This document discusses a study that prepared and characterized nitrendipine nanocrystals to improve its solubility and oral bioavailability. Nitrendipine nanocrystals were produced using high pressure homogenization and characterized using SEM, XRD and DSC. The nanocrystals had a narrow particle size distribution and crystalline form. In vitro dissolution and in vivo studies found the nanocrystals significantly improved dissolution rate and led to around 10-41 times higher AUC compared to physical mixtures and commercial tablets. The nanocrystal formulation enhanced nitrendipine's solubility and oral absorption.

1. Prepared by:
Priyanka Gresess Anand
Integral University
M . Pharm (Pharmaceutics)
Lucknow U.P

2.  Introduction
 Role of drug particle size in pharmaceuticals
 Manipulation of drug particle size
 Characterization of drug particle size
 Applications of drug particle size
 Marketed formulations
 Conclusions
 References
 Case study
2

3.  Particle size in solid dosage forms
 Particle size in parenterals
 Particle size in ophthalmic formulations
 Particle size in aerosol
 Particle size in semisolid dosage form

4.  Particle size is a notion introduced for comparing solid
particles (flecks), liquid particles (droplets), or gaseous
particles (bubbles).
 It has significant effects on drug product performance (e.g.,
dissolution, bioavailability, content uniformity, stability, etc.)
 It play an important role in pre-mixing/mixing, granulation,
drying, milling, blending, coating, encapsulation, and
compression.
Introduction

5.  Drug particle size enlargement
 Drug particle size reduction
Drug particle size enlargement process of transforming
fine particle into larger particles by the introduction of
external forces. There are many different reasons to
enlarge particle size including flowability and improved
product shape and appearance
Drug particle size reduction is also known as
communition and grinding.
Manipulation of drug particle size

6. Equipment Principle
Particle
size(µm)
Uses
Cutter mill Cutting
100-
80,000
Fibrous material
Hammer mill Impact 50-8,000 Brittle drug
Roller mill Compression 50-10,000 Soft material
Colloidal mill Attrition 1-50 Semisolid dosage form
Ball mill
Impact and
attrition
1-2,000
Moderately hard and
friable materials
Fluid energy
mill
Impact and
attrition
1-2,000 Thermo labile drugs
Principles of drug particle size reduction

7. Impact Attrition
Shear
Compression
Mechanisms of size reduction

8. Technique Method
Effective Measuring
range(µm)
Optical image analyser Direct imaging 3-150
SEM Direct imaging 0.01-150
LD
(Mastersizer)
Low-angle diffraction
ring measurement
0.5-1,000
DLS
(Zetasizer)
Measurement of light
intensity correlation from
particle in Brownian
motion
0.003-3
Coulter counter Electron-zone sensing 0.6-1,200
Characterization of drug particle size

9.  Solubility enhancement
 Bioavailability enhancement
 Flow property enhancement
 Stability enhancement
Solubility enhancement: Small particle size
Greater surface area
Fast rate of dissolution
Rapid drug absorption
Applications of drug particle size
manipulation

10.  Griseofulvin, Progesterone, Spironolactone diosmin, and
Fenofibrate.
 Drug - Carvedilol (poorly soluble (BCS Class II) drugs).
 Particle size enhanced by high pressure homogenization (HPH)
technique and produced nanoparticles( 120 nm to 300 nm).
 Prepared Carvedilol nanoparticles has three folders enhanced
saturation solubility and in vitro dissolution rate than the pure
drug
(Ashok K.J et al, 2015)
Bioavailability enhancement:
Smaller particle size Greater surface area High dissolution
and permeation High bioavailability
Solubility enhancement

11.  Acyclovir , Efavirenz, Albendazol
 Drug-Ibuprofen( NSAID with low oral bioavailability)
 particle size reduced by solvent/anti-solvent precipitation
technique and produced nanoparticles (300-400 nm).
 Prepared nanoparticles showed improved dissolution rate (2.3
times greater dissolution in purified water in first 30 min.
(Dizaj. M.S. et al, 2013)
Flow property enhancement: Reduction in particle size
increases the flow property of granules
Bioavailability enhancement

12.  Reduction in particle size increases the flow property of
granules through hopper during tablet formulation. And by the
enlargement of particle size stability enhances and the flow
property of powder.
Stability enhancement:
 The rate of sedimentation, agglomeration is affected by
particle size.
 Particle size play a key role, is in physical stability and
bioavailability of drug product.
 Examples;
 Squalene emulsions, suspension and emulsion

13. S.
No
Drug
Brand
name
Manufacturer Formulation
1 Indomethacin Indoflam Zydus Cadila Healthcare Ltd Drops
2 Albendazole
Alminth(10
ml)
Torrent Pharmaceuticals Ltd
Tabet
3 Fenofibrate
Fenolip(14
5mg)
Cipla Film coated
tablet
Marketed formulations

14.  Particle size affects solubility, bioavailability, flow property
and stability of various pharmaceuticals product.
 It makes problem regarding solubility and bioavailability in
the formulation of BCS Class II and Class IV drugs.
 There are various approaches to reduce the particle size like
micronization which can enhance solubility, bioavailability,
flow property, the particle size enhancement can be helpful
in increasing the flow properties of powders, granules and
stability of suspensions
Conclusions

15.  Khadka. P , Ro J, Kim. H, Kim.I , Kim .J, Yun .G, Lee. J., Pharmaceutical
particle technologies : An approach to improve drug solubility, Asian
Journals of Pharmaceutical Sciences, 2014, 1, 13-14, 2014
 Rezaei Mokarram A, Kebriaeezadeh A, Keshavarz M, Ahmadi A, Mohtat
B. Preparation and in-vitro evaluation of indomethacin nanoparticles.
DARU. 18,185, 2010.
 Lachman/Liberman, “Theory and Practice of Industrial Pharmacy”4th
Edition CBS Publishers.
 Harun.K. Effect of particle size on the dissolution of Glibenclamide.
International Journal of Pharmacy and Pharmaceutical Sciences, 5, 3, p,
2013
References

16. Nitrendipine Nanocrystals: Its Preparation,
Characterization, and In Vitro–In Vivo Evaluation
(Q. Peng. et, al. AAPS PharmSciTech, 12, 4, 28-32,
December,2011)
 Nitrendipine is a calcium channel blocker used as an
antihypertensive drug which is practically insoluble (about
1.9–2.1 μg/ml) in water and has poor oral bioavailability
 For such drug, the rate and degree of absorption from the
gastrointestinal tract are usually controlled and limited by the
dissolution process.

17.  Nanocrystal formulations contain much less excipient than
other drug nanoparticles, which means a potential reduction in
adverse effects caused by these pharmaceutical agents
 The techniques used for preparing nanocrystals can be
classified as bottom–up and top–down processes according to
differences in the production principles. The high pressure
homogenization (HPH) method is one of the best established
processes
 Scanning electron microscopy (SEM) was employed to
describe the morphology of nitrendipine crystals. The physical
properties of the nanocrystals were characterized by Xray
diffraction (XRD) and differential scanning calorimetry
(DSC).

18. 


Fig.1 SEM images and particle size distributions of the nitrendipine
A. Coarse powder B. Nitrendipine nanocrystals
(Q. Peng, et.al.2011)

19. Fig.2 Differential scanning calorimetry curves of the nitrendipine
A. coarse powder ,
B. blank excipients ,
C. physical mixture,
D. dry powders,
E. freeze-dried nanocrystals without mannitol

20. Fig.3 X-ray diffraction patterns of the nitrendipine
A. coarse powder
B. blank excipients
C. the physical mixture
D. the dry powders
E. freeze-dried nanocrystals without mannitol

21.  The coarse powder was irregular in shape with a broad particle
size distribution. In contrast, the nanocrystals were found to be
flaky in shape with a narrow particle size distribution.
 Differential scanning calorimetry and X-ray diffraction
analysis indicated that nitrendipine was present in crystalline
form. The in vitro dissolution rate of the nanocrystals was
significantly increased compared with the physical mixture
and commercial tablet.
 The in vivo testing demonstrated that the Cmax of the
nanocrystals was approximately 15-fold and 10-fold greater
than that of physical mixture and commercial tablet,
respectively.
 In addition, the AUC of the nanocrystals was approximately
41-fold and 10-fold greater than that of physical mixture and
commercial tablet.

22. Fig.4 Percentage of dissolved
nitrendipine from the
nanocrystals, the physical
mixture, and the commercial
tablet
Fig. 5 Average plasma drug
concentration versus time profiles
after oral administration of the
nanocrystals, the physical
mixture, and the commercial
tablet