Study of Formulation of Pharmaceutical Solution Form of Paracetamol in the Pediatric Clinical Practice

MED ARH. 2012; 66(1): 5-8 doi: 10.5455/medarh.2012.66.5-8

Received: October 12th 2011
Accepted: December 18th 2011
© Avicena 2012

Original paper

Study of Formulation of Pharmaceutical

Solution Form of Paracetamol in the Pediatric
Clinical Practice
Bedri Abdullahu1, Vehbi Shehu2, Azem Lajçi2, Hilmi Islami3
Department of Pharmacy, Faculty of Medicine, University of Prishtina, Clinical Centre, Prishtina, Kosova1
Drugs factory “Farmakos”, Prizren, Kosova2
Department of Pharmacology, Faculty of Medicine, University of Prishtina, Clinical Centre, Prishtina, Kosova3

A
im of the study was selection of 2 different formulations of paracetamol tion of the administration of the phen-
of 2.5% (125 mg/5 mL) in the Pediatric practice. Paracetamol is widely acetin with the increased incidence of
used in the form of the syrup, with usual percentage of acting ingredi- tumor manifestation (3, 4). Neverthe-
ent of 125mg/5mL. Material and methods: Both samples of the paracetamol less, scientific community could not de-
syrup were monitored each day regarding organoleptic features (potential velop a convincing animal model of the
changes in color, smell, transparency, crystallization, etc.), whilst in monthly research in order to prove the nephro-
intervals (1 month, 2 months, 3 months, 4 months and 5 months) content of toxic effect of the phenacetin, and the
the paracetamol was analyzed, with the spectrophotometric method (HPLC). mechanism of manifestation of these
effects remains yet unexplained.
Results and Discussion: Content of the paracetamol in both syrup formula-
Acetominophen as a primary me-
tions has not incurred any change even after a period of 6 months of storage,
tabolite of the phenacetin, does not
which showed that these two formulations are appropriate ones. From six manifest cancerogenesis effects, but in
different formulations of the paracetamol syrup in percentage of 2.5% (125 acute doses may cause bulbar centri-
mg/5ml) as more appropriate are: fifth formulation which can be considered, lobular necrosis in humans and exper-
without no doubt, as most appropriate one because of its relatively low cost, imental animals (5).
an stabilized pH, a quite likeable taste and as such also consequently accept- Therefore, a great importance today
able in the pediatric practice. In some cases, mainly during the winter, the is paid to the pharmaceutical products
crystallization of the paracetamol in the lid, walls and bottom of the bottle of paracetamol. According to the Brit-
was ascertained also. Conclusion: Syrup of paracetamol 2.5% (125mg/5mL) ish Pharmacopoeia, 2 basic methods
as per the formulation 5 experimented by our side can be recommended as of paracetamol analyses are described:
most appropriate to be produced in industrial conditions for purposes of spectrophotometric method for deter-
pediatric practice. Key words: Solutio paracetamol 2.5% (125 mg/5 mL). mination of paracetamol and HPLC
method for determination of 4-ami-
Corresponding author: prof. Hilmi Islami, MD, PhD. Institute of Clinical Pharmacology and Toxicology.
Faculty of Medicine. Prishtina University. Mob. Phone: 00377 45 437 415. Fax. 00 381 38 551 001.
nophenol. Meanwhile, in the monogra-
E-mail address: islamihilmi@hotmail.com phy as per USP 30, the HPLC method
is described for paracetamol, but with
no described methods for testing of the
1. INTRODUCTION great importance since that over dos- impurity of preparation (6).
Paracetamol is a preparation of an- age with paracetamol may cause the Nevertheless, many methods of de-
tipyretic and analgesic effects but it hepatic fulminant necroses and other fining the paracetamol in pharmaceu-
does not manifest any anti-inflamma- toxic effects (2). tical preparation are published in the
tory effect (1). In today’s time, in clin- Decrease in use of the acetomino- professional scientific literature and
ical practice, paracetamol is a safe al- phen and reduction of the administra- some of them determine also the per-
ternative for substitution of the aceto- tion of the phenacetin derives as a re- centage of 4-aminophenol in simulta-
acetic acid and the phenacetin. Due to sult which relies on some scientific re- neous manner (RP-HPLC, liquid mi-
its wide administration in the clinical searches which have researched the ac- croemulsion cromatography, capillary
practice, determination of paracetamol tion of phenacetin to kidneys and have electrophoresis, spectrophotometric
in pharmaceutical formulation is of a assumed the possibility of the connec- electrophoresis UV) (7).

MED ARH. 2012; 66(1): 5-8 • Original paper 5

Study of Formulation of Pharmaceutical Solution Form of Paracetamol in the Pediatric Clinical Practice

Propilenglycol 90 g
This is why pharmaceutical industry the best that both proposed and pre-
Alcohol 50 mL
usually utilizes granulates of the sub- pared formulations entirely fulfill re-
Cherry essence 1 mL
stance with narrow distribution (small quirements of the existing literature.
Lemon essence 0.1 mL
difference in the size of particles com- While analyzing the results of the
Citrus essence 0.1 mL
paring to average size of granulate) (8, content of paracetamol in two differ-
Mint essence 0.01 mL
9). In our pharmaceutical market, for- ent syrup formulations (125mg/mL; for-
mulations of paracetamol by different Nipagin 1g mulation 5 and 6), 6 months following
producers are also present and therefore Nipazol 0.1 g the preparation, we can conclude that
Distilled water up to 1000 mL
analyses of these formulations are im- even after this period of storage, pro-
portant regarding medical practice and Formulation 3 posed and prepared formulations have
scientific pharmaceutical community. Paracetamol 25 g not incurred any change in the percent-
Aim of this research was the analy- Sugar 500 g age of paracetamol.
ses of formulation, preparation, quality Sorbitol syrup 70% 200 mL It is a well known fact that industrial
control, and monitoring the stability of Propylene glycol 100 g preparation should have a storage time
six formulations of paracetamol syrups Alcohol 100 mL term (administration time term, valid-
Mint alcohol 1.65 mL
through HPLC and spectrophotometry ity time term) of at least 24 months, but
Peach essence 0.75 mL
methods with the UV zone, presenta- time frame for this magistral work of 6
Vanilla 0.2 g
tion and commensurate analyses of months is sufficient enough to form an
Nipagin 1.2 g
these results to regulative of Interna- opinion regarding lasting of the active
Nipazol 0.2 g
tional Pharmacopoeias. ingredients within the different phar-
Distilled water up to 1000 mL
maceutial preparations, respectively
2. MATERIAL AND METHODS Formulation 4 of the paracetamol in syrup. As nota-
Experimental work was done in the Paracetamol 25g ble, value of this coefficient is relatively
laboratory for research at the pharma- Alcohol 100 mL small , which means that changeability
ceutical factory “Farmakos”–Prizren. Glycerin (85%) 450 g of the results of the analyses from one
Prepared samples of the paracetamol Sorbitol syrup 70% 500 g sample to another is barely negligible.
syrup 2.5% (125mg/5mL) were ana- Distilled water up to 1000 mL As far as two studied formulation
lyzed in terms of their organoleptic fea- Formulation 5 are concerned (formulation 5 and 6) we
tures (potential changes in color, smell, Paracetamol 25 g think that formulation 5 is more appro-
transparency, crystallization, etc.), and Glycerin 200 g priate in terms of applying it in the prac-
the chemical stability (decrease of the Propylene glycol 100 g tice, because it has a lower cost than
content of paracetamol). Alcohol 100 mL other formulation, an stabilized pH by
Samples of the paracetamol syrup Nipagin 0.9 g the phosphatic buffered system (mix-
2.5% were monitored each day related to Nipazol 0.1 g ture of the monobasic phosphate with
their organoleptic features, while con- Monobasic sodium
15 g the dibasic phosphate) and a quite like-
phosphate
tent of the paracetamol was analyzed able and kids acceptable taste
Dibasic sodium phosphate 2.5 g
in the monthly intervals. Results presented in the below tables
Careful examination of the sam- Sugar 300 g indicate that content of paracetamol in
ples of the syrup for a time period of 6 Distilled water up to 1000 mL two formulations (5 and 6) are within
months showed no change of their or- Formulation 6 the forecasted norm.
ganoleptic features. Paracetamol 25 g
Results of analyses regarding con- Alcohol 357 mL
Formu-
Formula-
tent of paracetamol in different formu- Sorbitol 100 g Statistical indicators
tion 5
lation
Glycerin (85%) 450 g 6
lations is presented in the tables below.
Average () 24.78 24.88
See formulations 1, 2, 3, 4, 5 and 6. Nipagin 0.8 g
Standard deviation () 0.3545 0.478
Nipazol 0.2 g
Formulation 1 Coefficient variation (CV%) 1.43 1.92
Paracetamol 25 g Sodium saccharin 1g
Table 1. Results of the statistical processing
Alcohol 100 mL Distilled water up to 1000 mL
of data regarding content of the paracetamol
Sorbitol 357 g
Results gained from spectrophoto- (in percentage), in two different syrup
Glycerin (85%) 450 g formulations (2.5%) (Immediately after
metric definition of the paracetamol
Nipagin 0.8 g preparation).
in two different syrup formulations
Nipazol 0.2 g
Distilled water up to 1000 mL
(125mg/ml), 1 month, 2 months, 3
months, 4 months and 5 months follow- Statistical indicators
Formu- Formu-
lation 5 lation 6
Formulation 2 ing the preparation are presented in the
Average () 25.05 25.02
Paracetamol 25 g tables 1, 2, 3, 4, 5, 6 and 7 and the fig- Standard deviation () 0.327 0.387
Sugar syrup 400 mL ure 1. Results indicate that content of Coefficient variation (CV%) 1.306 1.546
Sorbitol syrup 70% 200 mL the active ingredient (paracetamol) has Table 2. Results of the statistical processing
not incurred any change, which shows of data regarding content of the paracetamol

6 MED ARH. 2012; 66(1): 5-8 • Original paper

 Study of Formulation of Pharmaceutical Solution Form of Paracetamol in the Pediatric Clinical Practice

(in percentage), in two different syrup

formulations (2.5%) (1 month after
as per BP, lies within a range of ±5% of lel samples, thus these results are much
preparation). the declared mass. In our research, av- reliable (14). In our case, this coefficient
erage mass of the analyzed formula- varies from 1.14% up to 1.68%, with an
tions has not exceeded this limit set as average value of 1.374%.
Formu- Formu-
Statistical indicators
lation 5 lation 6 per BP (10). Thus, author Roohullah et al. has
Average () 25.08 24.97 Paracetamol is a product of the me- defined the paracetamol disintegration
Standard deviation () 0.285 0.497
Coefficient variation (CV%) 1.14 1.99
tabolism of 4-aminophenol (p-amino- time in different percentage of polyvi-
phenol; AP) which has significant ne- nylpolividon in the temperature of 37
Table 3. Results of the statistical processing phrotoxic and teratogenic effect, there- ± 1°C in accordance to the method de-
of data regarding content of the paracetamol
fore presence of this metabolite ac- scribed in British Pharmacopoeia, 1998,
(in percentage), in two different syrup
formulations(25mg/mL) (2 months after
cording to the British Pharmacopoeia whilst the process of defining the disso-
preparation). should not exceed the rate of 0.005% lution was realized in the same condi-
in the active substance of paracetamol tions in terms of temperature according
(10). Whereas, presence of 4-aminophe- to the method also described in British
Formu- Formu-
Statistical indicators
lation 5 lation 6 nol in the pharmaceutical formulation Pharmacopoeia and realized in the Er-
Average () 24.98 25.015 of paracetamol may vary; in the mon- weka-DT equipment (15).
Standard deviation () 0.33 0.452
Coefficient variation (CV%) 1.33 1.81
ography of the paracetamol in Brit- In this research also time of disin-
ish Pharmacopoeia allowed amount of tegration was less than 15 minutes and
Table 4. Results of the statistical processing of
aminophenol in paracetamol tablet is authors concluded a positive correla-
data regarding content of the paracetamol, in
0.1% (10,12,13). tion in between the time of disintegra-
two different syrup formulations (25mg/mL)
(3 months after preparation) Permitted limit of presence of other tion and connective substance.
substances, respectively of different ex- While disintegration time of all the
cipient substances in different pharma- formulations, as per abovementioned
Formu- Formu-
Statistical indicators
lation 5 lation 6 ceutical forms, usually is not described authors, in T45 minutes was from 95 –
Average () 25.078 25.081 in a strict manner because they do not 99.2%, whereas disintegration time of
Standard deviation () 0.318 0.445 derive from the disintegration of the these formulations was from 15 minutes
Coefficient variation (CV%) 1.27 1.77
Table 5. Results of the statistical processing of
basic active substance, but their quan- up to 135 minutes. Authors in question
data regarding content of the paracetamol, in tity is determined in pharmacopoeias of have concluded that there is no correla-
two different syrup formulation s(25mg/mL) many different countries. On the other tion in between concentration of con-
(4 months after preparation) side, we are convinced that even after nective substance and disintegration
the expiry of the 6 months of storage, time (16). In our research, only 2 of first
Formu- Formu- content of the paracetamol can hardly formulations have met conditions of ve-
Statistical indicators
lation 5 lation 6 be subject to any reduction. In addi- locity of dissolution as per BP whereas
Average () 25.075 24.89 tion to this, it is well known that con- 2 last formulations have not met them.
Standard deviation () 0.422 0.45
Coefficient variation (CV%) 1.68 1.803 tent of the active ingredient reduces by Amount of dissolution of active sub-
10% (achieves an value of 90% of ini- stance in the solution (after 45 minutes)
Table 6. Results of the statistical processing of
data regarding content of the paracetamol, in tial content, or of the nominal value was not less than 70% of overall quan-
two different syrup formulations (25mg/mL) declared in the label), pharmaceutical tity of active substance. Amount of ac-
(5 months after preparation) preparations are considered to be sta- tive substance of paracetamol in phar-
ble and practically usable. In our case, maceutical formulations of paracetamol
Formu- Formu-
paracetamol syrup can be considered should be within limits of 95 – 105% of
Statistical indicators
lation 5 lation 6 stable and consequently approved le- the defined amount in the quantitative
Average () 25.063 25.07 gally to be administered, even though content of the pharmaceutical form
Standard deviation () 0.367 0.405
Coefficient variation (CV%) 1.464 1.62 content of the paracetamol would not (17, 18, 19).
Table 7. Results of the statistical processing of be 25mg/mL or (22.5mg/mL). Physical properties that have an im-
data regarding content of the paracetamol, in Regarding the accuracy of the im- portant role in defining of the dissolu-
two different syrup formulations (25mg/mL) plemented analytical method, besides tion velocity are size of granules, mo-
(6 months after preparation) values of the standard deviation, the lecular weight, hydrophilicity and crys-
calculated values of the coefficient tal structure (20). Regarding stability
of the variation provided in the table of paracetamol formulations in our re-
3. Results and discussion speaks also (1, 2, 3, 4, 5, 6 and 7). It is search, in a period following 3 months,
The results of our research were known that this statistical indicator no evident influential changes were
compared to the conditions, respec- (coefficient of the variation) assesses observed in the content of these for-
tively criteria, set by International Phar- the rate of the changeability of the val- mulations. Other authors also has as-
macopeia, respectively British Pharma- ues of results of analyses in some of the certed that there were observed no sig-
copeia (BP) and American Pharmaco- repeated proofs. Lesser the value of it, nificant changes in physical-chemical
peia (6, 10, 11). lesser is also the difference of the re- properties and dissolution velocity of
Permitted limit of mass deviation, peated analyses results in some paral- paracetamol, provided that it was stored

MED ARH. 2012; 66(1): 5-8 • Original paper 7

 Study of Formulation of Pharmaceutical Solution Form of Paracetamol in the Pediatric Clinical Practice
Graph.1. Average content of the paracetamol in two different formulation
of syrup 2.5% (within six months after preparation)
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2 months later 25.08 24.97 pulsing. Int J Pharm, 2008; 357: 132-138.
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25.078 25.081
sakoski M, Mannermaa JP, Yliruusi J. In-
4 months later
line moisture measurement during gran-
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6 months later 25.063 25.07 frared sensor: an evaluation of particle
Formulation F=1.85, p>0.24 size and binder effects. Eur J Pharm. Bi-
opharm, 2000; 50: 271-276.
Graph 1. Average content of the paracetamol in two different formulations of syrup 2.5% (within 10. British Pharmacopoeia, Paracetamol,
six months after preparation) Stationery Office, London. UK, 2004.
11. Eu ropea n Pha r macopoeia 6t h ed,
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3.
copoeia.RESULTS
In the marketAND DISCUSSION
there are many stored in appropriate conditions, as per
of a fluorimetric assay for 4-aminophenol
boxes for dispensing medicines to pa- recommendations of the existing liter- in paracetamol formulations. Talanta,
tientsofwhich
Results enable protection
our research of the with
were compared ature. Syrups prepared
conditions, as percriteria,
respectively both for-set by 2008; 75: 258-265.
paracetamol from air, humidity, and mulations resulted as stable regarding 13. Nemeth T, Jankovics P, Nemeth-Palota
International Pharmacopeia, respectively British Pharmacopeia (BP) and American J, Koszegi-Szalai H. Determination of
light by increasing the overall medi- organoleptic features, which even with
Pharmacopeia (6, 10, 11). paracetamol and its main impurity
cine compliance. Results of a research the expiry date (at least 6 months) have 4-aminophenol in analgesic prepara-
Permitted limitby
conducted ofHaywood
mass deviation, as per BP, not
and associates liesundergone
within a range of ±5%Content
any change. of the declared
of tions by micellar electrokinetic chroma-
mass.showed that paracetamol can be re- the paracetamol, defined by spectro- this
In our research, average mass of the analyzed formulations has not exceeded tography. Journal of Pharmaceutical and
limitpacked
set as per
andBP (10).in a dispensing bot- photometric method in the UV zone,
stored Biomedical Analysis, 2008; 47: 746-749.
14. Massart D. Evluation and Optimization
Paracetamol is a product
tle for medicines of the
to patients for ametabolism
period in of 4-aminophenol
both formulations of(p-aminophenol;
the paracetamol AP) of Laboratory Methods and Analystical
whichof 6has
weeks and to provide
significant adequateand
nephrotoxic pro-teratogenic
syrup haseffect,
not incurred any change
therefore presenceevenof this Procedure. New York, 1978; 58-59.
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metabolite according to the British Pharmacopoeia should not exceed the rate of 0.005% 6 months. 15. Roohullah ZI, Ali Khan J, Daud S,
by preserving physical-chemical prop- From both experimented formulations, Oba idu l la h BA . Prepa rat ion of
in the active substance of paracetamol (10). Whereas, presence of 4-aminophenol in the Paracetamol Tablets Using PVP-K30
erties of the paracetamol
pharmaceutical formulation (21).
of paracetamolwemay thinkvary;
that formulation 5 is more ap-
in the monography of the and K90 as Binders. Acta Pharmaceutica
Therefore, generally paracetamol propriate one, because it has a lower Turcica, 2003; 45: 137-145.
paracetamol in British Pharmacopoeia allowed amount of aminophenol in paracetamol
syrup indicates a high scale of stabil- cost, a very stable pH and quite like- 16. British Pharmacopoeia. Appendix XII
tablet is 0.1% (10,12,13).
ity. Results of our research enabled us able taste and as such is acceptable in A: British Pharmacopoeia Commission,
London, 2004.
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quantitative content of 6 formulations D: British Pharmacopoeia Commission,
of paracetamol that are in the pharma- 9 Conflict of interest: none declared. London, 2004.
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8 MED ARH. 2012; 66(1): 5-8 • Original paper