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Freeze drying: Exploring potential in development of orodispersible tablets of

sumatriptan succinate

Article in Drug Development and Industrial Pharmacy · January 2014

DOI: 10.3109/03639045.2013.871551 · Source: PubMed

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ISSN: 0363-9045 (print), 1520-5762 (electronic)

Drug Dev Ind Pharm, Early Online: 1–8

! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2013.871551

RESEARCH ARTICLE

Freeze drying: exploring potential in development of orodispersible

tablets of sumatriptan succinate
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by St Johns University on 01/04/14

Dalapathi Gugulothu, Preshita Desai, Pranav Pandharipande, and Vandana Patravale

Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N. P. Marg, Matunga, Mumbai, India

Abstract Keywords
The present investigation is aimed at development and characterization of sumatriptan Gelatin, in vitro disintegration time, in vitro
succinate orodispersible tablets (ODTs) prepared by freeze drying technology. The tablet drug release, lyophilization technology,
excipients were screened and the composition was optimized based on parameters which scanning electron microscopic analysis
involved general appearance, tablet size and shape, uniformity of weight, mechanical
properties, surface pH, moisture analysis, drug content, wetting time, in vitro and in vivo History
disintegration time. Furthermore, fourier transform infrared spectroscopy, differential scanning
calorimetry, scanning electron micrograph of cross-section of the tablet and in vitro dissolution Received 14 July 2013
studies were performed. Studies revealed that formulation containing gelatin–mannitol Revised 12 November 2013
(3.75% w/v and 3.5% w/v, respectively) with camphor as a volatile pore forming agent Accepted 17 November 2013
exhibited superior properties with disintegration time of less than 10 s. Furthermore, in vitro Published online 3 January 2014
For personal use only.

release studies revealed 90% release of drug from developed dosage form within 10 min, thus
suggesting rapid drug dissolution followed by faster onset of action, which forms a strong
rationale for development of ODTs of sumatriptan succinate. The developed technology is
simple, which involves few steps and can be easily scaled up. Thus, it holds enormous potential
for commercial exploitation.

Introduction which disintegrates rapidly, usually in matter of seconds, when

placed upon the tongue. European Pharmacopoeia (EP, 4th
Conventional tablets and capsules occasionally cannot be easily
edition) has accepted the term OD for official usage18. Owing
administered to certain group of patients, including, those with
to their suitability in use; ODTs are mainly being explored for
swallowing difficulties, geriatric, paediatric, bedridden and men-
treatment modules of dysphagia, geriatrics, paediatrics, bedridden
tally challenged patients1–7. Thus, patient compliance-oriented
or disabled patients and for patients who have little or no access to
research has resulted in bringing out many safer and newer drug
water8,19,20.
delivery systems and orodispersible tablets (ODTs) are one such
Various techniques employed for development of ODTs
example. The major advantages of this dosage form are admin-
include freeze drying technology, mass extrusion, direct com-
istration without water, high degree of content uniformity, quick
pression using super-disintegrant, tablet molding, etc.21, amongst
onset of action, enhanced bioavailability and stability8–17.
which the freeze drying/lyophilization technology is compara-
Furthermore, fast onset of action makes them lucrative for
tively a recent addition to ODT manufacturing; wherein the frozen
therapy modules wherein immediate medical intercession is
drug solution or suspension containing structure forming excipi-
essential for, e.g. in angina pectoris, migraine, acidity etc.1 Thus,
ents is subjected to vacuum that results in the removal of water by
such readily administrable dosage forms have wedged the
the sublimation and desorption process22. A new dimension can
attention of the pharmaceutical industry owing to their expedi-
be added to ODTs developed by this technology by the addition of
ency in use.
volatile ingredients, namely camphor, menthol which on removal
ODTs are also identified by varied terminologies, namely
during the process creates uniform porosity in the tablet that helps
mouth dissolving tablets, fast dissolving/disintegrating tablets,
in further rapid disintegration upon contact with saliva.
melt in mouth tablets, rapid melts, quick dissolving tablets,
Sumatriptan succinate (Figure 1) belongs to triptan class of
rapidly disintegrating tablets and porous tablets. United States
selective serotonin 5HT1B/1D receptor agonists medicinally
Food and Drug Administration (USFDA) has defined such dosage
indicated for treatment of migraine attack and cluster headaches.
forms as a solid dosage form containing medicinal substances
The underlying mechanism involves agonistic binding of
drug sumatriptan to 5-HT receptor which leads to constriction
of extra-cerebral blood vessels and thus inhibits the release of
Address for correspondence: Prof. Vandana B. Patravale, Department of
Pharmaceutical Sciences and Technology, Institute of Chemical
inflammatory mediators23.
Technology, N. P. Marg, Matunga, Mumbai 400019, India. Tel: Currently, sumatriptan succinate is commercially available as
+91-22-3361 2217. Fax: +91-22-3361 1020. E-mail: vbp_muict@ oral tablets with varying strengths of 25, 50 or 100 mg, nasal
yahoo.co.in spray (packaged in single-dose bottles containing either 5 or
 2 D. Gugulothu et al.
Figure 1. Molecular structure of sumatriptan succinate.
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by St Johns University on 01/04/14
20 mg of the drug) and injections (containing 6 mg drug/0.5 mL),
to be administered beneath the skin with an auto injector. The
reported absolute bioavailability of drug from these dosage forms
is about 14%, 15% and 96%, respectively24.
The low bioavailability upon oral and intranasal administration
is a major rate limiting step in achieving the desired efficacy and
faster onset of action and is presumably attributed to presystemic
metabolism and incomplete absorption of drug. Thus, ODTs of
sumatriptan succinate hold a strong rationale herein as it will
ensure its enhanced release for quick absorption by the blood
vessels in the oral mucosa, bypass the gastrointestinal tract and
first-pass metabolism in the liver and will further ensure faster
onset of action25–27.
Thus, in this study, sumatriptan succinate ODTs were prepared
with an aim to improve the dissolution rate and oral bioavail-
For personal use only.
ability of drug which will ensure the desired therapeutic efficacy
via the more comfortable and convenient oral delivery route and
will further preclude the requirement of invasive techniques.
Materials and methods
Materials
Sumatriptan succinate and gelatin were obtained as generous gift
samples from Sun Pharmaceuticals Pvt. Ltd. Vadodara, India, and
Panacea Biotech Ltd, Mumbai, India, respectively. Plasdone
K90DÕ was obtained as a gift sample from ISP Techno Inc.,
Hyderabad, India. Sorbitol and sucrose were provided by SRL
chemicals, Mumbai, India. Potassium dihydrogen orthophosphate,
sodium hydroxide, mannitol, disodium ethylene diamine tetra
acetic acid (disodium EDTA), magnesium stearate, camphor and
menthol were purchased from s.d. Fine Chemicals, Mumbai,
India. Xantural 75 (xanthan gum) was obtained as a gift sample
from Signet Chemical Corporation, Mumbai, India. Glycine SR
was procured from Merck chemicals and sucralose as a gift
sample from Tale and Lyle Sucralose, Inc., Decatur, IL. Double
distilled water was used throughout the study. All other chemicals
used were of analytical grade unless otherwise indicated.
Methods
Analytical method development by UV–visible spectrophotometric
analysis
The UV photometric analysis method for quantitative determin-
ation of sumatriptan succinate was successfully developed using
UV–visible double beam spectrophotometer (Shimadzu Model
1503V, Shimadzu Inc., Shimadzu, Japan).
The stock solution was prepared by dissolving accurately
weighed 10 mg of sumatriptan succinate in 100 mL of phosphate
buffer (pH 6.8) to attain a concentration of 100 mg/mL
and was scanned from 200 to 800 nm to obtain maximum
absorbance wavelength (max) for the drug under consideration.
Drug Dev Ind Pharm, Early Online: 1–8
The stock solutions were further serially diluted to obtain working
solutions with concentrations of 1, 2, 4, 6 and 8 mg/mL and were
employed in the development of standard curve. Linearity was
determined by plotting the curve of Absorbance versus
Concentration at max and regression coefficient, slope and
intercept was determined by statistically treating the data using
least-square regression analysis. The experiment was performed
in triplicate.
Formulation of ODTs of sumatriptan succinate
ODTs of sumatriptan succinate were prepared using freeze drying
technology wherein various excipients were screened toward
successful development of porous, fast disintegrating tablets with
acceptable mechanical strength and faster rate of dissolution28–30.
The roles of range of excipients employed are as described ahead,
gelatin and plasdone K90DÕ were used as matrix forming agents;
mannitol, sorbitol and glycine as diluents; magnesium stearate as
an anti-frictional agent; disodium EDTA as a chelating agent;
xanthan gum as a dispersing agent; sucralose as a sweetening
agent, and camphor and menthol were used as volatile pore
formers and flavor.
The formulation methodology involved the addition of gelatin/
plasdone K90DÕ to water heated to 40  C. Diluents, namely
mannitol, sucrose and glycine, were added and homogenized for
20 min using magnetic stirrer followed by the addition of xanthan
gum, disodium EDTA, magnesium stearate, sucralose and pore
forming agents. Furthermore, 1.5 mL of developed uniform
suspension (equivalent to 25 mg of sumatriptan succinate) was
poured in each pocket of a polyvinyl chloride (PVC) blister pack
with a diameter of 13 mm and 3-mm depth and was subjected to
freeze drying. The freeze drying protocol involved initial freezing
at 40  C for 12 h followed by primary drying for 12 h at pressure
of 0.250 mbar and temperature less than 15  C with further
secondary drying at 15  C for 20 h at pressure of 0.250 mbar. The
developed formulations were critically screened for various in vitro
parameters as described below toward the selection of best
acceptable formulation. Furthermore, the prepared ODTs were
stored in vacuum desiccators at room temperature until further use.
Characterization of ODTs of sumatriptan succinate
General appearance
The general appearance of a tablet dosage form, its visual identity
and overall elegance are important parameters for patient
acceptance. Thus, attributes pertaining to tablet appearance,
namely tablet’s size, shape, color, presence or absence of an odor,
surface texture, physical flaws and consistency and legibility of
any identifying marking of tablets were checked11,31–33. Herein,
tablet size was examined for 20 tablets and was described
dimensionally in terms of diameter and thickness using digital
vernier calliper (Mitutoyo, Japan).
Uniformity of weight
The test was carried out according to the EP (4th Edition)34.
Twenty tablets were randomly selected and were individually
weighed. Results are presented as mean value  standard
deviation (SD).
Mechanical properties of the tablets
Hardness of the tablet is a best measure to assess its mechanical
properties. Thus, a probe penetration test was performed to
determine hardness of the tablets using texture analyzer
‘‘TA-XT2Texture Analyzer’’ (Stable Micro Systems, Surrey,
England).
 DOI: 10.3109/03639045.2013.871551
In this method, each tablet was placed between two blank
plates of the assembly having an orifice of 1 cm diameter on the
top plate. The 5 mm cylinder probe (P4) with a 5 kg load cell was
operated at the test speed of 1 mm/s up to a distance of 2 mm
followed by a trigger force of 5 g, and a post-test speed of
10 mm/s. At this depth, the maximum force reading (i.e. the
resistance to penetration) was noted. From this observation,
the hardness of the sample was computed. A total of six tablets
were tested for final formulation and the values were reported as
mean  SD21,22,35.
Surface pH
Surface pH of tablets was determined in order to investigate
the possibility of any irritation to the buccal mucosa
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by St Johns University on 01/04/14
resulting from extreme acidic or alkaline pH. A combined
glass electrode was used for the purpose (Eutech Instruments,
Mumbai, India). Three tablets were allowed to swell by
keeping them in contact with 1.0 mL of double distilled water
for 2 h and pH was noted by bringing the electrode in contact
with the surface of the formulations and allowing it to
equilibrate36–38.
Moisture analysis
Residual moisture content of the tablets was analyzed using IR
moisture content analyser (A and D Instruments, Mumbai, India).
Six tablets were crushed homogenously and were placed in an
aluminum pan at 105  C until constant weight was achieved. Loss
on drying was expressed in terms of percentage and results are
For personal use only.
presented as mean value  SD36–38.
Content uniformity
Ten tablets were assayed for their drug content using the
developed UV-analytical method described previously. An indi-
vidual tablet was dissolved in 50 mL of double distilled water and
was further diluted to 100 mL. This stock solution was carefully
filtered and 1 mL of this stock solution was further diluted to
10 mL and the absorbance was recorded at 227 nm (max) using
UV–visible double beam spectrophotometer (Shimadzu Model
1503V). Drug content was calculated and compared with United
State Pharmacopoeia (USP) limits of 85–115%24,29,32,33.
Wetting time
Wetting time of tablets was determined by placing piece of twice
folded tissue paper (12 cm  10.75 cm) in a small petridish
(internal diameter: 6.5 cm) containing 6 mL of Sorenson’s buffer
pH 6.8. A tablet was placed on the paper and the time taken for
complete wetting was measured. The test results are presented as
mean value (n ¼ 3)  SD35,37.
Water absorption ratio (%)
A piece of tissue folded twice diametrically was kept in a petri
dish (internal diameter: 6.5 cm) containing 6 mL of double
distilled water. The tablet was then placed on the tissue paper
and allowed to wet completely as described in the previous
section. The wetted tablet was then removed and reweighted.
Water absorption ratio, R, was determined according to the
following equation:
R ¼ ðWa  Wb Þ=Wb ,
where Wa and Wb are the weight after and before water absorption,
respectively. The test results are presented as mean value
(n ¼ 3)  SD39,40.
FDT of sumatriptan succinate 3
In vitro disintegration test
The test was carried out on six tablets using the apparatus
specified in USP 2007, distilled water at 37  2  C was used as
disintegration medium and the time taken for complete disinte-
gration of the tablet with no palpable mass remaining in the
apparatus was measured. The test results are presented as mean
value  SD34,36.
In vivo disintegration test
The in vivo disintegration time of each of the prepared tablets
was evaluated in six human volunteers after obtaining informed
written consent. The volunteers had no history of any disease state.
Prior to the test, all volunteers were asked to rinse their mouth
with distilled water. Each of the six subjects was given a coded
tablet. Tablets were placed on the tongue and immediately the time
was recorded. They were allowed to move the tablet against the
upper palate of the mouth with their tongue to cause a
gentle tumbling action on the tablet without biting it or tumbling
it from side to side. Immediately after the last noticeable mass had
disintegrated, the time was recorded. The subjects were instructed
to spit out the contents of the oral cavity after test was performed
and wash their mouth with distilled water. The swallowing of
saliva was strictly prohibited during the test period, and oral
cavity was rinsed thoroughly to remove saliva after every
measurement. The test results are presented as mean value  SD36.
Fourier transform infrared spectroscopy (FTIR)
Fourier transform infrared (FTIR) spectroscopy was conducted
using a Perkin Elmer Spectrophotometer. The spectrum was
recorded in the wavelength region of 4000–45 cm1. The
procedure consisted of dispersing a sample (drug, physical
mixture, blank ODTs and drug-loaded ODTs) in KBr and
compressing into discs by applying a pressure. The spectrum
was recorded by placing the compressed disc in the light path of
the spectrophotometer.
Differential scanning calorimetry (DSC)
Differential scanning calorimetry (DSC) studies were performed
on a differential scanning calorimeter (Perkin Elmer, coupled with
Pyris software) with a thermal analyzer. Accurately weighed
sample (5 mg) was sealed in an aluminum pan before heating
under nitrogen flow (20 mL/min) at a scanning rate of 10  C/min
from 35  C to 300  C. An empty aluminum pan was used as a
reference. Thermograms for drug, ODTs with and without drug
were obtained.
Scanning electron microscopic (SEM) analysis
Cross-sections of selected tablet formulation were examined using
a Joel JSM-6386 LA, analytical scanning electron microscope,
(Tokyo, Japan). Cross-sections of samples were prepared by
cutting a thin slice of the tablet using a scalpel.
In vitro drug release studies
In vitro drug release studies were carried out using a USP XXIII
Dissolution Apparatus I (Cylinder type) [Electrolab Tablet
Dissolution Tester] at 50 rpm. The drug release profile was
studied in 1000 mL of phosphate buffer at pH 6.8 maintained at
37  0.5  C. Aliquots of 5 mL were withdrawn at intervals of 5,
10, 15, 30 and 60 min, filtered and the amount of drug released
was determined spectrophotometrically at conditions specified in
the previous section at 227 nm. Dissolution of six tablets was
determined and mean percentage cumulative drug release was
calculated34.
 4 D. Gugulothu et al. Drug Dev Ind Pharm, Early Online: 1–8

0.037
0.033
0.033
0.25
3.75
F19

100
3.5

0.4

0.2
Results and discussion

–
–

–
Analytical method development by UV–visible
spectrophotometry

0.037
0.033
0.033
F18

100
0.25
3.75
–

–
–

–
3.5

0.2

0.2
The max of the drug was observed to be 227 nm with linearity
over the concentration range of 1–8 mg/mL. The obtained

0.037
0.033
0.033
regression equation was Y ¼ 0.1144 X þ 0.0193 with

F17

100
0.35
0.25
3.75
–

–
–
–
–
3.5
R2 ¼ 0.9996, indicating very good linear relationship over the
concentration range.

0.037
0.033
0.033
F16

100
0.35
0.25
3.70
–

–
–
–

–
3.5
Development of freeze dried ODTs of sumatriptan
succinate

0.037
0.033
0.033
F15

100
0.25
3.75
–

–
–
–
–
3.5

0.2
Proper selection of polymer is the prime requisite to attain an
ODT with acceptable mechanical properties and faster release
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by St Johns University on 01/04/14

rates. Furthermore, polymers enabling amorphization of drug in

0.037
0.033
0.033
F14

100
0.25
3.75
–

–
–
–

–
matrix become the choicest option toward ODT development41,42.

3.5

0.2
Thus, various formulation trials were conducted for developing
freeze dried ODTs of sumatriptan succinate (F1–F19) as

0.037
0.033
0.033
F13

100
0.25
3.75
–

–
–
–
–
–
4.0
described in Table 1. Tablet intactness and elegance, uniformity,
ease of handling and disintegration time being the most crucial
parameters toward promising ODT formulation, the optimization

0.037
0.033
0.033
F12

100
0.25
3.75
–

–
–
–
–
–
was performed considering aforementioned factors as the critical

3.5
variables (Table 2). From all the batches screened, it was observed
that gelatin matrix tablets indicated better compatibility for freeze

0.037
0.033
0.033
F11

100
0.25
3.75
drying as compared with the tablets made from Plasdone K90DÕ

–
–
–
–
–
3.0
which were found to be non-uniform and underwent easy damage
during the handling process. Thus, gelatin was further optimized

0.037
0.033
0.033
F10

100
0.25
3.75
as tablet matrix forming agent over a concentration of 3–4% w/v.

–
–
–
–
–
2.5
The study revealed that the disintegration time of tablets
For personal use only.

increased proportionally with increase in gelatin concentration

0.037
0.033
0.033
100
up to a certain level beyond which tablets failed to disintegrate
0.25
3.75
F9

–
–
–

–
–
–
2.0
spontaneously and on contrary formed thick gel-like matrix. Thus,
the concentration of 3.75% w/v of gelatin was considered to be an

0.037
0.033
0.033
optimum concentration as it conferred ideal properties to ODTs

100
0.25
3.75
F8

–
–

–
–
–
–
and thus batch F19 was considered as optimized formulation for 2.0
further studies. The ODTs obtained from batch F19 were found to

0.037
0.033
0.033
be complying with desired tablets properties in terms of shape,

100
0.25
3.75
F7

–
–
–
–
–
2.0

appearance, uniformity, surface texture and disintegration time

which could be explained as follows. 0.037
0.033
0.033
Synonymous to most of the other dosage forms, even in case of

100
0.25
F6

–
–
–
–
–
–
–
4.0

ODTs, the generally described mechanism of disintegration

involves weakening of the intermolecular bonds upon penetration
of the disintegration medium in the tablet’s excipients resulting in
0.037
0.033
0.033
100
0.25
3.75
F5

–
–
–
–
–
–
–

complete disintegration of the tablet43. In the present study,

sublimation of water from the frozen gelatin solution during the
freeze drying process resulted in formation of porous three-
0.037
0.033
0.033
100
0.25
F4

–
–
–
–
–
–
–
3.5

dimensional gelatin networks. With increase in gelatin concen-

tration, the so formed network is anticipated to become more
stable and extensive owing to increase in the fiber cross links and
0.037
0.033
0.033
100
0.25
3.25
F3

inter chain H-bonds44 and could be attributed to corresponding

–
–
–
–
–
–
–

increase in disintegration time. On the contrary, beyond a certain

concentration, the gelatin matrix becomes so extensive and
0.037
0.033
0.033
100
0.25
F2

synonymously less porous that the interaction with disintegration

–
–
–
–
–
–
–
3.0
Table 1. Formulation trials of ODTs.

medium resulted in formation of thick cohesive gels that were

difficult to disintegrate. This observation could further be
0.037
0.033
0.033
100
0.25
F1

explained by reported phenomenon of formation of rough three-

–

–
–
–
–
–
–
3.0

dimensional gel network of gelatin at high concentration, formed

as result of quick cooling below 40  C, that upon contact, traps
Sumatriptan succinate

water in the formed mesh and results in formation of gel45.

Magnesium stearate

Furthermore, various diluents were screened, wherein the

Disodium EDTA
Plasdone K90D
Ingredients (g)

combination of gelatin–mannitol was found to be better over

Xanthan gum

Water qs to

gelatin–sorbitol (isomer of mannitol) or gelatin–glycine in terms

Sucralose
Camphor
Mannitol

Menthol

of tablet shape, appearance, surface texture and disintegration

Sorbitol
Glycine
Gelatin

time and it could be attributed to superior hydrophilicity of

mannitol over others and mannitol-induced porosity in tablets.
 DOI: 10.3109/03639045.2013.871551 FDT of sumatriptan succinate 5
Table 2. Physical appearance and disintegration time of formulation trials
(n ¼ 6).

Parameters
In vitro
Formulation disintegration
no. Physical appearance time (s)
F1 Non Uniform, difficult to handle – fragile –
F2 Difficult to handle – fragile –
F3 Difficult to handle – fragile –
F4 Difficult to handle – fragile –
F5 Easy to handle 65  2.0
F6 Easy to handle 91  1.0
F7 High moisture content –
F8 Tablet shape non-uniformity 100  2.0
F9 Tablet shape non-uniformity 110  4.0
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by St Johns University on 01/04/14

F10 Fragile –
F11 Uniform but less porous 65  4.0
F12 Uniform and porous, easy to handle 45  3.0 Figure 2. General appearance of ODT of sumatriptan succinate.
F13 Uniform and porous, easy to handle 70  2.0
F14 Uniform and porous, easy to handle 49  2.0
F15 Uniform and porous, easy to handle 53  1.0 Table 3. Results of tablet size, uniformity of weight, mechanical
F16 Uniform and porous, easy to handle 32  1.0 properties, surface pH, residual moisture content, drug content, wetting
F17 Uniform and porous, easy to handle 35  2.0 time, water absorption ratio, in vitro disintegration time and in vivo
F18 Uniform and porous, easy to handle 24  4.5 disintegration time.
F19 Uniform and porous, easy to handle 12.5  3.0
Parameter Mean values  SD

Additionally, tablets formed from gelatin–mannitol combination Size (mm) 17.99  1.25
Uniformity of weight (mg) 111.64  6.54
were found to be in conformity with previously reported Zydis Mechanical properties (kg) 1.509  0.13
technology for lyophilized tablets46. Further ODTs with gelatin– Surface pH 5.95  0.45
mannitol combination offered comfortable manual handling and
For personal use only.

Residual moisture content (w/w %) 3.614  0.915

retained the intactness of ODTs. This phenomenon can be
supported by the literature that proposes that when processed in
presence of water, generally observed bigger  crystal form of
mannitol gets converted to smaller b form which is reported to
enhance hardness of resulting tablet owing to increase in crystal-
specific surface area47,48.
Furthermore, to fasten disintegration time of ODTs various
approaches are being explored till date. The literature reports
formation of ODTs using direct compression wherein the
possible disintegration mechanisms investigated were super-
disintegration, effervescence and sublimation. The studies
revealed that combination of sublimation or effervescence with
super-disintegrants work synergistically toward faster tablet
disintegration41. In one other study, comparison between the
freeze drying and sublimation technique reveled that both
the methods individually can attain faster disintegration. Taking
lead from this, it was aimed to investigate if the combination of
freeze drying along with sublimation has any synergistic effect
on tablet disintegration49. Based on above assumption, an
intermediate batch with 3.75% w/v of matrix forming agent,
gelatin and 3.50% w/v mannitol as diluents was further screened
for selection of optimum volatilizing agent, namely menthol
and camphor. Batches containing 0.2% w/v camphor and
menthol showed higher disintegration time 49  2 and 53  1 s,
respectively, which was further decreased to 32  1 and 35  2 s,
respectively, by increasing the camphor and menthol concentration
to 0.35% w/v. This indicated that the disintegration time was
significantly affected by the concentration of volatilizing
agent. This phenomenon can be explained by formation of the
porous structure induced in the tablet matrix due to the
sublimation of camphor and menthol resulting in faster water
uptake, thus facilitating the swelling action and allowing
faster disintegration which is in conformity with reported
literature50,51. Thus, the subliming agents could be arranged in
a descending order of disintegration time as follows:
camphor4menthol.
Content uniformity (%) 97.99  7.41
Water absorption ratio 1.012  0.026
In vitro disintegration time (s) 12.5  3.1
In vivo disintegration time (s) 25.1  2.5
The addition of sucralose as a sweetening agent was done
to mask the bitter taste of sumatriptan succinate. For this,
blank samples were compared with 0.2% w/v, 0.4% w/v of
sucralose. Formulations with 0.4% w/v of sucralose were
sufficiently taste masked and could attain a desired sweetening
effect considering which it was chosen as the optimum concen-
tration. As discussed earlier, concomitant use of freeze drying
with sublimation lead to high degree of porosity in the ODT and
conversely affected the ease of manual handling and shape
intactness thus, xanthan gum was introduced to maintain the
proper shape of tablet without hampering the disintegration
behavior of ODT.
Based on aforementioned rationale batch F19 was considered
as the optimum ODT formulation and was considered for further
analysis.
Evaluation of freeze dried ODTs of sumatriptan succinate
The tablet indicated a stable unit entity with consistent pale white
colored appearance as shown in Figure 2. The upper surface of
tablets was porous and thick owing to water evaporation during
secondary drying. The tablets had mild but pleasant smell by
virtue of camphor.
The results of various analysis parameters for developed ODTs
are summarized in Table 3. Size and shape of the tablets were
found to be suitable for paediatric as well as geriatric patients.
Weight variation range of the prepared tablets was well within the
acceptable criteria.
The tablets with only gelatin offered poor mechanical proper-
ties which may have resulted from extra porous anatomical
 6 D. Gugulothu et al. Drug Dev Ind Pharm, Early Online: 1–8

architecture of the lyophilized ODT consisting of a
three-dimensional network of binder molecules.
In this study, though the use of 3.75% w/w gelatin stock
solution as a binder is anticipated to offered high resistance to
breakage, highly porous spongy structure of the ODTs made them
vulnerable toward external forces. However, increase in binder
concentration conferred a detrimental effect on the disintegration
time of the tablets due to increase in intermolecular attraction
between the binder molecules resulting in retardation in disinte-
gration time profile. Thus, incorporation of matrix supporting
agent like mannitol was selected as a solution.
The hardness of the ODTs was found to be 1.509  0.131 kg
which fits well within the USP limits that specify the limit up to
4 kg. Generally, the hardness of tablets is commonly governed by
the intermolecular bonding force and contact points between the
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by St Johns University on 01/04/14
and bending – 1434.96, 833.32, 879.19 cm1, C–N stretching and
bending – 1301.90 cm1, C–O stretching 1076.93, 1138.53,
1204.08 cm1 (alcoholic group), C¼O – 1707.57 cm1 (ketone
group), C–H – 2933.43 cm1 and C¼C – 1564.18 cm1 and thus
confirmed the drug-excipient compatibility (Figure 3).
To evaluate the crystalline state of sumatriptan succinate in
selected ODTs, DSC studies were carried out on sumatriptan
succinate, drug-loaded ODTs and blank ODTs. The DSC
thermogram of sumatriptan succinate showed a sharp endother-
mic peak at nearly 171  C corresponding to its melting transition
point. The thermogram of blank ODTs and drug-loaded ODTs
showed a small endothermic peak corresponding to the melting
point of mannitol, indicating the amorphous form of drug by the
process of lyophilization (Figure 4).
Scanning electron micrograph of the cross-sectional view of

excipients45. The extent of contact between the matrix forming ODTs is shown in Figure 5. The scanning electron micrograph
agents within the lyophilized ODTs is further influenced by the exhibited the highly porous nature of the prepared lyophilized
total porosity of the tablet, decrease in the porosity increases the
contact points between the matrix forming agents within the ODT
and thus the hardness. Hence, the higher porosity can be
anticipated as the major reason for low hardness which is a
desired attribute for ODTs52,53. Thus, the formulation was
optimized to achieve an elegant ODT formulation that though
has comparatively low hardness but allows safe manual
handling this further anticipates use of special alu alu packaging
for these ODTs.
Surface pH of the tablets was found to be around 5.95, a
weakly acidic value which is compatible for orodispersible
administration and as reported drug is also stable under acidic
pH conditions and thus falls in acceptable limits. The developed
For personal use only.

tablets showed residual moisture content of not more than 5%,

indicating that the lyophilization process was efficient in
removing water from the tablets. However, it can be suggested
that further increase in moisture content may lead to microbial
contamination, hydrolysis of drug, etc. and hence humidity during
packaging phase has to be constantly controlled. The mean
percent drug content of the tablet was found to be 97.99  7.41%
and individual drug content of each tablet was well within the
range of 85–115%. Thus, the requirements for content uniformity
were met as per British Pharmacopoeia (BP).
The average wetting time, water absorption ratio, in vitro and
in vivo disintegration time for the prepared ODTs are illustrated in
Table 3. ODTs showed a wetting time of less than about 11 s
which indicates highly porous nature of the tablet hydrophilic
matrix. Furthermore, tablets prepared by freeze drying technology
accelerate disintegration of tablets by virtue of their ability to
absorb a large amount of water when exposed to an aqueous
environment54. This was further corroborated with water absorp-
tion ratio analysis which was found to be 1.012  0.026 in case of
optimized ODTs which is indicative of secondary swelling and
rapture of inter particulate bonds in tablet resulting in faster
disintegration53,55.
Disintegration test for ODTs is not described specifically in
any of the referred pharmacopoeias. Conventionally, the oral
disintegration time of mouth-dissolved tablets is preferred to be
1 min or less, more preferably about 30 s or less42. The
investigated ODTs showed in vitro disintegration time of less
than 10 s whereas the in vivo disintegration time was observed to
be less than 30 s which was well within the acceptability range.
The observed difference between in vitro and in vivo disintegra-
tion time can be explained by the mechanical stress, which is
added during the in vitro experiment and the large amount of the
disintegration media used in contrast to in vivo conditions.
FTIR spectroscopic analysis of sumatriptan succinate
alone and in formulation showed presence of following peaks Figure 3. FTIR spectra of (a) sumatriptan succinate, (b) physical mixture,
substantive of sumatriptan succinate, namely C–H stretching (c) blank ODTs and (d) ODTs of sumatriptan succinate.
 DOI: 10.3109/03639045.2013.871551
Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by St Johns University on 01/04/14
Figure 4. DSC analysis of (a) sumatriptan succinate, (b) blank ODT and
(c) ODT of sumatriptan succinate.
For personal use only.
Figure 5. SEM of ODT of sumatriptan succinate.
Figure 6. In vitro drug release profile of ODT of sumatriptan succinate.
tablets, which appears on the surface as well as in the inner
structure. The highly porous nature of the tablets was thus
confirmed by SEM imaging and explains the rapid penetration of
water, which results in rapid wetting, disintegration and dissol-
ution in the oral cavity. These results indicate that the addition of
water-soluble polymer greatly affected the inner structure of the
tablet with subsequent impact on wetting, disintegration and
dissolution of the final tablet.
FDT of sumatriptan succinate 7
From drug release profile of the ODT formulation as shown in
Figure 6, it was observed that 76% of drug was released in initial
5 min while 100% release was observed in approximately 15 min.
These results indicate that the sublimation process used to prepare
the ODTs enhanced the extent and rate of dissolution of
sumatriptan succinate due to porous nature of tablets that
facilitates faster uptake of disintegration media.
Conclusion
In the present investigation, ODTs of sumatriptan succinate were
successfully developed using a freeze drying technique. These
tablets not only offered faster disintegration (less than 10 s) but
also assured faster dissolution and in turn faster onset of activity.
As a technology per se, a freeze drying technique offers a
commercially viable and an effective alternative approach to the
conventional ODT formulation techniques and thus holds an
enormous potential for its successful commercial exploitation as a
platform technology toward the development of ODTs.
Declaration of interest
The authors are grateful to University Grants Commission and
Department of Science and Technology for the financial assistance
provided for research work. The authors have declared no conflict of
interest.
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