10.innovation in Oral Liquids

SEMINAR ON
RECENT INNOVATIONS IN
LIQUIDS
PRESENTED BY:
JIGNASHA R. BHURIA
M.PHARM SEM-II
ROLL NO - 005
YEAR:-2010
DEPARTMENT OF PHARMACEUTICS &

PHARMACEUTICAL TECHNOLOGY LMCP. A’BAD -
09.
Classification of liquids:-
L.M. College of Pharmacy Ahmedabad-‘09(2010) Page

DOUCHES
ENEMAS
EYE DROPS
EYE LOTIONS
NASAL DROPS
INHALANTS
RECENT INNOVATION IN SUSPENSION
Nanosuspensions in drug delivery

 More than 40 per cent of the drugs coming from high-throughput screening are poorly
soluble in water. Obviously poorly water-soluble drugs show many problems in
formulating them in conventional dosage forms. One of the critical problems associated
with poorly soluble drugs is too low bioavailability and or erratic absorption.
 The problem is even more complex for drugs such as itraconazole and carbamazepine
(belonging to BCS Class II) as classified by BCS System as they are poorly soluble in
both aqueous and organic media, and for those drugs having a log P value of 2. The
performance of these drugs is dissolution rate-limited (for Class II and III drugs) and is
affected by the fed/fasted state of the patient. Dissolution rates of sparingly soluble
drugs are related to the shape as well as the particle size. Therefore decrease in particle
size results in an increase in dissolution rate.
 There are number of formulation approaches to resolve the problems of low solubility
and low bioavailability. The approaches include micronization, solublization using co-
solvents, use of permeation enhancers, oily solutions, surfactant dispersions, salt
formation and precipitation techniques.
 Other techniques like liposomes, emulsions, microemulsions, solid-dispersions and
inclusion complexes using Cyclodextrins show reasonable success but they lack in
universal applicability to all drugs. These techniques are not applicable to the drugs,
which are not soluble in both aqueous and organic medias. Hence there is need of some
different and simple approach to tackle the formulation problems to improve their
efficacy and to optimize the therapy with respect to pharmacoeconomics.
 Nanotechnology can be used to resolve the problems associated with these

conventional approaches for solubility and bioavailability enhancement. Nanotechnology
is defined as the science and engineering carried out in the nanoscale that is 10-9
meters. The drug microparticles/micronized drug powder is transferred to drug
nanoparticles by techniques like Bottom Up Technology (precipitation) and Top Down

Technologyor disintegration methods. Nano is a Greek word, which means 'dwarf'. Nano
means it is the factor of 10-9 or one billionth.
Methods of preparation
 Mainly there are two methods for preparation of nanosuspensions. The conventional
methods of precipitation (Hydrosols25) are called ‘Bottom Up technology’. In Bottom Up
Technology the drug is dissolved in a solvent, which is then added to non-solvent to
precipitate the crystals. The basic advantage of precipitation technique is the use of
simple and low cost equipments. The basic challenge of this technique is that during the
precipitation procedure the growing of the drug crystals needs to be controlled by
addition of surfactant to avoid formation of microparticles. The limitation of this
precipitation technique is that the drug needs to be soluble in atleast one solvent and
this solvent needs to be miscible with nonsolvent. Moreover precipitation technique is
not applicable to drugs, which are simultaneously poorly soluble in aqueous and
nonaqueous media.
 The ‘Top Down Technologies’ are the disintegration methods and are preferred over the
precipitation methods. The ‘Top Down Technologies’ include Media Milling
(Nanocrystals), High Pressure Homogenization in water (Dissocubes), High Pressure
Homogenization in nonaqueous media (Nanopure) and combination of Precipitation and
High-Pressure Homogenization (Nanoedege). Few other techniques used for preparing
nanosuspensions are emulsion as templates, microemulsion as templates etc
A) Media Milling (Nanocrystals or Nanosystems)
 The method is first developed and reported by Liversidge et.al. (1992) The
nanosuspensions are prepared by using high-shear media mills. The milling chamber
charged with milling media, water, drug and stabilizer is rotated at a very high shear rate
under controlled temperatures for several days (at least 2-7 days). The milling medium is
composed of glass, Zirconium oxide or highly cross-linked polystyrene resin. The high
energy shear forces are generated as a result of the impaction of the milling media with
the drug resulting into breaking of microparticulate drug to nanosized particles.
Advantages
1. Media milling is applicable to the drugs that are poorly soluble in both aqueous and organic
media.
2. Very dilute as well as highly concentrated nanosuspensions can be prepared by handling

1mg/ml to 400mg/ml drug quantity.
3. Nanosize distribution of final nanosize products.
Disadvantages

1. Nanosuspensions contaminated with materials eroded from balls may be problematic when it
is used for long therapy.
2. The media milling technique is time consuming.
3. Some fractions of particles are in the micrometer range.
4. Scale up is not easy due to mill size and weight.
B) Homogenization In Water (Dissocubes)
 R.H.Muller developed Dissocubes technology in 1999. The instrument can be operated

at pressure varying from 100 – 1500 bars (2800 –21300psi) and up to 2000 bars with
volume capacity of 40ml (for laboratory scale). For preparation of nano suspension, we
have to start with the micronized drug particle size less than 25µm to prevent blocking of
homogenization gap hence it is essential to prepare a presuspension of the micronized
drug in a surfactant solution using high speed stirrer.
Principle
In piston gap homogeniser particle size reduction is based on the cavitation principle. Particles
are also reduced due to high shear forces and the collision of the particles against each other.
The dispersion contained in 3cm diameter cylinder; suddenly passes through a very narrow gap
of 25µm. According to Bernoulli’s Law the flow volume of liquid in a closed system per cross
section is constant. The reduction in diameter from 3cm to 25µm leads to increase in dynamic
pressure and decrease of static pressure below the boiling point of water at room temperature.
Due to this water starts boiling at room temperature and forms gas bubbles, which implode
when the suspension leaves the gap (called cavitation) and normal air pressure is reached. The
size of the drug nanocrystals that can be achieved mainly depends on factors like temperature,
number of homogenization cycles, and power density of homogeniser and homogenization
pressure.
Advantages
1. It does not cause the erosion of processed materials.
2. Very dilute as well as highly concentrated nanosuspensions can be prepared by handling

1mg/ml to 400mg/ml drug quantity.
3. It is applicable to the drugs that are poorly soluble in both aqueous and organic media.
4. It allows aseptic production of nanosuspensions for parentral administration.
Disadvantages
1. Preprocessing like micronization of drug is required.
2. High cost instruments are required that increases the cost of dosage form.

C) Homogenisation In Nonaqueous Media (Nanopure)
 The drugs that are chemically labile can be processed in such nonaqueous media or
water-miscible liquids like polyethyleneglycol-400 (PEG), PEG1000 etc. The
homogenization can be done at room temperature, 0o C and below freezing point (-20o
C).
D) Combined Precipitation And Homogenization (Nanoedege)
 The precipitated drug nanoparticles have tendency to continue crystal growth to the size
of microcrystals. They need to be processed with high-energy forces (Homogenisation).
The are in completely amorphous, partially amorphous or completely crystalline which
create problems in long term stability as well as in bioavailability, so the precipitated
particle suspension is subsequently homogenized which preserve the particle size
obtained after the precipitation step.
E) Emulsification-solvent evaporation technique
 This technique involves preparing a solution of drug followed by its emulsification in

another liquid that is a non-solvent for the drug. Evaporation of the solvent leads to
precipitation of the drug. Crystal growth and particle aggregation can be controlled by
creating high shear forces using a high-speed stirrer.
Hydrosol method
This is similar to the emulsification- solvent evaporation method. The only difference
between the two methods is that the drug solvent is miscible with the drug anti-solvent.
Higher shear force prevents crystal growth and Ostwald ripening and ensures that the
precipitates remain smaller in size.
Characterization of nanosuspensions
The various essential parameters to be characterized for nanosusepnsions includes:
■Size and size distribution
■Particle charge (zeta potential)
■Crystalline status
■Dissolution velocity and saturation solubility.
For surface-modified nanosuspensions, a number of additional parameters have to be

investigated to obtain a complete picture, especially with relevance for the in-vivo
behavior:
■Adhesion properties (in case of mucoadhesive particles)
■Surface hydrophilicity/hydrophobicity
■Interaction with body proteins.

Nanosuspension technology applications
Nanosuspensions can play a critical role as an enabling technology for poorly water-
soluble and/or poorly permeable molecules having significant in vitro activity. Such
molecules pose problems at any or both of the following during new drug development
activities:
■Formulation of an intravenously injectable product for preclinical in vivo evaluation of
the new molecule to measure its toxicity and other pharmacokinetic characteristics.
■Poor absorption of the drug candidate from the GIT resulting into poor bioavailability
during preclinical as well as clinical development studies.
Pure drug nanosuspensions can provide solutions to both of these problems. A pure
drug nanosuspension contains pure drug particles suspended in an aqueous media. As
the particle size (usually below 400 nm) is way below the minimum particle size that can
be administered intravenously (ie, 5 µm), a nanosuspension can be administered
intravenously to conduct exploratory study with the candidate drug molecules.
Nanosuspension helps in administration of huge drug concentration of poorly water-
soluble drugs to brain with decreased systemic effects. Thus nanosuspension has
application to various route of administration like parenteral, oral topical, pulmonary and
targeted drug delivery system.
Evaluation of nanosuspensions:–
A) In-Vitro Evaluations
1. Particle size and size distribution
2. Particle charge (Zeta Potential)
3. Crystalline state and morphology
4. Saturation solubility and dissolution velocity
B) In-Vivo Evaluation
C) Evaluation for surface-modified Nanosuspensions
1.Surface hydrophilicity
2. Adhesion properties
3. Interaction with body proteins
1) Mean particle size and size distribution
The mean particle size and the width of particle size distribution (called Polydidpersity Index)
are determined by Photon Correlation Spectroscopy (PCS). Particle size and polydispersity
index (PI) governs the saturation solubility; dissolution velocity and biological performance. It is
proved that change in particle size changes saturation solubility and dissolution velocity. PCS

measures the particle size in the range of 3nm- 3 µm only. PI governs the physical stability of
nanosuspension and should be as low as possible for long-term stability. (Should be close to
zero). PCS is a versatile technique but has low measuring range. In addition to PCS analysis
nanosuspensions are analyzed by Laser Diffractometry (LD). LD measures volume size
distribution and measures particles ranging from 0.05- 80μm upto 2000µm. Atomic Force
Microscopy is used for visualization of particle shape.
2) Particle charge (Zeta Potential)
article charge determines the stability of nanosuspension. For electrostatically stabilized

nanosuspension a minimum zeta potential of ±30mV and for combined steric and electrostatic
stabilization it should be a minimum of ±20mV.
3) Crystalline state and particle morphology
Differential Scanning Calorimetry(DSC) determines the crystalline structure. When

nanosuspensions are prepared drug particles get converted to amorphous form hence it is
essential to measure the extent of amorphous drug generated during the production of
nanosuspensions. The X-Ray Diffraction (XRD) is also used for determining change in physical
state and extent of amorphous drug.
4) Saturation solubility and dissolution velocity
The nanosuspension increase the saturation solubility as well as dissolution velocity. Saturation
solubility is compound specific constant depending upon temperature and the properties of
dissolution medium. Kelvin equation and the Ostwald-Freundlich equations can explain increase
in saturation solubility.
Conclusion
Drugs with poor solubility and low bioavailability are called 'brick dust' candidates once
abandoned from formulation development work can be overcome by using novel
approach called nanosuspensions technology. The transformation of any drug to drug
nanoparticles leading to an increase in saturation solubility, dissolution velocity, and
providing the general feature of an increased adhesiveness to surfaces is one of the
most important achievement. A fusion of the novel nanosuspension technology with the
traditional dosage forms, e.g. incorporating drug nanoparticles into pellets or tablets for
oral delivery is also a note worthy advantage.
RECENT INNOVATION IN EMULSIONS
Microemulsions in drug delivery

 Microemulsions are clear, stable, isotropic liquid mixtures of oil, water and surfactant,
frequently in combination with a cosurfactant. The aqueous phase may contain salt(s)
and/or other ingredients, and the "oil" may actually be a complex mixture of different
hydrocarbons and olefins. In contrast to ordinary emulsions, microemulsions form upon
simple mixing of the components and do not require the high shear conditions generally
used in the formation of ordinary emulsions. The two basic types of microemulsions are
direct (oil dispersed in water, o/w) and reversed (water dispersed in oil, w/o).
 In ternary systems such as microemulsions, where two immiscible phases (water and
‘oil’) are present with a surfactant, the surfactant molecules may form a monolayer at the
interface between the oil and water, with the hydrophobic tails of the surfactant
molecules dissolved in the oil phase and the hydrophilic head groups in the aqueous
phase. As in the binary systems (water/surfactant or oil/surfactant), self-assembled
structures of different types can be formed, ranging, for example, from (inverted)
spherical and cylindrical micelles to lamellar phases and bicontinuous microemulsions,
which may coexist with predominantly oil or aqueous phases.
Uses
 Microemulsions have many commercially important uses. The fluid used in some dry
cleaning processes is a water-in-oil microemulsion. Some floor polishes and cleaners,
personal care products, pesticide formulations, and cutting oils are actually
microemulsions. Much of the work done on these systems have been motivated by their
possible use to mobilize petroleum trapped in porous sandstone for enhanced oil
recovery.
 A fundamental reason for the uses of these systems is that a microemulsion phase
sometimes has an ultralow interfacial tension with a separate oil or aqueous phase,
which may release or mobilize them from solid phases even in conditions of slow flow or
low pressure gradients.
Phase Diagrams
 The microemulsion region is usually characterized by constructing ternary-phase

diagrams.Three components are the basic requirement to form a microemulsion: an oil
phase, an aqueous phase and a surfactant. If a cosurfactant is used, it may sometimes
be represented at a fixed ratio to surfactant as a single component, and treated as a
single "pseudo-component". The relative amounts of these three components can be
represented in a ternary phase diagram. Gibbs phase diagrams can be used to show the

influence of changes in the volume fractions of the different phases on the phase
behavior of the system.
A typical phase diagram. The dotted line gives the anomalous behavior of water. The green lines
mark the freezing point and the blue line the boiling point, showing how they vary with pressure.
 The three components composing the system are each found at an apex of the triangle,
where their corresponding volume fraction is 100%. Moving away from that corner
reduces the volume fraction of that specific component and increases the volume
fraction of one or both of the two other components. Each point within the triangle
represents a possible composition of a mixture of the three components or pseudo-
components, which may consist (ideally, according to the Gibbs' phase rule) of one, two
or three phases. These points combine to form regions with boundaries between them,
which represent the "phase behavior" of the system at constant temperature and
pressure.
 The Gibbs phase diagram, however, is an empirical visual observation of the state of the
system and may, or may not express the true number of phases within a given
composition. Apparently clear single phase formulations can still consist of multiple iso-
tropic phases (e.g. the apparently clear heptane/AOT/water microemulsions consist
multiple phases). Since these systems can be in equilibrium with other phases, many
systems, especially those with high volume fractions of both the two imiscible phases,
can be easily destabilised by anything that changes this equilibrium e.g. high or low
temperature or addition of surface tension modifying agents.

 However, examples of relatively stable microemulsions can be found. It is believed that
the mechanism for removing acid build up in car engine oils involves low water phase
volume, water-in-oil (w/o) microemulsions. Theoretically, transport of the aqueous acid
droplets through the engine oil to microdispersed calcium carbonate particles in the oil
should be most efficient when the droplets are small enough to transport a single
hydrogen ion (the smaller the droplets, the greater the number of droplets, the faster the
neutralisation). Such microemulsions are probably very stable across a reasonably wide
range of elevated temperatures.
1) Design and Development of Microemulsion Drug Delivery System

of Acyclovir for Improvement of Oral Bioavailability
 The main purpose of this work was to develop an oral microemulsion formulation for
enhancing the bioavailability of acyclovir.
 A Labrafac-based microemulsion formulation with Labrasol as surfactant and Plurol
Oleique as cosurfactant was developed for oral delivery of acyclovir.
 Phase behavior and solubilization capacity of the microemulsion system were
characterized, and in vivo oral absorption of acyclovir from the microemulsion was
investigated in rats.
 A single isotropic region, which was considered to be a bicontinuous microemulsion, was
found in the pseudoternary phase diagrams developed at various Labrasol:Plurol
Oleique:Labrafac ratios. With the increase of Labrasol concentration, the microemulsion
region area and the amount of water and Labrafac solubilized into the microemulsion
system increased; however, the increase of Plurol Oleique percentage produced
opposite effects.
 The microemulsion system was also investigated in terms of other characteristics, such
as interfacial tension, viscosity, pH, refractive index, diffusion, and bioavailability.
 Acyclovir, a poorly soluble drug, displayed high solubility in a microemulsion formulation
using Labrafac (10%), Labrasol (32%), Plurol Oleique (8%), and water (50%).
 The in vitro intraduodenal diffusion and in vivo study revealed an increase of
bioavailability (12.78 times) after oral administration of the microemulsion formulation as
compared with the commercially available tablets.
Materials and Methods
Labrasol (caprylocaproyl macrogol-8-glycerides), Plurol Oleique (polyglyceryl-6-dioleate), and

Labrafac (medium-chain triglyceride, C8-C10 fatty acids),Double-distilled water was used
throughout the study.
Preparation of Microemulsion Formulation

Liquid microemulsions were prepared by dissolving Labrasol in Plurol Oleique. Acyclovir and
Labrafac were then dissolved, followed by gentle mixing with distilled water. The monophasic
formulations were formed spontaneously at room temperature. The final concentration of
acyclovir in the microemulsions was 5%.
Construction of Phase Diagrams
Pseudoternary phase diagrams were constructed to examine the formation of oil in water
microemulsions using 4 components: oil, surfactant, cosurfactant, and aqueous phase system.
Pseudoternary phase diagrams were constructed keeping the ratio of Labrasol and Plurol
Oleique constant and varying the remaining 2 components. For convenience, the phase
diagrams were constructed by drawing “water dilution lines” representing increasing water
content and decreasing surfactant-cosurfactant levels. The water was titrated along dilution
lines drawn from the surfactant-cosurfactant apex (100% surfactant-cosurfactant) to the
opposite oil side of the triangle. The line was arbitrarily denoted as the value of the line
intersection with the oil scale (eg, 20:80, 30:70). If turbidity appeared followed by a phase
separation, the samples were considered to be biphasic. If clear and transparent mixtures were
visualized after stirring, the samples were considered monophasic. The samples were marked
as points in the phase diagram. The area covered by these points was considered to be the
microemulsion region of existence.
Results and Discussion
Phase Diagram Study
A pseudoternary phase diagram of the investigated quaternary system water/Labrasol/Plurol

Oleique/Labrafac is presented in Figure 1. Formation of microemulsion systems (the shaded
area) was observed at room temperature. Phase behavior investigations of this system
demonstrated the suitable approach to determining the water phase, oil phase, surfactant
concentration, and cosurfactant concentration with which the transparent, 1-phase low-viscous
microemulsion system was formed.

Figure 1. Pseudoternary phase diagram of Labrasol, Plurol Oleique, Labrafac, and water. (a)
Km = 3, (b) Km = 4. Km indicates surfactant to cosurfactant ratio; STMix indicates surfactant +
cosurfactant.
The phase study revealed that the maximum proportion of oil was incorporated in
microemulsion systems when the surfactant-to-cosurfactant ratio (km) was 4:1. From a
formulation viewpoint, the increased oil content in microemulsions may provide a greater
opportunity for the solubilization of acyclovir. Moreover, when the composition (% wt/wt) of
surfactant mixture (Smix) in a microemulsion preparation was <40%, the formulation was less
viscous. The optimum formulation of microemulsion contained Labrafac (10%), Labrasol (32%),
Plurol Oleique (8%), and water (50%).
In Vitro Intestinal Permeability Study
In vitro intestinal permeability data are shown in Figure 2. The drug diffused at a faster rate from
the microemulsion system than from the tablet dosage form. The total percentage diffusion was
much higher for the microemulsion system than for the tablet dosage form. After 5 hours of
diffusion, 85% of the drug was diffused from the microemulsion system, as compared with 69%
diffused from the tablets.

Figure 2. Comparative in vitro diffusion profile of acyclovir through rat duodenum (–♦–) for
microemulsion (ME) and (–■–) for tablet.

Figure 3. Comparative plasma concentration of acyclovir after oral administration of (–♦–) ME
and (–■–) tablet. ME indicates microemulsion.
Figure 4. Plasma concentration of acyclovir after intravenous administration.
Conclusion
The study demonstrates that the microemulsion formulation can be employed to improve the
bioavailability of a poorly absorbed drug. The ratio of Labrasol:Plurol Oleique:Labrafac played a
major role in formulating the microemulsion. The optimum microemulsion formulation contained
Labrafac (10%), Labrasol (32%), Plurol Oleique (8%), and water (50%), which was a
transparent and less viscous system. After oral administration in rats, the microemulsion
showed an absolute bioavailability of 27.83%, which is 12.78 times higher than that of
commercially available tablets (Aquivir).
2) New vehicle based on a microemulsion for topical ocular

administration of dexamethasone
Aim: Eye drops are the most used dosage form by the ocular route, in spite of their low
bioavailability. Due to their properties and numerous advantages, microemulsions are promising
systems for topical ocular drug delivery. They can increase water solubility of the drug and
enhance drug absorption into the eye. The present study describes the development and
characterization of an oil-in-water microemulsion containing dexamethasone and the evaluation
of its pharmacokinetics in rabbits after topical ocular application.

Methods: The microemulsion was prepared by the titration technique. Its physico-chemical
characteristics and stability were determined. The ocular irritation test and the pharmacokinetics
of this system were studied in white rabbits.
Results: The developed system showed an acceptable physico-chemical behaviour and

presented good stability for 3 months. The ocular irritation test used suggested that the
microemulsion did not provide significant alteration to eyelids, conjunctiva, cornea and iris. This
formulation showed greater penetration of dexamethasone in the anterior segment of the eye
and also release of the drug for a longer time when compared with a conventional preparation.
The area under the curve obtained for the microemulsion system was more than twofold higher
than that of the conventional preparation (P < 0.05).
Conclusions: The microemulsion-based dexamethasone eye drop is advantageous for

ophthalmic use because it is well-tolerated in the eye and seemed to provide a higher degree of
bioavailability.
3) Study of Isopropyl Myristate Microemulsion Systems Containing

Cyclodextrins to Improve the Solubility of 2 Model Hydrophobic
Drugs
The objectives of this project were to evaluate the effect of alkanols and cyclodextrins on the
phase behavior of an isopropyl myristate microemulsion system and to examine the
solubility of model drugs. Triangular phase diagrams were developed for the microemulsion
systems using the water titration method, and the solubility values of progesterone and
indomethacin were determined using a conventional shake-flask method. The water
assimilation capacities were determined to evaluate the effective microemulsion formation in
different systems. The alkanols showed higher microemulsion formation rates at higher
concentrations. A correlation between the carbon numbers of the alkanol and water
assimilation capacity in the microemulsions studied was observed; isobutanol and
isopentanol produced the best results. The addition of cyclodextrins showed no effect or had
a negative effect on the microemulsion formation based on the type of cyclodextrin used.
Isopropyl myristate–based microemulsion systems alone could increase the solubility values
of progesterone and indomethacin up to 3300-fold and 500-fold, respectively, compared to
those in water. However, the addition of cyclodextrins to the microemulsion systems did not
show a synergistic effect in increasing the solubility values of the model drugs. In
conclusion, microemulsion systems improve the solubility of progesterone and
indomethacin. But the two types of cyclodextrins studied affected isopropyl myristate–based
microemulsion systems negatively and did not improve the solubilization of 2 model drugs.
Materials and Methods

Materials
Progesterone, indomethacin, IPM, 1-propanol, 1-butanol, 1-pentanol, Tween 20, Tween 40,
Tween 80, and Span 20 ,Ethanol ,Methanol and acetonitrile ,Trappsol, Captisol ,Soybean oil
Water used in the study was deionized and distilled.
Preparation of the Phase Diagram and ME Formulations
IPM and 1-butanol were selected as an oil component and cosurfactant, respectively, in the ME
systems. The surfactants (a 1:1 mixture of Tween 80 and Span 20) were prepared separately.
IPM and 1-butanol were added to the surfactant mixture. The pseudoternary phase diagrams of
oil, surfactant/cosurfactant, and water were set up using the water titration method. The mixture
of oil and surfactant/cosurfactant at predetermined weight ratios was diluted with water by
sequential addition of 10 µL of water using a micropipette. No heating was necessary during the
preparation. However, the system was stirred using a magnetic stirrer to ensure a thorough
mixing. After each mixing, the sample was allowed to settle and its physical condition (clarity
and flowability) was reviewed. If required, the sample was sonicated for 1 to 2 minutes to
remove air bubbles and to enable a better visual examination. Mixtures that did not show a
change in the meniscus after tilting to an angle of 90º were considered to be gels. Samples
were examined under a microscope, if necessary.
The mixture compositions at different points in the phase diagrams were defined by the
following equation:
(1
)
To study the effect of CDs on the formation of ME, a 50% wt/vol aqueous solution of each type
of CD was prepared. The densities of 50% wt/vol Captisol and 50% wt/vol Trappsol aqueous
solutions were 1.13 g/cc and 1.16 g/cc, respectively. Because the solutions were denser than
water pipettes used in the experimentation were calibrated with CD solutions. The ME region
was determined in the same way as it was determined for the ME system without CD.
Phase Behavior
The pseudoternary phase diagrams of the different ME systems are shown in Figures 1 and 2.
Isobutanol concentration was kept constant with respect to the oil phase (8:1) to facilitate the

construction of the phase diagram. The translucent and low-viscosity area is presented in the
phase diagrams as an ME area. No distinct conversion from water/oil to oil/water ME systems
was observed. Therefore, this single isotropic region was considered a bicontinuous ME. The
emulsion region is an area in which a milky white heterogeneous system is formed. The gel
area indicates the clear and high-viscosity region. The remainder of the phase diagram
represents the turbid region, represented as 2 phases and conventional emulsions based on
visual identification.
Figure 1. Pseudoternary phase diagrams of IPM-surfactant-water system at Tween 80:Span

20 ratios of 1:1, and IPM:1-butanol ratios of 8:1. ■ = ME, ● = emulsion, ▲ = gel, and ✴= 2
phases.
Figure 1 shows the phase diagram of the IPM Tween 80:Span 20 pseudoternary system. The
ME formation was favorable at high surfactant concentrations. At higher oil concentration, the
system tended to separate into 2 phases.
The influence of CD on the ME isotropic region can be observed in Figure 2. The ME area
decreased from about 30% in the blank ME to about 23% in the ME containing Captisol. These
numbers were calculated manually by finding out the number of small triangles covered by the
ME area in the phase diagram compared to the total number of small triangles in the phase
diagram. On the other hand, Trappsol did not hamper the formation of ME (30% to 29%), but
the shape of the ME region changed significantly. The results indicated that the formation of ME
could be influenced negatively by the presence of ionic CD. Captisol has a high affinity for

water, which might have affected the ME formation. The ME formation region improved at a
40% to 60% water level in the Trappsol system. The exact reason for this is not known at this
time. The higher surface activity of Trappsol compared to Captisol may have played a role.
Overall, from Figure 2, it was clear that ME could be formed in the presence of CDs, but the
type of CD could alter the ME region either positively or negatively.
Conclusion
The ME system comprising IPM, Tween 80, Span 20, isobutanol, and water showed a high
solubilization capacity for 2 model drugs, progesterone and indomethacin. The addition of CDs
in general affected the ME formation negatively and did not improve the solubility of
hydrophobic drugs in the ME systems tested.
RECENT ADVANCES IN SELF EMULSIFYING DRUG

DELIVERY SYSTEM
 Self-emulsifying drug delivery systems (SEDDS) are usually used to improve the
bioavailability of hydrophobic drugs.
 Approximately 40% of new chemical entities exhibit poor aqueous solubility and present
a major challenge to modern drug delivery system, because of their low bioavailability.
 From time to time many workers have claimed various rational applications of Self-
emulsifying formulation for enhancing bioavailability and site-specific targeting of highly
lipophilic drugs.
 SEDDS is ideally an isotropic mixture of oils and surfactants and sometimes co solvents.
 The multi-component delivery systems have optimized by evaluating their ability to self-
emulsify when introduced to an aqueous medium under gentle agitation, and by
determination of particle size of the resulting emulsion.
 Upon per oral administration,these systems form fine (micro) emulsions in the
gastrointestinal tract (GIT) with mild agitation provided by gastric mobility.
 These articles give an overview of the recent advances in the development of SEDDS
and the dosage forms along with the associated problems and the possible future
research directions in this field.
Composition of SEDDSs
The self-emulsifying process is depends on:

 The nature of the oil–surfactant pair
 The surfactant concentration
 The temperature at which self-emulsification occurs.
a) Oils. Oils can solubilize the lipophilic drug in a specific amount. It is the most important
excipient because it can facilitate self-emulsification and increase the fraction of
lipophilic drug transported via the intestinal lymphatic system, thereby increasing
absorption from the GI tract . Long-chain triglyceride and medium-chain triglyceride oils
with different degrees of saturation have been used in the design of SEDDSs. Modified
or hydrolyzed vegetable oils have contributed widely to the success of SEDDSs owing to
their formulation and physiological advantages. Novel semisynthetic medium-chain
triglyceride oils have surfactant properties and are widely replacing the regular medium-
chain triglyceride.
b) Surfactant. Nonionic surfactants with high hydrophilic–lipophilic balance (HLB) values
are used in formulation of SEDDSs (e.g., Tween, Labrasol, Labrafac CM 10,
Cremophore, etc.). The usual surfactant strength ranges between 30–60% w/w of the
formulation in order to form a stable SEDDS. Surfactants have a high HLB and
hydrophilicity, which assists the immediate formation of o/w droplets and/or rapid
spreading of the formulation in the aqueous media. Surfactants are amphiphilic in nature
and they can dissolve or solubilize relatively high amounts of hydrophobic drug
compounds. This can prevent precipitation of the drug within the GI lumen and for
prolonged existence of drug molecules.
c) Cosolvents. Cosolvents like diehylene glycol monoethyle ether (transcutol), propylene
glycol, polyethylene glycol, polyoxyethylene, propylene carbonate, tetrahydrofurfuryl
alcohol polyethylene glycol ether (Glycofurol), etc., may help to dissolve large amounts
of hydrophilic surfactants or the hydrophobic drug in the lipid base. These solvents
sometimes play the role of the cosurfactant in the microemulsion systems.
Formulation of SEDDSs
 With a large variety of liquid or waxy excipients available, ranging from oils through
biological lipids, hydrophobic and hydrophilic surfactants, to water-soluble cosolvents,
there are many different combinations that could be formulated for encapsulation in hard
or soft gelatin or mixtures which disperse to give fine colloidal emulsions
 The following should be considered in the formulation of a SEDDS:
 The solubility of the drug in different oil, surfactants and cosolvents. The selection of oil,
surfactant and cosolvent based on the solubility of the drug and the preparation of the
phase diagram.
 The preparation of SEDDS formulation by dissolving the drug in a mix of oil, surfactant
and cosolvent. The addition of a drug to a SEDDS is critical because the drug interferes
with the self-emulsification process to a certain extent, which leads to a change in the

optimal oil–surfactant ratio. So, the design of an optimal SEDDS requires
preformulation-solubility and phase-diagram studies. In the case of prolonged SEDDS,
formulation is made by adding the polymer or gelling agent.
Characterization of SEDDSs
 The primary means of self-emulsification assessment is visual evaluation. The efficiency

of self-emulsification could be estimated by determining the rate of emulsification,
droplet-size distribution and turbidity measurements.
 Visual assessment. This may provide important information about the self-emulsifying
and microemulsifying property of the mixture and about the resulting dispersion.
 Turbidity Measurement. This is to identify efficient self-emulsification by establishing
whether the dispersion reaches equilibrium rapidly and in a reproducible time.
 Droplet Size. This is a crucial factor in self-emulsification performance because it

determines the rate and extent of drug release as well as the stability of the emulsion.
Photon correlation spectroscopy, microscopic techniques or a Coulter Nanosizer are
mainly used for the determination of the emulsion droplet size. The reduction of the
droplet size to values below 50 μm leads to the formation of SMEDDSs, which are
stable, isotropic and clear o/w dispersions.
 Zeta potential measurement. This is used to identify the charge of the droplets. In
conventional SEDDSs, the charge on an oil droplet is negative due to presence of free
fatty acids.
 Determination of emulsification time. Self-emulsification time, dispersibility,

appearance and flowability was observed.
Application
 SEDDS formulation is composed of lipids, surfactants, and cosolvents. The system has
the ability to form an oil-in-water emulsion when dispersed by an aqueous phase under
gentle agitation.
 SEDDSs present drugs in a small droplet size and well-proportioned distribution, and
increase the dissolution and permeability. Furthermore, because drugs can be loaded in
the inner phase and delivered by lymphatic bypass share, SEDDSs protect drugs
against hydrolysis by enzymes in the GI tract and reduce the presystemic clearance in
the GI mucosa and hepatic first-pass metabolism.
Conclusion
 Self-emulsifying drug delivery systems are a promising approach for the formulation of
drug compounds with poor aqueous solubility. The oral delivery of hydrophobic drugs

can be made possible by SEDDSs, which have been shown to substantially improve oral
bioavailability. With future development of this technology, SEDDSs will continue to
enable novel applications in drug delivery and solve problems associated with the
delivery of poorly soluble drugs.
Drawbacks of SEDDS
 One of the advantages of SEDDS in relation to scale-up and manufacture is that they
form spontaneously upon mixing their components under mild agitation and they are
thermodynamically stable.
 The drawbacks of this system include chemical instabilities of drugs and high surfactant
concentrations. The large quantity of surfactant in self-emulsifying formulations (30-60%)
irritates GIT. Consequently, the safety aspect of the surfactant vehicle had to be
considered.
 Moreover, volatile cosolvents in the conventional self-emulsifying formulations are
known to migrate into the shells of soft or hard gelatin capsules, resulting in the
precipitation of the lipophilic drugs.
 There is a long list of water soluble, insoluble and surfactants, whichcan be used as
solubilizing excipients .
 Grinding is regularly used in the pharmaceutical industry to reduce particle size but it
generates heat, sound and vibration energy . It must be performed at a temperature
below the melting temperature. Cryogenic grinding is chosen because it is a process
carried out at low temperature with frozen samples, used for different biological materials
(plants, animal tissues)and unstable compounds (vitamins, volatile substances, etc.).
However, grinding induces mechanical activation and generation of energy can lead to
physical and chemical changes in crystalline solid which can affect its efficacy.
1) Preparation and In Vivo Evaluation of SMEDDS (Self-

Microemulsifying Drug Delivery System) Containing Fenofibrate.
 The present work was aimed at formulating a SMEDDS (self-microemulsifying drug

delivery system) of fenofibrate and evaluating its in vitro and in vivo potential. The
solubility of fenofibrate was determined in various vehicles. Pseudoternary phase
diagrams were used to evaluate the microemulsification existence area, and the release
rate of fenofibrate was investigated using an in vitro dissolution test. SMEDDS
formulations were tested for microemulsifying properties, and the resultant
microemulsions were evaluated for clarity, precipitation, and particle size distribution.
Formulation development and screening was done based on results obtained from
phase diagrams and characteristics of resultant microemulsions. The optimized
formulation for in vitro dissolution and pharmacodynamic studies was composed of
Labrafac CM10 (31.5%), Tween 80 (47.3%), and polyethylene glycol 400 (12.7%). The
SMEDDS formulation showed complete release in 15 minutes as compared with the
plain drug, which showed a limited dissolution rate. Comparative pharmacodynamic
evaluation was investigated in terms of lipid-lowering efficacy, using a Triton-induced

hypercholesterolemia model in rats. The SMEDDS formulation significantly reduced
serum lipid levels in phases I and II of the Triton test, as compared with plain fenofibrate.
The optimized formulation was then subjected to stability studies as per International
Conference on Harmonization (ICH) guidelines and was found to be stable over 12
months. Thus, the study confirmed that the SMEDDS formulation can be used as a
possible alternative to traditional oral formulations of fenofibrate to improve its
bioavailability.
Materials
Fenofibrate ,Labrafac CM10 , Maisine 35-1 (glyceryl monolinoleate), Lauroglycol FCC

(propylene glycol laurate), Labrafil 1944 CS (apricot kernel oil polyethylene glycol [PEG]
6 esters), and Labrafac PG (propylene glycol caprylate/caprate). Cremophor RH 40
(polyoxyl 40 hydrogenated castor oil), Cremophor EL (polyethoxylated castor oil), and
Solutol HS 15 (polyoxyethylene esters of 12-hydroxystearic acid, Gelucire 44/14 (PEG-
32 glyceryl laurate) and 50/13 (PEG-32 glyceryl palmistearate) ,Span 20 (sorbitan
monolaurate), Tween 80 (polyoxyethylene sorbitan monooleate), and PEG
400.Deionized water was prepared by a Milli-Q purification system .Acetonitrile and
methanol used in the present study were of high performance liquid chromatography
(HPLC) grade. All other chemicals were reagent grade.
Preparation of SMEDDS Formulations
A series of SMEDDS formulations were prepared using Tween 80 and PEG 400 as the
S/CoS combination and Labrafac CM10 as the oil (Table 1). In all the formulations, the
level of fenofibrate was kept constant (ie, 8.5% wt/wt of the total formulation weight).
Briefly, accurately weighed fenofibrate was placed in a glass vial, and oil, surfactant, and
cosurfactant were added. Then the components were mixed by gentle stirring and vortex
mixing and were heated at 40ºC on a magnetic stirrer, until fenofibrate was perfectly
dissolved. The mixture was stored at room temperature until further use.
Table 1. Developed Formulations With Their Compositions*
Components
(% wt/wt) Batch A Batch B Batch C Batch D Batch E Batch F Batch G Batch H
Fenofibrate 8.5 8.5 8.5 8.5 8.5 8.5 8.5 8.5
Labrafac CM10 28.5 29.5 30.5 31.5 32.5 31.5 31.5 31.5

S/CoS ratio 3:1 3:1 3:1 3:1 3:1 3.2:1 3.5:1 3.7:1
Tween 80 47.25 46.50 45.75 45.00 44.25 45.71 46.67 47.30
PEG 400 15.75 15.50 15.25 15.00 14.75 14.29 13.33 12.70
*S/CoS indicates surfactant/cosurfactant; PEG, polyethylene glycol.
1) Solubility Studies
 One important consideration when formulating a self-emulsifying formulation is avoiding

precipitation of the drug on dilution in the gut lumen in vivo.1 Therefore, the components
used in the system should have high solubilization capacity for the drug, ensuring the
solubilization of the drug in the resultant dispersion. Results from solubility studies are
reported in Figure 1. As seen from the figure, Maisine 35-1 and Labrafac CM10 showed
the highest solubilization capacity for fenofibrate, followed by Tween 80 and PEG 400.
Thus, for our study we selected Maisine 35-1 and Labrafac CM10 as oils and Tween 80
and PEG 400 as surfactant and cosurfactant, respectively.
Figure 1. Solubility of fenofibrate in various components. PEG indicates polyethylene glycol.

2) Pseudoternary Phase Diagrams
 Self-microemulsifying systems form fine oil-water emulsions with only gentle agitation,
upon their introduction into aqueous media. Surfactant and cosurfactant get
preferentially adsorbed at the interface, reducing the interfacial energy as well as
providing a mechanical barrier to coalescence. The decrease in the free energy required
for the emulsion formation consequently improves the thermodynamic stability of the
microemulsion formulation. Therefore, the selection of oil and surfactant, and the mixing
ratio of oil to S/CoS, play an important role in the formation of the microemulsion.
 In the present study both Maisine 35-1 and Labrafac CM10 were tested for phase
behavior studies with Tween 80 and PEG 400 as the S/CoS mixture. As seen from the
ternary plot (Figures 2 and 3), Labrafac CM10 gave a wider microemulsion region than
did Maisine 35-1 at all S/CoS ratios. Thus, Labrafac CM10 was selected as the preferred
vehicle for the optimized formulation. The microemulsion existence area increased as
the S/CoS ratio increased. However, it was observed that increasing the surfactant ratio
resulted in a loss of flowability. Thus, an S/CoS ratio between 3:1 and 4:1 was selected
for the formulation study.

Figure 2. Pseudoternary phase diagram of system with the following components: oil =
Labrafac CM10, surfactant = Tween 80, and cosurfactant = polyethylene glycol 400. S/CoS
ratio of A is 1:1, B is 2:1, C is 3:1, and D is 5:1. S/CoS indicates surfactant/cosurfactant.

Figure 3. Pseudoternary phase diagram of system with the following components: oil = Maisine
35-1, surfactant = Tween 80, and cosurfactant = polyethylene glycol 400. S/CoS ratio of A is
1:1, B is 2:1, C is 3:1, and D is 5:1. S/CoS indicates surfactant/cosurfactant.
 PEG 400 is reported to be incompatible with hard gelatin capsules when used in high
concentrations.19 Thus, while optimizing the S/CoS ratio, we tried to keep the
concentration of PEG 400 as low as possible (<15% wt/wt of total formulation), as we
had a final aim of putting the SMEDDS formulations into liquid-filled hard gelatin
capsules. Figure 4 shows phase diagrams in the presence of the drug. As seen from the
figure, the inclusion of drug narrowed the microemulsion existence area, because
inclusion of the drug in the lipid phase led to expansion of the lipid phase and
consequently a need for a higher S/CoS ratio for stabilization.

Figure 4. Pseudoternary phase diagram of system with the following components: oil = drug-
enriched Labrafac CM10, surfactant = Tween 80, and cosurfactant = polyethylene glycol 400.
S/CoS ratio of A is 1:1, B is 2:1, C is 3:1, and D is 5:1. S/CoS indicates surfactant/cosurfactant.
Conclusions
An optimized SMEDDS formulation consisting of Labrafac CM10 (31.5% wt/wt), Tween

80 (47.3% wt/wt), PEG 400 (12.7% wt/wt), and fenofibrate (8.5% wt/wt) was successfully
developed with an increased dissolution rate, increased solubility, and, ultimately,
increased bioavailability of a poorly water-soluble drug, fenofibrate. The developed
formulation showed higher pharmacodynamic potential as compared with plain
fenofibrate. Results from stability studies confirmed the stability of the developed
formulation. Thus, our study confirmed that the SMEDDS formulation can be used as a
possible alternative to traditional oral formulations of fenofibrate to improve its
bioavailability.

2) Development of prototype self-emulsifying lipid based
formulations
 It is well recognized that lipid-based formulations can enhance oral bioavailability of
poorly water-soluble drugs. Lipid containing formulations can be an oil, an emulsion or
SEDDS. SEDDS are isotropic mixtures of oil(s), surfactant(s), co-surfactant(s), co-
solvent(s) and drug. They form fine oil-in-water emulsions when introduced into aqueous
media under gentle agitation.The potential of SEDDS for enhancing the bioavailability of
poorly soluble drugs has been evident for at least a decade.One of the working
hypotheses in the present study is that particle size distribution of the emulsions can
influence the bioavailability.
PURPOSE
To develop prototype lipid based selfemulsifying drug delivery systems (SEDDS) and
self-microemulsifying drug delivery systems (SMEDDS) with the following characteristics:
 Clear single-phase pre-concentrate
 Mono-modal particle size distribution
 Digestible lipid containing formulation with highest possible sesame oil content
RESULTS & DISCUSSION
A filled triangle indicates that the pre-

concentrate is not single-phased. An
open circle indicates a single-phased
preconcentrate that do not self-
emulsify. A filled circle indicates a
single-phased and self-emulsifying
system (S(M)EDDS).
Figure 1 presents the physical appearance of the pre-concentrate and its ability to selfemulsify
as a function of the composition.Single-phased and self-emulsifying preconcentrates are only
obtained in two distinct composition ranges. Furthermore it is shown that a concentration of
ethanol higher than 10% is needed for the pre-concentrate to be self-emulsifying.

An open circle indicates a S(M)EDDS resulting in an (micro)emulsion with a bi-modal (poly-
disperse) particle size distribution. A filled circle indicates S(M)EDDS resulting in
an (micro)emulsion with a mono-modal particle size distribution.
 In figure 2 the particle size distribution of the resulting emulsions is presented as either
bimodal or mono-modal as a function of the composition. The formulations with low
Cremophor RH40 concentration correspond to a SEDDS and the formulations with high
Cremophor RH40 concentration correspond to a SMEDDS.
CONCLUSIONS
 Different ratios of Maisine 35-1 and sesame oil have been tested but the ratio 1:1
afforded the most promising selfemulsifying systems.
 Self-emulsifying systems with monomodal particle size distribution and distinct
different mean particle size have been developed.
 Mean particle size for the mono-modal self-emulsifying systems is dependent on the
ratio between Cremophor RH40 and oil phase.
3) Self-microemulsifying Drug Delivery Systems (SMEDDS)

of Nifedipine: Development and In Vitro - In Vivo
Evaluation
Purpose
 To develop and characterize self-microemulsifying drug delivery systems (SMEDDS) of
nifedipine and to evaluate their oral bioavailability in male Sprague-Dawley albino rats.
Methods
 Solubility of nifedipine was determined in different vegetable oils. Based on the solubility,
sesame oil was selected and pseudo-ternary phase diagram was constructed using
sesame oil, surfactants blend (Span 80 / Tween 80 at 3:7 ratio) and co surfactant (n-
butanol) at surfactant / co surfactant mixture ratio of 9/1. Five SMEDDS were prepared
by selecting different proportions from the self-emulsifying region of pseudo-ternary

phase diagram. The SMEDDS were characterized for the self-dispersibility, droplet size,
drug content and Fourier transformed-infrared spectroscopy (FT-IR). The in vitro drug
release from SMEDDS, pure drug and commercial products was compared. The
selected SMEDDS and pure drug were orally administered to rats and blood
concentrations of nifedipine at different time points were measured. T1/2, Tmax and
AUC0-24 were compared. Relative bioavalilability of SMEDDS was caluclulated.
Results
 All the SMEDDS showed good self-dispersibility, formed clear microemulsions with very
small droplet size (less than 0.2 μm) and drug content was found to be within the limits.
FT-IR study showed that there is no incompatibility between the SMEDDS ingredients
(sesame oil, Tween 80 and Span 80) and nifedipine. The prepared SMEDDS showed
faster drug release compared to pure drug and the two selected commercial
formulations. SMEDDS 4 and 5 gave the higher dissolution efficiency (DE) values DE10
and DE30 compared to pure drug, commercial formulations and the other prepared
SMEDDS. All the prepared SMEDDS, pure drug and commercial formulations followed
first order release. SMEDDS 4 and 5 were selected for the animal study, when
compared to same dose of pure drug, Cmax was increased by 4- and 3.5- fold, AUC0-24
was increased by 2.7 and 2 fold respectively. Both the Tmax and T½ values were similar
to the reported values. Relative % BA was found to be 267.81 and 196.99 for SMEDDS
4 & 5 respectively.
Conclusion
 These results indicate the usefulness of the SMEDDS for the improvement of the
dissolution rate and thereby oral bioavailability of poorly water soluble drugs like
nifedipine.
4) Self-nanoemulsifying drug delivery systems (SNEDDS)
for oral delivery of protein drug
RECENT INNOVATION IN IN-SITU GELS
1) Formulation and Evaluation of pH Induced In-situ

Nasal Gel of Salbutamol Sulphate
ABSTRACT: Nasal solutions of Salbutamol Sulphate were prepared for sustaining its release
and improving its bioavailability.
Carbopol was used as a key ingredient to effect pH induced sol to gel conversion of the
formulations.
Different formulations were prepared by varying the concentrations of Carbopol 934 and
Hydroxyl Propyl Methyl Cellulose.
These formulations were evaluated for parameters like pH, drug content, viscosity, gel strength
and drug release.
Release profile of some formulations showed rapid phase while some showed slow phase. At
extreme low concentrations of the polymers, the formulations drained out due to poor viscosity
while at higher concentrations of the same the formulations formed stiff gel and showed slow

release of drug.
Finally optimized formulation with specific concentrations of carbopol 934 and Hydroxyl
Propyl Methyl Cellulose showed pH induced sol-gel conversion, sustained release and higher
bioavailability.
Ingredients
Salbutamol sulphate
Carbopol 934
HPMC K4M
NaCl
Benzalkonium chloride
Sodium metabisulphiteDistilled water (ml)
Evaluation of in Situ Gels
1.Appearance
2. pH of the Gel
3. Gelation Studies
4. Drug Content
5. Viscosity Measurement
6. Measurement of Gel Strength
7. In Vitro Release Study
2) Study of an alginate/HPMC-based in situ gelling

ophthalmic delivery system for gatifloxacin.
 The poor bioavailability and therapeutic response exhibited by conventional ophthalmic
solutions due to rapid pre-corneal elimination of the drug may be overcome by the use of
in situ gel-forming systems that are instilled as drops into the eye and then undergo a
sol-gel transition in the cul-de-sac. The present work describes the formulation and
evaluation of an ophthalmic delivery system of an antibacterial agent, gatifloxacin, based
on the concept of ion-activated in situ gelation. Alginate (Kelton((R))) was used as the
gelling agent in combination with HPMC (Methocel E50Lv) which acted as a viscosity-
enhancing agent. The rheological behaviors of all formulations were not affected by the
incorporation of gatifloxacin. Both in vitro release studies and in vivo pre-corneal
retention studies indicated that the alginate/HPMC solution retained the drug better than
the alginate or HPMC E50Lv solutions alone. These results demonstrate that the
alginate/HPMC mixture can be used as an in situ gelling vehicle to enhance ocular
bioavailability and patient compliance.
3) DEVELOPMENT OF A NOVEL IN SITU GEL SYSTEM FOR ORAL
DRUG DELIVERY
Purpose.
The aim of this investigation was to develop a novel chitosan-glyceryl monooleate
(GMO) gel system that can be used for sustained oral delivery of drugs.
Methods.
Ketoprofen and dexamethasone were used as the model hydrophilic and hydrophobic

drugs, respectively. The optimal delivery system comprised of chitosan, 3% (w/v) and
GMO, 3% (w/v) in 0.33 M citric acid containing 1% (w/v) ketoprofen or 0.03% (w/v) of
dexamethasone. In vitro release of drug was carried out by adding 1.0 ml of the solution
to 40ml of Sorensen¡¯ s phosphate buffer (pH=7.4). The in situ gel formed was shaken
in a water bath at 80 rpm and 37°C. Drugs were analyzed by HPLC. Effect of
crosslinking (glutaraldehyde, 50% v/v) on the in vitro drug release was also evaluated.
Results.
Use of citric acid to dissolve the chitosan produced an optimal gel at pH 7.4 as
compared to acetic, lactic, and tartaric acid. Incorporation of GMO into the gel minimized
the initial burst effect of the drugs and enhanced its bioadhesive property.
The drug release from such a gel followed a matrix diffusion controlled mechanism.
Conclusion.
A novel in situ gel formulation containing chitosan and GMO was developed and tested.
The in vitro release of ketoprofen and dexamethasone from such gel was found to be
quick but could be controlled by incorporation of a crosslinker. This novel chitosan-GMO
system, with its enhanced bioadhesive property, can be used for sustained and targeted
delivery of a wide range of drugs.
RECENT INNOVATION IN LYOPHILIZED SUSPENSION
1) Lyophilized Lecithin Based Oil-Water Microemulsions as a New

and Low Toxic Delivery System for Amphotericin B
 Purpose. To develop and investigate lecithin based oil-water microemulsions as

potential amphotericin B (AmB) delivery systems and to evaluate their in vivo acute
toxicity.
 Methods. AmB was added to the microemulsion and its location was evaluated by
partitioning studies and UV-visible spectrophotometric analysis of the drug. Both, non-
lyophilized and reconstituted microemulsions were characterised and assessed for their
stability. Single-dose acute toxicity of the AmB microemulsion was studied on male
albino Webster-derived CD-1 mice and compared with Fungizone®.
 Results. The studies performed showed that AmB was intercalated on the oil-water
interface of the microemulsion as a complex formed with lecithin molecules. AmB
addition did not seem to modify the rheological properties of the original system, but had
an effect on its particle size distribution. Lyophilization of the microemulsion led to an oily
cake, easily reconstituted and stable at the conditions studied. Single-dose acute toxicity
studies proved that the LD50 of AmB microemulsions was of 4 mg kg–1 of animal weight,
compared with 1 mg kg–1 found for Fungizone®.
 Conclusions. Lyophilized lecithin based oil-water microemulsions appear to be valuable

systems for the delivery of AmB in terms of easy and low-cost manufacturing, stability
and safety compared with the formulations already in market.

2) The ophthalmic lyophilisate carrier system (OLCS): development
of a novel dosage form, freeze-drying technique, and in vitro
quality control tests
 The ophthalmic lyophilisate carrier system (OLCS) is a novel dosage form for delivery of
pharmacologically active ingredients or other substances improving the structure of the
tear film to the eye.
 A drop of lyophilisate containing the drug and bulk forming water-soluble or swelling
excipients is attached to a flexible hydrophobic carrier. Placebo OLCS and OLCS
containing several drugs commonly used in ophthalmology were compared to
conventional eye drops containing the same ingredients.
 A novel lyophilization procedure for the production of this dosage form is described,
which allows stricter control of the freezing and drying conditions and shortens the
production cycle by at least an order of magnitude.
 In clinical studies it was found that OLCS are easy to administer and well tolerated if the
force of adhesion between lyophilisates and carrier strips and the structural firmness of
the lyophilisates themselves are well controlled.
 These parameters are critical for convenient administration and complete delivery of the
dose of active ingredients incorporated, therefore suitable in vitro tests were developed
with which their values can be determined for the purpose of process validation.
 A study of fluorescein OLCS in humans indicated that concentration profiles in the

cornea and anterior chamber are significantly higher than after administration of equal
doses of the diagnostic in conventional eye drops.
References
 From Wikipedia, the free encyclopedia

 Pouton CW. Lipid formulations for oral administration of drugs: non-emulsifying, self-
emulsifying and ‘self-microemulsifying’ drug delivery systems. Eur J Pharm
Sci. 2000;11:S93-S98.
PubMed DOI: 10.1016/S0928-0987(00)00167-6
 Constantinides PP. Lipid microemulsions for improving drug dissolution and oral

absorption: physical and biopharmaceutical aspects. Pharm Res. 1995;12:1561-1572.
PubMed DOI: 10.1023/A:1016268311867

 The AAPS Journal 2007; 9 (3) Article 41 (http://www.aapsj.org).
 International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm
3)The Biopharmaceutics Classification System (BCS) Guidance, Office of Pharmaceutical

Science. Available from: http://www.fda.gov/cder/OPS/BCS_guidance.htm [last accessed
on 2008 Jan 12].

 RA Nash. Suspensions. In: J Swarbrick, JC Boylan (ed). Encyclopedia of
pharmaceutical technology. Second edition vol. 3. New York, Marcel dekker,
2002, p. 2045-3032.

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SEMINAR ON

DEPARTMENT OF PHARMACEUTICS &

L.M. College of Pharmacy Ahmedabad-‘09(2010) Page

RECENT INNOVATION IN SUSPENSION

Nanosuspensions in drug delivery

 Nanotechnology can be used to resolve the problems associated with these

L.M. College of Pharmacy Ahmedabad-‘09(2010) Page

A) Media Milling (Nanocrystals or Nanosystems)

2. Very dilute as well as highly concentrated nanosuspensions can be prepared by handling

3. Nanosize distribution of final nanosize products.

L.M. College of Pharmacy Ahmedabad-‘09(2010) Page

2. The media milling technique is time consuming.

3. Some fractions of particles are in the micrometer range.

4. Scale up is not easy due to mill size and weight.

B) Homogenization In Water (Dissocubes)

 R.H.Muller developed Dissocubes technology in 1999. The instrument can be operated

1. It does not cause the erosion of processed materials.

2. Very dilute as well as highly concentrated nanosuspensions can be prepared by handling

4. It allows aseptic production of nanosuspensions for parentral administration.

1. Preprocessing like micronization of drug is required.

L.M. College of Pharmacy Ahmedabad-‘09(2010) Page

D) Combined Precipitation And Homogenization (Nanoedege)

E) Emulsification-solvent evaporation technique

 This technique involves preparing a solution of drug followed by its emulsification in

For surface-modified nanosuspensions, a number of additional parameters have to be

L.M. College of Pharmacy Ahmedabad-‘09(2010) Page

1. Particle size and size distribution

2. Particle charge (Zeta Potential)

3. Crystalline state and morphology

4. Saturation solubility and dissolution velocity

C) Evaluation for surface-modified Nanosuspensions

1.Surface hydrophilicity

2. Adhesion properties

3. Interaction with body proteins

1) Mean particle size and size distribution

L.M. College of Pharmacy Ahmedabad-‘09(2010) Page

2) Particle charge (Zeta Potential)

article charge determines the stability of nanosuspension. For electrostatically stabilized

3) Crystalline state and particle morphology

Differential Scanning Calorimetry(DSC) determines the crystalline structure. When

4) Saturation solubility and dissolution velocity

RECENT INNOVATION IN EMULSIONS

Microemulsions in drug delivery

L.M. College of Pharmacy Ahmedabad-‘09(2010) Page

 The microemulsion region is usually characterized by constructing ternary-phase

L.M. College of Pharmacy Ahmedabad-‘09(2010) Page

L.M. College of Pharmacy Ahmedabad-‘09(2010) Page

1) Design and Development of Microemulsion Drug Delivery System

Materials and Methods

Labrasol (caprylocaproyl macrogol-8-glycerides), Plurol Oleique (polyglyceryl-6-dioleate), and

Preparation of Microemulsion Formulation

L.M. College of Pharmacy Ahmedabad-‘09(2010) Page

Construction of Phase Diagrams

Results and Discussion

Phase Diagram Study

A pseudoternary phase diagram of the investigated quaternary system water/Labrasol/Plurol

L.M. College of Pharmacy Ahmedabad-‘09(2010) Page

In Vitro Intestinal Permeability Study

L.M. College of Pharmacy Ahmedabad-‘09(2010) Page