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www.wjpps.com Vol 6, Issue 12, 2017.
Amareshwar et al. World Journal of Pharmacy and Pharmaceutical Sciences
DEVELOPMENT AND INVITRO CHARACTERIZATION OF
PROBENCID RAPIDLY DISINTEGRATING TABLETS BY USING
DIFFERENT CO-PROCESSED SUPER DISINTEGRANTS
Amareshwar S.*1, Swathi A.1, Prashanthi Y.2, Vishwanadham Y.3, Sreekanth D.4,
Vivekananda B.1
1St.Mary’s Pharmacy College Deshmukhi (V), Pochampally (M), Yadadri- Bhongir, TS.
2Nizam Institute of Pharmacy, Deshmukhi (V), Pochampally (M), Yadadri- Bhongir, TS.
3Vishnu Institute of Pharmaceutical Education and Research, (VIPER)Narsapur, Medak, TS.
4Palamuru University University, Hyderabad, TS.
ABSTARCT
In the present work, an attempt has been made to develop fast
disintegrating tablets of Probencid. Novel method of co processed
super disintegrates technology was employed to formulate the tablets.
All the formulations were prepared by direct compression method. The
blend of all the formulations showed good flow properties such as
angle of repose, bulk density, tapped density. The prepared tablets
were shown good post compression parameters and they passed all the
quality control evaluation parameters as per I.P limits. Among all the
formulations F4 formulation showed maximum drug release i.e.,
98.16% in 30 min hence it is considered as optimized formulation. The
F4 formulation contains CP2 as super disintegrate in the concentration
of 50 mg. (CP 2 contains CCS and CP in 1:2 ratio).
KEYWORDS: Probenecid, Co Processed Super Disintegrates, CCS and CP.
1. INTRODUCTION
Over the past three decades, orally disintegrating tablets (ODTs) have gained much attention
as a preferred alternative to conventional oral dosage forms such as tablets and capsules. An
ODT could be a solid dose type that disintegrates and dissolves within the mouth (either on or
below the tongue or within the buccal cavity).
Article Received on
19 Oct. 2017,
Revised on 10 Nov. 2017,
Accepted on 01 Dec. 2017,
DOI: 10.20959/wjpps201712-10638
*Corresponding Author
Amareshwar S.
St.Mary’s Pharmacy
College Deshmukhi (V),
Pochampally (M), Yadadri-
Bhongir, TS.
vishwanadham.y@gmail.com
amar.pharma99@gmail.com
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 6.647
Volume 6, Issue 12, XXX-XXX Research Article ISSN 2278 – 4357
www.wjpps.com Vol 6, Issue 12, 2017.
Amareshwar et al. World Journal of Pharmacy and Pharmaceutical Sciences
Solid oral dose forms, particularly tablets, stay one amongst the foremost widespread due to
benefits like patient convenience, easy storage and dispensing, dose accuracy and simple
manufacturability. Major challenge for tablets producing comes from the flow properties of
the materials to be compressed. Most of the formulations (> 70%) contain excipients at
higher concentration than active drug. In recent years drug formulation scientists have
recognized that single-component excipients don't invariably give the requisite performance
to permit bound active pharmaceutical ingredients to be developed or manufactured
adequately.
Hence, there's a need to possess excipients with multiple characteristics designed into them
like better flow, low/no moisture sensitivity, superior compressibility and fast disintegration
ability. Excipients with improved practicality will be obtained by developing new chemical
excipients, new grade of existing materials and new combination of existing materials. New
mixtures of existing excipients are an interesting possibility for up excipient functionality as a
result of all formulations contains multiple excipients. One such approach for up the
practicality of excipients is co-processing of 2 or additional excipients. Comparison of ODTs
and their typical various over as they disagree within the pharmacokinetic profile and
bioavailability of a similar dose of drug. Causative relationship for mentioned variations
could also be deemed to the drug chemistry property, formulation structure, producing
method or all of them. Pharmacokinetic profile variations by suggests that of upper drug
plasma levels and general exposure may be deemed to the pregastric absorption that permits
the avoidance of first-pass metabolism, so result the security and effectiveness of the drug.
the best characteristics of a drug allow dissolution within the mouth associate degreed
pregastric absorption from an ODT includes having no bitter style, dose as low as potential
little to moderate relative molecular mass, good solubility in water and saliva, partially non-
ionized property at the oral pH.
Conversely, having short half-life and wish for frequent dosing, heavily bitter or unsuitable
style while not presumably of masking, demand of changed release may incapacitate a drug
for ODTs. The quick dissolving property of the ODTs needs fast ingress of water into pill
matrix so needs some basic approaches like max imizing the porous structure of the tablet,
incorporation of appropriate disintegrating agent and use of extremely soluble excipients
within the formulation.
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Amareshwar et al. World Journal of Pharmacy and Pharmaceutical Sciences
Excipients used in ODTs contain a minimum of one superdisintegrant (having mecnanism of
wicking, swelling or both), a diluent, a lubricator and optionally a swelling agent, a
permeabilizing agent, sweeteners and flavorings. a part of the method of crucial if a product
is an ODT involves testing a product to see however long it takes to disintegrate.
Determination of disintegration time seems to be technique dependent. Some methods are
additional discriminating than others. to supply each a typical for and consistency in
disintegration testing, we have a tendency to advocate that candidates use the USP method
for disintegration testing. three but, alternative methods that may be related to with or ar
demonstrated to supply results equivalent to the USP method can also be used and submitted
to determine disintegration time.
2. Drug Profile
Drug name : PROBENECID
Synonyms : 4-((Dipropylamino)sulfonyl)benzoic acid, Probenecid acid, 4-
(N,N- Dipropylsulfamoyl)benzoesaeure
Description : The prototypical uricosuric agent. It inhibits the renal
excretion of organic anions and reduces tubular reabsorption of urate. Probenecid has also
been used to treat patients with renal impairment, and, because it reduces the renal tubular
excretion of other drugs, has been used as an adjunct to antibacterial therapy.
CAS NO : 57-66-9
Structure
Iupac name : 4-(dipropylsulfamoyl) benzoic acid
Molecular formula : C13H19NO4S
Molecular weight : 285.359
Solubility : Water : <0.1 g/100 mL at 20 ºC
Melting point : 194-196°C
Half-life : 6-12 hours
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Amareshwar et al. World Journal of Pharmacy and Pharmaceutical Sciences
3. METHODOLOGY
3.1 Materials: Probenecid, Microcrystalline cellulose, Cross carmellose sodium, Cross
povidone, Magnesium stearate, Talc
3.2 Equipment’s used: Weighing Balance, Tablet Compression Machine (Multistation),
Hardness tester, Vernier callipers, Roche Friabilator, DissolutionApparatus, UV-Visible
Spectrophotometer, pH meter, FT-IR.
3.3 Preformulation Studies
The goals of the preformulation study are
To establish the necessary physicochemical characteristics of a new drug substance.
To determine its kinetic release rate profile.
To establish its compatibility with different excipients.
Hence, preformulation studies on the obtained sample of drug include colour, taste, solubility
analysis, melting point determination and compatibility studies and flow properties.
3.4 Determination of absorption maximum (λmax): Absorption maximum is the
wavelength at which maximum absorption takes place. For accurate analytical work, it is
important to determine the absorption maxima of the substance. Probenecid was weighed
accurately 10 mg and transferred to 100 ml volumetric flask, dissolved in 6.8 pH phosphte
buffer and the final volume was made up to 100 ml with 6.8 pH phosphte buffer to get a stock
solution (100µg/ml). From the stock solution, 1 ml was pipette out in 10 ml volumetric flask
and the final volume was made up to 10 ml with 6.8 pH phosphte buffer to get 10µg/ml. Then
this solution was scanned at 200-400nm in UV-Visible double beam spectrophotometer (UV-
3200, Labindia, India) to get the absorption maximum (λmax).
3.5 Construction of Probenecid calibration curve with phosphate buffer PH 6.8
100mg of Probenecid was dissolved in 100ml of 6.8 pH phosphte buffer to give a
concentration of 1mg/ml (1000µgm/ml). From the above standard solution (1000µgm/ml)
1ml was taken and diluted to 100ml with). 1N HCL to give a concentration of 0.01mg/ml
(10µgm/ml). From this stock solution aliquots of 0.5, 1, 1.5,2 and 2.5ml were pipette out in
10ml volumetric flask and the volume was made up to the mark with )6.8 pH phosphate
buffer to produce concentration of 5, 10,1,20 and 25µgm/ml respectively. The absorbance
(abs) of each conc. was measured at respective (λmax) i.e., 259 nm.
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Amareshwar et al. World Journal of Pharmacy and Pharmaceutical Sciences
3.6 Drug- excipient compatibility studies by FT-IR
The compatibility between the pure drug and excipients was detected by FTIR spectra
obtained on Bruker FTIR Germany(Alpha T).The potassium bromide pellets were prepared
on KBr press by grounding the solid powder sample with 100 times the quantity of KBr in a
mortar. The finely grounded powder was then introduced into a stainless steel die and was
compressed between polished steel anvils at a pressure of about 8t/in2. The spectra were
recorded over the wave number of 8000 to 400cm-1.
Flow properties: Angle of Repose, Loose bulk Density, Tapped bulk density, Carr's
consolidation index, Hausner’s ratio.
3.7 Preparation of tablets
Composition of Probenecid Dispersible Tablet by direct compression is shown in table 6.4.
All the ingredients were weighed. Required quantity of drug and excipient mixed thoroughly
in a polybag. The blend is compressed using rotary tablet machine-10 station with 9mm flat
punch, B tooling. Each tablet contains 250 mg Probenecid and other pharmaceutical
ingredients.
Table. 1: Composition of various tablet formulations.
Ingredients
F1
F2
F3
F4
F5
F6
F7
F8
F9
Probenecid (mg)
250
250
250
250
250
250
250
250
250
CP 1(mg)
50
75
100
-
-
-
-
-
-
CP 2(mg)
-
-
-
50
75
100
-
-
-
CP 3(mg)
-
-
-
-
-
-
50
75
100
Mg St(mg)
3
3
3
3
3
3
3
3
3
Talc(mg)
3
3
3
3
3
3
3
3
3
MCC(mg)
Qs
Qs
Qs
Qs
Qs
Qs
Qs
Qs
Qs
Total wt(mg)
400
400
400
400
400
400
400
400
400
3.8 POST COMPRESSION PARAMETERS
Evaluation of uncoated tablets
Shape and colour: The tablets were examined under a lens for the shape of the tablet and
colour by keeping the tablets in light.
Uniformity of thickness
Randomly 10 tablets were taken from formulation batch and their thickness (mm) was
measured using a Vernier calipers.
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Amareshwar et al. World Journal of Pharmacy and Pharmaceutical Sciences
Hardness test
The hardness of the tablets was determined using Monsanto hardness tester. It is expressed in
Kg/cm2. Six tablets were randomly picked from each formulation.
Friability test
It is the phenomenon whereby tablet surfaces are damaged and/or show evidence of
lamination or breakage when subjected to mechanical shock or attrition. The friability of
tablets was determined by using Roche friabilator (Lab India, FT 1020). It is expressed in
percentage (%). Ten tablets were initially weighed [W(initial)] and transferred into friabilator.
The friabilator was operated at 25 rpm for 4 min or run up to 100 revolutions. The tablets
were weighed again [W (final)]. The percentage friability was then calculated by,
Weight variation test: The tablets were selected randomly from each formulation and
weighed individually to check for weight variation. The U.S Pharmacopoeia allows a little
variation in the weight of a tablet. The % deviation in weight variation is shown in table.
Table. 2: Limits of Weight variation.
Average Weight Of Tablet(mg)
%deviation
130mg or less
10
> 130or <324
7.5
> 324
5
Drug Content estimation
The content uniformity test is used to ensure that every tablet contains the amount of drug
substance intended with little variation among tablets within a batch.
10 tablets were weighed and triturated. The tablet triturate equivalent to 50 mg of the drug
was weighed accurately, dissolved in pH 1.2 buffer and diluted to 100 ml with the same.
Further dilutions were done suitably to get a concentration of 10 μg/ ml with simulated
gastric fluid pH 1.2. Absorbance was read at 259 nm against the reagent blank, and the
concentrations of drug in μg/ ml was determined by using the regression equation.
Drug content in mg / tablet = conc. μg/ml * dilution factor /1000
% Drug content = drug content in mg * 100 / label claim.
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Amareshwar et al. World Journal of Pharmacy and Pharmaceutical Sciences
3.9 In -vitro dissolution studies
In-vitro release studies were carried out using a modified USP XXIII dissolution test
apparatus (Lab India, DS-800).
The dissolution fluid was 500ml of 6.8 pH phosphate buffer at a speed of 50rpm at a
temperature of 370c were used in each test. Samples of dissolution medium (5ml) were
withdrawn for every 2min and assayed for Probenecid by measuring absorbance at 259 nm.
For all the tests 5ml of the test medium were collected at specified time intervals and replaced
with same volume of 6.8 pH phosphate buffer. Details:
Apparatus used : USP II Lab India
DS 800 Dissolution Medium : 6.8 pH phosphate buffer
Dissolution Medium volume : 500ml
Temperature : 370C
Speed of paddle : 50rpm
Sampling Intervals : 2, 4, 6, 8, 10, 15, 20,25 and 30 min
Sample withdrawn : 5ml
Absorbance measured : 259 nm.
4. RESULTS AND DISCUSSION
4.1 Standard Calibration curve of Probenecid
Table -3: Concentration and absorbance obtained for calibration curve of Probenecid in
6.8 pH phosphate buffer.
S. No.
Concentration
(µg/ml)
Absorbance*
(at 259 nm)
1
0
0
2
5
0.106
3
10
0.177
4
15
0.265
5
20
0.344
6
25
0.431
It was found that the estimation of Probenecid by UV spectrophotometric method at λmax
259.0 nm in 6.8 pH phosphate buffer had good reproducibility and this method was used in
the study. The correlation coefficient for the standard curve was found to be closer to 1.
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Amareshwar et al. World Journal of Pharmacy and Pharmaceutical Sciences
Fig. 1: Standard graph of Probe necid 6.8 pH phosphate buffer.
4.2 Evaluation Parameters for Fast Dissolving Tablets of Probenecid
4.2.1 Pre-compression parameters: The data’s were shown in Table 7.2.The values for angle
of repose were found in the range of 25°-30°. Bulk densities and tapped densities of various
formulations were found to be in the range of 0.41 to 0.50 (gm/cc) and 0.50 to 0.58 (gm/cc)
respectively. Carr’s index of the prepared blends was fall in the range of 13.06% to 18.18%.
The Hausner ration was fall in range of 1.14 to 1.22. From the result it was concluded that the
powder blends had good flow properties and these can be used for tablet manufacture.
Table. 4: Pre-compression parameters.
Formulations
Bulk Density
(gm/cm2)
Tap Density
(gm/cm2)
Carr’sIndex
(%)
Hausner
ratio
Angle Of
Repose(Ɵ)
F1
0.45
0.55
18.18
1.22
27.91
F2
0.47
0.55
14.54
1.17
28.23
F3
0.50
0.58
13.79
1.16
29.34
F4
0.46
0.55
16.36
1.19
26.71
F5
0.50
0.58
13.79
1.16
29.34
F6
0.47
0.55
14.54
1.17
28.23
F7
0.50
0.58
13.79
1.16
29.34
F8
0.41
0.50
18.34
1.21
26.78
F9
0.41
0.50
18.02
1.21
26.78
4.2.2 Post compression Parameters
Weight variation test: Tablets of each batch were subjected to weight variation test,
difference in weight and percent deviation was calculated for each tablet and was shown in
the Table 7.3. The average weight of the tablet is approximately in range of 407 to 398.5, so
the permissible limit is ±5% (>250mg). The results of the test showed that, the tablet weights
were within the pharmacopoeia limit.
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Amareshwar et al. World Journal of Pharmacy and Pharmaceutical Sciences
Hardness test
Hardness of the three tablets of each batch was checked by using Monsanto hardness tester
and the data’s were shown in Table 7.3. The results showed that the hardness of the tablets is
in range of 2.0 to 2.5 kg/cm2, which was within IP limits.
Thickness
Thickness of three tablets of each batch was checked by using Vernier Caliper and data
shown in Table-7.3 .The result showed that thickness of the tablet is raging from 4.56 to 5.34.
Friability
Tablets of each batch were evaluated for percentage friability and the data’s were shown in the
Table 7.3. The average friability of all the formulations lies in the range of 0.30 to 0.51%
which was less than 1% as per official requirement of IP indicating a good mechanical
resistance of tablets.
In vitro disintegration time
Tablets of each batch were evaluated for in vitro disintegration time and the data’s were
shown in the Table 7.3. The results showed that the disintegration time of prepared tablets
were in the range of 17 to 25.33 seconds.
Assay
Assay studies were performed for the prepared formulations. From the assay studies it was
concluded that all the formulations were showing the % drug content values within 97.23 -
100.26%.
Table. 5: Post-Compression parameters.
Formulation
code
Weight
variation (mg)
Hardness
(kg/cm2)
Thickness
(mm)
Disintegration
Time (sec)
Friability (%)
Assay (%)
F1
405.9
2.5
4.59
20.33
0.43
97.23
F2
404.4
2.3
4.64
23.66
0.34
98.55
F3
410.7
2.5
4.59
25.33
0.49
98.16
F4
409.2
2.4
4.58
19.00
0.47
99.34
F5
399.4
2.3
4.59
20.33
0.49
98.16
F6
402.4
2.6
4.64
22.66
0.34
98.55
F7
401.3
2.5
4.59
20.33
0.49
98.16
F8
407.3
2.3
4.56
17.00
0.34
99.25
F9
402.32
2.3
4.56
19.45
0.34
100.26
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Amareshwar et al. World Journal of Pharmacy and Pharmaceutical Sciences
4.3 In-vitro Dissolution studies
Table. 6: In-vitro dissolution data.
Time (Min)
F1
F2
F3
F4
F5
F6
F7
F8
F9
2
15.46
10.83
49.72
24.37
13.45
12.56
28.45
39.5
12.51
4
26.63
26.72
60.16
31.68
25.67
28.34
35.28
46.35
26.38
6
35.64
36.16
68.15
49.37
31.73
34.58
48.9
56.28
35.17
8
40.38
47.46
72.56
58.35
34.56
41.29
66.83
69.71
47.37
10
46.44
58.57
78.41
74.37
41.91
52.34
72.54
76.26
54.96
15
53.64
68.25
83.27
81.34
62.48
61.32
78.17
80.14
62.56
20
69.82
73.19
87.45
88.18
76.89
67.83
82.45
85.26
78.35
25
75.67
86.87
91.35
94.65
81.19
72.54
87.16
89.54
82.34
30
80.56
90.16
94.26
98.16
89.5
79.62
92.18
95.28
89.26
In-vitro dissolution studies were carried out by using 500ml of 6.8 pH phosphate buffer in
USP dissolution apparatus by using paddle method. The dissolution studies were carried out
for about 30 min. The dissolution data for all the formulations were given in the Table 7.4.
Fig. 2: Dissolution profile of formulations prepared with CP1 as super disintegrate.
Fig. 3: Dissolution profile of formulations prepared with CP2 as super disintegrate.
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Amareshwar et al. World Journal of Pharmacy and Pharmaceutical Sciences
Fig. 4: Dissolution profile of formulations prepared with CP3 as super disintegrate.
From the tabular column 7.4 it was evident that the formulations prepared with super
disintegrate CP2 shown better drug release that is 98.16% in 30 mins.
Fig. 5: FTIR graph of pure drug.
Fig. 6: FTIR graph of optimized formula.
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Amareshwar et al. World Journal of Pharmacy and Pharmaceutical Sciences
5. CONCLUSION
In the present work, an attempt has been made to develop rapidly disintegrating tablets of
Probenecid. Novel method of co processed super disintegrates technology was employed to
formulate the tablets. All the formulations were prepared by direct compression method. The
blend of all the formulations showed good flow properties such as angle of repose, bulk
density, tapped density. The prepared tablets were shown good post compression parameters
and they passed all the quality control evaluation parameters as per I.P limits. Among all the
formulations F4 formulation showed maximum drug release i.e., 98.16% in 30 min hence it is
considered as optimized formulation. The F4 formulation contains CP2 as super disintegrate
in the concentration of 50 mg. (CP 2 contains CCS and CP in 1:2 ratio).
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