1.1 origin of concept: particle engineering -...

Studies on Application of Particle Engineering Aspects in Designing

Efficient Pharmaceutical Dosage Forms Introduction

©Mayur B. Sangwai, Institute of Chemical Technology (ICT), Mumbai, India

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1 Introduction:

1.1 Origin of concept: Particle engineering

The selection of solids with suitable physical and chemical characteristics is a key factor

within pharmaceutical development strategies (Rabinow 2004a). Pharmaceutical

dosage forms necessitate the design of active pharmaceutical ingredients (APIs) and

excipients in such a way to achieve controllable, reproducible, and effective functional

responses (release rate, location of delivery, taste-masking, etc.) of the APIs in human

body (Hu et al. 2004). These functional responses greatly depend on the dosage form

and the way API and excipient particles are integrated into the superstructure of the

dosage form. Advances in pharmaceutical sciences in the last decade has generated

interest in the drug candidates; new and old, to be able to provide enhanced therapeutic

value by particle engineering (Patravale & Kulkarni 2004).

Figure 1.1 Drug Particle Engineering: Concept

Particle Engineering is an emerging discipline that combines elements of microbiology,

chemistry, formulation science, colloid and interface science, heat and mass transfer,

solid state physics, aerosol and powder science, and nanotechnology (Merisko-

Liversidge et al. 2003). Particle engineering offers tools and methodologies, both

experimental and numerical, to design the structure of particles so that the desired

responses of the API are enhanced significantly in the dosage form. It provides the




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theoretical framework for a rational design of structured micro/nanoparticles. Particles

and their surfaces can be designed and tailored in many different processes via different

formulation approaches (Hu et al. 2004).

The need for generating engineered drug particles for various therapeutic applications

is increasing with poor performance of conventional delivery systems and discovery of

new molecules (Lipinski 2001). The impact of the particulate nature of components of

the dosage form on therapeutic effect is of the utmost importance. Particle engineering

is being exceedingly and effectively used for enhancement in solubility poorly soluble

compounds, for precise pulmonary drug delivery, advanced controlled release

application, taste masking, generation of nanoscale particles for targeting specific drug

sites of action, protection of drugs against degradation, organ or tissue and delivery of

biological molecules such as protein, peptides and oligonucleotides (Elaine Merisko-

Liversidge & Liversidge 2011).

In more specific way, particle engineering referees to modification of specific

characteristics of drug or excipient or both particles, like size, shape, surface, crystal

structure, morphology etc. in order to improve or control technological and

biopharmaceutical properties of drug products. However, before opting for a particular

particle engineering strategy one needs to understand the biopharmaceutical and

physicochemical properties of drugs (Müller et al. 2012).

1.1.1 Biopharmaceutics Classification System (BCS)

Based on their solubility and intestinal permeability characteristics, drugs have been

classified into one of four categories according to the BCS classification (Amidon et al.

1995).




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Figure 1.2 Biopharmaceutics Classification System (BCS)

BCS Class I: High-solubility, high-permeability drugs. These compounds are generally

very well absorbed. For Class I compounds formulated as immediate release products,

dissolution rates generally exceed gastric emptying rates. Therefore, nearly 100%

absorption can be expected if at least 85% of a product dissolves within 30 min of in

vitro dissolution testing across a range of pH values. Accordingly, in vivo

bioequivalence data are not necessary to assure product comparability.

BCS Class II: Low-solubility, high-permeability drugs. The bioavailability of products

containing these compounds is likely to be dissolution-rate limited. For this reason, a

correlation between in vivo bioavailability and in vitro dissolution rate (IVIVC) may

be observed.

BCS Class III: High-solubility, low-permeability drugs. Absorption is permeability

rate limited but dissolution will most likely occur very rapidly. For this reason, there

has been some suggestion that as long as the test and reference formulations do not

contain agents that can modify drug permeability or GI transit time, waiver criteria

similar to those associated with Class I compounds may be appropriate.

BCS Class IV: Low-solubility, low-permeability drugs. These compounds have very

poor oral bioavailability. They are not only difficult to dissolve but often exhibit limited

permeability across the GI mucosa. These drugs tend to be very difficult to formulate

and can exhibit very large inter-subject and intra-subject variability (Kawabata et al.

2011; De et al. 2003).




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1.1.2 Key Particle Properties:

Nowadays much research dealing with pharmaceutical products is directed at the

factors that make them possible to convert into suitable dosage forms and also addresses

the failures that might occur during dosage from development. The properties of the

dosage form and a host of its qualities are a function of the neat drug. Characterisation

of the dosage form, therefore, requires characterization of the drug substance and what

its properties are, so that the sources of derivative properties in the dosage form can be

adequately assigned (Kesisoglou et al. 2007). Although many such failures stem from

manufacturing and excipients, many also stem from the drug substance itself. It is,

therefore, of importance to discuss the properties and testing approaches of the pure

drug to assess the properties and difficulties associated with the final product or dosage

form.

Tools exist, nowadays, that allow sharp definition of a solid. Such characterization of

solid-state forms encompass microscopy, infrared (IR) spectroscopy, differential

scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder

diffraction (PXRD) analysis and single-crystal X-ray diffraction.

A. Particle Shape:

Transport of particles in the body, regardless of the mode of administration, will be

affected by particle shape. Just as diameter dictates particle velocity, diffusion and

adhesion to walls in blood vessels, airways and intestine, shape will also affect these

properties but in more complex ways. Movement of spheres is easier to predict due to

their inherent symmetry, but non-spherical particles may align or tumble in the presence

of flow. Pharmacological implications of the particle shape are very critical (Decuzzi

2010; Desgrosellier & Cheresh 2010; Euliss et al. 2006). Receptor mapping and

molecular modelling coupled with high throughput screening have revealed numerous

drug candidates for various disease states. These receptors are located in a lipophilic

membrane, drug candidates having the best molecular configuration may by design, be

poorly water soluble in nature. The pathway of particle migration in the body directly

impacts the final destination, whether it be internalized in tumor cells or cleared from

the body by macrophages in the liver. Microparticles (~1–5 μm) typically are trapped

in the liver and phagocytosed by Kupffer cells, whereas larger microparticles are

typically trapped in the capillary beds. Alignment or tumbling issues will be

compounded when particles flow through filtering organs, such as the liver or spleen,

or when bifurcations in the vessels are encountered. For example, filtering units in the




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spleen are described as slits, implying that they are asymmetric (Desgrosellier &

Cheresh 2010).

Jia et.al. 2006 further explored the effect of particle shape and spatial confugration on

its dissolution behaviour using its 3D shape information and subsequent digital

dissolution simulations. Measuring size alone is sometimes insufficiently sensitive to

identify important but subtle differences between samples. Some batches of samples

may differ by such a small amount that this difference is lost during the translation to a

circle equivalent or spherical-equivalent diameter. It was observed that when the

particle shape alters, like from cylindrical, plate, ordered crystal the dissolution

behaviour changes significantly (Jia & Williams 2006).

Analytical Methods:

Particle shape is most commonly measured using imaging techniques. One measure of

shape is to quantify the ‘closeness’ to a perfect circle. For this we can use the parameter

Circularity which is defined as follows:

Where A is the particle area and P is its perimeter.

Figure 1.3 Illustration of circularity

Convexity is a measure of the surface roughness of a particle and is calculated by

dividing the “convex hull perimeter” by the actual particle perimeter. The easiest way

to visualize the “convex hull perimeter” is to imagine an elastic band placed around the

particle. Convexity also has values in the range 0-1. A smooth shape has a convexity of




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1 as the convex hull perimeter is exactly the same as the actual perimeter. A very ‘spiky’

or irregular object has a convexity closer to 0.

Figure 1.4 Illustration of convexity

Elongation is defined as [1-aspect ratio] or [1- width/length]. As the name suggests it

is a measure of elongation and again has values in the range 0-1. A shape symmetrical

in all axes such as a circle or square will have an elongation value of 0 whereas shapes

with large aspect ratios will have an elongation closer to 1.

Figure 1.5 Illustration of elongation shape

Through image analysis we can understand the exact shape of particle which we can

further correlate with its dissolution behaviour (Anon n.d.).




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C. Particle Size and Size Distribution:

The need for particle size and size distribution control in the manufacture of

pharmaceuticals is becoming increasingly apparent as the pharmaceutical industry

attempts to capitalize on some APIs with less-than-ideal solubility profiles. In

pharmaceutical industry, virtually all solid-dosage form products are routinely

subjected to dissolution testing, and the most common cause for product recalls is

failure of a product to meet dissolution specifications. Considering such failures, now

particle size limits are included in drug substance specifications, because particle size

affects both dissolution characteristics and mechanical properties like flow and

compression of drug substance (Elaine Merisko-Liversidge & Liversidge 2011). As the

particle size has a profound influence on almost every step in solid dosage

manufacturing, regulatory agencies are also showing increased concern about particle

size distribution of drug substances and emphasizing on inclusion of particle size

specifications in drug master files (DMF). Even addition of validated particle size

analysis methods is encouraged.

Nowadays many API manufacturing industries, speciality laboratories are engaged in

modifying synthetic procedures of API production to generate drug substances with

precisely controlled particle size distribution. Also, significant advances in drug

delivery have been made in which a finely divided API, with the concomitant increase

in specific surface area, has resulted in increased bioavailability.

The size of a particle would be easy to define, if the particle were either a sphere or a

cube, but once the shape of the particle deviates from that, analysis becomes more

difficult and needs more sophisticated analytical tools for exact determination. Precise

particle size control technologies have also assisted in the development of drug delivery

platforms for the delivery of a medicament to the lung. With the rapidly growing

popularity and sophistication of inhalation therapy, there is an increasing demand for

tailor-made inhalable drug particles capable of affording the most efficient delivery to

the lungs and the most optimal therapeutic outcomes (Chow & Tong 2007).

The effect of particle size on transport in vivo may seem obvious, but nonetheless is

crucial to the administration, circulation and destination of particles. The diameter of

particles administered in blood vessels, airways or gastro-intestinal tract dictates their

velocity, diffusion and adhesion to walls. Particle size also exerts a significant influence

on cutaneous penetration pathways: particles greater than 10 μ remain on the skin




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surface; particles between 3-10 μ concentrate in the hair follicles; particles smaller than

3 μ may penetrate both the follicles and stratum corneum. Bioavailability enhancement

for water-insoluble drugs in oral dosage forms may be achieved for drug nanoparticles,

through their enhanced suspension homogeneity and delivery efficiency as well as

increased residence time (reduced clearance) (Kohli & Alpar 2004). For oral

bioavailability, a typical increase of AUC by a factor 2.5 was observed with reduction

of particle size from 1,000 to 400 nm. The same study also reported a reduction of

feeding/fasting effects by a factor of 3-4. Other advantages include enhanced dose

proportionality and earlier onset of action. Nanoparticles were also shown to exhibit

increased bioadhesion and/or increased uptake in the intestinal and inflamed colonic

mucosa (Rabinow 2004b).

Analytical Methods:

Nowadays particle size analysis at micron and submicron level in both dry and wet

conditions can be effectively done with advanced analytical tools like Laser Diffraction

(LD) analysis, Photon Correlation Spectroscopy (PCS) and Small Angle Neutron

Scattering (SANS).

D. Surface charge:

An important characteristic of nanoparticles is the surface charge which determines the

physical stability in the formulation, in vivo distribution and targeting ability of

nanoparticles. The zeta potential is the measure of the amount of charge on the particle

and represents an index of particle stability. The zeta potential is determined by

measuring the electrophoretic particle velocity in an electrical field (O’Brien & White

1978). The electrophoretic mobility was converted to the zeta potential in mV using the

Helmholtz-Smoluchowski equation (Park & Lee 2008). At standard measuring

conditions (room temperature of 25°C, water) this equation can be simplified to the

multiplication of the measured electrophoretic mobility (μm/cm per V/cm) by a factor

of 12.8, yielding the ZP in mVA physically stable nanosuspension stabilized by

electrostatic repulsion should have a minimum zeta potential value of ± 30 mV.

Charged surfactants like sodium dodecyl sulphate (SDS) adsorb with the negatively

charged part of the molecule onto the particle surface and form the inner Helmholtz

layer. Adsorption takes place according to the theory of adsorption isotherms. The

surface coverage increases with an increasing SDS concentration until full surface

coverage is obtained (plateau of the adsorption isotherm). Consequently the potential




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of the inner Helmholtz layer increases with the increasing surface coverage, leading

subsequently to an increase of the zeta potential and an increase in the physical stability

of the suspensions. The zeta potential can also indicate whether the charged active

material is encapsulated within the center or adsorbed onto the surface of the

nanoparticles. Electrolytes are present in the gastrointestinal tract and the contact of the

nanocrystals with these electrolytes cannot be avoided. Electrostatic stabilisation is

reduced in its efficiency in an electrolyte containing environment. To compensate for

this it is ideal to use steric stabilisers, which are less impaired in their effect by

electrolytes, ideally one combines electrostatic and steric stabilisation Thus

consideration of the zeta potential is important in preventing aggregation of the particles

(Hans & Lowman 2002).

Analytical Methods:

Analysis of surface charge density at varying conditions of temperature and dilutions

can be accurately done with zeta potential measurement techniques.

E. Surface hydrophobicity:

Following intravenous administration, hydrophobic nanoparticles are easily recognized

by the mononuclear phagocytic system (III & Peppas 2006). Thus, they are rapidly

opsonized and massively cleared by macrophages of the liver, spleen, lungs and bone

marrow. Thus in order to minimize opsonization and prolong blood circulation of

nanoparticles in vivo, the surface of the hydrophilic nanoparticles must be modified.

There are two general approaches employed for this purpose. One is the surface coating

of nanoparticles with hydrophilic polymers such as polyethylene glycol (PEG),

chitosan or surfactants such as poloxamers or poloxamines. The second approach is the

use of biodegradable copolymers having hydrophilic segments such as PLA-PEG. PEG

functionalized nanoparticles are not taken up by the body and often called as “stealth

nanoparticles” (Petros & DeSimone 2010).

Analytical Methods:

Surface hydrophobicity or hydrophilicity can be determined with contact angle

measurement technique.




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G. Density:

In humans, particle density has been demonstrated to significantly impact gastric

residence, with heavier particles (e.g. 2.8 g/cm3) being retained substantially longer

than smaller particles (e.g. 1.5 g/cm3). Fed state motility is characterized by a pattern

of low amplitude contractions, which results in the relatively consistent GE of small

solids through the pylorus. The fed state size cut-off for non-digestible solids is

controversial with reports ranging from 2 mm to 7 mm. Particles beyond this margin

empty during the stronger contractions associated with Phase II and III of the fasted

state cycle. Rhie et al. concluded that the fed state size cut-off vary according to meal

composition and motility. Phase II governs the emptying of the larger pellets, while the

smallest pellets were able to empty during the fed state (Rhie et al. 1998). On the other

hand, they found that the altered drug absorption associated with meals appears to be

attributable primarily to altered fluid flow dynamics rather than to GI motility

alterations.

Analytical Methods:

The measurement of particle density can be done in a number of ways like helium gas

pycnometry, mercury porosimetry etc.

1.2 Modern particle engineering aspects in drug delivery

1.2.1 Nanonization:

1.2.1.1 Basics:

One of the major advancements in the areas of pharmaceutics and drug delivery in the

last decade has been the recognition of the benefits that can be gained by formulating

poorly-water soluble actives as nanometer-sized drug particles, frequently referred to

as nanosuspensions and/or nanoparticles. In addition to improving drug solubility with

commonly used practices such as the use of co-solvents or salt/pro-drug formation,

other approaches that have been employed include solid dispersions, cyclodextrins, soft

gelatin capsules, microemulsions, melt extrusion, liposomes, emulsions and micellar

systems. The use of particle size reduction approaches to form stable nanometer size

drug nanosuspensions or nanoparticles is relatively newer formulation strategy (Hu et

al. 2004).

Nanonization refers to the reduction of the active pharmaceutical ingredient (API)

particle size down to the sub-micron range. These nanoparticles can be formed by




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building particles up from the molecular state, as in precipitation, or by breaking larger

micron-sized particles down, as in milling (Müller et al. 2001).

A large proportion of new chemical entities coming from drug discovery are water

insoluble, and therefore poorly bioavailable, leading to hurdles in formulation

development efforts (Lipinski 2001). To address this need, a significant amount of

attention over the years has been focused on formulation strategies for this class of

molecule which includes molecules in BCS classification II (poorly soluble and

permeable) and Class IV (poorly soluble and impermeable).

The fundamental principles which govern the exceptional advantages provided by

nanonization are;

A. Increased saturation solubility (explained by Kelvin and Ostwald-

Freundlich equations) (Jacobs & Müller 2002).

B. Increased dissolution velocity (explained by the Noyes-Whitney and the

Prandtl equations ) (Jacobs & Müller 2002).

C. Increased adhesiveness to surfaces/cell membranes (Jacobs & Müller

2002).

A. Increased saturation solubility:

The Gibbs-Kelvin equation describes the vapor pressure over a curved surface of a

liquid droplet in gas. The vapor pressure increases with increasing curvature resulting

from decrease in particle size. This equation, describing the transition of molecules

from a liquid phase (droplet) to a gas phase, can also be applied to the transition of

molecules from a solid phase (drug particle) to a liquid phase. The vapor pressure is

then replaced by the dissolution pressure (px). The equilibrium between dissolving

molecules and molecules recrystallizing on particle surfaces (determining the extent of

saturation solubility) is shifted in favour of the dissolution process. As a result of this

increased dissolution tendency, the saturation solubility increases (Müller et al. 2001).

The dependency of the saturation solubility on the particle size is also explained in the

Ostwald Freundlich equation (Jacobs & Müller 2002). The saturation solubility Cs

increases with decreasing particle size according to the Ostwald– Freundlich equation:

where Cs is saturation solubility, C is solubility of the solid consisting of large particles,

σ is the interfacial tension substance, V is the molar volume of the particle material, R




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is gas constant, T is absolute temperature, ρ is the density of the solid and r is the radius.

The increase in Cs can be seen in the range below 1 μm (Müller & Peters 1998).

B. Increased dissolution velocity:

Particle size reduction of sparingly soluble drugs results in increased rate of solution.

This goes is in line with the Noyes Whitney equation, which is regularly used to

describe the process of dissolution of solid drugs:

Where, dm/dt is the rate of dissolution i.e. the rate of change of mass dissolved (m) with

time (t), D is the diffusion coefficient, A is the interfacial surface area through a static

layer of liquid of thickness h, and CS is the equilibrium solubility and C is the amount

dissolved at time t (Buckton & Beezer 1992). According to the Nernst–Brunner and

Levich modification of the Noyes Whitney dissolution model equation, the dissolution

velocity of the nanosuspension increases due to a dramatic increase in the surface area

of the drug particles from microns to nanometer size.

where dX/dt is the dissolution velocity, D is the diffusion coefficient, A is the surface

area of the particle, h is the diffusional distance, Cs is the saturation solubility of the

drug, X is the concentration in the surrounding liquid and V is the volume of the

dissolution medium (Merisko-Liversidge et al. 2003; Patravale & Kulkarni 2004). The

Noyes–Whitney equation also describes that the dissolution velocity dm/dt depends on

the concentration gradient (Cs −C)/h and the Prandtl equation describes that the

diffusional distance h is reduced for small particles. Thus, the simultaneous increase in

the saturation solubility Cs and the decrease in h lead to an increased concentration

gradient (Cs -C)/h, enhancing the dissolution velocity in addition to the surface effect

(Mauludin et al. 2009). The Prandtl equation describes the hydrodynamic boundary

layer thickness (hD) (in which diffusion dominates) which constitutes diffusional

distance (hH) for flow passing a flat surface:

where, L is the length of the surface in the direction of flow, k denotes a constant, V is

the relative velocity of the flowing liquid against a flat surface and hH is the




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hydrodynamic boundary layer thickness (Mosharraf & Nyström 1995; Patravale &

Kulkarni 2004). Here the diffusional distance hH is reduced for small particles (Müller

et al. 2001).

C. Increased adhesiveness to surfaces/cell membranes:

When the particles are of nanometer length scale, surface irregularities can play an

important role in adhesion, as the irregularities may be of the same order as the particles.

Nanoparticles can show a strong adhesion because of the increased contact area for van

der Waals attraction. The increased contact area can also be contributed to the large

number of surface molecules resulting in enhanced adhesiveness by whatsoever

interaction that may exists (Gupta & Kompella 2006).

1.2.1.2 Current strategies:

There are a number of methodologies available for producing nanometer sized drug

particles. All the approaches generate nanometer sized drug particles that are physically

stabilized via ionic and/or steric surface modification. The principle of nanosizing

poorly water soluble compounds rests primarily within the increased surface area that

results when a drug is fractured into nanometer sized particles. It is reasonable to

anticipate that nanosized drug particles will exhibit distinctive properties compared to

bulk materials (Patravale & Kulkarni 2004; Elaine Merisko-Liversidge & Liversidge

2011; Kesisoglou et al. 2007).




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Figure 1.6 Nannosizing strategies

A. Drug nanocrystals

Drug nanocrystals are nanoscopic crystal structures of the parent compound with

dimensions less than 1 µm. Drug nanocrystals are one of the most important strategies

to enhance the oral bioavailability of hydrophobic drugs. Several preparation methods

for drug nanocrystals have been investigated. Following are the several key methods,

including nanoprecipitation, high-pressure homogenization and media milling

(Patravale & Kulkarni 2004).

The majority of pharmaceuticals are developed in the most stable crystalline solid form.

This, however, can present issues in terms of poor solubility and bioavailability.

Without altering the chemistry of the drug molecule, the amorphous form can be

prepared but this often conversely lacks the required stability for manufacturing and




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shelf life. Nanocrystals are intermediates between the crystalline and amorphous states,

benefiting from enhanced dissolution due to higher surface energy and surface area.

Their preparation therefore cannot be conducted using conventional crystallization

approaches. Stabilization, filtration, and characterization also become more difficult as

a result of the reduced length scale.

Nanocrystals can be obtained directly through ‘bottom up’ by modified

crystallization/antisolvent precipitation but this approach is less common or indirectly

‘top down’ by mechanical breakage/attrition of a crystalline powder (Merisko-

Liversidge et al. 2003).

Nanocrystals by Milling:

Media milling has the longest track record for the production of drug nanocrystals.

Typically in this process, the milling chamber is charged with milling pearls, dispersion

media (e.g. water), drug powders and stabilizers. The pearls are rotated at a very high

speed to generate strong shear forces to disintegrate drug powers into nanoparticles (E

Merisko-Liversidge & Liversidge 2011).

Physical characteristics of the resulting nanocrystals depend on the number of milling

pearls, the amount of drug and stabilizer, and milling time, speed and temperature. The

potential shortcomings of media milling are difficulty in the removal of residual milling

media from the final product and the loss of drug owing to adhesion to the inner surface

of the milling chamber.

Mechanical milling can be carried out on dry powders by using high-energy ball

milling, cryo-milling or jet milling (micronization). In these examples, the process is

highly energetic, thus the likelihood of amorphous formation is not negligible, and

therefore monitoring will be needed as well as prevention of contamination from

milling equipment. On the other hand, milling of slurries reduces the likelihood of

generating amorphous material.

Wet ball milling (also referred to as pearl milling or bead milling) is by far the most

frequently used production method for drug nanocrystals in the pharmaceutical

industry. The milling procedure itself is rather simple; therefore this process can be

basically performed in almost every lab. The easiest way of doing Wet ball milling is

through low energy ball milling (LE-WBM) using a jar filled with milling media (often

just very simple glass beads). This system is charged with coarse drug substance,




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preferably in micronized form, which is suspended in dispersion medium containing at

least one stabilizing agent.

It is obvious that high energy mills require special milling media which has to be

properly selected based on the material of the inner surfaces of the mill, the agitator

types and other factors. Using just glass beads or zirconium oxide milling beads can

lead to significant contamination of the nanosuspension caused by the abrasion either

of the milling beads or parts of the milling chamber. With the commercial availability

of suitable equipment for small scale production up to the commercial scale production,

wet ball milling can be regarded as scalable approach. This aspect has definitely helped

for broader acceptance of this rather complex technology.

Nanocrystals by high pressure homogenization:

HPH can be regarded as the second most important technique to produce drug

nanocrystals. The broad acceptance of this approach is supported by many examples

from the literature. The application of HPH as particle size reduction method requires

the availability of special equipment; it cannot be tested with a system as simple as

“beads in a beaker”. Interestingly, high pressure homogenizers were already widely

available in the pharmaceutical industry as well as in the food industry at the time the

first nanosuspensions based on HPH have been developed. The use of homogenizers

was already described for the production of liposomes and emulsion systems. Today,

high pressure homogenizers can also be used for the production of solid lipid

nanoparticles or nanostructured lipid carriers. The possibility to employ the production

equipment for various formulation approaches (multipurpose production lines) is an

important advantage, as it is rather costly to establish production lines in-house.

Production of drug nanoparticles via the top-down disintegration mechanism generally

involves high-pressure homogenization (HPH) or media milling. Typically, HPH is

carried out in either water or a nonaqueous media (e.g. PEG 400). The nonaqueous

media is suitable for watersensitive drugs. In a standard procedure, a suspension of

crystalline drug and stabilizers is passed through the narrow gap of a homogenizer at

high pressure (500–2000 bar). The pressure creates powerful disruptive forces such as

cavitation, collision and shearing, which disintegrate coarse particles to nanoparticles.

Particle size depends on the number of cycles and the pressure and temperature of the

homogenization process (E Merisko-Liversidge & Liversidge 2011).




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The steps involved in producing nanosuspensions by means of HPH are similar and as

simple as for WBM. Normally, a premix of the coarse drug and the dispersion medium

is prepared using high speed stirrers. The dispersion medium contains normally similar

surfactant and/or stabilizer systems used for the WBM approach. Subsequently, this

coarse suspension (the so called “macro-suspension”) is passed several times through

the high pressure homogenizer. Typically, the applied pressure is increased step-wise

from 10% to 100% in order to avoid clogging of the narrow homogenization gap. At

production pressure, which spans between 1000 and 2000bar, the gap has an opening

of only a few micrometer. This explains the importance of the pre-mixing procedure

for de-agglomeration and wetting purposes, especially when relatively coarse material

is processed. The particle size reduction itself is caused by cavitation forces, shear

forces and collision. In general, several homogenization cycles are needed to reach the

minimal particle size. The number of passes (i.e. homogenization cycles) depends on

many factors.

HPH is a scalable process, which is applied not only in the pharmaceutical but also in

the cosmetics and food industry. Today high pressure homogenizers are available from

ml-scale to large production scale.

B. Nanoprecipitation

This method involves the formation of crystalline or semicrystalline drug nanoparticles

by nucleation and the growth of drug crystals. In a typical procedure, drug molecules

are first dissolved in an appropriate organic solvent such as acetone, tetrahydrofuran or

N-methyl-2-pyrrolidone at a supersaturation concentration to allow for the nucleation

of drug seeds. Drug nanocrystals are then formed by adding the organic mixture to an

antisolvent in the presence of stabilizers such as hydroxypropyl methylcellulose,

polyvinylpyrrolidone, Tween 80, Poloxamer 188 or lecithin. Nanocrystals of several

drugs prepared using nanoprecipitation are in preclinical development.

Crystallization/Precipitation

The production of nanosized particle by direct crystallization/precipitation can be

carried out using extreme supersaturation conditions in order to favor nucleation over

growth, but kinetic phase(s) will be promoted. This technique can be suitable for

preparing large quantities of material which has no polymorph issue, or if a metastable




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polymorph is required for formulation. The stability upon agglomeration during rapid

crystallization, needs to be assessed for development feasibility.

Spary/Freeze Drying

Spray drying or spray freeze drying uses the same approach as that of

crystallizing/precipitating particles within or on the surface of the droplet by

evaporation of solvent. The feed and the drying kinetics (operating conditions) will

determine the output material properties, but use of this equipment’s at larger scale can

be envisaged, and powder obtained from spray drying can be handled and used for

subsequent conventional formulation. Spray freeze drying combines both current spray

drying and freeze drying technology, whereby the atomized feed solution is frozen and

dried to produce monodispersed submicron spherical solute particles. This reduces the

time and cost associated with conventional lyophilization. Solubility can be further

controlled by the addition of polymers for encapsulation and solid dispersions. Porosity

and crystallinity can also be controlled by altering processing parameters.

In the spray drying process a feed solution containing the biopharmaceutical is

atomized into droplets that dry rapidly due to their high surface area and intimate

contact with the drying gas (compressed air). The drying time for droplets depends on

the process conditions such as flow rate, pump rate, aspiration rate and heat. This drying

time can range from less than 100 min to a few seconds. The temperature experienced

by the droplets is considerably lower than the temperature of the drying air due to

evaporative cooling. The dried powder is protected from overheating by rapid removal

of solvent from the drying zone. The final product can be removed from the air stream

by the use of cyclones or filters.

Spray Freeze Drying was first introduced in 1994. It was classified as a variant of dry

milling. It involves spraying a solution containing the macromolecule into a vessel

containing a cryogenic liquid such as nitrogen, oxygen or argon. Since the normal

boiling point for such a liquid is very low, the droplets are quickly frozen. Lyophilizing

these frozen droplets results in porous spherical particles suitable for inhalation. It has

been established that these droplets may begin to freeze during the time of flight

through the cold vapour phase and then completely freeze upon contact with cryogenic

liquid. Although this technique has been used for producing protein particles, it is faced

with the limitations of stresses associated with freezing and drying, which may cause




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irreversible damage to the protein. This is manifested as structural denaturation,

aggregation and loss of biological activity upon rehydration. Similar to spray drying,

loss of stability due to unfolding and aggregation remains a major challenge.

1.2.1.3 Market status:

Nanonization techniques have been started with greater interest in various

pharmaceutical industries. Table 1.1 shows the approved nanoparticulate technologies

for clinical trials prepared by different methods.

Table 1.1 Representative nanoformulations of water-insoluble drugs that are

approved for clinical use or under clinical trials

Nanonization strategy

Trade

name Drug Indication Dosage

form Developer,

status High-pressure

Homogenization Triglide® Fenofibrate Hyperchole-

sterolemia Oral

tablet SkyePharma/Scie

le approved in 2005

Media milling Rapamune® Sirolimus Immuno- suppression

Oral

tablet Elan/Wyeth, approved in 2000

Emend® Aprepitant Antiemetics Oral

capsule Elan/Merck, approved in 2003

Tricor® Fenofibrate HyperChole

-sterolemia Oral

tablet Elan/Abbott, approved in 2004

Megace ES® Megestrol Antianorexia cachexia

Oral

suspensi

on

Elan/Par Pharmaceuticals, approved in 2005

Invega® Paliperidon

e palmitate Schizo-

phrenia IM

suspensi

on

Elan/Johnson & Johnson,

approved in 2009

1.2.1.4 Future aspects:

Although multiple nanonization products have been clinically approved in the past

decade, major challenges inhibit their widespread adoption. The size, shape,

composition and surface properties of nanocarriers need to be precisely controlled and

their effects on drug pharmacokinetics and pharmacodynamics need to be clearly

elucidated. The US Food and Drug Administration (FDA) has recognized the

importance and promise of nanomedicine and begun to create and implement necessary

regulatory policy. The characterization of product quality and pharmacological

evaluation of absorption, distribution, metabolism and excretion (ADME) are emerging

as the new focus for assessing the safety and efficiency of various nanoformulations.

Accurate assessment of the risk and benefit of nanoformulations will be essential to

realize the clinical potential of this novel model of treatment.




20

1.2.2 Amorphisation:

1.2.2.1 Basics:

Amorphous forms of drug substances are characterized by a disordered molecular

arrangement, that is, a lack of long-range translational and orientational order. The main

reason of interest of pharmaceutical companies in amorphous forms of drugs is their

enhanced solubility in comparison with their crystalline counterparts. The reason

behind this theory is that with high internal energy, amorphous materials generally have

greater molecular motion and enhanced thermodynamic properties compared to the

crystalline state, which leads to higher solubility as well as dissolution rate. These

benefits however, come at a cost and can be lost easily since the high internal energy

and enhanced molecular mobility of amorphous materials are also responsible for their

higher chemical reactivity and a tendency to crystallization, which can happen during

manufacturing, storage or dissolution (Hancock & Parks 2000).

Amorphous forms can be prepared either by initially transforming the crystalline

material to a thermodynamically stable non-crystalline form (melt or solution), or by

direct solid conversion into an amorphous solid. Further, Stable amorphous

formulations can be obtained by solid dispersion techniques. Amorphous solid

dispersion is defined as a distribution of active ingredients in molecular and amorphous

forms surrounded by inert carriers. The amorphous solid dispersion formulations can

be prepared by spray drying, melt extrusion, lyophilization, and use of super critical

fluids with polymeric carriers and/or surfactant. Numerous studies have demonstrated

the marked enhancement of oral absorption by amorphous solid dispersion approaches.

1.2.2.2 Current strategies

Binary co-amorphous mixtures/ solid dispersions:

It has been known for a long time that addition of certain excipients, such as surfactants,

anti-plasticizers and other crystallization inhibitors can offer a significant improvement

in the physical stability of amorphous drugs. Recently, interest toward the potential of

binary amorphous systems, comprising of small molecules instead of polymers, has

increased. It has been reported that small molecules, such as citric acid, sugars, urea,

and nicotinamide can be used as carriers in solid dispersions.




21

Binary/ternary cyclodextrin complexation:

The formulation of poorly water-soluble drugs is one of the most challenging tasks to

the formulation experts. The aqueous solubility plays an important role in the

development of new chemical entities as successful drugs. An enhancement in the

solubility and the dissolution rate can improve the oral bioavailability of such drugs,

which further improves the therapeutic efficacy and patient compliance. Various

formulation methods were used to enhance the solubility of poorly soluble drugs.

Complex system of hydrophobic drug is one of the techniques to enhance the solubility

and dissolution rate of poorly soluble drug. In complex system binary and ternary

complex system are sub-categorized. Ternary complex system could be association or

inclusion ternary complex system. Cyclodextrin inclusion complex of hydrophobic

drug is one of the techniques to enhance the solubility and dissolution rate of poorly

soluble drug. Cyclodextrins and their derivatives (collectively, CDs) are also well

known for their solubility enhancing properties for lipophilic poorly soluble drugs.

Natural CDs are cyclic oligosaccharides containing at least 6 D (+) glucopyranose units

attached by α- (1–4) glucosidic bonds. These cyclic glucopyranose molecules form a

truncated cone with a lipophilic inner cavity and a hydrophilic outer surface. The

solubility enhancing properties of CDs can be described by a dynamic inclusion

mechanism by which lipophilic structures form a complex with the inner cavity of the

CDs. In addition, CDs can solubilise compounds by other noncomplex related

phenomena, for example, by means of drug–cyclodextrin aggregates (Loftsson &

Brewster 2012).

In comparison with the natural CDs, cyclodextrin derivatives are often substituted with

additional polar groups and thus show enhanced aqueous solubility, while still

providing the hydrophobic cavity which can interact with lipophilic compounds,

resulting in solubilisation. New CD derivatives, for example, sulfobuthyl- ether-b-CD

sodium (SBE-b-CD) and hydroxybutenyl-b-CD (HBen-b-CD) have been examined and

successfully utilised to enhance solubility and dissolution of BCS class II compounds

in different studies.

A ternary complex system consists of poorly water soluble drug, cyclodexrin derivative

and water soluble ternary component. Generally third component is added to modulate

the solubility of the binary system (cyclodextrin + drug) which show moderate water

solubility by virtue of their high molecular weight.




22

Figure 1.7 Ternary component

As such, CDs can interact with appropriately sized molecules to result in the formation

of inclusion complexes. Depending on the molecular capability (polarity, size and

three-dimensional structure) of the guest molecule to form a non-covalent complex,

CDs can either host the whole drug molecule or the non-polar part. In addition, CD

complexation is often accompanied by a variety of additional physicochemical

advantages for the drug-molecule, most notably the stability of the drug or taste

masking. One of the few disadvantages of the natural CDs has been their limited water

solubility (1.85 g/100 mL for β-CD). In order to act as a guest molecule in CDs, the

drug compound has to fulfill some requirements such as a linear molecular structure

and the ability to establish hydrophobic interactions with the CD molecule.

Hydrophobic interaction and Van der Wall’s forces are the important interactions for

the no-covalent complex formation.

Hot-melt extrusion

The hurdle of solubility enhancement for improvement in dissolution and

bioavailability of poorly soluble drugs can be overcome by various approaches such as

particle size reduction, cyclodextrin complexation, solubilization, co-solvency, solid

dispersion, salt formation, polymorphs, solvates or hydrates, pro-drugs and

microparticulate systems. Out of various solubility enhancement approaches, solid

dispersion is a technique where dispersion of hydrophobic drugs with

pharmacologically inert, polymeric ingredients leads to improved dissolution velocity.

Hot melt extrusion (HME) is a significant step forward to cover the technology related

issues and makes the solid molecular dispersion approach a viable option. HME is

considered as a potential approach for the development of drug delivery systems. It can

be employed for the synthesis of pharmaceutical drug delivery systems such as pellets,

granules, immediate and modified release tablets, oral fast dissolving systems,

transdermal, transmucosal, transungual delivery systems and implants.




23

1.2.2.3 Market status

A number of methods have been applied to enhance solubilization efficiency of drug

by using cyclodextrins. Some of them are listed in Table 1.2 (Loftsson & Brewster

2010).

Table 1.2 Cyclodextrin-containing pharmaceutical products

Drug Trade name Formulation Country

Cephalosporin (ME 1207) Meiact Tablet Japan

Chlordiazepoxide Transillium Tablet Argentina

Dexamethasone Glymesason Ointment Japan

Iodine Mena-Gargle Solution Japan

Nicotine Nicorette, Nicogum

Sublingual

tablet,Chewing

tablet

Europe

Nimesulide Nimedex Tablet Europe

Nitroglycerin Nitropen

Sublingual

tablet,Chewing

tablet

Japan

Omeprazol Omebeta Tablet Europe

There are various solid dispersion systems as pharmaceutical products on the market

utilizing HME for solubility enhacement utilizing amorphization of drug, some of them

are shown in Table 1.3. A classic example for a marketed ME pharmaceutical product

is Meltrex Kaletra® tablets, which was developed by SOLIQSTM(Germany) to improve

patient compliance and hence their adherence to the highly active anti-retroviral

therapy.

Table 1.3 Currently marketed and developed drug products produced utilizing

hot melt extrusion technology

Product Indication HME purpose Company

Norvir® (Ritonavir) Anti-viral (HIV) Amorphous

dispersion

Abbott

Laboratories

Kaletra®

(Ritonavir/Lopinavir) Anti-viral (HIV)

Amorphous

dispersion

Abbott

Laboratories

Anacetrapib (Under

development) Atherosclerosis

Amorphous

dispersion Merck

Posaconazole (Under

development) Development)

Amorphous

dispersion Merck




24


What is currently known, is that molecular interactions play an important role in both

co-amorphous and mesoporous silica-based systems. However proving and even more

so, predicting the existence of these interactions in multi component amorphous

systems, can be challenging. Little is known about the molecular arrangement of these

systems and vibrational spectroscopy is usually used to gain information on molecular

interactions such as hydrogen bonding interactions. However, the experimental spectra

of even single amorphous substances can be difficult to analyse because changes in the

vibrational modes due to solid state changes or molecular interactions might only be

minor or get lost in the complexity of the spectra. This becomes even more complicated

in amorphous mixtures.

In this regard, computational methods could provide a clearer insight, helping to

support and interpret experimentally obtained vibrational spectra. Using quantum

mechanical calculations to predict vibrational spectra for various possible molecular

interactions could be used and may provide insight in to changes in experimental

spectra.

1.2.3 Nanoemulsification:

1.2.3.1 Basics:

Colloidal delivery systems are widely used in the food and pharmaceutical industries

to encapsulate functional lipophilic components so that they can be dispersed within

aqueous media. The lipophilic components encapsulated include a variety of different

kinds of molecules with different functional attributes, such as triacylglycerols

(clouding agents, carrier oils, nutrients, and bioactive lipids), citrus oils (flavoring

agents), essential oils (antimicrobials), phytosterols (nutraceuticals), carotenoids

(colorants, antioxidants, and nutraceuticals), oil-soluble vitamins (essential nutrients)

and lipophilic drugs. These lipophilic components vary in their molecular and

physicochemical properties, such as polarities, surface activities, densities, viscosities,

melting points, and boiling points. Consequently, different colloidal delivery systems

are often needed for different kinds of lipophilic components and for different types of

food or pharmaceutical matrices (Shah et al. 2010; Qian & McClements 2011).

Three of the most widely used colloidal delivery systems consist of small lipid particles

dispersed within an aqueous phase: microemulsions; nanoemulsions; and, emulsions.




25

The main differences between these three colloidal systems are their thermodynamic

stability and particle dimensions. Microemulsions are thermodynamically stable

dispersions of oil, water and surfactant (and possibly cosurfactants) that typically

contain lipid particles with radii less than 100 nm. Nanoemulsions (r < 100 nm) and

emulsions (r > 100 nm) are both thermodynamically unstable dispersions that can be

distinguished according to their droplet size. There are certain advantages and

disadvantages to the commercial utilization of each of these colloidal delivery systems.

Microemulsions and nanoemulsions contain small particles that only scatter light

weakly and so they tend to be optically clear or only slightly turbid.

The formation of nanoemulsions using low-energy approaches relies on the

spontaneous formation of fine oil droplets within surfactant-oil-water (SOW) mixtures

when their composition and/or environment are altered. Various physicochemical

mechanism depending on system composition and preparation method. A number of

low energy approaches used to prepare oil-in-water nanoemulsions rely on inducing a

phase inversion from a W/O to a O/W system, e.g., phase inversion temperature (PIT),

phase inversion composition (PIC), and emulsion inversion point (EPI) methods. These

approaches can be further categorized according to their underlying physicochemical

principle as either transitional or catastrophic phase inversion methods.

Nanoemulsions are also referred to as miniemulsions, ultrafine emulsions and

submicron emulsions. Phase behavior studies have shown that the size of the droplets

is governed by the surfactant phase structure (bicontinuous microemulsion or lamellar)

at the inversion point induced by either temperature or composition (Lovelyn & Attama

2011).

The capacity of nanoemulsions to dissolve large quantities of hydrophobics, along with

their mutual compatibility and ability to protect the drugs from hydrolysis and

enzymatic degradation make them ideal vehicles for the purpose of parenteral transport.

Further, the frequency and dosage of injections can be reduced throughout the drug

therapy period as these emulsions guarantee the release of drugs in a sustained and

controlled mode over long periods of time. Additionally, the lack of flocculation,

sedimentation and creaming, combined with a large surface area and free energy, offer

obvious advantages over emulsions of larger particle size, for this route of

administration. Their very large interfacial area positively influences the drug transport

and their delivery, along with targeting them to specific sites (Lovelyn & Attama 2011).




26

Reducing droplet sizes to the nanoscale leads to some very interesting physical

properties, such as optical transparency and unusual elastic behaviour. In the world of

nanomaterials, nanoemulsions hold great promise as useful dispersions of deformable

nano scale droplets that can have flow properties ranging from liquid to highly solid

and optical properties ranging from opaque to nearly transparent. Moreover, it is very

likely that nanoemulsions will play an increasingly important role commercially, since

they can typically be formulated using significantly less surfactant than is required for

nano structured lyotropic microemulsion phases. Nanoemulsions are part of a broad

class of multiphase colloidal dispersions. Although some lyotropic liquid crystalline

phases, also known as “micellar phases”, “mesophases”, and “microemulsions”, may

appear to be similar to nanoemulsions in composition and nanoscale structure, such

phases are actually quite different. Lyotropic liquid crystals are equilibrium structures

comprised of liquids and surfactant, such as lamellar sheets, hexagon- ally packed

columns, and wormlike micellar phases, that form spontaneously through

thermodynamic self-assembly. By contrast, nanoemulsions do not form spontaneously;

an external shear must be applied to rupture larger droplets into smaller ones. Compared

to microemulsion phases, relatively little is known about creating and con- trolling

nanoemulsions. This is primarily because extreme shear, well beyond the reach of

ordinary mixing devices, must be applied to overcome the effects of surface tension

to rupture the droplets into the nanoscale regime (Mason et al. 2006).

1.2.3.2 Current strategies:

Nanoemulsions are non-equilibrium systems of structured liquids, and so their

preparation involves the input of a large amount of either energy or surfactants and in

some cases a combination of both. As a result, high energy or low energy methods can

be used in their formulation. The high-energy method utilizes mechanical devices to

create intensely disruptive forces which break up the oil and water phases to form nano-

sized droplets. This can be achieved with ultrasonicators, microfluidiser and high

pressure homogenisers. Particle size here will depend on the type of instruments

employed and their operating conditions like time and temperature along with sample

properties and composition. This method allows for a greater control of particle size

and a large choice of composition, which in turn controls the stability, rheology and

colour of the emulsion. Although high-energy emulsification methods yield

nanoemulsions with desired properties and have industrial scalability, they may not be




27

suitable for thermolabile drugs such as retinoids and macromolecules, including

proteins, enzymes and nucleic acids (Lovelyn & Attama 2011).

Nanoemulsion can be prepared by a low-energy emulsification method, which has been

recently developed according to the phase behavior and properties of the constituents,

to promote the formation of ultra-small droplets. These low-energy techniques include

self- emulsification, phase transition and phase inversion temperature methods. The low

energy method is interesting because it utilizes the stored energy of the system to form

small droplets. This emulsification can be brought about by changing the parameters

which would affect the hydrophilic lipophilic balance (HLB) of the system like

temperature, composition, etc. (Wang et al. 2007).

Energy is usually required in emulsion formulation because the process may be non-

spontaneous. The production of nanoemulsions costs more energy than that required to

produce macroemulsions. Presence of surfactants help lower the surface tensions

between oil and water. Small molecules such as non-ionic surfactants lower surface

tension more than polymeric surfactants such as poly (vinyl alcohol). Another

important role of the surfactant is its effect on the interfacial dilatational modulus.

During emulsification an increase in the interfacial area takes place and this causes a

reduction in surface excess. The equilibrium is restored by adsorption of surfactant from

the bulk, but this takes time (shorter times occur at higher surfactant activity). Because

of the lack or slowness of equilibrium with polymeric surfactants, dilatational modulus

will not be the same for expansion and compression of the interface. In practice,

surfactant mixtures are used and these have pronounced effects on surface tension and

dilatational modulus. Some specific surfactant mixtures give lower surface tension

values than either of the two individual components. Polymer-surfactant mixtures may

show some synergistic surface activity (Tadros et al. 2004).

Another important role of the emulsifier is to prevent shear-induced coalescence during

emulsification. The requirement is that the continuous phase has a significant excess of

surfactant. This excess enables new surface area of the nanoscale droplets to be rapidly

coated during emulsification, thereby inhibiting shear-induced coalescence. This excess

is generally in the form of surfactant micelles in the continuous phase. These micelles

dissociate into monomers that rapidly adsorb onto the surfaces of newly created

droplets (Mason et al. 2006).




28

Microfluidization

Microfluidization is a patented mixing technology, which makes use of a device called

microfluidizer. This device uses a high-pressure positive displacement pump (500 -

20,000 psi), which forces the product through the interaction chamber, consisting of

small channels called “microchannels”. The product flows through the microchannels

on to an impingement area resulting in very fine particles of submicron range. The two

solutions (aqueous phase and oily phase) are combined together and processed in an

inline homogenizer to yield a coarse emulsion. The coarse emulsion is introduced into

a microfluidizer where it is further processed to obtain a stable nanoemulsion. The

coarse emulsion is passed through the interaction chamber of the microfluidizer

repeatedly until the desired particle size is obtained. The bulk emulsion is then filtered

through a filter under nitrogen to remove large droplets resulting in a uniform

nanoemulsion. Highpressure homogenization and microfluidization can be used for

fabrication of nanoemulsions at laboratory and industrial scale, whereas ultrasonic

emulsification is mainly used at laboratory scale (Shah et al. 2010).

Phase Inversion Temperature Technique

Studies on nanoemulsion formulation by the phase inversion temperature method have

shown a relationship between minimum droplet size and complete solubilization of the

oil in a microemulsion bicontinuous phase independently of whether the initial phase

equilibrium is single or multiphase. Due to their small droplet size nanoemulsions

possess stability against sedimentation or creaming with Ostwald ripening forming the

main mechanism of nanoemulsion breakdown. Phase inversion in emulsions can be one

of two types: transitional inversion induced by changing factors which affect the HLB

of the system, e.g. temperature and/or electrolyte concentration, and catastrophic

inversion, which can also be induced by changing the HLB number of the surfactant at

constant temperature using surfactant mixtures (Tadros et al. 2004).

Phase inversion temperature (PIT) method employs temperature-dependent solubility

of nonionic surfactants, such as polyethoxylated surfactants, to modify their affinities

for water and oil as a function of the temperature. It has been observed that

polyethoxylated surfactants tend to become lipophilic on heating owing to dehydration

of polyoxyethylene groups. This phenomenon forms a basis of nanoemulsion

fabrication using the PIT method. In the PIT method, oil, water and nonionic surfactants




29

are mixed together at room temperature. This mixture typically comprises o/w

microemulsions coexisting with excess oil and the surfactant monolayer exhibits

positive curvature. When this macroemulsion is heated gradually, the polyethoxylated

surfactant becomes lipophilic and at higher temperatures, the surfactant gets completely

solubilized in the oily phase and the initial o/w emulsion undergoes phase inversion to

w/o emulsion. The surfactant monolayer has negative curvature at this stage. This

method involves heating of the components and it may be difficult to incorporate

thermolabile drugs, such as tretinoin and peptides, without affecting their stability.

Although it may be possible to reduce the PIT of the dispersion using a mixture of

components (surfactants) with suitable characteristics, in order to minimize degradation

of thermolabile drugs (Solans et al. 2005).

Solvent Displacement Method

The solvent displacement method for spontaneous fabrication of nanoemulsion has

been adopted from the nanoprecipitation method used for polymeric nanoparticles. In

this method, oily phase is dissolved in water-miscible organic solvents, such as acetone,

ethanol and ethyl methyl ketone. The organic phase is poured into an aqueous phase

containing surfactant to yield spontaneous nanoemulsion by rapid diffusion of organic

solvent. The organic solvent is removed from the nanoemulsion by a suitable means,

such as vacuum evaporation. Spontaneous nanoemulsification has also been reported

when solution of organic solvents containing a small percentage of oil is poured into

aqueous phase without any surfactant.

Solvent displacement methods can yield nanoemulsions at room temperature and

require simple stirring for the fabrication. Hence, researchers in pharmaceutical

sciences are employing this technique for fabricating nanoemulsions mainly for

parenteral use. However, the major drawback of this method is the use of organic sol-

vents, such as acetone, which require additional inputs for their removal from

nanoemulsion. Furthermore, a high ratio of solvent to oil is required to obtain a

nanoemulsion with a desirable droplet size. This may be a limiting factor in certain

cases. In addition, the process of solvent removal may appear simple at laboratory scale

but can pose several difficulties during scale-up (Date et al. 2010).

Phase Inversion Composition Method (Self-Nanoemulsification Method)

This method has drawn a great deal of attention from scientists in various fields

(including pharmaceutical sciences) as it generates nanoemulsions at room temperature




30

without use of any organic solvent and heat. Kinetically stable nanoemulsions with

small droplet size (~50 nm) can be generated by the stepwise addition of water into

solution of surfactant in oil, with gentle stir-ring and at constant temperature. The

spontaneous nanoemulsification has been related to the phase transitions during the

emulsification process and involves lamellar liquid crystalline phases or D-type

bicontinuous microemulsion during the process. Nanoemulsions obtained from the

spontaneous nanoemulsification process are not thermodynamically stable, although

they might have high kinetic energy and long-term colloidal stability (Date et al. 2010).

1.2.3.3 Market Status:

In spite of some difficulties, certain nanoemulsion formulations have been translated

into commercial products, available in the market for use. Some commercial

nanoemulsion formulations are listed in Table1.4.

Table 1.4 Commercial nanoemulsion formulations

Drug /Bioactive Brand Name Manufacturer Indication

Palmitate alprostadil Liple Mitsubishi

Pharmaceutical,

Japan

Vasodilator,

platelet inhibitor

Dexamethason Limethason Mitsubishi

Pharmaceutical,

Japan

Steroid

Propofol Diprivan Astra Zaneca Anaesthetic

Flurbiprofenaxtil Ropion Kaken

Pharmaceutical,

Japan

NSAID

Vitamins A, D, E and K Vitalipid Fresenius Kabi

Europe

Parenteral

nutrition


Nanoemulsion since its emergence has proved to be versatile and useful novel drug

delivery system. Nanoemulsions are proposed for numerous applications in pharmacy

as drug delivery systems because of their capacity of solubilizing non-polar active




31

compounds. Future perspectives of nanoemulsion are very promising in different fields

of therapeutics or application in development of cosmetics for hair or skin. One of the

versatile applications of nanoemulsions is in the area of drug delivery where they act

as efficient carriers for bioactives, facilitating administration by various routes. Their

parenteral delivery has been adopted for supplying nutritional requirements, controlled

drug release, vaccine delivery and for drug targeting to specific sites. The advantages

and applications of oral drug delivery through these vehicles are numerous where the

droplet size is related to their absorption in the gastrointestinal tract. Nanoemulsions

have also been studied for their use in ocular delivery where pharmacological drugs are

more sustained compared to their respective solutions. Pulmonary and transdermal

routes are other successful ways of administering nanoemulsified delivery system.

Although there have not been many reports of nanoemulsion applications in other

fields, there is a great potential for nanoemulsion applications in other areas, such as in

chemical and physical sciences, agriculture and engineering.

In the production of nanoemulsions there are some limitations, but pharmaceutical and

food industries have to adjust their technologies to accommodate nanoemulsion

production. Considering the versatile platforms nanoemulsions offer to formulation

scientists in many fields, retooling of production facilities or outright change in

technology of industries originally involved in production of parenteral and macro

emulsions will lead to a lot economic windfall on the long run. This is because the effect

of difficulty in preparation and the high energy input that may be involved in the

production of nanoemulsion may just be felt on the short run. In as much as the cost of

acquiring the technology for nanoemulsion production may be high, the production of

nanoemulsions involves only a few steps, compensating the many steps involved in the

production of some other products of lower versatility. Due to the renewed interest in

herbal drug formulation, nanoemulsion may be the ideal delivery platform for these

difficult-to-formulate phytopharmaceuticals. Novel nanoemulsion dosage forms of

herbal drugs will lead to higher remuneration for the pharmaceutical industries.

With the advent of new instruments for high pressure homogenization and the

competition between various manufacturers, the cost of production of nanoemulsions

will decrease. Fundamental research in investigation of the role of surfactants in

nanoemulsion production process will lead to optimized emulsifier systems and more

economic use of surfactants will emerge. Nanoemulsions can be manipulated for




32

targeted delivery and this hold significant promise in the area of oncology for the

treatment of tumors and drug delivery to the brain.

1.1 origin of concept: particle engineering -...

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