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Gaikwad et al. World Journal of Pharmacy and Pharmaceutical Sciences
FORMULATION AND CHARAC TERIZATION OF SOLID LIPID
NANOPARTICLES OF QUETIAPINE FUMARATE TO IMPROVE
SOLUBILITY
Maya Y. Gaikwad*, Amol S. Deshmukh and Vijay R. Mahajan
SMBT College of Pharmacy, Nandi- Hills Dhamangaon, Nashik Maharashtra, India.
ABSTRACT
Quetiapine fumarate is an antipsychotic drug with plasma half-life 6
hr. and having poor oral bioavailability (9%) because of first pass
metabolism. The aim of the present study was to develop an optimal
SLN formulation of Quetiapine fumarate to improve solubility and oral
bioavailability. Liquid dispersion of SLN were framed with Oleic acid
as oil phase, Cremophor RH 40 and Tween 20 as surfactant and
Transcutol P as co-surfactant after screening several vehicles. The
prepared formulation was constructed by using phase diagram to
optimize the system. Solidification of SLN was done by using spray
drying technique using Aerosil 200 as solid carrier. The drug release study shows that the
release of Quetiapine fumarate was enhanced in SLN formulation as compared to plain drug
and marketed formulation. Stability study shows that there was no sign of change in drug
content was observed.
KEYWORDS: Pseudoternary phase diagram, Quetiapine fumarate, SLN, Oral
bioavailability.
INTRODUCTION
Currently, majority of the new drug molecules being discovered are lipophilic and exhibits
poor water solubility which results in low bioavailability, intra and inter subject variation and
lack of dose proportionality. Limited water solubility have a challenge in developing optimum
oral solid dosage form in terms of formulation design, bioavailability and marketing of new
pharmaceutical products. Several formulation approaches have been approved to overcome
these challenges either by means of altering the solubilization or maintaining the drug in
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 7.632
Volume 9, Issue 2, 943-963 Research Article ISSN 2278 – 4357
*Corresponding Author
Maya Y. Gaikwad
SMBT College of Pharmacy,
Nandi- Hills Dhamangaon,
Nashik Maharashtra, India.
Article Received on
06 Dec. 2019,
Revised on 27 Dec. 2019,
Accepted on 17 Jan. 2020
DOI: 10.20959/wjpps20202-15453
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dissolved form throughout gastric transit time. These strategies may consist of the surfactants,
cyclodextrins, Micronization, salt formation pH change, nano size delivery, solid dispersions
and permeation enhancer. In fact, most commonly used approaches are, digestion of the active
pharmaceutical ingredient into inert lipids such as oils and surfactant dispersions, SLN, self-
emulsifying formulations, emulsions and liposomes.[1]
Solid lipid nanoparticle (SLN) is the term introduced in early 90s which is an alternative carrier
system to traditional colloidal carriers corresponds to emulsions, liposomes, polymeric nano
and microparticles. SLN are sub-micron colloidal carriers ranging from 50 to 1000 nm, which
are composed of physiological lipid, dispersed in water or in aqueous surfactant solution. SLN
suggest distinctive properties like large surface area, high drug loading, small in size and the
interaction of phases at the interface that also have likely to improve performance of
pharmaceuticals. The reasons for the enhancing interest in lipid based system are –
1. Lipids improve oral bioavailability of drug and ultimately decreases plasma profile
variability.
2. Better characterization of lipoid excipients.
3. Enhanced capacity to address the key issues of technology transfer and manufacture scale
up.[2]
The majority of orally administered drugs gain access to the systemic circulation by absorption
into portal circulation. However, some extremely lipophilic drugs (log P > 5, solubility in TG
> 50 mg/ml) gain access to the systemic circulation via lymphatic route, which avoids hepatic
first pass metabolism. Therefore, highly metabolized lipophilic drugs are suitable candidates
for solid lipid nanoparticles, a lipid based delivery. Compounds showing increased
bioavailability in the presence of lipids (dietary or lipid-based formulation) are absorbed via
the intestinal lymph as they are generally transported in association with the long chain TGs
lipid core of intestinal lipoproteins which is formed in the enterocyte after re-esterification of
free FAs and MGs. Short chain TGs are mostly absorbed in the portal blood. Hence it is likely
that the drug transport via the lymphatic needs co administration of lipid to stimulate
lipoprotein formation.[3]
Quetiapine Fumarate is chemically 2-[2-(4-{2-thia-9azatricyclo[9.4.0.0{3,8}]pentadeca-
1(11),3(8),4,6,9,12,14-heptaen10-yl}piperazin-1-yl)ethoxy]ethan-1-ol is an atypical
antipsychotic agent which acts as an antagonist of dopamine and serotonin receptors.
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Quetiapine Fumarate is an antipsychotic BCS class II drug having low solubility and high
permeability. It is reported to have very low oral bioavailability (9%) reason being its limited
absorption due to moderate solubility in water and extensive hepatic metabolism.[4] Possible
methods to avoid first-pass metabolism include transdermal, buccal, rectal, and parenteral
routes of administration. Oral route is the most frequently used and ideal route for the delivery
of drugs, although some factors like pH of GIT, residence time, and solubility can affect drug
absorption or availability by this route. Lymphatic delivery is an alternative option to avoid
first-pass metabolism in oral drug delivery. The main purpose of the lymphatic system is to
facilitate absorption of long-chain fatty acids via chylomicron formation. Two different lipid-
based approaches are known to enhance the lymphatic transport, which comprise of
construction of a highly lipophilic prodrug and incorporation of drug in a lipid carrier.[5]
MATERIALS AND METHODS
Present investigation was carried out in the year 2019 at S. M. B. T. College of Pharmacy,
Dhamangaon, Pune University, and Maharashtra, India.
Materials: Quetiapine fumarate was received as a gift sample from Akums Drugs and
Pharmaceuticals Ltd., Haridwar. Lipids including Capryol 90, Isopropyl myristate, Oleic acid,
Castor oil and Olive oil; Surfactants including Tween 20, Tween 80, Span 80, Labrasol and
Cremophor RH 40; Co- surfactants including Ethanol, Isopropyl alcohol, Propylene glycol,
PEG 400 and Transcutol P all are received from Research Lab Fine Chem Industries and
Gattefosse Foundation Lab Industries. All the chemicals and solvents used were of analytical
grade.
Method
UV Method: Weighed accurately 10 mg of Quetiapine fumarate and transferred to 100 ml
volumetric flask. The drug was dissolved in methanol and make up the volume. This was
used as the standard stock solution for further dilutions. Appropriate quantities of aliquots
(0.2 ml to 1 ml) of the standard stock solution were taken in 10 ml volumetric flask. The
absorbance of solutions was recorded at 248 nm by using the Thermo-fisher UV-2600 double
beam spectrometer.[6]
Solubility studies: Screening of excipients can be done by determining the equilibrium
solubility of Quetiapine Fumarate in different oil, surfactant, and co-surfactant. The solubility
of in different oils, surfactant and co-surfactant was determined using shake flask method. An
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excess amount of Quetiapine fumarate was added to each vial containing 2ml of each
excipients, and mixed by vortexing in order to facilitate proper mixing of Quetiapine
fumarate with the vehicles. Vials ware then shaken for 48hrs in a thermostatically controlled
shaking water bath at 37± 1°C followed by equilibrium for 24 hrs. in order to separate the
undissolved drug, the supersaturated sample was centrifuged at 3000 rpm for 10 min. The
supernatant was then filtered using a membrane filter (0.45μm, Whatman filter, and paper) and
suitably diluted with methanol. The drug concentration was obtained via UV validated method
at 248nm.[7]
Construction of Phase Diagram: In water titration method, the mixture of oil and surfactant
(A+B) /co-surfactant (S/CoS) at certain volume ratios was diluted with water in a drop wise
manner. The ratios of surfactant (A+B) /co-surfactant were prepared in specific manner, i.e.
1:1, 2:1, and 3:1(w/w). Each of these ratios was mixed with increasing percentage of oil, i.e.
10%, 20%, 30% up to 90% to get phase diagram. Phase diagram was constructed using
Chemix School 4_00.[8]
Preparation of Liquid dispersion of SLN: Liquid dispersion of SLN were prepared by
dissolving drug in lipid heated above its melting point followed by addition of surfactant
(A+B) and co-surfactant maintaining same temperature by pouring in ice cold water, vortex the
mixture to get aqueous dispersion of SLN.[9]
Characterization of Liquid dispersion of SLN
Drug content determination: Amount of drug present in aqueous dispersion formulation
was determined by UV Spectrometric method. Weighed accurate quantity of liquid
formulation equivalent to 10 mg of drug (Quetiapine fumarate) in 100ml volumetric flask and
was diluted with methanol to make up volume upto 100 ml. Further 1 ml of the solution was
diluted to 10 ml using methanol to make 10μg/ml solutions. The drug content was analysed
by taking UV absorbance at 248 nm.[10]
Drug release study: The in vitro dissolution study of liquid formulations and plain drug were
carried out using dissolution test apparatus no. 1 as per IP. Quantity equivalent to 10 mg of
liquid formulation was added to dissolution media. Samples of 5 ml at 5 min interval were
withdrawn at regular time 5 min to 60 min and filtered using Whatman filter paper. An equal
volume of respective dissolution medium was added to maintain the volume constant. Drug
release was analyzed using UV-spectrophotometer at 248 nm.[11,12]
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Precipitation assessment: Liquid formulations was diluted upto 100 times with distilled
water with continuous stirring on magnetic stirrer to form emulsion. Precipitation was
evaluated by visual inspection of the resultant emulsion after 24 hrs. The formulations were
categorized as clear (transparent, or transparent with bluish tinge), non-clear (turbid), stable
(no precipitation at the end of 24 hours, or unstable (showing precipitation within 24 hrs).[13]
Refractive Index: Refractive index proved to the transparency of formulation. The refractive
index of the system is measured by Abbe refractometer by placing drop of solution on slide
and recording the refractive index. Oleic acid, Tween 20, Transcutol P and liquid formulation
were noted.[14]
Zeta potential measurement: Liquid formulation containing 10 mg of Quetiapine fumarate
was diluted to 20 ml with distilled water in a flask and was mixed gently by inverting the
flask. The particle size so formed was determined by dynamic light scattering (DLS)
technique using Zetasizer (Nano ZS, Malvern Instruments, UK). With the zeta potential
Electrophoretic mobility was also determined.[15]
Stability study of aqueous dispersion of SLN.[16-18]
1. Thermodynamic Stability Studies: The liquid formulation were filled in vials and was
kept at different temperature condition to check the stability of the formulation. This study
was performed for 3 month and any change in the formulation was reported. The sample
were kept at various temperature condition like-
25°C-Room temperature
40°C-Stability Oven
2. Centrifugation test: Prepared liquid formulation was centrifuged at 3500 rpm speed for
about 30 min. The phase separation after 30 min was observed. If the formulation shows
the phase separation then the formulation is unstable and if no phase separation is
observed the formulation is stable and hence, can be used for the further studies.
Solidification of Aqueous Dispersion Of Sln
Solidification can be done by spray drying technique. Colloidal Silicon Dioxide (Aerosil 200)
was used as the carrier for the conversion of liquid formulation to SLN. Aerosil 200 (5 gm)
was dissolved in 150 ml methanol by magnetic stirring. The liquid formulation (10 gm) was
then added with constant stirring, and the solution was kept at 50°C for 10 min to obtain a
good emulsion. After the completion of drying process, fraction of dried Nanoparticles were
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collected from different parts of spray dryer, i.e. drying chamber, first cyclone separator and
collector attached to it. These fractions were then mixed in polybag for 15 min to ensure the
uniform mixing of blend.
RECONSTITUTION PROPERTIES OF SOLID LIPID NANOPARTICLES
Visual observation: SLN (100 mg) was introduced into 100 ml of double distilled water in a
glass beaker that was maintained at 37°C and the contents mixed gently using a magnetic
stirrer. The tendency to emulsify spontaneously and progress of emulsion droplets were
observed with respect to time.[19]
Particle size: Particle size of SLN was determined by laser scattering technique using Malvern
zetasizer (Zetasizer Ver.6.20 Serial No. MAL 1051945 Malvern Ltd). All measurements were
performed at a 25±2°C.[15]
CHARACTERIZATION OF SLN[19-21]
Powder Flow Properties: Spray dried product was evaluated for Angle of repose, bulk
density, Tapped density, Compressibility index, and Hausner ratio.
Drug content determination: Drug content of SLN was determined by adding sufficient
amount of methanol to spray dried powder then the UV absorbance was measured at 248nm.
By the calculation 150 mg of SLN contain 10 mg of the drug, so for the drug content
determination 150 mg of SLN powder were taken.
In-vitro Dissolution Study: The in-vitro dissolution study of SLN was carried out using
dissolution test apparatus no. 1 as per IP. Quantity equivalent to 10 mg of SLN powder added
to dissolution media. Samples of 5 ml at specific time interval was withdrawn and filtered
using 0.45µm filter paper. An equal volume of respective dissolution medium was added to
maintain the volume constant. Drug release from sample was analyzed using UV-
spectrophotometer at 248 nm.
Differential Scanning Calorimetry: The physical state of Quetiapine fumarate in SLN was
characterized by the differential scanning calorimetry (DSC Instruments, METTLER, and
STAR SW 10.00). The samples were placed in standard aluminium pans, and dry nitrogen
was used as effluent gas. All samples were scanned at a temperature range speed of 5°C/min.
the DSC thermogram of Quetiapine fumarate, SLN containing Quetiapine fumarate and
Aerosil 200 with each other.[23]
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Scanning Electron Microscopy: Surface topography of the SLN was investigated by
Scanning Electron Microscopy (SEM).
Powder X-ray Diffraction: X-ray powder diffraction pattern of SLN containing
Colloidal Silicon Dioxide were recorded. Peaks present in the sample were measured.
Stability study of SLN powder[16-18]
1. Visual observation: The SLN powder were filled in vials and was kept at different
temperature condition to check the stability of the formulation. This study was performed
for 1 month and any change in the formulation was reported. The sample were kept at
various temperature condition like-
-20°C=Defreeze
25°C=Room Temperature
40°C=Stability Oven
2. Drug Content: Drug content was determined from initial level to 1 month. The samples
kept at different temperature condition at every weeks were added to sufficient amount of
methanol and the UV absorbance was measured at 248 nm. The results from initial level
to 1 month was compared.
RESULT AND DISCUSSION
Solubility study: Solubility of Quetiapine fumarate on different oil, surfactant and co-
surfactant are shown in FIG. 1, 2, and 3. Solubility study of Quetiapine fumarate in lipid/oil
revel that oleic acid show very good solubility as compare to others.
Fig. 1: Solubility of Quetiapine Fumarate in Different Lipids/Oils.
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Depending on the solubility study of Quetiapine fumarate in surfactants like Span 80, Tween
20 and Cremophor RH 40 showed more solubility than the other surfactants.
So these surfactants were selected for the further study.
Fig. 2: Solubility of Quetiapine Fumarate in Surfactants.
Depending on solubility of Quetiapine fumarate in different co-surfactant like Transcutol P
and Propylene glycol showed more solubility than other co-surfactants.
Fig. 3: Solubility of Quetiapine Fumarate In Co-Surfactants.
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Table 1: Preliminary Screening of Oil/Lipid, Surfactants With Different Co-
Surfactants.
Oil Surfactant Co-surfactant Observation
Oleic acid
Tween 20
Transcutol P Clear aqueous dispersion
Ethanol Turbid dispersion
Propylene Glycol Phase separation
Tween 80
Transcutol P Turbid dispersion
Ethanol Phase separation
Propylene Glycol Phase separation
Cremophor RH 40
Transcutol P Clear aqueous dispersion
Ethanol Turbid dispersion
Propylene Glycol Phase separation
Table 2: Finally Selected Excipients for The Sln Formulation.
Oil Surfactant Co-surfactant
Oleic acid Tween 20
Transcutol P Cremophor RH 40
Construction of Pseudo-Ternary Phase Diagram
A pseudo ternary phase diagram of the investigated system Oleic acid (Lipid), Tween 20 and
Cremophor RH 40 (Surfactant), Transcutol P (Co-surfactant).
For the construction of Pseudo ternary phase diagram different ratio of Surfactant and co-
surfactant are prepared (Smix). Ratios are prepared as follows-
Lipid + Smix (1:1)
Lipid + Smix (2:1)
Lipid + Smix (3:1)
Water was added in a drop wise manner to each oily mixture under proper magnetic stirring at
37°C until the mixture became clear at a certain point. The concentrations of the components
were recorded in order to complete the pseudo ternary phase diagram, and then the contents of
lipid, surfactant, and water at appropriate ratios were selected based on these results. The
boundaries of the emulsification region in the phase diagrams were determined by connecting
the points representing formation of the nanoparticles.
Ternary phase diagram of different ratio are shown in FIG. 4, 5, 6.
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Fig. 4: Phase Diagram Of Oleic Acid, Tween 20+ Cremophor Rh 40, Transcutol P (1:1)
and Water.
Fig. 5: Phase Diagram of Oleic Acid, Tween 20+ Cremophor Rh 40, Transcutol P (2:1)
And Water.
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Fig. 6: Phase Diagram of Oleic Acid, Tween 20+ Cremophor Rh 40, Transcutol P (3:1)
And Water.
Phase diagram indicated that the Smix ratio 1:1 and 2:1 shows less emulsification region than
the other therefore these ratios was rejected. In case of the phase diagram 3:1 shows larger
emulsification region than other ratios. Therefore the Smix ratio 3:1 will be selected for
further study.
PREPARATION OF AQUEOUS DISPERSION OF SLN
Drug Loading[22]
The aqueous dispersion of SLN formulation containing 2%w/w, 4%w/w, 6%w/w, 8%w/w,
10%w/w, 12%w/w and 14%w/w drug does not show any precipitation of drug while the
formulation containing 16%w/w drug (formulation Q8) shows precipitation within 12 hr. Thus,
in liquid formulation maximum 15%w/w drug can be loaded without any precipitation.
CHARACTERIZATION OF AQUEOUS DISPERSION OF SLN
Drug content determination
Amount of drug present in the liquid formulation was determined by UV Spectrometric
method.
Table 3: Drug Content of Different Liquid Sln Formulation.
Sr.no. Formulation
code
Drug
Content(%w/w)
1 S1 93.59
2 S2 96.86
3 S3 95.25
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Drug Release Study
In vitro drug release study was performed for Quetiapine fumarate and liquid SLN. Results
are shown in table.
Table 4: In-Vitro Drug Release Study of Quetiapine Fumarate and Liquid Sln.
Sr.no. Time
(min)
% DR
Plain Drug S1 S2
1 5 0.696 42.318 45.372
2 10 3.269 58.068 60.436
3 15 9.754 69.049 76.083
4 30 15.965 75.877 81.196
5 45 17.475 88.642 89.740
6 60 21.696 96.294 96.843
Fig. 7: Comparison of Dissolution Profile of Plain Drug, Liquid Formulation (S1 And
S2).
In vitro release study results revels that only 21.696%w/w drug was released from plain
Quetiapine fumarate filled in capsule in 60 min while 96.294%w/w, 96.843%w/w drug
release from the liquid formulation S1, S2 formulation respectively within 60 min.
Precipitation Assessment
The formulated liquid formulation diluted with the 100ml of distilled water and the diluted
formulation observed for the precipitation and results was shown in Table no. 33.
Table 5: Precipitation Assessment of Different Liquid Formulation.
Sr.no. Formulation
code Precipitation after 24 hrs.
1 S1 Transparent, clear liquid, no precipitation, stable
2 S2 Transparent, clear liquid, no precipitation, stable
3 S3 Precipitation after 24 hrs.
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From precipitation assessment S1 and S2 formulation found to be transparent, clear liquid with
no precipitation and found to be stable. S3 formulation forms whitish precipitate within 12
hrs.
Therefore S3 formulation will be rejected. S1 and S2 formulation may be selected for further
study but drug content for S1 formulation was found low therefore only S2 formulation will
be selected for further study.
Refractive Index
Refractive index of the Oleic acid, surfactant, co-surfactant and liquid formulation are shown
in table.
Table 6: Refractive Index.
Sr.no. Component Refractive Index
1 Oleic acid 1.458
2 Tween 20 1.460
3 Cremophor RH 40 1.454
4 Transcutol P 1.427
5 Liquid formulation 1.452
Zeta potential
The zeta potential is used to identify the charge of the droplet. The value of zeta potential
indicates the degree of electrostatic repulsion between particles in the dispersion. Zeta
potential measurement is shown in following table no. 7 and figure no. 8.
Table 7: Zeta Potential Measurement of Liquid Formulation.
Formulation Zeta potential Conductivity(mS/cm)
Liquid formulation (Q2) -18.8 0.536
Fig. 8: Zeta Potential Measurement.
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RECONSTITUTION PROPERTIES OF SLN
Visual observation
Reconstitution property of SLN was determined by stirring powder with distilled water for 5
min and observed visually. SLN showed rapid dispersion without any lump or agglomeration.
This dispersion when observed visually after incubation for 60 min room temperature was
well dispersed without phase separation.
Particle size determination
Particle size and polydispersity index of SLN is as follows-
Table 8: Particle Size and Polydispersity Index of Sln.
Formulation Particle size(nm) Polydispersity Index
SLN 485.8 1.000
Fig. 9: Histogram of Particle Size Distribution of Sln.
CHARACTERIZATION OF SLN
Powder flow properties
Table 9: Flow Properties of Spray Dried Product.
Sr. no. Parameter Result Inference
1 Bulk density 0.90 g/ml -
2 Tapped density 1.11 g/ml -
3 Carr’s Index 18.91% -
4 Hausner ratio 1.23 Passable
5 Angle of Repose 21.20°C Passable
The flow property of SLN was found to be passable because of floppy mass of Aerosil 200
and also it contain lipid, surfactant, co-surfactant adsorbed on Aerosil 200.
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Drug Content Determination
Table 10: Drug Content In Sln.
Sr.no. Formulation % Drug Content
1 SLN 96.45
In vitro Dissolution study
In vitro dissolution profile of Plain drug, liquid formulation, SLN, and Marketed formulation
are compared together. SLN formulation shows more % drug release than the liquid
formulation, marketed formulation and the plain drug.
Table 11: In Vitro Dissolution Data of Plain Drug, Liquid Formulation, Sln and
Marketed Formulation.
Sr.no. Time
(min)
% Drug Release
Plain drug Liquid
formulation SLN
Marketed
formulation
1 5 0.696 45.372 48.426 28.524
2 10 3.269 60.436 61.534 35.690
3 15 9.754 76.083 79.171 46.327
4 30 15.965 81.196 82.088 59.016
5 45 17.475 89.740 91.799 68.128
6 60 21.696 96.843 98.730 70.269
Fig.10: Comparison of Dissolution Profile of Plain Drug, Liquid Formulation, Sln and
Marketed Formulation.
Differential Scanning calorimetry
DSC of Quetiapine fumarate (plain drug) and its SLN were performed.
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Fig. 11: Dsc Spectra of Quetiapine Fumarate.
Fig. 12: Dsc Spectra of Quetiapine Fumarate Sln.
DSC of Quetiapine fumarate exhibits a sharp melting point at 174.27°C with onset 171.96°C
and endset or recovery at 176.54°C. The DSC of nanoparticle does not show the sharp peak.
The absence of sharp melting peak indicates that the lipids and Aerosil 200 inhibits the
crystallization of drug i.e. is in amorphous form or in solubilized form in SLN.
Scanning Electron Microscopy
Scanning Electron Microscopy (SEM) was used to determine the particle morphology of
optimized SLN.
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Fig. 13: Sem Images of Quetiapine Fumarate Sln.
Revels that the Quetiapine fumarate SLN shows irregular shape granular particle. The SEM
of Quetiapine fumarate SLN does not show any rectangular crystals of drug on the surface of
Aerosil 200 indicate that the drug present in the soluble form in lipid (SLN) formulation;
which is adsorbed on the surface of Aerosil 200.
Powder X-ray Diffraction
The X-ray diffraction pattern of Quetiapine fumarate SLN was done.
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Fig. 14: X-Ray Diffraction Peaks of Quetiapine Fumarate.
The absence of sharp peak in SLN formulation revels that the drug (Quetiapine fumarate) is
present in the amorphous form or present in solubilized form in SLN.
STABILITY STUDY
1. Stability study of aqueous dispersion of SLN
Table 12: Thermodynamic Stability Studies.
Formulation Temperature Time period
Initial 1 month 2 month 3 month
Aqueous
dispersion of
SLN
25°C
(Room Temp)
Clear and
transparent
liquid
Clear and
transparent
liquid
Clear and
transparent
liquid
Clear and
transparent
liquid
40°C
Clear and
transparent
liquid
Clear and
transparent
liquid
Clear and
transparent
liquid
Clear and
transparent
liquid
2. Centrifugation Test
Passed SLN was centrifuged at 3500 rpm for 30 min using centrifuge (Remi motors Ltd.),
there was no phase separation found.
This proves that the liquid SLN formulation are stable when subjected to centrifugation test.
Stability study of SLN powder
1. Thermodynamic Stability Studies
Stability study of SLN at Freeze temperature (-20°C) , Room temperature (25°C) and High
temperature (40°C) was done for 1 month and evaluated for following parameters.
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2. Visual Observation
Visual observation study (shown in reveals that there is no change in color observed during
stability study for 1 month.
3. Drug Content
Drug content of SLN was done after 1 month and results were shown in Table no.37. The drug
content data shows that there is no change in drug content of SLN. This proves that the
formulated SLN are stable.
Table 13: Drug Content Determination (Stability Study).
Formulation Temperature Time period
SLN powder
Initially After 1 month
-20°C 95.69
25°C 96.45 96.40
40°C 96.02
The visual observation study and Drug content determination study evidence that SLN is stable
at -20°C, 25°C, 40°C.
CONCLUSION
The optimized formulation was found to be the better formulation on the basis of results of
pseudo ternary phase diagram, in vitro drug release, particle size and other parameters. The
present study was clearly indicated that the usefulness of SLN in the improvement of the
dissolution rate and there by oral bioavailability of poorly water soluble drug Quetiapine
fumarate without incompatibility between the ingredients.
ACKNOWLEDGEMENT
The authors are thankful to Akums Drugs and Pharmaceutical Ltd. Haridwar, India for
providing a gift sample of Quetiapine fumarate and S. M. B. T. college of Pharmacy,
Dhamangaon, Nashik.
CONFLICT OF INTEREST
The authors have no conflict of interest regarding to the content of manuscript.
REFERENCES
1. Qureshi MJ, Mallikarjun C, and Kian WG: Enhancement of solubility and therapeutic
potential of poorly soluble lovastatin by SMEDDS formulation adsorbed on directly
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compressed spray dried magnesium aluminometasilicate liquid loadable tablets: A study in
diet induced hyperlipidemic rabbits. Asian journal of pharmaceutical sciences, 2014;
1-17.
2. Shylaja PA, Mathew MM: A Review on Solid Lipid Nanoparticles. International journal
of Universal pharmacy and Biosciences, 2016; 5(3): 276-302.
3. Nikam S, Chavan M. Solid Lipid Nanoparticles: A Lipid Based Drug Delivery. Innovations
in Pharmaceuticals and Pharmacotherapy, 2014; 2(3): 365-376.
4. Parvathi M, Prathyusha A: Preparation and Evaluation of Quetiapine fumarate
Microemulsion: A novel delivery system. Asian journal of Pharmaceutical and Clinical
Research, 2014; 7: 208-213.
5. Narala A, Veerabrahma K: Preparation, Characterization and Evaluation of Quetiapine
fumarate Solid Lipid Nanoparticles to Improve the Oral Bioavailability. Journal of
Pharmaceutics, 2013.
6. Yang R, Huang X, Dou J, Zhai G, Su L. Self-micro emulsifying drug delivery system for
improved oral bioavailability of oleanolic acid: Design and Evaluation. International
Journal of Nanomedicine, 2013; 8: 2917-2926.
7. Pimple SS, Yeole SE, Chaudhari PD. Formulation and evaluation of self-micro emulsifying
drug delivery system for poorly water soluble drug Risperidine. International Journal of
Pharmaceutical Sciences Review and Research, 2013; 23(1): 155-162.
8. Puttachari S, Kalyane NV, Gupta S. Design and evaluation of self-micro emulsifying drug
delivery systems of Acyclovir. International journal of Pharmacy and pharmaceutical
sciences, 2014; 6(4): 677.
9. Rajkumar Aland, Ganeshan M and Rajeswara Rao P. Voriconazole Solid Lipid
Nanoparticles: Optimization of Formulation and Process Parameters. Der Pharmacia
Lettre, 2018; 10(2): 52-59.
10. Rao BP, Baby B, Durgaprasad Y, Ramesh K, Rajarajan S, Keerthi B, Sreedhar C.
Formulation and Evaluation of SMEDDS with Capmul MCM for enhanced dissolution rate
of Valsartan. Rajiv Gandhi University of health sciences, Journal of Pharm Sciences,
2013; 3(2): 33-40.
11. Kang JH, Dong HO, Oh YK, Yong CS, Choi HG. Effects of solid carriers on the crystalline
properties, dissolution and bioavailability of Flurbiprofen in solid self-nano emulsifying
drug delivery system (solid SNEDDS). European journal of pharmaceutics and
biopharmaceutics, 2012; 80: 289-297.
12. Patil PR, Biradar SV, Paradkar AR. Extended release Felodipine self-nano emulsifying
www.wjpps.com Vol 9, Issue 2, 2020.
963
Gaikwad et al. World Journal of Pharmacy and Pharmaceutical Sciences
system. AAPS Pharm Sci Tech, 2009; 10(2): 515-523.
13. Hyma P. Formulation and characterization of novel self-nano emulsifying drug delivery
system of Glimepride. The experiment International journal of science and technology,
2014; 24(1): 1640-1648.
14. Pandya BD, Shah SH, Shah N. Bioavailability enhancement of poorly soluble drugs by
self-nano emulsifying drug delivery system (SNEDDS): A Review. Journal of
pharmaceutical science and Bioscientific research (JPSBR), 2015; 5(2): 187-196.
15. Deshmukh A, Kulkarni S. Novel self-emulsifying drug delivery system of Efavirenz.
Journal of chemical and pharmaceutical research, 2012; 4(8): 3914-3919.
16. Sneh Priya, Sucheta Kumari and Marina Koland. Nanoemulsion components screening of
Quetiapine fumarate: Effect of surfactant and co-surfactant. Asian Journal of
Pharmaceutical and Clinical research, 2015; 8(6): 136-140.
17. Dr. Sunitha M. and Sowjanya N. Formulation and in-vitro characterization of Solid Self-
Nano emulsifying Drug Delivery System of Simvastatin. Journal of Pharmaceutical
Science and Research, 2015; 7(1): 40-48.
18. Puttachari S, Kalyane NV, Gupta S. Design and evaluation of self-micro emulsifying drug
delivery systems of Acyclovir. International journal of Pharmacy and pharmaceutical
sciences, 2014; 6(4): 677.
19. Patel MJ, Patel SS, Patel MM, Patel NM. A self-micro emulsifying Drug Delivery System.
International Journal of Pharmaceutical Science Review and Research, 2010; 4(3): 29-35.
20. Chen ZQ, Liu Y, Zhao JH, Wang L, Feng NP. Improved oral bioavailability of poorly water
soluble Indirubin by a supersaturable self-micro emulsifying drug delivery system.
International Journal of Nanomedicine, 2012; 7: 1115-1125.
21. Baek MK, Lee JH, Cho YH, Kim HH, Lee GW. Solid self-nano emulsifying drug delivery
system for improved oral bioavailability of Pranlukast hemihydrate: Preparation and
Evaluation. International Journal of Nanomedicine, 2013; 8: 167-176.
22. Pachava S, Puttachari S, Shariff A, Thakur RS. Formulation and Evaluation of Solid Lipid
Nanoparticles of A Selective Second Generation Cephalosporin Antibiotic. International
Journal of Pharmaceutical Sciences Review and Research, 2014; 24(2): 176-181.
23. Gaspar P, Eleuterio C, Grenha A, Blanco M, Almedia A. Microencapsulated Solid Lipid
Nanoparticles as a Hybrid Platform for Pulmonary Antibiotic Delivery. Molecular
Pharmaceutics, 2017; 14(9): 2977-2990.
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