INNOVATIVE NANOCRYSTAL TECHNOLOGY FOR POORLY WATER SOLUBLE DRUGS

About Author:
Dhananjay R. Abhang*, Sudhir S. Waghmode, Raju K.Hire, GangurdeA.B, Kasar S.A, Bairagi V.A
K.B.H.S.S.Trust’s Institute of Pharmacy, Bhaygaon road,
Malegaon camp, Malegaon,
Dist: Nasik– 423 105, Maharashtra, India.
*dhananjay.abhang@rediffmail.com

Abstract
Drug care considered as one of the most important formulation approaches for poorly soluble drugs.Nanocrystal dispersions comprise water, active drug substance and a stabilizer. They are physically stable due to the presence of stabilizers that prevent reagragregation of the active drug substance. Different techniques can be used to prepare nanocrystal formulations of a drug powder such as high-pressure homogenization, sol gel method, micro fluidization, co precipitation, spray drying and milling. Nanocrystals are considered as first choice in case simpler formulation approaches as. The number of poorly soluble actives which cannot be formulated by traditional approaches is steadily increasing. In addition optimised nanocrystals formulations can reduce distinctly side effects; therefore they might also replace existing products. Each system can be improved which was achieved with the smart Crystals as second generation of drug nanocrystals. There are several advantages of nanocrystal formulations such as, enhanced oral bioavailability, improved dose proportionality, reduced food effects, suitability for administration by all routes and possibility of sterile filtration due to decreased particle size range.

REFERENCE ID: PHARMATUTOR-ART-1758

Introduction
Nanotechnology is a science of atomic scale phenomenon and mostly deals with particles ranging from 100 nm – 0.1 nm. Drug nanocrystals are pure solid drug particles with a mean diameter below 1000 nm. A nanosuspension consists of drug nanocrystals, stabilizing agents such as surfactants and/or polymeric stabilizers, and a liquid dispersion medium. The dispersion media can be water, aqueous solutions, or nonaqueous media. The term drug nanocrystals imply a crystalline state of the discrete particles, but depending on the production method they can also be partially or completely amorphous. Drug nanocrystals have to be distinguished from polymeric nano particles, which consist of a polymeric matrix and an incorporated drug. Drug nanocrystals do not consist of any matrix material. There is quite a number of formulation approaches for poorly soluble drugs which can be specified as "specific approaches". These approaches are suitable for molecules having special properties with regard to their chemistry (e.g. solubility in certain organic media) or to the molecular size or conformation (e.g. molecules to be incorporated into the cyclodextrins ring structure). Of course it would be much smarter to have a "universal formulation approach" applicable to any molecule apart from few exceptions. Such a universal formulation approach to increase the oral bioavailability is micronization, meaning the transfer of drug powders into the size range between typically 1-10μm. However, nowadays many drugs are so poorly soluble that micronization is not sufficient. The increase in surface area, and thus consequently in dissolution velocity, is not sufficient to overcome the bioavailability problems of very poorly soluble drugs of the biopharmaceutical specification class II. A consequent next step was to move from micronization to nanonization. Since the beginning of the 90s, the company Nanosystems propagated the use of nanocrystals (instead of microcrystals) for oral bioavailability enhancement, and also to use nanocrystals suspended in water (nanosuspensions) for intravenous or pulmonary drug delivery. Drug nanocrystals can be used for a chemical stabilization of chemically labile drugs. The drugpaclitaxel can be preserved from degradation when it is formulated as a nanosuspension [2-3]. The same result was found for the chemically labile drug omeprazole. When formulated as a nanosuspension, the stability was distinctly increased in comparison to the aqueous solution [4]. The increased stability can be explained by a shield effect of the surfactants and the drug protection by a monolayer made of degraded drug molecules which reduce the accessibility for destructive agents [5].It has now become possible to handle individual atoms; pick them up or place them from one place to another. Nanoparticles, now has endless uses and applications like manufacture of fogless car mirrors, fabric which does not absorb ink, mirror of TiO2, nanosensors, carbon nanotubes etc. This multidisciplinary scientific field involves creation and utilization of materials, devices or systems which has enabled the development of an amazing variety of methods for fabricating nanoparticles in recent years. This technology is equally innovative and has a critical role in controlled release of drug delivery.Research into the rational delivery and targeting of pharmaceutical, therapeutic, and diagnostic agents is at the forefront in nanomedicine. These involve the identificationof precise targets (cells and receptors) related to specific clinical conditions and choice of the appropriate nanocarriers to achieve the required responses while minimizing the side effects. Mononuclear phagocytes, dendritic cells, endothelial cells, and cancers (tumor cells, as well as tumorneovasculature) are key targets. Today, approaches to particle design and formulation are expanding the market for many drugs and are forming the basis for a highly profitable niche within the industry, but some predicted benefits are hyped. The development of a wide spectrum of nanoscale technologies is beginning to change the foundations of disease diagnosis, treatment, and prevention. These technological innovations, referred to as nanomedicines by the National Institutes of Health (Bethesda, MD, USA), have the potential to turn molecular discoveries arising from genomics and proteomics into widespread benefit for patients. Nanomedicine is a large subject area and includes nanoparticles that act as biological mimetics (e.g., functionalized carbon nanotubes), "nanomachines" (e.g., those made from interchangeable DNA parts and DNA scaffolds such as octahedron and stick cube), nanofibers and polymeric nanoconstructs as biomaterials (e.g., molecular self-assembly and nanofibers of peptides and peptideamphiphiles for tissue engineering, shape-memory polymers as molecular switches, nanoporous membranes), and nanoscalemicrofabrication-based devices (e.g., silicon microchips for drug release and micromachined hollow needles and two-dimensional needle arrays from single crystal silicon), sensors and laboratory diagnostics (Moeinet al, 2005).

Nanopharmaceuticals are of two types-
(1) Those where the therapeutic molecules are themselves the drug (i.e., the therapeutic compound itself also functions as its own carrier); and
(2) Those where the therapeutic molecules are directly coupled (functionalized, entrapped, or coated) to a Nanoparticles carrier.

Nanocrystal Technology
Preparation of drug nanocrystals is basically a nanosizing method, which is utilized to enhance the oral bioavailability of poorly water-soluble drugs. Drug nanocrystals are nanoscopic crystals of the drug with dimensions less than 2000 nm as defined in the first patents in this field (21-23). Nanocrystal dispersions contain dispersion media (water, aqueous solutions or nonaqueous media), active drug substances and surface active agents or polymers required for stabilization (24). If necessary, other substances such asbuffers, salts and sugars can be added.

Some 'Nano' Definitions

Cluster
- A collection of units (atoms or reactive molecules) of up to about 50 units

Colloids
- A stable liquid phase containing particles in the 1-1000 nm range. A colloid particle is one such 1-1000 nm particle.

Nanoparticle
- A solid particle in the 1-100 nm range that could be noncrystalline, an aggregate of crystallites or a single crystallite

Nanocrystal
- A solid particle that is a single crystal in the nanometer range

Advantages

proportionality,Improved dose
Increased rate of absorption,
Increased oral bioavailability,
Rapid effect,
Reduction in required dose,
Applicability to all routes of administration inany dosage form. Contrary to micronized drugs,nanocrystals can be administered via severalroutes. Oral administration is possible in the form of tablets, capsules, sachets or powder; preferablyin the form of a tablet. Nanosuspensions canalso be administered via the intravenous routedue to very small particle size, and in this way,bioavailability can reach 100 %.
Reduction in fed/fasted variability,
Rapid, simple and cheap formulation development(19, 25, 26).
Possibility of high amounts (30-40 %) of drugloading,
Increased reliability. Usually side effects areproportional to drug concentration, so decreasingthe concentration of active drug substances leadsto an increased reliability for patients (27, 28).
Sustained crystal structure. Nanocrystaltechnology leads to an increase in dissolution ratedepending on the increase in surface area obtainedby reduction of the particle size of the active drugsubstance down to the nano size range preserving the crystal morphology of the drug (29).
• Improved stability. They are stable systemsbecause of the use of a stabilizer that preventsreaggregation of active drug substances duringpreparation (19). Suspension of drug nanocrystalsin liquid can be stabilized by adding surface activesubstances or polymers.
Applicability to all poorly soluble drugs becauseall these drugs could be directly disintegrated intonanometer-sized particles.

Nanoparticles: Size Dependent Properties

Delocalization of valence electrons can beon the order of nanoparticle size.
Structure also changes with size.
This leads to

Size dependent physical and chemical properties:

Optical properties
Bandgap
Melting point
Specific heat
Surface reactivity

• Even for nanoparticles consolidated into “bulk” solids,new properties can result:enhanced plasticitynano-porosityshape selective reactivity .For semiconductors such as ZnO, CdS, and Si, the bandgapchanges with size.When the bandgaps lie in the visible spectrum,changing bandgap with size means a change in color

• For magnetic materials such as Fe, Co, Ni, Fe3O4, etc.,magnetic properties are size dependent .The ‘coercive force’ (or magnetic memory) needed toreverse an internal magnetic field within the particle issize dependent.

The strength of a particle’s internal magnetic field can besize dependent
Heat Capacity
C = ΔQ/mΔT

i.e., the amount of heat ΔQ required to raise T by ΔT of a sample of mass m
• Specific heat of polycrystalline materials given by Dulong-Petit law C of solids at room temp. (inJ/kg·K) differ widely from one to another;but the molar values (in J/moles·K) are nearly the same at high T:26 J/mol ·K; Cv = 3 R/M where R=gas constant, M = molecular weight.
• Cv of nanocrystalline materials are higher than the bulk.Reflect the quantum confinement effects and higher surface energy

Examples:
Pd: 48% ↑ from 25 to 37 J/mol.K at 250 K for 6 nm crystalline
Cu: 8.3% ↑ from 24 to 26 J/mol.K at 250 K for 8 nm
Ru: 22% ↑ from 23 to 28 J/mol.K at 250 K for 6 nm

Lowering of the melting point is proportional to 1/r

• canbe as large as couple of hundred degreeswhen the particle size gets below 10 nm.

• Usually, the surface tension coefficient is unknown;by measuring the melting point as a function of radius,can be estimated.

• Note: For nanoparticles embedded in a matrix,melting point may be lower or higher, depending on thestrength of the interaction between the particle and matrix.

Method Of preparation

There are a wide variety of techniques that are capable of creating nanostructures with various degrees of quality, speed, and cost. These manufacturing approaches fall under two categories:
1. Bottom-up Technique

It involves the building of nanostructures atom by atom or molecule by molecule.
Drug is dissolved in a solvent, which is then added to non?solvent that causes precipitation of the fine drug particles.
Simple and low expenditure. In this technique, the drug needs to be soluble in at least one solvent which is miscible with nonsolvent. During the precipitation growing of the crystals need to be controlled by addition of surfactant to avoid formation of microparticles.

2. Top down technique-

It involves starting with a larger piece of material, and etching, milling, or machining a nanostructure from it by removing material.
Grinding or milling is the oldest mechanical unit operation for size reduction of solids and for producing large quantities of particulate materials.

3. Ball-milling technology

Milling container filled with larger-sized balls.
The container can be static and the milling material is moved by a stirrer;
The complete container is moved in a complex movement leading to movement of the milling balls.
Material used- steel, glass and zircon oxide.
Polymer used- hard polystyrene.
Limitation erosion from the milling material during the milling process.

4. High-pressure homogenization

Currently used in the food industry, e.g., homogenization of milk.
In the pharmaceutical industry parenteral emulsions are produced by this technology.
Typical pressures for the production of drug nanosuspensions are 1000–1500 bar; the number of required homogenization cycles varies from 10 to 20 depending on the properties of the drug.

5. Sol gel method

Aqueous or alcohol-based Involves use of molecular precursors, mainly alkoxides.
Alternatively, metal formates Mixture stirred until gel forms Gel is dried @ 100°Cfor 24 hours over a water bath, then ground to a powder.
Allows mixing of precursors at molecular level better control High purity Low sintering temperature High degree of homogeneity particularly suited to production of nano -sized multi-component ceramic powders.

6. Microfluidization

In this technique, suspension of the drug is guided through specialized chambers under high pressure.
The chambers consist of narrow openings through which the suspension is forced to pass at high velocities.
The chamber geometry divides the suspension into two different streams and these streaming liquid jets are then made to impinge against each other in the impingement area where particle size reduction occurs.
Particle size reduction is achieved by high energy impact, cavitation, and shear forces.

Classification of Nanopharmaceuticals
A. Nanosuspension

B. Nanogels

C. Nanocarriers
1. Polymer micelle
2. Dendrimers
3. Liposomes
4. Niosomes

D. Nanoemulsion

E. Nanospheres

A. Nanosuspension

A pharmaceutical nanosuspension is defined as very finely dispersed solid drug particles in an aqueous or organic vehicle for either oral and topical use or parenteral and pulmonary administration.
The particle size distribution of the solid particles in nanosuspensions is usually less than one micron with an average particle size ranging between 200 and 600 nm.

B. Nanogels

Nanogels are cross-linked particles of sub- micrometer size made of hydrophilic polymers.
They are soluble in water, but have properties different from linear macromolecules of similar molecular weight.
These are formed either through covalent bonds for stable and insoluble three-dimensional networks or unstable (physical) gels via hydrogen bonds, van der Waals forces, and chain entanglements or through formation of crystalline regions.

C. Nanocarriers

Nanocarriers are colloidal particulate systems with size ranging between 10-1000 nm.
It utilized in the diagnosis, treatment and monitoring of various diseases.
There are various types of nanocarriers are introduced now days such as:

Polymer micelle
Dendrimers
Liposomes
Niosomes

Polymeric micelles
* Polymeric micelles are nano -sized particles

* That are made up of polymer chains and are usually spontaneously formed by self-assembly in a liquid, generally as a result of hydrophobic or ion pair interactions between polymer segments.

* The core of the micelles, which is either the hydrophobic part or the ionic part of the nanoparticles, can contain small (or bigger) molecules such as therapeutic drugs, while the shell provides interactions with the solvent and make the nanoparticles thereby stable in the liquid.

Dendrimers
* Dendrimer is a highly branched polymer and consists of a core where a monomer unit is attached.

* Dendrimers are large and complex molecules with very well-defined chemical structures.

* Dendrimers are built from a starting atom, such as nitrogen, after a repeating series of chemical reactions, carbon and other elements was added into it; produce a spherical branching structure.

* As the process repeats, result is a spherical macromolecular structure. Tree-like polymers, branching out from a central core and subdividing into hierarchical branching units

Not more that 15 nm in size, Mol. Wt very high
Very dense surface surrounding a relatively hollow core

Dendrimers consist of series of chemical shells built on a small core molecule
- Surface may consist of acids or amines Þmeans to attach functionally group
- Each shell is called a generation (G0, G1, G2….)
- Branch density increases with each generation
- Contains cavities and channels Þcan be used to trap guest molecules for various applications.

Liposomes
Nanoliposomes are nanometric version of liposomes, which are one of the most applied encapsulation and controlled release systems.

Liposomes are nano size artificial vesicles of spherical shape that can be produced from natural phospholipids and cholesterol

Liposomes are broadly classified by their structure.

* Multilamellar liposomes:
Spherically concentric multilamellar (many bilayers ) structures

* Unilamellar liposomes:
Spherical concentric unilamellar (one bilayer) structures
The size, lamellarity lipid composition of the bilayers influence many of the important properties like
The fluidity,
Permeability,
Stability and
Structure.
These can be controlled and customized to serve specific needs.

Niosomes

Niosomes are non-ionic surfactant vesicles, are widely studied as an alternative to liposomes
These vesicles appear to be similar to liposomes in terms of their physical properties
They are also prepared in the same way and under a variety of conditions, from unilamellar or multilamellar structures.
Niosomes alleviate the disadvantages associated with liposomes, such as chemical instability, variable purity of phospholipids and high cost.

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Drug Loading And Release
There are three major methods for loading drugs into polymer micelle cores :

chemical conjugation,
physical entrapment or solubilization
Polyatomiccomplexation (e.g. ionic binding).

Techniques of nano crystal

Transport processes—nanomaterials as agents for transporting chemicals, molecules, etc.
Bio-selective surfaces—nanomaterials with enhanced or reduced ability to bind or hold specific molecules and/or organisms.
Bio-separation—nano-materials or -processes with ability to separate molecules, biomolecules, or organisms.
Microfluidics/MEMs—liquid streams used to separate, control, or analyze at the nanoscale. They might have special flow properties at this scale. Microelectromechanical systems (MEMs) are also included here. They are devices with channels and wells, electrodes for detection, connectors, and fluidic input/output ports.
Nano-bioprocessing—use of nanoscale technology and/or biological processes to create a desired compound or material from a defined stock. The product itself may be bulk or nanoscale.
Nucleic acid bioengineering—use of DNA as building blocks to form nano-particles or use of nano-particles for genetic engineering.
Drug delivery—use of nanoparticles or nanomethods to deliver drugs to animals.
Modeling—use of nanotechnology to build models of systems, or the modeling of nanoparticles in systems.

Evalution Parameters

1. Particle size and size distribution

2. Zeta potential

3. Crystalline state and morphology

4. Saturation solubility and dissolution velocity

5. Drug entrapment efficiency

1. Particle size and size distribution

Mean particle size and Size Distribution;- The most important characterization parameter Governs the physicochemical properties like saturation solubility, dissolution velocity, physical stability and even biological performance.
Methods for determining particle size distribution: Photon correlation spectroscopy (PCS),
Electron microscopy(EM)
Laser diffraction (LD),

2. Zeta potential

It determines the physical stability of nanosuspension.
In order to obtain a nanosuspension exhibiting good stability, for an electrostatically stabilized nanosuspension a minimum zeta potential of ± 30mv is required.

3. Crystalline state and morphology

The X-Ray Diffraction (XRD) is used for determining change in physical state and extent of amorphous drug.
Differential Scanning Calorimetry (DSC) determines the crystalline structure.

4. Saturation solubility and dissolution velocity

Nanosuspension increases the dissolution velocity and saturation solubility.
An increase in solubility that occurs with relatively low particle size reduction may be mainly due to a change in surface tension leading to increased saturation solubility.
Depend upon temperature and properties of dissolution medium

Unique Properties of Nanoscale Materials

• Quantum size effects result in unique mechanical, electronic, photonic, and magnetic properties of nanoscale materials

• Chemical reactivity of nanoscale materials greatly different from more macroscopic form, e.g., gold

• Vastly increased surface area per unit mass, e.g., upwards of 1000 m² per gram

• New chemical forms of common chemical elements, e.g., fullerenes, nanotubes of carbon, titanium oxide, zinc oxide, other layered compounds

Nanoscale
Atoms and molecules are generally less than a nm and we study them in chemistry. Condensed matter physics deals with solidswith infinite array of bound atoms. Nanoscience deals with thein-between meso-world

• Quantum chemistry does not apply (although fundamental lawshold) and the systems are not large enough for classical laws of physics

• Size-dependent properties

• Surface to volume ratio
- A 3 nm iron particle has 50% atoms on the surface
- A 10 nm particle 20% on the surface
- A 30 nm particle only 5% on the surface

Many existing technologies already depend on nanoscale materialsand processes
- Photography, catalysts are “old” examples
- developed empirically decades ago

• In existing technologies using nanomaterials/processes, role of nanoscale phenomena not understood until recently; serendipitousdiscoveries
- With understanding come opportunities for improvement

• Ability to design more complex systems in the future is ahead
- Designer material that is hard and strong but low weight
- self-healing materials

Application

Bioavailability enhancement
Ocular administration
Intravenous administration
Pulmonary administration
Targeted drug deliver
Topical formulations
LEDs, solar cells, solid state lighting
Biomedical

- Bioindicators
- Lateral flow assays
- DNA/gene identification, gene chips
- Cancer diagnostics

Biological Labeling Agent

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