Journal of Drug Delivery Science and Technology 88 (2023) 104980

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Journal of Drug Delivery Science and Technology

journal homepage: www.elsevier.com/locate/jddst

Development and characterization of trimethobenzamide hydrochloride

containing orally disintegrating tablets
Ozge Didem Uluhan, Tugba Gulsun, Selma Sahin *
Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 06100, Ankara, Türkiye

A R T I C L E I N F O A B S T R A C T

Keywords: Orally disintegrating tablets have been developed to rapidly disintegrate in saliva within seconds after admin­
Direct compression istration, without the need for drinking water or any specific administration conditions. Therefore, they are more
Freeze drying suitable dosage forms than conventional tablets for use in patients with swallowing difficulties or neurological
Ludiflash®
diseases, pediatric and geriatric patients. Nausea and vomiting are diseases that are common in the clinic and
Orally disintegrating tablet
Parteck®
limit the daily life of the patients. Trimethobenzamide hydrochloride is an antiemetic drug widely used in the
Trimethobenzamide hydrochloride acute treatment of nausea and vomiting. In this study, orally disintegrating tablet formulations of trimetho­
benzamide hydrochloride were developed using direct compression and freeze-drying techniques. Physico­
chemical characterization studies were carried out on the developed formulations. All formulations except F4,
F8, F11 and F12 were disintegrated within 3 min in both distilled water and simulated saliva (pH 6.8).
Permeability studies across Caco-2 cell lines proved that excipients used in the formulations increased the
permeability of trimethobenzamide hydrochloride. Based on the results, it can be concluded that, trimetho­
benzamide hydrochloride containing orally disintegrating tablets may be beneficial in patients where rapid onset
of action is required.

form suspension that can be easily swallowed by the patients. The drug
in suspension can be quickly absorbed through the pregastric epithelium
1. Introduction and/or gastrointestinal epithelium, thus desired effect is produced in a
shorter time compared to the other solid dosage forms [8]. Besides ease
Oral drug administration is the safest, most convenient and economic of use, ODTs have many clinical advantages over other solid dosage
route with the highest patient compliance. Although capsules and tab­ forms such as accelerated drug absorption, rapid onset of action,
lets are commonly used solid dosage forms, they still have some limi­ increased bioavailability with reduced dose and therefore, decreased
tations such as difficulty in swallowing and choking especially when side effects [9,10]. Moreover, ODTs may be useful for patients with
used by pediatric, geriatric, or patients with mental disorders [1]. Orally severe nausea from motion sickness and for those who do not have easy
disintegrating tablets (ODTs) have been developed to improve patient access to water, such as travelers [11].
compliance for such patients [2,3]. In the literature, ODTs are also Nausea and vomiting are common physiological responses to various
termed as orodispersible, orodispersing, rapidly disintegrating, rapidly stimuli such as infection, secondary disease, medications, chemo­
dissolving, fast disintegrating, fast dissolving, fast dispersing, fast therapy, pregnancy, toxins, operation, or motion sickness and limit the
melting, mouth-dissolving, melt-in-mouth tablets [4,5]. According to daily life of patients [12]. The emetic center that coordinates nausea and
European Pharmacopeia (EP), ODTs are defined as “uncoated tablets vomiting reflex is located in the medulla and receives all afferent inputs
intended to be placed in the mouth where they disperse rapidly before from different origins (chemoreceptor trigger zone, the cortex, the
being swallowed” and tablets should disintegrate within 3 min [6]. vestibular apparatus and the gastrointestinal tract) and then sends to the
United States Food and Drug Administration (FDA) defines ODTs as “a salivation center, abdominal muscles, respiratory center and cranial
solid dosage form containing medicinal substances which disintegrate nerves to cause vomiting to occur [13]. Antiemetic drugs usually aim to
rapidly, usually within a matter of seconds, when placed upon the antagonize receptors that stimulate an emetic response, such as sero­
tongue” [7]. tonin (5-HT3), histaminic (H1), dopaminic (D2), muscarinic and
ODTs are rapidly dispersed in saliva when placed on the tongue and

* Corresponding author.
E-mail address: [email protected] (S. Sahin).

https://doi.org/10.1016/j.jddst.2023.104980
Received 11 April 2023; Received in revised form 6 September 2023; Accepted 19 September 2023
Available online 19 September 2023
1773-2247/© 2023 Elsevier B.V. All rights reserved.
O.D. Uluhan et al. Journal of Drug Delivery Science and Technology 88 (2023) 104980

superdisintegrants (Ludiflash® and Parteck®) and disintegrants (cro­

Abbreviations scarmellose sodium and sodium starch glycolate) in different concen­
trations, and freeze-drying technique using gelatin as matrix former/
BCS Biopharmaceutics Classification System binder in 2 different concentrations. Physicochemical characterization
DMEM Dulbecco’s Modified Eagle’s Medium studies were performed on powder mixtures of direct compression for­
DSC Differential scanning calorimetry mulations, while physicochemical characterization of tablets was per­
EP European Pharmacopeia formed for both directly compressed and freeze-dried ODTs. In addition,
FDA United States Food and Drug Administration the potential effects of the excipients used in ODT formulations on the
FT-IR Fourier-transform infrared spectroscopy permeability of TMB were determined using Caco-2 cell lines.
HBSS Hank’s Balanced Salt Solution
HEPES Hydroxyethyl piperazine ethanesulfonic acid 2. Materials and methods
HPMC Hydroxypropylmethylcellulose
LOD Limit of detection 2.1. Materials
LOQ Limit of quantification
ODT Orally disintegrating tablet Trimethobenzamide hydrochloride was a generous gift from Kurtsan
PEG Polyethylene glycol Group Companies (Türkiye). Ludiflash® and Parteck® were purchased
SD Standard deviation from BASF (Germany) and Merck (Germany), respectively. Hydrox­
SEM Scanning electron microscopy ypropylmethylcellulose (HPMC), gelatin, Pluronic F68®, polyethylene
TEER Transepithelial electrical resistance glycol (PEG) 4000, simethicone, sodium alginate were all obtained from
TMB Trimethobenzamide hydrochloride Sigma (USA) and colloidal silicon dioxide (Aerosil®) from Avonik
USP United State Pharmacopeia (Singapore). Croscarmellose sodium (Ac-Di-Sol®) was purchased from
UV Ultraviole DFE Pharma (Germany) and mannitol (Pearlitol 200 SD®) from
XRD X-Ray diffraction Roquette Freres (France). Sodium starch glycolate was kindly provided
by Atabay (Türkiye). The orange flavor was obtained from Aromsa
(Türkiye). Spray dried lactose monohydrate, sodium stearyl fumarate,
acesulfame potassium were generously provided by İlko Pharmaceuti­
neurokinin-receptor (NK1). Therefore, antiemetic drugs are usually
cals (Türkiye). Caco-2 cells were purchased from ATCC (USA). Dulbec­
classified as 5-HT3 receptor antagonists (e.g. ondansetron, granisetron),
co’s Modified Eagle’s Medium (DMEM), Hank’s Balanced Salt Solution
D2 receptor antagonists (e.g. metoclopramide, chlorpromazine, halo­
(HBSS), hydroxyethyl piperazine ethanesulfonic acid (HEPES) were
peridol), H1 receptor antagonists (e.g. cyclizine, diphenhydramine),
purchased from Biochrom AG (Germany) and fetal bovine serum (FBS)
anticholinergic (antimuscarinic) drugs (e.g. scopolamine) and NK1 re­
from Cegrogen (Germany). Penicillin-streptomycin solution and cell-
ceptor antagonists (substance P antagonists) (e.g. aprepitant) [14].
culture inserts (ThincertsTM; 1 μm), were purchased from Life Tech­
Trimethobenzamide hydrochloride (TMB) is an antiemetic drug
nologies, Inc. (USA) and Greiner Bio-one (Germany), respectively. All
commonly used for the treatment of nausea and vomiting induced by
other chemicals were of analytical grade and used as received.
medications, radiation, infection, gastroenteritis, motion sickness and
also postoperative vomiting. Although its mechanism of action has not
been clarified yet, it has been reported to have an antiemetic effect on 2.2. Methods
dopamine and serotonin receptors in the chemoreceptor trigger zone
and medulla [15]. The relative bioavailability of the TMB capsule 2.2.1. Preparation of ODT formulations
dosage form compared to the oral solution is 100%. Following intra­
muscular (200 mg) and oral (300 mg capsule) administration, the time 2.2.1.1. Selection of excipients. Direct compression and freeze-drying
(tmax) to reach maximum plasma concentration (Cmax) is 30 and 45 min, techniques were used for the manufacturing of TMB containing ODTs.
respectively. The plasma concentration-time profile was reported to be For ODTs prepared with direct compression technique, two types of
similar in both administrations. The elimination half-life of TMB after ready-to-use commercial excipients (Ludiflash® and Parteck®), cro­
oral administration is 7–9 h [16]. TMB is mainly metabolized by the scarmellose sodium (Ac-Di-Sol®) and sodium starch glycolate were used
liver [15]. 30–50% of the administered dose is excreted unchanged in as disintegrants, spray dried lactose monohydrate (Lactopress®) and
the urine 48–72 h after administration [17]. Recommended doses of mannitol (Pearlitol 200 SD®) as filler, sodium stearyl fumarate as a
TMB are 250–300 mg for oral administration, 200 mg for intramuscular lubricant, colloidal silicon dioxide (Aerosil®) as a glidant, acesulfame
injection and 200 mg for rectal administration 3–4 times daily [18]. potassium as a sweetener agent and orange flavor as a flavoring agent.
Although various pharmaceutical dosage forms (e.g. capsules, tablets, Gelatin is used as a matrix former/binder, sodium alginate and
suppositories, intramuscular injection, intravenous injection and oral HPMC as a binder, mannitol (Pearlitol 200 SD®) as a filler, PEG 4000
drops) of TMB are commercially available, to our knowledge, there are and Pluronic F68® as disintegration enhancer and simethicone as an
no commercially available ODT formulations containing TMB. Accord­ antifoaming agent for ODTs prepared by freeze-drying technique.
ing to literature search, there is only one published conference abstract
regarding ODT formulations of TMB. In this abstract, ODT was prepared 2.2.1.2. Preparation of trimethobenzamide hydrochloride-based ODTs by
by the wet granulation method using crospovidone as the super­ direct compression technique. Different ODT formulations containing
disintegrant [19]. Our study differs from this conference abstract in 200 mg TMB were developed and prepared by direct compression
regard to superdisintegrants we used (croscarmellose sodium and so­ technique using different types and amounts of the superdisintegrants
dium starch glycolate) and the preparation methods (direct compression (Ludiflash® and Parteck®) and disintegrants (Ac-Di-Sol® and sodium
and freeze-drying methods). In addition, a part of our study was pre­ starch glycolate) (Table 1). Initially sweetening and flavoring agents
sented as a poster presentation at the 19th International Pharmaceutical (mixture A); superdisintegrants and disintegrants (mixture B) were
Technology Symposium (IPTS-19) in 2018 confirming that our study has mixed separately using a roller mixer. Then mixture A and B were
novelty [20]. blended and fillers were added to this mixture (mixture C). TMB was
In this study, to improve quality of life and patient compliance for the added to mixture C (mixture D). Meanwhile, glidant and lubricant were
treatment of nausea and vomiting, ODT formulations containing TMB mixed (mixture E) and then mixture D was blended with mixture E to
were developed for direct compression method using 2 ready-to-use obtain the final blend. All mixing steps were performed progressively for

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O.D. Uluhan et al. Journal of Drug Delivery Science and Technology 88 (2023) 104980

Table 1
Composition of developed ODT formulations.
Material Function Amount (mg)

F1a F2a F3a F4a F5a F6a F7a F8a F9a F10a F11a F12a F13b F14b

TMB Active substance 200 200 200 200 200 200 200 200 200 200 200 200 200 200
Ludiflash® Superdisintegrant 200 212.5 200 212.5 – – – – – – – – – –
Parteck® Superdisintegrant – – – – 200 212.5 200 212.5 – – – – – –
Sodium starch glycolate Disintegrant – – – – – – – – 25 37.5 25 37.5 – –
Ac-Di-Sol® Disintegrant 60 60 30 30 60 60 30 30 60 60 30 30 – –
Lactopress® Filler 25 12.5 55 42.5 25 12.5 55 42.5 25 12.5 55 42.5 – –
Pearlitol 200 SD® Filler – – – – – – – – 175 175 175 175 264 254
Sodium stearyl fumarate Lubricant 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 – –
Aerosil® Glidant 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 – –
Acesulfame potassium Sweetener 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 – –
Orange flavor Flavoring agent 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 – –
Gelatin Matrix former/binder – – – – – – – – – – – – 10 20
Sodium alginate Binder – – – – – – – – – – – – 0.5 0.5
PEG 4000 Disintegration enhancer – – – – – – – – – – – – 7.5 7.5
Pluronic F68® Disintegration enhancer – – – – – – – – – – – – 7.5 7.5
HPMC Binder – – – – – – – – – – – – 10 10
Simethicone Antifoaming agent – – – – – – – – – – – – 0.5 0.5

Total tablet weight (mg) 500 500 500 500 500 500 500 500 500 500 500 500 500 500
a
Formulations developed by direct compression technique.
b
Formulations developed by freeze-drying technique.

3–5 min until a homogenous mixture was obtained. After powder ana­ obtained by heating at a rate of 10 ◦ C/min (10–250 ◦ C) under nitrogen
lyses were performed, final blends were directly compressed using gas (50 ml/min).
Erweka AR 400 Korsch (Germany) to obtain 500 mg of TMB ODTs.
2.2.2.5. Ultraviolet (UV) spectrum. UV spectrum of TMB was recorded
2.2.1.3. Preparation of trimethobenzamide hydrochloride containing ODTs in distilled water between 200 and 800 nm wavelengths and the
by freeze-drying technique. Different ODT formulations were developed wavelength where maximum absorbance (λmax) was obtained, was
using different amounts of binder (gelatin) and filler (mannitol) and reported.
manufactured by freeze-drying technique (Table 1). Gelatin was swollen
with pre-heated (40–50 ◦ C) distilled water (5 ml). Afterwards, sodium 2.2.3. Determination of physical properties of the powder mixtures for
alginate, Pearlitol 200 SD®, PEG 4000, Pluronic F68® and HPMC were direct compression
added one by one to the gelatin-water mixture with continuous stirring
on the magnetic stirrer. After adding distilled water (45.5 ml) and 2.2.3.1. Powder flow and angle of repose. According to the United State
simethicone, the mixture was stirred until a final homogenous solution Pharmacopeia (USP) <1174> Powder Flow monograph, a closed-ended
was obtained. A sufficient volume of solution (0.65 ml) was transferred glass funnel with suitable dimensions was fixed in place and 50 g of each
into each blister well and then frozen at − 20 ◦ C overnight. Frozen powder blend was filled into the funnel. The closed end of the funnel was
blisters were then freeze-dried for 24 h (− 55 ◦ C and 0.44 mbar) using a opened and the powder blend was allowed to flow to obtain a cone-
freeze-drier (Labconco-USA). shaped powder pile. The height (h) and radius (r) of the cone-shaped
powder were measured and the angle of repose was calculated using
2.2.2. Characterization of TMB and ODT formulations Eq. (1) [21]. Analysis was repeated three times and the results were
reported as the mean ± standard deviation (SD).
2.2.2.1. Fourier-transform infrared spectroscopy (FT-IR). To determine
tan α = h/0.5r (Eq. 1)
the potential interaction between TMB and the excipients used in the
formulations, the FT-IR spectrum of TMB, excipients and one crushed
tablet of each formulation were recorded between 600 and 4000 cm-1 2.2.3.2. Bulk density and tapped density. According to the USP <616>
using Perkin Elmer FT-IR (USA). Bulk Density and Tapped Density of Powders monograph, 50 g of each
powder blend was filled into the graduated cylinder of the apparatus
(Aymes Company, Türkiye). Bulk volume (V0; ml) and tapped volumes
2.2.2.2. X-Ray diffraction (XRD) analysis. XRD analyses were per­
after 10, 500, 1250 and 2500 taps were measured. Bulk density and
formed on TMB and the selected ODT formulations (F2, F5, F9 and F13)
tapped density were then calculated using Eq. (2) and Eq. (3) respec­
a using Rigaku X-ray Diffractometer (Japan) at 40 kV/30 mA with a
tively [22]. Analysis was repeated three times and the results of the bulk
0.02◦ /min scanning rate at 2θ angle between 4◦ and 40◦ .
volume (V0; ml) and final volume (V2500; ml) which is volume after 2500
taps were reported as mean ± SD.
2.2.2.3. Scanning electron microscopy (SEM). The surface morphology
of TMB and the selected ODT formulations (F2, F5, F9 and F13) were Pb = m/V0 (Eq. 2)
examined after coating with a gold sputter and SEM micrographs (x
2000 and 5000 fold) were obtained using scanning electron microscopy where Pb is bulk density (g/ml), m is the weight of blend (g), V0 is un­
(Jeol SEM-6400, Japan). settled apparent volume.
Tapped density (g / ml) = m/V2500 (Eq.3)
2.2.2.4. Differential scanning calorimetry (DSC) analysis. Differential
scanning calorimetry analyses were performed to measure the thermal where m is the weight of blend (g), V2500 is tapped volume (ml) after
properties of TMB and a crushed tablet of selected ODT formulations 2500 taps.
(F2, F5, F9 and F13) using a DSC Q100 (TA Instruments, USA). Samples
(5 mg) were placed in an aluminum pan and DSC thermograms were

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O.D. Uluhan et al. Journal of Drug Delivery Science and Technology 88 (2023) 104980

2.2.3.3. Compressibility index and hausner ratio. Compressibility index

R = 100 (Wa − Wb ) / Wb (Eq. 7)
and Hausner ratio were calculated using bulk volume (V0;ml) and tap­
ped volume after 2500 taps (V2500; ml) using Eq. (4) and Eq. (5),
respectively [21,22]. 2.2.4.6. Dissolution study. Dissolution studies were carried out in 900
ml distilled water (37 ± 0.5 ◦ C) for 45 min using Sotax CH 4123
Compressibility index = ((V0 − V2500 ) x 100) / V0 (Eq. 4) (Switzerland) dissolution apparatus according to the USP Trimetho­
benzamide Hydrochloride Capsules monograph. USP Apparatus II
Hausner ratio = V0 /V2500 (Eq. 5) (paddle, 50 rpm) was used for dissolution studies of the ODTs [27,28].
Samples (5 ml) were removed at predetermined time intervals (1, 3, 4, 5,
2.2.3.4. Moisture content. The moisture content of a powder blend (3 g) 10, 15, 30, 45 min) and then replaced with 5 ml of distilled water to keep
was determined by heating at 105 ◦ C using a moisture analyzer (Ohaus the volume constant. Samples were filtered through a 0.45 μm syringe
Corporation, USA) for 10 min until powder weight was constant. The filter and then analyzed using a UV spectrophotometer (Shimadzu 1800)
results were reported as percent (%). at 259 nm wavelength.

2.2.4. Physicochemical characterization studies of developed ODTs 2.2.4.7. Porosity analysis. Porosity analyses were performed on the
Thickness, diameter and hardness, weight uniformity, friability, selected ODTs (F2, F5, F9 and F13) using Quantachrome Corporation,
disintegration, water absorption ratio, dissolution tests were performed Poremaster 60 Mercury Porosimeter (Germany) under low pressure (up
on all ODT formulations to determine the physicochemical properties of to 50 psi). Porosity results (%) of ODTs were compared with each other.
the ODTs developed by direct compression and freeze-drying tech­
niques. Based on the results obtained from these analyses, one ODT 2.2.5. Determination of TMB permeability across Caco-2 cells
formulation with the best analysis results was selected from each TMB permeability and potential effects of excipients used in ODT
formulation group, and porosity, SEM, XRD and DSC analyses were formulations on TBS permeability were investigated using Caco-2 cells.
performed. Caco-2 cells (passage number: 24–30) suspended in DMEM supple­
mented with 10% of FBS, 50 units/ml of penicillin and 50 μg/ml of
2.2.4.1. Determination of thickness, diameter and hardness of ODTs. streptomycin, were seeded on a 12-well-plate (0.4 μm; ThinCertsTM) at
Tablets were selected randomly to determine thickness, diameter (mm, a density of 100.000 cells/well and incubated in an incubator (Sanyo,
n = 20) and hardness (N, n = 10) using a Pharma test PTB (Germany) Osaka, Japan) under 5% CO2 atmosphere at 37 ◦ C. The medium was
apparatus. Results were reported as mean ± SD. refreshed every 2 days for 21 day. After 21 day, transepithelial electrical
resistance (TEER) values of Caco-2 cells were measured using Millicell-
2.2.4.2. Weight uniformity. According to EP 11.0–2.9.5. Uniformity of ERS-2 Epitel voltohmmeter (USA). The cells with TEER ≥400 Ω cm2
Mass of Single-Dose Preparations monograph, weight uniformity anal­ were used for permeability studies. Hank’s Balanced Salt Solution
ysis were performed on each ODT as ODTs weighed more than 250 mg (HBSS) containing 25 mM of D-glucose and 10 mM of HEPES was used as
[23]. Twenty tablets were selected randomly and weighed individually. the transport buffer. After crushing ODTs, a sufficient amount of powder
The mean weight and 5% deviation were calculated and the results were (containing 9.56 mg of TMB) or 9.56 mg of raw TMB were dissolved with
evaluated according to the limits given in the EP monograph [23]. transport buffer to obtain 20 μM TMB concentration. A transport buffer
containing TMB (20 μM, 500 μl) was added to the apical side and a blank
2.2.4.3. Friability test. Friability tests were performed according to the transport buffer (1000 μl) to the basolateral side. After 2 h of incubation
EP 11.0–2.9.7 Friability of Uncoated Tablets monograph. Randomly on a horizontal shaker at 37 ◦ C and 50–60 rpm, samples (200 μl) were
selected and accurately weighted (W0; g) twenty tablets were placed into collected from the basolateral side and then analyzed using a UV spec­
the drum of the friability test apparatus (Pharma test PTB, Germany) and trophotometer at 259 nm. The apparent permeability (Papp, cm/s) was
rotated at 25 rpm/min for 4 min (100 rotation). Then, tablets were de- calculated using Eq. (8).
dusted gently and accurately weighed again (W1; g). Weight loss (%) of /
Papp = (Vb Cb ) (C0 AT) (Eq. 8)
tablets due to abrasion was calculated using Eq. (6). The maximum
weight loss should be not greater than 1.0% according to the EP
where Papp: apparent permeability (cm/s); Vb: volume of basolateral side
monograph [24].
(cm3); Cb: drug concentration on the basolateral side; C0: initial drug
Friability % = ((W0 − W1 ) x 100) / W0 (Eq. 6) concentration on the apical side; A: surface area of insert (1.13 cm2); and
T: time period of the experiment (s).
2.2.4.4. Disintegration study. In vitro disintegration time of ODTs was
determined in 1000 ml distilled water and simulated saliva medium (pH 2.2.6. Assay
6.8) at 37 ± 2 ◦ C separately using Pharma test PTB (Germany) disinte­ Analysis of TMB in obtained samples was performed using two
gration apparatus. Simulated saliva medium was prepared using sodium different UV spectroscopic methods. Method-I was used for the deter­
chloride (8 g/l), potassium phosphate monobasic (0.19 g/l) and sodium mination of TMB in dissolution samples and Method-II was used for the
phosphate dibasic (2.38 g/l) [25]. According to the EP 11.0–2.9.1. The analysis of TMB in permeability samples. Distilled water and transport
Disintegration of Tablets and Capsules monograph, after placing one buffer (HBSS containing 25 mM of D-glucose and 10 mM of HEPES) were
tablet in each tube of the apparatus, apparatus was operated and com­ used as the medium for Method-I and Method-II, respectively. Analysis
plete disintegration time of six tablets was recorded. ODTs should be was performed at 259 nm maximum wavelength for both methods. Both
disintegrated within 3 min in the specified medium according to the EP methods were validated as to linearity, accuracy, precision, specificity,
monograph [26]. the limit of detection (LOD), the limit of quantification (LOQ) and sta­
bility parameters according to the ICH Q2(R1) CPMP/ICH/381/95
2.2.4.5. Water absorption ratio. A tissue paper (10 cm) was placed into guidance [29].
the Petri dish (10 cm) and wetted with distilled water (5 ml) or simu­
lated saliva medium (pH 6.8, 5 ml). Randomly selected ODTs (n = 6) 2.2.7. Statistical analysis
were pre-weighed (Wb) and gently placed on the tissue paper. ODTs Statistical analyses were performed using GraphPad Prism 8.2.0.
were re-weighed (Wa) after completely wetted and the water absorption Kruskal Wallis and Mann-Whitney U tests were used for statistical
ratio (R) was calculated using Eq. (7). evaluation of the results (diameter, thickness, hardness, wetting time

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O.D. Uluhan et al. Journal of Drug Delivery Science and Technology 88 (2023) 104980

and water absorption ratio and permeability analyses) obtained for ODT the powder flow [46]. Therefore, colloidal silicon dioxide was selected
formulations prepared by direct compression and freeze-drying tech­ as the glidant added at 0.5% concentration before tabletting to enhance
niques, respectively. The 95% confidence interval was determined. p < powder flow and obtain a more uniform powder mixture [46].
0.05 was considered statistically significant. Sweeteners and flavorings are commonly added to ODT formulations
to improve the taste of the tablets after disintegration in the mouth and
3. Results and discussion ultimately increase patient compliance. Known for its favorable flow
properties, acesulfame potassium requires less quantity (<5%) to ach­
3.1. Selection of excipients ieve the desired tablet taste compared to other sweeteners. Considering
the literature, it was decided to use acesulfame potassium at 0.5%
3.1.1. Direct compression technique concentration as a sweetener in our study. Additionally, orange flavor
Superdisintegrants and disintegrants have a positive effect on the was included at the same concentration as a flavoring agent to further
disintegration of tablets at low concentrations without any adverse ef­ enhance the taste of ODTs.
fect on tablet mechanical strength. In this study, Ludiflash® and Par­
teck® were selected as ready-to-use superdisintegrants and 3.1.2. Freeze-drying technique
croscarmellose sodium and sodium starch glycolate as disintegrants for Binders are used to improve tablet integrity during the freeze-drying
preparation of ODTs by direct compression technique. Ludiflash® and process and achieve sufficient mechanical strength and tablet hardness.
Parteck® facilitate tablet compressibility due to good flowability. Also, The type and concentration of the binder affect not only the tablet
ODTs containing these superdisintegrants have good tablet strength, hardness but also the disintegration and dissolution of the formulations.
short disintegration and wetting time [30,31]. Both Ludiflash® and Gelatin, alginates, maltodextrin, methylcellulose are widely preferred
Parteck® are frequently used in formulation developments in concen­ binders in ODTs. These matrix-forming binders increase tablet porosity
trations of 10–60% [32–34]. It is recommended that Ludiflash® be used and cause easy disintegration [48–50].
in formulations more than 38% to accelerate disintegration and less than In the literature, it is stated that the addition of gelatin at concen­
42% to increase mechanical strength [35]. Based on these information, trations of 20–50 mg/g can increase the hardness of freeze-dried ODT
it was decided to use Ludiflash® and Parteck® at two different levels formulations and also reduce the disintegration time [48]. The recom­
(40% or 42.5%) in the our formulations. mended gelatin concentration in freeze-dried ODT formulations is usu­
The crosslinked polymers such as carboxymethyl cellulose, cro­ ally between 2% and 5% [51,52]. Consistent with these findings, gelatin
scarmellose sodium and sodium starch glycolate, have high water ab­ was used at 2% and 4% concentrations as a binder in our study. We also
sorption and swelling capacities. According to the literature, both investigated the use of additional binders to increase the mechanical
disintegrants have a better effect on tablet disintegration and dissolution strength of freeze-dried ODT formulations. In addition to gelatin, HPMC
at 5% concentration than other disintegrants [36,37]. (2%) and sodium alginate (0.1%) were chosen as alternative binders.
It is recommended to use sodium starch glycolate at concentrations This selection was aimed at optimizing the overall mechanical integrity
between 2% and 8%, with the optimum concentrations between 6% and of freeze-dried ODT formulations.
8% [38,39]. In the presence of sodium starch glycolate, disintegration of In the literature, it has been reported that the tablet disintegration
tablets occurs due to rapid water uptake followed by rapid and emor­ time increases as a result of the increase in hardness with high binder
mous swelling. In our study, we investigated the effect of sodium starch concentration in the formulation. Therefore, in the ODT formulation, it
glycolate on disintegration at two concentration levels (5% and 7.5%), is recommended to add the filler in addition to the binder to reduce
considering the literature. disintegration time and achieve appropriate mechanical tablet strength
In our ODT formulations, we used two concentrations of cro­ [48]. For this purpose, Pearlitol 200 SD® was selected as the filler
scarmellose sodium (Ac-Di-Sol®) (6% and 12%) to evaluate its effect on (50.8% and 52.8%) for freeze-dried ODT formulations to obtain the
the disintegration. The concentration selection was based on the liter­ desired total tablet weight.
ature recommended concentration (0.5–12%) of this disintegrating Hydrophilic biopolymers such as PEG, polyvinylpyrrolidone improve
agent [40–43]. disintegration and dissolution of freeze-dried ODTs. PEG 4000 decreases
Fillers are commonly used in ODTs to achieve predetermined total disintegration time and increases dissolution by increasing tablet surface
tablet weight. For this purpose, spray dried lactose monohydrate and [53]. Additionally, poloxamers are known to be useful for improving
mannitol (Pearlitol 200 SD®) were chosen as fillers in our formulations. tablet disintegration and dissolution due to gel matrix formation [54,
Although different concentrations (2.5–11%) of spray dried lactose 55]. It is stated in the literature that the use of PEG 4000 at concen­
monohydrate (Lactopress®) were used in different formulation, fixed trations above 5% prolongs the disintegration time of the tablets,
amount (35%) of mannitol (Pearlitol 200 SD®) was selected to achieve therefore, in our study, PEG 4000 was used at a concentration of 1.5%.
the required total tablet weight. Pluronic F68® and PEG 4000 were also added to our freeze-dried for­
Lubricants help compact the tablet compression by minimizing mulations as disintegration enhancers. Poloxamers, such as Pluronic
friction between punches and tablets. When using Ludiflash® and Par­ F68® are often used to form a gel-matrix, accelarate both disintegration
teck® as superdisintegrant, it is recommended to use sodium stearyl and dissolution of ODT formulations [54,55]. In accordance with the
fumarate and magnesium stearate at a concentration of 0.5–2.0%. In literature, the Pluronic F68® concentration was adjusted to 1.5% in our
addition, it was reported that the disintegration time was shorter in the freeze-dried ODT formulations [55].
formulation using sodium stearyl fumarate as a lubricant compared to During the freeze-drying process, air bubbles and foaming in the
magnesium stearate [30]. Sodium stearyl fumarate is known to have less aqueous solution should be prevented to obtain a homogenous solution
negative effects on tablet strength and disintegration than magnesium and sufficient tablet mechanical strength. For this purpose, simethicone
stearate, so sodium stearyl fumarate was used as a lubricant in our ODT at a concentration of 0.1% was used in the formulations.
formulations (1.5%) [44,45].
Powder homogenity and optimal powder flow are important pa­ 3.2. Characterization of TMB and ODT formulations
rameters to ensure that each tablet contains the amount of active
ingredient specified in the formulations. Glidants are an integral part of 3.2.1. Fourier-transform infrared spectroscopy (FT-IR) spectrum
the ODTs to enhance powder homogeneity [46]. Colloidal silicon di­ FT-IR analysis is utilized to identify the chemical structure of the
oxide (Aerosil®) is one of the glidants often used for this purpose at ratio drug substances. The intermolecular bond is characterized based on the
of 0.1%–0.5% in ODTs [47]. However, the available literature suggests measurements of radiation frequencies absorbed by the molecules and
that colloidal silicon dioxide exceeding 0.5% does not further improve vibration produced as a result of absorbed radiation [56,57]. In the

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O.D. Uluhan et al. Journal of Drug Delivery Science and Technology 88 (2023) 104980

FT-IR spectrum of TMB, N–H stretch appears at 3285.86 cm− 1; a tertiary behavior of the drug substance [60,62]. The crystalline nature of TMB is
amine stretch at 2443.58 cm− 1; an aromatic C– – O–N stretch at 1626.53 seen in the SEM micrographs of TMB (Fig. 4), supporting the XRD
cm− 1; an aromatic C– – C stretch at 1581.51 cm− 1; an aromatic C–C diffraction pattern.
stretch at 1464.03 cm− 1 and 2 adjacent hydrogens on phenyl ring at SEM analysis is a microscopic technique used to characterize the
846.43 cm− 1 (Fig. 1). Also, there is no impurity peak in the spectrum of particle morphology of the tablets. It gives useful information about the
TMB. All these indicate that the chemical structure of TMB agrees well porous structure of the tablets as well as the visible interactions between
with the literature [58]. Additionally, FT-IR analysis was performed on excipients and drugs used in the formulation [60,63]. SEM micrographs
the tablets to determine potential interactions between drugs and ex­ of selected ODT formulations (F2, F5, F9 and F13) and TMB revealed
cipients used in the formulations [59]. Comparison of the FT-IR spectra that the crystalline structure of TMB is observed in the micrographs of all
of excipients and selected ODT formulations (F2, F5, F9 and F13) with ODTs (Fig. 4). SEM micrographs demonstrated that F9 has a more tight
that of TMB clearly showed characteristic peaks of TMB in the spectra of porous structure than other formulations, and F13 has the most porous
ODTs (Fig. 2). All these demonstrate that the chemical structure of TMB structure. These results are consistent with the porosity values obtained
was conserved during the preparation of ODTs. from the porosity analysis (porosity value for F9: 45.62% and porosity
value for F13: 78.71%). These results also confirmed that the ODT for­
3.2.2. X-ray diffraction (XRD) analysis mulations prepared by freeze drying were more porous.
XRD analysis of tablets is useful for detecting chemical in­
compatibilities between the excipients used in the formulation, physical 3.2.4. Differential scanning calorimetry (DSC) analysis
interactions between drug and excipients, changes in amorphous/crys­ DSC analysis is a useful thermal analytical technique to obtain
talline structure and changes in polymorphism during the preparation of quantitative information about the thermal properties of the drug sub­
tablets [60,61]. XRD diffraction patterns of TMB and selected ODT stance by measuring energy differences between sample and reference
formulations (F2, F5, F9 and F13) were given in Fig. 3. Sharp peaks pan [60,64]. DSC thermogram of TMB shows that the endothermic
appearing at 2θ between 10◦ and 40◦ show the crystalline nature of TMB melting peak is at 185 ◦ C and the main sharp endothermic peak at
(Fig. 3). Also, XRD diffraction patterns of all ODTs have peaks that 188.86 ◦ C (Fig. 5) which is compatible with the literature [58]. DSC
belong to TMB, indicating the crystalline structure of TMB preserved analysis of tablets is performed to determine the interactions between
during preparation. drugs and excipients used in the formulations. Comparison of DSC
thermograms of selected ODT formulations (F2, F5, F9 and F13) with
3.2.3. Scanning electron microscopy (SEM) analysis that of TMB (Fig. 5) revealed that the main endothermic peak was
SEM analysis is used to determine the surface morphology without observed at around 140–150 ◦ C in the termograms of F2 and F5, how­
giving any information about the chemical structure or thermal ever, there was no peak specific to TMB at around 188 ◦ C. This result was

Fig. 1. FT-IR spectrum of TMB.

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O.D. Uluhan et al. Journal of Drug Delivery Science and Technology 88 (2023) 104980

Fig. 2. FT-IR spectrum of selected ODTs (F2, F5, F9 and F13).

Fig. 3. XRD diffraction pattern of TMB and selected ODT formulations (F2, F5, F9 and F13).

attributed to lactose monohydrate that gives an endothermic peak at attributed to lactose monohydrate as there is no endothermic peak was
140 ◦ C due to dehydration [65,66]. It is transformed to a crystalline observed for TMB. Similarly, no endothermic peak of TMB was observed
structure under high temperature and moisture conditions and decreases in the DSC thermogram of F9, possibly due to incompatibility with so­
the melting point of the powder [67,68]. Therefore, the endothermic dium starch glycolate [69,70]. Moreover, there were no endothermic
peaks observed in the DCS thermograms of F2 and F5 formulations were peaks observed in the thermogram of F13. PEG 4000 completely melts

7
O.D. Uluhan et al. Journal of Drug Delivery Science and Technology 88 (2023) 104980

Fig. 4. SEM micrographs of TMB selected ODT formulations (F2, F5, F9 and F13) at ×2000 and ×5000 magnifications.

Fig. 5. DSC thermograms of TMB and selected ODT formulations (F2, F5, F9 and F13).

during the DSC analysis, therefore, the drug substance was dissolved in 3.3. Physical properties of the powder mixtures for direct compression
the molten PEG 4000, and TMB peaks were not observed in the DSC
thermograms [71–74]. The absence of a peak in the DSC thermogram of 3.3.1. Powder flow
F13 was associated with melting of PEG 4000 due to heating of the tablet The flowability of powder is one of the most critical parameters
and dissolving the tablet in molten PEG 4000 during DSC analysis. during the tableting process in the pharmaceutical industry. Free flow­
Therefore, further studies using non-thermal methods are recommended ability of the powder ensures mixing homogeneity resulting in better
to confirm whether TMB is incompatible with lactose monohydrate, weight uniformity and easier tablet compressibility [75]. According to
sodium starch glycolate and PEG 4000. USP <1174> Powder Flow monograph, flow properties of powders with
a 25◦ –30◦ angle of repose is characterized as “excellent”; 31◦ –35◦ as
“good”; 36◦ –40◦ as “fair”; 41◦ –45◦ as “passable”; >46◦ as unacceptable
[21]. The angle of repose values of the powder mixtures in this study

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O.D. Uluhan et al. Journal of Drug Delivery Science and Technology 88 (2023) 104980

were in the range of 11.34◦ –14.24◦ (±0.65◦ ) (Table 2), which fully silicate and various lubricants. Based on the results obtained, it was
meets the free flow characteristics [21]. Based on this information, all concluded that the superdisintegrant such as croscarmellose sodium
powder mixtures prepared in our study are considered to have excellent increases the moisture absorption over time. These findings confirm our
flow properties without a significant difference between them (p > results with croscarmellose [80].
0.05).
3.4. Physicochemical characterization studies of ODTs
3.3.2. Compressibility index and hausner ratio
Compressibility index and Hausner ratio are widely used compendial 3.4.1. Determination of thickness, diameter and hardness of ODTs
methods to investigate the flow behavior of powder mixtures for the The thickness and diameter results of ODTs are tabulated in Table 3.
direct compression technique [76]. According to the limits set in the USP Low variability was obtained in thickness and diameter values of ODT
<1174> Powder Flow monograph, for powder mixtures to be consid­ formulations prepared by direct compression technique (F1–F12) indi­
ered to have acceptable flow properties, the compressibility index must cating reproducibility of the tablet compression for each tablet. On the
be less than 25% and a Hausner ratio less than 1.34. In this study, other hand, because freeze-dried ODTs (F13 and F14) were not prepared
compressibility index and Hausner ratio results of powder mixtures were by the compression technique, the variability in the corresponding
16.52 ± 1.07%–29.85 ± 1.14% and 1.20 ± 0.02%–1.43 ± 0.04%, values was higher.
respectively (Table 2). Based on this information, powder mixture of F1, Compression force and thus hardness is an important parameter for
F5 and F9 have “fair”; F2 and F6 have “passable”; other formulations ODTs since it has a significant effect on porosity, disintegration, wetting
have “poor” flow properties. Based on our results, a higher concentra­ time and dissolution. Higher compression force is reported to increase
tion of lactose monohydrate is considered to have a negative effect on tablet hardness and prolong disintegration time [80]. It is also known
powder flow due to its cohesive characterization, which increases
inter-particle friction. Table 3
Results of physicochemical characterization studies for the developed ODTs.
3.3.3. Bulk and tapped densities Thickness Diameter Hardness Weight Friability
Bulk and tapped densities are also other compendial indicators for (mm) (mm) (N) uniformity (%)
powder flow. Bulk density is the measurement of density calculated (n = 20) (n = 20) (n = 10) (mg) (n = 20)
based on powder volume poured into a container without any (Mean ± (Mean ± (Mean ± (n = 20)
SD) SD) SD) (Mean ± 5%)
compression and tapped density is the density calculated based on the
volume of powder measured after a determined amount of taps [76–78]. F1 3.99 ± 0.27 11.82 ± 41.95 ± 474.1–524.0 0.49
In this study, the bulk and tapped density results of the powder mixtures 0.18 14.41
F2 3.87 ± 0.19 11.62 ± 37.01 ± 475.2–525.2 0.39
were between 0.42 and 0.55 g/ml and 0.59–0.68 g/ml, respectively 0.09 10.62
(Table 2). Patil et al. formulated orally disintegrating tablet containing F3 3.77 ± 0.09 11.57 ± 47.52 ± 474.9–524.9 0.59
tramadol hydrochloride by mass extrusion technique and determined 0.02 12.28
bulk and tapped densities of the powder before tabletting. The reported F4 3.67 ± 0.06 11.56 ± 57.49 ± 475.3–525.3 0.48
0.03 10.19
results were in the range of 0.431–0.529 g/cm3 and 0.536–0.675 g/cm3,
F5 3.98 ± 0.22 11.60 ± 39.37 ± 474.5–524.5 0.70
respectively [79]. Therefore, the bulk and tapped density results of our 0.02 3.63
study are in line with the literature. F6 3.99 ± 0.23 11.61 ± 55.66 ± 476.3–526.5 0.52
0.04 11.52
3.3.4. Moisture content F7 3.86 ± 0.06 11.59 ± 52.91 ± 474.6–524.6 0.52
0.06 7.73
The moisture content of a powder is considered an important F8 3.82 ± 0.08 11.58 ± 56.26 ± 474.3–524.3 0.56
parameter for the high quality of ODTs. Because the high moisture 0.05 9.50
content of the powder increases the cohesion due to its strong liquid F9 3.92 ± 0.25 11.60 ± 43.67 ± 473.7–523.5 0.91
bridging structure, while the low moisture content improves the powder 0.02 3.12
F10 3.87 ± 0.16 11.65 ± 43.02 474.2–524.2 0.63
flow with its lubricant effect. The moisture content of the powder mix­ ±
0.09 8.13
tures is summarized in Table 2. The results show that formulations with F11 3.77 ± 0.07 11.60 ± 80.26 ± 475.0–525.0 0.46
higher croscarmellose contents (F2, F5, F6, F9 and F10) have higher 0.07 5.28
moisture content because croscarmellose sodium is a hygroscopic F12 3.68 ± 0.05 11.57 ± 58.10 ± 474.6–524.6 0.54
excipient known to increase powder moisture [80]. Similarly, powder 0.01 6.55
F13 5.12 ± 0.42 13.29 ± 31.19 406.4–449.2 0.95
mixtures containing Parteck® had a higher moisture content than for­
±
0.28 6.18
mulations containing Ludiflash®, which was attributed to Parteck’s F14 5.32 ± 0.33 13.67 ± 33.75 ± 337.3–372.9 0.10
croscarmellose content. Late et al. evaluated the effects of humidity (75, 0.47 2.26
85 and 95% relative humidities) on the ODTs developed with calcium

Table 2
Physical properties of the powder mixtures prepared for the direct compression technique (mean ± SD; n = 3).
Formulation Angle of repose (◦ ) Bulk density (g/ml) Tapped density (g/ml) Compressibility index (%) Hausner ratio Moisture Content (%)

F1 12.84 ± 1.44 0.55 ± 0.03 0.68 ± 0.01 19.13 ± 3.84 1.24 ± 0.06 1.17 ± 0.05
F2 12.89 ± 1.47 0.46 ± 0.03 0.61 ± 0.00 23.58 ± 5.46 1.31 ± 0.10 2.23 ± 0.03
F3 13.55 ± 1.99 0.43 ± 0.01 0.59 ± 0.01 27.84 ± 1.86 1.39 ± 0.04 1.23 ± 0.05
F4 12.96 ± 1.48 0.42 ± 0.01 0.59 ± 0.01 29.84 ± 1.92 1.43 ± 0.04 1.47 ± 0.09
F5 14.24 ± 0.65 0.49 ± 0.02 0.61 ± 0.01 19.61 ± 2.57 1.24 ± 0.04 1.70 ± 0.06
F6 14.20 ± 1.97 0.46 ± 0.00 0.61 ± 0.01 23.55 ± 0.76 1.31 ± 0.01 3.37 ± 0.10
F7 12.96 ± 1.74 0.45 ± 0.01 0.62 ± 0.01 27.22 ± 1.06 1.37 ± 0.02 1.40 ± 0.03
F8 11.61 ± 0.88 0.45 ± 0.00 0.63 ± 0.01 28.30 ± 1.15 1.39 ± 0.02 1.43 ± 0.05
F9 13.75 ± 0.88 0.51 ± 0.01 0.61 ± 0.01 16.52 ± 1.07 1.20 ± 0.02 2.30 ± 0.08
F10 13.17 ± 0.87 0.45 ± 0.01 0.64 ± 0.01 29.85 ± 1.14 1.43 ± 0.02 2.43 ± 0.04
F11 14.13 ± 1.20 0.46 ± 0.01 0.65 ± 0.00 28.45 ± 1.27 1.40 ± 0.02 1.63 ± 0.05
F12 11.34 ± 0.65 0.48 ± 0.01 0.65 ± 0.02 25.99 ± 1.38 1.35 ± 0.03 1.97 ± 0.05

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O.D. Uluhan et al. Journal of Drug Delivery Science and Technology 88 (2023) 104980

that a lower hardness value causes higher porosity and shorter disinte­ 3.4.4. Disintegration study
gration, resulting in higher dissolution. Although there is no defined Disintegration is an important physicochemical characterization
limit for hardness in the pharmacopeias, it is reported that ODTs with parameter for the optimization of ODTs. Disintegration provides the
hardness values around 3–4 kP (30–40 N) have good mechanical prop­ tablet to break up into fine particles where surface area is increased and
erties that provide good disintegration and dissolution results [80,81]. therefore, improves dissolution [85]. The disintegration time is closely
In our study, the hardness values for ODTs prepared by direct related to the concentration and type of superdisintegrant/disintegrant
compression technique were in the range of 37.0–80.3 N (Table 3) and used in the formulation and the preparation technique of the ODTs [86,
the difference was significant (p < 0.05). It is stated in the literature that 87]. According to the EP “Orodispersible Tablets” monograph, ODTs
the hardness of ODT formulations containing croscarmellose sodium at should disintegrate in 3 min. For ODT formulations prepared by direct
concentrations exceeding 10% is reduced due to its hygroscopic prop­ compression technique (F1–F12), all ODT formulations except F12 were
erties. Therefore, these differences can be attributed to the hygroscopic disintegrated within 3 min in distilled water and all ODT formulations
properties of croscarmellose sodium [80–83]. In addition, the differ­ except F4, F8, F11 and F12 were disintegrated within 3 min in the
ences in the hardness values for ODTs produced using the direct simulated saliva medium (pH 6.8). For ODT formulations prepared by
compression technique in this study can be related to the various freeze-drying technique (F13 and F14), both ODT formulations were
compression forces used during the compression of the ODTs. disintegrated within 3 min in both media (Table 4).
On the other hand, hardness values for ODTs (F13 and F14) prepared Our results showed that in formulations containing higher cro­
by freeze-drying technique were very similar (31.19 N vs 33.75 N; scarmellose sodium (12%; F1, F2), the higher Ludiflash® concentration
Table 3). Although tablet hardness increased with increasing gelatin (42.5%) shortened the disintegration time in both media (30 s in
concentration due to the increased number of hydrogen bonds between distilled water and 35 s in artificial saliva medium pH 6.8). On the other
crosslinked gelatin fibers [63], this difference was not significant (p > hand, in ODT formulations containing croscarmellose sodium (6%; F3,
0.05). All these results are compatible with the literature [63,80–82]. F4, F7 and F8), Ludiflash® and Parteck® prolonged the tablet disinte­
gration time (Table 4). In addition, it was observed that increasing
3.4.2. Weight uniformity croscarmellose sodium concentration from 6% to 12% in all ODT for­
According to pharmacopoeias, a certain degree of weight variation is mulations in our study resulted in a decrease in the disintegration time
acceptable due to variations in powder density and partial underfilling in both media (Table 4). Similarly, it has been reported in the literature
of molds. Pharmacopeias specify the acceptable limits of weight varia­ that disintegration times are shortened by increasing croscarmellose
tions. According to EP 11.0–2.9.5. Uniformity of Mass of Single-Dose sodium from 6 to 12% in ODT formulations [86], confirming that our
Preparations, uncaoated and film-coated tablets with an average mass results are in good agreement with the literature. All these results can be
≥250 mg should not deviate more than 5% for all 20 tablets [23]. The attributed to swelling ability and water wicking capacity of cro­
average weights of all ODTs (Table 3) met the acceptance criteria of the scarmellose sodium. This leads to formation of hydrophilic and highly
EP monograph and did not deviate more than 5%, indicating that the absorbent tablet with a good swelling property, leading to tablet
powder mixtures maintain homogeneity throughout the process. expansion and rapid disintegration [88,89].
Therefore, it can be thought that, different flow properties of the powder In addition, the disintegration time of ODT containing 7.5% sodium
mixtures do not have a significant effect on the weight uniformity of for starch glycolate was longer than that of ODTs containing 5% sodium
ODTs prepared by direct compression technique. starch glycolate (F9–F12) in both media. It is reported that the increase
in sodium starch glycolate concentration adversely affects the disinte­
3.4.3. Friability test gration time as it prevents the tablet getting wet and disintegration by
Friability is one of the critical parameters determining the mechan­ forming a viscous gel layer between sodium starch glycolate particles
ical strength of tablets and is affected by tablet hardness [63,84]. Ac­ [85], which confirms our results. In addition, among the ODT formu­
cording to the EP 11.0–2.9.7 Friability of Uncoated Tablets monograph, lations containing sodium starch glycolate as disintegrant, the least
loss in the weight of each tablet should be less than 1%. The friability disintegration time was observed in F9 formulation containing 5% of
results of all ODTs meet this criterion (Table 3), and show that all ODTs sodium starch glycolate and 12% of croscarmellose sodium. This result
have sufficient mechanical strength to withstand harsh conditions dur­ can be attributed to the presence of higher croscarmellose sodium
ing manufacturing, packaging and shipping processes. concentration in the formulation as explained above.
For ODTs prepared by freeze-drying technique (F13 and F14),

Table 4
Results of physicochemical characterization studies for the developed ODTs (continued; n = 6).
Wetting time Wetting time (artificial saliva Water absorption Water absorption ratio Disintegration time Disintegration time (artificial
(Distilled water) (s) medium, pH 6.8) (s) ratio (R) (R) (Distilled water) saliva medium, pH 6.8)
(Mean ± SD) (Mean ± SD) (Distilled water) (artificial saliva (s) (s)
(Mean ± SD) medium, pH 6.8)
(Mean ± SD)

F1 33.77 ± 7.78 14.58 ± 5.61 20.13 ± 9.58 28.83 ± 11.25 60 90

F2 24.67 ± 3.78 23.67 ± 3.50 30.38 ± 16.13 32.74 ± 6.98 30 35
F3 33.93 ± 8.58 26.75 ± 6.65 21.16 ± 13.98 17.25 ± 9.88 120 150
F4 24.42 ± 6.47 28.09 ± 4.63 18.10 ± 4.56 15.59 ± 6.98 150 300
F5 22.04 ± 2.12 21.94 ± 9.27 29.55 ± 11.22 36.59 ± 14.13 55 45
F6 19.83 ± 5.00 22.67 ± 5.50 31.10 ± 13.79 31.62 ± 12.93 84 66
F7 28.92 ± 4.60 29.20 ± 6.71 24.21 ± 5.64 21.16 ± 12.98 120 110
F8 27.21 ± 4.87 31.74 ± 3.15 15.33 ± 8.65 12.85 ± 5.75 150 250
F9 40.52 ± 6.54 33.92 ± 5.10 55.19 ± 9.06 52.60 ± 5.99 53 57
F10 25.33 ± 4.55 27.50 ± 3.02 30.33 ± 8.75 30.17 ± 7.10 165 175
F11 32.54 ± 3.92 25.81 ± 3.11 12.39 ± 6.39 16.58 ± 6.77 150 225
F12 28.11 ± 2.11 24.10 ± 2.07 13.50 ± 3.16 14.94 ± 3.06 241 285
F13 16.26 ± 6.73 10.65 ± 3.16 NDa NDa 58 50
F14 10.40 ± 4.82 8.75 ± 3.43 NDa NDa 65 110
a
ND: Not detected.

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O.D. Uluhan et al. Journal of Drug Delivery Science and Technology 88 (2023) 104980

disintegration time was prolonged with increase in gelatin concentra­ values were not calculated since tablets were completely disintegrated
tion. It has been reported in the literature that increasing gelatin con­ during the analysis.
centration has a negative effect on the disintegration time due to
cohesive and stable gel formation. This prevents the tablet breaking into 3.4.6. Dissolution study
more pieces and disintegrating easily [63]. Dissolution of active ingredients from the dosage form is one of the
rate-limiting steps prior to absorption from the gastrointestinal tract.
3.4.5. Wetting time and water absorption ratio ODTs are developed to rapidly disintegrate in contact with saliva. Due to
The hydrophilicity of disintegrants used in the ODT formulations their rapid disintegration, improved dissolution and absorption prop­
affects not only wetting but also the disintegration mechanisms. In the erties, ODTs have higher bioavailability compared to conventional
presence of sodium starch glycolate, disintegration occurs by rapid up­ tablets [92]. In vitro dissolution studies are commonly used to predict in
take of water followed by swelling, while croscarmellose sodium con­ vivo properties of a new medicinal product prior to the clinical phase. In
tributes to the disintegration by wicking mechanism due to its fibrous addition, in vitro dissolution studies provide useful information about
structure and shows minimum gelation during disintegration [90,91]. It suitable excipients for formulations [93,94]. It is reported that if the USP
has been reported in the literature that the wetting and disintegration Apparatus I (basket) is used in dissolution studies, dispersed drug par­
times of formulations containing sodium starch glycolate are longer than ticles in the basket may aggregate during the analysis and therefore,
formulations containing croscarmellose sodium and crospovidone. drug dissolution in the medium may not be complete. Therefore, the USP
Consistent with the literature, evaluation of sodium starch glycolate Apparatus II (paddle) is considered the most suitable apparatus for
containing formulations (F9–F12) revealed that F11 and F12 had lower dissolution testing with 50 rpm [27,28,95]. Based on this information,
water absroption ratios and had longer disintegration times than F9, F10 we performed dissolution studies in 900 ml distilled water (37 ± 0.5 ◦ C)
and the other ODT formulations containing Ludiflash® and Parteck®. using USP Apparatus II (paddle) at 50 rpm. The Biopharmaceutics
These observations can be due to the higher sodium starch glycolate Classification System (BCS) classifies drugs as very rapidly dissolving
concentration and the lower croscarmellose sodium concentration, when 85% or more of their labeled amount dissolves within 15 min and
which have a negative effect on water absorption capacity and disinte­ rapidly dissolving when 85% or more of their labeled amount dissolves
gration of the tablet. within 30 min in three different media (pH 1.2, pH 4.5 and pH 6.8) [96,
The differences in the wetting time and water absorption ratio results 97]. For all ODT formulations, the amount dissolved was less than 85%
of ODTs prepared with the direct compression technique (F1–F12) were (Fig. 6) at 15 min. Among ODT formulations containing 40% super­
statistically significant (p < 0.05; Table 4). ODTs with longer disinte­ disintegrant (F1, F3, F5, F7), the highest dissolution was obtained with
gration times (F3, F4, F7 and F8) also had longer wetting times and the F3 formulation (80.2% at 45 min). In ODT formulations containing
lower water absorption in both media. It was considered that lower 42.5% of superdisintegrant (F2, F4, F6, F8), the dissolution values
concentration of croscarmellose sodium decreased the water absorption decreased in the order of F4 (77.7%), F8 (73.0%), F2 (63.2%), F6
capacity of the tablets and prolonged the wetting time accordingly. (58.5%). F3 and F4 have the highest dissolution values compared to all
ODTs prepared with the freeze-drying technique (F13 and F14) have other ODTs prepared with the direct compression technique. Based on
shorter wetting times in both media compared to ODTs prepared with dissolution profiles, it was concluded that Ludiflash® improved disso­
the direct compression technique (F1–F12). It is known that with lution of TMB compared to Parteck®. Dissolution results for ODTs
increasing concentration of gelatin, crosslinks between gelatin fibers containing sodium starch glycolate (F9: 73.0%; F10: 55.0%; F11: 74.1%;
increase, thus the tablet form is improved [63]. In our study, the dif­ F12: 70.9%) were very similar except for F10. These results indicate that
ferences in wetting time with increasing gelatin concentration in F13 sodium stach glycolate concentration has no significant effect on
and F14 formulation were not statistically significant (p > 0.05). For dissolution. Lower dissolution obtained with F10 can be attributed to the
ODTs prepared by the freeze-drying technique, water absorption ratio lower Lactopress® concentration. The more porous and friable structure

Fig. 6. Dissolution profiles of ODTs (mean ± SD; n = 6).

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O.D. Uluhan et al. Journal of Drug Delivery Science and Technology 88 (2023) 104980

of ODTs prepared by freeze-drying technique improves the dissolution 3.5. Determination of TMB permeability across Caco-2 cells
property compared to ODTs prepared by direct compression technique
[98,99]. The dissolution results of ODTs prepared by freeze-drying Caco-2 cell lines are commonly used to evaluate the intestinal
technique (82.4% and 82.7% for F13 and F14, respectively) confirm permeability of drug substances and the dosage form during the drug
this expectation (Fig. 6). Based on the results we can conclude that development process [103–105]. To evaluate the effect of excipients
gelatin concentration did not have a significant effect on the dissolution used on TMB permeability, the permeability of TMB and ODTs were
properties of freeze-dried ODTs. determined using Caco-2 cells. Permeability results showed that
permeability of TMB in ODTs was significantly higher than that of raw
3.4.7. Porosity TMB (Fig. 8) indicating that excipients increased TMB permeability
Disintegration time is affected by tablet porosity and hardness. significantly (p < 0.05). Although the highest permeability value was
Therefore, ODTs are formulated to have a more porous structure to obtained with the F11 formulation, the differences in the permeability
facilitate disintegration in the mouth. The highly porous structure of the results of all ODT formulations were not statistically significant (p >
tablet increases the tablet surface area, reducing the wetting time and 0.05). To our knowledge, there is no study on the permeability of TMB
disintegration time [91,92]. In our study, an ODT formulation with the from Caco-2 cells. In the literature drug substances are classified as
best analysis results (F2, F5, F9 and F13) obtained from physicochemical poorly absorbed (0–20%; Papp < 1 × 10− 6 cm/s), moderately absorbed
characterization studies was selected from each formulation group and (20–70%; Papp 1–10 × 10− 6 cm/s) and well absorbed (70–100%; Papp >
porosity analyses were performed on these formulations. The porosity 10 × 10− 6 cm/s) according to their Caco-2 permeability [106]. Based on
values of the formulations prepared by the direct compression technique this information, TMB is considered a moderately absorbed drug
(F2, F5 and F9) were found to be between 38.97 and 69.71% (Table 5). substance.
These porosity values correlate well with the disintegration time of
tablets (30 s and 35 s for F2; 55 s and 45 s for F5; 53 s and 57 s for F9 in
distilled water and saliva medium, respectively), and indicates that as 3.6. Assay
the porosity increases, the disintegration time decreases. It has been
reported that the porosity of the tablet containing Parteck® is higher Two different assay methods were used (UV method, 259 nm) to
and the wetting and disintegration times are shorter than the tablet measure TMB concentration in the samples obtained from dissolution
containing Ludiflash® [100]. In line with the literature, ODT containing and cell culture studies. Determination coefficients (R2) for Assay
Parteck® (F5) had higher porosity and slightly shorter wetting time than Method-I and Method-II were close to 1 (0.9996 and 0.9995, respec­
ODT containing Ludiflash® (F2) in our study. However, disintegration tively), indicating that correlation between absorbance and concentra­
time of ODT containing Parteck® (F5) was longer than the ODT con­ tion were linear within the concentration range (10–50 μg/ml) used for
taining Ludiflash® (F2). Although porous structure favors the wetting of the validation studies. In addition, the results of accuracy, precision,
tablet and facilitates disintegration, it is not the only parameter that specificity, the limit of detection (LOD), the limit of quantification
affects the disintegration time. It can be stated that disintegranting agent (LOQ) and stability parameters were within the limits given in the ICH
is more important than porous structure for rapid disintegration of Q2(R1) CPMP/ICH/381/95 guidance.
tablets.
In addition, it is stated that ODTs prepared by freeze-drying tech­ 4. Conclusion
nique have a highly porous structure with lower mechanical strength
than ODTs prepared by direct compression technique [101]. Our results This study was designed to develop orally disintegrating tablet for­
showed that the porosity of freeze-dried ODT formulation (F13; 78.71%) mulations containing trimethobenzamide hydrochloride using direct
was higher than ODTs prepared by direct compression technique compression and freeze-drying techniques. All ODTs were evaluated by
(38.97–69.71% for F2, F5, F9). means of physicochemical characterization studies such as thickness,
The pore size and volume of the selected formulations were given in diameter and hardness, weight uniformity, friability, disintegration,
Fig. 7. Pore size and volume distribution in a narrow range were water absorption ratio, dissolution tests. Additionally, ODT formulations
considered homogeneous. In ODTs prepared by direct compression with the best analysis results obtained from physicochemical charac­
technique (F2, F5, F9), F2 has the most homogeneous pore distribution. terization studies were selected from each formulation group (F2, F5,
In addition, since the pore size and volume of F13, which was prepared F9, and F13) and FT-IR, XRD, SEM, DSC, and porosity analysis were
by freeze-drying technique, were distributed in a narrow range, the pore performed on these selected formulations. Results showed that, there
distribution was considered quite homogeneous. Inhomogeneous pore was a correlation between the water absorption ratio and disintegration
size and volume distribution can be attributed to non-uniformity of the time. It was observed that formulations that have shorter disintegration
powder mixture or presence of bubbles in the powder mixtures. time also have higher water absorption ratios due to hydrophilic struc­
In addition, it is well-known that compression force applied during ture. All formulations (except F4, F8, F11 and F12) were disintegrated
the tabletting has a great impact on the porous structure of tablets. within 3 min in both distilled water and simulated saliva (pH 6.8). None
Higher compression force reduces interparticle distance and strengthens of the formulations dissolved very rapidly in distilled water (i.e. 15 min).
the interparticle bonds; this causes the tablets to be denser and thiner But dissolution profiles showed that while Ludiflash® has a positive
but less porous [101,102]. The same observation is valid in our study impact on the dissolution of TMB compared to Parteck®, sodium starch
according to the thickness and porosity values of F2, F5, F9 and F13. glycolate, and gelatin concentration have no significant effect. Perme­
ability studies across Caco-2 cell lines demonstrated that excipients used
in the formulations increased the permeability of trimethobenzamide
hydrochloride. Based on the results, we can conclude that, trimetho­
benzamide hydrochloride containing ODTs may be beneficial in patients
Table 5 where rapid onset of action is required.
Porosity results for selected ODTs (%).
Porosity (%) Funding
F2 38.97
F5 69.71 This project was supported by Hacettepe University Scientific
F9 45.62 Research Projects Coordination Unit (Project number THD-2018-
F13 78.71
17646).

12
O.D. Uluhan et al. Journal of Drug Delivery Science and Technology 88 (2023) 104980

Fig. 7. Pore size histograms of selected ODT formulations (F2, F5, F9 and F13).

Fig. 8. Permeability values of TMB and ODTs across Caco-2 cell line (Papp, (cm/s; mean ± SD, n = 4).

Author statement Data availability

Ozge Didem Uluhan: Conceptualization, Methodology, Formal The authors do not have permission to share data.
analysis, Investigation, Writing - Original Draft, Tugba Gulsun:
Conceptualization, Methodology, Formal analysis, Investigation, Acknowledgment
Writing - Original Draft, Selma Sahin: Conceptualization, Methodology,
Resources, Writing - Review & Editing, Supervision. The authors would like to thank Kurtsan Group Companies-Türkiye
and İlko Pharmaceuticals-Türkiye for the kind gift of the active sub­
Declaration of competing interest stance and the excipients used in this project.

The authors declare that they have no known competing financial

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