Drug Development and Industrial Pharmacy

ISSN: 0363-9045 (Print) 1520-5762 (Online) Journal homepage: https://www.tandfonline.com/loi/iddi20

Sustained Release formulation of Ondensetron Hcl

Using Osmotic drug Delivery Approach

Ramakant Gundu, Sanjay Pekamwar, Santosh Shelke, Santosh Shep &

Deepak Kulkarni

To cite this article: Ramakant Gundu, Sanjay Pekamwar, Santosh Shelke, Santosh
Shep & Deepak Kulkarni (2020): Sustained Release formulation of Ondensetron Hcl
Using Osmotic drug Delivery Approach, Drug Development and Industrial Pharmacy, DOI:
10.1080/03639045.2020.1716372

To link to this article: https://doi.org/10.1080/03639045.2020.1716372

Accepted author version posted online: 15

Jan 2020.

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Sustained Release formulation of Ondensetron Hcl Using Osmotic drug Delivery Approach

Ramakant Gundu*1, Sanjay Pekamwar1, Santosh Shelke2, Santosh Shep3, Deepak Kulkarni2

1
School of Pharmacy, Swami Ramanand Teerth Marathwada University, Vishnupuri, Nanded,
Maharashtra, India.
2
Srinath College of Pharmacy, Bajaj Nagar, Waluj MIDC, Aurangabad-431136, Maharashtra,

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India.
3
Dr.Y.S.Khedkar College of Pharmacy, N-6, Cidco, Aurangabad-431003, Maharashtra, India.

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*Corresponding author:
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Mr. Ramakant K. Gundu

School of Pharmacy, Swami Ramanand Teerth Marathwada University,
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Vishnupuri, Nanded-431606, Maharashtra, India.

E-mail id: [email protected]
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Mob: +91 9527003393

Abstract
Ondansetron HCl (OSH) is a 5-HT3 receptor antagonist indicated for the prevention of nausea
and vomiting associated with radiotherapy (adults: 8 mg, t.i.d) and/or chemotherapy (adults: 8
mg, b.i.d to t.i.d) and prevention of postoperative nausea and/or vomiting (adults: 8 mg, b.i.d). In
elderly subjects, bioavailability may be somewhat higher (65%) and lower clearance, presumably
due to reduced hepatic first-pass metabolism. OSH is extensively distributed in the body; about
70 to 75% of the drug in plasma is protein bound and terminal elimination half-life is about 3
hours after oral administration. The study was aimed to develop Push-pull Osmotic Pump

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(PPOP) bi-layered tablets for Ondansetron HCl ER tablets. The granulation was carried out using
non-aqeous solvents followed by compression, seal coating, semi permeable coating, laser

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drilling (0.6mm) and drug film coating with loading dose. The drug release was controlled by
swelleable osmotic polymers of pull layer and push layer and orifice on the surface of tablet. The

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formulations were optimized for its core composition, extended release coating
(Semipermeable membrane) polymer as to plasticizer ratio and orifice diameter. Optimized
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formulations were evaluated for micromeritic properties and in-vitro drug release. The analytical
methods were developed and validated to estimate In-vitro drug potency, drug release and
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In-vivo pharmacokinetic parameters. Stability studies were done as per the ICH guidelines. The
results of In-vivo study concludes that the once OSH ER dose consistently maintains plasma
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concentration of drug within the therapeutic window over a period of 24 hours.

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Keywords: Ondansetron HCl; Push-pull osmotic pump; Extended release; Tablet; Osmotic
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release.
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Introduction
Last century has witnessed spectacular developments in the field of pharmaceutical sciences
especially novel drug delivery systems. The goal of such systems has been to provide a
therapeutic amount of drug to a proper site in the body to achieve promptly and then maintain the
desired drug concentration. This well-defined objective incorporates two aspects which are most
important for the clinical use of such systems. They are spatial placement and temporal delivery
of a drug.

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Spatial placement is concerned with the targeting of a drug to a specific organ or tissue, whereas

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temporal delivery is responsible for controlling the rate of drug delivery to the target tissue [1].

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An appropriately designed controlled release drug delivery systems can be very effective in
solving these problems. It is for this reason that the science and technology of dosage form

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design for the development of controlled release formulations are the focus of great deal of
attention in both industrial and academic laboratories. Currently, there exist numerous controlled
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release dosage forms which cover a wide range of prolonged action formulations providing
continuous release of their active ingredients at a predetermine rate and for a predetermined time
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[2,3,4]. The majority of these formulations are designed for oral administration that satisfies the
temporal aspect of drug delivery; however, recently such devices have also been introduced for
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parenteral administration, ocular insertion and for transdermal application [ 5 ]. The most
important objective for development of these systems is to furnish an extended duration of action
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and thus assure greater patient compliance. Such formulations may also exhibit reduced
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incidence and intensity of adverse effects, more uniform blood concentrations and produce more
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consistent and prolonged therapeutic effect. Ideally the optimization of therapeutic efficacy and
safety may be attained as a result of providing a nearly constant pharmacological response,
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thereby avoiding the normal peak and valley pattern associated with multiple dosing of
conventional drugs.

Ondansetron HCl is the prominent drug used prevention of nausea and vomiting associated with
highly emetogenic cancer chemotherapy [6]. Dose of Ondansetron HCl as immediate release
dosage form is available as 4 mg, 8mg and 24mg with terminal elimination half-life of about 3
hours after oral administration [ 7 , 8 ]. The patient suffering from nausea requires frequent
administration of Ondansetron HCl. To avoid this frequent administration the Push-pull Osmotic
Pump (PPOP) bi-layered tablets for Ondansetron HCl ER tablets, was developed [9].

Osmotic systems utilize the principle of osmotic pressure for the delivery of drugs [10]. Drug
release from these systems is independent of pH and other physiological parameter to a large
extent and it is possible to modulate the release characteristic by optimizing the properties of
drug and system. Osmosis refers to the net movement of solvent molecules across a
semipermeable membrane from higher to lower solute concentration [11]. Push pull osmotic

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pump tablet characterized by swellable pull layer which pull the drug outside from osmotic pump

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after pushing by swellable push layer [12]. It is a bilayer tablet coated with a semi permeable

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membrane. The upper compartment contained the drug; lower compartment contained high
viscosity polymers, osmogent and was connected to the outside environment via a small delivery

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orifice. Polyethylene Oxide (around 50-70%) was most commonly used polymer in pull and push
layer. The system also had the disadvantage of higher cost compare to other extended release
products [13].
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Materials and methods
Materials: Ondansetron hydrochloride USP (Dr.Reddy’s lab), Polyethylene Oxide NF (Dow
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Chemicals), Mannitol USP (Roquette), Isopropyl alcohol NF (S.D.Fine Chem Ltd),

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Hypromellose USP (Dow Chemicals), Magnesium Stearate NF (Mallinckrodt Inc), Polyethylene

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Oxide NF (Dow Chemicals), Iron Oxide Red NF (Rockwood Pigments), Sodium Chloride
USP(Merck), Hydroxypropyl Cellulose NF (Nippon Soda), Polyethylene Glycol 400 NF (BASF
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chemicals), Polyethylene Glycol 3350 NF (Clariant Chemicals),Cellulose Acetate NF (Eastman

Chemicals), Acetone NF (SI Group India Ltd).
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Methodology
Compatibility studies of Ondensetron HCl (OSH) and excipients by Differential Scanning
calorimetry
The objective of compatibility study of OSH and excipients is to screen excipients for further
formulation development. The ratio of inactive ingredients and drug were selected based on
worst case scenario and their functionality. The thermograms of the drug and the physical
mixture of the drug and excipients were recorded using a DSC (Mettler Taledo DSC-82’e, India)
under the inert atmosphere maintained by purging with nitrogen. Samples of OSH, excipients
and physical mixture (drug and excipient) were collected and stored in a glass vials (closed with
Teflon stoppers) individually. Vials were subjected to 25°C/60%RH and 40°C ± 2°C/75% ± 5%
RH for 4 weeks. Each sample (5mg) were weighed and transferred to DSC aluminium pan.
Crimping was done on the pan to ensure sufficient heat transmission and scanned in the
temperature range of 30-300°C where, empty pan was used as a reference. Samples were heated
at a scanning (heating) rate of 10°C/min and 50 mL/min nitrogen flow. The obtained

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thermograms were recorded to confirm the compatibility of the drug and the excipients.

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Preparation of Ondensetron HCl Extended Release tablets
Drug layer

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Ondansetron HCl, Mannitol USP (Pearlitol SD 200), Polyethylene Oxide NF (Polyox WSR N80)
& Hypromellose USP (METHOCEL E5) and intra-granular ingredients were accurately
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weighed. Ondansetron HCl and intragranular ingredients were passed through sieve 20 # ASTM.
Mannitol was added to maintain the constant weight of 450mg. significant amount of Isopropyl
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alcohol was measured for granulation process. All sifted materials were placed in rapid mixer
granulator and granulation was carried out using Isopropyl alcohol. Wet granules were passed
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through sieve 20 # ASTM. Collected granules were dried in fluid bed dryer (FBD) at 60°C for
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approximately 60 min to achieve LOD 1.0 to 2.0, dried granules were sifted through sieve #30
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mesh. Retained lumps were milled through co-mill with 40G screen (Screen no. 1016).
Thereafter milled granules were collected and mixed with #30 mesh passed granules. Extra-
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granular ingredient magnesium stearate was weighed as per yield and sifted through sieve #60
ASTM and blended with the dried granules in double cone blender for 3 mins at 23±1 RPM.
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Push layer
Polyethylene Oxide NF (Polyox 303), Iron Oxide Red, Hypromellose USP (METHOCEL E5) &
Sodium Chloride USP were weighed accurately. Iron oxide red and other intra-granular
ingredients were sifted through sieve 20 # ASTM. Significant amount of Isopropyl alcohol was
measured for granulation process. All sifted materials were placed in rapid mixer granulator and
granulation was carried out using Isopropyl alcohol. Wet granules were sifted through sieve 20 #
ASTM. Granules were dried in fluid bed dryer (FBD) at 60°C for approximately 60 min to
achieve LOD 1.0 to 2.0%. Dried granules were sifted through sieve #30 mesh. Retained lumps
were milled through Co-mill mesh passed granules. Extra-granular ingredient magnesium
stearate was weighed as per yield and sifted through sieve #60 ASTM and blended with the dried
granules in double cone blender for 3 mins at 23±1 RPM [14].

Compression
Compressed the lubricated blend on double rotary compress tablet machine with 10 mm,
Circular, standard concave punches.

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Coating and drilling of tablets

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Preparation of seal coating solution
Solvent Isopropyl alcohol was taken in suitable stainless steel container. Under stirring PEG 400

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followed by Hydroxypropyl Cellulose (Nisso HPC SSL) were added to Isopropyl alcohol. This
mixture was stirred for about 45 minutes to get a transparent solution. Tablets were coated with
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seal coating solution to achieve desired weight gain. Solid content of coating solution was 5%
w/w.
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Preparation of Extended Release (ER) Coating Solution:
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Coating solution was prepared by using the solvent mixture of acetone and water in ratio 99:1
respectively. At the given ratio both the solvents are miscible to form clear solution with the
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polymer. Initially, cellulose acetate was dissolved in acetone with part by part addition and
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stirred slowly to obtain a clear solution. Separately, dissolve Polyethylene glycol 3350 in
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required quantity of water. Thereafter, add Polyethylene glycol 3350 solution (aqueous solution)
to cellulose acetate solution with continuous stirring. This mixture was stirred for about 1 hour to
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get a transparent solution. Tablets were coated with extended release coating solution to achieve
desired weight gain.

Laser drilling
Extended release (ER) coated tablets were drilled using laser drilling machine (Control Micro
System, USA) with one drill (orifice) on white layer (Drug layer) side of tablets with orifice size
0.6mm ± 0.05mm (600 µm ± 50µm) [15]
Drug coating
Isopropyl alcohol, NF and Purified water, USP was taken in suitable stainless steel container.
Under stirring Hydroxypropyl Cellulose NF (Nisso HPC SSL) followed by Ondansetron
hydrochloride USP were added to Isopropyl alcohol NF and Purified water USP mixture. This
mixture was stirred for about 30 minutes to get dispersion. Tablets were coated with drug coating
dispersion to achieve desired weight gain. Solid content of coating solution was 5 %w/w.

Production yield

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The production yield (%) was calculated after weighing the coated tablets, known as practical
yield using the following formula:

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𝑃𝑟𝑎𝑐𝑡𝑖𝑐𝑎𝑙𝑦𝑖𝑒𝑙𝑑
Production yield (%) = ∗ 100
𝑇ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙𝑦𝑖𝑒𝑙𝑑

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Factorial Design and Optimization of formulation an
Optimization of formulation was done using response surface methodology. Statistical
validations of the polynomial equations were generated by Design Expert (Stat-Ease Inc.,
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Minneapolis, version 11) using factorial design (Minimum run resolution-IV, 2FI model with 5
center points) considering most influential parameters. The effect of parameters on their response
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was studied using the response surface methodology [ 16 ]. Table 3 illustrates the selected
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variables for the design of experiment.

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Considering the preliminary studies formulations were optimized for concentration of

Polyethylene Oxide (Polyox WSR N80) (mg), Polyethylene Oxide (Polyox WSR 303) Cellulose
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Acetate CA 398-10 (% ratio), Polyethylene glycol 3350 (% ratio) and Orifice diameter (mm)
which plays significant role in drug release. These five factors were selected as the independent
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variables, whereas % drug release at 1h, 6h, 12h and 24h were considered as dependent
variables.

Micromeritic properties
The micromeritic evaluation of powder blend was done to estimate the flow properties; packing
properties and porosity of powder to determine its suitability for tableting [17]. A weighed
quantity of powder blend was transferred into a graduated cylinder from each batch to determine
the bulk and tapped density using USP-I tapped density tester (TD 1025, Lab India Instruments,
Mumbai, India). A fixed funnel method was used to study the angle of repose (θ). The bulk
characterization parameters selected to study flow properties were determined by using the
following formulas.
𝑔 𝑀𝑎𝑠𝑠 𝑜𝑓 𝑝𝑜𝑤𝑑𝑒𝑟
𝑎. 𝐵𝑢𝑙𝑘 𝐷𝑒𝑛𝑠𝑖𝑡𝑦 ( )=
𝑚𝐿 𝑉𝑜𝑙𝑢𝑚𝑒
𝑔 𝑀𝑎𝑠𝑠 𝑜𝑓 𝑝𝑜𝑤𝑑𝑒𝑟
𝑏. 𝑇𝑎𝑝𝑝𝑒𝑑 𝐷𝑒𝑛𝑠𝑖𝑡𝑦 ( ) =
𝑚𝐿 𝑉𝑜𝑙𝑢𝑚𝑒
𝑇𝑎𝑝𝑝𝑒𝑑 𝑑𝑒𝑛𝑠𝑖𝑡𝑦 − 𝐵𝑢𝑙𝑘 𝑑𝑒𝑛𝑠𝑖𝑡𝑦

t
𝑐. 𝐶𝑎𝑟𝑟’𝑠 𝐼𝑛𝑑𝑒𝑥 = ∗ 100
𝑇𝑎𝑝𝑝𝑒𝑑 𝑑𝑒𝑛𝑠𝑖𝑡𝑦

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𝑇𝑎𝑝𝑝𝑒𝑑 𝑑𝑒𝑛𝑠𝑖𝑡𝑦
𝑑. 𝐻𝑎𝑢𝑠𝑛𝑒𝑟’𝑠 𝑟𝑎𝑡𝑖𝑜 =

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𝐵𝑢𝑙𝑘 𝑑𝑒𝑛𝑠𝑖𝑡𝑦
e. 𝐴𝑛𝑔𝑙𝑒 𝑜𝑓 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒 𝑇𝑎𝑛𝜃 = ℎ/𝑟

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Evaluation of tablets an
Tablets were evaluated for weight variation, friability, hardness and dissolution studies. Weight
variations of the tablets were done by weighing 20 random tablets. Average weight of the tablet
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was used to determine the weight variation. The tablets meet the test if not more than two tablets
are outside the limit and if no tablet differs by more than two times the limit. The weight of tablet
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was measured in terms of mg. Friability is the measure of tablet strength. USP friability
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apparatus (Electrolab, Mumbai, India) was used for testing the friability of the tablets. Ten
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tablets were weighed and placed in friabilator and the instrument was operated for 100
revolutions for 4 min (25 rpm.) The tablets were then dusted and reweighed. The friability of
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tablets was calculated by using following formula:

Initial wt. of tablets – Final wt. of tablets
𝑭𝒓𝒊𝒂𝒃𝒊𝒍𝒊𝒕𝒚 = × 𝟏𝟎𝟎
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Initial wt. of tablets

The hardness of tablet of each formulation was measured by hardness tester (Erweka, Germany).
The hardness was measured in terms of kg/cm2.

In-vitro dissolution and drug release kinetics

Drug release study was carried out using USP dissolution apparatus. The dissolution study was
carried out in Purified water. Prior to start of the experiment, instrument was set as per
parameters. 900 mL of purified water was added to each vessel which has been previously
equilibrated to 37 °C ± 0.5. Once the parameters are set for given temperature and rpm,
instrument was operated for 24 hours at 50 rpm. Thereafter, 15ml of aliquots were withdrawn
from each vessel and the solution was filtered through 0.45 µm Nylon filter. 5 ml of filtrate was
collected after discarding first 5 mL and was diluted to 20mL with dissolution medium. Release
mechanism from the optimized formulations was studied for various kinetic profiles to interpret
relationship. The data were processed for regression analysis using MS - Excel based statistical
tool (DD solver, 1.0 (Trial version), Nanjing, China) [18].

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Impact of osmotic pressure of the dissolution medium on drug release
In order to confirm the osmotic mechanism of drug release, the release study of the optimized

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formulation was conducted in a media of different osmotic pressure. To modify the osmotic
pressure of the dissolution medium, 1 mol/L and 2 mol/L solutions of sodium chloride in water

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were prepared this results in the osmotic pressure of 25 atm and 50 atm of the solution
respectively. Release study was conducted in 900 ml of dissolution medium in USP type II
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apparatus at 50 rpm for 24 h. The samples were collected at predetermined intervals and
analysed.
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Verification / Validation of DOE model

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DOE model was verified / validated on the basis of results obtained from In-vitro dissolution and
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drug release kinetics with reference to statistical analysis of factorial design optimization.
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In-vivo study
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Male/female beagle dogs (weight 10-12kg) of age 2-4 years were selected for the
pharmacokinetic studies. Three dogs were used each for test formulation and reference
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formulations. Animals were housed under standard recommended environment condition at

room temperature 22ºC ± 3ºC and relative humidity 30 to 70% RH with a 12 hours light (8.00
am to 8.00pm) and 12 hours dark cycle. Dogs were provided free access to RO treated water and
normally fed ad-libitum with standard diet. Prior to start of the experiment, dogs were fasted for
18 hours. The Institutional Animals Ethical Committee (IAEC) Guidelines approved the methods
and procedures described in the present report. Ondansetron HCl ER tablets 24mg OROS tablets
(Test product, Batch No. OSH-S19) was administered once (24 mg single dose, o.d) to each dog
by intended route (Oral) and blood samples were collected from cephalic vein [ 19]. Following
fasting, the blood samples (approximately 0.7mL) were withdrawn from forearm vein (Vena
cephalica) before drug administration (0 hour) and 1, 3, 5, 8, 9, 11, 13, 16, 17, 19, 21 and 24
hours after drug administration. Whereas, Zofran® tablets 8mg (Reference Product, B.No.
3ZP3000, GlaxoSmithKline) was administered three times a day (24mg total dose, 8mg dose at
each 8 hours interval, t.i.d) to each dog by intended route (Oral) and blood samples were
collected from cephalic vein [ 20 ]. Blood samples were centrifuged to separate plasma using
Heraeuas Biofuge centrifugation. Resulting plasma samples were stored at -70 ºC ± 10ºC with

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proper labeling to include ‘Dose group, Animal ID, Batch number, Time point, Sample ID and

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date of collection’. Frozen samples were stored until analysis, at the end of in-life period. Drug

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content in plasma samples were measured using LC/MS method.

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Bio-analytical method for estimation of Ondansetron HCl in Dog Plasma
Chromatography-tandem mass spectrometric (LC-MS/MS) developed and validated method was
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found suitable for estimation of Ondansetron HCl in dog plasma using as internal standard [21].
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Preparation of In-vivo study sample for Ondansetron HCl
Preparation of plasma blank
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Transferred accurately 180 µL blank plasma (Blood collection in Heparin + NaF tube) to 1.5 ml
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eppendorf tube. Add 20 µl of methanol mixed the content, transferred 50 µL of this mixture to
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1.5 ml eppendorf tube containing 400µL of acetonitrile add 50 µL of methanol and vortex it for
1 min
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Preparation of plasma blank with IS

Transferred accurately 180 µL blank plasma (Blood collection in Heparin + NaF tube) to 1.5 ml
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eppendorf tube. Added 20 µl of methanol mixed the content transfer 50 µL of this mixture to 1.5
ml eppendorf tube containing 400 µL of acetonitrile add 50 µL of IS and vortex it for 1 min
Preparation of study sample
Transferred accurately 50 µL of dog plasma study sample to 1.5 mL centrifuge tube containing
400 µL of acetonitrile and vortex it for 1 min. Added 50 µL of IS (IS solution B1) ,vortex and
centrifuged for 5 min at 10000 rpm and transferred the supernatant to auto sampler vial and
injected on LC-MS-MS [22].
Methodology
Mobile phase was injected as a blank followed by system suitability sample (6 times) to
determine the % C.V. of the response.
Peak area of Analyte⁄
𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒 = Peak area of internal standard

The sequence is run after identifying the % C.V. (≤10%) including the plasma blank, with
internal standard and calibration standards. Correlation coefficient and % deviation of the

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amount found to the nominal concentration of the calibration standards.

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Stability study of optimized batch
Stability studies of the optimized formulation (Batch No. OSH-S19) was carried out at as per the

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ICH guidelines. The samples were packed in blister pack with a forming laminate of PVC (250-
micron thickness) and Aluminium lidding foil (20-micron thickness) and were kept at 40˚C ±
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2˚C / 75% RH ± 5%, for six months (1,2,3 and 6 months) and 25˚C ± 2˚C / 60% RH ± 5% for
twelve months (3,6 and 12 months) evaluated for their physical characteristics, drug content
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(Assay) and drug release at specific interval of time per ICH guidelines.
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Result and Discussion
Compatibility study by DSC
The DSC studies were carried out to confirm the compatibility of the excipients with the drug
used in the formulation. The DSC thermogram for the pure drug and for mixtures of drug and
different excipients are illustrated in the (Fig. 1), whereas the data obtained from the DSC studies
are reported in the Table5. The observations indicate no significant change in the peaks of drug-
excipient mixtures in comparison to pure drug, indicating the compatibility of excipients with the
drug.

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Preparation of Push-pull osmotic tablets

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The proposed extended release formulation for Ondansetron HCl ER tablets 24 mg is developed
for once a day dosing, based upon clinical, pharmacokinetic and physicochemical

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characterization of the Innovator product. A push-pull osmotic pump tablet formulation
(OROS® Technology based) is designed to deliver the Ondansetron HCl active substance in a
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controlled manner over the period of 24 hours. The system deploys an osmotic gradient across a
semi-permeable membrane for the delivery of the active substance in a controlled manner with
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zero order release kinetics (Fig. 2).
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Micromeritic properties
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The micromeritic properties like bulk density, tapped density, angle of repose, Hausner’s ratio,
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Carr’s index were determined all factorial batches of Ondansetron HCl ER tablet and data is
reported in the Table 6. It was observed that all the blends of different factorial batches are
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having good angle of repose and Carr’s Index indicating good flow properties and
compressibility.
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Evaluation of tablets
Ondansetron HCl ER tablets were evaluated for its weight variation, dimensions, hardness and
friability for both core tablet and osmotic pump tablet (table 7). The tolerance of tablets to
shipping or breakage, under circumstances of storage, transportation and handling prior to usage
depends on the hardness. All the evaluation parameters were found to be within the limit.
In-vitro dissolution and drug release kinetics
Release kinetics were processed for all DOE batches for regression analysis using DD solver
12.39 (Trial version) (MS excel based software tool) .The in vitro release data was fitted to
various kinetic models like Zero order, First order, Peppas, Higuchi and Hixon–Crowell. Release
kinetics of the drug followed Korsmeyer Peppasmodel kinetics for batches OSH-1 to OSH-17
with R2 0.931 to 0.994 and The release exponent n between 0.526 to 0.868 indicates release
occurs by anomalous transport (non-fickian diffusion i.e. the rate of solvent penetration and drug
release are in the same range) kinetics. Batch OSH-10 also shows R2 0.995 for Higuchi model

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kinetic. Zero order, First order and Hixon–Crowell batches (none of the batch), results are

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illustrated in the (Fig. 3).

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Impact of osmotic pressure of the dissolution medium on drug release

Difference in the osmotic pressure of the solution on either side of the semipermeable membrane
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can acts as driving force for drug release. Hence a release study of the optimized formulation
was conducted in media of different osmotic pressure. The release data were shown in the Table
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------ and in the Figure 4. Optimized formulation (B.No.OSH-S19), drug release rate decreased
with increase in osmotic pressure of the release media; however, the lag time was prolonged with
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varying osmotic pressure (0, 25 and 50 atm). This finding confirms that the mechanism of drug
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release is by the osmotic pressure.

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Factorial Design and Optimization of formulation

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Significant advantage is assured if the experiment is so designed that the effect of changing any
one variable can be assessed independently of the others. One way of achieving this object is to
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decide a set of values, or levels for each of the factors to be studied, and to carry out one or more
trials of the process with experiment i.e. Factorial experiment. Centre points are duplicated at
both the low and high levels of each categorical factor. This doubles the number of center points
for each categorical factor in the design. DOE screening was performed to identify the most
critical formulation variables impacting the dissolution performance. Further to screening, final
optimization would be taken for the most critical factors to achieve the target composition for In-
vivo screening.
Half-Normal Plot and Pareto Chart (fig. 5) depicted the high influence of Factor C (CA 398-
10), Factor A (Polyox N80)on response dissolution at 1hr time point.. Factor C, i.e., CA 398-10
was the most significant variable influencing dissolution at 1 hr followed by Polyox N80. Less
significant impact observed for Fator D (PEG3350), Fator B(Polyox 303) and Factor E (Orifice
diameter) showed relatively less influence on the response.Response suface analysis
(fig. 5) analysis revealed that with increase in corresponding levels of Polyox 303; drug release
at 1hr tended to little increase. Opposite effect was observed in case of Polyox N80; where
corresponding increase in its level tended to decreasedrug release at 1hr. Factors BC, ABC, AB,

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AC showed significant interaction among as well. Half-Normal Plot and Pareto Chart (fig. 6)
depicted the high influence of Fator B(Polyox 303), on response dissolution at 24hr time point.

cr
Fator Bi.e Polyox 303 was the most significant variable influencing dissolution at 24hr. Less
significant impact observed for Factor A (Polyox N80), D (PEG3350), Factor E (Orifice

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diameter) and Factor C (CA 398-10) showed relatively less influence on the response. Response
suface analysis (fig. 6) analysis revealed that with increase in corresponding levels of Polyox
an
303; drug release at 24hr tended to increase. Opposite effect was observed in case of Polyox
N80; where corresponding increase in its level tended to decrease drug release at 24hr. Factors
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AB, AC showed less significant interaction among as well.
d

Verification / Validation of DOE model

e

The regression equation obtained for percent drug release at 1h, 6h, 12h and 24h for coded
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factors, along with the regression parameters is tabulated in Table 11. The actual drug release
ce

values obtained for above mentioned Ondansetron HCl was close to the predicted values and
were within 95% prediction interval.
Ac

Bio-analytical method for estimation of Ondansetron HCl in Dog Plasma

A simple and rapid liquid chromatography/tandem mass spectrometry (LC-MS/MS) method has
been developed and applied for estimation of Ondansetron HCl concentration levels in dog
plasma after administration of Ondansetron HCl extended release tablets (24 mg, once a day) and
Zofran® Immediate Release Tablets (8mg, three times a day). Chromatography-tandem mass
spectrometric (LC-MS/MS) developed method was found suitable for estimation of Ondansetron
HCl in dog plasma .The developed method was successfully employed to support the
pharmacokinetic study of Ondansetron HCl formulations in dogs.

Pharmacokinetic study
The formulation was optimized in terms of all in-vitro evaluation parameters and then subjected
for PK study in beagle dogs to establish the conceived concept. The study comparing
Ondansetron HCl ER tablets 24mg (Osmotic) and Zofran® tablet; Table12 and fig. 7. As
expected, the in-vitro drug release and in-vivo release rate profiles for once a day (o.d) extended

t
ip
release Ondansetron HCl osmotic tablet 24mg provided typical order release and a constant
plasma concentration of drug over 24 hour period compared to thrice a day (t.i.d) immediate

cr
release commercially available OSH tablet 8mg (Zofran® IR tablets 8mg) in beagle dog. Initial
loading dose of 4mg Ondansetron HCl helps in achieving faster onset of therapeutic action by

us
crossing the minimum effective concentration within one hour of administration. In the present
study, the advantage of osmotic formulations over immediate release are like constant and less
an
fluctuating plasma concentration over 24 hours, yet maintaining the desired safety, efficacy and
pharmacological effects of the drug. This was successfully demonstrated with the correlation of
M
PK data obtained in these studies.
d

Stability study of optimized batch

e

Stability testing pursues two particular aims determination of the optimum formulation during
pt

pharmaceutical technological development and derivation of the stability of a product, which

guarantees the full activity of the drug up to the end of its shelf-life. The results of the stability
ce

studies revealed no significant change in the parameters throughout the study therefore, the
developed formulation Ondansetron HCl is considered to be stable (Table 13)
Ac
Conclusion
Push-pull Osmotic Pump (PPOP) bi-layered tablets for Ondansetron HCl ER tablets, 24mg by
the use of swellable osmotic polymers like polyethylene oxide (PEO N80) in pull layer (20 mg
drug part) and polyethylene oxide (PEO 303) in push layer were developed with non-aqueous
granulation followed by compression, seal coating, semi permeable coating, laser drilling to
make orifice on coated tablet surface of about 0.6mm and finally drug film coating with loading
dose (Remaining 4mg drug part).Process parameters for compression of single and bi-layered
osmotic tablets, coating of seal, semipermeable membrane, drug coating were also optimized.

t
ip
The study comparing Ondansetron HCl ER tablets 24mg (Osmotic) and Zofran® IR tablets 8mg
(Immediate Release) thrice daily was carried out and the results were statistically analyzed using

cr
Phoenix WinNonlin® 5.1 software. The results of study confirms once daily Ondansetron HCl
ER (Osmotic) formulation is able to consistently maintains plasma concentration of drug within

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the therapeutic window over a period of 24 hours.
an
Conflict of Interests
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The authors of the paper have no direct financial relationship with any commercial
identity mentioned in this paper that could lead to a conflict of interest for any of the authors.
e d

Acknowledgements
The authors thank Wockhardt Research Centre, Aurangabad for providing the gift
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samples of drug, excipients and animal study facility. The authors are grateful to School of
ce

Pharmacy, Swami Ramanand Teerth Marathwada University, Vishnupuri, Nanded, Maharashtra,

India for providing facilities to carry out the research work.
Ac
Figure Captions
Fig 1: DSC peaks of the pure drug and the mixture of drug and excipients
Fig 2: PPOP drug release mechanism
Fig 3: Release kinetics of DOE batches Ondansetron HCl
Fig. 4: Osmotic pressure impact on drug release
Fig 5: Percent drug release at 1h (Acid stage) showing Half-Normal Plot, Pareto Chart, counter
plot and Response surface graph.
Fig 6: Percent drug release at 24h (Buffer stage) showing Half-Normal Plot, Pareto Chart,

t
ip
counter plot and Response surface graph.
Fig 7: Comparative mean plasma concentration of Ondansetron HCl osmotic tablets and

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Zofran® IR tablets

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an
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e d
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 t
ip
cr
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an
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e d
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Fig 1: DSC peaks of the pure drug and the mixture of drug and excipients
 Fig 2: PPOP drug release mechanism

t
ip
cr
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Comparative Dissolution Profile of Trials OSH 1 to OSH 17
OSH-1
100
OSH-2

90 an OSH-3
OSH-4
80
% Cumulative Drug Release

OSH-5
70 OSH-6
M
OSH-7
60
OSH-8
50 OSH-9
d

40 OSH-10
OSH-11
e

30 OSH-12

20 OSH-13
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OSH-14
10
OSH-15
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0 OSH-16
0 2 4 6 8 10 12 14 16 18 20 22 24 OSH-17
Time (h)
Ac

Fig 3: Release kinetics of DOE batches Ondansetron HCl

 120
Dissolution profile at diffrent osmotic pressure

0 atm
100
25 atm
% Release 80 50 atm

60

40

20

t
ip
0
0 2 5 8 11 14 18 20 24
Time in hr.

cr
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Fig. 4: Osmotic pressure impact on drug release

an
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e d
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 Half-normal plot Pareto chart
Design-Expert® Software
Design-Expert® Software Trial Version
Trial Version
Pareto Chart
Percent drug release at 1hr
Half-Normal Plot Percent drug release at 1hr
C
5.88
A: A:Polyethylene Oxide (Sentry Polyox WSR N-80)
Error estimates
B: Polyethylene Oxide NF (Sentry Polyox WSR 303)
99 C: Cellulose Acetate CA 398-10
A: A:Polyethylene Oxide (Sentry Polyox WSR N-80)
D: Polyethylene glycol 3350
B: Polyethylene Oxide NF (Sentry Polyox WSR 303)
E: Orifice diameter
C: Cellulose Acetate CA 398-10
4.41

Half-Normal % Probability
D: Polyethylene glycol 3350
E: Orifice diameter 95 C Positive Effects Bonferroni Limit 4.10481
Negative Effects

t-Value of |Effect|
Positive Effects
90
Negative Effects
A
80 D 2.94
A
70 B t-Value Limit 2.36462

BC D B
50 ABC
1.47 BC ABC
AB
20 AB
E E
AC

t
0 AC

0.00

ip
0.00 1.24 2.47 3.71 4.95
1 2 3 4 5 6 7 8 9 10 11

|Standardized Effect|

cr
Rank

Contour polt Response surface graph

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Design-Expert® Software

Design-Expert® Software
Trial Version
Trial Version Factor Coding: Actual
Factor Coding: Actual
Percent drug release at 1hr (%)
B: Polyethylene Oxide NF (Sentry Polyox WSR 303) (mg)

115 Percent drug release at 1hr (%)

Percent drug release at 1hr (%)
(adjusted for curvature)

15
Design Points
23
109
15
an
(adjusted for curvature)
Design points below predicted value
23

X1 = A: A:Polyethylene Oxide (Sentry Polyox WSR N-80)

24

X1 = A: A:Polyethylene Oxide (Sentry Polyox WSR N-80) 20

X2 = B: Polyethylene Oxide NF (Sentry Polyox WSR 303)
X2 = B: Polyethylene Oxide NF (Sentry Polyox WSR 303) 22
Percent drug release at 1hr (%)

Actual Factors
Actual Factors
103 20
M
C: Cellulose Acetate CA 398-10 = 95 C: Cellulose Acetate CA 398-10 = 95
D: Polyethylene glycol 3350 = 5 D: Polyethylene glycol 3350 = 5
E: Orifice diameter = 0.6
E: Orifice diameter = 0.6 5 19 18

97
16

14
d

91 18

115 230
e

85 109 220
103 210
170 180 190 200 210 220 230 200
97 190
B: Polyethylene Oxide NF (Sentry Polyox WSR 303)
91 (mg) A: A:Polyethylene
180 Oxide (Sentry Polyox WSR N-80) (mg)
pt

A: A:Polyethylene Oxide (Sentry Polyox WSR N-80) (mg) 85 170

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Fig. 5: Percent drug release at 1h showing Half-Normal Plot, Pareto Chart, counter plot and
Response surface graph.
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 Half-normal plot Pareto chart
Design-Expert® Software Design-Expert® Software
Trial Version Trial Version

Percent drug release at 24hr

Half-Normal Plot Pareto Chart
Percent drug release at 24hr
B
Error estimates
5.58
A: A:Polyethylene Oxide (Sentry Polyox WSR N-80)
B: Polyethylene Oxide NF (Sentry Polyox WSR 303)
99
Shapiro-Wilk test C: Cellulose Acetate CA 398-10
W-value = 0.997 D: Polyethylene glycol 3350
p-value = 0.988 E: Orifice diameter

Half-Normal % Probability
B 4.19
A: A:Polyethylene Oxide (Sentry Polyox WSR N-80) 95 Positive Effects
B: Polyethylene Oxide NF (Sentry Polyox WSR 303)
Bonferroni Limit 3.75131
Negative Effects

t-Value of |Effect|
C: Cellulose Acetate CA 398-10
90
D: Polyethylene glycol 3350
D
E: Orifice diameter
80 A 2.79
Positive Effects
t-Value Limit 2.26216
Negative Effects 70
A D

50
1.40
AB
20 AC
E AB AC
C E C

t
0
0.00

ip
0.00 0.20 0.41 0.61 0.82 1.02 1.23 1.43 1.64 1.84 1 2 3 4 5 6 7 8 9 10 11

|Standardized Effect| Rank

cr
Contour polt Response surface graph

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Design-Expert® Software
Trial Version Design-Expert® Software
Factor Coding: Actual
Percent drug release at 24hr (%) Trial Version
B: Polyethylene Oxide NF (Sentry Polyox WSR 303) (mg)

115 Factor Coding: Actual

Percent drug release at 24hr (%)
(adjusted for curvature)

97
Design Points
101

X1 = A: A:Polyethylene Oxide (Sentry Polyox WSR N-80)

109
100

99.5
an Percent drug release at 24hr (%)
(adjusted for curvature)

97
Design points above predicted value
Design points below predicted value
101
101

X2 = B: Polyethylene Oxide NF (Sentry Polyox WSR 303)

X1 = A: A:Polyethylene Oxide (Sentry Polyox WSR N-80)
100

Percent drug release at 24hr (%)

Actual Factors X2 = B: Polyethylene Oxide NF (Sentry Polyox WSR 303)
103
M
C: Cellulose Acetate CA 398-10 = 95
D: Polyethylene glycol 3350 = 5 Actual Factors

E: Orifice diameter = 0.6

C: Cellulose Acetate CA 398-10 = 95 99
5
99 D: Polyethylene glycol 3350 = 5
E: Orifice diameter = 0.6
97 98

97
d

91 98.5

98
115 230
e

85 109 220
103 210
170 180 190 200 210 220 230 200
97 190
B: Polyethylene Oxide NF (Sentry Polyox WSR 303)
91 (mg) A: A:Polyethylene
180 Oxide (Sentry Polyox WSR N-80) (mg)
pt

85 170
A: A:Polyethylene Oxide (Sentry Polyox WSR N-80) (mg)
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Fig. 6: Percent drug release at 24h showing Half-Normal Plot, Pareto Chart, counter plot and
Response surface graph.
 16
8
Plasma Concentration

4
2
(mcg/ml)

1
0.5
Zofran® IR tablets 8mg
0.25
Ondansetron HCl ER tablets 24mg
0.125
0.0625

t
0.03125

ip
0 1 3 5 8 9 11 13 16 17 19 21 24
Time (h)

cr
Fig. 7: Comparative mean plasma concentration of Ondansetron HCl osmotic tablets and
Zofran® IR tablets

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an
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List of Tables

Table 1: Composition of Ondansetron HCl tablet

Table 2: Seal Coating and ER Coating Composition
Table 3: Details of design layout for Ondansetron HCl ER tablets
Table 4: Linearity solutions for spiking Ondansetron HCl
Table 5: DSC data of the peak values of the pure drug and the mixture of drug and excipients
Table 6: Micromeritic properties of blend samples
Table 7: Evaluation parameters of core tablets

t
ip
Table 8: Dissolution study for Ondansetron HCl ER tablets
Table 9: Release kinetics of DOE batches OSH-1-OSH-17

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Table 10: Osmotic pressure impact on drug release

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Table 11: ANOVA analysis for Ondansetron HCl ER tablets DOE batches
Table 12: The regression equation obtained for percent drug release
an
Table 13: Pharmacokinetic parameters summary of Ondansetron HCl osmotic tablets vs
Zofran® IR tablets
Table 14A: DSC Excipient compatibility study of drug with various Excipients at 25°C/60%RH
M
and 40°C/75%RH
Table 14B: Stability data Ondansetron HCl ER tablets 24mg
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 Table: 1 Composition of Ondansetron HCl tablet

mg/tabl
S. No. Ingredients/Grade % w/w
et
A) Layer I (Pull layer)
Intra-granular
1 Ondansetron hydrochloride USP 6.66 20
2 Mannitol USP (Pearlitol SD 200) 20.00 60
Polyethylene Oxide NF

t
3 66.66 200

ip
(Polyox WSR N80)
Hypromellose USP

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4 6.00 18
(METHOCEL E5)

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Binder Solution
5 Isopropyl alcohol NF q.s q.s
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Extra-granular
Magnesium Stearate NF (Veg
6 0.66 2
M
grade)
Layer I weight (mg) 100 300
d

B) Layer II (Push layer)

e

Intra-granular
pt

Polyethylene Oxide NF (Polyox

1 66.66 100
303)
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2 Iron Oxide Red NF (Sicovit Red) 0.66 1

Hypromellose USP (METHOCEL
3 12
Ac

8
E5)
4 Sodium Chloride USP 24 36
Binder Solution
5 Isopropyl alcohol NF q.s q.s
Extra-granular
Magnesium Stearate NF (Veg
6 0.66 1
grade)
 Layer II weight (mg) 100 150
Core tablet weight (mg) 450

Table 2: Seal Coating, ER Coating and IR (Immediate release) drug coating Composition

Seal Coating Composition ER Coating Composition Drug Coating Composition

(IR)

t
Sr.N % mg/ % mg/
Ingredients Ingredients Ingredients % mg/

ip
o. w/w tablet w/w tablet
w/w tablet
Seal coated +

cr
Seal coated
1 Core tablet -- 450 -- 464 ER coated tablet -- 520
tablet
weight (mg)

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Hydroxypropyl Cellulose Ondansetron
2 Cellulose 85.71 12 Acetate CA 95 53.2 HCl 28.57 4
(Nisso HPC SSL) 398-10
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Polyethylene Hydroxypropyl
Polyethylene glycol
glycol 3350 NF Cellulose NF 71.43 10
3 400 NF 14.29 2 5 2.8
(Polyglykol (Nisso HPC
(Lutrol E 400)
M
3350 P) SSL)
Isopropyl
Isopropyl alcohol Acetone NF
4 -- q.s. -- q.s. alcohol NF -- q.s
NF (99% part )
d

(90% part)
Purified water Purified water
e

Solid Content -- q.s

5 USP (1% -- q.s. USP (10% part)
(%w/w)
pt

part)
Target Weight Solid Content Solid Content
3 3 5
Gain (%w/w) (%w/w) (%w/w)
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Seal coated tablet Target Weight Target Weight

464 11 2.7
weight (mg) Gain (%w/w) Gain (%w/w)
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Seal coated + Final PPOP

ER coated tablet 534
-- -- 520
tablet weight (mg)
(mg)
 Table 3: Details of design layout for Ondansetron HCl ER tablets

Factor 1 Factor 2 Factor 3 Factor 4 Factor 5

C:Cellulose
A:Polyox B: Polyox D:Polyethylene E:Orifice
Acetate
B.No WSR N80 WSR 303 glycol 3350 diameter
CA 398-10
mg mg % ratio % ratio mm
OSH 1 200 100 95 5 0.6

OSH2 170 70 97.5 7.5 0.5

OSH 3 170 70 97.5 2.5 0.5

t
ip
OSH 4 200 100 95 5 0.6

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OSH 5 200 100 95 5 0.6

OSH 6 200 100 95 5 0.6

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OSH 7 170 130 97.5 7.5 0.7

OSH 8 230

230
70

130
an 92.5

92.5
2.5

7.5
0.5

0.7
OSH 9
M
OSH 10 170 130 92.5 7.5 0.5

OSH 11 230 70 97.5 7.5 0.5

d

OSH 12 230 130 92.5 2.5 0.7

e

OSH 13 230 70 97.5 2.5 0.7

pt

OSH 14 200 100 95 5 0.6

ce

OSH 15 170 70 92.5 7.5 0.7

OSH 16 230 130 97.5 2.5 0.5

Ac

OSH 17 170 130 92.5 2.5 0.7

Note: Concentration of Mannitol was adjusted to maintain the constant weight of 450 mg.
 Table 4: Linearity solutions for spiking Ondansetron HCl.

Volume Effective approximate conc. of

Solution Volume of solution C
Diluent diluted to each analyte in linearity
No. (µL)
(ml) solution (ng /ml)
C10 10 µL of Solution A 1 1000

C9 500 µL of C10 1 500

C8 500 µL of C9 1 250

C7 500 µL of C8 1 100

t
ip
C6 500 µL of C7 1 50
Methanol
C5 500 µL of C6 1 25

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C4 500 µL of C5 1 10

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C3 500 µL of C4 1 5

C2 500 µL of C3 an 1 2.5

C1 500 µL of C2 1 1
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Table 5: DSC data of the peak values of the pure drug and the mixture of drug and
excipients

S.No Ingredients API: Excipient Peak value

ratio (°C)
1 Ondansetron HCL (API) - 188.20
2 API +Polyethylene glycol 3350 1: 0.25 189.79
API +Hydroxypropyl Cellulose NF (Nisso HPC 189.19
3 1: 1
SSL)
4 API +Cellulose acetate 398-10 1: 5 190.17

t
ip
5 API + Magnesium Stearate 1:0.25 185.95
6 API + Sodium chloride 1: 5 188.80

cr
7 API + Mannitol USP (Pearlitol SD 200) 1: 10 185.30

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8 API + Iron oxide red NF (Sicovit Red) 1:0.1 190.08
9 API + Polyethylene Oxide NF (Polyox WSR N80) 1: 10 187.92
10 API + Polyethylene Oxide NF (Polyox 303)
an 1: 10 188.01
11 API + Hypromellose USP (METHOCEL E5) 1: 2 187.01
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 Table 6: Micromeritic properties of blend samples

B.No Angle of Bulk Density Tapped Carr’s Index Hausner’s

Repose (°) (g/cm3) Density(g/cm3) ratio

OSH 1 27.58 ± 0.11 0.469 ±0.02 0.555 ±0.03 14.56 ±0.1 1.11 ±0.02

OSH 2 27.32 ±0.20 0.472 ±0.02 0.551 ±0.01 14.60 ±0.09 1.14 ±0.01

OSH 3 26.95 ±0.11 0.468 ±0.02 0.548 ±0.02 14.58 ±0.1 1.21 ±0.02

OSH 4 26.84 ±0.12 0.475 ±0.02 0.557 ±0.03 14.55 ±0.07 1.15 ±0.01

t
ip
OSH 5 27.18 ±0.14 0.462 ±0.01 0.550 ±0.02 14.51 ±0.03 1.22 ±0.01

cr
OSH 6 27.39 ±0.13 0.470 ±0.02 0.556 ±0.01 14.46 ±0.05 1.20 ±0.09

OSH 7 27.25 ±0.12 0.467 ±0.02 0.546 ±0.02 14.52 ±0.05 1.18 ±0.08

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OSH 8 27.19 ±0.16 0.476 ±0.02 0.551 ±0.03 14.57 ±0.06 1.16 ±0.09

OSH 9 27.48 ±0.11 0.473 ±0.01

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0.558 ±0.02 14.54 ±0.1 1.19 ±0.03

OSH 10 27.10±0.12 0.472 ±0.03 0.549 ±0.01 14.51 ±0.02 1.12 ±0.04
M
OSH 11 26.79 ±0.09 0.466 ±0.02 0.553 ±0.02 14.58 ±0.03 1.17 ±0.05

OSH 12 27.20±0.09 0.471 ±0.01 0.546 ±0.02 14.53 ±0.05 1.17 ±0.06
e d

OSH 13 27.15 ±0.14 0.464 ±0.01 0.551 ±0.02 14.56 ±0.06 1.22 ±0.09
pt

OSH 14 27.36 ±0.17 0.469 ±0.03 0.548 ±0.03 14.54 ±0.09 1.18 ±0.01
ce

OSH 15 27.43 ±0.13 0.473 ±0.02 0.555 ±0.03 14.59 ±0.04 1.23 ±0.1

OSH 16 27.24 ±0.12 0.470 ±0.02 0.554 ±0.04 14.60 ±0.09 1.15 ±0.1
Ac

OSH 17 27.09 ±0.10 0.475 ±0.02 0.558 ±0.03 14.55 ±0.05 1.17 ±0.09
 Table 7: Evaluation parameters of core and push-pull osmotic pump tablets
Evaluation parameters of core tablets Parameters of developed osmotic pump tablets
Drug
Weight Diameter Thickness Hardness Friability Weight Diameter Thickness
B. No content
(mg) (mm) (mm) (kg/cm2) (%) (mg) (mm) (mm)
(%)
OSH 1 535 ±5 10.62 ±0.01 6.96 ±0.01 101.30 ±0.7
451±8 10.02 6.51 ±0.01 14.65 ±2 0.06
OSH 2 390 ±5 10.02 6.30 ±0.03 11.29 ±2 0.02 470 ±7 10.50 ±0.01 6.60 ±0.02 100.60 ±0.8

OSH 3 390 ±4 10.01 6.27 ±0.03 10.57 ±2 0.05 475 ±8 10.55 ±0.02 6.65 ±0.02 99.95 ±0.5

OSH 4 449 ±7 10.02 6.49 ±0.01 12.26 ±2 0.07 531 ±4 10.72 ±0.01 6.99 ±0.02 102.40 ±0.4

t
533 ±5 10.62 ±0.01 6.96 ±0.02 101.50 ±0.1

ip
OSH 5 451 ±3 10.02 6.65 ±0.03 14.37 ±2 0.03

OSH 6 452 ±5 10.02 6.69 ±0.02 13.91 ±2 0.08 538 ±10 10.61 ±0.02 6.97 ±0.01 103.70 ±0.1

cr
OSH 7 450 ±8 10.02 6.51 ±0.02 12.76 ±1 0.05 532 ±9 10.59 ±0.01 7.01 ±0.02 98.75 ±0.2

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OSH 8 453 ±3 10.03 6.53 ±0.03 11.59 ±2 0.06 535 ±5 10.61 ±0.02 6.92 ±0.01 100.32 ±1

OSH 9 510 ±4 10.03 6.71 ±0.01 13.5 ±2 0.04 593 ±7 10.70 ±0.02 7.25 ±0.01 103.65 ±0.9

OSH 10 448 ±5 10.02 6.5 0±0.03 14.89 ±1

an
0.05 534 ±3 10.64 ±0.01 6.92 ±0.02 101.24 ±1

OSH 11 446 ±5 10.02 6.51 ±0.02 15.14 ±1 0.06 531 ±10 10.61 ±0.01 6.94 ±0.02 102.84 ±1
M
OSH 12 510 ±7 10.02 6.72 ±0.02 15.44 ±1 0.02 591 ±8 10.73 ±0.02 7.15 ±0.01 99.75 ±0.4

OSH 13 451 ±8 10.03 6.54 ±0.02 13.42 ±2 0.04 522 ±9 10.64 ±0.01 6.98 ±0.02 102.47 ±0.5
d

OSH 14 455 ±4 10.03 6.48 ±0.01 13.67 ±2 0.03 524 ±4 10.61 ±0.01 6.95 ±0.01 101.14 ±2
e

OSH 15 390 ±3 10.02 6.21 ±0.02 14.01 ±1 0.05 476 ±5 10.50 ±0.02 6.98 ±0.02 100.58 ±1
pt

OSH 16 510 ±4 10.01 6.63 ±0.02 15.57 ±2 0.06 599 ±8 10.69 ±0.01 7.27 ±0.01 101.33 ±2
ce

OSH 17 452 ±8 10.01 6.49 ±0.01 12.72 ±1 0.04 530 ±9 10.63 ±0.01 6.95 ±0.02 99.10 ±0.3
Ac
 Table 8: Dissolution study for Ondansetron HCl ER tablets

Response Response Response

Factor 1 Factor 2 Factor 3 Factor 4 Factor 5 Response 1
2 3 4
Percent Percent Percent
C:Cellulose Percent drug
B.No A:Polyox B: Polyox
Acetate CA
D:Polyethylene E:Orifice
release at
drug drug drug
WSR N80 WSR 303 glycol 3350 diameter release at release at release at
398-10 1hr
6hr 12hr 24hr
mg mg % ratio % ratio mm % % % %
OSH 1 200 100 95 5 0.6 18 42 59 100

OSH 2 170 70 97.5 7.5 0.5 18 48 78 99

t
OSH 3 170 70 97.5 2.5 0.5 17 46 74 98

ip
OSH 4 200 100 95 5 0.6 16 40 54 100

cr
OSH 5 200 100 95 5 0.6 17 41 58 99

OSH 6 200 100 95 5 0.6 16 43 57 100

us
OSH 7 170 130 97.5 7.5 0.7 20 53 81 99

OSH 8 230 70 92.5 2.5 an 0.5 18 44 64 98

OSH 9 230 130 92.5 7.5 0.7 22 49 77 99

OSH 10 170 130 92.5 7.5 0.5 23 58 89 100

M
OSH 11 230 70 97.5 7.5 0.5 18 32 47 97

OSH 12 230 130 92.5 2.5 0.7 20 45 65 99

d

OSH 13 230 70 97.5 2.5 0.7 16 27 40 92

e

OSH 14 200 100 95 5 0.6 18 41 60 99

pt

OSH 15 170 70 92.5 7.5 0.7 22 56 88 100

OSH 16 230 130 97.5 2.5 0.5 15 30 45 94

ce

OSH 17 170 130 92.5 2.5 0.7 21 49 67 100

Ac
 Table 9: Release kinetics of DOE batches OSH-1 to OSH-17

Un OS OS OS OS OS OS OS OS OS OS OS OS OS OS OS OS OS
Trials
it H-1 H-2 H-3 H-4 H-5 H-6 H-7 H-8 H-9 H- H- H- H- H- H- H- H-
10 11 12 13 14 15 16 17
K0 5.53 6.21 6.06 5.44 5.53 5.53 6.40 5.52 6.01 6.62 4.85 5.69 4.08 5.53 6.69 4.31 5.90
Zero Order 2 2 5 1 0 7 9 1 2 8 9 9 4 5 3 0 9
0.93 0.91 0.93 0.93 0.92 0.93 0.87 0.91 0.86 0.79 0.92 0.93 0.91 0.94 0.83 0.94 0.91
R2
6 7 0 8 8 8 6 3 5 1 8 1 2 6 1 0 2
K 0.10 0.12 0.12 0.09 0.10 0.09 0.14 0.10 0.12 0.17 0.07 0.10 0.06 0.09 0.16 0.06 0.11
First order 0 9 1 5 0 9 5 3 7 0 7 7 0 9 8 5 7
0.92 0.95 0.94 0.91 0.93 0.92 0.96 0.96 0.97 0.98 0.88 0.95 0.90 0.92 0.98 0.92 0.95

t
R2
9 2 6 5 2 2 8 4 4 2 4 2 1 5 3 5 4

ip
n 0.71 0.64 0.67 0.76 0.69 0.74 0.57 0.62 0.55 0.49 0.86 0.66 0.76 0.75 0.52 0.79 0.62
6 6 7 7 6 1 2 1 1 0 8 6 4 1 6 4 7

cr
KorsmeyerP KK 11.5 15.6 14.0 10.0 12.2 10.8 19.5 14.7 19.3 24.9 6.87 13.5 7.57 10.6 22.9 7.38 15.6
eppas P 99 10 68 05 21 74 01 92 10 50 3 98 2 09 31 0 10
0.97 0.98 0.98 0.95 0.96 0.96 0.99 0.99 0.99 0.99 0.93 0.98 0.93 0.97 0.99 0.95 0.98

us
R2
0 3 1 8 9 4 2 0 7 5 3 5 1 0 4 4 6
KH 19.8 22.3 21.7 19.4 19.8 19.7 23.2 19.9 21.8 24.3 17.2 20.4 14.5 19.7 24.4 15.3 21.3
Higuchi 04 86 88 06 32 82 74 34 76 20 27an 90 73 65 54 45 22
0.93 0.96 0.95 0.91 0.94 0.92 0.98 0.97 0.99 0.99 0.87 0.96 0.89 0.93 0.99 0.90 0.97
R2
8 5 6 5 1 6 6 7 4 5 0 3 2 0 3 6 2
KH 0.02 0.03 0.03 0.02 0.02 0.02 0.03 0.02 0.03 0.04 0.02 0.02 0.01 0.02 0.04 0.01 0.03
M
Hixon– c 8 5 3 7 8 8 8 8 4 4 2 9 8 7 4 9 2
Crowell
0.94 0.96 0.96 0.93 0.94 0.93 0.97 0.96 0.96 0.97 0.90 0.96 0.90 0.93 0.98 0.93 0.95
R2
1 4 0 0 1 5 1 3 9 5 1 0 8 9 5 4 8
e d

Table 10: Osmotic pressure impact on drug release

pt

B.No OSH-S19
ce

Time points 0 atm 25 atm 50 atm

(Hrs)
0 0 0 0
Ac

2 18±4 5±1 4±1

5 30±3 10±2 9±1
8 42±3 21±2 15±2
11 51±3 34±3 23±2
14 59±2 43±2 29±2
18 83±2 53±2 36±3
20 98±2 57±2 43±3
24 100±1 64±2 49±3
 Table 11: ANOVA analysis for Ondansetron HCl ER tablets DOE batches

Response Source Sum of Mean F value p-value Remarks

Df
Squares Square
Percent drug Model 64.47 9 7.16 24.26 0.0005 significant
Residual 1.77 6 0.2952
release at 1hr
Cor Total 80.12 16
Model 1095.25 7 156.46 51.72 < 0.0001 significant
Percent drug
Residual 24.20 8 3.02
release at 6hr
Cor Total 1159.06 16

t
Model 2946.83 9 327.43 54.42 < 0.0001 significant

ip
Percent drug
Residual 36.10 6 6.02
release at 12hr

cr
Cor Total 3403.76 16
Model 64.47 9 7.16 24.26 0.0005 significant
Percent drug
1.77 6 0.2952

us
Residual
release at 24hr
Cor Total 80.12 16

an
M
e d
pt
ce
Ac
 Table 12: The regression equation obtained for percent drug release
Response Regression Equation for coded factors R2 Adjusted Predicted R2
R2

=+97.54-1.63*A+0.375*B-
Percent drug 1.63*C+0.2500*D-
0.9733 0.9502 0.9309
release at 1hr 1.00*E+0.285*AB+0.107*AC+1.14*BE-
0.875*ABC

Percent drug =+44.75-6.13*A+0.875*B-

0.9855 0.9690 0.9332
release at 6hr 5.13*C+2.50*D+0.00*AB-2.75-0.125

t
ip
Percent drug =+70.88-9.75*A+0.650*B-
release at 7.15*C+5.50*D-0.8510*E- 0.9879 0.9697 0.9335

cr
12hr 3.25*AC+2.12*AD+6.00*AE+6.75*BC

us
Percent drug =+97.54-1.63*A+0.375*B-
1.63*C+0.250*D-
release at an 0.9733 0.9565 0.9065
1.00*E+0.285*AB+0.107*AC-1.14*BE-
24hr 0.875*ABC
M
e d
pt
ce
Ac
Table 13: Pharmacokinetic parameters summary of Ondansetron HCl osmotic tablets vs
Zofran® IR tablets
OndansetronHCl ER
Zofran® IR tablets 8mg
Product tablets 24mg
(Immediate Release)
(Osmotic)

B.No OSH-S19 3ZP3000

OndansetronHCl
Analyte (ng/mL) measured in OndansetronHCl (ng/mL) measured in dogs
dogs

t
Single dose First dose Second dose Third dose Cumulative

ip
Parameter average results
(0-24 hrs) (0-8hrs) (09-16hrs) (17-24hrs) (0-24hrs)

cr
Cmax(ng/mL) 5.947 (0.872) 12.472 (2.525) 12.061(1.610) 12.100 (1.104) 13.669 (1.196)

us
Tmax(h) 1.000 (0.000) 1.000 (0.000) 1.000 (0.000) 1.000 (0.000) 1.000 (0.000)

AUC(ng.h/mL) 63.670 (6.649) an

34.994 (5.432) 33.081(3.490) 33.887 (1.261) 101.858(3.626)

T1/2 (h) 1.253 (0.011) 1.931 (0.078) 1.564(0.083) 1.744 (0.194) 1.745 (0.144)
M
e d
pt
ce
Ac
 Table 14A: DSC Excipient compatibility study of drug with various Excipients at
25°C/60%RH and 40°C/75%RH

S. Ingredients API: Initial Physical Physical

No. Observation Observations at Observations at
Excipient
25°C/60%RH 40°C/75%RH

2W 4W 2W 4W

white to off-
1 Ondansetron HCL (API) - NC NC NC NC
white powder

t
ip
API +Polyethylene glycol white to off-
2 1: 0.25 NC A A A
3350 white powder

cr
API +Hydroxypropyl
white to off-
3 Cellulose NF (Nisso HPC 1: 1 NC NC NC NC
white powder

us
SSL)
API +Cellulose acetate white to off-
4 1: 5 NC NC NC NC
398-10 white powder
5 API + Magnesium Stearate 1:0.25
an
white to off-
white powder
NC NC NC NC
white to off-
6 API + Sodium chloride 1: 5 NC NC NC NC
M
white powder
API + Mannitol USP white to off-
7 1: 10 NC NC NC NC
(Pearlitol SD 200) white powder
d

API + Iron oxide red NF Red powder

8 1:0.1 NC NC NC NC
(Sicovit Red)
e

API + Polyethylene Oxide white to off-

9 1: 10 NC NC NC NC
NF (Polyox WSR N80) white powder
pt

API + Polyethylene Oxide white to off-

10 1: 10 NC NC NC A
NF (Polyox 303) white powder
ce

API + Hypromellose USP white to off-

11 1: 2 NC NC NC NC
(METHOCEL E5) white powder
Ac
 Table 14B: Stability data Ondansetron HCl ER tablets 24mg

B.No.OSH-S19 Packing: 10's Tablets in blister pack

S.No Tests Specification Initial 40˚C ± 2˚C & 25˚C ± 2˚C &
75 % ± 5% RH 60 % ± 5% RH
1M 2M 3M 6M 3M 6M 12M
White to light
pink colored
round biconvex

t
tablet with No No No No No No No No

ip
1 Description
preformed change change change change change change change change

cr
passageway at
the center of the

us
tablets
NLT 90% &
2 Assay (%) 99.8 99.4 100.2
an 99.9 99.4 99.7 100 99.2
NMT 110%
Dissolution
3
(% drug release)
M
1 hr NMT 25% 18 16 16 21 19 17 18 15
Between 35%-
d

6 hr 42 43 40 43 44 41 41 39
50%
e

Between 55%-
12 hr 59 57 54 61 63 58 60 55
pt

70%
24 hr NLT 80% 100 100 100 99 99 101 100 99
ce
Ac
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cr
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