It gives a brief idea on how a drug nanocrystals can be formulated. Your suggestions are welcome.

1. DRUG
NANOCRYSTALS.
BY
PRIYANKA CHAKOTE
PHARMACEUTICS-03
VES COLLEGE OF PHARMACY,
CHEMBUR,MUMBAI.

2. FLOW OF PRESENTATION.
• INTRODUCTION.
• NEED OF IT.
• PROPERTIES.
• METHODS OF PREPARATION
• APPLICATIONS.

3. Difference between Nano
crystals and drug Nano crystals.
 Nano crystals are the substances in which the
drug is combined with the polymer like PVP.
 Whereas drug Nano crystals includes only the
drug which is in the Nano crystals form.

4. INTRODUCTION.
➢ What is DRUG NANOCRYSTALS?
 Drug Nano crystals are pure solid drug particles with a mean
diameter below 1000 nm.
 The term drug Nano crystals implies a crystalline state of the
discrete particles, but depending on the production method they
can also be partially or completely amorphous.
 Drug Nano crystals have to be distinguished from polymeric
nanoparticles, which consist of a polymeric matrix and an
incorporated drug.
 These do not consist of any matrix material.
 Drug Nano crystals are formed by decreasing the particle size ,
causing an increase in solubility of the drug.
 Thus this technology is explored to increase the bioavailability of
sparingly water soluble drugs.

5. NEED OF DRUG NANOCRYSTALS
 At present , about 40% of the drugs in the developing stage are
poorly water soluble and these also shows problems in the
formulation of dosage form.
 70% of the potential drug candidates are discarded due to low
bioavailability.
 For class II drugs like itraconazole and carbamazepine which are very
poorly soluble in aqueous and organic phase , the problem is much
more complex.
 Various approaches are made to resolve the problems of solubility
and bioavailability of drugs by following methods: Micronization , co
- solvency , salt formation , micro emulsions , etc.

6.  Many of these techniques are not universally applicable to all drugs
nor they are applicable to drugs which are not soluble in both
aqueous and organic media.
 A different but simple approach is needed to tackle the formulation
problem to improve their efficacy and to optimize the therapy with
respect to pharmacokinetics.

7. METHODS OF PREPARATIONS
 Media Milling method
 High-pressure homogenization
 Precipitation are the main methods employed for the
production of drug Nano crystals.

8. BOTTOM – UP TECHNIQUES
PRECIPITATION TECHNIQUE:
A poor water-soluble drug is dissolved in an
organic medium, which is water miscible.
Pouring of this solution into a non solvent, such as
water, will cause a precipitation of finely
dispersed drug Nano crystals.

9. Lyophilization is recommended to preserve
the particle size .
The increased viscosity of the aqueous phase
can reduce particle growing. But this
technology has not been applied to a product
to date.
 A problem associated with this technology is
that the formed nanoparticles need to be
stabilized to avoid growth in micrometer
crystals.

10. TOP – DOWN TECHNIQUES
1. Pearl/ball milling method:
Marketed preparations includes Megace ES, Rapamune , Tricor.
2. High pressure homogenisation technique:

11. TOP – DOWN TECHNIQUE
PEARL / MILLING TECHNIQUE:
 Small milling pearls or large milling balls are used as
milling media.
 With a reduction in the size of grinding media in a media
mill, the number of contact points is increased
exponentially resulting in improved grinding and
dispersing action (i.e., leading to smaller particles).

12.  The pearls or balls consist of ceramics (cerium- or
yttrium-stabilized zirconium dioxide), stainless
steel, glass, or highly cross-linked polystyrene resin-
coated beads.
 PROBLEM ASSOCIATED:
With the pearl milling technology is the erosion
from the milling material during the milling process.

13. COMBINATION TECHNIQUE

14.  Combination
Technologies
:Nanoedge®
Technology
(Microprecipitati
on™ and High
Shear Forces
(NANOEDGE™)
 Nanopure®
Technology

15. ADVANTAGES
Enhanced oral bioavailability.
Reduced food effects.
Suitable for administration by all routes.
Sterile filtration due to decreased particle size.
Enhanced solubility.

18. 1.Increase of dissolution velocity by
surface area enlargement
Noyes Whitey equation, where dX/dt =dissolution rate, Xd =amount
dissolved, A=particle surface area, D=diffusion coefficient, V=volume of
fluid available for dissolution, Cs=saturation solubility, h=effective
boundary layer thickness.
↓size ↑surface area
By Noyes
Whitney
Equation
So, micronization is
done to ↑
bioavailability
→dissolution of rate
limiting
Moving to
nanonization→
↑ surface area &
dissolution
velocity

19. 2. Increase in saturation solubility
Is a constant depends on
COMPOUND<DISSOLUTIO
N MEDIUM
& TEMPERATURE
Drug Nanocrystal
has ↑ saturation
solubility
This ↑ with ↓
particle size.

20. APPLICATIONS

21. ORAL DRUG DELIVERY
Drug Absorption IN
GIT
Dissolution in aq.
Luminal fluid
Transporting drug
across GI
Epithelium

22. ADVANTAGES
Fast onset of
action.
Reduces gastric
irritancy.
Complete drug dissolution
↑dissolution velocity
& saturation
solubility

23. OPHTHALMIC DRUG DELIVERY
 Ex: Budesonide, Dexamethasone, Hydrocortisone,
Prednisolone And Fluorometholone.
Causes
Improved
bioavailability
Long lasting drug
action.
SIGNIFICANCE
Absence of
irritancy due to
smaller size &
aqueous medium
Muco
adhesiveness
causing ↑
bioavailability.

24. PARENTERALS
Particles >5µm is not used
Smallest size of blood capillary is 5µm→capillary blockade &
embolism
Also, Administration into body cavities is also of great interest,
as it ↑ tolerability
To achieve a local treatment or to have a depot with slow release
(e.g. into the blood).

25. RESPIRATORY
↓
occurrence
of local
irritation
↓ Drug
loss in
upper
airway
Deposition
into back
of mouth &
throat.
compared
to other
dosage
forms
which
causes
Prolong
residence
time at
absorptio
n site
Quick
onset
of
action.

26. Case study 1
EVALUATION OF NANOCRYSTALS OF VALSARTAN
(antihypertensive) FOR SOLUBILITY ENHANCEMENT.
1. PREPARATION OF VALSARTAN NANOCRYSTALS
Valsartan nanocrystals were prepared by antisolvent precipitation
technique, introduction of the drug solution to the antisolvent (water).
It is beneficial if it solubilize the drug in large amount and possesses a
fast diffusion rate to the antisolvent water; while the stabilizer need to
have good affinity for drug crystals and possess a fast diffusion rate
and effective adsorption onto the drug crystals surface in the water-
solvent mixture.
In this work, among the water-miscible solvent candidates ethanol
and acetone, acetone was selected due to its highest capacity to
solubilize valsartan (>100 mg/ml).

27. •Nine batches of valsartan nanocrystals were prepared containing
drug (valsartan):polymer (PVP K30) in the ratio of 1:1, 1:5, 1:9 under
1000 rpm, 900 rpm and 800 rpm respectively.
EVALUATION OF VALSARTAN NANOCRYSTALS
In- vitro dissolution of pure Valsartan and Valsartan Nanocrystals

28. The dissolution studies for pure valsartan and optimized
formulation of Valsartan Nanocrystals (V2) were carried out in
0.1N HCl using USP Type II apparatus at 50 rpm and
37˚C.Valsartan nanocrystals released 86.32 % of drug in
solution after 40 min where pure drug released 48.44

29. DISCUSSION:
 It was observed that dissolution rate of
the drug is more in Valsartan nanocrystals
than pure drug.
It can be concluded that dissolution rate
has been enhanced with nanocrystals .

30. Case study 2
Preparation And Characterization Of Simvastatin Nanosuspension By
Homogenization Method.
Preparing Nanosuspension:
Simvastatin nanosuspension is prepared by high pressure
homogenization method. Simvastatin powder (1% w/v) was dispersed
in aqueous surfactant solution using magnetic stirrer. After drug
dispersion first size reduction step is carried out using ultra turax T25
basic homogenizer at 9500 rpm for 10 min. Then obtained mixture is
homogenized using micron lab 40 homogenizer (APV systems,
Germany). The homogenization steps includes first two steps with
100 bar pressure and next two cycles with 500 bar pressure as
initial step. Finally the suspension is homogenized for 15 cycles with

31. In-Vitro Drug Release Studies:
The in-vitro release of simvastatin and the nanosuspension was carried
out in USP dissolution test apparatus using paddle method at a rotation
speed of 50 RPM. The dissolution profile of was carried out in freshly
prepared acidic buffer (pH-1.2) and also in phosphate buffer (pH 7.0)
containing 0.5% sodium lauryl sulphate. 10 mg of pure drug and
nanosuspension equivalent to 10 mg of plain simvastatin was taken and
placed in dissolution medium. The volume and temperature of
dissolution medium were 900 ml and 37.0 ± 0.2°c, respectively. 5ml of
samples were withdrawn at fixed time interval and were filtered. An
equal volume of freshly prepared dissolution medium was replaced to
maintain the sink condition. The filtered samples were analysed at 238
nm using Shimadzu UV Visible spectrophotometer.

33. Table of invitro drug release studies.

34. RESULTS & DISCUSSIONS.
The particle size distribution studies showed that all the formulation
particle size was in the range of 240-244 nm and where as
unprocessed drug shows 31.49 μm sizes. All the formulations having
a particle size in the nanometer range and showing ideal surface
morphology.
In-vitro drug release data shows the increased dissolution rate of
formulations compared to unprocessed drug.
Also, the FN3 showed comparatively an increased solubility and
permeability as compared to other formulations and unprocessed
drug.

35. REFERENCES
Advanced Drug Delivery Reviews 63 (2011) 456–469
International Journal Of Pharmtech Research , July- sept 2009, Vol.1, No.3, Pg
682-694
Sarnes A, Liu P, Puranen J, Rönkkö S, Laaksonen T, Kalesnykas G, Oksala O, Ilkka J,
Laru J, Järvinen K, Hirvonen J, Peltonen L. Brinzolamide Nano Crystal Formulations
For Ophthalmic Delivery: Reduction Of Elevated Intraocular Pressure In Vivo.
Submitted Manuscript, 2013.
World Journal Of Pharmacy And Pharmaceutical Sciences , Volume 3, Issue 3,
1414-1427, Research Article, ISSN 2278 – 4357
International Journal Of Pharmtech Research, CODEN (USA): IJPRIF ISSN : 0974-
4304 Vol.5, No.1, Pg 193-197, Jan-mar 2013.

36. ANY
QUESTIONS????