105
EVALUATION OF SPRAY AND FREEZE DRIED EXCIPIENT BASES
CONTAINING DISINTEGRATION ACCELERATORS FOR THE
FORMULATION OF METOCLOPRAMIDE ORALLY
DISINTEGRATING TABLETS
Fars K. Alanazi
‫اكتسبت األقراص الفموية رةري التفتةت جةباً لهتتمةًأ ثك ةر اةق األقةراص التة خاية اًنة اًلمسةب ل مر ة الةبيق‬
‫لايهم اشك في الب ع ا ل األطفًل وكبةً السةق والمر ة الممةواخق واخةر الةةً يق تةبص األقةراص تفتةت فةي الفةم‬
‫ااون اضغ ثو إ ًف اخًص لهً في الفم إل اآلن تمًك ال ايا اق اةرااا اخاتةرال لهةبص األقةراص ولكةق تمةًك الة خةل‬
‫فةة اةق األاثةًل الممشةو د تةةاث البثةي الثةًلي تةو ثضةخر ثقةةراص اختوك وارااخةا رةري التفتةت اةًلفم ا قةةود‬
‫اخكًنخكخ كًفخ و فتت رريع اق قواعا اثضرد اًرةتدااأ ةمخةً التيمخةا اةًلرل والتيمخةا التيفخفةي ولةةا ارةتداات‬
‫ نةةو يوأ‬،‫ ك و يةةون‬،‫رةةول‬-‫ اي‬- ‫اسةرعً ادت فة ل تفتةةت لتثضةةخر األقةةراص الفموية رةري التفتةةت فمويةةً ا ةةل ث‬
‫ اةةبيا يةةًيري تةةو الكثةةول األضخ ةةي والثمةةن األاخمةةي ج خسةةخق ولةةةا ارةةتداأ عةةةً اختوك وارااخةةا‬، ‫نشةةًج خكوخ‬
‫المضً ل ةخئ كةمم وايةي فةي األقةراص رةري التفتةت فمويةً المثضةرد ولةةا لةو أ ثن رةرع التفتةت الفمةوي فةي‬
‫األقراص المثضرد ي تما ع اخرتفً د اق اسرعً التفتت فةي كةل اةق ةمخةً التيمخةا اةًلرل والتيمخةا التيفخفةي‬
‫ نةول‬،‫لتثضخر قواعا قرنخ لألقراص الفموي رري التفتت وكبلك ال واال المت ةا د األاةرم ا ةل عم خة التيفخةع‬
‫اسرعً التفتت وإ ًف اسرعً التفتت قبل ثو ا ا عم خ التيفخع ولةا عزيت ررع التفتت لألقراص المثضةرد‬
‫إل الترطخا الممتًز لمكونً الةرص ا ا ثن م ريضهً ل م خً التيفخع وقا بةخق ثنةب اا ةًف اسةرعً التفتةت‬
‫إل قواعا األقراص قبل عم خ التيفخع يمتج عمب إطًل لوقت التفتت اةً ن اا ًفتهً إل قواعا األقراص ا ا عم خة‬
‫التيفخع ويمكق يبخق تبص الا ار ع ث وي ثارم فةي نةخًاً رةري التفتةت تفتةت فةي التيويةع الفمةي و لةك‬
‫لتهخئ ااتصًص ثررل اق يويع الفم وا ا لةك يكتمةل اخاتصةًص فةي اةخة اليهةًز الهضةمي وثيضةً ل ت ةا ع ة‬
‫ن وا الب ع‬
Orally disintegrating tablets (ODT) are gaining attractiveness over conventional tablets specially
for patients having difficulty in swallowing such as pediatric, geriatric, bedridden and disable
patients. ODT technologies render the tablets disintegrate in the mouth without chewing or
additional water intake. So far there have been many patents for ODT, but only few publications
are dealing with this dosage form. The aim of the present study was to formulate metoclopramide
in ODT with sufficient mechanical strength and fast disintegration from bases prepared by both
spray (SD) and freeze drying (FD) techniques. Different disintegration accelerators (DA) were
utilized to prepare the proper ODT using various super-disintegrants (Ac-Di-Sol, Kollidon and
sodium starch glycolate), a volatilizing solvent (ethanol) and an amino acid (glycine).
Metoclopramide, an antiemetic medication, was used as a model drug in the formulated ODT. It
was noted that the disintegration of ODT depends on utilization of DA in both SD and FD
techniques to prepare tablet bases for ODT and so many other factors such as drying process, type
of DA, and the addition of DA before or after the drying processes. The good disintegration
property of the prepared tablets was related to the excellent wettability of the ingredients after
being subjected to the drying processes. Results also showed that the addition of DA to the tablet
bases before drying process results in lengthening of the disintegration time in comparison to their
addition to the tablet bases after the drying process. These findings could be utilized for many
Department of Pharmaceutics, College of Pharmacy, King Saud
University, P.O. BOX 2457, Riyadh 11451, Saudi Arabia.
Email: afars@ksu.edu.sa
Saudi Pharmaceutical Journal, Vol. 15, No.2, April 2007
106
ALANAZI
drugs and they may be considered versatile in the applications. Also, the disintegration of the
ODT in the buccal cavity may favor fast absorption via the mucus membrane in the oral cavity.
Key words: Spray drying, Freeze drying, Orally disintegration tablet, Metoclopramide,
Disintegration accelerators, Dissolution rate, Super-disintegrants.
Introduction
Recent advances in drug delivery systems seek
enhancing the safety and efficacy of drug molecules
by formulating them in conveniently administrated
dosage forms (1). Dysphagia, difficult in swallowwing, is common among all age groups and it is
experienced by patients such as pediatric, geriatric,
bedridden and disabled patients (2). The most
common complaint about the difficulty in swallowwing of tablets is their large sizes (3). Therefore,
improving the compliance and quality of life of such
patients by using orally-fast disintegrating tablet is a
promising alternative to conventional tablets (4).
During the last decade, great deal of attention
has been drawn to orally disintegrating tablet (ODT)
technologies that make such tablets disintegrate in
the mouth without chewing or additional water
intake (5). These tablets disintegrate into smaller
granules or melt in the mouth from a hard rigid solid
to a gel like structure, allowing easy swallowing by
patients. The saliva of patients (1-2 ml) is the
dissolving medium and it would be enough to
disintegrate these tablets (4).
Orally disintegrating tablets (ODT) have been
reported to be prepared by different technologies
including molding, sublimation, direct compression,
wet granulation, freeze drying and spray drying (6).
So far there have been many patents for ODT, but
only few publications are dealing with this dosage
form (7). Spray drying (SD) and freeze drying (FD)
are considered novel techniques to prepare
excipients for ODT. SD technique provides a fast
and economic way of evaporating solvents, subsequent drying and producing highly amorphous
spherical, fine powders suitable for ODT (8). On the
other hand, FD; lyophilization, is a process in which
the solvent is sublimed from a frozen drug solution
or suspension containing structure-forming excipients. Glassy amorphous porous structure of excipients as well as the drug substance produced with FD
leading to the enhancing of dissolution (9). In the
literature, there is no study comparing between SD
and FD as techniques in the efficiency of preparation
of ODT bases. In addition, there is lack of
information about the effect of SD and FD
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
techniques on the efficiency of disintegration accelerators (DA).
The aim of the present study was to formulate
ODT with sufficient mechanical strength and fast
disintegration from bases prepared by both SD and
FD techniques. Different disintegration accelerators
(DA) were also utilized to prepare the proper ODT
using various super-disintegrants (Ac-Di-Sol,
Kollidon and sodium starch glycolate), a volatile
solvent (ethanol) and an amino acid (glycine).
Metoclopramide, an antiemetic medication, was
used in the present study as a model drug. It is
administrated by group of patients who have motion
sickness (10) and may not have an access to water at
the time of administration. Examples of these
patients are aeroplane passengers and pregnant
women during walking.
In the light of that,
metoclopramide is a good candidate for ODT and
formulating it in ODT is beneficial for certain
patients.
Materials and Methods
Materials:
Metoclopramide and glycine were purchased
from Sigma (USA). Crosslinked sodium carboxymethyl cellulose (Ac-Di-Sol), sodium starch glycollate (SSG), and Kollidon CL (crosslinked polyvinyl
pyrrolidone) were kindly donated from Al-Jazerah
Pharm. Ind. (Riyadh, Saudi Arabia). All other
chemicals and solvents used were of pharmaceutical
grades.
Methods
A. Preparation of spray-dried tablet bases:
Tablet bases, composed of microcrystalline
cellulose, mannitol, saccharine and DA (Table 1),
were suspended in deionized water and then heated
to 40 oC bending to SD process. All batches of
suspension bases were spray-dried using Buchi 190
mini spray drier (Büchi Labortechnik AG, Germany)
with 0.5mm nozzle. The suspension bases were fed
to the nozzle via peristaltic pump (spray flow rate of
12 ml/min.). The suspension was sprayed as
atomized droplets by the force of the compressed air
EVALUATION OF SPRAY AND FREEZE DRIED EXCIPIENT BASES
(air flow rate of 4 pound per square inch). The
solvent in the droplets was evaporated in the drying
chamber by the blown hot air (inlet air temperature
of 135 oC and outlet air temperature of 70 oC). The
dried tablet bases were collected in collection vessel
and stored at room temperature for further
manipulation.
B. Preparation of freeze-dried tablet bases:
The tablet bases, composed of microcrystalline
cellulose (MCC), mannitol, saccharine and DA
(Table 1), were suspended in deionized water and
the suspensions were heated to 40 o C. Suspension
bases were pre-cooled (-5 o C) prior to FD. The
frozen bases were lyophilized using freeze dryer
(ALPHA 1-4LD-2, Martin Christ, Osterode, Germany) under the following conditions (temperature =
-59, vacuum = 0.001 mp) for 48 hrs. The dried bases
were collected and transferred to well-closed
containers and stored at room temperature (25 o C)
bending to evaluation and formulation experiments.
C.
Particle size analysis of the prepared tablet
bases:
The samples were dispersed in liquid paraffin (1
mg/ 1 ml) and mounted on microscopic slides.
Particle diameters of the bases were measured using
Reichert Microscope (Depew, NY, USA) and using
eyepiece of magnification of 40X. The microscope is
equipped with a special projection system connected
to the eyepiece which allows the measurement on
the surface of the projection screen. The readings
were measured in millimeter and converted to
micrometer using the microscope provided equation
[diameter (m) = measurement in mm X (1000/
magnification power)]. The diameters measured are
number parameters (i.e. numbers distribution) (11).
The mean particle diameters were the average of at
least 100 particles.
D. Measurement of Angle of repose of the prepared
tablet bases:
The angle of repose was measured for the SD
and FD bases, so as to observe the flow properties of
such bases. The method employed a funnel secured
with its tip at a given height (H), above the graph
paper placed on horizontal surface. Treated base
powders were poured through the funnel until the
apex of conical pile touched the tip of the funnel.
The angle of repose was calculated using the
following formula, tan  = H/R where  is the angle
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
107
of repose and R is the radius of conical pile (12). The
angle of repose was calculated as the mean of three
determinations.
E.
Determination of moisture content of the
prepared tablet bases:
Weight loss on drying was determined using a
Mettler moisture balance (Meltter PM 480 Delta
Range, Switzerland). Five gms of each prepared base
powder was put in the pan of the balance. Heating
temperature was set at 100 oC and the time mode
was set at 30 seconds which means continuous
heating of the sample after removal of the free water
content for the 30 seconds (13). The percentage
moisture content was directly recorded. The test was
carried out on triplicate for each base and the mean
values were considered.
F. Determination
of
bulk
density
and
compressibility of the prepared tablet bases:
The bulk density was determined by filling the
processed base powders into a tarred graduated
cylinder to the 100 ml mark. The graduated cylinder
was weighed and the bulk density (VB) was
calculated as the ratio of the sample weight to the
sample volume (14). The graduated cylinders were
then tapped (for 3 mins which was found practically
to be enough time) from a height of about 2 inches
till constant volume was obtained. The tap density
(VT) was calculated as the ratio of the sample weight
to the final sample volume. The trial was carried out
on triplicate and the mean values were calculated.
Carr’s Index and Hausner factor were calculated for
the prepared ODT bases as evaluation parameters for
compressibility (15). The changes occurring in
packing arrangement during the tapping procedure
were expressed as Carr’s Index (I) as shown by the
following equation , I = [( 1- VB)/ VT] X 100.
Hausner factor (HF) was calculated from the
following equation, HF = VT/ VB.
G.
Scanning
electron
microscopic
(SEM)
examination for the prepared bases:
SD and FD tablet base morphologies were
examined under the scanning electron microscope
(Jeol, JSM-6360LV scanning microscope, Tokyo,
Japan). Before microscopy, the base powders were
mounted at carbon tape and were sputter-coated
using gold (Jeol, JFC-1100 fine coat ion sputter,
Tokyo, Japan). The photomicrographs were taken at
an acceleration voltage of 20 kV (16).
108
ALANAZI
H.
Preparation of ODT by direct compression
technique:
The ODT were prepared using the SD and FD
processed bases after the addition of metoclopramide
and sodium stearyl fumarate (SSF), (Table 1). The
tablet constituents were weighed and mixed first in
the mortar (triturating) and mixed furtherly in tubula
mixer (Erweka S27, Frankfort, Germany) for 2 mins
which was found practically as the efficient mixing
time. The tablet ingredients after mixing were
compressed by EKO single punch tablet machine
(Korsch, Berlin, Germany) using punch 0.6 cm in
diameter and weighing 110 mg.
I.
Determination of the prepared ODT hardness:
The hardness of the ODT was measured using
Erweka TBH-28 hardness tester (Frankfort, Germany). Hardness is the breaking strength value of
the tablet reported in kilograms (12). Minimum of
six tablets were used and the mean value was
considered.
J.
Determination of the prepared ODT friability:
Friability (f) of the tablets was determined using
Erweka TA3R friabilitor (Frankfort, Germany) at 25
rpm/min for 4 min. The tablets were weighed and
loss in weight (%) was calculated (17). Twenty
tablets were used in such determination.
K.
Determination of wetting time for the prepared
ODT:
Wetting time was determined by the method
described previously (18). In brief, a piece of tissue
paper folded twice was placed in small culture dish
(internal diameter = 6.5 cm) containing 6 ml of
water. Then, the tablet was placed on the wetted
paper and the time for complete wetting was
calculated. The test was carried out on triplicate and
the mean value was considered.
L.
Measurement of disintegration time for the
prepared ODT:
Disintegration time was determined using USP
disintegration test apparatus (Erweka ZT4,
Frankfort, Germany) without disk for six tablets. The
disintegration medium was 900 ml of distilled water
kept at 37 ± 0.5 oC and stirred at a rate of 30 ± 2
cycles/ min (13).
M.
Measurement of in vitro drug dissolution from
the prepared ODT:
The dissolution measurements were performed
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
using USP dissolution apparatus II (Caleva Ltd.,
Model 85T, Philips, UK) adopting a continuous
automated monitoring system which consists of an
IBM computer PS 830 series and PU 860/60
dissolution test software, Philips VIS/UV single
beam, six cells, spectrophotometer model PU 8620,
Epson FX 850 printer, and Waston-Marlow
peristaltic pump. In each flask, 1 L of distilled water
was used as the dissolution medium (USP 23). The
temperature was maintained at 37 ± 0.5 oC and
paddles speed was kept at 50 rpm. Percent drug
dissolution was determined at specified time
intervals by assaying the collected samples
spectrophotometerically for drug content at 308 nm
(19). It was found that all additives included in the
tablet formulation didn’t interfere with the
spectrophotometric assay of the drug. The
dissolution studies were carried out in triplicate. The
time required for 50% of the drug to be dissolved
(T50 %) was calculated graphically (16) which was
used as a comparison parameter in drug dissolution
evaluation. Relative dissolution rate (RDR) was
obtained by dividing the dissolution percent of the
drug in the specific formula at the determined time
by the dissolution percent of the pure drug which
processed under the same condition (SD and FD) at
the same time. Dissolution efficiency (DE) is
defined as the area under dissolution curve up to the
time (t) which was expressed as a percentage of the
area of the rectangular described by 100 %
dissolution in the same time (10).
N.
Statistical analysis of the obtained results:
One-way analysis of variance (ANOVA) and ttest were performed using Statgraphics plus 2
software to compare the mean values for all
formulations. Multiple Range Test (Fisher’s least
significant difference procedure, LSD) was also used
to determine which means are significantly different
from the others. The level of confidence was set to
be 95% (20).
Results and Discussions
SD technique yielded spherical particles as
shown in Fig 1. However, in case of FD technique
the products were in the form of spongy matrices
with very porous structures. Exception to these
findings is in case of glycine, SD powder is not
spherical but tubular like structure (Fig 2: SD-F). It
was also observed that SD powder containing SSG is
EVALUATION OF SPRAY AND FREEZE DRIED EXCIPIENT BASES
spherical in shape (Fig 2: SD-B2), yet their base
surface is not smooth like the rest of superdisintegrants (Fig 1: SD-B1 and SD-B3). This
surface is composed of small tubular particles joined
together to form bigger spherical particles. This
could be because SSG may adsorb water during its
presence in the sprayed suspension which results in
resistance in water removal by SD due to SSG high
water affinity. This finding can be also supported by
the data obtained from the moisture content (Table
2) in which SSG has the highest moisture content
109
(1.8 %) compared to other SD bases. It worth
mentioning that the particle morphology, structure
and shape of these bases affect their compressibility
into tablets and consequently tablet properties.
Photomicrographs taken by scanning electron
microscopy for the prepared ODT base particles
show differences in morphologies of SD and FD
particles compared to that of controls. This
difference may lead to variation in the interaction
with water as well as differences in water solubility
and disintegration.
Table 1: Formulation of orally disintegrating tablets of metoclopramide.
Formulations
Tablet
Drug
(mg)
A1
A2
A3
B1
B2
B3
C
D
E
F
10
10
10
10
10
10
10
10
10
10
MCC Mannitol Ac-Di-Sol
(mg)
(mg)
(mg)
10
10
10
10
10
10
10
10
10
10
84.9
84.9
84.9
84.9
84.9
84.9
89.9
89.9
89.9
84.9
5
—
—
5
—
—
—
—
—
—
SSG
(mg)
Kollidon
CL (mg)
Volatilizing
agent % *
Amino acid
(mg)
SC
(mg)
SSF
(mg)
Total tablet
Formula
weight (mg)
—
5
—
—
5
—
—
—
—
—
—
—
5
—
—
5
—
—
—
—
—
—
—
—
—
—
10 %
—
—
—
—
—
—
—
—
—
—
—
—
5
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
110.2
110.2
110.2
110.2
110.2
110.2
110.2
110.2
110.2
110.2
MCC= microcrystalline cellulose, Ac-Di-Sol = crosslinked sodium carboxymethyl cellulose, SSG = sodium starch
glycolate, SSF = sodium stearyl fumarate, Amino acid = glycine, Volatilizing agent = ethanol. SC= saccharine
* ethanol added to suspending medium (water) in v/v %.
A = disintegrants added after drying process. B = disintegrants added before drying process.
C = ethanol composed of 10 % suspending medium before drying. D = bases alone (negative control).
E = bases alone dried by freezing and spraying techniques (positive control). F =amino acid added to the bases before drying.
Figure 1. Photomicrographs taken by scanning electron
microscope for the prepared excipient bases. B1 and B3:
formulations containing ODT bases and superdisintegrants Ac-Di-Sol and Kollidon CL.
FD: freeze-dried base. SD: spray-dried base
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
Figure 2. Photomicrographs taken by scanning electron
microscope for the prepared excipient bases. C, B, and F:
formulations containing ODT bases and with alcohol
treatment (C) , the super-disintegrant SSG (B2) , glycine (F).
FD: freeze-dried base. SD: spray-dried base.
110
ALANAZI
Table 2: Physical characterization of the SD and FD prepared tablet bases
Base symbols
B1
SD-B1
FD-B1
B2
SD-B2
FD-B2
B3
SD-B3
FD-B3
SD-C
FD-C
D
SD-E
FD-E
SD-F
FD-F
Particle size (
77.9 ±37.1
119 ±9.5
128 ±11.5
71.1 ±36.4
207 ±18.3
169 ±15.2
70.8 ±36.2
212.8 ±19.1
191.7 ±17.2
52.67 ±4.7
144.1 ±12.8
104 ±9.6
127.9 ±10.2
117 ±9.3
86.5 ±7.7
179.4 ±16.2
Ø
44.57 ±1.13
44.83 ± 0.45
45.32 ± 0.78
45.76 ± 0.44
36.6 ± 0.43
49.02 ± 1.44
44.62 ± 0.15
37.3 ± 1.28
50.2 ± 0.58
49.9 ± 0.43
47.6 ± 0.57
46.2 ± 0.92
45.8 ± 0.57
49.7 ± 0.75
44.6 ± 0.16
46.6 ± 1.2
Carr’s index %
37.08 ± 1.0
38.37 ± 0.38
39.89 ± 0.16
37.08 ± 2.18
33.3 ± 0.9
46.1 ± 1.06
41.3 ± 1.81
37.42 ± 1.48
44.37 ±0.52
27.3 ± 0.08
53.58 ± 1.09
35.13 ± 0.5
43.01 ± 0.45
44.5 ± 0.44
22.6 ± 1.1
23.6 ± 1.01
Hausner factor
1.58 ± 0.02
1.61 ± 0.02
1.66 ± 0.01
1.58 ± 0.04
1.50 ± 0.01
1.85 ± 0.03
1.70 ± 0.03
1.59 ± 0.04
1.82 ± 0.03
1.38 ± 0.01
2. 15 ± 0.05
1.54 ± 0.01
1.75 ± 0.01
1.8 ± 0.02
1.29 ± 0.02
1.31 ± 0.02
Moisture content %
1.1 ± 0.1
1.1 ± 0.2
1.2 ± 0.3
1.1 ± 0.1
1.8 ± 0.1
2.1 ± 0.3
1.1 ± 0.1
1.00 ± 0.1
0.99 ± 0.1
1.1 ± 0.1
1.1 ± 0.2
1.00 ± 0.1
1.1 ± 0.1
1.1 ± 0.3
1.1 ± 0.1
1.1 ± 0.1
Technique
Spray drying
Tablet
Formula symbol
Disintegration time (s)
SD-A1
15 ± 4.0
SD-B1
53.33 ± 20.6
SD-E
50 ± 5.0
FD-A1
13 ± 2.0
FD-B1
45.83 ± 21.5
FD-E
60 ± 7.0
Freeze drying
B
80
60
40
20
0
20
25
30
35
40
Wetting time (s)
Disintegration time (s)
A
Disintegration time (s)
FD = freeze dried base. SD = spray dried base, Ø= angle of repose. B1, B2 and B3= formulations containing
metoclopramide and super-disintegrants Ac-Di-Sol, SSG, and kollidon, respectively.
B = disintegrants added before drying process.
C= ethanol composed 10 % of suspending medium before drying.
D= bases alone (negative control).
E= bases alone dried by freezing and spraying techniques (positive control).
F= amino acid added to the bases before drying.
80
C
60
40
20
0
3.2
3.4
3.6
3.8
4
0.36
0.48
Hardness (kg)
B1
60.83 ± 9.1
D
70 ± 8.0
D
80
Disintegration time (s)
Controls
60
40
20
0
0
0.12
0.24
Friability %
Figure 3. disintegration time of ODT containing metoclopramide and the super-disintegrant Ac-Di-Sol (A),
disintegration time of the tablets as a function of wetting time (B), disintegration time of the tablets as a
function of hardness (C), disintegration time of the tablets as a function of friability (D).
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
A
Technique
Tablet
Formula symbol
Disintegration time (s)
SD-A2
Disintegration time (s)
EVALUATION OF SPRAY AND FREEZE DRIED EXCIPIENT BASES
111
B
150
100
50
0
19.2 ± 3.7
15
30
45
60
75
SD-B2
63.33 ± 12.1
SD-E
50 ± 5.0
FD-A2
22.8 ± 3.1
FD-B2
135 ± 13.7
FD-E
60 ± 7.0
B2
42.5 ± 9.8
D
70 ± 8.0
Freeze drying
Controls
C
150
100
50
0
3.2
3.4
3.6
3.8
4
4.2
Hardness (kg)
Disintegration time (s)
Spray drying
Disintegration time (s)
Wetting time (s)
D
150
100
50
0
0
0.1
0.2
0.3
0.4
0.5
Friability %
A
Technique
Tablet
Formula symbol
Disintegration time (s)
SD-A3
18 ± 2.1
SD-B3
51.67 ± 21.1
Disintegration time (s)
Figure 4. disintegration time of ODT containing metoclopramide and the super-disintegrant sodium starch
glycolate (SSG) (A), disintegration time of tablets as a function of wetting time (B), disintegration time of
tablets as a function of hardness (C), disintegration time of tablets as a function of friability (D).
B
100
75
50
25
0
0
SD-E
50 ± 5.0
FD-A3
18.1 ± 3.1
Freeze drying
FD-B3
16.67 ± 2.5
FD-E
60 ± 7.0
B3
70.83 ±16.8
D
70 ± 8.0
30
45
60
C
100
75
50
25
0
3.3
3.4
3.5
3.6
3.7
3.8
3.9
4
Hardness (kg)
Disintegration time (s)
Controls
15
Wetting time (s)
Disintegration time (s)
Spray drying
D
80
60
40
20
0
0
0.2
0.4
0.6
Friability %
Figure 5. disintegration time of ODT containing metoclopramide and the super-disintegrant kollidon (A),
disintegration time of tablets as a function of wetting time (B), disintegration time of tablets as a function of
hardness (C), disintegration time of tablets as a function of friability (D).
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
112
ALANAZI
B
Disintegration time (s)
150
A
90
60
30
0
Disintegration time (s)
SD-C
120 ± 2.0
SD-E
50 ± 5.0
FD-C
25 ± 6
FD-E
60 ± 7.0
D
70 ± 8.0
Spray drying
Freeze drying
0
50
100
150
200
250
Wetting time (s)
C
150
Disintegration time (s)
Technique
Tablet
Formula symbol
120
120
90
60
30
0
3.5
Control
3.6
3.7
3.8
3.9
4
Hardness (kg)
D
Disintegration time (s)
150
120
90
60
30
0
0
0.15
0.3
0.45
0.6
Friability %
Disintegration time (s)
Figure 6. disintegration time of ODT containing metoclopramide and ethanol as a volatile agent (A),
disintegration time of tablets as a function of wetting time (B), disintegration time of tablets as a function of
hardness (C), disintegration time of tablets as a function of friability (D).
A
Disintegration time (s)
SD-F
205 ± 10
SD-E
50 ± 5.0
FD-F
170 ± 8
FD-E
60 ± 7.0
200
150
100
50
0
0
Spray drying
Freeze drying
30
60
90
120
150
Wetting time (s)
Disintegration time (s)
Technique
Tablet
Formula symbol
B
250
250
C
200
150
100
50
0
3.5
3.6
3.7
3.8
3.9
Hardness (kg)
18 ± 2.0
D
70 ± 8.0
Disintegration time (s)
G
Controls
250
D
200
150
100
50
0
0.15
0.3
0.45
0.6
Friability %
Figure 7. disintegration time of ODT containing metoclopramide and glycine as disintegration adjuvant (A),
disintegration time of tablets as a function of wetting time (B), disintegration time of tablets as a function of
hardness (C), disintegration time of tablets as a function of friability (D).
G= glycine was added to the tablet base after drying (positive control).
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
EVALUATION OF SPRAY AND FREEZE DRIED EXCIPIENT BASES
113
A
T 50 % (min)
4
3.5
3
2.5
2
1.5
1
0.5
0
SD-A1
B
Tablet
Formulation
FD-A1
SD-B1
PD 5 min
RDR 5 min
FD-B1
C
100
DE 10 min
B1
SD-A1
85.2
91.6
26.8
SD-B1
76.1
81.7
23.9
FD-A1
74
79.5
24.3
FD-B1
81.8
87.9
24.9
B1
69.1
74.2
22.6
% Released
80
60
SD-A1
SD-B1
40
FD-A1
FD-B1
20
B1
0
0
5
Time (min)
10
Figure 8. In vitro dissolution parameters of ODT formed from spray dried and freeze dried excipient bases
and super-disintegrant Ac-Di-Sol. (A) T50 % data which is the time in which 50% of the drug was released.,
(B) PD is the percent drug dissolution at 5 min, RDR is the relative dissolution rate in 5 min in comparison to
pure drug, DE is the dissolution efficiency, (C) dissolution profiles. SD-A1 = disintegrants added after spray
drying process, SD-B1= disintegrants added before spray drying process, FD-A1= disintegrants added after
freeze drying process, FD-B1= disintegrants added before freeze drying process, B1= control consist of base
plus AC-Di-Sol without drying.
A
T 50 % (min)
3
2.5
2
1.5
1
0.5
0
SD-A2
Tablet
Formulation
SD-B2
FD-A2
FD-B2
RDR 5 min
DE 10 min
SD-A2
97.6
100
26.9
SD-B2
96.7
100
26.8
FD-A2
97.5
100
26.8
FD-B2
89.5
96.2
25.9
B2
87.8
94.4
25.6
B2
C
100
PD 5 min
% Released
B
80
60
SD-A2
SD-B2
40
FD-A2
FD-B2
20
B2
0
0
5
Time (min)
10
Figure 9. In vitro dissolution parameters of ODT formed from spray and freeze dried excipient bases and
super-disintegrant SSG. (A) T50 % data which is the time in which 50% of the drug was released, (B) PD is
the percent drug dissolution at 5 min, RDR is the relative dissolution rate in 5 min in comparison to pure drug,
DE is the dissolution efficiency, (C) dissolution profiles. SD-A1 = disintegrants added after spray drying
process, SD-B1= disintegrants added before spray drying process, FD-A1= disintegrants added after freeze
drying process, FD-B1= disintegrants added before freeze drying process, B1= control consists of base plus
SSG without drying.
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
ALANAZI
T 50 % (min)
114
A
3.5
3
2.5
2
1.5
1
0.5
0
SD-A3
SD-B3
FD-A3
FD-B3
B3
B
C
100
PD 5 min
RDR 5 min
DE 10 min
SD-A3
98.1
100
29.8
SD-B3
87.3
93.8
25.5
FD-A3
98.9
100
29.9
FD-B3
98.8
100
27.1
B3
77.5
83.3
24.1
% Released
Tablet
Formulation
80
SD-A3
60
SD-B3
40
FD-A3
FD-B3
20
B3
0
0
5
10
Time (min)
Figure 10. In vitro dissolution parameters of ODT formed from spray dried and freeze dried excipient bases
and super-disintegrant Kollidon. (A) T 50 % data which is the time in which 50% of the drug was released, (B)
PD is the percent drug dissolution at 5 min, RDR is the relative dissolution rate in 5 min in comparison to pure
drug, DE is the dissolution efficiency, (C) dissolution profiles. SD-A1 = disintegrants added after spray drying
process, SD-B1= disintegrants added before spray drying process, FD-A1= disintegrants added after freeze
drying process, FD-B1= disintegrants added before freeze drying process, B1= control consists of base plus
Kollidon without drying.
A
T 50 % (min)
5
4
3
2
1
0
SD-C
Tablet
Formulation
FD-C
SD-E
FD-E
100
PD 5 min
RDR 5 min
SD-C
62.2
66.8
20.9
FD-C
95.2
100
28.4
SD-E
78.2
84.1
22.8
FD-E
84.7
91.1
25.4
D
89.5
96.2
24.5
D
C
DE 10 min
% Released
B
80
SD-C
60
FD-C
40
SD-E
FD-E
20
D
0
0
5
10
Time (min)
Figure 11. In vitro dissolution parameters of ODT formed from spray dried and freeze dried excipient bases
and alcohol as a volatile agent. (A) T 50 % data which is the time in which 50% of the drug was released, (B)
PD is the percent drug dissolution at 5 min, RDR is the relative dissolution rate in 5 min in comparison to
pure drug, DE is the dissolution efficiency, (C) dissolution profiles. SD-A1 = disintegrants added after spray
drying process, SD-B1= disintegrants added before spray drying process, FD-A1= disintegrants added after
freeze drying process, FD-B1= disintegrants added before freeze drying process, B1= control consists of base
alone without drying.
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
EVALUATION OF SPRAY AND FREEZE DRIED EXCIPIENT BASES
115
T50 % (min)
A
6
5
4
3
2
1
0
SD-F
FD-F
G
B
% Released
100
C
80
Tablet
Formulation
PD 5 min
RDR 5 min
DE 10 min
SD-F
54.5
58.6
20.7
FD-F
55.6
59.7
21.6
20
G
86
92.5
27.1
0
60
SD-F
40
FD-F
G
0
5
10
Time (min)
Figure 12. In vitro dissolution parameters of ODT formed from spray dried and freeze dried excipient bases
and glycine as a disintegrant. (A) T 50 % data which is the time in which 50% of the drug was released, (B) PD
is the percent drug dissolution at 5 min, RDR is the relative dissolution rate in 5 min in comparison to pure
drug, DE is the dissolution efficiency, (C) dissolution profiles. SD-A1 = disintegrants added after spray drying
process, SD-B1= disintegrants added before spray drying process, FD-A1= disintegrants added after freeze
drying process, FD-B1= disintegrants added before freeze drying process, B1= control consists of base and
glycine without drying.
The prepared ODT bases were evaluated for their
physical characteristics (Table 2). The mean particle
diameters of the prepared ODT bases were in the
range of 70. 8 to 212 m (Table 2). The results
revealed size enlargement after SD or FD as
indicated by larger particle size of both SD and FD
products compared with the corresponding control
(unprocessed mixture).
Flow properties of the powder, resistance to
particle movement, can be judged from the angle of
repose. This measurement gives qualitative and
quantitative assessment of the internal cohesive and
frictional force under low levels of external loading,
as might be applied in mixing and tableting. Values
of angle of repose < 40 o indicate good flow
potential and values > 50 o indicate poor flow
properties (17). Values for angle of repose for SD
and FD treated bases were found in the range of 36.6
to 50.2 o, showing that the prepared bases have
reasonable flow properties. Thus, these bases can be
used for tablet manufacture.
The SD excipient bases show lower angle of
repose (better flow properties) than the FD excipient
bases (Table 2), which is probably due to the
spherical structure of the SD prepared bases (21).
Controversy of this was observed in case of bases
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
containing volatilizing agent (SD-C and FD-C) in
which the angle of repose was lower in the FD
excipient bases. No distinct pattern could be
obtained between presence of disintegratingadjuvant (i.e. super-disintegrants, a volatilizing
agent, and an amino acid) and the flow properties.
Compressibility index (Carr’s index) of the ODT
prepared bases falls in the range of 33.3 and 53.58 %
indicating some kind of complexity in compressibility of the prepared bases. This was also supported
by Hausner factor values which were in the range of
1.5 and 2.15. Moisture content values of the different
bases were very minute and readings were around 1
%. Exception to that was observed in formulation
containing SSG which showed values around 2 %
indicating a relatively high moisture content which
could adversely affect the flowability.
Direct compression technique was adopted for
the preparation of ODT because it is the cheapest,
easiest and the fastest tableting technique. Also, it is
considered the best method to prepare ODT since the
prepared tablets might be of higher disintegration
due to absence of binder and low moisture content.
The prepared tablets were evaluated for their
hardness and friability. Mechanical integrity is of
paramount importance in successful formulation of
116
ODT. Thus the hardness of the tablets was
determined and was found to be in the range of 3.4
to 4 kg. Friability of the tablets was observed
between 0.11–0.48 %, which was below 1%
indicating sufficient mechanical integrity and
strength of the prepared tablets.
Wetting time is used as an indicator for the ease
of the tablet disintegration in the buccal cavity (10).
It was observed that the wetting time of the prepared
tablets is in the range of 15.1 to 220 seconds. It has
been noted in all cases that the addition of DA to the
tablet bases before drying process results in
elongation of the wetting time in comparison to their
addition to the tablet bases after passing the drying
process which causes the reverse (p < 0.05). That is
because addition of DA through drying processing of
these tablet bases minimizes their wetting efficiency
as they become hydrated through processing.
Additionally, results show that on comparing
super-disintegrants the bases containing sodium
starch glycolate (SSG) prepared by SD and FD
processes take more wetting time (23.7 % and 50.1
%, respectively, calculated as percentage increment)
than that of Ac-Di-Sol and Kollidon. Wetting is
related to the inner structure of the tablets and the
hydrophobicity of the components. This may be due
to the fact that SSG is disintegrated by swelling
mechanism leading to longer wetting time. Kollidon
and Ac-Di-Sol perform their disintegrating action by
wicking through capillary action and fibrous
structure, respectively, with minimum gelling (22).
Also, the effect of passing of the super-disintergrants
through drying processing was maximum for SSG
bases, in which the adsorbed moisture could
decrease its dryness and swelling mechanism and
consequently lengthens its wettability (Table 2).
Results also show that the addition of superdisintegrants to SD or FD treated bases (after drying)
leads to shorten the wetting time of prepared tablets
in comparison to their addition to non-dried bases
(formula B1, B2 and B3) (p < 0.05). This finding is
explained by the results derived from the comparison
in wetting time between bases alone dried by SD and
FD techniques (positive controls, SD-E and FD-E)
and bases alone without drying (negative control, D),
which yields shortening in the wetting time of
prepared tablets by 7.9 % for SD and 10.5 % for FD
due to the drying process alone without addition of
DA. Meaning that drying the tablet base by SD and
FD also assists in fastening the wetting time.
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
ALANAZI
Surprisingly, the addition of the volatilizing
agent (ethanol) results in lengthening of the wetting
time to 220 ± 16 seconds for SD bases perhaps due
to more binding of the base, while it results in
shortening of the wetting time to 27.1 ± 1.1 seconds
for FD bases in comparison to 35 ± 4 seconds and 34
± 3 seconds in case of positive spray (SD-E) and
freeze dried (FD-E) controls, respectively, which
may be explained by the wider spongy holes caused
by the volatilization of ethanol by FD technique.
Also, results show that the addition of the amino
acid (glycine) before drying of the bases results in
elongation of wetting time significantly (p< 0.05).
For SD bases containing glycine, wetting time was
130 ± 14 seconds and for that of FD was 61 ± 13
seconds. Notably, the wetting time was very short
(22 ± 3 seconds) when glycine was added to the base
after drying. These results indicate that glycine is a
good DA when added to dried bases. However, the
addition of glycine before SD or FD process leads to
passing it through contacting as well as solublizing
in water and thus producing complex-dried particles.
The production of these particles could make
changes in glycine properties as DA consequently.
Glycine was reported to enhance wetting of the
tablet due to its polar surface free energy which
comprises about 75 % of its component (23). As
results of its presence in solution and drying process
after that, the packing of glycine molecules in dried
base particles may lead to reduction or minimization
of the action of polar component and consequently
the wetting of the tablet.
Disintegration time is very important for ODT
which is desired to be less than 60 seconds for ODT
(10). That is because rapid disintegration in ODT
assists swallowing conveniently. It may also play a
role in assistance of drug absorption to take place in
the buccal cavity, thus promoting its bioavailability.
Disintegration time was found in the range of 15
- 205 seconds (Figs 3 - 7). Results show that the
addition of DA to the tablet bases before drying
process results in lengthening of the disintegration
time in comparison to their addition to the tablet
bases after passing the drying process (p < 0.05).
That is because of the effect of drying processes on
their wetting action and disintegration efficiency as a
result.
For the super-disintegrants, results show that
disintegration time was in order of Kollidon < AcDi-Sol < SSG for both SD and FD bases when
EVALUATION OF SPRAY AND FREEZE DRIED EXCIPIENT BASES
super-disintegrants added before drying process
(difference is statistically insignificant, p < 0.1).
Results of disintegration time for adding superdisintegrants after drying of the tablet bases resulted
in a similar rank Ac-Di-Sol < Kollidon < SSG in
which tablets made from SSG gave the longest
disintegration time (p < 0.05). This finding is in
agreement with the results obtained from wetting
time since SSG swells with more gelling than AcDi-Sol and Kollidon which extend wetting and
disintegration times as a result.
Results also show that the addition of the
investigated super-disintegrants to the SD or FD
bases (after drying) leads to a shortening the
disintegration time of prepared tablets in comparison
to their addition to non-dried bases (formula B1, B2
and B3) (p < 0.05). This finding is in agreement with
wetting time data. This observation can be explained
by the results derived from the comparison in
disintegration time between bases alone dried by SD
and FD techniques (positive controls, SD-E and FDE) and bases alone without drying (negative control,
D), which yields shortening of the disintegration
time of the prepared tablets by (28.5 % for SD and
14.3 % for FD) due to drying process alone without
addition of DA. Meaning that drying the tablet base
by SD and FD also assists in fastening of
disintegration time.
Notably, the presence of a volatilizing agent
with FD process decreases disintegration time by
41.6 % (FD-C), while with SD process increases
disintegration time by 140 % (SD-C) in comparisons
with controls (Fig 6-A). That is because residual
ethanol may cause strong binding of the ingredients
in case of SD bases which results in delaying
disintegration time. Oppositely, in case of FD the
complete removal of ethanol causes more porosity in
the matrix thus shortening of the disintegration time
more than the controls (SD-E and FD-E) (p < 0.05).
Also results show that the addition of the amino
acid (glycine) before drying of the bases results in
elongation of disintegration time significantly (p <
0.05) (Fig 7). For SD treated bases containing
glycine, disintegration time was 205 ± 10 s (SD-F)
and for that of FD was 170 ± 8 s (FD-F). Notably,
the disintegration time was very short (18 ± 2
seconds) when glycine was added to the base after
drying (p < 0.05) (Fig 7-A). That is because when
glycine is added after the drying process, it didn’t
loose its disintegrating properties. These results
indicate that glycine is a good DA when added to
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
117
dried bases. However, addition of glycine before
spray or freeze drying process leads to its passing
through contacting as well as solublizing in water
thus producing complex-dried particles. The
production of these particles could make changes in
glycine properties as DA consequently. Glycine was
reported to enhance disintegration of the tablet due
to its dispersion surface free energy which is
comprises about 25 % of its component (23). As
results of its presence in solution and drying process
after that, the packing of glycine molecules in dried
base particles may lead to reduce or minimize the
action of dispersion component.
The relationship between tablet wetting time and
tablet disintegration time is shown in Figs 3-7, part
B. It is observed that the tablets with the shortest
wetting time have the minimum disintegration time.
Also, the results show a good correlation between
disintegration time and wetting time. In addition the
strongest correlation was found for glycine bases (r2
= 0.817). Disintegration time as a function of
hardness is presented in Figs 3-7, part C. It is
observed that the tablets with the least hardness have
the minimum disintegration time. Also, results show
a good correlation between disintegration time and
hardness. In addition, the highest correlation was
found for kollidon bases )r2 = 0.834). The
relationship between tablet friability and tablet
disintegration time is shown in Figs 3-7, part D. It is
observed that the tablets with the least friability have
the minimum disintegration time. That is because the
friability values of the prepared tablets are very near
to each other and lie between 0.11 and 0.48. Also,
results show a good correlation between
disintegration time and friability. In addition, the
highest correlation was found for ethanol treated
bases )r2 = 0.637).
In vitro drug dissolution studies are presented in
Figs 8-12. For the super-disintegrants, results show
maximum dissolution when they were added after
SD or FD for the tablet bases compared to their
addition to the bases before the drying process. That
is because addition of the super-disintegrants
through the processing of these bases (before drying)
may lead to minimization of their efficiency as DA
by decreasing their affinity to adsorb water and
consequently decreasing their swelling behavior.
T50 % is used as a comparison parameter for the
dissolution in this study (16). It was found in the
range of 0.83 – 3.3 min (Figs 8-10, part A). T50 %
was the least when super-disintegrants were added
118
ALANAZI
after SD or FD of the tablet bases (p < 0.05).
Relative dissolution rates (RDR5 min) at 5 min and
dissolution efficiencies (DE 10) of the tablets were
maximum with the addition of super-disintegrants
after SD or FD process (Figs 8-10, part B). This
finding is in agreement with the results obtained
from wetting and disintegration time evaluations.
The more rapidly wetted and the more rapidly
disintegrated tablets exhibited faster dissolution.
Presence of ethanol in the SD process (i.e.
before drying) resulted in delaying of the dissolution
rates, while with FD process resulted in expedite the
dissolution rate in compassion with the controls (Fig
11) (p < 0.05). T 50 % was the longest when ethanol
present with SD process (4.1 min) and the least with
freeze drying process (1.4 min) (p < 0.05), (Fig 11,
part A). Relative dissolution rates at 5 min (RDR5
min) and dissolution efficiencies (DE 10) of the tablets
were maximum (100 and 28.4, respectively) with the
presence of ethanol in the freeze drying process (p <
0.05) (Fig 11, part B). These results also are in
agreement with the results obtained from wetting
and disintegration time evaluations.
The effect of the addition of the amino acid
(glycine) before drying processes on dissolution rate
is presented in Fig 12. The addition of the amino
acid before drying of the bases resulted in delaying
of dissolution rate significantly (p < 0.05). T 50 %
was the longest when glycine was added with SD
(4.5 min) and FD (4.2 min) processes, (Fig 12, part
A). T50 % was minimum (1.5 min) when glycine was
added to the dried base (p < 0.05). Relative
dissolution rates at 5 min (RDR5 min) and dissolution
efficiencies (DE 10) of the tablets were minimum
with addition of the amino acid before drying of the
bases. Also, this is in agreement with results
obtained from wetting and disintegration time
evaluations. The more wetted and the more
disintegrated tablets exhibited faster dissolution.
Conclusion
The methods adopted to prepare ODT bases via
SD or FD techniques were successful to dry the
excipient bases. Rapidly oral disintegrating tablets
containing certain various super-disintegrants, a
volatile solvent (ethanol) and an amino acid
(glycine) using SD and FD techniques have been
prepared successfully using direct compression
technique. It was concluded that utilization of DA
and both SD and FD techniques to prepare tablet
Saudi Pharmaceutical Journal, Vol. 15, No. 2, April 2007
bases for ODT depends on so many factors such as
type of DA, drying process and the mode of superdisintegrant addition (before or after drying
processes). The good disintegration property of the
tablets was closely related to the excellent wetting
nature of the ingredients after passing the drying
processes. These findings could be applied and
utilized for many drugs and they may be considered
versatile in the preparation of ODT.
Acknowledgment
The author would like to thank Dr. Gamal
Mahrous for his help in running some experiments in
base and tablet evaluations. Also, the gratitude is
extended to Al Jazerah Pharmaceutical Industries
(Riyadh, Saudi Arabia) for their kind support by
gifting the super-disintegrants.
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