Journal of Pharmaceutical Innovation

https://doi.org/10.1007/s12247-020-09455-z

ORIGINAL ARTICLE

Formulation and Evaluation of Fast-disintegrating Tablets

of Flurbiprofen and Metoclopramide
Maria Mushtaq 1 & Nosheen Fazal 1 & Amna Niaz 1

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Purpose The present study was aimed to formulate and evaluate fast-disintegrating tablets (FDTs) having Flurbiprofen (FP) and
Metoclopramide HCl (MHCl) in combination.
Method Direct compression was used to formulate FDTs of FP and MHCl as a combination regimen in six formulations. FDTs
are defined as solid oral dosage form that disintegrates rapidly within seconds when placed in the oral cavity. FDT-1, FDT-2,
FDT-3, FDT-4, FDT-5, and FDT-6 were formulated using crospovidone, croscarmellose sodium, and sodium starch glycolate as
superdisintegrants each in two formulations. Several pre-compression tests (angle of repose, bulk density, tapped density,
Hausner’s ratio, and compressibility index), post-compression evaluation (weight variation, friability, hardness, disintegration
time, wetting time, assay, in vitro dissolution study, release kinetics study, statistical analysis, and stability study), and drug
compatibility study were done for all six formulations.
Results Pre-compression evaluation showed good flow properties of powder blend. Drug compatibility study showed no inter-
actions between active drugs and excipients. Disintegration and wetting time of all the formulations were in seconds indicating
immediate release of drug. Optimized formulation (FDT-6) containing sodium starch glycolate in 15 mg gave 100% release in
15 min for MHCl and in 20 min for FP. Optimized formulation was found stable after being placed at accelerated stability
conditions for 6 months. Release kinetics study showed that all formulations followed Korsmeyer-Peppas model indicating drug
release from modified release dosage form. Statistical analysis revealed no significant difference statistically (p > 0.05) between
drug release rate of all prepared formulations.
Conclusion FDTs improved the release rate that assured that this tactic may be beneficial to increase the dissolution rate of FP and
MHCl in order to increase patient compliance.

Keywords Fast-disintegrating tablets (FDTs) . Flurbiprofen (FP) . Metoclopramide HCl (MHCl) . Superdisintegrants . In vitro
dissolution study . Release kinetics study

Introduction addition to greater surface area provided by mucosal lining

enhancing adsorption and absorption [1], but there are some
Oral administration is the most desirable approach for delivery hurdles of hepatic first-pass metabolism, less aqueous solubil-
of pharmaceuticals in different dosage forms like capsules, ity and reduced dissolution rate, drug degradation at acid gas-
tablets, syrups, suspension, and solution because of greater tric environment, and by gastric enzymes prohibiting the ad-
flexibility in design of formulations. It is a highly recommend- ministration of certain classes of drugs especially peptides and
ed route due to ease of manufacturing because it does not proteins. So, achieving greater solubility, stability, and higher
require sterile conditions, it is cost-effective due to no special oral bioavailability of many drugs became challenging for
packaging requirements, and there is patient compliance in pharmaceutical researchers [2]. Since the past few decades,
pharmaceutical researchers faced a major challenge of low
aqueous solubility and decreased dissolution rates for
* Maria Mushtaq Biopharmaceutical Classification System Class II (BCS-II)
mariamushtaq72@gmail.com
and Class IV drugs (BCS-IV) [3].
Multiple techniques are used by manufacturers to aid in
1
Department of Pharmaceutics, Riphah Institute of Pharmaceutical enhancing aqueous solubility of drugs such as melt
Sciences, Riphah International University, Islamabad, Pakistan
 J Pharm Innov

granulation, micronization, solvent evaporation, adsorption,

liquid solid compacts, ordered mixing of drug and excipients,
and direct compression [4]. Manufacturing by these methods
e m p l o y c a r r i e r s l i k e su r f ac t a n t s , p o l y m e r s , a n d
superdisintegrants that decrease wetting time of tablet by for-
mation of porous structure, increase solubility by decreasing Fig. 2 Structural formula of Metoclopramide HCl
particle size, increase permeability by disruption of tight junc-
tions and hence increase bioavailability of drug via gastroin-
testinal tract (GIT). formulate these two drugs in combination as FDTs. This will
Among new oral drug delivery systems such as adhesive be fruitful to treat the acute conditions like emesis associated
gels, ointments, co-crystals, patches, and nanoparticles, FDTs with migraine, dysmenorrhea, post-operative pain, and to re-
have also gained interest in recent years. FDTs are defined as duce their side effects which were reported to occur on
solid oral dosage form that disintegrate rapidly within seconds prolonged use and to increase patient compliance by getting
when placed in the oral cavity [5]. FDTs, as the name indi- relief from emesis-related pain instantly. Besides that, FP pos-
cates, display rapid disintegration and subsequent dissolution sesses low solubility and formulating it in the form of FDTs
in the mouth due to the presence of superdisintegrants, for would be helpful in achieving faster disintegration, dissolution
example, croscarmellose sodium, sodium starch glycolate, and, hence, increase solubility.
and crospovidone as an important ingredient in the formula- FP is available in the market as conventional tablet only
tion. The property of fast disintegration for FDTs makes them with trade name Ansaid® manufactured by Pfizer, New York.
superior to conventional tablet dosage form through which Recently, pharmaceutical researchers have prepared its FDT
absorption as well as onset of therapeutic actions are enhanced successfully. MHCl is available in the market as FDT as an
[6]. These tablets are designed for children, elderly, bedrid- innovator with trade name Metozolv® ODT manufactured by
den, or for any kind of patient who feels difficulty in Salix Pharmaceuticals, USA. FP and MHCl when prescribed
swallowing tablets. In addition to these advantages, FDTs separately as plain tablet dosage form to an individual patient
can also be used in the treatment of different acute conditions, may require frequent administration or high dose for instant
which requires urgent treatment, for example, motion sick- treatment. Moreover, these drugs also have serious adverse
ness, nausea/vomiting, sudden episodes of coughing, psycho- reactions on prolonged use that may be experienced by the
sis, stroke, and repeated emesis [7]. patient. MHCl in combination with FP is usually used in the
Flurbiprofen (FP) (structure shown in Fig. 1) is a phenyl- treatment of vomiting and nausea linked with painful condi-
alkanoic acid derivative belonging to the non-steroidal anti- tions (Britain 2018). Migraine, post-operative pain, and dys-
inflammatory drugs and is a BCS Class II drug. It acts by menorrhea cause emesis or nausea that decreases the patient’s
inhibiting cyclooxygenase enzymes (COX-I and COX-II) compliance, hence, these conditions require to be treated
non-selectively and prostaglandin (PGE2) synthesis. FP is simultaneously.
used in the treatment of rheumatic pain, musculoskeletal ill- The pathophysiology of emesis associated with pain can be
ness, migraine, post-operative pain, and pain associated with explained as the stimulus of pain can modulate different neu-
dysmenorrhea [8, 9]. rotransmitters like acetylcholine, dopamine, substance P (NK-
Metoclopramide HCl (MHCl) (structure shown in Fig. 2) is 1 receptor), histamine (H-1 receptor), and serotonin (5-HT3
a BCS-III (high solubility and low permeability) drug and an receptor) at CTZ located in the medulla oblongata or other
antagonist of dopamine-2 in chemoreceptor trigger zone vomiting centers [11, 12]. When nociceptive afferent nerves
(CTZ) located in the central nervous system resulting in potent transmit signals of pain to the brain by releasing neurotrans-
anti-nausea and anti-emetic actions. It is used for management mitters like substance P or peptide molecules and serotonin,
of radiation-induced nausea, vomiting, and alleviation of nau- the vomiting center gets activated and results in emesis [13].
sea associated with migraine [10, 11]. Various methods have been reported for preparation of
There has been no research work on FP and MHCl as FDTs like direct compression, wet granulation, molding,
combination in neither conventional dosage form nor as spray drying, freeze drying, and sublimation. Among these,
FDTs in recent years, hence, it will be advantageous to direct compression is the easiest and cost-effective method
due to conventional equipment, commonly available excipi-
ents, and a limited number of processing steps. Due to this
fact, direct compression has been applied to formulate FDTs
in the present study. Different studies have been reported
where various drugs such as clozapine, proclorperazine male-
ate, rizatriptan benzoate, and aceclofenac have been prepared
Fig. 1 Structural formula of Flurbiprofen (FP) by direct compression method using crospovidone,
J Pharm Innov

carboxymethylcellulose, and croscarmellose sodium as FDTs of FP and MHCl have been prepared using direct com-
superdisintegrants [14–17]. pression method and assessed for pre-compression studies (angle
The present study is aimed at overcoming challenges asso- of repose, compressibility index, tapped density, bulk density, and
ciated with conventional dosage forms of FP and MHCl by Hausner’s ratio) and post-compression studies (assay, weight var-
achieving objectives, to formulate and evaluate FDTs of FP iation, friability, hardness, disintegration time, wetting time,
and MHCl, to enhance dissolution rate to achieve rapid onset in vitro dissolution studies, release kinetics study, drug compati-
of action, to treat emesis associated with painful conditions in bility studies, statistical analysis). The details are given as follows.
short time periods, and to improve patient compliance by
combination drug dose.
Pre-compression Testing

Material and Methods Angle of Repose

Material Angle of repose is a property linked to interparticulate resis-

tance to movement between particles. Mixture of each formu-
All materials used were of analytical grade. Details are men- lation was poured into the funnel which flowed through and
tioned in Tables 1, 2, and 3. fall freely onto a surface. The angle of repose was calculated
by measuring the height of the heap and diameter of the fallen
powder by applying this equation [18];
Table 1 Detail of material used in preparation of FDT of MHCl/FP
h
Sr. Ingredient name Grade Percentage Ingredient Tan θ ¼ ð1Þ
r
no. purity (%) manufacturer
where θ is angle of repose, h is height, and r is radius of the
1. Flurbiprofen Analytical 100 Sigma Aldrich
flowed powder.
grade
2. Metoclopramide Analytical 84.60 Sigma Aldrich
HCl grade Bulk Density
3. Crospovidone Analytical 100 Alberq, Pakistan
grade
4. Croscarmellose Analytical 100 Qingdao sun Bulk density was found out by pouring a weighed mixture of
grade chemical Co Ltd., each formulation into measuring cylinder without tapping
China using the formula [19]:
5. Sodium starch Analytical 100 Anhui sunhere
glycolate grade pharmaceuticals Bulk Density ðρb Þ
excipients Co.,
Ltd., China Weight of powder ðgÞ
¼ ð2Þ
6. Microcrystalline Analytical 100 FMC international, Volume of powder without tapping ðmLÞ
cellulose grade Ireland
7. Mannitol Analytical 98–102 Star shine, China
grade Tapped Density
8. Aspartame Analytical 98–102 Alberq, Pakistan
grade
9. Talcum Analytical 100 Guangxi longguang The tapped density is an increased bulk density attained after
grade talc development mechanically tapping a container containing the powder
Co. Ltd., China sample.
10. Magnesium Analytical 100 Anhui sunhere Tapped density was obtained by mechanically tapping
stearate grade pharmaceuticals
excipients Co.,
(10–500 taps) a graduated measuring cylinder containing
Ltd., China powdered sample and readings were taken until the very little
11. Sodium Analytical 99–100 Merck, Pakistan further volume change (less an equal to 2 mL) was observed
hydroxide grade [20] (USP-42/NF-37). The powdered sample was settled
(NaOH) enough till 500 taps, hence, there was no need of tapping more
12. Potassium Analytical 98–100.5 Merck, Pakistan
than 500 or till 1250. This density was found out by this
dihydrogen grade
phosphate formula.,
(KH2PO4)
13. Methanol Analytical 99.5 Merck, Pakistan Weight of the powder ðgÞ
Tapped density ¼ : ð3Þ
grade Volume of the tapped powder ðmLÞ
 J Pharm Innov

Table 2 Detail of equipment used

in preparation of FDT of Sr. Equipment name Model Manufacturer
MHCl/FP no.

1. Disintegration tester BKBJ-3 Biobase Biotech, China

2. Dissolution tester RC-8DS Tianjin Guoming Medicinal Co., Ltd.,
China
3. UV-visible spectrophotometer UV-1601 Shimadzu, Japan
4. Fourier Transform Infrared IR-Prestige-21 Shimadzu, Japan
Spectrophotometer
5. Single punch compression machine 021801 Shanghai Tianfan Pharmaceutical
Machine, China
6. Hardness tester PTB-D-63512 Pharma Test, Germany
Hainburg
7. Tablet friability tester y-2A Pharmlab, China
8. Stability chamber SDH-02 Shanghai Jianheng, China
9. pH meter PHS-3BW Biobase Biotech, China
10. Analytical balance BL-210 Sartorius, Germany

ρtap
Hausner Ratio ¼ ð5Þ
ρb
Compressibility Index
where ρb is bulk density sand ρtap is tapped density.
The compressibility index can be used to measure bulk den- The official criteria of pre-compression tests is mentioned
sity, shape, size, surface area, moisture content, and attraction in Table 7.
of materials.
It was found out by simply using both tapped and bulk
densities into the following formula [18]: Preparation of Fast-disintegrating Tablets


ρtap −ρb FDTs were prepared by direct compression method
Compressibility Index ¼  100 ð4Þ
ρtap comprising three main steps: dispensing, sieving/mixing,
and direct compression [18]. Firstly, all ingredients (ac-
where ρb is bulk density and ρtap is tapped density. tive and excipients) were weighed, dispensed, and la-
beled properly in beakers. Active ingredients were
passed through sieve no. 80 and all excipients were
Hausner Ratio sieved through sieve no. 60. The sieve sizes are decided
on the basis of powder nature, powder flowability, and
Flow properties of sample were checked by finding out in vitro dissolution rates. Fine powder should be used to
Hausner ratio along compressibility index by the following improve flowability of powder and in vitro drug disso-
formula: lution rate. In the current research study, sieve 80 and
60 have been used for the concern of fast in vitro drug
dissolution rate and improved powder flow. The active
Table 3 Glassware used in preparation of FDT of MHCl/FP ingredients were mixed with superdisinetgrants
(crospovidone, croscarmellose, sodium starch glycolate),
Sr. no. Glassware Grade Manufacturer
avicel and mannitol for 5 min. Talcum and magnesium
1. Pippete Grade A Science Centre, Pakistan stearate were added in this mixture and mixed for fur-
2. Measuring cylinder Grade A Science Centre, Pakistan ther 5 min. Geometric mixing was done in order to
3. Volumetric flask Grade A Science Centre, Pakistan ensure equal distribution of both drugs in a resultant
4. Beaker Grade A Science Centre, Pakistan formulation. Combined mixture was compressed into
5. Funnel Grade A Science Centre, Pakistan tablets by using 8-mm round flat punches by using a
6. Petri dish Grade A Science Centre, Pakistan single punch tablet machine (021801, Shanghai Tianfan,
China). Six formulations were prepared by combining
J Pharm Innov

Table 4 Detail of ingredients used in preparation of FDT of MHCl/FP

Sr. no. Ingredients FDT-1 FDT-2 FDT-3 FDT-4 FDT-5 FDT-6

1. Flurbiprofen 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg
2. Metoclopramide HCl 5.91 mg 5.91 mg 5.91 mg 5.91 mg 5.91 mg 5.91 mg
3. Crospovidone 16 mg – – 14 mg – –
4. Croscarmellose – 13 mg – – 15 mg –
5. Sodium starch glycolate – – 13 mg – – 15 mg
6. Microcrystalline cellulose 80 mg 80 mg 80 mg 80 mg 80 mg 80 mg
7. Mannitol 30 mg 25 mg 25 mg 27 mg 27 mg 27 mg
8. Aspartame 1 mg 1 mg 1 mg 3 mg 3 mg 3 mg
9. Talcum 2 mg 2 mg 2 mg 2 mg 2 mg 2 mg
10. Magnesium stearate 1 mg 1 mg 1 mg 1 mg 1 mg 1 mg
Theoretical tablet weight 185.91 mg 177.91 mg 177.91 mg 182.91 mg 183.91 mg 183.91 mg

all these ingredients in different quantities [18]. Details the remaining tablets and the results were noted which
are mentioned in Table 4. were displayed over the tester screen.

Post-compression Testing Friability

Weight Variation Friability is one of the important parameters in order to

cope up with handling, packing material, and transfer of
The uniformity of weight of each tablet of all six for- tablets. It can be defined as loss of tablet weight due to
mulations was confirmed by taking the weight of ten damage to the tablet surface during handling, transfer,
tablets from each formulation one by one by using an- and packaging. Ten tablets from each formulation were
alytical balance (BL-210, Sartorius, Germany). Variation weighed (W1) individually before placing the tablets in
in weight of each tablet weighed individually was tablet friability tester (y-2A, Pharmlab, China). These
checked and compared by taking average weight of tablets were then placed in tablet friability, where tab-
ten tablets with the help of following formula. lets fell at a distance of 6 in. for 4 min at 25 rpm. After
4 min, these tablets were de-dust and weighed (W2)
Weight Variation% again one by one. The result was calculated by follow-
Average weight−Individual Weight ing formula.
¼  100 ð6Þ
Average Weight
ðW1−W2Þ
Friability% ¼  100 ð7Þ
W1
Hardness

Tablet hardness is one of the important parameters to

check the strength of tablet. Hardness of all six FDTs Disintegration Time
was determined by using the hardness tester (Type PTB
311-511-E) (Pharma test D-63512, Hainburg, Germany). Disintegration tester (BKBJ-3, Biobase Biotech, China)
Six tablets from each formulation were taken and placed was used for the determination of disintegration time of
in hardness tester into the sample holder. At first, the all six formulations prepared, as this is the important
unit kg/cm2 was selected followed by placing the tablet parameter to be checked. Six tablets from each formu-
in upright position into the thickness jaw. The driven lation were taken in each tube in basket. The apparatus
jaw came forward, touched, and forced the tablet at its was filled with 1 L distilled water maintained at 37 ±
higher point to measure the thickness and reversed back 2 °C. The disintegration time was determined by mea-
so that the tablet falls at horizontal position to find out suring the time from stopwatch in which the tablet dis-
the thickness and hardness. This test was repeated for integrates properly.
 J Pharm Innov

Wetting Time and in acidic solvents [10, 23]. So, on the basis of the solubil-
ity of respective drugs, assay of both drugs was performed
It is the capability of a liquid to get absorbed by the solid separately in different solvents.
surface (tablet) resulting from intermolecular interactions
when these two have been brought together. The purpose of In Vitro Dissolution Study
this test is just to determine the time required by the tablet to
get absorbed. The sooner the tablet gets absorbed by water, the In Vitro Dissolution Study for MHCl and FP
faster the rate of swelling, disintegration followed by dissolu-
tion. The facial tissue paper was used for this test. Three tab- The USP dissolution apparatus type II-paddle (RC-8DS,
lets from all six formulations were randomly taken and placed Tianjin Guoming Medicinal, China) was used to calculate
over the tissue paper in petri dish containing 6 mL water. The the dissolution time and dissolved content of active ingredi-
time taken by tablets to absorb the water was measured by ents. As this is the most important test for FDTs which used
using a stop watch [21]. to dissolves the tablets in specific medium shows dissolution
profile of formulation. Six tablets from each prepared formu-
Assay lation were taken in each basket containing paddle and medi-
um (pH 6.8 buffer for FP and 0.1 N HCl for MHCl) by setting
Assay for MHCl all the dissolution conditions of dissolution tester. This test
was performed for 45 min in case of MHCl and for 30 min
To determine the content of MHCl in each formulation, ten in case of FP, in which after every 5 min, 20 mL of sample
tablets were taken, weighed, and crushed properly. One tablet from each basket was collected which was replaced by 20 mL
that weighed powder equivalent to 10 mg of MHCl was taken of fresh media and analyzed by using UV-visible spectropho-
in a 50-mL volumetric flask by the addition of 0.1 N hydro- tometer at specific wavelengths (309 nm for MHCl and
chloric acid (HCl) as a solvent. This dilution was sonicated for 247 nm for FP). The results were calculated by using the
5–10 min followed by filtration. Five milliliters was pipetted formula [22]:
out from this filtered mixture and taken in another 50-mL
volumetric flask by making volume up to the mark by the
½AbsorbanceðsampleÞ
same solvent. The absorbance of resultant and standard solu- Drug release% ¼
½Absorbanceðreference standardÞ
tion was observed and calculated at a wavelength of 309 nm
with the help of UV-visible spectrophotometer (UV-1601,  100 ð9Þ
Shimadzu, Japan) [22].
The drug dissolution should not be less than 80% [24].
In order to avoid contamination or immiscibility, to get the
Assay for FP accurate results, maximum absorbance, samples after collection
in case of FP were diluted with methanol as FP dissolves easily
For the determination of quantity of FP in all formulations, ten in polar solvents. pH 6.8 buffer (0.89 g of NaOH and 0.8 g of
tablets were taken, weighed, and crushed. One tablet that KH2PO4 in 1 L water) was used as dissolution medium for FP.
weighed powder equivalent to 50 mg of FP was taken in
100-mL volumetric flask by the addition of methanol as a
solvent up to the mark. This dilution was sonicated for 5– Drug-excipient Interaction Studies
10 min followed by filtration. One milliliter was pipetted out
from this filtered mixture and taken in 50-mL volumetric flask Differential Scanning Calorimetry (DSC)
by making volume up to the mark by the same solvent. The
absorbance of resultant and standard solution was observed To find out the possible interactions between the active and
and measured at wavelength of 247 nm. The percentage drug inactive ingredients, DSC was conducted on pure ingredients
content can be determined with the help of UV-visible spec- and optimized formulation. The powdered sample was
trophotometer by using the formula [18]. weighed and placed in DSC sample pan at a standard heating
rate of 10 °C/min over a temperature range of 50–350 °C and
½AbsorbanceðsampleÞ the results were determined [18].
Drug content% ¼
½Absorbanceðreference standardÞ
 100 ð8Þ Infrared Spectroscopy

FP is water soluble at neutral pH to some extent but easily FTIR (IR-Prestige 21, Shimadzu, Japan) was used to find out
soluble in polar solvents, while MHCl is freely water soluble the compatibility between active and inactive ingredients used
J Pharm Innov

in the formulation. The powdered sample in small quantity of greater the drug release and vice versa. First-order kinetics can
each formulation and active ingredients was placed at sample be explained by following equations:
plate one by one and analyzed by examining the resultant
dC=dt ¼ −Kc ð12Þ
spectra at wavenumber 400 to 4000 cm−1 by using IR-
solution software at FTIR [18]. Where K = first-order rate constant, dC/dt = rate of drug
release in time t, and c = quantity of drug dissolved in time t.
Stability Study Equation (12) can be written as:

The assessment of stability of developed formulations was Log C ¼ log C o −Kt=2:303 ð13Þ
done according to WHO guidelines of accelerated stability
where C0 = initial concentration of drug, C = quantity of drug
study at 40 °C ± 2 °C and 75% ± 5% RH in a stability chamber
dissolved in time t, and K = first-order rate constant.
(SDH-02, Shanghai Jianheng, China) for about 6 months.
The data obtained from in vitro drug release studies is plot-
ted between the log of cumulative amount of drug released
Release Kinetics Study verses time. This model can be used to describe the drug
dissolution, absorption, and elimination of dosage forms with
To determine the drug release from all six formulations pre-
high water soluble drugs [25, 26].
pared, release kinetics study was done using the approaches:
model dependent approaches, model independent approaches, Higuchi Model The description of drug release from ma-
and statistical analysis.
trix tablet system depends on hypothesis made by
Higuchi. This hypothesis states that (i) the initial
Model-dependent Approaches amount of drug in the matrix is greater than its solubil-
ity, (ii) drug diffusion occurs in one dimension only,
Drug release rate can be assessed by different model- (iii) system thickness is greater than drug particle size,
dependent approaches such as zero-order kinetics, first-order (iv) dissolution or matrix swelling is negligible, and (v)
kinetics, Higuchi, Hixson and Crowell approach, and perfect sink conditions are maintained. This model can
Korsmeyer-Peppas model using DD-Solver or Microsoft be expressed using the following equation:
Excel simply. These approaches are used to find out which pffiffiffiffiffiffiffi
model will best fit the dissolution profile of pharmaceutical ft ¼ Q ¼ A ¼ Cst ð14Þ
products [25, 26].
where ft = fraction of drug released in time t, Q = quan-
Zero-order Kinetics Model This model can be explained as the tity of drug released in unit area A at time t, C = initial
system where the drug release rate is independent of its con- drug concentration, Cs = drug solubility in matrix me-
centration. This model explains slow drug release from dosage dia, and D = diffusion coefficient The dissolution data
form and can be represented by the following equations: of the formulations, when the drug amount is lower
than its solubility, is expressed as
Qo −Qt ¼ K o t: ð10Þ
pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
Rearranging the Eq. (10): ft ¼ Q ¼ Dδð2C‐δCsÞCst
ð15Þ
Qt ¼ Qo þ K o t ð11Þ τ
where ft = fraction of drug released in time t, Q = quantity of
where Qt = quantity of drug dissolved in time t, Qo = initial
drug released in unit area A at time t, C = initial drug concen-
quantity of drug in solution, and Ko = zero-order release con-
tration, Cs = drug solubility in matrix media, D = diffusion
stant [25, 26].
coefficient, δ = porosity of matrix, and τ = tortuosity of matrix
To study the release kinetics, data obtained from in vitro
(dimension of radius and branching of the pores in the matrix).
drug release study is plotted between the percentage cumula-
Higuchi model is expressed as:
tive amount of drug released and time. This model can be used
to describe the drug dissolution of several dosage forms such f t ¼ Q ¼ KH  t1=2 ð16Þ
as transdermal drug delivery systems, osmotic systems, and
coated matrix tablet systems [25, 26]. where ft = fraction of drug released in time t, Q = quantity of
drug released in unit area A at time t, and KH = Higuchi dis-
First-order Model When the rate of drug dissolution is directly solution constant.
proportional to the drug concentration, it is known as first- The data obtained is plotted between cumulative amount of
order release of drug. The greater the drug concentration, the drug released and square root of time. Higuchi model is
 J Pharm Innov

applied to modified release dosage forms, i.e., transdermal factor (f1). The difference factor (f1) measures the percent error
systems and matrix tablet system [25, 26]. between two different formulations over all time periods and
is represented by the following equation:
Hixson and Crowell Model Hixson and Crowell derived an n  
equation that explained that the area of particles is proportion- ∑ R j −T j 
j¼1
al to the cube root of its volume, described in following man- f1 ¼  100 ð19Þ
n
ner: ∑ Rj
j¼1
W o 1=3 −W t 1=3 ¼ kt ð17Þ
Where n = number of samples, Rj and Tj = the percent
where Wo = initial concentration of drug, Wt = remaining dissolved of the reference and test formulations at each
quantity of drug at time t, and k = constant. This model applies time, respectively. The percent error is zero when the
to the effect of change in diameter and surface area of particles test and reference formulation dissolution profiles are
on drug release. similar and increases with increase in dissimilarity be-
The data obtained is plotted between cube root of cumula- tween them [27].
tive amount of released drug and time. This model is most The similarity factor (f2) defines the similarity of dissolu-
commonly applied to conventional tablets, dispersible tablets, tion profile of different formulations by taking log reciprocal
or immediate release tablets [25, 26]. square root of sum of errors over all times and is determined
by following equation:
Korsmeyer-Peppas Model Once it has been ascertained that
the mechanism of drug release is diffusion controlled from f 2 ¼ 50
Higuchi plot, then to ascertain the release of drug follows 8" #−0:5 9
< n  2 =
which type of mechanism, the release data is fitted to model  log 1 þ ð1=nÞ ∑ w j R j −T j   100
proposed by Korsmeyer and Peppas. This model explains the : j¼1 ;
drug release from a polymeric dosage form or modified re-
ð20Þ
lease dosage forms when the release mechanism is not well
known or when more than one type of release phenomena Where wj = weight factor, n = number of samples, and
could be involved. The drug release is represented by the Rj and Tj = the percent dissolved of the reference and
following equation: test formulations at each time, respectively. This method
M t =M ∞ ¼ Ktn ð18Þ is more suitable for dissolution profile comparison when
more than three time points are available. The dissolu-
where Mt/M∞ = fraction of drug released, K = release rate con- tion data is fitted from 0 to 100. One hundred means
stant, and n = release exponent. The value of n identifies the test and reference formulations are similar and zero
release mechanism of drug as described in Table 5. To study means they are dissimilar. The similar dissolution pro-
release kinetics, a graph is plotted between log % cumulative files must have f1 value close to 0 and f2 value close to
drug release log (Mt/M∞) versus log time (log t) [25, 26]. 100 [28, 29].

Model Independent Approaches

Statistical Analysis
Dissolution profile of six formulations was determined by
using this technique with the help of DD-Solver software. This study involves the application of one way ANOVA tech-
Using model-independent approach, drug dissolution data nique to the drug dissolution profile of all six formulations
can be compared using similarity factor (f2) and difference using DD-Solver or simply by Microsoft Excel.

Table 5 Evaluation of diffusional release mechanisms from polymeric films

Release exponent (n) Drug transport phenomenon Rate as a function of time Release type

0.5 Fickian diffusion t−0.5 Diffusion release, square root of time dependent
0.45 < n = 0.89 Non-Fickian transport tn−1 Diffusion and swelling, release is time dependent
0.89 Case II transport Zero order release Swelling controlled release, release rate independent of time
> 0.89 Super case II transport tn−1 Swelling controlled release, release rate independent of time
J Pharm Innov

mW
Fig. 3 DSC graphs of FDT-6, FP, Sample: FDT DSC, 5.4000 mg

and MHCl 1

-1

-2

-3

-4

-5

-6

-7

-8

40 60 80 100 120 140 160 180 200 220 240 260 280 °C

mW Sample: FP DSC, 4.5000 mg

-5

-10

-15

-20

-25

-30

-35

40 60 80 100 120 140 160 180 200 220 240 260 280 °C

mW
Sample: MHCL DSC, 5.2000 mg

-2

-4

-6

-8

-10

-12

-14

-16

-18

40 60 80 100 120 140 160 180 200 220 240 260 280 °C
J Pharm Innov
 J Pharm Innov

ƒFig. 4 IR graphs of MHCl, FP, FDT-1, FDT-2, FDT-3, FDT-4, FDT-5, 2461.17–2357.01 cm−1, N=C=O stretching of isocyanate at
and FDT-6 2256.71 cm −1 , C-H bending of aromatic compound at
1693.50 cm−1, C=O stretching of anhydride at 1620.21–
1562.34 cm−1, C-H bending of alkane at 1481.33 cm−1, S=O
Results stretching of sulfate at 1413.82 cm−1, O-H bending of phenol
at 1323.17 cm −1 , C-O stretching of aromatic ester at
Drug Excipient Interaction Study 1257.59 cm −1 , C-O stretching of alkyl aryl ether at
1 2 1 5. 1 5 c m − 1 , C - O s t r e t c hi n g o f v i ny l e t he r a t
Drug interaction study was done using DSC that determined 1128.36 cm−1, S=O stretching of sulfoxide at 1074.35–
the thermal properties of both APIs and optimized formulation 1062.78 cm−1, C-Cl stretching of halo compound at 873.75–
(FDT-6) by changing temperature conditions. DSC is used for 800.46 cm−1, and C-Br stretching of halo compound at
the verification/validation of compatibility results that is why 682.80–524.64 cm−1 [30].
it was done just for optimized formulation. DSC thermograms The FTIR spectra (Fig. 4) of both drugs MHCL/FP and six
showed sharp endothermic peaks related to the melting point formulations were observed and compared which revealed
of FP and MHCl were observed at 119.83 °C and 183.50 °C, that all the six formulations had similar functional groups:
respectively, showing the crystalline behavior of both these alcohol, aliphatic amine, carboxylic, carbon dioxide, nitro,
APIs. Whereas endothermic peaks of FP and MHCl in opti- sulfate, phenol, thiol, amide, ketone, alkane, aromatic ester,
mized formulation were observed at 115.50 °C and 167.33 °C, alkyl aryl ether, and sulfoxide at almost nearer peaks against
respectively, indicating the amorphous form of both drugs. both active drugs. This means that all the six formulations
Results (Fig. 3) showed no extra peak of phase transition prepared were compatible with both active drugs and excipi-
indicating no interaction between drugs and excipients. ents. The FTIR spectra of both drugs MHCL/FP and six for-
FTIR spectras of both drugs and all six formulations were mulations were observed and compared with standard values
recorded in between wave number 4000 and 400 cm−1. The which revealed that all the six formulations had similar func-
different functional groups and peaks observed in IR spectra tional groups at almost nearer peaks against both active drugs
of MHCl as shown in Fig. 4 were O-H stretching of strong indicating intact active ingredients with no intermolecular
bond of alcohol at 3394.72–3371.57 cm−1, N-H stretching of forces developed.
aliphatic primary amine at 3302.13 cm−1, O-H stretching of
weak bond of alcohol at 3192.19–2711.92 cm −1 , O-H
stretching of carboxylic group at 2623.19–2586.54 cm−1, Pre-compression Studies
O=C=O stretching of carbon dioxide at 2484.32–
2330.01 cm −1 , N-O stretching of nitro compound at The results of pre-compression studies (Table 6) showed that
1500.62–1537.27 cm −1 , S=O stretching of sulfate at the angle of repose of all formulations lied between 25.10° ±
1400.32 cm −1 , O-H bending of phenol at 1371.39– 1.63 and 32.07°± 0.46 indicating the excellent powder flow
1321.24 cm−1, C-Cl stretching of halo compound at 837.11– property of all formulations according to the official criteria
769.60 cm−1, and C-Br stretching of halo compound at (Table 7). The bulk and tapped densities of all formulations
678.94–524.64 cm−1 [30]. lied between 0.428 g/cm3 ± 0.13 to 0.441 g/cm3 ± 0.12 and
The different functional groups and peaks observed in IR 0.487 g/cm3 ± 0.11 to 0.531 g/cm3 ± 0.39, respectively, which
spectra of FP as shown in Fig. 4 were N-H stretching of amine were used to determine compressibility index. The compress-
salt at 3074.53–2827.64 cm−1, O-H stretching of alcohol at ibility index lied between 11.38% ± 1.88 and 17.64% ± 1.28
2723.49 cm −1 , S-H stretching of thiol at 2613.55– indicating that the FDT-1 was having fair flow properties and
2524.82 cm −1, O=C=O stretching of carbon dioxide at other formulations were having good flow property results.

Table 6 Results of pre-

compression evaluation Formulation Angle of Bulk density Tapped density Compressibility Hausner’s ratio
repose ± SD g/cm3 ± SD g/cm3 ± SD index % ± SD % ± SD (n = 3)
(n = 3) (n = 3) (n = 3) (n = 3)

FDT-1 31.49 ± 0.62 0.437 ± 0.60 0.531 ± 0.39 17.64 ± 1.28 1.21 ± 0.47
FDT-2 28.31 ± 0.42 0.428 ± 0.13 0.494 ± 0.11 13.25 ± 0.76 1.15 ± 0.50
FDT-3 32.07 ± 0.46 0.429 ± 0.13 0.487 ± 0.11 11.83 ± 1.18 1.13 ± 0.50
FDT-4 25.10 ± 1.63 0.452 ± 0.22 0.510 ± 0.11 11.38 ± 1.88 1.12 ± 0.51
FDT-5 25.71 ± 0.97 0.441 ± 0.12 0.512 ± 0.19 11.79 ± 1.14 1.13 ± 0.50
FDT-6 26.85 ± 0.17 0.438 ± 0.12 0.509 ± 0.11 11.73 ± 1.07 1.13 ± 0.50
 J Pharm Innov

Hausner’s ratio of all formulations lied between 1.12 ± 0.51 80% in 30 min which ultimately met the standard dissolution
and 1.21 ± 0.47 which showed that all the formulations were criteria [33]. The active drug in all six formulations has been
having good flow properties when compared with standard released 80–90% within 15 min but FDT-6 showed the best
values. results which completely dissolved in 20 min as compared to
The pre-compression studies were conducted to know the other formulations. The results of both the drugs were satis-
flow properties of formulations. For the current used method factory whereas the results may vary due to the different con-
(direct compression), the flowability of the prepared formula- centrations of superdisintegrants.
tion mixture is important which in turn is important for the
uniformity of tablet mass and in vitro drug dissolution. Stability Study

Post-compression Testing It was clearly observed from the results (Table 9) that opti-
mized formulation (FDT-6) has passed all the tests after being
There were different tests performed for evaluation of all six placed in stability chamber for 6 months which indicated that
formulated FDTs like weight variation, friability, hardness, FDT-6 was stable under accelerated stability conditions.
assay, disintegration time, in vitro dissolution time, release
kinetic study, wetting time study, and stability studies. Release Kinetics Study
Results (Table 8) of weight variation revealed that there was
no variation in weights of all the formulations and the results Drug release kinetics was studied by applying two ap-
were in limit of standard criteria. Hardness of tablets of all six proaches: model-independent approach and model-
formulations met the criteria as all the values lied between 5 dependent approach which are explained as under. Upon ob-
and 6 kg/cm2. Friability of all formulations met the criteria as serving the results of model-dependent approaches for MHCl
the results lied between 0.560% ± 0.25 and 0.640% ± 0.87 or (Table 10) and FP (Table 11), it was clear that Korsmeyer-
less than 1%. This showed that the tablets will cope up with Peppas model best fitted in our formulations because all for-
handling and shipment of tablets. mulations had > 0.98 and > 0.88 correlation coefficients, re-
All the formulations showed disintegration time (Table 8) spectively, and 60% of the drug released was best fitted with
within seconds which met the criteria of disintegration time of Korsmeyer-Peppas model [34, 35]. The correlation coefficient
orodispersible tablets less than 3 min [31]. Wetting time of all values obtained from Korsmeyer-Peppas model were higher
the formulations showed that they got absorbed by water with- as compared to other models for all formulations. So,
in seconds which complied the criteria of fast-dissolving tab- Korsmeyer-Peppas model was applied for fast-disintegrating
lets. The results of content of both drugs (Table 8) in all six tablets (modified release). This model explains the drug re-
FDTs lied between standard criteria of 90–110% [32]. The lease type of diffusion and swelling from a polymeric dosage
results of assay and in vitro drug release were shown higher form or modified release dosage forms (containing
than 100 because of the formulated tablets were compressed at superdisintegrants) while having n = 0.602 [25, 26].
upper weight. As tablet’s theoretical weight is different rather In model-independent approaches, optimized formulation
than actual weight of each prepared formulation. (FDT-6) was used as a standard reference in order to compare
UV spectroscopy has been used to analyze both APIs the drug release of other formulations as there was no refer-
depicted at different lambda max (247 nm for FP and ence standard of combination of FDT of MHCl/FP available
309 nm). There was no overlapping of peaks as shown in in market. By applying this technique for the dissolution data
graphs (Figs. 5 & 6). There was no interference observed of MHCl (Table 12), it was clear from the results that FDT-3,
between these two APIs. Both were eluted at different wave- FDT-4, and FDT-5 have passed the test but the FDT-4 showed
lengths and absorbance time using different solvents. the lowest f1 value and largest f2 value which indicated that
this formulation was close to optimized formulation. Release
In Vitro Dissolution Study kinetics study for FP (Table 12) showed that all the formula-
tions have passed the test but the FDT-3 showed the lowest f1
The in vitro dissolution study of all six formulations for MHCl value and largest f2 value which revealed that this formulation
(Fig. 7) showed that the drug release was not less than 80% in was close to optimized formulation.
45 min which ultimately met the standard dissolution criteria
[24]. The active drug has been released 90–100% within Statistical Analysis
15 min in FDT-3, FDT-4, FDT-5, and FDT-6 but FDT-6
showed the best results which completely dissolved in This study was analyzed by applying one way ANOVA tech-
15 min as compared to other formulations. The results of nique to the drug release data of all prepared formulations. In
in vitro dissolution study of all six formulations for FP this technique, two hypotheses were made: null hypothesis
(Fig. 8) were showed that the drug release was not less than and alternate hypothesis. Null hypothesis stated that all the
J Pharm Innov

Table 7 Official criteria of pre-

compression tests Flow properties Angle of repose (degrees) Compressibility index (%) Hausner’s ratio

Excellent 25–30 ≤ 10 1.0–1.1

Good 31–35 11–15 1.12–1.18
Fair 36–40 16–20 1.19–1.25
Passable 41–45 21–25 1.26–1.34
Poor 46–55 26–31 1.35–1.45
Very poor 56–65 32–37 1.46–1.59
Very very poor > 66 > 38 > 1.6

prepared formulations were dissolved whereas alternate hy- dissolution. For direct compression, the flowability of the for-
pothesis stated that all the formulations were not dissolved. mulation mixture is important which in turn is significant for
The criterion to meet this test is that null hypothesis should be the uniformity of mass of the tablets. The flow of the formu-
accepted and alternate hypothesis should be rejected when the lation mixtures were analyzed before compression to tablets.
level of significance (α) or critical value taken as 0.05 (3.05) is The angle of repose of all six formulations was found to be in
greater than the ratio of mean squares between and within the the range of 25.10° ± 1.63 to 32.07° ± 0.46 which indicates
groups. By applying this technique, we came to know that our that all formulations had excellent powder flow properties
null hypothesis was correct and accepted but alternate hypoth- [36]. Bulk densities and tapped densities of formulations were
esis was rejected as the p value is greater than 0.005 and F- determined in order to calculate compressibility index and
critical value is greater than F value (Table 13). Hausner’s ratio. Bulk and tapped density were found to be
in the range of 0.428 g/cm3 ± 0.13 to 0.441 g/cm3 ± 0.12 and
0.487 g/cm3 ± 0.11 to 0.531 g/cm3 ± 0.39, respectively.
Discussion Compressibility index was found to be in the range of
11.38% ± 1.88 to 17.64% ± 1.28 which showed that all formu-
FDTs are one of the novel drug delivery systems that can be lations had passed the standard criteria of good flow properties
used to overcome the shortcomings regarding conventional [32] (USP-42/NF-37). Hausner’s ratio was also found to be
tablets. FDTs of FP and MHCl were aimed to be formulated between 1.12 ± 0.51 and 1.21 ± 0.47 which indicates that all
in combination to instantly treat emesis associated with differ- the formulations had good flow properties [32] (USP-42/NF-
ent painful conditions instantly. FDTs of FP and MHCl were 37).
prepared by direct compression method using three The percentage content of both APIs was determined by
superdisintegrants (croscarmellose, crospovidone, and sodi- measuring the absorbance of sample and standard solutions.
um starch glycolate). All six prepared formulations were eval- The results of assay of FP in six formulations showed that the
uated for pre-compression studies, i.e., angle of repose, bulk drug content was within official limits (90–110%) in all for-
density, tapped density, compressibility index, and Hausner’s mulations and that the drug was uniformly distributed
ratio. The pre-formulation studies were conducted to know the (Table 8) [37] (USP-42/NF-37). Whereas assay content of
flow properties of formulations. The flowability of the pre- MHCl in all formulations showed that the drug content lied
pared formulation mixture is important which in turn is im- in the range of 90–110% meeting the standard criteria of assay
portant for the uniformity of tablets mass and in vitro drug content (Table 8) [33] (USP-42/NF-37).

Table 8 Results of post-

compression evaluation Formulation Average Hardness Friability % Wetting D time (s) FP MHCl
weight mg (kg/ ± SD time (sec) ± SD assay assay
±SD (n = 10) cm2) ± SD (n = 10) ± SD (n = 6) % %
(n = 6) (n = 3)

FDT-1 189.35 ± 0.97 6 ± 0.85 0.638 ± 0.96 42 ± 1.36 18 ± 1.20 104.8 104.05
FDT-2 184.3 ± 0.38 5.5 ± 0.94 0.591 ± 0.41 55 ± 1.04 28 ± 1.86 106.23 102.52
FDT-3 183.66 ± 0.54 6 ± 0.85 0.571 ± 0.46 54 ± 1.06 25 ± 1.64 106.34 102.89
FDT-4 187.29 ± 0.84 5 ± 1.65 0.640 ± 0.87 45 ± 1.29 09 ± 0.98 104.55 103.25
FDT-5 186.33 ± 0.53 5.6 ± 0.92 0.569 ± 0.56 48 ± 1.19 25 ± 0.52 101.14 102.43
FDT-6 185.49 ± 0.24 5 ± 1.65 0.560 ± 0.25 40 ± 1.43 15 ± 1.23 106.21 101.05
 J Pharm Innov

Fig. 5 UV spectra of assay of FP of FDT-1, FDT-2, FDT-3, FDT-4, FDT-5, and FDT-6
J Pharm Innov

Fig. 6 UV spectra of assay of MHCl of FDT-1, FDT-2, FDT-3, FDT-4, FDT-5, and FDT-6
 J Pharm Innov

Fig. 7 Graphical presentation of 120

in vitro drug dissolution release of
MHCl 100

80

Dissolution (%)
FDT-1
FDT-2
60
FDT-3
FDT-4
40
FDT-5
FDT-6
20

0
0 5 10 15 20 25 30 45
Time (min)

The weight variation results (Table 8) showed that there The wetting time is closely related to the inner structure of
was negligible variation in weights of tablets for all formula- the tablet and mimics the action of saliva in contact with the
tions indicating that the tablets lied within the limits of stan- tablet to illustrate the water uptake and subsequent wetting of
dard criteria, i.e., 80 mg ≥ 250 mg ± 7.5% [38] (BP 2018). tablet. The rapid wetting process in almost all formulations
Prepared tablets were of acceptable weight variation lied in may be due to the ability of swelling and also capacity of water
the range from 183.66 mg ± 0.54 to 189.35 mg ± 0.97 due to absorption, i.e., the ability of tablets of all formulations to
uniform die fill. absorb water. The results indicated that all the formulations
The hardness was determined to check the strength of tab- have been wetted completely in water within seconds which
lets of all six formulations. The results showed that all six complied the criteria of fast dissolving tablets.
formulations lied between 5 and 6 kg/cm2 showing that all The disintegration time was performed to determine
formulation tablets had a fine mechanical strength and were the time for FDTs to completely dissolve when in con-
within the limits of standard criteria [39]. tact with saliva. All the formulations had passed the test
The friability was determined to check the loss of weight of and fulfilled the criteria of disintegration (less than
tablets of all six formulations. The results indicated that the 3 min) whereas FDT-4 and FDT-6 disintegrated in the
friability of all formulations was less than 1%, i.e., between shortest time, i.e., 09 s ± 0.98 and 15 s ± 1.23, respec-
0.560% ± 0.25 and 0.640% ± 0.87 [32] (USP-42/NF-37). This tively, [31] (BP 2019). The results of all the tablets lied
showed that the tablets will cope up with handling and ship- within the official limits and fulfilled the criteria of fast
ment without any loss of weight. dissolving tablets.

Fig. 8 Graphical presentation of 140

in vitro drug dissolution release of
FP 120

100
Dissolution (%)

FDT-1
80
FDT-2
FDT-3
60
FDT-4
FDT-5
40
FDT-6

20

0
0 5 10 15 20 25 30
Time (min)
J Pharm Innov

Table 9 Evaluation results of

stability study Sr. no. Tests Initial After 6 months

1. Physical appearance White circular shaped tablet White circular shaped tablet
2. Assay FP 106.21% 106.15%
MHCl 101.05% 101.00%
3. Disintegration time 15 s 15 s
4. Dissolution FP 105.36 in 20 min 105.31 in 20 min
MHCl 109.52 in 15 min 109.50 in 15 min

The in vitro dissolution release study is considered as an showed that while keeping the standard concentrations of so-
important parameter in order to fulfill the criteria of fast dis- dium starch glycolate and crospovidone, the formulations
integration. The results for MHCl from FDT-1 to FDT-6 with sodium starch glycolate showed improved release mak-
showed that the drug release was not less than 80% within ing tablets more porous for water penetration [41].
45 min of study meeting the standard dissolution criteria [24]. Drug interaction study was carried out by applying DSC,
The drug released from all the formulations lied within stan- used to determine the chemical integrity of APIs and selected
dard criteria, i.e., not less than < 80% in 45 min whereas FDT- formulation (FDT-6) by changing temperature conditions.
4 and FDT-6 showed maximum drug release of 86.42% and DSC thermograms of both drugs and optimized formulation
80.05% within 15 min, respectively, while all other formula- showed no extra peak by varying temperature indicated no
tions showed drug release < 80% in same time. Hence, FDT-4 interaction between drugs and excipients and the formulation
and FDT-6 with MHCl as API, were selected as best formu- remains intact showing chemical integrity of drugs [18].
lations as FDTs. The in vitro dissolution results for formula- Drug interaction was also analyzed using FTIR spectropho-
tions with FP as API showed the drug release of not less than tometer to confirm the chemical interaction between APIs and
80% within 30 min, meeting the standard dissolution criteria excipients used in the study. FTIR spectra of both FP and
[40]. FDT-6 showed maximum drug release in the shortest MHCl and all six formulations showed similar functional groups.
period of time, i.e., 20 mins and rapid dissolution and hence, Hence, the APIs and excipients used to develop the formulations
is regarded as best formulation as FDT. The increase in dis- and found to be compatible in the present study.
solution rates can be attributed to formation of porous struc- Stability studies predict that whether or not our formulation
ture on the surface of tablet enhancing water penetration aided is efficient enough to meet the standard criteria to be
by the presence of disintegrants. This might have led to in- marketed. Results (Table 9) showed that selected formulation
creased wetting action, short disntegration time, and faster (i.e., FDT-6) was found stable after 6 months under acceler-
dissolution rates. It was also observed that with the increase ated stability study conditions of temperature and humidity.
of concentration of sodium starch glycolate in FDT-6 Release kinetics studies were conducted to detect and ana-
(Table 4) as compared to FDT-3, the dissolution rate increased lyze the quantitative and qualitative changes in the formula-
while decreasing the concentration of crospovidone in FDT-4 tions that may affect drug release and its activity [25]. Values
as compared to FDT-1 caused an increase in the dissolution of drug release were fit into various mathematical models to
rates. The usual concentration of sodium starch glycolate used observe the mechanism of release. The correlation coefficient
in tablet formulations prepared by direct compression is 2%– values were obtained for all the five models. The results of
8% while that of crospovidone is 2%–5%. The results also model-dependent approaches for MHCl and FP (Table 10 and

Table 10 Details of drug (MHCl)

release profile with the help of Formulation Zero-order First-order Higuchi model Hixson Korsmeyer-
model dependent methods kinetic model kinetic model Crowell model Peppas model

K∘ R2 K R2 K R2 K R2 K R2

FDT-1 2.808 0.750 0.060 0.832 15.284 0.883 0.016 0.845 11.927 0.889
FDT-2 4.476 0.865 0.089 0.807 19.119 0.848 0.024 0.830 8.837 0.883
FDT-3 5.573 0.881 0.123 0.928 21.798 0.955 0.032 0.937 17.391 0.959
FDT-4 7.530 0.925 0.176 0.978 25.970 0.989 0.046 0.995 20.854 0.993
FDT-5 5.914 0.821 0.156 0.994 23.40 0.996 0.041 0.996 26.238 0.997
FDT-6 7.777 0.947 0.184 0.955 26.732 0.988 0.047 0.973 19.427 0.997
 J Pharm Innov

Table 11 Details of drug (FP) re-

lease profile with the help of Formulation Zero-order First-order Higuchi model Hixson Crowell Korsmeyer-
model-dependent methods kinetic model kinetic model model Peppas model

K∘ R2 K R2 K R2 K R2 K R2

FDT-1 4.417 0.627 0.152 0.948 21.201 0.963 0.048 0.935 32.66 0.990
FDT-2 4.898 0.525 0.168 0.965 21.803 0.927 0.044 0.931 42.56 0.996
FDT-3 4.915 0.620 0.157 0.984 21.773 0.961 0.041 0.961 35.95 0.998
FDT-4 4.870 0.631 0.149 0.969 21.550 0.958 0.038 0.946 34.90 0.990
FDT-5 4.239 0.573 0.138 0.963 20.416 0.947 0.035 0.945 33.41 0.983
FDT-6 6.159 0.734 0.191 0.980 24.541 0.979 0.048 0.969 35.78 0.997

Table 11) showed that all the formulations followed specifically the geriatrics, pediatrics, mentally ill, and those
Korsmeyer-Peppas model indicated that the drug has been suffering with acute conditions like nausea, vomiting, and
released from modified release dosage form, i.e., FDT. dysphagia. To overcome these shortcomings, FDTs have been
The results (Table 12) of model-independent approaches chosen to be formulated in this present study to enhance pa-
for MHCl indicated that FDT-3, FDT-4, and FDT-5 passed tient compliance by oral administration of drug without the
the criteria of f1 factor (0–15) and f2 factor (50–100). FDT-4 use of water to get instant relief.
showed the least f1 factor (7.82) and highest f2 factor (56.72). It is concluded from the present research study that the six
Hence, FDT-4 showed least difference and greater similarity formulations as FDTs of FP/MHCl in combination have been
against selected formulation (FDT-6). Whereas the results successfully prepared using sodium starch glycolate,
(Table 12) for FP indicated that all formulations passed criteria croscarmellose sodium, and crospovidone as superdisintegrants.
for model independent approach. FDT-3 showed the least f1 On evaluating all the six prepared formulations by performing
factor (6.13) and the highest f2 factor (59.00) indicating that different tests, it has been determined and observed that FDT-6
the said formulation has least difference and greater similarity was the best and stable among all prepared formulations even to
with selected formulation (FDT-6). select for stability studies and release kinetics studies because
Statistical analysis of dissolution profile data for MHCl and FDT-6 showed maximum drug release in the shortest period of
FP showed that F value was greater than F critical value in time. This research study proved to formulate FDTs of FP/MHCl
both cases (i.e., MHCl: F = 0.484, Fcrit = 2.438, FP: F = 0.028, to increase the dissolution rate in less time and to be used in the
Fcrit = 2.477). Therefore, there was a significant difference in treatment of emesis associated with painful conditions that ulti-
drug release from all formulations. Hence, our null hypothesis mately enhance patient compliance. Yet there are still some as-
(all the prepared formulations were dissolved) was correct and pects that can be studied in the future like in-vivo studies including
accepted while alternate hypothesis (all the prepared formula- pharmacokinetics, pharmacodynamics aspects, NMR study, and
tions were not dissolved) was rejected as the p value was comparison of formulated FDTs of FP/MHCl with single FDT of
greater than 0.05 and F-critical value was greater than F value. MHCl and FP.

Acknowledgments The authors are thankful to Shaigan Pharmaceuticals

Pvt. Ltd. Rawalpindi, Pakistan for providing Metoclopramide HCl
Conclusion (MHCl), crospovidone, croscarmellose sodium, and sodium starch
glycolate as gift samples.
Oral drug delivery is the most desirable and convenient ap- The authors gratefully acknowledge the help of Saba Sohail, Quaid-i-
proach for drug administration for patients but many people or Azam University, Islamabad, Pakistan for differential scanning calorimet-
ric analysis of samples.
patients express difficulty while oral administration

Table 12 Details of model-

independent approach Factor FDT-1 vs FDT-6 FDT-2 vs FDT-6 FDT-3 vs FDT-6 FDT-4 vs FDT-6 FDT-5 vs FDT-6

MHCl
F1 31.25 16.82 12.08 7.82 8.49
F2 22.49 30.22 44.35 56.72 52.80
FP
F1 9.01 6.41 6.13 6.97 8.68
F2 53.54 59.36 59.00 57.12 53.27
J Pharm Innov

Table 13 Results of statistical

analysis Source of Sum of Degree of Mean F P F critical
variation squares freedom squares value value

MHCl in 0.1 N HCl

Between groups 3418.44 5 683.69 0.484 0.786 2.438
Within groups 59,290.24 42 1411.67
Total 62,708.68 47
FP in pH 6.8 buffer
Between groups 188.05 5 37.61 0.028 1.00 2.477
Within groups 47,706.79 36 1325.19
Total 47,894.84 41

Author’s Contribution All authors contributed to the study conception 12. Wikipedia. Chemoreceptor trigger zone: Wikipedia. https://en.
and design. The experimental work and analysis were performed by wikipedia.org/wiki/Chemoreceptor_trigger_zone. Accessed 14
Maria Mushtaq. The first draft of the manuscript was written by Maria Apr 2020.
Mushtaq. 13. Vanderah TW. Pathophysiology of pain. Med Clin North Am.
Nosheen Fazal and Amna Niaz commented on previous versions of 2007;91(1):1–12.
the manuscript. All authors read and approved the final manuscript. 14. Shirsand S, Suresh S, Swamy P, Para M, Kumar DN. Formulation
design of fast disintegrating tablets using disintegrant blends. Indian
Compliance with Ethical Standards J Pharm Sci. 2010;72(1):130–3.
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Conflict of Interest The authors declare that they have no conflict of
Pharm Sci. 2008;70(4):526–8.
interest.
16. Bhardwaj S, Jain V, Jat R, Mangal A, Jain S. Formulation and
evaluation of fast dissolving tablet of aceclofenac. Int J Drug
Deliv. 2010;2(1):93–7.
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