Advanced Pharmaceutical Bulletin, 2013, 3(1), 217-225

doi: http://dx.doi.org/10.5681/apb.2013.036
http://apb.tbzmed.ac.ir/

Formulation, Characterization and Physicochemical Evaluation of

Potassium Citrate Effervescent Tablets
Abolfazl Aslani*, Fatemeh Fattahi
Department of Pharmaceutics, School of Pharmacy and Novel Drug Delivery Systems Research Center, Isfahan University of
Medical Sciences, Isfahan, Iran.

ARTICLEINFO ABSTRACT

Article Type: Purpose: The aim of this study was to design and formulation of potassium citrate
Research Article effervescent tablet for reduction of calcium oxalate and urate kidney stones in patients
suffering from kidney stones. Methods: In this study, 13 formulations were prepared
Article History: from potassium citrate and effervescent base in different concentration. The flowability
Received: 7 November 2012
Revised: 18 November 2012
of powders and granules was studied. Then effervescent tablets were prepared by direct
Accepted: 22 December 2012 compression, fusion and wet granulation methods. The prepared tablets were evaluated
ePublished: 7 February 2013 for hardness, friability, effervescent time, pH, content uniformity. To amend taste of
formulations, different flavoring agents were used and then panel test was done by
Keywords: using Latin Square method by 30 volunteers. Results: Formulations obtained from
Effervescent tablets
Potassium citrate direct compression and fusion methods had good flow but low hardness. Wet
Direct compression method granulation improves flowability and other physicochemical properties such as
Fusion method acceptable hardness, effervescence time ≤3 minutes, pH<6, friability < 1%, water
Wet granulation method percentage < 0.5% and accurate content uniformity. In panel test, both of combination
flavors; (orange - lemon) and (strawberry - raspberry) had good acceptability.
Conclusion: The prepared tablets by wet granulation method using PVP solution had
more tablet hardness. It is a reproducible process and suitable to produce granules that
are compressed into effervescent tablets due to larger agglomerates.

Introduction
Effervescent tablets were designed to produce solutions a wet form as an aqueous or hydroalcoholic solution.
that release carbon dioxide simultaneously. Usually, Mannitol, PEG 6000 and water in small amounts can be
these tablets are prepared by compressing the active used as effective binder.5,6
ingredients with mixture of sodium bicarbonate and Low relative humidity (maximum of 25% or less) and
organic acids such as citric and tartaric acid.1 moderate to cool temperatures (about 25 °C or 77 °F)
Generally, these tablets are included drugs that are in the environment are essential to prevent sticking
solved rapidly when entered to water and they are granule or tablets to tablet press machine.5
recommended as a clear and palatable solution.2 So, In producing direct compression method, the mixtures
they can be prescribed to patients who suffered from of powder with excellent flowability, and without
swallow capsules or tablets.3The main advantages of particles segregation are needed and particle size of all
effervescent tablets are quick production of solution. raw materials should be equal. It is necessary to prepare
Thus, it is faster and better to absorb.4 granules, if particle size is small.3,7
As a source of acid, citric acid is the most used acid. In fusion method, mostly monohydrate citric acid,
Also other acids such as tartaric, fumaric, adipic, malic released its water at 54 °C in order to obtain the
acid and anhydrides and salts of acid can be used. granules by agglomeration of the particles. Granulation
Potassium and sodium carbonate, sodium and with nonreactive solution contain of ethanol or
potassium bicarbonate, arginine carbonate are used as a isopropanol, that the most components of tablets are
sources of alkali. Sodium bicarbonate is one of the insoluble in them. So, a very small amount of water
most used carbonate because of high solubility, severe (0.1-0.5%) is active solution.5
reaction and low cost.5 So, excepients such as water Effervescent tablets are produced and controlled same
soluble lubricants (e.g. PEG 4000, 6000 and sodium as conventional tablets. These controls are included
benzoate), sweeteners, flavorings and water-soluble physicochemical properties such as hardness, weight
colors are applied.5 variation, friability, solution time, pH and content
Polyvinylpyrolidone (PVP) is an effective binder of uniformity.5
effervescent tablets. It can be added as dry powder or in

*Corresponding author: Abolfazl Aslani, Department of Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of
Medical Sciences, Isfahan, Iran. Tel: +98(311)7922617, Fax: +98(311)6680011, Email: [email protected]
Copyright © 2013 by Tabriz University of Medical Sciences
Aslani and Fattahi

Potassium citrate is very soluble in water and almost convenience consumption for patients suffering from
insoluble in alcohol with very salty taste. Each g of calcium oxalate and urate kidney stones.
potassium citrate (monohydrate) consists of about 9.3
mmol of potassium and 3.08 mmol of citrate.8 Materials and Methods
Potassium citrate is used to replace sodium bicarbonate Material
in the treatment of metabolic acidosis in patients, Potassium citrate (monohydrate), sodium bicarbonate,
alkalizing agent of urine and symptomatic relief of mild citric acid (monohydrate), tartaric acid, PEG 6000,
urinary tract infections. Studies were shown that it is sodium benzoate, manitol, sorbitol and aspartame were
effective in reduction of calcium oxalate and urate procured by Merck (Darmstadt, Germany). Povidon k-
kidney stones formation and prevent from bone loss.9-12 30 (PVP) was purchased from Rahavard Tamin
So, studies are shown that oral supplements of (Tehran, Iran). Orange flavoring agent was procured
potassium prevents hyperkalaemia from it due to the from Kagawa (China) and raspberry, strawberry, cherry
high absorption from the gastrointestinal tract but and lemon flavoring agents were prepared by Farabi
slowly.12 pharmaceutical Company, (Isfahan, Iran).
Products of potassium citrate are available in
pharmaceutical world market in the forms of: tablet (5, Preformulation
10, and 15 mEq potassium citrate, Urocit®-K), Firstly, the formulas were made up in the different
effervescent powder (1500 mg equivalent to 13 mEq stoichiometric ratios from tartaric acid, citric acid and
potassium citrate, Effercitrate®) and oral solution.8 sodium bicarbonate based on below reactions.
Although the mentioned dosage form are available in According to Table 1, materials of each formulation
the pharmaceutical market, none of them are held were weighed and then 2700 mg of monohydrate
accountable for patient requirement, because high potassium citrate was added to each formulation.
doses of drug are needed for patients with calcium and Finally, after preparation of appropriate mixture, the
urate kidney stones. lubricants including 30 mg of PEG 6000 and 10 mg of
These patients are using the drug into two forms: 1) a sodium benzoate were added the mixture and then the
pharmaceutical dosage form with a low dose and high tablets compressed by using a single-punch press
frequency consumption or 2) the bulk of the raw machine (KILIAN & CO, Germany). For next stages,
materials. Until now in the pharmaceutical market, this the better stoichiometric ratios were selected with
potassium citrate effervescent tablet with 25 meq does regard to three factors: solubility, effervescence time
not exist. It is a new and applications design. and pH.
The aim of this study is design, formulation and
preparation of the potassium citrate effervescent tablets H3C6H5O7.H2O+3NaHCO3 Na3C6H5O7+4H2O+3 CO2
containing 25 mEq monohydrate potassium citrate.
These tablets will help to physicians prescribing and H2C4H4O6 + 2NaHCO3 Na2C4H4O6 + 2H2O + 2CO2

Table 1. Composition of preliminary formulations (ratio) with their effervescence time, pH and solubility (Mean ± SD).

Formulations Tartaric acid Citric acid Na bicarbonate Effervescent time(s) pH *Solubility

S1 - 0.5 0.5 105 ± 2.08 5.9 ± 0.05 3
S2 - 0.5 1 40 ± 1.52 6.2 ± 0.1 3
S3 1 0.5 1 39 ± 1.51 6.1 ± 0.04 1
S4 0.5 1 1 36 ± 2 6.1 ± 0.05 2
S5 - 1 1 50 ± 2.13 5.9 ± 0.06 5
S6 1 1 1 48 ± 2.01 6.1 ± 0.06 2
S7 1.5 0.5 1 52 ± 1.8 6.1 ± 0.1 2
S8 2 0 1 55 ± 1.83 6.1 ± 0.08 1
S9 - 1 1.5 43 ± 1.51 6.1 ± 0.7 4
S10 - 1 0.5 30 ± 3.11 5.6 ± 0.4 4
S11 - 1.5 1.5 25 ± 2.13 5.6 ± 0.05 5
S12 - 1.5 1 49 ± 1 5.6 ± 0.04 4
S13 - 2 2 20 ± 2.07 5.5 ± 0.06 4
*Solubility was defined by Likert Scale from 1= very poor, 2 = poor, 3 = average, 4 = good and 5 = excellent

218 | Advanced Pharmaceutical Bulletin, 2013, 3(1), 217-225 Copyright © 2013 by Tabriz University of Medical Sciences
Formulation and Evaluation of Potassium Citrate Effervescent Tablets

Methods of Potassium Citrate Effervescent Tablets punch press machine (KILIAN & CO, Germany), with
Production 25 mm punch set. Finally, they were dried and packed
Direct Compression with the previous methods.
According to Table 2, raw materials of each
formulation were weighed and were mixed in a Wet granulation Method
tumbling cubic blender for 15 minutes. Wet granulation was performed on F5 and F6
After the preparation of the primary powder mixtures, formulations. First, citric acid and sodium bicarbonate
sweeteners including aspartame, sorbitol, mannitol and and potassium citrate were milled by using miller so
fruit flavoring agents were passed through the that all powders were passed through sieve No. 35 and
appropriate mesh and were added to the powders and were blended for 10 minutes. Then 9.5 % w/v PVP
these were mixed altogether for 5 minutes. Finally, the solution in absolute ethanol was added with the
selective lubricants including sodium benzoate (10 mg) mixture, so that white pasty mass was formed. This wet
and PEG 6000 (30 mg) were added and again mixed for mass was passed through sieve No. 20 and the granules
about 2-5 minutes with other material. were dried in an oven at 54 °C for 75 minutes. So, the
Then, the powders were compressed into tablets by dried mass was passed through sieve No. 20 and the
using a single-punch press machine (KILIAN & CO, other ingredients were added to them like as fusion
Germany), with 25 mm punch set. Weight of each method. The granule mixtures were compressed into
tablet was considered about 4.5 g. At the end, the tablets by using a single-punch press machine (KILIAN
tablets were dried in an oven with air circulation at & CO, Germany), with 25 mm punch set. Prepared
54°C for 1 hr and after cooling were packed in plastic tablets were dried in an oven with air circulation at 54 °
tubes. C for 90 minutes, then were wrapped in Aluminum foil
and were packaged in plastic tubes.
Table 2. Different components of prepared tablets from the
direct compression (D) and fusion (f) methods.
Precompression Tests
Formulations Particle Size Analysis
Ingredients (mg) The average particle size of powder mixture was
F1 F2 F3 F4 F5 F6 determined by sieve analysis method. 100 grams of
powder mixtures and granules poured on the upper
K citrate 2700 2700 2700 2700 2700 2700 sieve. Series of sieve were placed on ERWEKA
Citric acid 570 850 850 850 850 850 shaking apparatus for 10 minutes after this period; the
amount remaining on each sieve was measured.13
Na bicarbonate 500 750 750 750 750 750 The mean diameter of the powders was calculated by
equation (1).
Mannitol - - 60 120 - 60 𝑋𝑖 𝑑𝑖
𝑑= Eq.1
100
Sorbitol - - - - 60 -
xi = The average size of both upper and lower sieve
Aspartame - - - - - 1.5 di = The percentage of the amount of i in limited area
by two sieves.
Fusion Method Flowability
According to the formulations which are shown in For evaluation of powder flow, the angle of repose,
Table 2, amounts of citric acid, sodium bicarbonate, compressibility index and Hausner´s ratio can be used.
potassium citrate and mannitol (sorbitol) were weighted
accurately and were mixed for about 15 minutes in a Angle of Repose (α): The powder or granule mass was
tumbling cubic blender. Then, the obtained mixture passed from the funnel. Angle of repose was
was placed in an oven at 54 °C. The powder was mixed determined by equation 2.
regularly until the crystallization water of citric acid The average of three measurements was interpreted
was released as binder factor (approximately 30 according to USP NF. 2008.14
minutes). After obtaining an appropriate pasty mass, 𝐻𝑒𝑖𝑔 ℎ𝑡
this wet mass was passed through sieve No. 20 and the tan α = Eq. 2
0.5 Base
obtained granules were dried in an oven at 54 °C for 1 Height: The height of the formed cone
hr. After drying, for second times the granules were Base: Diameter of the formed cone
passed through sieve No. 20.
In the next stage, sweeteners and flavors were added Compressibility Index and Hausner´s Ratio: For
with the granule mass and mixed for 5 minutes with measurement of bulk density, 100 grams of powders
other material. and granules was poured into the graduated cylinder
At last, the lubricants including sodium benzoate (10 (250 ml) using a glass funnel and its volume is
mg) and polyethylene glycol 6000 (30 mg) were added recorded.
and mixed for 2-5 minutes with other material. The m
ρ bulk = Eq. 3
granule mixtures compressed into tablets by a single- V bulk

Copyright © 2013 by Tabriz University of Medical Sciences Advanced Pharmaceutical Bulletin, 2013, 3(1), 217-225 | 219
Aslani and Fattahi

Tapping to cylinder containing the powder continued dissolution end. The obtained weight difference was
until no further volume changes occur. Tapped density shown the amount (mg) of CO2 per tablet. The CO2
is obtained from the following equation. content reports are averages of 3 determinations.15
m
ρ tapped = Eq. 4
V tapped Evaluation of the Water Content
Compressibility Index and Hausner´s ratio parameters 10 tablets of each formulation were dried in a
obtained by using the mean of three measurements desiccator containing of activated silica gel for 4 hours.
from ρbulk and ρtapped and were compared according to Water content of 0.5% or less is acceptable.15
the USP NF.2008.14
ρ tapped −ρ bulk Assay
Compressibility Index = 100 × Eq. 5
ρ tapped
The first, 3 effervescent tablets of potassium citrate was
ρ tapped
Hausner´s Ratio = Eq. 6 triturated and 347 mg of crushed powder (Equivalent to
ρ bulk
200 mg of anhydrous potassium citrate) accurately
Post compression Tests weighed and was dissolved in 25 ml of acetic acid
Measurement of Tablet Hardness glacial. Added 2 drops of crystal violet TS solution and
Hardness of tablets was determined according to the titrated with 0.1N perchloric acid VS (USP) to a green
USP for 10 tablets of each formulation by using a end point. The same steps was done on a blank solution
hardness tester (Erweka, 24-TB, Germany). prepared from effervescent tablets of potassium citrate
Hardness of effervescent tablets is usually lower than without active ingredient and was made any necessary
conventional tablets and minimum of acceptable correction. In the titration, the prepared blank was
hardness of uncoated tablets is 40 N approximately.1 consumed perchloric acid and corrected volumes were
required. Each ml of 0.1N perchloric acid is equivalent
Measurement of Tablet Thickness to 10.21 mg of anhydrous potassium citrate. 14 2700 mg
The thickness of 10 tablets from each formulation was of hydrated potassium citrate is equivalent to 2550.194
determined by using calibrated collies. Average anhydrous potassium citrate. Of course, in this assay
fluctuations of thickness, should not exceed more than other alternative methods such as atomic absorption
5 % of its normal limits.1 can also be used.
mg
N × V corrected by blank = Eq.7
Friability 108 .14
20 tablets of each formulation was taken randomly and N: Normality of standardized acid by potassium
after weighting altogether, were placed in the friabilator biphthalate according to USP
chamber (Erweka, TAP, Germany) for 4 minutes at 25 mg: milligram of hydrated potassium citrate
rpm. If weight loss is greater than 1% is unacceptable.1 108.14: Eq of hydrated potassium citrate

Evaluation of Weight Variation Evaluation of Content Uniformity

20 tablets of each formulation were weighed 10 tablets of each formulation were selected at random
individually and the mean of weight were determined. to measurement of the active ingredient amount. None
According to the USP for tablets with weight more than of the tablets should not be out of range (90-110 %) of
324 mg, among 20 tablets; just two tablets can be out mention amounts in formula, and coefficient of
of the 5% of the average weight and none deviated by variation (CV) should not be more than 6. If only one
more than twice that percentage.14 tablet was out of previous range and range of 80 – 120
%, 20 tablets must be tested. Among these 20 tablets,
Measurement of Effervescence Time anything of them should not be out of range 90-110
A single tablet was placed in a beaker containing 200 percent.14
ml of purified water at 20 °C ± 1 °C. Whenever a clear
solution without particles was obtained effervescence Determination of the Equilibrium Moisture Content
time has finished.15 Three desiccators were prepared containing saturated
The mean of three measurements of each formulation salt solutions of potassium nitrate (for creation 90%
was reported. RH, at 18 °C), sodium chloride (for creation 71% RH,
at 18 °C) and sodium nitrite (for creation 60% RH, at
Determination of Effervescent Solution pH 18 °C). Three tablets of each formulation were placed
pH solution was determined with one tablet in 200 ml in desiccators. Then, the equilibrium moisture content
of purified water at 20 ± 1 °C by using pH meter was determined by Karl Fischer method and the
(Metrohm, 632, Switzerland), immediately after autotitrator device (Mettler, TOLEDO-DL53,
completing the dissolution time.15 This experiment was Switzerland) in the first day and after 7 day.14
repeated 3 times for each formulation.
Evaluation of Prepared Tablets Taste
Measurement of CO2 Content Before beginning the evaluation, the taste ability of
One effervescent tablet solved in 100 ml of 1N sulfuric volunteers was measured by four base tastes (salt,
acid solution and weight changes were determined after

220 | Advanced Pharmaceutical Bulletin, 2013, 3(1), 217-225 Copyright © 2013 by Tabriz University of Medical Sciences
Formulation and Evaluation of Potassium Citrate Effervescent Tablets

sweet, sour, bitter) by 20 ml of 0.2% sodium chloride, In all time of experiments, the standard conditions of
2% sucrose, 0.07% citric acid, and 0.07% caffeine in panel test were considered such as temperature equal to
water respectively.16 21°C, 20 minutes distance from the previous samples,
To evaluate the taste, panel tests were performed by samples with similar concentrations of drugs and have
Latin Square method. The first, with the help of 5 been done without exchanging the volunteers' idea.16
volunteers, 7 flavors which were added to F6
formulation (optimum formulation), were examined Results
(Table 3). Thus, the volunteers were asked to score Results of preformulation study is shown that
each of the formulation from 1 = very bad, 2 = bad, 3 = formulations with stoichiometric ratios 1:1 and 1.5:1.5
no taste, 4 = good and 5 = excellent taste based on (S5, S11) were selected as the appropriate base
Likert Scale. formulations in tableting process, and with better
At next stage, another 30 volunteers were asked to give physicochemical characteristics.
points to the 2 selected flavors of early stages from 1 = Results from characterization of the powder
very bad, 2 = bad, 3 = no taste, 4 = good and 5 = formulations containing of the particle size distribution,
excellent taste based on Likert Scale. angle of repose, compressibility index and Hausner´s
ratio are given in the Tables 4, 5 and Figure 1.
Table 3. Different flavors were used for panel test of potassium The results of obtained from tablets evaluation are
citrate effervescent tablets. presented for hardness, friability, tablet thickness,
Code Flavoring agent Amount (mg) effervescence time, pH, weight variation, water and
CO2 content, content uniformity and equilibrium
A Raspberry 4.4
moisture content properties are given in the Tables
B Strawberry 4.4 5,6,8, too.
C Cherry 4.4 The particle size distribution of three manufacturing
D Orange 4.4 methods is listed in Tables 4 and 5. The mean
E Lemon 8.8 diameters of granules were greater than the powders.
Figure 1 shows the particle size distribution diagram of
F Orange & Lemon 4.4 & 8.8
F5 formulation which has normal distribution.
G Raspberry & strawberry 4.4 & 4.4

Table 4. The mean diameter, particle size distribution and percentage on each sieve of the obtained formulations from direct
compression (D) and fusion (f) methods.

Sieve number
Formulations Mean diameter(μ)
<20 20-25 25-30 30-35 35-40 40-70 70-100 >100

D1 1.69 1.46 5.64 5.29 1.62 47.9 16.13 20.28 311.42

f1 2.59 3.08 8.06 5.74 1.25 48.41 12.73 18.15 340.63

D2 1.9 2.73 6.62 6.66 1.28 45.42 16.1 19.29 326.08

f2 2.33 2.17 6.57 6.62 1.44 67.74 7.08 6.05 360.47

D3 1.52 2.01 4.59 5.67 1.17 48.04 13.63 23.38 307.95

f3 3.05 3.47 7.69 7.91 1.92 55.45 12.41 8.09 367.03

D4 1.8 2.09 5.25 4.52 1.6 44.47 13.85 26.42 304.59

f4 7.02 4.31 7.39 6.64 0.62 51.63 8.76 13.62 381.84

D5 1.84 2.24 3.06 6.56 12.55 50.86 12.51 10.38 347.48

f5 3.02 2.74 3.9 6.26 12.94 57.55 8.08 5.51 373.05

D6 1.41 2.06 4.5 4.43 1.77 44.66 16.36 24.82 299.12

f6 8.53 3.07 6.33 5.04 0.75 44.93 13.36 17.98 363.39

Copyright © 2013 by Tabriz University of Medical Sciences Advanced Pharmaceutical Bulletin, 2013, 3(1), 217-225 | 221
Aslani and Fattahi

Table 5. Particle size distribution, mean diameter and flowability of obtained granules in wet granulation method together with tablets
characteristics for G5 and G6 formulations.

Formulations - G5 G6

<16 0.28 0.04

16-20 2.26 2.68
20-25 7.73 21.17
25-30 11.09 33
Sieve number
30-35 16.08 6.74
35-40 22 0.51

40-70 33.66 30.33

>70 6.9 5.52
Mean diameter (μ) 471.2 556.71
Hausner´s ratio 1.06±0.01 1.08±0.02
Flow Properties Compressibility index 5.73±0.66 7.6±2.14
Angle of repose 15.076±0.12 14.713±0.59
Weight variation 4.401 ± 0.113 4.416 ± 0.063
Hardness 78.85 ± 2.26 65.05 ± 2.72

Content uniformity, (%CV) 2744 ± 97.5 (3.55) 2742 ± 54.9 (2.0)

Water content 0.0405 ± 0.01 0.0096 ± 0.005
Tablet thickness 5.97 ± 0.06 6.048 ± 0.06
Tablets characteristics
Effervescence time(s) 132 ± 2 112.7 ± 2.52
pH solution 5.8 ± 0.02 5.8 ± 0.02
CO2 content 313 ± 13 423 ± 16

Assay (mg) 2700 ± 40 2720 ± 20

Friability (%) 0.973±0.02 0.936±0.05

Range of hardness in obtained formulations of direct

compression method (D) was varied from 15 N to 22 N
and obtained granules from the fusion method (f) were
shown a slight increase from 20 - 25 N (Table 6).
Produced tablets were evaluated by hardness, weight
variation, tablet thickness, friability, effervescent time,
pH, content uniformity, water and CO2 content. These
values are reported in Table 5. In Table 5, hardness was
shown threefold increase in wet granulation method.
In this study, at 60 % RH and 18°C, the variation in
percentage of equilibrium moisture content after 7 days
was nothing, but, at 90 % RH and 18°C, it was most.
For correcting the potassium citrate effervescent tablet
tastes, in the first stage, volunteers selected orange –
Figure 1. Particle size distribution diagram of F5 in direct lemon and strawberry - raspberry flavors. Figure 2 is
compression (D), fusion (f) and wet granulation (G) methods shown means of obtained results from the 30 volunteers
in the panel test by Latin Square method. Both of
According to the results in Table 7, PVP 0.5 % (w/w) desirable flavors had good acceptability.
and sieve No. 20 were chosen considering hardness and
effervescence time.

222 | Advanced Pharmaceutical Bulletin, 2013, 3(1), 217-225 Copyright © 2013 by Tabriz University of Medical Sciences
Formulation and Evaluation of Potassium Citrate Effervescent Tablets

Discussion
The pharmaceuticals which are suitable for formulation
of the effervescent tablets should have specific
particulars such as quick absorption of drug, good
dissolution in water and high dose.17 These particulars
were existed in potassium citrate.
Potassium citrate recommended for the people who
suffer from urate and calcium kidney stones. One study
which was done on 500 patients with recurrent kidney
stones showed potassium citrate have been reduced the
prevalence of kidney stones from two stone to half
stone in a year.8 Also, these patients need to consume
large amount of water daily, thus, solution of
effervescent tablet in the water could remove this need.
Currently, patients are taking potassium citrate into
form of raw material powder. This kind of usage is not
desirable for flavor and is not the exact for the
consumption dosage. Therefore, the main objective of
this study is design and formulation of potassium
citrate effervescent tablets which have good taste and
Figure 2. Evaluation of prepared tablets taste by Latin Square also have certain dosage. The main uses of these tablets
method. are reduction of calcium oxalete and urate stones in
patients with kidney stones.

Table 6. Flowability properties and hardness of tablets obtained from direct compression (D) and fusion (f) methods (Mean ± SD).

Formulations
Flowability properties
F1 F2 F3 F4 F5 F6

Angle of repose (D) 27.42±1.06 29.9±0.75 26.7±0.02 26.06±0.85 27.05±0.0 26.38±1.37

Angle of repose (f) 24.03±1.17 25.17±1.13 24.48±1.33 24.12±1.73 26.06±0.99 24.9±1.76
Hausner´s ratio(D) 1.103±0.06 1.142±0.0 1.099±0.01 1.087±0.01 1.13±0.01 1.12±0.0
Hausner´s ratio (f) 1.083±0.01 1.095±0.01 1.073±0.01 1.066±0.0 1.083±0.01 1.08±0.01
Compressibility index (D) 9.33±1.94 12.48±0.64 9.08±1.33 7.99±0.66 11.50±1.02 11.07±0.65
Compressibility index (f) 8±0.78 8.75±1.26 6.813±0.75 6.2±0.62 7.677±0.7 7.437±0.64
Hardness (Newton) (D) 15±2.34 17±3.54 17±3.96 17.5±5.11 22±4.26 17.5±5.16
Hardness (Newton) (f) 20±4.81 20±5.21 20±2.85 23±3.49 25±6.53 22±4.73

Table 7. Relationships between (%PVP /tablet, Sieve No) and (hardness, effervescence time) in formulation G6 (Mean ± SD).

Independent properties Dependent properties

PVP (% W/W) /tablet Sieve No. Hardness (N) Effervescence time (s)
0.34 20 52.9±6.5 125±1.11
0.36 20 55.5±4.81 138±1.52
0.43 40 68.25±5.49 180±1.83
0.43 20 68.75±3.51 162±1.74
0.45 16&20 53.5±4.16 140±2.21
0.45 20&25 36.66±2.32 130±1
0.5 20 66.75±2.12 170±2.03
0.67 16&20 112.4±3.95 187±0.57
1 20 90.83±4.45 240±1.51

Copyright © 2013 by Tabriz University of Medical Sciences Advanced Pharmaceutical Bulletin, 2013, 3(1), 217-225 | 223
Aslani and Fattahi

Table 8. Equilibrium Moisture Content (%) in the G5 and G6 effervescent tablets (Mean ± SD).

G5 G6
Microclimates
1st Day 7th Day Variation 1st Day 7th Day Variation

60% RH, 18°C 11.31±0.96 11.42±0.77 0.10 10.02±0.46 10.13±0.74 0.11

71% RH, 18°C 11.81±0.47 14.86±0.51 3.05 10.64±0.84 13.51±1.43 2.88

90% RH,18°C 12.09±1.1 22.39±0.96 10.30 11.28±0.61 14.44±0.82 3.15

Ratios of effervescent components in the formulations Thickness of the tablets must be between 6.1 ± 0.3 mm,
of S5 and S11 were led to better solubility, pH less than that the results are acceptable regarding to
6, and an appropriate effervescent reaction. In the next pharmacopoeia standards (USP NF.2008).
steps, this stoichiometric ratios were used for the According to the USP, in the tablets which their weight
preparation of effervescent tablets (Table 1). In are more than 324 mg, among 20 tablets, just 2 tablets
comparison of formulations containing tartaric acid, can be exceed from ± 5 % of the weight average (for G5
this result was obtained: tartaric acid should remove ± 221.14 and for G6 ± 221.21) that the result are
from the formulations because of low solubility and acceptable.14
much precipitation. pH less than 6 is necessary to increase the absorption of
The mean diameter of particles in the wet granulation effervescent tablets, that pH of two optimum
method is larger than the average diameter of the formulations is less than 6. The equal pHs in different
particles in the two other methods due to the adhesion samples of one formulation indicate that granule
of smaller particles and formation of larger particles mixtures are uniform. In other study on effervescent
(Tables 4 and 5). granules containing citric acid and sodium bicarbonate
Accordingly to Figure 1, diagram peak of f5 is drawn has been done, solution pH which is obtained from
upward and is drawn to the right for G5 which is dissolving granules was measured at 5.64. It is
representative of particle size increase in granulation. comparable with the results in this study.15
Angle of repose is lessened in the produced granules Effervescence time of tablet must be less than 3
due to shape changing into sphere and contact level minutes that the results are indicated this subject.15
deduction. In the studied formulations, CO2 contents of G5 and G6
As results showed, angle of repose reduced in fusion were 313 and 423 mg, respectively. One study has been
and wet granulation methods. For example, angles of shown that amount of carbon dioxide in 2.5 g
repose of D6, f6, G6 (the same formulations, but effervescent tablets containing of aspirin (prepared by
different manufacturing methods) report: 26.38, 24.496 direct compression method) were measured at 242 mg19
and 14.713, respectively (Tables 5 and 6). Hausner´s and other study reported that in each grams of formulas
ratio and compressibility index are reduced in fusion containing of citric acid and sodium bicarbonate CO2
and wet granulation methods. Granulation (fusion or content was 292 mg which is comparable with the
wet) increases flowability and decreases angle of results.15 In the formulation G5, lower level of CO2 was
repose due to increasing of particle size and shape obtained. In this formulation, sorbitol exists which is a
changing into sphere, but these changes are higher in hygroscopic matter. Absorbed moisture by sorbitol
the wet granulation. In other study, the results were causes beginning of an effervescent reaction in the
extracted similar to our results.18 small scale.
Tablets' hardness of D5, f5 and G5 (the same As Table 5 shows, the friability of tablets was
formulations but different manufacturing methods) satisfactory, attributed by the acceptable hardness.
were 22, 25, and 78.85 respectively. Wet granulation In the formulation G5 and G6, water content was gained
improves hardness of tablet due to internal porosity 0.0405 and 0.0096, respectively. Reason of higher
granules and the plastic deformation.18 Also, for water content in formulation G5 is the presence of
hardness increasing, the dry forms of binder such as sorbitol and the absorption of moisture. The prepared
mannitol , sorbitol and PVP were used, but, the desired tablets by the wet granulation have very low water
results were not found. Then wet granulation method content due to getting temperate during drying process.
using PVP was performed on the best formulations (G5 Effervescent materials are hygroscope highly and they
and G6).These formulations were better because of are susceptible for degradation by air humidity. Of
flowability and they had not capping and sticking in the course potassium citrate is a hygroscopic substance
manufacturing process. Increasing PVP percentage was since potassium citrate effervescent tablets are
found to enhance the hardness and effervescence time containing large amounts of active ingredient; much
(Table 7). In the other study was shown that wet ability will have to absorb moisture. Consequently,
granulation technique could improve compressibility possibility of effervescent reaction beginning and
and flowability properties and hardness that the results instability is high in these tablets. So it is necessary to
were in agreement with this study.15 determined that the provided tablets are stable up to

224 | Advanced Pharmaceutical Bulletin, 2013, 3(1), 217-225 Copyright © 2013 by Tabriz University of Medical Sciences
Formulation and Evaluation of Potassium Citrate Effervescent Tablets

what moisture percent. At 60 % RH and 18°C, the systems. 8th ed. Philladelphia: Lippincott Williams
variation in percentage of equilibrium moisture content & Wilkins; 2010.
after 7 days was alittle, thus, the granules ready to be 3. Swarbrick J, Boylan JC. Encyclopedia of
compressed into tablets aren't hygroscopic mostly up to 60 pharmaceutical technology. New York: Marcel
% RH at 18°C. Also G5 formulation equilibrium moisture Dekker; 2002.
content after 7 days showed more variation because the 4. Altomare E, Vendemiale G, Benvenuti C, Andreatta
presence of sorbitol that is a hygroscopic substance. P. Bioavailability of a new effervescent tablet of
Since, the amount of active ingredient (hydrated ibuprofen in healthy volunteers. Eur J Clin
potassium citrate) can fluctuate in ranges from 2430 to Pharmacol 1997;52(6):505-6.
2970 mg and coefficient of variation percents (CV %) 5. Monrle R. Effervescent tablet in: Liberman HA,
were not upper than 6%, content uniformity of G5 and Lachman I, Schwartz J. Pharmaceutical dosage form:
G6 were in the acceptable range and the prepared tablets tablets, 2nd ed. New York: Marcel Dekker Inc; 1980.
have USP standard about amount of active ingredient 6. Callhan JC, Cleary GW, Elafant M, Kaplan G,
and the content uniformity. Kensler T, Nash RA. Equilibrium Moisture Content
As depicted in Figure 2, volunteer gave more scores to of Pharmaceutical Excipients. Drug Dev Ind Pharm
both the combination flavor of orange-lemon and 1982 8(2):355-69.
raspberry-strawberry. Strawberry-raspberry flavors 7. Saleh SI, Boymond C, Stamm A. Preparation of
took more scores compare to orange–lemon but closed direct compressible effervescent components:
results showed, selection of flavor is depending on spray- dried sodium bicarbonate. Int J pharmaceut
individual relish. 1988; 45(1-2):19-26.
8. Sweetman SC. Martindle: The complete drug
Conclusion refrence, 35th ed. London: pharmaceutical press;
In this work, it was tried to produce potassium citrate 2007.
effervescent tablets by using direct compression, fusion 9. Tekin A, Tekgul S, Atsu N, Bakkaloglu M, Kendi
and wet granulation techniques. The results of this S. Oral potassium citrate treatment for idiopathic
study show that wet granulation is a suitable method to hypocitruria in children with calcium urolithiasis. J
produce effervescent tablets of potassium citrate due to Urol 2002;168(6):2572-4.
the large size of these tablets in the pharmaceutical 10. Pak CY, Sakhaee K, Fuller C. Successful
industry. Wet granulation is one of the most common management of uric acid nephrolithiasis with
methods used for granulation in the industry. This potassium citrate. Kidney Int 1986;30(3):422-8.
method is obtained by adding a solution with (or 11. Pak CY, Peterson RD, Poindexter J. Prevention of
without) adhesive to the powder to form a wet mass. In spinal bone loss by potassium citrate in cases of
this study, the prepared tablets were acceptable under calcium urolithiasis. J Urol 2002;168(1):31-4.
the terms of pharmacopoeia standards only when PVP 12. McEvoy GK. AHFS Drug information. Bethesda,
was added as a binder during the granulation process. MD: American society of health-system
Due to particle adhesion, the prepared tablets through pharmacists; 2005.
wet granulation technique had better compression and 13. Aulton ME. The science of dosage form design. 2nd
uniformity. They had not processing problems such as ed. New York: Churchil living stone; 2002.
sticking, capping, and friction. 14. United States Pharmacopeia 31/National Formulary
Among the studied formulations, only the formulation 26. Rockville MD USA: United States
G6 was desirable for all physiochemical characteristics, Pharmacopeial Convention; 2008.
including effervescent time under 3 minutes or less, pH 15. Yanze FM, Duru C, Jacob M. A process to produce
<6, friability under 1 percentage, the water content effervescent tablets: Fluidized bed dryer melt
below 0.5 percentage, low weight variation, and correct granulation. Drug Dev Ind Pharm
content uniformity. Finally, its taste was also amended 2000;26(11):1167-76.
by adding strawberry - raspberry flavor. 16. Brich GG, Green LF, Coulson CB. Sweetness and
These tablets will help to convenience consumption of sweetners. London: Applied science publisher LTD;
potassium citrate and more acceptances of patients who 1981.
are affected by urate and calcium kidney stones. 17. Prabhakar CH, Krishna KB. A review on
effervescent tablet. Int J Pharm Technol 2011; 3(1):
Conflict of Interest 704-12.
The authors report no conflicts of interest in this work. 18. Agrawal R, Naveen Y. Pharmaceutical processing –
A review on wet granulation technology. Int J
References Pharm Front Res 2011; 1(1): 65-83.
1. Lachman L, Liberman HA, Kanig JL. The theory 19. Amela J, Salazar R, Cemeli J. Methods for the
and practice of industrial pharmacy. 3rd ed. determination of the carbon dioxide released from
Philadelphia: lea and febiger; 1986. effervescent pharmaceuticals. J pharm bely 2000;
2. Allen LV, Popovich NG, Ansel HC. Ansel's 55(2): 53-6.
pharmaceutical dosage forms and drug delivery

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