Ibuprofen based carbopol emogel

Faculty Of Health & Life Science
Ibuprofen Based
Carbopol Emogel for
Transdermal
Delivery
Supervisor: Dr A. Abioye
Mohammed Abdullah
12/15/2010

Ibuprofen Based Carbopol Emogel for Transdermal Delivery
1. Introduction
An effective emulsion is primarily dependant on the use of effective emulsifiers, which in essence
present the oil phase to the aqueous in a more compatible manner. The inclusion of an emulsifier at
or near the interface significantly lowers interfacial tension therefore decreasing the rate of
separation amongst the two phases. However emulsifiers have a disadvantage as they are unable to
overcome thermodynamic instability issues, instead they can only postpone or prevent the outcome
of separation.
Microemulsions are prescribed to be the only type of emulsion that are thermodynamically stable, in
contrast to macroemulsions this single, optically isotropic stable liquid solution carries a droplet
diameter usually within the range of 10-100nm [Tenjarla S., 1999], this is only about one fifth of the
wavelength of visible light in effect being about 100nm or less. However other literature states that
in relevance to microemulsions or suspensions particle size range can go as far as being >1000nm
[Rieger M.M, 2000] in essence producing nanoemulsions or suspensions. Furthermore
microemulsions have many advantages that highlight them to be a potential candidate when
regarding drug delivery systems, for example their isotropic nature and optical clarity allows their
study using spectroscopic techniques to be more straightforward. In addition to this, the existence of
microdomains of different polarity existing within the same single phase solution provides solubility
of both water-soluble and oil-soluble materials [Lawrence, M.J and Rees, G.D., 2000].
Much attention has been placed upon topical delivery using microemulsions as well as other
potential delivery systems for drugs such as Ibuprofen. Ibuprofen, a derivative of propanoic acid and
non-steroidal anti-inflammatory drug (NSAID) first dis overed i the 96 ’s, is generally applicable as
a reliever of mild or moderate pain but, is also highly effective for systemic treatment of rheumatoid
arthritis and osteoarthritis. Ibuprofen has previously been formulated into many topical
formulations primarily in order to prevent first-pass metabolism and potential side effects of the
drug.
This NSAID works by inhibiting the enzyme cyclooxygenase- a key enzyme generating thromboxane
A2 leading to the formation of platelet aggregates resulting in the formation of blood clots.
Furthermore ibuprofen is believed to be a non-selective COX inhibitor- meaning it inhibits two
isoforms of cyclooxygenase (COX-1 and COX-2).
The anti-inflammatory activity of NSAIDs is attained mainly through inhibition of COX-2, COX-2 is
triggered by inflammatory stimuli and produces prostaglandins relating to general effects of pain
and swelling, whereas on the other hand inhibition of COX-1 is constitutive and produces
prostaglandins that protect the GI tract, stomach and kidney as well as being responsible for
unwanted effects on platelet aggregation [Rao P, Knaus EE., 2008]. With reference to the above it
can be established that selective COX-2 inhibitors should be anti-inflammatory without side effects
on the kidney and stomach [Vane J.R and Botting R.M., 1998].
Ibuprofen in many respects provides such characteristics, However previous research has found that
Ibuprofen also carries potential disadvantages, common adverse effects include nausea, vomiting,
tinnitus, rash, and dizziness, but in particular a key disadvantage of Ibuprofen with relevance to
topical formulations is that, it is difficult to maintain concentration levels of Ibuprofen due to its
poor skin permeation ability. However research highlights Ibuprofen is relatively good compared to
other commonly used NSAIDs [Yano et al., 1986 & Babar. et al 1990].
1.1 Previous Research Conducted
Previous studies have explored permeability issues of Ibuprofen and various approaches such as
supersaturated solutions [Irevolino, M., 2001], eutectic systems [Stott, P.W. et al., 1998], muco-
adhesive patches [Perioli. L., 2004], vehicle containing non-ionic surfactants or fatty acids have been
investigated to achieve this. Similarly microemulsions have also been exploited as potential medians
to enhance drug permeability through the skin [Chen, H., et al 2004].

Previous studies conducted upon Ibuprofen concerned investigations on the diffusion of Ibuprofen
from supersaturated solutions through the human epidermis. The study was conducted in order to
enhance the penetration of Ibuprofen through the epidermis using supersaturated solutions.
Supersaturated solution provided an enhanced diffusion flux upon which further analysis is held.
Hydroxypropyl methylcellulose (HPMC) when incorporated with Ibuprofen and used as an additive
was found to be efficient in maintaining the high activity state at high degrees of saturation (DS), the
ascend in flux was proportional to the degree of saturation.
When introducing 2-hydroxypropyl-b-cyclodextrin (CD), the degree of saturation at (DS) 2 and 3 a
lower diffusion flux was established in comparison to HPMC. However at DS 5 a significantly higher
diffusion flux enhancement than the current was found highlighting that (CD) might act as a
penetration enhancer at certain CD to drug ratios [Irevolino, M., 2001]. From this it can be
established that CD may be a potential chemical that can be incorporated into microemulsions in
order to enhance the skin permeability of Ibuprofen.
Another study involved the use of microemulsions to enhance permeability aspects of a specific
drug. The study investigated microemulsion systems for transdermal delivery of triptolide; this highly
toxic anti-cancer drug requires microemulsions that provide controlled, sustained and prolonged
delivery of triptolide via a transdermal route expecting them to reduce the side effects. The
transdermal efficacy of triptolide was studied using Franz diffusion cells fitted with mouse skins
simulating in vitro conditions, the amount of triptolide was analysed using HPLC.
The loading dose of triptolide in microemulsions on the permeation rate was also evaluated. Results
showed an enhanced in vitro permeation through the mouse skins for the triptolide loaded
microemulsions in comparison to an aqueous solution of 20% propylene glycol containing 0.025%
triptolide. No obvious skin irritation was observed with regards to the microemulsion however the
aqueous solution of propylene glycol revealed signs of skin irritation. The results highlighted that
microemulsions systems provide to be promising vehicles in delivering drugs such as triptolide
(Chen, H., et al 2004).
Considering the above, microemulsions in essence provide a thermodynamically stable drug delivery
system but also a vehicle with the potential to enhance the permeability of the dispersed drug.
Furthermore such systems also provide monitored and controlled dosage parameters that would
provide a series of beacons to steer you through channels potentially leading to a development in
drug delivery.
Moving on transdermal delivery from eutectic systems has also been an area for investigation.
Eutectic systems between Ibuprofen and seven terpene skin penetration enhancers were formulated
and studied; the consequence of melting point depression upon transdermal permeation rate of
these mixtures was also investigated. Several Ibuprofens to terpene mixtures were melted together,
cooled and re-crystallised which were further investigated using FT-IR to analyse the nature of
interaction.
The permeation of ibuprofen across the human epidermis was measured and then compared to the
diffusion flux obtained from a saturated aqueous solution also permeating across normal skin as well
as skin pre-treated with terpenes. Results showed that the eutectic systems produced provided a
significant increase in the diffusion flux in comparison to a saturated aqueous solution applied to
untreated and pre-treated terpene skin. To conclude results highlighted that it is hydrogen bonding
between the terpene permeation enhancers and Ibuprofen that contribute to forming a eutectic
mixture between the two, furthermore the melting point suppression of the delivery system
correlates directly in producing an increase in transdermal penetration (Stott, P.W. et al., 1998).
Each of the above has principally investigated techniques to enhance the skin permeability for
specific drugs. Similarly the aim of this study is in many respect also is trying to enhance the skin
permeability of Ibuprofen, but most of all it provides an insight into assessing the effectiveness of
topically applied non-steroidal anti-inflammatory drugs (NSAIDs) using a nano encapsulated design

in order to treat muscular pain. This in essence will enable comparing its properties to oral NSAIDs
providing a better understanding with regards to current types of dosage forms and as to why there
are many issues that detriment the use of this class of drug.
Specific objectives of this study include determining the solubility of ibuprofen in a range of different
oils highlighting the most appropriate, formation of a microemulsion which is then homogenised to
develop nano sized particles producing nanoemulsions and lastly the characterisation of these
formulations determining the ideal emulsion which can then be formulated into a gel for further
characterisation and development.
2. Materials & Method
2.1 Materials
Ibuprofen [2-(4-isobutylphenyl)-propanoic acid], Lauric Acid (sodium salt), Triacetin (TA), Castor Oil
(CO) Ethyl Oleate (EO), Hydro-chloric (HCl) Acid & Tween 80 were purchased from Sigma-Aldrich
Chemicals LTD. Isopropyl Myristate(IPM), Propylene Glycol (PG) were obtained from Loveridge (LTD)
and Isopropyl Palmitate (IPP), Potassium di-hydrogen orthophosphate & Di-sodium hydrogen
orthophosphate anhydrous were purchased from Fisher Scientific LTD.
2.2 Oil screening for Microemulsions
In order to distinguish a suitable oil to be utilised as an oil phase as well as to provide sufficient skin
permeation rates for ibuprofen, the solubility of ibuprofen within the following oils was measured:
IPP, EO, CO, IPM, TA and PG, with water as a reference. Firstly the oils were mixed with excess
ibuprofen using a magnetic stirrer for 10 minutes and left to super saturate over the duration of 7
days at 25°C; after which they were assayed for drug content.
Super saturation plays an important role when enhancing penetration, not only is it effective in
determining the degree of solubility of a drug over a duration of time but, it also is a key aspect that
can be regarded when formulating microemulsions in order to enhance the penetration of a poorly
soluble drug [Irevolino, M., 2001], this in essence would produce a super saturated oil phase
theoretically enhancing permeation.
Ibuprofen Calibration Curve
Calibration involves the establishment of a relationship between the measured response in effect
the analytical signal, for example the absorbance for spectrophotometry and one or more solutions
known as standards containing a known amount of substance. Practically one proceeds by preparing
a set of standards either of known amounts or concentration of a substance. The response from
these standards is then measured via the use of a spectrophotometer. The underlying relationship
between these data can be established in a graphical form as a calibration curve. It is important to
highlight that according to the Beer Lambert Equation
� � = � � � �
In reference to the above equation the relationship between absorbance and concentration should
in essence be linear. These can then be further utilised due to the fact that they are linear in order to
determine either the amounts of concentration of the substance in one or more test samples whose
concentration are originally unknown.

y = 25,851x + 0,0039
R² = 0,9919
0
5
10
15
20
25
30
0 0,2 0,4 0,6 0,8 1 1,2
Absorbance(nm)
Concentration (mg)
Solubility Calibration Curve
Firstly in order to generate a sufficient calibration curve 50mg of Ibuprofen was dissolved in 2ml of
Tween 80, the mixture was then topped up to a volume of 100ml using 0.1M HCl, this will in essence
provided as a stock solution of (0.5mg/ml) from which further dilutions can be conducted. The above
mixture was then diluted 10 times using a 2 fold dilution theoretically providing a sufficient
calibration curve (Fig 1).
2.2.1 Assaying super saturated oil/drug mixtures
The super saturated oil mixtures were assayed to identify the total amount of drug consumed. This
was established by analyzing the mixtures using a UV-spectrophotometer at 260 nm. Once the most
efficient solubilising oil was identified it was then used as the dispersed phase within 8 different
microemulsions containing 1.5%w/v Ibuprofen, 1.5%v/v Oil, 15%v/v Surfactant & Co-surfactant &
then made up to 50ml with water.
2.2.2 Microemulsions Formulations
Table 1 Compositions of the selected microemulsion formulations
Amounts
Number Ibuprofen(mg) Ethyl
Oleate(mg)
Tween 80(mg) Lauric Acid
(mg)
Purified
Water (ml)
Emulsion 0 1500 1500 7500 0 Up to 50
Emulsion 1 1500 1500 7500 5 Up to 50
Emulsion 2 1500 1500 7500 10 Up to 50
Emulsion 3 1500 1500 7500 25 Up to 50
Emulsion 4 1500 1500 7500 50 Up to 50
Emulsion 5 1500 1500 7500 100 Up to 50
Emulsion 6 1500 1500 7500 250 Up to 50
Emulsion 7 1500 1500 7500 500 Up to 50
Emulsion 8 1500 1500 7500 1000 Up to 50
Initially the mixture of surfactant and co-surfactant were varied as 1:0, 1:0.5, 1:1, 1:2, 1:5, 5:1, 2:1,
0.5:1, 0:1 ratios of Lauric acid (sodium salt) to Tween 80, however the quantities of Lauric acid
(sodium salt) that were obtained with reference to these ratios produced high amounts of foam
when homogenising the 50ml microemulsion, this in essence caused an overflow of foam resulting in
Figure 1 Calibration curve of Ibuprofen for solubility of oils

the loss of formulation. Therefore the amounts were revised (Table 1) from which microemulsions
were developed and characterised.
2.3 Preparation of microemulsion.
The general ingredients required to make microemulsions consist of an oil phase, an aqueous phase,
a primary surfactant and a co-surfactant, furthermore when considering microemulsions it becomes
apparent to the formulator that unlike coarse emulsions the formulation of a microemulsion is more
specific and therefore limited in variety [Henri L., et al 1988]. Taking this into consideration it is
important that lipophilic and hydrophilic ingredients are identified and dissolved either in the oil or
water phase accordingly.
Ibuprofen being hydrophobic was firstly weighed and dissolved in ethyl oleate using a magnetic
stirrer and hot plate set at 45°C. This mixture was then added to the surfactant and co-surfactant
(S/CoS) with varying quantities as described in Table 2. Both the S/CoS being hydrophilic meant that
they had to be dissolved in 35ml of purified water at 45°C.
A constant temperature of 45°C was maintained over a water bath, the reason for this being is
because 45°C relates to a Kf
�°�
of 3.9. When a non-volatile solute is added to a liquid solvent, the
freezing point of the solvent is lowered by an amount that is proportional to the molar
concentration of the solute. This lowering (depression) of the freezing point of the solvent is
considered as the Kf.
Kf known as the freezing point depression is in essence a physical characteristic of a material
referred to as the "cryoscopic constant", which is a measure of the response of a material's freezing
point with respect to the presence of a solute dissolved in the material [Kingston Col., 2010]. When
relating this information to the current study, the temperature relating to the Kf is considered the
melting point and a stage at which micellar formation takes place and therefore a point where the
drug being studied is either encapsulated or rejected within the micelles formed. It is important to
maintain such a temperature as fluctuation may cause discrepancies in results due to spontaneous
micellar formation and deformation.
Once both S/CoS had been completely dissolved in water, both aqueous and oil phases were
monitored to ensure they were at the same temperature (45°C) and then the oil phase was added to
the aqueous producing a opaque mixture. The mixture was then homogenised for 20 minutes at
ambient temperature with 5 minute intervals in between.
2.4 Characterisation of Ibuprofen loaded Microemulsions
Optical transparency
When assessing such a property the qualitative approach utilized by [Dhamankar A.K., et al 2009]
was also used within the current study. Here the optical transparencies of the microemulsions were
assessed visually by inspecting the sample in clear and transparent containers under the presence of
good lighting conditions. To further assess this property visually, assessment was also conducted
with the microemulsions placed against black and white illuminated backgrounds.
Determination of pH
Each microemulsion was pH tested over a period of 7 days using the 1IS1670 - Hand Held pH Meter
supplied and standardised with pH 7.0 buffer solutions & calibration tool. In order to ensure
accuracy among results the pH meter after every test was subjected to the buffer solution and the
pH if needed was re adjusted to 7.0.
Viscosity
When considering the viscosities of microemulsions the method found within [Jadhav K.R., Shetye
S.L., et al 2010] was used. The viscosities of the microemulsions were measured by a Brookfield
Digital DV-I Model LVDVI+ Viscometer equipped with Spindle N0
4. Assessment was conducted in
order to determine the difference in rheological behaviour with increasing shear rate; dial readings
were noted at 0.3, 0.6, 1.5, 3.0, 6.0, 12.0 & 30 rpm’s. All measurements were conducted at ambient

temperature and were taken thrice in order to obtain accurate results.
Centrifugation
The stress testing method used by [Jadhav K.R., Shetye S.L., et al 2010] was also used in this study.
Microemulsions systems were subjected to centrifugation at 3000 RPM for 30 minutes each samples
were analysed after every 5 minutes to identify any phase separation.
Conductivity
In order to assess whether the microemulsions are O/W or W/O it is important to carry out
conductivity testing identifying what type of microemulsion has formed as a result of
experimentation. To characterise the conductivity of the microemulsions (Get conductivity meters
spec here) was used.
Amount of separation after 7 days
A key stability attribute when considering any emulsion is the degree of separation. This
characteristic is vital in determining the stability of emulsions as well as concluding whether both
phases are compatible with one another. Therefore the amount of separation was measured among
microemulsions after the duration of 7 days.
Freeze-thaw cycles
Such tests are conducted in order to test for robustness and durability. The experiment conducted
by [Nagaraju M.P., et al., 2010] involved subjecting microemulsions to -20°C for 24h. After this they
were stored at room temperature for another 24h. A similar approach has also been utilised in the
current study allowing one to assess the durability and in many respects stability of the
microemulsions systems when exposed to adverse conditions.
Globule Size Analysis
Each of the acquired emulsions were analysed for globule size upon a (Microscope name) in order to
determine the actual globule size and identify if the emulsions would over time exhibit problems of
creaming and separation. Furthermore such a test also highlighted if the emulsions formulated had
successfully been nano sized.
2.5 Preparation of microemulsion based Hydrogel
After characterising the microemulsions prepared, various microemulsion systems were selected
based on their results and performance throughout the various tests they were subjected to. From
this key candidates selected, further tests would be conducted in order to select a suitable and in
theory an unsurpassed gel with the potential to be further developed and act as a future drug
delivery system.
Firstly a 2% carbopol gel was prepared by dissolving 2g of carbopol into 100ml of distilled water with
constant stirring and agitation. The mixture obtained was left aside for 30 minutes in order to
identify any solids still present. After the carbopol had fully dissolved within 100ml of water, the
thickening agent triethyl acetate was added producing the hydrogel into which the microemulsion of
choice would be introduced.
After constant agitation the desired gel matrix was acquired and could be utilised further. A weight
of 50g of gel was measured upon grease proof paper to which 50ml of microemulsion was added
and stirred in a conical measure till a 100g homogenous gel was obtained.
2.6 Characterisation of Ibuprofen microemulsion loaded gels.
Viscosity Testing
After incorporating the microemulsions into a gel, assessment with regards to rheological behaviour
was necessary. This not only would highlight rheological behaviour but also helps to monitor the
effects of vehicle consistency and effects of a microemulsion being incorporated into a 3D delivery
matrix known as a gel. A Brookfield Digital DV-I Model LVDVI+ Viscometer equipped with Spindle N0
4 was used and the effects of rheological behaviour with increasing shear rate were studied. Dial

readings ranged from 0.3, 0.6, 1.5, 3.0, 6.0, and 12.0 were investigated. The speed was then
successively lowered and the corresponding dial readings were noted. After each measurement, the
viscometer was washed, rinsed and dried.
pH Testing
In order to successfully evaluate the pH of the gels formulated, 2 gm of formulation was dispersed
and dissolved into 20 mL of distilled water from which the pH was investigated. Such a test had
previously been conducted by [Bazigha K. A. R., et al., 2010] and [Dhamankar A.K., et al 2009] for a
transdermal gel formulation of Ketoprofen. Ketoprofen is another propionic acid class of non-
steroidal anti-inflammatory drug that has been developed as a topical gel currently on the market.
Taking this into consideration previous investigations and testing methods that have led to the
success of such a formulation are potential medians that can be utilised in order to achieve similar
results with an Ibuprofen based carbopol gel for transdermal delivery.
Drug release profile of Ibuprofen Hydrogels
Ibuprofen release profiles over time from the various hydrogel formulations were investigated. In
order to mimic the pH of the skin it was important to formulate a buffer simulating the pH and
conditions of the skin. Firstly, 500ml of a 6.7 pH buffer solution was prepared using Di-sodium
hydrogen orthophosphate & Potassium di-hydrogen orthophosphate.
Calculations for Buffer solution
Di-sodium hydrogen orthophosphate: Mass from the BP for dodecahydrate form = 28.80g
Mr from BP for dodecahydrate form = 358.1
Potassium di-hydrogen orthophosphate: Mass required for buffer from BP = 11.45g
In order to get the moles of Di-sodium hydrogen orthophosphate (dodecahydrate form) for the:
.
.
= .
When generating the buffer an anhydrous form of Di-sodium hydrogen orthophosphate was only
present to utilise, where the calculation above from the BP relates to a hydrous form. Due to this,
the moles of Di-sodium hydrogen orthophosphate (dodecahydrate form) acquired had to be
multiplied by the molecular weight of the anhydrous form of Di-sodium hydrogen orthophosphate
(141.96) in order to obtain the mass required to produce a sufficient buffer:
.
.
× . = .
Mass of Di-sodium hydrogen orthophosphate: 11.41g
Mass of Potassium di-hydrogen orthophosphate: 11.45g
After calculating the required amounts of chemical needed, they were mixed and dissolved in a 1ltr
beaker containing 500ml of distilled water and then transferred into a round bottom flask, this was
then placed into a water bath set at 37°C to heat the buffer to 37°C. The pH was checked in order to
regulate as to whether the required pH was achieved or needed achieving. Successfully a pH of 6.7
was achieved and utilised for the dissolution medium in order to investigate the drug release profile
of the Ibuprofen hydrogels.
3g of Ibuprofen hydrogel was weighed out and placed into a diffusion cell ready to be covered with
visking tubing. Previously the visking tubing had been boiled in 100ml of distilled water this would
expand and expose the tubing structure from the original flat film. Once the tube centre was
exposed, it was cut open producing thin visking films that could be placed over the diffusion cell
acting as a semi permeable barrier and in essence simulating further skin conditions.

y = 0,0535x - 0,0119
R² = 0,9995
-0,2
0
0,2
0,4
0,6
0,8
1
1,2
1,4
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Absorbance(nm)
Concentration (mg/ml)
Dissolution calibration curve
Once the diffusion cell was prepared it was then submerged into the dissolution medium. In order to
disperse the drug release throughout the medium mechanical drills were prepared stirring the
medium continuously, which equally dispersed the drug content throughout the medium over
experimental duration.
In order to successfully assay drug content 5ml of medium was removed over times: 5, 10, 15, 20,
25, 30, 40, 50, and 60, 70, 80, 90, 100, 110, 120. During the duration of the experiment for every 5ml
of medium removed for assaying, 5ml of fresh medium from another previously prepared buffer
solution was replaced in order to keep conditions constant and accurate.
Ibuprofen Drug release profile Calibration Curve.
To accurately identify the amount of drug released over time it was necessary to produce a
calibration curve relating to the drug release profile of Ibuprofen. In order to establish this 50mg of
Ibuprofen was dissolved in 2ml of Tween 80.
When considering drug release and dissolution it is important to note that the matrix or medium in
which the testing is taking place plays a significant role in analysing and generating results. During
the assaying ibuprofen content within oil mixtures, it was sufficient to use 0.1M HCl to generate a
successful calibration curve. However, for dissolution this cannot be done as the matrix has changed
to the buffer solution.
Bearing this in mind the pre-dissolved mixture of ibuprofen and Tween 80 was then topped up to
volume using pH 6.7-buffer solution. Theoretically, this would provide an adequate stock solution for
further experimentation. The stock solution having a concentration of (0.5mg/ml) was diluted 10
times using a two-fold dilution providing the calibration curve (Fig 2).

3. Results & Discussion
Assaying super saturated oil/drug mixtures
Due to time and experimental constraints identification as to which oil would sufficiently provide a
high solubility rate of ibuprofen was unable to be investigated. However, from previous literature
and research ethyl oleate has been identified as an entity in which the solubility of ibuprofen is
considerably high [Chen H, Chang T., et al. 2006] [Dhamankar A.K., et al 2009]. Taking this into
consideration ethyl oleate was utilised as the oil phase when formulating the ibuprofen
microemulsions.
3.1 Discussion upon characterisation of Ibuprofen microemulsion systems.
Optical transparency
When subjecting the 8 microemulsion formulations to adequate lighting conditions as well as black
and white backgrounds, the results achieved through optical analysis showed that all 8
microemulsions were translucent, clear and elegant in nature.
Determination of pH
Over the duration of time the pH values of all 8 microemulsions was noted, the results extrapolated
showed pH values ranging from 4.4 to 7.2. This in fact demonstrates that there is a wide pH range
among the microemulsions, which can be manipulated according to the pH required. Furthermore
from (Table 2) & (Fig 3) a key point to be noted is that as there is an increase in the amount of lauric
acid (sodium salt) the pH of the microemulsion gradually decreases resulting in a pH of a more acidic
nature. Although a weak acid, lauric acid (sodium salt) has shown to have a significant effect upon
the pH of microemulsions as a result of its increasing concentrations.
Table 2 pH values of Microemulsions over 7 days
Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Emulsion 0 7.2 7.16 7.14 7.14 7.13 7.12 7.1 7.1
Emulsion 1 7.11 6.99 6.97 6.93 6.9 6.87 6.87 6.85
Emulsion 2 6.86 6.79 6.78 6.74 6.7 6.69 6.67 6.67
Emulsion 3 6.38 6.32 6.31 6.31 6.3 6.27 6.25 6.25
Emulsion 4 6.06 5.9 5.9 5.88 5.84 5.82 5.8 5.8
Emulsion 5 5.58 5.55 5.55 5.53 5.5 5.48 5.48 5.48
Emulsion 6 5.29 5.24 5.22 5.21 5.2 5.18 5.15 5.15
Emulsion 7 5 4.95 4.9 4.88 4.85 4.83 4.8 4.8
Emulsion 8 4.7 4.62 4.58 4.55 4.52 4.5 4.47 4.47
Figure 2 Calibration curve for dissolution studies

4,3
5,3
6,3
7,3
Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
pH
Time (Days)
pH testing of Microemulsions over 7 days
Emulsion 0
Emulsion 1
Emulsion 2
Emulsion 3
Emulsion 4
Emulsion 5
Emulsion 6
Emulsion 7
Emulsion 8
Viscosity
Over time viscosity testing has become a potential method for elucidating and analysing the internal
physiochemical states of microemulsions. The viscosity acts as a key candidate in providing first hand
information upon the internal consistency of solutions. From the results (Table 3) & (Fig 4) it is
apparent that all 8 microemulsions exhibit lamellar or Newtonian behaviour, in essence this means
that has the shear rate increases so does the viscosity of microemulsions. Moreover according to
literature previous studies have also shown similar results with regards to microemulsion systems
validating such behaviour and results generated [Škoviera, F., Ža ka, M., ] [Kizilbash N.A., et al.
2011]
Furthermore according to [Bidyut K.P., Moulik S.P., 2000] Microemulsions can exhibit varied flow
behaviour, this either being lamellar (Newtonian) or non lamellar (non-Newtonian). In addition to
this further commentary highlights that microemulsion systems which posses a low viscosity may be
of a lamellar or Newtonian nature [Talegaonkar S et al., 2008].
When applying this to the current study and results generated it comes to attention that the
microemulsions exhibit a significantly low degree of viscosity. Taking this in account in conjunction
with what has previously been stated by [Bidyut K.P., Moulik S.P., 2000] it is certain that the
microemulsions generated are of a low viscosity and exhibit Newtonian behaviour.
This in many instances is beneficial for formulations such as oral, parenteral, pulmonary or even
ocular delivery. However microemulsions of a more viscous nature are required for topical delivery
formulations [Lawrence, M.J and Rees, G.D., 2000]. Furthermore suitable systems for such drug
delivery would include microemulsions which have been thickened through specific gelling agents
[Trotta M., Morel S., Gasco M.R., 1997] [Kantaria S., Rees G.D., Lawrence M.J., 1999].
This in essence suggests that microemulsions systems of such a nature are unwanted candidates
when applied to topical drug delivery. However with the aid of gelling agents such microemulsion
systems can be incorporated into potential drug delivery mechanisms. In summary this highlights a
further need for products consisting of an ibuprofen microemulsion based carbopol gel.
Another particular trend or pattern arising during viscosity testing is the decrease in viscosity as a
result of increased co surfactant concentrations. In theory the primary surfactant is responsible for
determining the initial curvature of the dispersed phase, this being a result of absorption at the
oil/water interface. Similarly the co surfactant also absorbs at the interface to produce mixed duplex
films. Appearing in a dynamic state the co surfactant initially causes a transitory lowering of the
Figure 3 pH graphs of Microemulsion systems

interfacial tension required for dispersion [Henri L., et al 1988].
Table 3 Viscosity values of Microemulsion systems
When considering the above and applying it to the current study, a possible result for the rheological
behaviour can be explained. With reference to the above the co surfactant is primarily responsible in
lowering the interfacial tension during initial dispersion; this in essence could have an effect upon
the overall surface tension inducing it to become lower even after the transitory period.
Furthermore both Lauric acid (sodium salt) and Tween 80 are surfactants and in essence lower
surface tension therefore increasing the volume among either one will in essence increase the
degree to which the surface tension is lowered.
Further literature states microemulsions displaying low rheological behaviour are most probably
considered as Winsor I or Winsor II types. Multiphase systems firstly investigated by P. Winsor where
key distinctions were made with regards to multiphase systems [Bidyut K.P., Moulik S.P., 2000]:
- Winsor 1) Two phases, the lower microemulsions phase in equilibrium with the upper excess
oil phase.
- Winsor 2) Two phases, the upper microemulsions phase in equilibrium with the lower excess
water phase.
- Winsor 3) Three, phases, middle microemulsion phase in equilibrium with the upper oil
excess oil and lower excess water phases.
- Winsor 4) Single phase, oil, water and surfactant and are homogeneously mixed and one is
dispersed in the other.
Taking this into consideration and what has previously been mentioned, it is apparent that the
microemulsions produced are either of Winsor I or Winsor II types simply based upon their
rheological behaviour.
Lastly as a result of a lower surface tension the viscosity would in theory also be lower. Applying this
to what has previously been suggested an increasing co surfactant concentration would lower
viscosity as a result of lowering the initial surface tension and surface tension as a whole. Therefore
results displayed fortunately follow expectation and scientific reasoning.
Emulsion
0
Emulsion
1
Emulsion
2
Emulsion
3
Emulsion
4
Emulsion
5
Emulsion
6
Emulsion
7
Emulsion
8
0 0 0 0 0 0 0 0 0 0
0.3 57 60 54 46 48 37 32 32 30
0.6 150 139 130 142 130 127 109 108 106
1.5 186 180 174 167 156 150 138 136 133
3 213 206 197 208 193 187 179 176 172
6 233 221 216 217 199 192 183 183 179
12 240 232 228 225 214 205 198 199 190
30 241 232 228 227 213 207 199 199 190

Figure 4 Viscosity graphs of Microemulsion systems
Centrifugation
A centrifugation technique in theory helps to determine behaviour of small particles in the presence
of a gravitational field, this in particular can be utilised in order to provide a full scale identification
regarding a microemulsions system. Fortunately microemulsions systems did not show signs of
separation when centrifuging at 3000 rpm for 30 minutes. This is beneficial as it highlights that the
microemulsion systems analysed are stable and robust to a specified degree.
On the other hand when researching literature it is apparent that in order to analyse phase
separation among microemulsions, centrifugation speeds as high as 6 , rp ’s [Hwan R.N., Miller
C.A & Fort T., 1979] have been utilised in the past. Other studies have utilised speeds of 5,000
[Gasco M.R., et al., 1979] and current more recent studies have used 10,000 to 13,000rp ’s
[Dhamankar A.K., et al 2009] [Darole P.S., Hegde D.D., Nair H.A., 2007].
Upon reviewing this literature it is apparent that the centrifugation speeds required when assessing
the stability of a microemulsion is variable. Unlike macroemulsions consisting of average sized
globules and thermodynamics microemulsions systems are far more complex and minute in terms of
globule size. Taking into consideration the nature of microemulsions, it is suggested that in order to
successfully strip the interfacial films around globules within micronized systems a high degree of
energy and therefore higher G forces are required.
Applying this knowledge to the experiment at hand, one can conclude as to the fact that the
centrifugation speeds applied to the microemulsion systems were insufficient and therefore results
produced are classed as inconsistent and inaccurate. In order to avoid such trivial mistakes when re
conducting such an experiment one can attempt to use higher speeds ranging between 15,000-
, rp ’s atte pti g to over o e the a ove o strai ts a d i essence provide more accurate
results.
Conductivity
A fundamental method employed when characterising microemulsions is conductivity. Conductivity
is a method used to determine whether the microemulsion system is of an oil/water or water/oil
nature. Combined with this conductivity is also a tool used to monitor percolation of phase inversion
phenomena. After commencing testing it was found that all microemulsion systems generated were
successfully of an oil/water nature.
0
50
100
150
200
250
0 0,3 0,6 1,5 3 6 12 30
ViscositycP
Shear Rate (RPM)
Viscosity Testing of Ibuprofen Microemulsions
Emulsion 0
Emulsion 1
Emulsion 2
Emulsion 3
Emulsion 4
Emulsion 5
Emulsion 6
Emulsion 7
Emulsion 8

0,1
0,6
0,4
0 0 0 0 0 0
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
AmountofCream(cm)
Emulsion No
Measuring the amount of seperation after 7
days.
Emulsion 0
Emulsion 1
Emulsion 2
Emulsion 3
Emulsion 4
Emulsion 5
Emulsion 6
Emulsion 7
Emulsion 8
Amount of separation after 7 days
After the duration of seven days microemulsion systems were examined for phase separation in
effect cracking or creaming among the microemulsion systems (Table 4) & (Fig 5). As can be
seen from the results three particular emulsions have shown signs of phase separation or some
degree of cracking or creaming .
As stated previously the concentrations of co surfactant can have a significant effect upon the
characteristics of microemulsion systems. When applying such a phenomenon to this study it is
suggested that, due to insufficient levels of co surfactant, the initial dispersion crucial to take place
at transitory stages has not been able to establish efficient miscibility among phases. As a result of
this phase separation has occurred after seven days.
However after the system is given an adequate amount of co surfactant that can aid within the initial
dispersion stages, microemulsion systems do not show signs of phase separation behaviour. This in
fact further strengthens the above argument that limited amounts of co surfactant among the first
two emulsions and the reference has resulted in production of globules aggregating and producing a
cream. Or due to ample amounts of co surfactant the two phases have not been able to efficiently
mix resulting in further the emulsion cracking.
Table 4 Measuring amount of separation after 7 days
Amount of creaming (cm)
Emulsion 0 0.1
Emulsion 1 0.6
Emulsion 2 0.4
Emulsion 3 0
Emulsion 4 0
Emulsion 5 0
Emulsion 6 0
Emulsion 7 0
Emulsion 8 0
Freeze-thaw cycles
Figure 5 Measuring the amount of seperation after 7 days

The method used for this experiment was that of [Nagaraju M.P., et al., 2010]. Upon reviewing the
microemulsions after storage in these conditions, a key observation made was that each and every
microemulsion system had cracked. Cracking is in essence a distinct separation of the two phases
from one another. Ideally such a result detriments the efficacy and stability of the systems produced
almost excluding them as potential drug delivery systems.
However when analysing the method used for such a test it is apparent that, the sole purpose of
such a method is to crack the emulsions. This is because temperature cycling is not permitted when
testing is being conducted. Rather microemulsion systems are exposed to adverse conditions from
the beginning instead of them being analysed over a range of temperatures.
After evaluation such a test could be conducted at temperatures ranging from:
- -5°C to-8°C
- Room Temperature
- 40°C to 45°C
Each microemulsion would be subjected to the above temperatures for no longer than 2 days. Such
a method would not only provide versatility within the temperatures the microemulsion is exposed
to but also give a better indication with regards to the general stability of the microemulsion
systems. Another possible methodology that could be utilised is that proposed by [Kumar B., Jain
S.K., Prajapati S.K., 2011] here six cycles between refrigerator temperature (4°C) and 45°C were
what microemulsions had to be subjected to for no longer than 48h. Formulations that proved
to be stable at these temperatures were then further exerted to adverse conditions of
temperatures between –21°C and 25°C.
In practice this method has firstly utilised the practice of heat-cool cycles in order to exhibit
microemulsions to mild but stringent conditions. Secondly it has then exposed them to harsh
conditions like those of [Nagaraju M.P., et al., 2010]. This method basically allows formulators to
assess the efficacy of such formulations at realistic temperatures those being of -4° to 45°C, then
upon exertion to adverse condition it indicates the degrees of stability and how tolerant the
microemulsion system is to conditions of an abnormal nature.
Both provide insight into the general efficacy of microemulsion systems present within everyday
conditions as well as giving information on the boundaries of stability of the microemulsion system
when placed in adverse conditions.
Globule Size Analysis
An attempt was made to review the microemulsion systems under a standard light microscope. This
in essence would allow one to analyse globule size over a specific duration highlighting discrepancies
and problems of aggregation leading to undesirable effects of creaming. However this attempt was
unsuccessful as the resolutions upon the microscope could not provide sufficient magnification to
analyse the systems formulated.
Conversely this can be considered as beneficial, due to the fact that nothing could be seen upon the
light microscope a possible suggestion is made as to whether the system has successfully formulated
micronized globules encapsulating drug particles which characterise to be that small they cannot be
observed. Although this may not be the case such a possibility can still exist giving rise to further
experimentation and characterisation if necessary.
After characterising the various different microemulsions, certain considerations were taken into
account. A key consideration was the problem of creaming that had occurred within microemulsions
1 and 2, this is an undesirable property and therefore due to the fact that the mentioned
microemulsions highlighted such a characteristic their performance had been detrimented excluding
them as potential candidates to be further developed into hydrogels.
Similarly undesirable characteristics had been demonstrated within microemulsions 6 & 8.
Unfortunately when considering microemulsion 8 although it had acceptable characteristics the co
surfactant used as previous generated a very high degree of foam. This in essence caused an

overflow of formulation resulting in its loss. Due to inconsistent volumes of the emulsion it could not
be successfully developed into a hydrogel. Microemulsion 6 also highlighted undesirable
characteristics of microbial contamination due to external factors and therefore it too could not be
incorporated into a hydrogel.
Due to the above disappointments and limitations the microemulsion systems successful that were
developed into hydrogel formulations are: Microemulsion 0 (ref), 3, 4, 5 & 7.
3.2 Discussion upon characterisation of Ibuprofen based microemulsion hydrogels
Viscosity
Results indicate that all 5 microemulsion systems have demonstrated pseudoplastic behaviour. This
in fact is a desirable attribute in a microemulsion formulation. At a low rpm these microemulsions
show high viscosity, upon increasing the shear rate the viscosity drops which would in essence allow
ease of application upon the skin surface.
Table 5 Viscosity values of Ibuprofen based Microemulsion hydrogels
Emogel 0 Emogel 3 Emogel 4 Emogel 5 Emogel 7
0.3 889,000 806,000 936,000 974,000 814,000
0.6 616,000 533,000 568,000 644,000 440,000
1.5 290,000 254,000 280,000 308,000 222,000
3 169,000 149,000 162,000 180,000 129,000
6 100,000 89,400 96,000 110,000 77,500
12 0 0 0 0 46,000
6 99,900 89,500 96,200 100,000 77,900
3 171,000 151,000 163,000 180,000 131,000
1.5 294,000 254,000 281,000 309,000 220,000
0.6 618,000 530,000 585,000 634,000 462,000
0.3 1,090,000 930,000 1,060,000 1,090,200 826,000

0
100.000
200.000
300.000
400.000
500.000
600.000
700.000
800.000
900.000
1.000.000
1.100.000
0,3 0,6 1,5 3 6 12 6 3 1,5 0,6 0,3
Viscosity(cP)
Shear Rate (RPM)
Viscosity Testing of Ibuprofen Hydrogels
Emogel 0 Emogel 3 Emogel 4 Emogel 5 Emogel 7
pH Testing
Ibuprofen based microemulsion hydrogels were cream in colour and pH values displayed ranged
between 7.7-4.7. Ideally a pH of 4.5-5.0 is required as such a pH is compatible with normal skin pH in
healthy people [Hadgraft J., 2001]. Taking this into consideration the only hydrogels to provide a
desirable pH are 5 & 7. Hydrogel formulation 3 & 4 provide more alkali pH conditions deviating from
that which is required for skin conditions.
Table 6 pH values of Ibuprofen based microemulsion hydrogels over 5 days.
Day 0 Day 1 Day 2 Day 3 Day 4 Day 5
Emulsion 0 7.2 7.16 7.14 7.14 7.13 7.12
Emulsion 3 6.35 6.33 6.29 6.22 6.2 6.2
Emulsion 4 6.1 5.95 5.95 5.88 5.84 5.8
Emulsion 5 5.28 5.23 5.21 5.19 5.19 5.18
Emulsion 7 4.83 4.83 4.79 4.76 4.74 4.71
A possible explanation for this as stated before maybe because of the presence of lauric acid
(sodium salt). Even though lauric acid (sodium salt) is considered a weak acid it has proved to
significantly affect both microemulsion and hydrogel formulations, not only does this validate the
fact that lauric acid is playing a significant role in manipulating the pH of these drug delivery
formulations but it also highlights that salt forms of weak acids can provide adequate manipulation
of pH values.
Figure 6 Viscosity graph of Ibuprofen based Microemulsion hydrogels

4,5
5
5,5
6
6,5
7
7,5
Day 0 Day 1 Day 2 Day 3 Day 4 Day 5
pHofIbuprofenHydrogels
Time (Days)
pH Testing of Ibuprofen Hydrogels over 5
days
Emulsion 0
Emulsion 3
Emulsion 4
Emulsion 5
Emulsion 7
4. Conclusion
The potential for nano-particle drug delivery to the skin has progressed over the last dozen years to
an extent where there are now well characterised tools ready to be utilised. From solid lipid nano
particles, to nano particles devised to increase or decrease the flux, or to customise the drugs site of
action, right up to selectively permeablising the stratum corneum, drug delivery has been exploited
to its core [Prow T.W., et al., 2011].
The current study has highlighted the efficacy of microemulsion systems and their application alone
as potential drug delivery mechanisms. Microemulsion systems reviewed provide to be limited in
physical characteristics such as viscosity, pH and to a minute degree thermodynamic stability.
However when incorporated into a hydrogel formulation the previous limitations are excluded and
efficacious and stable drug delivery mechanism are developed providing adequate drug delivering
capacities. Taking this into consideration and acknowledging all previous research conducted it is
apparent that Ibuprofen although a problem drug can be persuaded
Figure 3 pH graph of Ibuprofen based microemulsion hydrogels

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