müller, R. H. 2010. Antioxident quercetin: 

preparation and characterization of 

nanocrystals, AAPS Annual Meeting, W4134, 

New Orleans. 

36. Möschwitzer, J., Achleitner, G., Pomper, H., 

Müller, R.H. 2004. Development of an 

intravenously injectable chemically stable 

aqueous omeprazole formulation using 

nanosuspension technology. Eur. J. Pharm. 

Biopharm. 58 (3), 615–619. 

37. Fichera, M.A., Keck, C.M. Müller, R.H. 2004. 

Nanopure Technology - Drug Nanocrystals for 

the Delivery of Poorly Soluble Drugs, in 

Particles. Orlando. 

38. Bushrab, N.F., Müller, R.H. 2003. 

Nanocrystals of Poorly Soluble Drags for Oral 

Administration. New Drugs 5, 20-22. 

39. Keck, C.M., Bushrab, N.F. Müller, R.H. 2004. 

Nanopure® Nanocrystals for Oral Delivery of 

Poorly Soluble Drugs, in Particles. Orlando. 

40. Kipp, J.E., Wong, J.C.T., Doty, M.J., et al. 

2003. Microprecipitation method for 

preparing submicron suspensions. US Patent 

6607784; USA. 

41. Fichera, M.A., Wissing, S.A., Müller, R.H. 

2004. Effect of 4000 Bar Homogenisation 

Pressure on Particle Diminution in Drug 

Suspensions, in APV. Niirnberg. 

42. Kobierski, S., Hanisch, J., Mauludin, R., 

Müller, R. H., Keck, C. 2008. Nanocrystal 

production by smartCrystal combination 

technology, Int. Symp. Control. Rel. Bioact. 

Mater. 35, #3239, New York City. 

43. Möschwitzer, J., Müller, R. H. 2005. 

Development of a New Two-Step Process for 

the Effective Production Drug Nanocrystals 

By, AAPS Annual Meeting, Nashville, 

W5124. 

44. Möschwitzer, J., Müller, R. H. 2004. Final 

Formulations for Drug Nanocrystals: Pellets, 

AAPS Pharmaceutics and Drug Delivery 

Conference, Philadelphia, PA. 

45. Mauludin, R., Möschwitzer, J., Müller, R. H. 

2005. Development of Effervescent and Pellet 

Formulations Containing Ibuprofen Drug 

Nanocrystals Produced by High Pressure 

Homogenization, AAPS Annual Meeting, 

Nashville, W5115. 

46. Möschwitzer, J., Müller, R. H. 2006. Spray 

coated pellets as carrier system for 

mucoadhesive drug nanocrystals, Eur. J. 

Pharm. Biopharm. 62, 282-287. 

47. Hanna, M. H., York, P. 1998. Method and 

apparatus for the formulation of particles. US 

Patent 5,851,453.1998. USA. 

48. Hu, J. 2002. Improvement of dissolution rates 

of poorly water soluble APIs using novel spray 

freezing into liquid technology. Pharm. Res., 

19, 1278–1284. 

49. Hu, J., Johnston, K. P., Williams, R. O. 3rd. 

2004. Nanoparticle engineering processes for 

enhancing the dissolution rates of poorly water 

soluble drugs. Drug. Dev. Ind. Pharm., 30, 

233–245. 

50. Rogers, T. L., Johnston, K. P., Williams, R. O. 

3rd. 2001. Solution-based particle formation of 

pharmaceutical powders by supercritical or 

compressed fluid CO2 and cryogenic sprayfreezing 

technologies. Drug Dev. Ind. Pharm., 

27, 1003–1015. 

51. Pace, G. W. 2001. Process to generate 

submicron particles of water insoluble 

compounds. US Patent 6, 103. 2001. USA 

52. Young, T. J. 2000. Rapid expansion from 

supercritical to aqueous solution to produce 

submicron suspensions of water-insoluble 

drugs. Biotechnol. Prog. 16, 402–407. 



53. Li, Z. 2008. Preparation of griseofulvin 

microparticles by supercritical fluid expansion 

depressurization process. Powder Technology. 

182, 459-465. 

54. Young, T. J. 1999. Encapsulation of lysozyme 

in a biodegradable polymer by precipitation 

with a vapor-over-liquid antisolvent. J. Pharm. 

Sci. , 88, 640–650 

55. Turk, M., Lietzow, R. 2004. Stabilized 

nanoparticles of phytosterol by rapid 

expansion from supercritical solution into 

aqueous solution. AAPS PharmSciTech. 2004 , 

5(4). Article 56, 1-10. 

56. Chen, X. 2002. Preparation of cyclosporine A 

nanoparticles by evaporative precipitation into 

aqueous solution. Int. J. Pharm., 242, 3–14. 

57. Eickhoff, W.M., Engers, D.A., Mueller, K.R. 

1996. Nanoparticulate NSAID compositions, 

Application. US 95-385614, 5518738. 

58. Jacobs, C., Kayser, O., Müller, R.H. 2001. 

Production and characterisation of 

mucoadhesive nanosuspensions for the 

formulation of bupravaquone. Int. J. Pharm. 

214 (1-2), 3–7. 

59. Müller, R.H., Jacobs, C. 2002. Buparvaquone 

mucoadhesive nanosuspension: preparation, 

optimisation and long-term stability. Int. J. 

Pharm. 237 (1-2), 151–161. 

60. Hussain, N., Jaitley, V., Florence, A.T. 2001. 

Recent advances in the understanding of 

uptake of microparticulates across the 

gastrointestinal lymphatics. Adv. Drug Deliv. 

Rev. 50 (12), 107–142. 

61. Mauludin, R., Müller, R. H. 2006. 

Investigation of crystalline state of dry powder 

ibuprofen nanocrystals produced by high 

pressure homogenization technique, AAPS 

Annual Meeting, San Antonio. 

62. Kayser, O., Olbrich, C., Yardley, V., Kiderlen, 

A.F., Croft, S.L. 2003. Formulation of 

Amphotericin B as nanosuspension for oral 

administration. Int. J Pharm 254, 73-75. 

63. Vergote, G.J. 2001. An oral controlled release 

matrix pellet formulation containing 

nanocrystalline ketoprofen. Int. J. Pharm. 21; 

219(1-2), 81-7. 

64. Hanafy, A., Spahn, H., Vergnault, G., Grenier, 

P., Grozdanis, M.T., Lenhardt, T. 2007. 

Pharmacokinetic evaluation of oral Fenofibrate 

nanosuspension and SLN in comparison to 

conventional suspensions of micronized drug. 

Adv. Drug Del. Rev. 59, 419-426 . 

65. Singla, A.K., Garg, A., Aggarwal, D. 2002. 

Paclitaxel and its formulations. Int. J Pharm. 

235(1–2), 179–192. 

66. Peters, K., Leitjke, S., Diederichs, J.E., 

Vorner, K., Hahn, H., Müller, R. H., Ehlers, S. 

2000. Preparation of a clofazimine 

nanosuspension for intravenous use and 

evaluation of its therapeutic efficacy in murine 

Mycobacterium avium infection. J. 

Antimicrob. Chemother. 45, 77–83. 

67. Rainbow, B., Kipp, J., Papadopoulos, P., 

Wong, J., Gass, J., Sun, C.S., Wielgos, T., 

White, R., Cook, C., Barker, K., Wood, K. 

2007. Itraconazole IV nanosuspension 

enhances efficacy through altered 

pharmacokinetic in the rat. Int. J. Pharm. 339, 

251-260. 

68. Na, G.C., Stevens, Jr. J., Yuan, B.O., 

Rajagopalan, N. 1999. Physical stability of 

ethyl diatrizoate nanocrystalline suspension in 

steam sterilization. Pharm. Res. 16(4), 569– 

574. 


Nanosuspensions for the formulation of poorly 

soluble drugs. In: Nielloud F, Marti-Mestres 

G, eds. Pharmaceutical Emulsions and 

Suspensions. New York: Marcel Dekker, 

S383–407. 

70. Moghimi, S.M., Hunter, A.C., Murray, J.C. 

2001. Long-circulating and target-specific 

nanoparticles: theory to practice. Pharmacol. 

Rev. 53, 283–318. 

71. Pandey, R., Khuller, G.K. 2004. Subcutaneous 

nanoparticle-based antitubercular 

chemotherapy in an experimental model. J. 

Antimicrob. Chemother. 54, 266–268. 

72. Müller, R.H., Jacobs, C. 2002. Production and 

characterization of a budenoside 

nanosuspension for pulmonary administration. 

Pharm. Res. 19, 189-94. 

73. Hernandez-Trejo, N., Kayser, O., Steckel, H., 

Müller, R.H. 2005. Characterization of 

nebulised buparvaquone nanosuspension – 

effect of nebulization technology. J. Drug 

Target. 13(8-9), 499-507. 

74. Sharma, A., Sharma, S., Khuller, G.K. 2004. 

Lectin-functionalized poly (lactide-coglycolide) 

nanoparticles as oral/aerosolized 

antitubercular drug carriers for treatment of 

tuberculosis. J. Antimicrob. Chemother. 54, 

761–766. 

75. Peterson, R. 2006. Nanocrystals for use in 

topical cosmetic formulations and method of 

production thereof. US Patent Application No. 

60/8866, 233. 

76. Shegokar, R., Keck, C. M., Müller, R. H., 

Gohla, S., 2011. Cosmetic nanocrystals: 

products and dermal effects, P 123, 6th Polish- 

German Symposium on Pharmaceutical 

Sciences: Perspectives for a new decade, 

Düsseldorf, 20-21 May 2011. 

77. Al Shaal, L., Shegokar, R., Müller, R. H., 

2010. Novel UV skin protective antioxidant 

nanocrystals, AAPS Annual Meeting, W4089, 

New Orleans. 

78. Pignatello, R. 2002. Eudragit RS100 

nanosuspensions for the ophthalmic controlled 



delivery of ibuprofen. Eur. J. Pharm. Sci., 16: 

53–61. 

79. Kassem, M. A. 2007. Nanosuspension as an 

ophthalmic delivery system for certain 

glucocorticoid drugs. Int. J. Pharm., 340: 126– 

133. 

80. Kayser, O. 2000. Nanosuspensions for the 

formulation of aphidicolin to improve drug 

targeting effects against Leishmania infected 

macrophages. Int. J. Pharm. 196, 253-256. 

81. Schroeder, U., Sommerfeld, P., Sabel, B. 

1998. Efficiency of oral dalargin-loaded 

nanoparticle delivery across the blood brain 

barrier. Peptides 19(4), 777-780. 

82. Lamprecht, A., Schafer, U., Lehr, C.M., 2001. 

Pharm. Res. 18, 788–793. 

83. Takeuchi, H.,Yamamoto, H., Kawashima,Y., 

2001. Adv. Drug Deliv. Rev. 47, 39–54 

84. Ponchel, G., Montisci, M.-J., Dembri, A., 

Durrer, C., Duchene, D., 1997. Eur. J. Pharm. 

Biopharm. 44, 25–31. 

85. Cevc, G., Gebauer, D., Stieber, J., Schatzlein, 

A., Blume, G., 1998. Biochim. Biophys. Acta 

1368, 201–215. 

86. Kayser, O. 2001. A new approach for 

targeting to Cryptosporidium parvum using 

mucoadhesive nanosuspensions: research and 

applications. Int. J. Pharm. 214, 83-85. 

87. Kohno, S., Otsubo, T., Tanaka, E., Maruyama, 

K., Hara, K. 1997. Amphotericin B 

encapsulated in polyethylene glycol 

immunoliposomes for infectious diseases. 

Adv. Drug Del. Rev. 24, 325-329.

Nanocrystals: Current Strategies and Trends - International Journal ...

Create successful ePaper yourself

Delete template?

Save as template?