Solubility Enhancement and Formulation Development of ......formulation also showed comparative...

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.



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.



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



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

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