This document discusses drug nanocrystals, which are nanosized crystals of drug compounds less than 1 μm in size. They can enhance the bioavailability of BCS class II and IV drugs with poor water solubility. The key methods discussed for preparing nanocrystals are top-down and bottom-up approaches, as well as combination methods. Characterization techniques include measuring particle size, zeta potential, and performing XRD, DSC, and drug content analysis. Several marketed products containing drug nanocrystals are mentioned. In conclusion, drug nanocrystals show promise for improving solubility and bioavailability of poorly soluble drugs.

1. Prepared by
Dheeraj Kumar
M.S. (Pharm) 2nd sem
Id No 443/17
Under the supervision of
Dr. Rahul Shukla
RAEBARELI

2.  Introduction
 Properties of nanocrystals
 BCS class II and class IV drugs
 Special features of nanocrystals to enhance bioavailability
 Methods of Preparation
 Characterization of Nanocrystals
 Products in market/clinical trails
 Conclusion
 References
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3.  Drug nanocrystals are nanosized crystals of parent
drug compound with the dimension of less than 1 μm.
 Composed of 100% drug and they do not contain any
carrier.
 Stabilized by stabilizers. E.g.- Poloxamer 188
 NCs can be formulated as solid nanocrystals or
nanosuspension.
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4. 4 June 2018 4
Fig 1 Properties of Nanocrystals

5. In Biopharmaceutical Classification System (BCS), 90%
compounds have poor water solubility. These compounds
belong to BCS class II (70%) or class IV (20%).
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Class I
(High solubility and high
permeability)
Class III
(High solubility and low
permeability)
Class II
(Low solubility and high
permeability)
Class IV
(Low solubility and High
permeability)
BCS classification
Fig 2 BCS Classification

6. 1) Saturation solubility Enhancement
 Saturation solubility is a compound-specific constant,
which is depending on physicochemical properties of the
compound, dissolution medium and temperature.
 For the particle size aspect, the saturation solubility is also
a function of particle size when a critical size is below 1-2
µm.
 The saturation solubility increases with decreasing particle
 size below 1000 nm.
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7. 2) Increase in Dissolution velocity
Nanocrystals possess an increased dissolution velocity
that can be explained by the Noyes Whitney equation
3) Increased adhesiveness to surface/cell membrane
Comparing with microparticles, drug nanocrystals
increase adhesiveness to surface/cell membranes which in
turn increases absorption of drug
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8. 4 June 2018 8
Fig 3 Methods of Preparation of Nanocrystals

9.  Bottom Up Approach
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Fig 4 Bottom up Approach for preparation of Nanocrystals

10.  Top Down approach
Starts from large crystals in the macrometer range and
goes down to the nanodimension by diminuting the
crystals; such as performing a milling process and using
high pressure homogenization.
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11.  Combination method
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Combination
Process
H69 H42 H96
Precipitation +
High Pressure
Homogenization
Lyophilization +
High pressure
Homogenization
Spray Drying +
High Pressure
Homogenization
Novel tri-combination technology - “Precipitation-lyophilization-homogenization
(PLH)

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• Particle size, zeta potential (ZP), poly-
dispersity index (PDI) and analysis
• X-ray Diffraction studies
• Differential Scanning Calorimetry (DSC)
• Surface Morphology
• Drug content Analysis
• In-vitro release Studies

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S No Name of Drug Brand Name Indication Company
Status of
product
1 Paclitaxel Paxceed® Antiinflammatory Angiotech Phase III
2 Rapamycin Rapamune® Immunosupressive Wyeth marketed
3 Fenolfbrate Tricor® Hypercholesterolemia Abbott marketed
4 Aprepitant Emend® Antiemetic Merck Marketed
5
Paliperidone
palimtate
Invega Sustenna® schizophrenia
Johnson and
Johnson
Marketed
6 Thymectacin Therafux® Therafux® Celmed Phase II
7 Silver Nucryst® Antibacterial
Nucryst
Pharmaceuticals
Phase II
8 Guanyl hydrazone Semapimod® TNF α inhibitor
Cytokine
Pharmasciences
Phase II
Table 1 Products in Market/Clinical trails

14.  Drug nanocrystals can be applied to poorly soluble drugs
to overcome their solubility and bioavailability problems.
 At present, drug nanocrystals are paid increasing attention
as a promising approach owing to many reasons such as
an increasing number of poorly soluble drugs in drug
development process, pharmacoeconomic value, easier
production, safer composition and other advantages.
 In the future, drug nanocrystals with certain surface
proteins attached to the surface can be prepared for
targeting the particular tissue or cell.
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15.  Junghanns, J.U.A.H., Müller, R.H., 2008. “Nanocrystal
technology, drug delivery and clinical applications”. Int. J.
Nanomed. 3 (3), 295
 Muller, R.H., Bohm, B.H.L., 1998. “Emulsions and
Nanosuspensions for the Formulation of Poorly Soluble
Drugs”. Medpharm Scientific Publishers, Stuttgart, pp. 149–
174.
 Keck CM, Muller RH. “Drug nanocrystals of poorly soluble
drugs produced by high pressure homogenization”. Eur J
Pharm Biopharm 2006; 62:3-16.
 Mishra, P.R., Al Shaal, L., Muller, R.H., Keck, C.M., 2009.
“Production and characterization of Hesperetin
nanosuspensions for dermal delivery”. Int. J. Pharm. 371,
182–189
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16.  Gao, L., Zhang, D., Chen, M., 2008. “Drug nanocrystals for the
formulation of poorly soluble drugs and its application as a
potential drug delivery system”. J. Nanopart. Res. 10, 845–862.
 Gao, L., Liu, G., Ma, J., Wang, X., Zhou, L., Li, X., Wang, F., 2013.
“Application of drug nanocrystal technologies on oral drug
delivery of poorly soluble drugs”. Pharm. Res. 30, 307–324.
 Hecq, J., Deleers, M., Fanara, D., Vranckx, H., Amighi, K., 2005.
“Preparation and characterization of nanocrystals for solubility
and dissolution rate enhancement of nifedipine”. Int. J. Pharm.
299, 167–177.
 Zhai X, Lademann J, Keck CM, et al. “Nanocrystals of medium
soluble actives e novel concept for improved dermal delivery and
production strategy. Int J Pharm 2014; 470:141e150.
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