Development of Microemulsion For Solubility Enhancement of Poorly Water Soluble Drug Valsartan
Development of Microemulsion For Solubility Enhancement of Poorly Water Soluble Drug Valsartan
Development of Microemulsion For Solubility Enhancement of Poorly Water Soluble Drug Valsartan
Research Article
MCM, castor oil, rice bran oil, oleic acid, labrafil 1944 CS 650 nm with distilled water taken as blank and three
and captex 355 were taken for the studies. Also various replicates were performed for each sample.6,8,11
surfactants like tween 80, span 20, cremophor EL, and
pH determination
cremophor RH 40 were taken and co-surfactants like iso-
propanlol, ethanol, transcutol HP, transcutol P, capryol The apparent pH of all the selected micro emulsions and
90, polyethylene glycol (PEG) 400 and propylene glycol the plain micro emulsion was determined at 25°C by
(PG) were taken for solubility studies. 2 ml of each of the immersing the electrode directly into the micro emulsion
selected vehicle were added to each cap vial containing using a digital pH meter.8,12
an excess of valsartan. After sealing, mixtures were
o Refractive index
shaken with shaker at 25 C for 48 hr. After reaching
equilibrium, each vial was centrifuged at 500 rpm for 15 Refractive indices of the prepared micro emulsions were
min, and excess insoluble valsartan was discarded by determined at 25°C by Abbe’s refractometer by placing
filtration using a membrane filter (0.45 µm, 13 mm, one drop of micro emulsion on the slide.6,9
Whatman). The concentration of valsartan was
Viscosity measurement
determined in each oils, surfactants, and co-surfactants
by UV spectrophotometer at their respective wavelength Micro emulsions are generally low viscosity systems. The
250 nm.6 viscosity of the prepared micro emulsion was measured
at 25°C at 60 rpm by LV spindle no. 63 using a Brookfield
Pseudo-ternary phase diagram
viscometer (model LVDVE230; Brookfield Engineering
Pseudo-ternary phase diagrams were constructed to Laboratories, Inc).6,8,12
obtain the appropriate components, and their
Determination of Drug Content in the micro emulsion
concentration ranges that resulted in a large existence
area of micro emulsion were chosen. In order to optimize The drug content of the micro emulsion formulation was
the concentration of oil phase, surfactant and co- determined by dissolving 1 ml (equivalent to 10 mg drug)
surfactant, different batches of varied concentration were of the formulation in 10 ml of methanol. After suitable
prepared and titrated with distilled water till dilutions with methanol, absorbance was determined
transparency persisted. Ternary phase diagram was using the UV spectrophotometer keeping blank micro
prepared by using a constant ratio of surfactant to co- emulsion as control at wavelength 250 nm and three
surfactant. Four ratios of surfactant (Cremophor EL) and replicates were performed for each sample.5,6,8
co-surfactant (Transcutol HP) were selected (1:1, 2:1, 3:1
Particle size Determination
and 4:1). At each specific Smix weight ratio, the ratio of
oil to the Smix was varied as 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, The particle size of the plain micro emulsion and final
7:3, 8:2 and 9:1. Each mixture of oil, surfactant and co- formulation F4 was determined by using particle size
surfactant, at specific weight ratio were titrated with analyzer Nanophox (NX0088) Sympatec, Germany
water along water dilution lines. If clear and transparent performed at Sinhagad Institute of Pharmacy, Pune.9
mixtures were visualized after stirring, the samples were
Drug release studies
considered to be monophasic and were marked as points
in the phase diagrams and areas covered by these points In-vitro drug release
were considered as the micro emulsion region of The diffusion study was carried out using a modified Franz
existence region. Maximum micro emulsion region was diffusion cell. The receptor compartment was filled with
optimized for further studies and four ratios of the 30 ml of Phosphate buffer (pH 5.5). The donor
optimized formulation were characterized. compartment was fixed with cellophane membrane and it
Preparation of Valsartan micro emulsion system contained micro emulsion (Valsartan) and plain drug
suspension separately. At predetermined time intervals of
Valsartan containing micro emulsion was prepared by
30 minutes samples were withdrawn from receptor
water titration method. Valsartan was first dissolved in
compartment and analyzed for drug content by UV
the pre-measured volume of oil by stirring on a magnetic 10
Spectrophotometer at 250 nm.
stirrer. A mixture of the surfactant and co-surfactant at a
fixed ratio (v/v) was added to the above resulting In-vitro intestinal permeability study
mixture. Finally this mixture was titrated with distilled The methods employed were modified from experimental
water. The optimized micro emulsion drug delivery procedures. Male albino rats (250-300 g) were killed by
8
system was also subjected for accelerated stability study. overdose with pentobarbitone administered by
Characterization of micro emulsion intravenous injection. To check the intra-duodenal
permeability, the duodenal part of the small intestine was
Percentage Transmittance
isolated and taken for the in vitro diffusion study. Then
Transparency of micro emulsion formulation was this tissue was thoroughly washed with cold Ringer’s
determined by measuring percentage transmittance solution to remove the mucous and lumen contents. The
through U.V. Spectrophotometer (UV-1601 SHIMADZU) at equivalent dose of optimized micro emulsions and plain
drug solution were prepared. One side of the intestine
International Journal of Pharmaceutical Sciences Review and Research
Available online at www.globalresearchonline.net 247
Int. J. Pharm. Sci. Rev. Res., 22(2), Sep – Oct 2013; nᵒ 45, 246-251 ISSN 0976 – 044X
F1 F2 F3 F4
Figure 1: Ternary phase diagrams representing the micro emulsion formed with Capmul MCM (oil), Cremophor EL
(surfactant) and Transcutol HP (co-surfactant).
Pseudo-ternary phase diagram formed. Thus, four ratios of the optimized formulation
were selected.
Pseudo-ternary phase diagrams were constructed by sing
Capmul MCM (oil), Cremophor EL (surfactant) and Characterization of the micro emulsion
Transcutol HP (co-surfactant) to identify the micro
The optimized formulations were further studied for
emulsion existing zone from which appropriate
percent transmittance, drug content, pH determination,
concentration ranges of components of micro emulsion
refractive index and viscosity of the different ratios of the
can be obtained. The ternary phase diagrams of all the
selected system:
ratios are shown in figure 1. Formation of micro emulsion
systems (the shaded area) was observed at room Percentage Transmittance
temperature. Phase behavior investigations of this system
The percent transmission carried out on UV
demonstrated the suitable approach to determine the
spectrophotometer at 650 nm was found to be in the
water phase, oil phase, surfactant concentration, and
range of 98.23 % to 99.37 % for formulations F1 to F4
cosurfactant concentration with which the transparent,
along with the plain formulation which confirms good
one-phase, low-viscous microemulsion system was
transparent nature of formulations.
Figure 2: Shows the particle size determination of the drug loaded formulation.
Drug release studies In-vitro intestinal permeability study
In-vitro drug release study From the figure 4, it was seen that after 4 hours of
diffusion, 99.478% of the drug was released from the
It was seen that after 4 hours of diffusion, the drug
formulation F1 which is higher than that of the other
released from the formulation F1 faster and more than
ratios. Hence, F1 formulation was selected as optimized
that of the other ratios i.e., 93.410%. The results are
formulation and was considered for comparison with the
shown in figure 3.
plain drug suspension. From the comparison study of F1
formulation and plain drug suspension, it can be
concluded that the extent of diffusion of valsartan from
the Capmul micro emulsion is greater than the plain drug
suspension as shown in figure 5.
Stability studies
Stability studies of selected formulation were carried out
at 30°C±2°C, 4°C±2°C and 40°C±5°C. The results of
stability are shown in table 3.
The optimized micro emulsion formulation F1 containing 6. Srinivas C, Sagar SV, Enhancing the Bioavailability of
Simvastatin Using Micro emulsion Drug Delivery System,
Capmul MCM as oil (2%), Cremophor EL as surfactant
Asian Journal of Pharmaceutical and Clinical Research, 5,
(18%), Transcutol HP as co-surfactant (18%) and distilled 2012, 134-139.
water (62%) was a transparent, clear and low viscosity
system, with particle size 51.32 nm. The percent 7. Mandal S, Mandal SS, Micro emulsion drug delivery system:
transmission and the refractive index was found to be A Platform for improving dissolution rate of poorly water
soluble drug, International journal of pharmaceutical
99.37% ± 0.16% and 1.3620 respectively which shows the
sciences and nanotechnology, 3, 2011, 1214-1219.
good clarity of the prepared micro emulsion. The micro
emulsion showed the viscosity 66.66 ± 5.7 cp. The pH was 8. Mandal S, Mandal SS, Surti N, Patel VB, Design And
found to be 3.76 ± 4.20 and the drug content was found Development Of Saquinavir Micro emulsion For The Oral
Bioavailability Enhancement, International Journal of
to be 99.42% ± 0.31%. After the in vitro intestinal
PharmTech Research, 1, 2009, 1442-1448.
9. Madhav S, Gupta D, A Review On Micro emulsion Based 11. Sarkar BK, Hardenia SS, Micro emulsion Drug Delivery
System, International Journal of Pharmaceutical Sciences System: For Oral Bioavailability Enhancement of Glipizide,
and Research, 2, 2011, 1888-1899. Journal of Advanced Pharmacy Education & Research, 1,
2011, 195-200.
10. Ghosh PK, Majithiya RJ, Umrethia ML, Murthy RSR, Design
and Development of Microemulsion Drug Delivery System 12. Joyce NM, Chandrasekaran N, Mukherjee A, Enhanced
of Acyclovir for Improvement of Oral Bioavailability, Solubilization of Aqueous Insoluble Anti-Hypertensive Drug,
American Association of Pharmaceutical Scientists, 7, 2006, International Journal of Pharmacy and Pharmaceutical
E1- E6. Sciences, 4, 2012, 366-368.