INTERNATIONAL JOURNAL OF PHARMACEUTICAL RESEARCH AND BIO-SCIENCE - IJPRBS 1319.pdf · 2016-12-26 · Research Article CODEN: IJPRNK Impact Factor: 5.567 ISSN ... Ali Saeed Owayez,

Research Article CODEN: IJPRNK Impact Factor: 5.567 ISSN: 2277-8713 Ali Saeed Owayez, IJPRBS, 2016; Volume 5(6): 71-107 IJPRBS

Available Online at www.ijprbs.com 71

FORMULATION, OPTIMIZATION, AND STABILITY STUDY OF TERBUTALINE

SULPHATE SUSTAINED RELEASE TABLETS USING KOLLIDON SR

ALI SAEED OWAYEZ, GALAL MAHMOUD ABD EL-GHANY, IRHAN IBRAHIM ABU HASHIM

Pharmaceutical department, Faculty of Pharmacy, Mansoura University, Eygpt

Accepted Date: 19/11/2016; Published Date: 27/12/2016

Abstract: The study was designed to develop and optimize a sustained release (SR) matrix tablets of terbutaline sulphate (TBS) using different concentration of Kollidone SR (KSR) (40%, and 60%); Various types of fillers such as spray dried lactose (Sp.D.L), Avicel pH 101 (AV), and emcompress (EMS); As well as magnesium stearate, as lubricant, were all used. The physical characteristics of the prepared tablets were evaluated with regard to (tablets weight, thickness, friability, hardness, and disintegration time) and dissolution rate. Characterization of the optimized formulations using Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC) showed that there was no potential incompatibility of the drug with the polymer. Moreover, the in vitro release profiles of TBS formulations were investigated in different dissolution media (0.1N HCl, distilled water (DW), or phosphate buffer pH 7.2). The results revealed that the release characteristic of TBS were affected by the fillers used, concentration of KSR, and pH of the dissolution media. Kinetic analysis of the release data was also determined. Finally, stability study was investigated and the results showed that the physicochemical properties and release profile of TBS stored at 30oC/atmospheric humidity were not affected, while those stored at 40oC/75% RH were affected. In conclusion, SR formulation of TBS could be developed employing 40% KSR as rate-controlling matrix. The kinetic mechanism of drug release from all previous formulations were best described to be controlled by higuchi model for most formulae.

Keywords: Terbutaline sulphate, kollidone SR, spray dried lactose, Avicel pH 101, and emcompress.

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Ali Saeed Owayez, IJPRBS, 2016; Volume 5(6): 71-107



INTRODUCTION

Terbutaline sulphate is an effective bronchodilator and relatively short acting β2- adrenergic

agonists used in the treatment of bronchial asthma, chronic bronchitis and emphysema

(Kola et al., 2013). It exerts its effect as bronchial smooth muscle relaxant by direct action

on β2-adrenergic receptors through the accumulation of cAMP at β-adrenergic receptor

sites leading to bronchodilation, diuresis, CNS, and cardiac stimulation as well as uterine

smooth muscle relaxation (Skidmore-Roth, 2015).

The oral bioavailability of Terbutaline is about 14-15% if it is taken on an empty stomach.

The maximum plasma concentration of the drug is reached within 3 h. It is extensively

metabolized by conjugation with sulphate and some glucuronide in the liver and gut wall,

followed by excretion as inactive sulphate conjugate and unchanged terbutaline

(Martindale, 2014). Oral dosage forms of Terbutaline have duration of action from 4–8 h

(Brunton and Parker, 2008).

Although the currently available oral treatments for asthma and bronchitis are generally

effective, they are limited by the necessity for frequent drug administration and/or the

possibility of unpleasant or debilitating side effects (Khattab et al., 2009).

Kollidon SR (KSR) is a relatively new matrix retarding agent consisting of 80% polyvinyl

acetate (PVA) and 20% polyvinyl pyrrolidone (povidone) (PVP). Because of its excellent

flowability, this formulated combination allows sustained release dosage forms to be

manufactured by the simple direct compression process. Polyvinyl acetate is insoluble in

water. It is a plastic material that produces a coherent matrix even under low compression

forces maintaining tablet core structure during dissolution (Reza et al., 2002; Narla et al.,

2010).

Previous studies described the preparation of sustained release matrix tablets using KSR and

other polymers containing diltiazem hydrochloride (Islama et al., 2008), ciprofloxacin (Al-

Mamun et al., 2012), theophylline (Reza et al., 2002; Kabir et al., 2015), timolol maleate

(Ramu et al., 2015), or chlorpheniramine maleate (Fouad et al., 2015).

Other investigators reported the preparation of sustained release matrix tablets from KSR

alone containing theophylline (Vinaya and Revikumar, 2012), or diltiazem HCl (Merekar and

Kuchekara, 2014).

Previously, Harish et al. (2011) prepared a sustained release matrix tablets of TBS by wet

granulation technique using polyvinyl chloride and ethylcellulose. Citric acid was used to set

up a system which would bring about gradual release of the drug.

Another study made an attempt to formulate TBS in sustained release tablet with different

concentrations of hydroxypropyl methylcellulose (HPMC K4M and K15M) (Kola et al., 2013).



Therefore, the present study deals with the preparation of sustained release matrix tablets

of TBS by direct compression technique using KSR in different concentrations(40%, or 60%)

with various selected fillers including: Spray dried lactose (Sp.D.L), Avicel pH 101 (AV), and

Emcompress (EMS).

Materials and methods

Materials

Terbutaline sulphate and KSR were purchased from Provizer Pharma, India; Spray-dried

lactose (Sheffield Products, Norwich, NY, USA); Avicel pH 101 (FMC Corporation

Philadelphia, PA, USA); Emcompress (Stauffer Chemical Company, Westpot, CT); and

Magnesium stearate (Mallinckrodt, St. Louis, Mo).

Methods

Preparation of TBS matrix tablets

Different formulae of TBS were prepared according to illustration in Table (1). Terbutaline

Sulphate was mixed with KSR in a geometric dilution for 5 min, followed by mixing with each

of the remaining ingredients (SP.D.L, AV, or EMS) for 10 min. Magnesium stearate was then

added and mixed for an additional 5 min. Tablets were directly compressed using Erweka-

Apparatebau single punch tablet machine with a concave faced punches and a diameter of

0.31 inch. The tablet weight was 100 mg.

Preparation of TBS matrix tablets (200 mg) with maintaining amount of TBS

The amount of KSR and fillers were increased with maintaining their percentage to the

whole tablet weight, and also kept the amount of TBS constant, the tablet weight was

increased from 100 to 200 mg (T10 and T11) according to the Table (2).

Characterization of TBS matrix tablets

Powder flow characteristics

The flow characteristics of the powder mixtures of all formulae were evaluated in terms of

their bulk density, tapped density, Carr's index and Hausner ratio. The results were

expressed in Table (3, 4).

Fourier transform infrared (FT-IR) spectroscopy

The Fourier transform infrared spectra of TBS, KSR, AV, and EMS were investigated. Also,

ternary physical mixture of drug-KSR-AV and drug-KSR-EMS were recorded using thermo

scientific FT-IR spectrophotometer, USA. Each sample (2 mg) was mixed with 200 mg of

potassium bromide and pulverized into a fine powder to be compressed into discs using a



hydraulic press. Each disc was scanned over a wave number region of 400–4000 cm–1. The

results were illustrated in Fig. 1.

Differential Scanning Calorimetry (DSC)

The DSC measurements were performed on a DSC-60 (Shimadzu Instruments, Japan)

differential scanning calorimeter with a thermal analyzer. All accurately weighed samples

(about 5 mg of TBS, KSR, AV pH 102, EMS, ternary physical mixture of drug-KSR-AV, and

drug-KSR-EMS) were placed in sealed aluminum pans before heating under nitrogen flow

(20 mL/min) at a scanning rate of 10°C min−1 from 25 to 400°C. An empty aluminum pan was

used as reference. The results were illustrated in Fig. 2.

Evaluation of physical properties of TBS matrix tablets

Tablet weight

Twenty tablets were weighed and the average weight was calculated. Such tablets were

individually measured, and the standard deviation from the mean tablet weight was

calculated and recorded in Table (5, 6). All values are expressed as mean ±SD (n=20).

Tablet thickness

The thickness of the prepared tablets was measured using a micrometer screw gauge. The

mean thickness of 20 tablets for each formula± standard deviation was calculated and

recorded in Table (5, 6). All values are expressed as mean ±SD (n=20).

Tablet friability

Twenty tablets were accurately weighed and placed in an Erweka friabilator with revolution

of 25 rpm for 4 min. The tablets were dropped through a distance of 6 inches with each

revolution and reweighed after 100 revolutions. Brushing and reweighing the tablet and the

% friability was calculated according to the following equation:

Friability (%) =(Initial wt.of tablets − Final wt.of tablets)

Initial wt.of tablets×100 (Vueba et al., 2004).

The results were recorded in Table (5, 6). All values are expressed as mean ±SD (n=20).

Tablet hardness

For each formulation, six tablets were measured using an Erweka hardness tester. The

average ± S.D were recorded in Table (5, 6). All values are expressed as mean ± SD (n=6).

Disintegration time (D.T.)

The disintegration time test was done in Erweka disintegration test apparatus according to

the USP30-NF25 requirements. Six tablets from each formula were used for the test. The



disintegration media were 800 mL of DW, 0.1N HCI, or phosphate buffer pH 7.2 maintained

at 37 ± 2°C. The disintegration time was determined as the mean time required for the

tablets to break into small particles that can pass through a mesh screen into the

disintegration medium. The results were recorded in Table (5, 6). All values are expressed as

mean ± SD (n=6).

Dissolution rate of TBS tablets containing KSR

The in vitro release rate of TBS from the prepared tablets were performed using the USP

XXVII dissolution apparatus-2, paddle type. The dissolution media (200 mL) were DW, 0.1N

HCl, and phosphate buffer pH 7.2 maintained at 37±0.5oC with rotation speed of 100 rpm.

Five mL samples were withdrawn at different time intervals and filtered by 0.45 μm

Millipore filters to remove any suspended particles. The volume withdrawn was replaced

with a same volume of fresh dissolution medium at the same temperature. The drug

concentration in each sample was quantified spectrophotometrically at 276 nm.

Statistics analysis

Data were expressed as the mean ± SD of three experiments. Statistical analysis of the data

were carried out using Graphpad Prism software (version 5.01, San Diego, USA).

The dissolution profile was statistically analyzed using dissolution similarity factor ƒ2

according to the following equation:

ƒ2 =50 log {[1+ (1/ n)∑(Rt – Tt)2]-0.5×100}

Where n is number of time points, Rt and Tt are dissolution of reference and test products

at time t (Hossain et al., 2013). The ƒ2 value between 50 and 100 suggest that the

dissolution is similar. The ƒ2 values of 100 suggest that the test and reference profile are

identical and as the value becomes smaller, the dissimilarity between releases profile

increases (Wadher et al., 2013).

Drug release kinetic and mechanism

Different mathematical models were applied for describing the release kinetics of TBS from

the prepared tablets. Such as; Zero-order model (Dash et al., 2010), First-order model

(Pundir et al., 2013), Higuchi model (Higuchi, 1963), and Korsmeyer-Peppas semi-empirical

model (Korsmeyer et al., 1983).



Table (1): Formulation of TBS matrix tablets

Formula code TBS %(w/w)

KSR % (w/w)

Mg stearate % (w/w)

SP.D.L %(w/w)

AV % (w/w)

EMS %(w/w)

T1 10 0 1 89

T2 10 0 1 89

T3 10 0 1 89

T4 10 40 1 49

T5 10 40 1 49

T6 10 40 1 49

T7 10 60 1 29

T8 10 60 1 29

T9 10 60 1 29

Table (2): Formulation of TBS matrix tablets of 200 mg weight

Results and discussion

Powder flow characteristics

The powder flow characteristics of different TBS formulae, as depicted by Table (3) showed

that T1, T3, T4, T6, and T9 had Carr’s Index 9.10, 8.36, 7.68, and 5.38, and hausner ratio

1.10, 1.09, 1.08, and 1.06, respectively; T5, T7, and T8 had Carr’s Index 13.45, 13.97, and

13.70, and hausner ratio 1.16, 1.16, and 1.16, respectively; T2 had Carr’s Index 24.92, and

hausner ratio 1.33. According to this results, T1, T3, T4, T6, and T9 were found to be

excellent; T5, T7, and T8 were good; and T2 was passable according to the generally

accepted scale of flowability.

Powder flow characteristics of (200 mg) formulae

The powder flow characteristics of different TBS formulae showed that T10 had Carr’s Index

5.23, and hausner ratio 1.06, and T11 had Carr’s Index 19.73, and hausner ratio 1.25 as

shown in Table (4). According to this results, T10 was found to be excellent, while T11 was

fair according to the generally accepted scale of flowability.

Formula

code

TBS

%(w/w)

KSR

% (w/w)

Mg stearate

% (w/w)

AV

% (w/w)

EMS

%(w/w)

T10 5 40 1 54

T11 5 40 1 54



Table (3): Powder characteristics of different TBS formulae

Table (4): Powder characteristics of (200) mg formulae

Fourier Transform Infrared Spectroscopy (FT-IR)

The FT-IR spectrum of pure TBS showed the following peaks: 3331cm-1 (OH stretch), 3056

cm-1 (aromatic CH stretch), 2975-2815 cm-1 (C-H stretching of CH3 and CH2 group), 1610 cm-

1 (C=C ring stretching), 1608 & 1485 cm–1 (aromatic ring stretch), 1382 cm–1(t-butyl

symmetric bend), 1205 cm-1 (phenolic C-O stretch), 1067 cm–1 (secondary alcohol stretch)

and 864 cm-1 (substituted phenyl ring). FT-IR patterns of pure KSR, EMS, AV, and SP.D.L

showed their characteristic peaks (Fig. 1). Frequencies of functional groups of pure TBS was

Formula

code

Bulk

volume

Tapped

volume

Bulk

density

Tapped

density

Carr’s

Index

Hausner

ratio

T1 2.20 2.00 0.91 1.00 9.10 1.10

T2 4.00 3.00 0.50 0.67 24.92 1.33

T3 2.40 2.20 0.83 0.91 8.36 1.09

T4 2.60 2.40 0.77 0.83 7.68 1.08

T5 4.50 3.90 0.44 0.51 13.45 1.16

T6 2.78 2.63 0.72 0.76 5.38 1.06

T7 2.85 2.45 0.70 0.82 13.97 1.16

T8 3.65 3.15 0.55 0.64 13.70 1.16

T9 3.05 2.75 0.66 0.73 9.77 1.11

Formula

code

Bulk

volume

Tapped

volume

Bulk

density

Tapped

density

Carr’s

Index

Hausner

ratio

T10 2.40 2.28 0.83 0.88 5.23 1.06

T11 4.20 3.38 0.48 0.59 19.73 1.25



observed in T10 and T11 (Fig. 1). These results suggest that the interaction of the drug with

KSR and fillers used for the preparation of different formulations was negligible.

Differential Scanning Calorimetry (DSC)

As shown in Fig. (2), the DSC curve 0f TBS exhibited a sharp endothermic peak at 270.2°C.

This peak matched with the crystal form A of TBS which ranges from 264 to 271°C. No

reliable purity value can be determined since TBS melts with decomposition (Florey, 1990).

Differential scanning calorimetry thermogram of KSR showed two endothermic peaks. The

former was the glass transition temperature which began at 40.7oC, with a broad

endotherm peak at 69.2oC indicating the presence of residual moisture in polymers and the

later was the degradation temperature which began at 325oC. In the DSC thermogram of

EMS, a broaden transition due to loss of water followed by the melting endotherm with

maximum peak of transition at 192.1oC. The thermogram of AV displayed two broad

endothermic peaks at 66.9 and 333.0°C that might correspond to volatilization of adsorbed

water followed by melting decomposition with charring of the crystalline cellulosic material.

The thermogram of SP.D.L showed an early peak at 147.787oC due to the bound water

present in lactose. The DSC profile of drug loaded matrix formulae showed an endothermic

peak at a temperature corresponding to TBS melting point but with loss of its sharp

appearance. Since the amount of drug used within the studied formulations was much less

than the amount of the other excipients, only a small endothermic peak related to TBS is

observed within the formulations′ thermograms. The sharp endothermic peaks in 146°C and

191.1°C pertain to EMS. The wider peak at 358.7°C pertain to both AV and KSR

decomposition. This ensures that none of the materials used for the preparation of the

tablets may have physicochemical interactions (Fig. 2).



Fig. (1): FT-IR spectrum of: A) TBS B) KSR C) EMS D) AV F) T10 G) T11

Fig. (2): DSC thermograms of A) TBS B) KSR C) EMS D) AV F) T10 G) T11

Physical Characteristics of TBS Tablets:

Table (5) illustrates that all the tested tablets showed accepted weight uniformity that

comply with the pharmacopeia limits. The thickness of the produced tablets ranged from

Tra

nsm

itta

nce (

%)

Wavenumber (cm 1)

A)

B)

C)

D)

E)

F)

50 100 150 200 250 300 350 399.94

Exoth

erm

icE

ndoth

erm

ic 192.1

333.0

191.4

358.7

A)

B)

C)

D)E)

F)

Temperature (oC)

270.2

69.2

66.9

272.6

272.6

192.1

191.4



2.360±1.74 (T4) to 2.915±0.83 mm (T9). The coefficient of variation did not exceed 2%

indicating excellent uniformity of thickness (ElShaboury, 1990). In formulae T2 to T9, the

friability percent was in the range of 0.101 to 0.852%. The highest friability value was

1.777% (T1), while the lowest value was 0.101% (T5). The high friability percent of T1 might

be due to its low hardness as a result of high porosity of EMS. The friability values of

formulae T2 to T9 were less than 1% indicating that formulated tablets were mechanically

accepted. The hardness values were ranged from 1.900±0.15 (T1) to 10.22±1.19 (T5). In case

of using AV in tablet formula (T2), the hardness was higher than other corresponding

excipient (T1, T3), which might be due to excellent compressibility, binding, and the

formation of hydrogen bond bridges between AV particles (Bolhuis, 1996; Tsai et al., 1998;

Lee et al., 2000; Yousuf et al., 2005). Increasing the percent of KSR from zero% to 40% (T4,

T5, and T6) resulted in increasing tablet hardness which might be due to combination of the

very plastic polyvinyl acetate and strongly binding povidone in KSR (Merekar and Kuchekarb,

2014). Further increase of KSR from 40% to 60% (T7, T8, and T9) resulted in decrease tablet

hardness, but still above zero% KSR formulae.

Increasing the tablet weight from 100 mg to 200 mg with maintaining the same amount of

TBS (10 mg) results in tablets of T10 and T11 with mean weight of 0.2002±0.039 and

0.1968±1.490 g, respectively. Tablet thickness within each formulations were parallel to the

type of contents (formula T11 containing AV was thicker (3.767±0.55 mm) than T10

(3.377±1.15 mm) which contains EMS due to the high bulk volume of AV). The loss in total

weight of the tablets due to friability was 0.800 and 0.699% of T10 and T11, respectively.

These values were less than 1% indicating that formulated tablets were mechanically stable

and in accordance with the USP 30-NF 25 Pharmacopoeia requirements. The hardness of

T11 (10.02±12.02) was higher than T10 formula (6.700±8.19) due to excellent

compressibility and binder characteristic of AV gave high hardness (Table 6).

Disintegration time (D.T.)

Effect of different filler on the D.T of TBS tablet

The D.T. of T3 (containing SP.D.L) was 13.8±0.84 min, D.T of T2 (containing AV) was

151.6±9.64 min, and D.T. of T1 (containing EMS) was > 360 min (Table 5). The fastest D.T of

T3 might be due to the soluble characteristic of SP.D.L. in aqueous media (Grund, 2013). The

intermediate D.T of T2 might be related to the disintegration property of AV (Ferrari et al.,

1996). The slowest D.T of T1 might be due to water insolubility of its filler (Rowe et al,

2009). The D.T. in DW was arranged in the following order: T3 < T2 < T1. Upon changing the

medium into phosphate buffer pH 7.2, the same pattern was observed with some difference

in the time of disintegration in comparison to D.W. The pattern changed as the medium was

changed to 0.1N HCl, where T3 had the fastest D.T. 13.4±0.55 min, followed by T1 with D.T.

of 31.8±3.96 min as EMS was reported to behaved like soluble ingredient at acidic medium

(Mohylyuk and Davtian, 2015), then followed by T2 with D.T. 189.8±9.68 min. Replacing



equivalent % of the filler with 40% KSR (T4, T5, and T6) or 60% KSR (T7, T8, and T9) resulted

in negligible effect of the filler on the D.T of the prepared tablets.

Effect of percent of KSR on the D.T. of TBS tablet

It was found that the D.T. of T3 (Tablets with 0% KSR) in DW was 13.8±0.84 min, as the

concentration of KSR increased to 40% in T6, the D.T. was >360 min, further increase in KSR

to 60% (T9) resulted in D.T. >360 min (Table 5). This might be due to the lower porosity of

the matrices of KSR, hence, delayed the disintegration of tablets (Shao, 2001; Siepmann et

al., 2010). The same pattern was observed as the filler was changed to AV (T2, T5, and T8) or

EMS (T1, T4, and T7). Also, changing disintegration medium to 0.1N HCl or phosphate buffer

pH 7.2 resulted in the same pattern noticed above.

Effect of pH of disintegration medium on D.T. of TBS tablet

The D.T. of T2 in D.W. was 151.0±9.64 min. When the disintegration fluid was changed to

phosphate buffer, the D.T. was increased to 179.7±7.03 min. This effect might be due to the

ionic strength of phosphate buffer medium. As the medium changed to 0.1N HCl, the D.T.

was increased to 189.00±9.68 min (Table 5).

Table (5): Physical characteristics of TBS tablets prepared with different concentrations of

KSR and additives.

Formula

code

Mean tablet

Weight

(g)±SD

Mean

thickness

(mm)

±C.V (%)

Mean

hardness

(Kg/cm2)

± SD

Friability

(%)

D.T.(min.)

in

DW ±SD

D.T.(min.)

in

0.1N HCl

±SD

D.T.(min.)

in

Phosphate

buffer pH

7.2±SD

T1 0.1215±0.000 2.373±0.59 1.900±0.15 1.777% >360 31.8±3.96 >360

T2 0.0999±1.001 2.470±1.57 6.633±0.18 0.289%

151.6±9.64

189.8±9.68 179.0±7.03

T3 0.1063±0.000 2.581±1.05 2.008±0.61 0.658% 13.8±0.84 13.4±0.55 12.0±0.71

T4 0.1025±0.000 2.360±1.74 7.250±0.62 0.506% >360 >360 >360

T5 0.0983±0.001 2.628±1.48 10.22±1.19 0.101% >360 >360 >360

T6 0.1033±0.000 2.880±0.52 3.333±0.43 0.461% >360 >360 >360

T7 0.1025±0.001 2.746±1.24 3.292±0.37 0.852% >360 >360 >360

T8 0.1020±0.001 2.874±0.91 5.883±0.84 0.530% >360 >360 >360

T9 0.1039±0.001 2.915±0.83 3.608±0.89 0.713% >360 >360 >360



Table (6): Physical characteristics of TBS tablets (200 mg).

The pattern was changed in T1 which might be related to the acidic solubility of EMS. The

pattern was also changed in T3 as the SP.D.L is more water soluble than other fillers. The

effect of pH on the D.T. of tablets containing 40% KSR (T4, T5, and T6) and those containing

60% KSR (T7, T8, and T9) was negligible.

The D.T of T10 and T11 was > 360 min in each of DW, 0.1 N HCl, or phosphate buffer pH 7.2

(Table 6). The effect of fillers, KSR, or pH of disintegration medium on the D.T. of tablets

containing 40% KSR was negligible.

In vitro release study

Effect of fillers on the release of TBS matrix tablets

Figure (3A) shows that there was a significant difference in the drug release rate in

comparing T1 (containing EMS) to T2 (containing AV), T1 to T3 (containing SP.D.L), and T2 to

T3, where the similarity factor values (ƒ2) were 26, 17, and 32, respectively.

Upon decreasing the % of fillers from 89% to 49% (T4, T5, and T6) due to increase KSR from

0% to 40%, their effect still present, and the release profile of drug was significantly

difference, where the similarity factor was 46, 26, and 26 in comparing of T4 (containing

EMS) to T5 (containing AV), T4 to T6 (containing SP.D.L), and T5 to T6, respectively (Fig. 3B).

Further decreasing the % of the fillers from 49% to 29% (T7,T8, and T9) due to increase KSR

from 40% to 60%, resulted in a significant difference in the release profile of drug, where

the similarity factor were 28 and 30 in comparing T7 (containing EMS) to T9 (containing

SP.D.L) and T8 (containing AV) to T9, respectively. On the other hand, there was insignificant

difference in the release profile of drug comparison of T7 to T8 (ƒ2 = 52) (Fig. 3C). This

insignificant difference might be related to the lower hardness of T7 and hence more

porosity, in addition to the high disintegrating property of AV (filler of T8).

Formula

code

Mean tablet

Weight

(g)±SD

Mean

thickness

(mm)

±C.V (%)

Mean

hardness

(Kg/cm2)

± SD

Friability

(%)

D.T.(min.)

in

DW ±SD

D.T.(min.)

in

0.1N HCl

±SD

D.T.(min.)

in

Phosphate

buffer pH

7.2±SD

T10 0.2002±0.039 3.377±1.15 6.700±0.55 0.800% >360 >360 >360

T11 0.1968±1.490 3.767±0.55 10.02±1.68 0.699% >360 >360 >360



When the medium was changed to 0.1N HCl, The release of TBS from T1 was insignificantly

different compared with T2 (ƒ2= 54), while there were a significant difference in the release

profile of TBS from T1 in comparing to T3 (ƒ2= 29), and in comparing T2 to T3 (ƒ2= 23) (Fig.

4A). This might be attributed to the difference in their fillers solubility as the SP.D.L. has high

solubility in acidic medium.

Similar release behavior of TBS from tablet matrices containing 49% filler was observed. The

results revealed that there was insignificant difference in the release rate of the drug from

T4 with respect to T5 (ƒ2=61), while there were a significant difference in the release rate of

the drug from T4 in comparing with T6 (ƒ2=28), and T5 with respect to T6 (ƒ2=24).

Further decreasing the % of the fillers from 49% to 29% (T7, T8, and T9) due to increase in

KSR from 40% to 60% was associated with an effect of the fillers used, and the release

profile of drug was significant different in comparing T7 to T8 (ƒ2= 44), T7 to T9 (ƒ2= 44)

which might be due to low hardness of T7 and increased solubility of its filler in acidic

medium. Also, significant difference in the drug release profile was observed between T8

and T9 (ƒ2= 30) (Fig. 4C).

The same filler effect was noticed in phosphate buffer pH 7.2 medium when compared to

that in DW, where there was a significant difference in the release of TBS between T1, T2,

and T3 (ƒ2 < 50) (Fig. 5A). Upon using 49% fillers, TBS was released in the following order;

T6>T5>T4 (Fig. 5B). The fast release of drug from T6 with respect to T5 and T4 (ƒ2 was 20

and 22, respectively) might be related to the water solubility of its filler. Also, T5 had faster

release in comparing T4 (ƒ2= 47) which might be due to disintegration characteristic of its

filler (AV). When the percent of fillers decreased to 29%, their effect still present between

T7 and T9 (ƒ2= 28) and between T8 and T9 (ƒ2= 33), while their effect disappeared between

T7 and T8 (ƒ2= 52) (Fig. 5C).



Fig. (3): Effect of KSR on TBS release in DW:

A) 0% KSR B) 40% KSR C) 60% KSR

T1, T4, and T7 (containing EMS)

T2, T5, and T8 (containing AV)

T3, T6, and T9 (containing SP.D.L)

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100T1

T2

T3

Time(min.)

perc

ent o

f TBS

relea

se

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100T4

T5

T6

Time(min.)

perc

ent o

f TBS

relea

se

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100T7

T8

T9

Time(min.)

perc

ent o

f TBS

relea

se

A)

B)

C)

Per

cent

of T

BS

rele

ased

Per

cent

of T

BS

rele

ased

Per

cent

of T

BS

rele

ased



Fig. (4): Effect of KSR on TBS release in 0.1N HCl:

A) 0% KSR B) 40% KSR C) 60% KSR




0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100T1

T2

T3

Time(min.)

perc

ent o

f TB

S re

leas

e

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100T4

T5

T6

Time(min.)

perc

ent o

f TB

S re

leas

e

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100T7

T8

T9

Time(min.)

perc

ent o

f TB

S re

leas

e

A)

B)

C)

Per

cen

t of

TB

S r

elea

sed

Per

cen

t of

TB

S r

elea

sed

Per

cen

t of

TB

S r

elea

sed



Fig. (5): Effect of KSR on TBS release in phosphate buffer pH 7.2:

A) 0% KSR B) 40% KSR C) 60% KSR




0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100T1

T2

T3

Time(min.)

perc

ent

of T

BS

rel

ease

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T4

T5

T6

Time(min.)

perc

ent

of T

BS

rel

ease

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T7

T8

T9

Time(min.)

perc

ent

of T

BS

rel

ease

A)

B)

C)

Per

cen

t o

f T

BS

rel

ease

dP

erce

nt

of

TB

S r

elea

sed

Per

cen

t o

f T

BS

rel

ease

d



Effect of KSR on the release of TBS tablets

As shown in Fig. (6A), there was insignificant difference in the rate of drug release between

T4 to T7 (ƒ2 = 58). However, there was a significant difference between T4 to T1 (ƒ2 = 30) &

T1 to T7 (ƒ2 = 31). It has been concluded that the use of KSR in about 40% of tablet weight

was associated with a decrease in the release rate of the drug, but further increasing in KSR

concentration will insignificantly decrease drug release.

When the medium was changed into 0.1N HCl (Fig. 6A) or phosphate buffer pH 7.2 (Fig. 6B),

the same pattern was observed.

Upon changing the filler to AV as in formula T2 (0% KSR), T5 (40% KSR), and T8 (60% KSR), it

was found that the release rate of drug in the three media had the same pattern. There

were a significant difference in drug release rate of T2 in DW when compared to T5 (ƒ2 = 18)

and T8 (ƒ2 = 18), but insignificant difference between T5 to T8 (ƒ2 = 53) (Fig. 7A). In 0.1N HCl,

the similarity factor of T2 in comparison to T5 was (ƒ2 = 24), and to T8 was (ƒ2 = 23), while it

was (ƒ2 = 51) in comparison of T5 to T8 (Fig. 7B). In phosphate buffer pH 7.2, the release rate

of TBS were significantly different when comparing T2 to T5 (ƒ2 = 19) and T2 to T8 (ƒ2 = 22),

but insignificant difference between T5 to T8 (ƒ2 = 63) (Fig. 7C).

Also, changing the filler to SP.D.L resulted in the same pattern observed with that of AV.

There were a significant difference in drug release rate of T3 (had no KSR) in DW when

compared to T6 (40% KSR) (ƒ2 = 28) and T9 (60% KSR) (ƒ2 = 28), but insignificant difference

between T6 to F9 (ƒ2 = 80) (Fig. 8A). In 0.1N HCl, the similarity factor of T3 in comparison to

T6 was (ƒ2 = 32), and to T9 was (ƒ2 = 24), while it was (ƒ2 = 64) in comparison of T6 to T9 (Fig.

8B). In phosphate buffer pH 7.2, the release rate of TBS were significantly different when

comparing T3 to T6 (ƒ2 = 33) and T3 to T9 (ƒ2 = 27), but insignificant difference between T6

to T9 (ƒ2 = 68) (Fig. 8C).



Fig. (6): Effect of KSR percent on TBS release from tablets containing EMS in

A) DW B) 0.1N HCl C) Phosphate buffer pH 7.2

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T4

T1

T7

Time(min.)

perc

en

t o

f T

BS

rele

ase

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T4

T1

T7

Time(min.)

perc

en

t o

f T

BS

rele

ase

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T4

T1

T7

Time(min.)

perc

en

t o

f T

BS

rele

ase

A)

B)

C)

Per

cen

t o

f T

BS

rel

ease

dP

erce

nt

of

TB

S r

elea

sed

Per

cen

t o

f T

BS

rel

ease

d



Fig. (7): Effect of KSR percent on TBS release from tablets containing AV in


0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T5

T2

T8

Time(min.)

per

cen

t o

f T

BS

rel

ease

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T5

T2

T8

Time(min.)

per

cen

t o

f T

BS

rel

ease

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T5

T2

T8

Time(min.)

per

cen

t o

f T

BS

rel

ease

A)

B)

C)

Per

cen

t o

f T

BS

rel

ease

dP

erce

nt

of

TB

S r

elea

sed

Per

cen

t o

f T

BS

rel

ease

d



Fig. (8): Effect of KSR percent on TBS release from tablets containing SP.D.L. in


0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T6

T3

T9

Time(min.)

per

cen

t o

f T

BS

rel

ease

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T6

T3

T9

Time(min.)

per

cen

t o

f T

BS

rel

ease

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T6

T3

T9

Time(min.)

per

cen

t o

f T

BS

rel

ease

A)

B)

C)

Per

cen

t of

TB

S r

elea

sed

Per

cen

t of

TB

S r

elea

sed

Per

cen

t of

TB

S r

elea

sed



Effect of pH on the release of TBS matrix tablets

As shown in Fig. (9A), there was a significant difference in the release of TBS from T1

between 0.1N HCl and phosphate buffer pH 7.2 (ƒ2=32), and between 0.1N HCl and DW

(ƒ2=36). On the other hand, there was insignificant difference in the release rate of TBS

between phosphate buffer pH 7.2 and DW (ƒ2=63). This pattern was changed upon

incorporation of KSR at 40% (T4) of tablet weight as shown in Fig. (9B). It was found that

there was insignificant difference in the release of TBS between 0.1N HCl and DW (ƒ2=55), as

well as between DW and phosphate buffer pH 7.2 (ƒ2=71), But there was slight difference

between 0.1 N HCl and phosphate buffer pH 7.2 (ƒ2 = 48) which might be due to the

retardive effect of high concentration of KSR.

When the percent of KSR increased up to 60% (T7) of tablet weight, the pattern of drug

release slightly changed. It was found that there was insignificant difference in the release

of TBS between 0.1N HCl and DW (ƒ2=51), between 0.1N HCl and phosphate buffer pH 7.2

(ƒ2=50), as well as between DW and phosphate buffer pH 7.2 (ƒ2 = 77) (Fig. 9C).

As shown in Fig. (10A), when changing the filler into AV (T2), there was a significant

difference between 0.1N HCl and DW (ƒ2=38), also, between 0.1N HCl and phosphate buffer

pH 7.2 (ƒ2=48), while there was insignificant difference between DW and phosphate buffer

pH 7.2 (ƒ2 = 50) as its drug release from matrix systems was influenced by the aqueous

solubility of its filler and the drug behavior at different pH. This pattern was disappeared

upon increasing the concentration of KSR to 40% (T5) of tablet weight, as there were

insignificant difference between the three media. The similarity factor were 64, 77, and 68

between 0.1N HCl to DW, 0.1N HCl to phosphate buffer pH 7.2, and DW to phosphate buffer

pH 7.2, respectively (Fig. 10B). Also, this new pattern was observed when the concentration

of KSR increased to 60% (T8) of tablet weight. The similarity factor were 57, 51, and 78

between 0.1N HCl to DW, 0.1N HCl to phosphate buffer pH 7.2, and DW to phosphate buffer

pH 7.2, respectively, hence, insignificant difference were observed in the three media (Fig.

10C).

As the filler was changed to SP.D.L., it was found that there were insignificant difference in

the three media of each T3, T6, and T9 (Fig. 11) which might be due to high aqueous

solubility of SP.D.L, in spite of its high acidic solubility (Lotfipour et al., 2004).

When the concentration of KSR was 40 or 60%, the effect of pH of the media on the release

profile of TBS was negligible.



Fig. (9): Effect of pH of dissolution medium on TBS release from tablets containing EMS

A) T1 B) T4 C) T7

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

DW

Hcl

phosphate buffer

Figure 2: Effect of pH of the dissolution medium Brc release (F1)

Time(min.)

Mean

perc

en

t B

rc r

ele

ase

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100Hcl

D.W

Phosphate buffer

Figure 9: Effect of pH of the dissolution medium on Brc release (F7)

Time(min.)

Me

an

pe

rce

nt

Brc

re

lea

se

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

Hcl

D.W

phosphate buffer


Time(min.)

Mean

perc

en

t B

rc r

ele

ase

A)

B)

C)

Mea

n p

erce

nt

TBS

rele

ase

Mea

n p

erce

nt

TBS

rele

ase

Mea

n p

erce

nt

TBS

rele

ase

Perc

ent

of T

BS

rele

ase

Perc

ent

of T

BS

rele

ase

Perc

ent

of T

BS

rele

ase

Perc

ent

of T

BS

rele

ase

Per

cen

t of

TB

S r

elea

sed

Per

cen

t of

TB

S r

elea

sed

Per

cen

t of

TB

S r

elea

sed



Fig. (10): Effect of pH of dissolution medium on TBS release from tablets containing AV

A) T2 B) T5 C) T8

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

Hcl

DW

phosphate buffer


Time(min.)

Mea

n p

erce

nt

Brc

rel

ease

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

DW

Hcl

phosphate buffer

Figure 3: Effect of pH of the dissolution medium Brc release (F2).

Time(min.)

Mea

n p

erce

nt

Brc

rel

ease

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

Hcl

DW

Phosphate buffer


Time(min.)

Mea

n p

erce

nt

Brc

rel

ease

A)

B)

C)

Mea

n pe

rcen

t TBS

rele

ase

Mea

n pe

rcen

t TBS

rele

ase

Mea

n pe

rcen

t TBS

rele

ase

Perc

ent

of T

BS r

elea

sePe

rcen

t of

TBS

rel

ease

Perc

ent

of T

BS r

elea

seP

erce

nt

of T

BS

rel

ease

dP

erce

nt

of T

BS

rel

ease

dP

erce

nt

of T

BS

rel

ease

d



Fig. (11): Effect of pH of dissolution medium on TBS release from tablets containing SP.D.L.

A) T3 B) T6 C) T9

As shown in Fig. (12A), there was a significant difference in the release rate of TBS from T10

between phosphate buffer pH 7.2 and DW (ƒ2=45). While there was insignificant difference

in the release of TBS between 0.1N HCl and phosphate buffer pH 7.2 (ƒ2=59), and between

0.1N HCl and DW (ƒ2=58). In case of formula T11, there was a significant difference in the

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

Hcl

D.W

Phosphate buffer


Time(min.)

Mean

perc

en

t B

rc r

ele

ase

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

DW

Hcl

phosphate buffer

Figure 4: Effect of pH of the dissolution medium on Brc release (F3).

Time(min.)

Mean

perc

en

t B

rc r

ele

ase

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

Hcl

D.W

Phosphate buffer


Time(min.)

Mean

perc

en

t B

rc r

ele

ase

C)

B)

A)M

ean

perc

ent T

BS re

leas

eM

ean

perc

ent T

BS re

leas

eM

ean

perc

ent T

BS re

leas

ePe

rcen

t of

TB

S re

leas

ePe

rcen

t of

TB

S re

leas

ePe

rcen

t of

TB

S re

leas

eP

erce

nt

of

TB

S r

elea

sed

Per

cen

t of

TB

S r

elea

sed

Per

cen

t of

TB

S r

elea

sed



release of TBS between 0.1N HCl and phosphate buffer pH 7.2 (ƒ2=30), and between

phosphate buffer pH 7.2 and DW (ƒ2=37). While there was insignificant difference in the

release rate of TBS between 0.1N HCl and DW (ƒ2=57) (Fig. 12B). In both formulae, the drug

release rate was higher in phosphate buffer pH 7.2 than DW and 0.1N HCl which might be

related to the effect of ionic strength of the buffer.

Fig. (12): Effect of pH on TBS release in different dissolution media where

A) T10 B) T11

Stability of TBS Matrix Tablet Formulations

Tablets containing EMS with200 mg tablet weight (T10) was selected for the stability study

due to its excellent flow characteristic and best release profile. It was subjected to the

stability study by storing them for three months at different temperatures;

30±1oC/atmospheric humidity and 40±1oC/75% RH.

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

HCl

phosphate buffer

DW


Time(min.)

perc

en

t o

f T

BS

rele

ase

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

Hcl

phosphate buffer

DW

Figure 13: Effect of pH of the dissolution medium on Brc release (F11)Time(min.)

perc

en

t o

f T

BS

rele

ase

A)

B)

Per

cen

t o

f T

BS

rel

ease

dP

erce

nt

of

TB

S r

elea

sed



The mechanical and physical characteristics of the prepared tablets

As summarized in Table (7), it was noted that formula (T10) stored at 30oC/atmospheric

humidity had mean weight of 0.2010±0.001, 0.2009±0.001, and 0.2001±0.001 g after 1, 2,

and 3 months, respectively, was insignificantly difference from the initial mean weight

(0.2006±0.001 g), while tablets stored at 40oC/75% RH showed an increase in their mean

tablet weight of 0.2010±0.001, 0.2014±0.001, and 0.2015±0.001 g after 1, 2, and 3 months,

respectively, from the initial one 0.2006±0.001 g, which could be attributed to the water

sorption behavior of KSR, which is expected based on the high hygroscopicity of the PVP

component in KSR (Sadek and Olsen, 1981), hence, highly significant increased (p < 0,001) in

their weight was observed. It was found that the formula T10 stored at 30oC/atmospheric

humidity showed thickness of 3.433±0.78, 3.432±0.70, and 3.424±1.10 mm after 1st, 2nd,

and 3rd month, respectively, which was insignificantly different. On the other hand,

thickness of tablets stored at 40oC/75% RH after 0, 1st, 2nd, and 3rd month was 3.429±0.04,

3.400±0.88, 3.392±0.89, and 3.345±0.84 mm, respectively, which was insignificantly

different too.

Formula stored at 30oC/atmospheric humidity showed hardness of 10.70±2.29,

9.750±12.73, and 10.30±6.58 mm after 1st, 2nd, and 3rd month, respectively, which was

insignificantly different. On the other hand, those stored at 40oC/75% RH showed an

increase in their hardness (>15 kg/cm2) after each of the three months of storage time from

the initial one (10.50±1.32 kg/cm2), which might be related directly to the KSR content in

these tablets indicating that a change in the structural properties in the KSR component of

the matrix and its elasticity was responsible for the increased mechanical strength of the

tablets (AlKhatib et al., 2010). This increased hardness was highly significant difference (p <

0.001). It was noted that T10 At 40oC/75% RH of storage condition showed decrease in their

tablet friability % (0.184, 0.184, and 0.162%) after 1st, 2nd, and 3rd month of storage,

respectively, in comparison to initial one (0.431%). It was noted that increasing the time of

storage was associated with a less friability loss in tablet formulations which might be due to

their increased hardness. The friability values were less than 1% indicating that formulated

tablets were mechanically stable and in accordance with the USP 30-NF 25 pharmacopoeia

requirements. Those stored at 30oC were less variable and in accordance with their

hardness. The in vitro D.T for all tested formulations was >360 min. As the concentration of

KSR 40% or more, tablets still intact and not disintegrated.



Table (7): Effect of storage on physical characteristics of TBS tablets prepared with 40%

concentrations of KSR and additives.

Formula code

Month Mean tablet weight (g)±SD

Mean thickness (mm)± C.V (%)

Mean hardness (Kg/cm2)±S.D

Friability (%)

D.T.(min.) in DW±SD

D.T.(min.) in HCl±SD

D.T.(min.) in Phosphate buffer±SD

T10 Initial 0.2006±0.001 3.429±0.04 10.50±1.32 0.431 >360 >360 >360

T10(40oC)

1st 0.2010±0.001 3.400±0.88 >15 0.184 >360 >360 >360

T10(40oC) 2nd 0.2014±0.001 3.392±0.89 >15 0.184 >360 >360 >360

T10(40oC) 3rd 0.2015±0.001 3.395±0.84 >15 0.162 >360 >360 >360

T10 Initial 0.2006±0.001 3.429±0.04 10.50±1.32 0.431 >360 >360 >360

T10(30oC) 1st 0.2010±0.001 3.433±0.78 10.70±0.24 0.453 >360 >360 >360

T10(30oC) 2nd 0.2009±0.001 3.432±0.70 9.750±1.24 0.433 >360 >360 >360

T10(30oC) 3rd 0.2001±0.003 3.424±1.10 10.30±0.69 0.438 >360 >360 >360

In vitro release characteristics of TBS tablets at 30oC/atmospheric humidity

There was no difference in the release profile of TBS in DW and phosphate buffer pH 7.2

media during the overall storage conditions of the three months. These results were

supported by similarity factor (ƒ2) which was found to be more than 54 for all the periods. In

0.1N HCl, the release profile was not different in 1st month from the zero time (64% after 6

h), whereas, there was a difference occurred in 2nd month, where the rate of TBS released

from matrix tablet was higher than that of freshly prepared one by about 12% as evidenced

by ƒ2 which was 44. This might be attributed to lowering of Tg temperature of KSR and

changing to rubbery state that facilitated the high release of TBS (Wiranidchapong et al.,

2015). After 3rd month, the release of TBS returned to be similar with the initial which might

be due to coalescence of KSR particles, resulting in the reduction of the porosity inside the

matrix tablet. Therefore, the rate of drug release decreased after storage for 3rd month in

relation to the 2nd month (Wiranidchapong et al., 2015) (Fig. 13).

In vitro release characteristics of TBS tablets at 40oC/75% RH

It was found that the release of TBS in 0.1N HCl decreased in the 1st month (52% after 6 h)

than initial (64% after 6 h), then returned to be similar to initial one after 2nd month (57%

after 6 h). Change was observed in the 3rd month (52% after 6 h) compared with the initial

release profile. These results were evidenced by similarity factor (ƒ2) as the values were 48,

52, and 48 after 1st, 2nd, and 3rd month, respectively. These results could be attributed to the

transition of KSR from glassy to rubbery state resulted in increasing rate of drug release. On

the other hand, coalescence of polymer particles resulted in reduction of the porosity inside

the matrix tablet and decreased drug release after storage for 3 months (Wiranidchapong et

al., 2015).

In DW, it was found that the release profile of TBS was not affected in the 1st month (52%

after 6 h). It decreased in 2nd month (48% after 6 h) compared with the initial one (58% after



6 h), then returned to be parallel with the initial one after 3rd month (50% after 6 h). These

results was supported by similarity factor (ƒ2) as the values were 55, 49, and 52 after the 1st,

2nd, and 3rd month, respectively.

In phosphate buffer pH 7.2, the release profile of TBS changed after 1st month (68% after 6

h), then it returned to be not different with the initial one (81% after 6 h) after 2nd & 3rd

month (69 % 70% after 6 h, respectively). These results was evidenced by similarity factor

(ƒ2) were the values after 1st, 2nd, and 3rd month were 49, 54 & 55, respectively (Fig. 14).

Fig. (13): Dissolution profiles of TBS tablets containing 40% KSR and EMS (T10) after

storage (1, 2, and 3 months) at 30oC in different dissolution media

A) 0.1N HCl B) DW C) Phosphate buffer pH 7.2

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T10 (0 time)

T10 (1st M)

T10 (2nd M)

T10 (3rd M)

Figure 22(A) : percent release of Brc in Hcl medium at different temperatures after threemonths of stability test

Time (min.)

pe

rce

nt

of

TB

S r

ele

as

e

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100 T10 (0 time)

T10 (1st M)

T10 (2nd M)

T10 (3rd M)

Figure 23(A) : percent release of Brc in distilled water medium at different temperaturesafter three months of stability test

Time (min.)

pe

rce

nt

of

TB

S r

ele

ase

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T10 (0 time)

T10 (1st M)

T10 (2nd M)

T10 (3rd M)

Figure 24(A) : percent release of Brc in phosphate buffer medium at different temperaturesafter three months of stability test

Time (min.)

pe

rce

nt

of

TB

S r

ele

as

e

A)

B)

C)

Per

cent

of

TB

S re

leas

edP

erce

nt o

f T

BS

rele

ased

Per

cent

of

TB

S re

leas

ed



Fig. (14): Dissolution profiles of TBS tablets containing 40% KSR and EMS (T10) after

storage (1, 2, and 3 months) at 40oC/75% RH in different dissolution media


0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T10 (0 time)

T10 (1st M)

T10 (2nd M)

T10 (3rd M)

Figure 22(B) : percent release of Brc in Hcl medium at different temperatures after threemonths of stability test

Time (min.)

pe

rce

nt

of

TB

S r

ele

as

e

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100T10 (0 time)

T10 (1st M)

T10 (2nd M)

T10 (3rd M)

Figure 23(B) : percent release of Brc in distilled water medium at different temperaturesafter three months of stability test

Time (min.)

pe

rce

nt

of

TB

S r

ele

as

e

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T10 (0 time)

T10 (1st M)

T10 (2nd M)

T10 (3rd M)

Figure 24(B) : percent release of Brc in phosphate buffer medium at differenttemperatures after three months of stability test

Time (min.)

pe

rce

nt

of

TB

S r

ele

as

e

A)

B)

C)

Percen

t of

TB

S r

ele

ase

dP

ercen

t of

TB

S r

ele

ase

dP

ercen

t of

TB

S r

ele

ase

d



Comparison of in vitro release characteristic of TBS tablets at 30oC/atmospheric humidity

to 40oC/75% RH

The release profile of TBS from formula T10 in 0.1N HCl was significantly different in the 1st

and 2nd month at the two selected storage conditions. After 3rd month, the release profile of

TBS was insignificantly different between each mentioned storage conditions. These results

were supported by similarity factor (ƒ2) where its values were 44, 33, and 50 after 1st, 2nd,

and 3rd month (Fig. 15A).

In DW, the release profile of TBS was insignificantly different in the three months of storage

conditions. These results was supported by similarity factor (ƒ2) as its value were 67, 74, and

94 in 1st , 2nd , and 3rd month, respectively (Fig. 15B).

In phosphate buffer pH 7.2, the release profile of TBS between the two selected storage

conditions were not different after 1st, 2nd, and 3rd month. These results was evidenced by

similarity factor (ƒ2) as the values after 1st, 2nd, and 3rd months were 69, 61 & 78,

respectively (Fig. 15C). This might be related to the mentioned reasons previously explained.

Fig. (15): Comparison of dissolution profile of TBS from formula T10 at (0, 1, 2, and 3

months) of the two selected storage conditions in different dissolution media


0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T10 (0 time)

T10(30oC)(1st M)

T10(40oC)(1st M)

Figure 24 : percent release of Brc in phosphate buffer medium at differenttemperatures after three months of stability test

T10(30oC)(2nd M)

T10(40oC)(2nd M)

T10(30oC)(3rd M)

T10(40oC)(3rd M)

Time(min.)

perc

ent o

f TBS

rele

ase

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T10 (0 time)

T10(30oC)(1st M)

T10(40oC)(1st M)

Figure 23 : percent release of Brc in distilled water medium at different temperaturesafter three months of stability test

T10(30oC)(2nd M)

T10(40oC)(2nd M)

T10(30oC)(3rd M)

T10(40oC)(3rd M)

Time(min.)

perc

ent o

f TBS

rele

ase

0 60 120 180 240 300 3600

10

20

30

40

50

60

70

80

90

100

T10 (0 time)

T10(30oC)(1st M)

T10(40oC)(1st M)

Figure 22 : percent release of Brc in Hcl medium at different temperatures afterthree months of stability test

T10(30oC)(2nd M)

T10(40oC)(2nd M)

T10(30oC)(3rd M)

T10(40oC)(3rd M)

Time(min.)

perc

ent o

f TBS

rele

ase

A)

B)

C)

Perc

ent o

f TBS

relea

sed

Perc

ent o

f TBS

relea

sed

Perc

ent o

f TBS

relea

sed



Drug release kinetics and mechanism

As shown in Table (8), where the medium was 0.1N HCl, it was found that r2 ranged between

0.8705 for T9 and 0.9995 for T3. The release data were best fitted with Higuchi model for most

formulae (diffusion model), followed by first-order in case of T4, T5 and T7 (r2 was 0. 9839,

0.9944, and 0.9452, respectively). An exception was observed with T6, where it did not follow a

definite kinetic model as the highest values of their r2 was 0.7650.

To confirm the diffusion mechanism, the data were fitted into Korsmeyer’s equation

(Korsmeyer et al., 1983). The slope (n values) were < 0.45 for the all formulae (porous

diffusion), except T2, T3, and T11 where n values were > 0.45 (n= 0.5481, 0.5204, and 0.5152,

respectively) (non-Fickian diffusion).

In DW medium (Table 9), the r2 ranged between 0.8436 for T6 and 0.9915 for T11. The release

data was best fitted with Higuchi model (diffusion model) for most formulae, followed by first-

order in case of T6 and T9 (r2 was 0. 8436 and 0.8595, respectively).

The slope (n values) were < 0.45 for the most formulae (porous diffusion), and > 0.45 for T1, T2,

and T5 (n= 0.4817, 0.4750, and 0.4596, respectively) (porous diffusion).

When the medium was phosphate buffer pH 7.2 (Table 10), it was found that r2 ranged

between 0.9939 for T5 and 0.9035 for T9, the release data were best fitted with Higuchi model

for most formulae (diffusion model), followed by first-order in case of T5, T7 and T9 (r2 was 0.

9939, 0.9342, and 0.9035, respectively). An exception was observed with T6, where it did not

follow a definite kinetic model as the highest values of their r2 was 0.7514.

The n values were > 0.45 for T1 and T5 (n= and 0.4888 and 0.5133, respectively) (non-Fickian

diffusion), and < 0.45 for the other formulae (porous diffusion).

These results showed a coupling of the diffusion and erosion mechanism and indicated that the

drug release was controlled by more than one process.



Table (8): Release kinetics of TBS from the prepared tablets in 0.1N HCl

Formula The correlation coefficient

(r2)

Release

order

Korsmeyer

model

Main

transport

mechanism

Zero

order

First

order

Higuchi

model

r2 n

T1 0.8193 0.8193 0.9689 Diffusion 0.9790 0.4434 Fickian

T2 0.9481 0.8228 0.9916 Diffusion 0.9789 0.5481 Non-Fickian


T4 0.8802 0.9839 0.9797 First 0.9521 0.3683 Fickian

T5 0.9284 0.9944 0.9841 First 0.9240 0.4452 Fickian

T6 0.5079 0.7650 0.7266 - 0.9590 0.1528 -

T7 0.7738 0.9452 0.9282 First 0.9731 0.2670 Fickian







Table (9): Release kinetics of TBS from the prepared tablets in DW

Formula The correlation coefficient

(r2)

Release

order

Korsmeyer

model

Main

transport

mechanism

Zero

order

First

order

Higuchi

model

r2 n






T6 0.6026 0.8436 0.8133 First 0.9413 0.2016 Fickian



T9 0.6069 0.8595 0.8149 First 0.9404 0.1982 Fickian





Table (10): Release kinetics of TBS from the prepared tablets in phosphate buffer pH7.2

CONCLUSIONS

Based on the obtained results it could be concluded that: The formulated tablets containing

various percent of KSR with other additives (SP.D.L, AV, or EMS) have good physical properties.

The hardness was affected by the type of filler used and KSR concentration, where tablets

containing AV had higher hardness than others. Also, further increase in KSR above 40% did not

affect the hardness values. The prepared formulae had powder flow properties ranged from fair

to excellent. The results of FT-IR and DSC of TBS in all the physical mixtures of prepared

formulae indicated that there was no interaction between the drug and the utilized excipients.

The type of filler used in the preparation of tablets had an effect on D.T. of the prepared tablets

with an order of SP.D.L < AV < EMS in DW and phosphate buffer pH 7.2 and in an order of

SP.D.L < EMS < AV in 0.1N HCl. Also, KSR gave remarkable effect on the disintegration time of

the prepared tablets, and as the KSR concentration was increased to 40% and more, the time

taken for disintegration was increased > 630 min. There were an effect of the pH of

disintegration media on the disintegration time of the prepared tablets, and this depend on the

type of the filler and percent of KSR used. The best sustained release property was attained

with formulae containing 40% KSR. The rate of drug release from tablets containing various

additives at 0% of KSR was arranged as follows; SP.D.L> AV> EMS irrespective of pH of the

dissolution media. The drug release from prepared tablets was retarded by increasing the KSR

percent to 40% using different fillers in different dissolution media. Further increase in KSR

percent up to 60% resulted in no difference with that of 40%, irrespective of filler type used or

pH of dissolution media. The drug release from prepared tablets was affected by the pH of the

Formula The correlation coefficient (r2)

Release order

Korsmeyer model

Main transport mechanism Zero

order First order

Higuchi model

r2 n





T5 0.9331 0.9939 0.9811 First 0.9321 0.5133 Non-Fickian

T6 0.4824 0.7514 0.7010 - 0.9370 0.1420 -

T7 0.7047 0.9342 0.8891 First 0.9624 0.2369 Fickian


T9 0.6435 0.9035 0.8530 First 0.9741 0.2371 Fickian





dissolution media depending on the type of the filler used. Increasing KSR percent to 40 and

60% resulted in negligible effect of pH of dissolution media except T4 in in 0.1N HCl when

compared to other media. Therefore, KSR is suitable for the manufacturing of potent drug

(<25% of tablet weight) sustained release matrix tablets. The high temperature and humidity of

storage conditions (40oC/75% RH) had an effect on physicochemical properties of the drug

tablets by increasing their weight and hardness with time. While those stored at 30oC were not.

It was noted that increasing the time of storage at 40oC/75% RH was associated with a less

friability loss in tablet formulations, while those stored at 30oC were less variable and in

accordance with their hardness. Disintegration time was not affected by storage conditions.

Tablet formulations of TBS prepared with different additives and stored at 40oC/75% RH had

difference in their stability. While those stored at 30oC were mostly not affected. The

mathematical analysis of the release data of drug showed that two mechanisms were present,

in which higuchi model was more predominant than first order.

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