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The mixing process in the production of paracetamol suspension and its

stability

Article in International Journal of Engineering Business and Management · January 2020

DOI: 10.22161/ijebm.4.3.1

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 International journal of Engineering, Business and Management (IJEBM)
Open Access [Vol-4, Issue-3, May-Jun, 2020]
https://dx.doi.org/10.22161/ijebm.4.3.1
ISSN: 2456-7817

The mixing process in the production of

paracetamol suspension and its stability
Alia Hassan Adi, Hussin Johari, Sabah Sibai

Al-Baath University, Syria.

Abstract— The mixing process is a common and important process in the chemical, food and
pharmaceutical industries with the objective of producing suspensions and emulsions and increasing the
process rate of mass and heat transfer.
In this paper, the mixing process was studied during the production of paracetamol syrup in a new formula
with a concentration of (10 g / 100 ml). For this purpose, a four-blade mixer was designed and the factors
affecting the mixing process and the stability of the final product were studied including the mixing time
and speed of rotation.
Keywords— Paracetamol, Stability Studies, Mixing Process.

I. INTRODUCTION II. MATERIAL AND METHODS

Paracetamol or acetaminophen is the common name for 1. Paracetamol production
the compound N-Acetyle-P-aminophenol or 4-Hydroxy A number of solvents (PEG 400 - PEG 6000 -
acetanilide with a molecular formula of C8H9NO2. This Glycerol) were used in the preparation of the paracetamol
compound is a white crystalline powder with a molecular syrup. The solvents were used in different proportions as
weight of 151.2 and a melting point of (168-172 ºC). It is shown in Table 1.The paracetamol sample and all the
soluble in alcohol, but has low solubility in ether or substances mentioned in Table 1 were obtained from the
methylene chloride and it dissolves partially in water (1.0 - Aphamia Pharmaceutical Industries Lab.
5.0 g / 100 ml). Similarly to phenol, it has weak acid
Initially the first phase was prepared at a temperature of
properties, as the pH of its solution is in the range (5.5-
40ºC consisting of PEG400 with paracetamol and stirred
5.6). In view of the market's need for paracetamol in high
until dissolving (we note that paracetamol does not
concentrations (10 g / 100 ml) and the lack of a suitable
dissolve until the addition of the second phase), then we
method for its production, this study was undertaken for
prepare the second phase by adding methyl paraben with
the production and stability of this drug with the required
propyl paraben and PEG 6000 to boiling distilled water and
concentrations and the production of paracetamol
stirring until dissolving. We cool the second phase to the
suspension using new solvents. A spectrophotometer was
temperature of the first phase and add local materials,
used to study the mixing process of the paracetamol
antioxidants and acidity control materials, and then we add
suspension. As is well known, the UV visible spectrum is
the second phase to the first phase, at the end we add
one of the most common techniques used in
flavorings and complete the volume with distilled water
pharmacological analysis which depends on measuring the
and then adjust the pH of the solution between (4-6).
amount of UV or visible radiation absorbed by the material
in the solution.

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 International journal of Engineering, Business and Management (IJEBM)
Open Access [Vol-4, Issue-3, May-Jun, 2020]
https://dx.doi.org/10.22161/ijebm.4.3.1
ISSN: 2456-7817

Table 1: Paracetamol Formulation

USE gr Formula Parameters
Active 100 gr C8H9NO2 Paracetamol
Solubilizer 360 ml C2nH4n+2On+1 400Polyethylene glycols
n = 8.2 to 9.1
Solubilizer 100 gr H(OCH2CH2)nOH Polyethylene glycol 6000
Solubilizer 120 ml C3H8O3 Glycerol
Preservative 1.8 gr C8H8O5 Methyl parabenSodium
Preservative 0.2 gr C10H12O3 Propyl parabenSodium
- 420 ml H2O Water
sweetening Agent 2 gr C12H19Cl3O8 Sucralose
Sweetening Agent 12 gr C4H4KNO4S Acesulfame
Flavouring Agent 2 ml - Strawberry
Flavouring Agent 2 ml - Grape flavor
Flavouring Agent 0.2 ml - Orange flavor
Colouring Agent 0.08 gr - E120Red colored
Antioxidant 1.3 gr C4H6O5 Malic acid
Acidifier 1.5 gr Na3C6H5O7 Trisodium citrate

Evaluation of Syrup:
1. Determination of pH
The pH value conventionally represents the acidity or
alkalinity of an aqueous solution. The pH value of a
solution was determined potentiometrically by means of
glass electrode. A digital pH meter could stabilize. Then
the pH meter was standardized using buffer tablets. The
suspension formulation was placed in the pH meter. The Fig.1: A four-blade electric mixer blade
reading was noted when there is no fluctuation in the pH
meter.
An experimental mixing unit consisting of:
2. Determination of density
 Electric mixer type Heidolph RZR 2020.
A pre weighed 50 ml volumetric flask was taken and the
 A four-blade electric mixer blade fig 1.
oral syrup was added up to the mark. The net volume was
 Double jacket reactor.
noted. Then the volumetric flask was weighed and the
density calculated. As the blade is designed in Figure (1) according to
the following dimensions of the mixing vessel:
3. Study the mixing process
- Internal diameter (7 cm).
The blade of a four-blade electric blender was
- External diameter (9.5 cm).
manufactured with a diameter (3.36 cm) as shown in
- Internal length (9 cm).
Figure 1. That was used in the design of the mixing unit.
- External length (12.5).
(Cheremisinoff, 2000)
- Nozzle diameter (4 cm).
- Internal nozzle height (6.5 cm).

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 International journal of Engineering, Business and Management (IJEBM)
Open Access [Vol-4, Issue-3, May-Jun, 2020]
https://dx.doi.org/10.22161/ijebm.4.3.1
ISSN: 2456-7817
- Diameter of the input and output nozzles (2.5 volume and thus we will have prepared the standard
cm). solution -1- with a concentration of (5 ppm), then to
 Water bath. prepare the standard solution - 2- It was taken from a
Spectral measurements were performed by a device type standard paracetamol solution (0.7 ml) with a standard
A simtronics UV/ Visible recording spectrophotometer pipette and the solution is placed in a volumetric flask
(single beam)Model: SE 807.with matched quartz cells (1 (100 ml) and we dilute the distilled water until the volume
cm). is complete and the solution concentration is (7 ppm), and
to prepare the standard solution -3- take (1 ml) as well
And the use of a sensitive balance type Sartorius.
From a standard paracetamol solution with a standard
(Robert H. Perry, 2008) pipette and placed in a volumetric flask (100 ml ) capacity
Standard preparation (100 mg/ml): and extended with distilled water until the volume is
0.025 g active substance (Paracetamol) was dissolved in a complete and the concentration of the solution is (10
quantity of distilled water and was shaken well. Then the ppm), then for Preparation of standard solution No. -4- A
volume was increased to (250 ml) capacity with distilled volume of (1.5 ml) is taken from the standard paracetamol
water. (Siladitya Behera*, 2012) solution by a standard volumetric pipette. The volume is
placed in a volumetric flask (100 ml) and extended with
Preparation of the calibration curve:
distilled water until the volume is complete. The
To prepare standard chain solutions, we carefully concentration of the solution is here (15 ppm). To prepare
measured (100.0 mg) of standard paracetamol and the standard solution -5- The volume (2 ml) of the
dissolved with an appropriate amount of distilled water, standard paracetamol solution is taken by a standard
then transferred to a 100 ml volumetric flask and volumetric pipette and the volume is placed in a
complete the volume with distilled water. volumetric flask (100 ml) and the solution is extended
Then it is taken from the standard paracetamol solution with distilled water until the volume is complete and the
with a standard pipette volume (0.5 ml) of the solution solution concentration here (20 ppm), as shown in table
and placed in a volumetric flask with a capacity of (100 (3).
ml) and extended with distilled water until the full
Table 2: Data stability studies for Final Formulation.
S.NO PARAMETERS INITIALS TIME PERIODS
1 MONTH 2 MONTHS 3 MONTHS
1. Color Red color Red color Red color Red color
2. Appearance Clear Clear Clear Clear
Solution Solution Solution Solution
3. Odor Stable Stable Stable Stable
4. Taste Sweet Sweet Sweet Sweet
5. pH 5.1 5.1 5 4.9
6. Assay 100.00 99.87 99.79 99.58

In this method, a series of standard solutions with known coordinate axis Y, then a straight line is taken parallel to
concentrations of the substance whose concentration is to the coordinate axis X until it cuts the straight calibration
be prepared are prepared. After reading the absorption of curve, then a straight line is dropped parallel to the
each solution at a fixed wavelength, we draw the coordinate axis Y on the coordinate axis X and the
absorption readings in terms of concentration to obtain the intersection point with the coordinate axis X The
calibration curve, and from this curve we can determine the concentration of the unknown substance.
concentration of the unknown solution after knowing its Or by the following equation:
absorption that Give her the device. The concentration is
Ctest = ( Atest × Cstd ) Astd
found by the coordinate projection process, where the
absorbance of the unknown solution is fixed on the (Siladitya Behera*, 2012)

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 International journal of Engineering, Business and Management (IJEBM)
Open Access [Vol-4, Issue-3, May-Jun, 2020]
https://dx.doi.org/10.22161/ijebm.4.3.1
ISSN: 2456-7817
Table 3: Concentrations of Paracetamol Standard chain In order to increase the picture clarity, the relationship
Solutions between the concentration and the number of mixing
Standard Concentratio Absorbance cycles was drawn at different times.
solution n The following curves were obtained as a result of the
study:
-1- 5 ppm 0.349
Absorbance curve with wavelength and at different
-2- 7 ppm 0.486
rounds number:
-3- 10 ppm 0.701
Figure 3 expresses the relationship of the absorbance with
-4- 15 ppm 1.023 the wavelength at the maximum wavelength of (λ = 243
-5- 20 ppm 1.317 nm) and at the number of rounds.
(n1 = 2000 rpm, n2 = 1650 rpm, n3 = 1300 rpm, n4 = 1060
rpm, n5 = 800 rpm)
We determine the absorbances of the standard chain
solutions by means of a UV spectrophotometer at a Table 4: Shows the relationship between the five curves of
wavelength (243 nm), and then draw the straight line wavelength with absorbance at the all rounds number.
passing through the largest number of points that express Rounds number Absorbance
the absorbances of the standard chain solutions against
2000 rpm 0.770
their concentrations, so we get the standard curve Figure 2.
1650 rpm 0.751
1.4
1.2 1300 rpm 0.745
1 1060 rpm 0.725
0.8
ABSORBANCE

800 rpm 0.710

0.6
0.4 y = 0.0647x + 0.0374
0.2 R² = 0.9986 1

0 0.8 2000 rpm

0 10 20 30 1650 rpm
0.6 1300 rpm
ABSORBANCE

CONCENTRATION
0.4 1060 rpm
800 rpm
Fig.2: Standard curve of paracetamol 0.2
Whereas, the absorbance calculations that were performed 0
190
203
216
229
242
255
268
281
294
307
320
333
346
359
372
385
on the entire research within the field mentioned in the 398

standard curve.
WAVELENGTH
1- Study the factors affecting the mixing process
of paracetamol suspension:
0.77
The mixing process was studied using the A four-blade
electric mixer blade on the experimental unit, where the
0.75
factors affecting the speed of the mixing process were 2000rpm
ABSORBANCE

studied: 0.73 1650rpm

1. Rounds number: The process was studied at the 1300rpm

0.71 1060rpm
round number (2000, 1650, 1300, 1060, 800) rpm.
2. Mixing time: The experiments were conducted at 800rpm
0.69
times (15, 30, 45, 60, 75, 90) min.
190
202
214
226
238
250
262
274
286
298
310
322
334
346
358
370
382
394

During the work, absorptivity curves with wavelength were

WAVELENGTH
drawn at the rounds number and times mentioned
previously.
Fig.3: The relationship between absorbance and
wavelength

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 International journal of Engineering, Business and Management (IJEBM)
Open Access [Vol-4, Issue-3, May-Jun, 2020]
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ISSN: 2456-7817
syrup was packed in 100 ml Pet bottle. The packed bottles
Curved concentration with rounds number: were placed in stability chamber maintained at 40 + 2 °C
and 75 + 5% RH for 3 months. Samples were collected at
The mixing process was studied by determining the
days 0, 30, 60 and 90. The analyses comprised chemical
concentration and absorption of the resulting solution at
testing of quantifiable parameters, which could possibly
different times (30, 60, 90) min.
change during storage, such as pH, drug contents, color,
In order to show the image in its graphic form, the taste, odor and drug release.
relationship between concentration and rounds number
(2000, 1650, 1300, 1060, 800) rpm, was drawn at different
times (90, 60, 30) min, As shown in the figure4. III. RESULTS
Evaluation of Syrup was carried out for various parameters
105
100
like confirmation of formation of precipitation, pH, odor,
95 and taste.
90
CONCENTRATION

85 Accelerated Stability Studies:

80
75 Conclusion:
70
65 The experimental results that started with preparing a new
60 formula for paracetamol syrup with a concentration of (10
55
50 g / 100 ml) and studying the mixing process and the factors
90 min 60 min 30 min
45 affecting it from the moment of adding the raw materials
800 1060 1300 1650 2000
and ending with obtaining the final product according to
ROUNDS NUMBER
the fixed mixing conditions of 40 ºC temperature and the
type of fixed mixer, by designing a four-blade mixing fan
Fig.4: The relationship between concentration and rounds
As in Figure (1) in proportion to the dimensions of the
number
mixing vessel used in conducting experiments and the
Curves of concentrations with times and at a different conditions for mixing changing from time and rounds
rounds number: number, and using solvents available at the local market -
Mixing time is one of the important parameters affecting PEG400, PEG6000, Glycerin - and the alternative to the
the mixing process. common solvents, the process of their stability has been
In this field, depending on the experimental results, the studied where results showed Operation It is proven that
relationship between mixing time and concentration time the new formula of paracetamol suspension is stable and
was determined at the number of different rounds: (2000, suitable for drug use.
1650, 1300, 1060, 800) rpm, As shown in the figure5. The results of the study of the factors affecting the mixing
process, first relying on drawing the standard curve of
paracetamol, through which the concentrations of the
105
95 experimental samples subsequently were determined, that
85 by increasing the number of cycles the concentration of the
75 resulting solution of paracetamol syrup increases until
65 2000 rpm reaching the complete dissolution of the paracetamol
CONCENTRATION

55
1650 rpm granules, which is necessary in producing this. The type of
45
35 1300 rpm syrup that has high concentrations as it forms transparent
25 1060 rpm crystals after a short period of time, and this indicates that
15 800 rpm
5
it does not dissolve completely, and therefore the syrup is
-5 unstable in this case and is not accepted.
0 15 30 45 60 75 90 105
TIME
This was illustrated by Figure 4, which shows the
relationship of the rounds number to the concentration
Fig.5: The relationship between concentration and time according to three times. The figure shows three curves,
representing the time curve (30) min partial dissolution of
Accelerated stability study
paracetamol with the highest dissolution rate of the
material by up to (52.7) % at the rounds number (800) rpm

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 International journal of Engineering, Business and Management (IJEBM)
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ISSN: 2456-7817
And (71.9)% at the rounds number (2000) rpm and at the [7] Maheshwari, R. K., & Rajagopalan, R. (2012). Formulation
time curve (60) min the mixing ratio increases to (75)% at and evaluation of paracetamol syrup made by mixed-
the rounds number (800) rpm and (90.9)% at the rounds solvency concept. Der Pharmacia Lettre, 4(1), 170-174.
[8] Doble, M. Perry’s Chemical Engineers’ Handbook.
number (2000)rpmand finally the ideal time is The mixing
[9] Dahlstrom, D. A., Bennett, R. C., Emmett, R. C., Harriott,
process is (90) min, which achieves degradation when the
P., Laros, T., Leung, W., & McCleary, C. (1997). Liquid-
rounds number (800) rpm reaches (98.6) % and achieves a solid operations and equipment. Perry's Chemical Engineers'
percentage (100) % at the number of cycles (2000) rpm, as Handbook, 60-125.
Figure 5 emphasized this by a concentration curve with [10] David, J. W. (1996). Effect of temperature on crystal growth
Time is in a wider field of time (15, 30, 45, 60, 75, 90) min and crystal properties of paracetamol. Journal of the
and at all rounds number (2000, 1650, 1300, 1060, 800) Chemical Society, Faraday Transactions, 92(3), 439-444.
rpm, and thus each of the following four rounds is: (2000 [11] McCabe, W. L., Smith, J. C., &Harriott, P. (1993). Unit
rpm, 1650 rpm, 1300 rpm, 1060 rpm) check the mixing operations of chemical engineering (Vol. 5, p. 154). New
York: McGraw-hill.
process in the mentioned blade pattern.
[12] Mourad,M.Bitar,D.Y.(2014).Stability Studies of
Thus, we have produced paracetamol suspension, studied Levocetirizine and Pseudoephedrine Combination in Liquid
the stability of the sample, designed a mixing blade with Dosage Forms.Faculty of Pharmacy. University of Aleppo.
the appropriate dimensions of the available mixing vessel [13] Coulson, J. M., & Richardson, J. F. (2002). Coulson &
and achieved an appropriate mixing time and complete Richardson's Chemical Engineering. V. 5. Solutions to the
dissolution of the studied paracetamol suspension as an Problems in Chemical Engineering from Volume 2.
Butterworth-Heinemann.
active substance.
The following will be studied later:
• Use mixers with other different models and compare the
experimental results obtained with the results of
experiments with new mixers that can be studied in the
future (three-blender mixer number two right-direction -
and traditional mixer three-blade number two left direction
- mixer blade number two).
• Determination of the energy consumed by the mixing
process for the selected models for experimental study, the
purpose of carrying out the necessary economic study.

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[4] Chandratilleke, G. R., Yu, A. B., &Bridgwater, J. (2012). A
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[6] Cheremisinoff, N. P. (2000). Handbook of chemical
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