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Pharmaceutical Resonance 2018 Vol.1 - Issue 1
© Published by DYPIPSR, Pimpri, Pune - 411 018 ( MH ) INDIA 26
RESEARCH ARTICLE
Solubility Enhancement and Formulation Development
of Ziprasidone Immediate Release Oral Drug Delivery
Saish R. Pawar, Rupali N. Kale*, Sohan S. Chitlange
Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune : 411018
1. Introduction
Schizophrenia is a devastating disorder affecting more
than 1% of population worldwide. From a layman’s
perspective two types of medications are used in the
treatment of schizophrenia, the traditional antipsychotic
medications and the newer, atypical antipsychotic
medications. According to NICE guidelines, oral atypical
antipsychotics are recommended as first-line treatment for
patients with newly diagnosed schizophrenia. Ziprasidone
is a new atypical anti-psychotic agent, approved by
USFDA and proved to be effective for acute and long
term treatment of schizophrenia and bipolar disorder
symptoms [1,2].
Since ziprasidone is poorly soluble drug with intrinsic
solubility of 0.3g/mL, it takes more time to get absorbed
in gastrointestinal tract leading to poor bioavailability of
60%. In presence of food, specifically high calorie fat
meal, ziprasidone shows 2-fold increase in rate and extent
of absorption which might be due to micellar
solubilisation due to bile acids, reduced rate of hepatic
clearance, delayed stomach emptying or reduction of first
pass metabolism [3,4,5]. Therefore it is always
recommended to have oral dose of ziprasidone along with
food. But compliance of such dosing regimen is a big
issue in schizophrenic patients.
Oral immediate release tablet, capsule, suspension and
intramuscular formulations are commercially available
formulations of ziprasidone. Over single-unit oral dosage
forms, multiple-unit dosage forms such as pellets are more
preferred since it helps maximising GI absorption by free
drug dispersion in GI fluid. Dose tailoring, reduction of
inter and intra-patient variability by maintaining peak
plasma concentration are some other advantages of pellets
as oral dosage form [6,7].
It is hypothesized that, in the fasted state, ziprasidone due
to its poor solubility shows dissolution rate limited
absorption. So in the current study, attempts have been
made to improve ziprasidone solubility by preparing its
cyclodextrin inclusion complex. Inclusion complex
showing highest solubility was further formulated in the
form of pellets as multiparticulate dosage form which is
now a day’s widely preferred dosage form due to its
various clinical and technological advantages [8].
Main objective of the proposed study is solubility
enhancement of ziprasidone which was tried by preparing
its cyclodextrin inclusion complex and it was further
formulated into oral pellet formulation as multiparticulate
immediate release oral drug delivery system.
* Dr. Rupali N. Kale
Assistant professor, Dept. of Pharmaceutical Chemistry
Dr. D. Y. Patil Institute of Pharmaceutical Sciences and
Research, Pimpri, Pune
Email : [email protected]
ABSTRACT : Ziprasidone is a poorly soluble BCS class-II drug prescribed for psychological disorder. Its poor solubility
and bitter test limits its application as oral dosage form due to lower patient compliance. The objective of present
investigation is solubility enhancement at ziprasidone using β-cyclodextrin and further formulation development of pellet as
multi-particulate immediate release oral dosage form.
Solubility enhancement of ziprasidone was attempted by preparation of inclusion complex with β-cyclodextrin by kneading
method at different concentration ratios. The ratio showing enhanced solubility was further selected for formulation
development of pellets using extrusion-spheronization technique. Formulations were characterized for various
physicochemical properties, surface properties by SEM and in-vitro drug release. Optimized formulation was compared
with pure drug and marketed tablet formulation for comparative drug release.
Phase solubility study indicated formation of drug: β-cyclodextrin inclusion complex of 1:2 M in solution with 759.68 M-1
apparent stability constant (Kc). Differential scanning calorimetry, fourier transform infrared spectroscopy confirmed
formation of drug- β-CD inclusion complex. The optimized pellet formulation prepared using extrusion spheronization
technique consisting drug: β-CD inclusion complex showed rough surface of pellets with more than 80% drug release
within 60 minutes which was comparative to marketed tablet formulation.
Keywords: Ziprasidone, β-cyclodextrin, inclusion complex, immediate release, extrusion spheronization.
Pharmaceutical Resonance 2018 Vol.1 - Issue 1
© Published by DYPIPSR, Pimpri, Pune - 411 018 ( MH ) INDIA 27
2. Materials and methods
2.1 Materials
Ziprasidone was received as a gift sample from Torrent
pharmaceutical Ltd. β-cyclodextrin was procured from
Himedia Laboratories Pvt. Ltd, India. All the ingredients
used for formulation and analysis were of AR and HPLC
grades.
2.2 Methods
2.1 Phase solubility studies
Based on the method described by Higuchi and Connors
[9,10], solubility study of ziprasidone was performed by
adding an excess of drug (50 mg) to 10 mL distilled water
having β-CD in concentration of 0.1x10-2 to 0.6 x10-2
mol/L respectively. These solutions were shaken on a
rotating shaker for 48 h. Resulting solutions were filtered
and analysed by validated HPLC method at 317nm.
Solubility of ziprasidone at all concentrations of β-CD
was calculated and phase solubility diagram was
generated.
The apparent stability constant (Kc) was calculated using
the equation where, S0 is the solubility of the drug in the
absence of cyclodextrin.
2.2 Preparation of inclusion complexes by kneading
method
Ziprasidone- β-cyclodextrin inclusion complexes were
prepared applying by kneading technique. The drug and β-
cyclodextrin was transferred to mortal pestle for
trituration. Sufficient quantity of water was added slowly
to this triturated powder to get the wet mass, which was
further dried at 50º C for 1 hr. Dried mass was passed
through sieve #100 after pulverization and stored in
dessicator for further use. Inclusion complex formed were
evaluated for solubility of ziprasidone.
2.3 Characterization of inclusion complex
2.3.1 Infrared spectral studies
Inclusion complexes of ziprasidone and β-cyclodextrin
prepared in different molar ratios were characterized by
FT-IR spectrophotometer (Shimadzu) by KBr pellet
method.
2.3.2 DSC studies
DSC thermograms of prepared inclusion complexes were
recorded by using differential scanning calorimeter
Shimadzu DSC-60 (Kyoto, Japan).
2.4 Preparation of pellets using inclusion complex
Pellet formulations of ziprasidone- β-cyclodextrin
inclusion complex exhibiting higher solubility were
prepared by extrusion spheronization technique using lab
spheronizer (Shakti Pharma)
2.4.1 Preparation of wet mass
Accurately weighed quantity of selected inclusion
complex (equi. to 200mg of ziprasidone) MCC, lactose
was mixed together. Binder solution of PVPK-30 prepared
in purified water: IPA (9:1) was added slowly to above
mixture to prepare wet mass of appropriate consistency.
2.4.2 Extrusion
Wet mass prepared was immediately extruded through
sieve number 14 (B.S.S) to get cylindrical shaped
extrudates.
2.4.3 Spheronization
Spheronization of obtained extrudates was done using lab
spheronizer using 5mm friction plate, at 900 rpm for 110
seconds to get spherical shaped pellets. These pellets were
dried at 50oC in hot air oven.
Formula was further optimized by evaluating pellets for its
physicochemical properties, disintegration time and in-
vitro drug release. SEM was performed for optimized
pellet formulation to check its surface properties.
2.5 In-vitro dissolution studies of ziprasidone pellets
In-vitro dissolution studies were performed for all the
formulation using USP Dissolution Apparatus-1(Basket
type). An accurately weighed sample of pellets containing
equivalent amount of 20 mg of ziprasidone was dropped
into 900 ml of Phosphate buffer (pH 7.4) maintained at a
temperature of 37ºC ± 0.5ºC and stirred at a speed of 50
rpm. At different time intervals, a 10ml aliquot of the
sample was withdrawn and the volume was replaced with
an equivalent amount of plain dissolution medium kept at
37ºC. The collected samples were filtered and samples
were analysed by validated HPLC method. In-vitro drug
release of optimized formulation was compared with pure
drug and marketed product.
3. Results and discussion
3.1 Phase solubility studies
Phase solubility diagram generated inclusion complex
between ziprasidone and β-CD in water showed initial
rising portion indicating increase in solubility followed by
a plateau region and then decreasing concentration of
ziprasidone which may be due to precipitation of complex.
The apparent stability constant (Kc) calculated from the
straight-line position of solubility diagram applying
Higuchi and Connors method [9,10] was found to be
759.68 M-1. Phase solubility diagram of ziprasidone and β
-cyclodextrin in water is shown as figure 1.
Pharmaceutical Resonance 2018 Vol.1 - Issue 1
© Published by DYPIPSR, Pimpri, Pune - 411 018 ( MH ) INDIA 28
3.2 Infrared spectral studies
The IR spectra of pure drug and cyclodextrin complex
showing highest solubility [1:2M] are shown in Figure 2.
IR spectrum of ziprasidone exhibited peaks at 3362 cm-1
which was shifted to 3346.61cm-1 after formation of
inclusion complex due to N-H stretching, 3047-3053.42
cm-1 for aromatic C-H stretching and at 1722 to 1707cm-
1 for C=O stretching indicating slight shift. Inclusion
complex prepared by kneading method showing highest
solubility indicated reduction in intensity of the peak at
1707cm-1 which might be due to interaction in
ziprasidone and cyclodextrin.
3.3 DSC Studies
The DSC studies were performed to check complexation
of ziprasidone with β-CD. The thermogram of pure drug
and inclusion complex (1:2M) is shown are shown in
figure 3.
DSC thermogram of inclusion complex showed two
peaks. The peak at approx 143°C is due to dehydration
process of β-CD, and peak at 216.37°C is the shift of drug
peak to a lower temperature, indicating interaction of β-
CD with drug which normally happens due to
complexation reaction in drug and β-CD.
Inclusion complex of ziprasidone and β-CD showing
highest solubility were processed for formulating pellets
with other excipients such as MCC and lactose as diluent,
PVP K30 as binder and magnesium stearate and talc as
lubricant. All the formulations were evaluated and
optimized on the basis of % drug release.
Photomicrograph obtained by scanning electron
microscopy (SEM) showed irregularly spherical and
slightly rough beads without cracks as shown in figure 4.
From the technological point of view, slight surface
roughness can help in improvement of flow properties
[11].
Fig. 1: Phase solubility diagram of ziprasidone and β-
cyclodextrin in water
Fig. 2: FTIR Spectra a. Pure drug: ziprasidone, b.
Ziprasidone- β-CD inclusion complex
Fig. 3: DSC thermogram a. Pure drug: ziprasidone, b.
Ziprasidone- β-CD inclusion complex
Fig. 4: Photomicrograph (SEM) of pellet
Pharmaceutical Resonance 2018 Vol.1 - Issue 1
© Published by DYPIPSR, Pimpri, Pune - 411 018 ( MH ) INDIA 29
3.4 In-vitro dissolution studies
The formulated pellets were subjected to dissolution study
in phosphate buffer (pH 7.4). Formulation showing more
than 80% drug release within 60 minutes was compared
with pure drug and marketed formulation (Zipsydone by
Sun pharma) for its dissolution profile. Comparative
dissolution profiles are shown in figure 5.
Dissolution efficiency was found to be increased with
ziprasidone containing pellets formulated using
cyclodextrin inclusion complex [1:2 M] as compared to
pure ziprasidone and results found to be comparative with
marketed tablet formulation.
The improvement in dissolution characteristics of pellet
formulation may be due to cyclodextrin inclusion of
ziprasidone which can be readily soluble in dissolution
media. Cyclodextrin also helps in increasing wettability of
drug particles by reducing its crystallanity [12].
Evaluation results of pellets formulated using ziprasidone-
β-CD inclusion complex showed suitability of pellets for
conversion into final dosage form such as capsules.
The results of the proposed study indicated inclusion
complex formation of ziprasidone and β-CD in ratio of 1:2
M. Stability constant was found to be 759.68 M-1. Pellet
formulations prepared using inclusion complexes of
ziprasidone and β-CD (1:2 M) exhibited higher dissolution
efficiency compared to pure drug suggesting enhanced
bioavailability after oral administration. Prepared pellet
formulation also showed comparative dissolution profile
to commercial tablet formulation.
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Fig. 5: Comparative in-vitro dissolution of Pure drug,
Formulation F7 (Optimised) and marketed formulation