Pharmacology & Pharmacy, 2010, 1, 18-26
10.4236/pp.2010.11003 Published Online July 2010 (http://www.SciRP.org/journal/pp)
Preparation and Evaluation of Rapidly
Disintegrating Fast Release Tablet of
Diazepam-Hydroxypropyl-β-Cyclodextrin
Inclusion Complex
——Rapidly Disintegrating Fast Release Tablet
Tapan Kumar Giri, Biswanath Sa*
Centre for Advanced Research in Pharmaceutical Sciences, Department of Pharmaceutical Technology, Jadavpur University,
Kolkata, India.
Received June 1st, 2010; accepted July 8th, 2010.
ABSTRACT
This study was undertaken to develop tablets of diazepam-hydroxypropyl-β-cyclodextrin inclusion complex that disinte-
grate within 3 minutes and release 85% of drug within 30 minutes to provide rapid action of the drug through
oro-mucosal route. Formation of inclusion complex was verified using X-ray diffraction and differential scanning calo-
rimetric studies. Enhanced of aqueous solubility, as evident from phase solubility study, and dissolution of the drug
were related with the formation of inclusion complex. Among the various formulations, tablet containing inclusion
complex of drug/hydroxypropyl-β-cyclodextrin in a molar ratio of 1:2, and a combination of microcrystalline cellu-
lose/lactose in a ratio of 4:1 disintegrated in 13 seconds and released 85% drug within 9 minutes. Addition of 10% w/w
polyvinyl pyrrolidone in the tablet formulation further enhanced the drug release. Accelerated stability study indicated
that mean dissolution time of the drug from the tablet did not change significantly within 6 months.
Keywords: X-Ray Diffraction, Phase Solubity, Dissolution Efficiency, Mean Dissolution Time, Stability
1. Introduction
Though conventional oral and parenteral routes are used
widely to achieve systemic action of drugs, various mu-
cosae are being explored as possible alternative routes
for drug delivery. Since the invention of nitroglycerin
sublingual tablets, the oral mucosal route is drawing at-
tention of both academia and industries as a substitute
drug delivery approach. Several constraints like difficulty
in swallowing experienced by many paediatrics and geri-
atrics [1], and in chewing by edentulous [2]; nausea and
vomiting experienced with certain drugs when released
in stomach [3]; degradation and metabolism of suscepti-
ble drugs in gastrointestinal tract [4]; tissue necrosis and
irritation from repeated administration of parenterals [5],
high expenses due to sterile manufacturing [6] are
avoided through oromucosal delivery of drugs. In certain
diseases like epilepsy, rapid onset of drug action is nec-
essary to suppress convulsion and terminate seizures.
Thus early termination of seizures by initiating therapy
as soon as possible, preferably at home, has been empha-
sized as a key to minimize morbidity of these seizures
[7-9].
Benzodiazepines are used for the acute management of
severe seizures and have a rapid onset of action once
delivered into the central nervous system and are safe.
[10] Diazepam, a benzodiazepine, is included in the
“WHO Essential Drug list” for the treatment of convul-
sion and epileptic seizure [11-14]. Although intravenous
therapy is the most rapid way to suppress epileptic con-
vulsion, it may produce toxic manifestation due to exces-
sive drug concentration [15,16], requires great care and
caution to avoid thrombophlebitis and irritation [17] and
may not be feasible where adequate medical facilities are
not available in the immediate vicinity. While absorption
of diazepam from intramuscular route is poor and erratic

Preparation and Evaluation of Rapidly Disintegrating Fast Release Tablet of
Diazepam-Hydroxypropyl-β-Cyclodextrin Inclusion Complex
19
[18], the time to reach peak plasma concentration fol-
lowing oral administration is 1-2 hours [19] and is ac-
companied with acid hydrolysis and extensive liver me-
tabolism [10].
If diazepam is formulated in a rapidly disintegrating
fast dissolving tablet dosage form, the high vascularity
and rich blood supply of oral mucosa [20] may provide
rapid absorption and faster onset of action [21] and could
enable a patient for self medication even without the aid
of water in a situation where onset of convulsion is ap-
prehended.
Two principle criteria appear to be important for de-
veloping rapidly disintegrating fast dissolving tablets: 1)
disintegration time preferably < 3 minutes [22] and 2)
rapid drug dissolution: time required for 85% dissolution
(t85%) less than 30 minutes [23]. Valuable research re-
ports for formulation of rapidly disintegrating tablets are
available [24]; also, various technologies for improving
dissolution property of poorly water soluble drugs have
been documented to enhance bioavailability following
oral absorption [25]. Among the various strategies, for-
mulation of solid dispersions with hydrophilic carriers
especially polyethylene glycols (PEGS) have been suc-
cessfully used for enhancing dissolution of poorly water
soluble drugs [26-29]. However, development of dosage
forms like tablet and capsule using the solid dispersion
encounters problems in pulverization/sifting of the solid
dispersion which are usually soft and tacky and exhibits
poor flow properties. In recent years, inclusion com-
plexes of poorly water soluble drugs with cyclodextrins
especially hydroxypropyl-β-cyclodextrins (HPβCD) have
become popular to enhance the solubility and bioavail-
ability of drugs.
Loftsson [30] reported that the solubility of diazepam
and various poorly water soluble drugs improved in solu-
tion with the natural cyclodextrins and their derivatives.
Subsequent studies also shows that the incorporation of
hydrophilic polymer such as sodium carboxymethyl cel-
lulose, hydroxypropyl methyl cellulose and polyvinyl
pyrrolidone increase the solubilizing effect of the cyclo-
dextrins and reduce the amount of cyclodextrin required.
The objective of this study was to develop a rapidly
disintegrating fast dissolving tablet of diazepam that can
disintegrate in less than 3 minutes and release/dissolve
85% of the drug within 30 minutes in the oral cavity. The
initial part of this work involved preparation of diaze-
pam-HPβCD inclusion complex by kneading method and
characterization of the complex using X-ray diffrac-
tion(XRD) and differential scanning calorimetric (DSC)
studies. The subsequent phase involved the preparation
of tablets of diazepam-HPβCD complex by direct com-
pression method to meet the specified time limits of dis-
integration and drug dissolution. Finally the optimized
tablets were subjected to accelerated stability study.
2. Experimental
2.1 Materials
Diazepam (East India Pharmaceutical Works Ltd., Kol-
kata, India), Saccharin-Na, Crosscarmellose sodium
(Ac-Disol), Microcrystalline Cellulose (Avicel, PH-102)
[Dey’s Medical Stores (Mfg.) Ltd., Kolkata, India], Hy-
droxypropyl beta cyclodextrin (HPβCD) [Dr Reddy’s
Lab, Hyderabad, India] were obtained as gift samples.
Mannitol, lactose monohydrate and sorbitol (Merc, India),
PVP-K30 (Qualigens, Mumbai, India), magnesium stearate
and all other ingredients were obtained commercially and
used as received.
2.2 Preparation of Solid Complexes
Solid inclusion complexes of diazepam-HPβCD were
prepared in 1:1 and 1:2 ratio by kneading method with
and without the addition of polyvinyl pyrrolidone (PVP).
PVP was added at a concentration of 10% (w/w) of the
solid complex. Mixture was triturated for one hour in a
mortar with a small volume of water to obtain a homo-
geneous paste. During the process, the water content of
the paste was empirically adjusted to maintain the con-
sistency of the paste. The paste was dried at 45°C for 48
hours, pulverized and passed through sieve # 100.
2.3 Thermal Analysis
Differential thermal analysis of diazepam, HPβCD, di-
azepam/HPβCD physical mixture, and inclusion complex
were carried out using Perkin-Elmer instrument (Pyris
Diamond TG/DTA, Singapore) equipped with a liquid
nitrogen subambient accessory. About 4 mg samples
were kept in aluminum pan, hermetically sealed and
scanned at a rate of 5°/min between 30°-210°C under ni-
trogen atmosphere.
2.4 X-Ray Diffraction Study
X-ray powder diffraction patterns of diazepam, HPβCD,
diazepam/HPβCD physical mixture, and inclusion com-
plex were conducted with a X-ray powder diffractometer
(Rigaku-MiniFlax, Tokyo, Japan.) using a copper Kα
target with a nickel filter at 30 kV voltage, 15 mA cur-
rent and at scanning speed of 1°/min over a 2θ range of
5°-60°.
2.5 Phase Solubility Study
Phase solubility studies were carried out by adding ex-
cess amounts of drug to 10 ml of USP phosphate buffer
solution (pH 5.8) containing various concentrations of
HPβCD (3-15 mM) in stoppered conical flasks. The
flasks were shaken at 50 revolutions per minute in a
shaking incubator (Model KMC 8480 SL, Vision Scien-
tific Company, Ltd., Seoul, South Korea) at 37 ± 0.5°C

Preparation and Evaluation of Rapidly Disintegrating Fast Release Tablet of
Diazepam-Hydroxypropyl-β-Cyclodextrin Inclusion Complex
20
until equilibrium (about 90hours) was reached. The re-
sulting mixtures were filtered and aliquots, following
suitable dilutions, were analyzed using a spectropho-
tometer (Genesyis, 10 UV, Thermo Electron Corporation,
Wisconsin, USA.) at 230 nm against blanks prepared in
the same concentration of HPβCD in USP phosphate
buffer solution (pH 5.8). Phase solubility studies were
conducted with and without the addition of PVP. The
PVP was added at a concentration of 0.5% w/v to the
solution containing HPβCD. The solubility experiments
were conducted in triplicate.
2.6 Preparation of Placebo Tablet by Direct
Compression Method
Microcrystalline cellulose (MCC), lactose or mannitol or
sorbitol and crosscarmellose sodium were mixed without
drug for 10 minutes. The resulting mixture was lubri-
cated with magnesium stearate and mixed for 5 minutes.
The final powder mixture was then compressed into tab-
let using concave punches (approx 9.5 mm diameter) in a
10 station Minipress tablet machine (RIMEK, Karnavati
Engineering Ltd, Gujarat, India).
2.7 Preparation of Tablet with Drug by Direct
Compression Method
MCC, lactose or mannitol or sorbitol and crosscarmel-
lose sodium were mixed with drug (as such or solid in-
clusion complexes) for 10 minutes. The resulting mixture
was lubricated with magnesium stearate and mixed for 5
minutes. The final powder mixture was then compressed
into tablet using concave punches (approx 9.5 mm di-
ameter) in a 10 station Minipress tablet machine (RIMEK,
Karnavati Engineering Ltd, Gujarat, India).
2.8 Measurement of Disintegration Time
Disintegration times were measured using a modified
disintegration test method. [31] To determine disintegra-
tion time, 10ml of USP phosphate buffer solution (pH 5.8)
was taken in a petridish (10 cm diameter) and a tablet
was carefully placed in the centre and agitated mildly.
Time for the tablet to completely disintegrate into fine
particles was noted using a stop watch.
2.9 Measurement of in Vitro Drug Release
Dissolution profiles of the diazepam tablets were deter-
mined using USP II dissolution rate test apparatus (mod-
el TDP-06P, Electrolab, Mumbai, India).The dissolution
medium was 500ml of USP phosphate buffer solution
(pH 5.8) maintained at 37 ± 0.5°C and stirring speed was
50 rpm. At appropriate time intervals, 10ml samples
were withdrawn, suitably diluted, and analyzed spectro-
photometrically for diazepam content at 230 nm. The
initial volume of dissolution medium was maintained by
adding 10ml of fresh medium. The amount of drug re-
leased was determined from the calibration curve. The
reliability of the above analytical method was judged by
conducting recovery analysis in the presence or absence
of the excipients. Low, middle, and high concentrations
of drug solution were spiked and recovery was found to
vary from 99.05 to 100.83%.
2.10 Stability Study
The stability of the drug in the optimized tablet was as-
sessed by keeping the tablets in a sealed glass bottle and
subsequently placing the bottle in a Stability Test Cham-
ber (Humidity Cabinet, Testing instruments manufactur-
ing company, Kolkata) at 40°C and 75% RH for different
periods of time. The tablets were analyzed immediately
(0 month), and after 1, 3 and 6 months for appearance,
hardness, friability, drug content, disintegration time and
dissolution profiles of the drug.
3. Results and Discussion
Diazepam-HPβCD inclusion complexes were prepared
by kneading method. The resulting complex was ana-
lyzed by XRD, DSC, and phase solubility studies.
Thermal behavior of diazepam, HPβCD, diazepam/
HPβCD physical mixture, and diazepam/HPβCD inclu-
sion complex are shown in Figure 1. The DSC thermo-
gram of diazepam shows one sharp endothermic peak at
133°C which corresponds to the melting point of the drug.
The DSC trace of HPβCD did not show any endothermic
peak. The thermal event of the physical mixture demon-
strated the appearance of a sharp peak having diminished
intensity at 133°C which was assigned to the melting
point of the drug. The DSC thermogram of the inclusion
Figure 1. Differential scanning calorimetric thermograms of
a) diazepam, b) HPβCD, c) physical mixture, d) inclusion
complex

Preparation and Evaluation of Rapidly Disintegrating Fast Release Tablet of
Diazepam-Hydroxypropyl-β-Cyclodextrin Inclusion Complex
21
complex revealed that although the intensity of the melt-
ing endotherm of the drug at 133°C decreased to a great
extent, it was not abolished completely. The decrease in
endothermic peak of the drug was due to entrapment of
the crystalline drug within the cavity of HPβCD. This
indicates the formation of an inclusion complex of di-
azepam with HPβCD. During the preparation of solid
dispersion using melting method [32] solvent/co-evap-
oration method [33], the crystalline drugs are completely
converted into amorphous form and consequently, no
thermal event is evident in the DSC scan. On the other
hand the endothermic melting peak of a crystalline drug
may not be abolished, although may be diminished to a
great extent, when a drug forms solid complex with
HPβCD by kneading method [32].
The XRD patterns of drug, HPβCD, physical mixture,
and inclusion complex are shown in Figure 2. The dif-
fractogram of the drug exhibited a series of intense peaks
due to its crystalline structure. The XRD pattern of
HPβCD was an amorphous halo. The diffractogram of
the physical mixture appeared to represent the superim-
position of each components spectrum although the drug
crystallinity reduced considerably. A no. of sharp peaks,
although of reduced intensity, were still present in the
diffractogram of the solid complex .Close examination of
the diffractogram revealed that many peaks of the drug
disappeared(2θ of 26.12°, 26.69°, 27.56°, 28.28°) and
many new peaks emerged (2θ of 25.67° and 26.99°).
Similar to the DSC results, the XRD analysis does not
show diffraction pattern of drugs when the solid disper-
sions are prepared by melting method [32] or solvent/
co-evaporation method [33]. However, the inclusion
complexes prepared by kneading process still show peaks
on the diffractogram [32]. These results indicate the for-
mation of inclusion complex.
Phase solubility diagram (Figure 3) demonstrated a
linear increase in the aqueous solubility of diazepam with
the concentration of HPβCD. The improved solubility of
various poorly soluble drugs through complexation with
HPβCD is well documented in scientific journals [34,35].
The complexation of diazepam with HPβCD was type AL
[36] and as the slope of the straight line of concentration
of diazepam verses concentration of HPβCD plots was <
1, the complexation took place in 1:1 molar ratio. The
apparent stability constant (KC) was calculated from the
slope of the linear plot of the phase solubility diagram
following the equation KC = Slope/So (1-Slope), where So
is the solubility of the drug in the absence of HPβCD.
The value of KC (Table 1) indicated that the complex
was quite stable.
Tablets formulated using MCC and low-substituted
hydroxypropyl cellulose has been reported to disintegrate
and dissolve rapidly in the saliva of humans [37]. How-
ever, such tablets provide a gritty mouth feel due to the
Figure 2. X-ray diffraction pattern of a) diazepam, b)
HPβCD, c) physical mixture, d) inclusion complex
Figure 3. Phase solubility diagrams of diazepam-hydroxy-
propyl β-cyclodextrin complex in the presence (■) and
absence (◆) of PVP
Table 1. Effect of PVP on stability constant (KC) and solubi-
lizing efficiency of diazepam-HPβCD complexes†
Sample KC (M-1) Solubilizing Efficiency٭ .
D-HPβCD 499.087 3.880
D-HPβCD-PVP 515.094 4.271
†HPβCD indicates hydroxypropyl β-cyclodextrin; PVP, polyvinyl
pyrrolidone; and D, diazepam.
٭Ratio of drug solubility in USP buffer solution(pH 5.8) (15mM) of
cyclodextrin (with or without PVP) to drug solubility in buffer.
presence of insoluble crystalline cellulose [38].
To formulate tablets that can disintegrate rapidly and
reduce gritty mouth feel characteristics, several water
soluble diluents like sorbitol, manitol and lactose were
selected, and 9 placebo tablets containing of MCC and

Preparation and Evaluation of Rapidly Disintegrating Fast Release Tablet of
Diazepam-Hydroxypropyl-β-Cyclodextrin Inclusion Complex
22
either sorbitol, manitol or lactose in the ratios of 1:1, 2:1,
and 4:1 were prepared by direct compression method.
The compositions of the placebo tablets are shown in
Table 2.
The blended powder of each formulation exhibited
good flowability as evident from the measurement of
angle of repose (measured by conventional method) that
varied from about 31.3° to 34° (Table 3). Angle of repose
below 40° is an indication of good flowability of pow-
der/granules [39]. The compression force during tablet-
ting was adjusted in such a way that the hardness (meas-
ured using Monsanto type hardness tester) of the tablets,
each weighing 300 mg, was 2 Kg-F. The friability of the
tablets (determined using Friabilator, Veego instrument,
Mumbai, India) was found between 0.03 to 0.29% that
was below 1% indicating sufficient mechanical integrity
and strength of the placebo tablets.
The disintegration time of tablets (P1) which were
prepared using MCC and sorbitol in 1:1 ratio was 42.85
seconds. The tablets P2 and P3 which consisted of MCC
and sorbitol in a ratio of 2:1 and 4:1 respectively disinte-
grated in 29.03 and 27.34 seconds. The result indicates
that increase in MCC/sorbitol ratio decreased the disin-
tegration time of the tablets and this decrease was found
significant at 95% confidence limit (p < 0.05). MCC is
considered as one of the most versatile excipients in tab-
let manufacturing. In addition to its performance as dilu-
ents and dry binder, it is also regarded as an excellent
disintegrant for tablets prepared by direct compression
method. This property is related to its wicking action due
to which water penetrates into the tablet and the devel-
oped hydrostatic pressure causes break down of the tablet.
The rate and extent of water penetration is related to the
porosity (determined using laboratory pycnometer) it
provides in the tablets. The greater the amount of MCC,
the greater will be the porosity in the tablet matrix. Table
3 shows that as the ratio of MCC/sorbitol increased, the
porosity of the tablets increased significantly (p < 0.05)
that provided faster penetration of water. Determination
of wetting time (determined by the method described by
Bi et al. [40]) demonstrated that the wetting time of the
tablets decreased significantly (p < 0.05) with increase in
the amount of MCC (Table 3) indicating faster penetra-
tion of water into the tablets. Similar observations were
noted for the tablets prepared using MCC/manitol (tab-
lets P4, P5, P6) and MCC/lactose (tablets P7, P8, P9).
Table 2. Composition of placebo tablets (without drug) prepared by direct compression method
Ingredients(mg/tablet) P1 P2 P3 P4 P5 P6 P7 P8 P9
MCC 144.25 193 230.8 144.25 193 230.8 144.25 193 230.8
Lactose - - - - - - 144.25 96.5 57.7
Mannitol - - - 144.25 96.5 57.7 - - -
Sorbitol 144.25 96.5 57.7 - - - - - -
Crosscarmellose-Na 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5
Mg-St. 1 1 1 1 1 1 1 1 1
Saccharin-Na 3 3 3 3 3 3 3 3 3
Total 300 300 300 300 300 300 300 300 300
Table 3. Physical characteristics of placebo tablets (without drug) prepared by direct compression method
P1 P2 P3 P4 P5 P6 P7 P8 P9
Angle of Repose 34.03
(0.33)
33.56
(0.39)
31.47
(1.4)
33.99
(0.29)
32.66
(0.69)
32.49
(1.13)
35.38
(0.8)
32.37
(1.02)
31.29
(0.96)
Porosity 9.99
(0.13)
15.21
(0.21)
22.39
(0.21)
17.26
(0.14)
21.28
(0.16)
26.17
(0.28)
19.31
(0.19)
24.34
(0.42)
31.87
(0.7)
Disintegration time, seconds 42.85
(1.89)
29.03
(0.67)
27.34
(0.62)
43.29
(0.77)
18.76
(0.25)
15.3
(0.9)
26.49
(1.36)
17.25
(0.17)
13.23
(0.46)
Wetting time, seconds 119.92
(1.63)
92.69
(2.1)
84.78
(1.85)
82.56
(1.86)
52.69
(2.81)
42.53
(1.7)
80.67
(1.78)
50.3
(1.07)
35.43
(1.62)
Figures in parentheses indicate ± SD; n = 6 for disintegration time and ± SD, n = 3 for Angle of Repose, porosity and wetting time

Preparation and Evaluation of Rapidly Disintegrating Fast Release Tablet of
Diazepam-Hydroxypropyl-β-Cyclodextrin Inclusion Complex
23
It was also noted that the type of soluble diluents in-
fluenced the porosity, wetability and disintegration time
of the tablets considerably. The tablets prepared with
MCC/lactose combination exhibited higher % of porosity,
and shorter wetting and disintegration times followed by
the tablets prepared with MCC/manitol and MCC/sorbi-
tol. Change of soluble excipient from sorbitol to mannitol
to lactose significantly increased (p < 0.05) the porosity
and decreased the wetting time and disintegration time of
the tablets. These observations were found in each of the
ratios of MCC/soluble diluents. The solubility data [41]
indicate that aqueous solubility of the above used ex-
cipients increased in the following order: lactose > man-
nitol > sorbitol. Higher solubility of lactose was respon-
sible for its rapid solution. As lactose dissolves quickly it
creates pores rapidly encouraging penetration of water
into the tablets and this led to quick disintegration of the
tablets. Decrease in solubility of the excipients delayed
both the wetting and disintegration of tablets.
The subsequent study involved the preparation of
drug-loaded tablets that will disintegrate rapidly and pro-
vide rapid dissolution of the drug contained therein.
Considering the results of the above study, the formula of
tablet P9 which consisted of MCC/lactose in a ratio of
4:1 and disintegrated in the shortest period of time (13.2
seconds) was selected for incorporation of diazepam or
diazepam-HPβCD inclusion complex. The composition
of the tablets is represented in Table 4 and the physical
characteristics of the blended powder and the tablets are
shown in Table 5.
Statistical analysis in the form of Students t-test re-
vealed that the angles of repose of the blended powder
containing either diazepam or inclusion complex of di-
azepam-HPβCD in 1:1 and 1:2 molar ratios did not
Table 4. Composition of tablets prepared by direct com-
pression method using either diazepam or inclusion com-
plex
Ingredients
(mg/tablet) Q1 Q2 Q3 Q4 Q5
MCC 226.8 207.136 204.768 187.472 183.1392
Lactose 56.7 51.784 51.192 46.868 45.7848
HPβCD - 24.58 24.58 49.16 49.16
PVP - - 2.96 - 5.416
Diazepam 5 5 5 5 5
Crosscarmel-
lose-Na 7.5 7.5 7.5 7.5 7.5
Mg-St. 1 1 1 1 1
Saccharin-Na 3 3 3 3 3
Total 300 300 300 300 300
Table 5. Physical characteristics of tablets containing either
diazepam or its inclusion complex
Q1 Q2 Q3 Q4 Q5
Angle of Repose 31.45
(0.84)
31.64
(1.26)
34.15
(0.8)
32.59
(0.88)
35.44
(0.77)
Porosity 31.13
(0.42)
33.47
(0.11)
30.14
(0.11)
31.14
(0.08)
27.82
(0.04)
Disintegration
time, seconds
13.12
(1.32)
12.84
(0.97)
14.09
(0.42)
13.3
(1.06)
19.06
(0.92)
Wetting time,
seconds
36.22
(1.12)
34.24
(1.06)
40.42
(0.73)
38.57
(1.05)
56.52
(2.13)
t85%,minutes
125.43
(1.25)
10.24
(0.17)
8.86
(0.13)
8.98
(0.007)
7.48
(0.30)
DE10minutes
21.10
(0.59)
54.68
(1.23)
59.44
(0.35)
57.66
(0.92)
62.56
(0.16)
Figures in parentheses indicate ± SD; n = 6 for disintegration time and
± SD, n = 3 for Angle of Repose, porosity, wetting time, t85% and
DE10minutes.
change significantly (p < 0.05) from that of the blended
powder used to prepare placebo tablet P9. Similarly, no
significant changes were noted (p < 0.05) in porosity,
disintegration time and wetting time of the tablets due to
incorporation of either the drug or its inclusion com-
plexes. The release profiles of the drug from various tab-
lets are shown in Figure 4.
While the time required for 85% (t85%) of diazepam to
be released from tablet Q1 was 125.4 minutes, the same
from the tablet (Q2) containing inclusion complex of
diazepam in 1:1 molar ratio drastically reduced to 10.24
minutes. For the tablets Q4 containing diazepam/
HPβCD in a molar ratio of 1:2, the t85% further reduced to
8.98 minutes. In addition to one point comparison using
t85%, the entire drug release profiles were compared using
dissolution efficiency (DE) to ascertain the differences in
Figure 4. Dissolution profiles of diazepam from various
tablet formulations

Preparation and Evaluation of Rapidly Disintegrating Fast Release Tablet of
Diazepam-Hydroxypropyl-β-Cyclodextrin Inclusion Complex
24
the release of the drug from various tablets. The DE is
defined as the area under the dissolution curve upto a
certain time, t, expressed as a percentage of the area of
the rectangle described by 100% dissolution in the same
time [42].
0
100
.
D.E 100%
.
t
ydt
yt








where y is the drug percent dissolved in time t.
DE can have a range of values depending on the time
interval chosen. However, while comparing a set of data,
a constant time interval should be selected. In the present
study, DE10minutes (dissolution efficiency upto 10 minutes)
were calculated from the dissolution profile of each tab-
let and used for comparison. It was found that in com-
parison to DE10minutes obtained from tablet containing
diazepam, a 2.59 and 2.73 fold increase in DE10minutes
were obtained from the tablets prepared using diazepam/
HPβCD inclusion complex in molar ratios of 1:1 and 1:2
respectively. These increase in DE10minutes were found to
be statistically significant (p < 0.05). Faster release of
diazepam from the tablets prepared using its inclusion
complexes was related to the enhanced solubility of the
drug because of the formation of complex with HPβCD.
In another two batches of tablets namely Q3 and Q5
containing respectively 1:1 and 1:2 diazepam-HPβCD
complex, PVP, a hydrophilic polymer was added at a
concentration of 10% w/w of the solid complexes (Table
4) to investigate its effect on the various physical char-
acteristics which are shown in Table 5. Incorporation of
PVP in the formula increased the angle of repose of the
blended powders and decreased the porosity of the tab-
lets significantly (P < 0.05). Moreover, PVP increased
both the disintegration time and wetting time of the tab-
lets significantly (p < 0.05). The larger the amount of
PVP, the higher the disintegration time and the wetting
time. PVP which acts as a binder densified the powder
resulting in decreased flowability of the powder blend
and reduced the porosity of the tablets. Reduced porosity,
in turn, protracted the wetting and the disintegration of
the tablets. Addition of PVP in the tablet formulations,
however, further reduced t85% and increased DE indicat-
ing that drug dissolution took place faster than that from
the tablets without containing PVP. Addition of PVP in
the complex also increased the solubility linearly having
a slope < 1 as evident from phase solubility diagram
(Figure 3). At each point of determination, the solubility
of the drug was higher than that produced by the com-
plex in absence of PVP. The stability constant was also
found to be higher (Table 1). The potentiated solubility
of diazepam in complex form in the presence of PVP was
evaluated by determining the solubilization efficiency,
which is defined as ratio of solubility of drug in USP
phosphate buffer solution (pH 5.8) of 15 mM HPβCD
(with or without PVP) and the solubility of the drug in
buffer solution. Table 1 show that while HPβCD without
PVP produced 3.88 fold increases, the same in presence
of PVP produced 4.27 fold increases in the solubility of
diazepam. It, therefore, appears that presence of hydro-
philic polymer like PVP enhances the solubilizing effi-
ciency of HPβCD.
Accelerated stability test on the tablets (Q5) was con-
ducted at 40°C and 75% RH in accelerated stability test
chamber (Humidity Cabinet, Testing instruments manu-
facturing company, Kolkata) and the physical character-
istics of the tablets observed after different periods of
time are shown in Table 6.
The physical characteristics such as appearance, fri-
ability and drug content did not change and were con-
fined within the specified limits upto 6 months of time.
The disintegration time and t85% of the tablets upto one
month storage did not change significantly when com-
pared to those of the fresh tablets. However, marginal
Table 6. Various characteristics of Diazepam tablets stored at 40°C and 70% RH
Storage
Time (month) Conditions
Appearance Friability (%)Content (mg)DT (seconds)t85% (minutes) MDT (minutes)
Specifications White,round-flat tablet < 1% 95-105% <3 minutes < 30 minutes -
Initial Complies
0.140
(0.010)
4.96
(0.015)
19.53
(0.395)
7.56
(0.15)
2.85
(0.045)
1 Complies
0.147
(0.012)
4.98
(0.015)
20.26
(0.352)
7.90
(0.17)
2.848
(0.049)
3 Complies
0.177
(0.012)
4.94
(0.006)
20.84
(0.40)
8.22
(0.16)
2.847
(0.050)
6
40°C /75% RH
Complies 0.157
(0.025)
4.97
(0.006)
21.71
(0.262)
8.21
(0.11)
2.677
(0.12)

Preparation and Evaluation of Rapidly Disintegrating Fast Release Tablet of
Diazepam-Hydroxypropyl-β-Cyclodextrin Inclusion Complex
25
changes in the two characteristics were observed after 3
and 6 months storage. Although, the changes were statis-
tically significant, the tablets complied with the specified
limits even after 6 months. To further investigate the
effect of storage conditions on drug dissolution, mean
dissolution time (MDT) were calculated from the release
profiles of the tablets kept under stressed condition for
different periods of time and were compared with that
from freshly prepared tablet. MDT was calculated from
the following equation:
1
1
n
mid
i
n
i
tM
MDT
M






where tmid is the time at the midpoint between i and i-1,
and M is the additional amount of drug dissolved be-
tween i and i-1.
Table 6 shows that MDT values of the tablets did not
differ significantly (p < 0.05). This indicates that the drug
dissolution from the tablets (Q5) which were kept under
stressed condition were similar to that from the freshly
prepared tablets upto 6 months.
4. Conclusions
Tablets of diazepam were prepared by direct compres-
sion method that disintegrated quickly (in 13.3 seconds)
and released 85% drug rapidly (in 8.98 minutes). Rapid
disintegration was achieved using MCC and lactose as
excipients in a ratio of 4:1. Rapid drug dissolution was
obtained through the formulation of inclusion complex of
the drug with HPβCD. Inclusion of PVP further in-
creased the drug dissolution. Such tablets seem to be
suitable for achieving rapid onset of action of the drug
through oro-mucosal route.
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