Потенціометричне кількісне визначення хондроїтин натрію сульфату з використанням іонселективних електродів
Chondroitin sodium sulfate is an anionic polysaccharide widely used in pharmaceutical practice as an active ingredient of mono- and multicomponent medicinal products, and its quantitative determination is an essential stage of the quality control. It has been found that the application of potentiome...
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| Опубліковано в: | Журнал органічної та фармацевтичної хімії |
|---|---|
| Дата: | 2026 |
| Том: | 23 |
| Випуск: | 4 |
| Сторінки: | 3-11 |
| ISSN: | 2518-1548 |
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| Автори: | , , , , , |
| Формат: | Стаття |
| Мова: | Англійська |
| Опубліковано: |
National University of Pharmacy
2026
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| Назва журналу: | Journal of Organic and Pharmaceutical Chemistry |
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Репозитарії
Journal of Organic and Pharmaceutical Chemistry| _version_ | 1874273860899045376 |
|---|---|
| author | Koptielov, Andrii S. Plyska, Vitaliia I. Bevz, Olena V. Rudakova, Olha V. Bevz, Nataliia Yu. Studenyak, Yaroslav I. |
| author_facet | Koptielov, Andrii S. Plyska, Vitaliia I. Bevz, Olena V. Rudakova, Olha V. Bevz, Nataliia Yu. Studenyak, Yaroslav I. |
| author_institution_txt_mv | [
{
"author": "Andrii S. Koptielov",
"institution": "National University of Pharmacy of the Ministry of Health of Ukraine",
"orcid": ""
},
{
"author": "Vitaliia I. Plyska",
"institution": "State University “Uzhhorod National University”",
"orcid": ""
},
{
"author": "Olena V. Bevz",
"institution": "National University of Pharmacy of the Ministry of Health of Ukraine",
"orcid": ""
},
{
"author": "Olha V. Rudakova",
"institution": "The Professional College of the National University of Pharmacy",
"orcid": "0000-0003-4216-0590"
},
{
"author": "Nataliia Yu. Bevz",
"institution": "National University of Pharmacy of the Ministry of Health of Ukraine",
"orcid": ""
},
{
"author": "Yaroslav I. Studenyak",
"institution": "State University “Uzhhorod National University”",
"orcid": ""
}
] |
| author_orcid_str_mv | 0000-0003-4216-0590 |
| author_sort | Koptielov, Andrii S. |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 11 |
| container_issue | 4 |
| container_start_page | 3 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 23 |
| datestamp_date | 2026-08-22T19:01:53Z |
| description | Chondroitin sodium sulfate is an anionic polysaccharide widely used in pharmaceutical practice as an active ingredient of mono- and multicomponent medicinal products, and its quantitative determination is an essential stage of the quality control. It has been found that the application of potentiometric titration with ion-selective electrodes can increase the accuracy and objectivity of the quantitative analysis, which is of great importance for ensuring the quality and safety of medicines.
The aim of the study was to develop and validate a potentiometric method for the quantitative determination of chondroitin sodium sulfate in the substance and in a combined medicinal product in the form of the sachet powder.
The study objects were chondroitin sodium sulfate substance and a combined medicinal product containing chondroitin sodium sulfate in combination with D-glucosamine sodium sulfate, methylsulfonylmethane, sodium hyaluronate, ascorbic and citric acids, and sorbitol. The conditions of the potentiometric titration with 0.001 M solution of cetylpyridinium chloride were studied using an ion-selective electrode based on cetylpyridinium ionic associates with some lipophilic anions. The titrant was standardized using sodium dodecyl sulfate as a primary standard, as well as the substance itself. The equivalence point was determined from the titration curve and its mathematically processed forms (differential curve, first derivative, and Gran functions).
It has been found that the plasticized membrane ion-selective electrodes based on cetylpyridinium associates with dodecyl sulfate and tetraphenylborate anions are characterized by a stable near-Nernstian response in the operating range of cetylpyridinium concentrations of 10-3-10-6 mol L-1. The analytical characteristics of the electrodes remained stable for at least 30 consecutive titrations. The selectivity of the reaction between chondroitin sodium sulfate and cetylpyridinium chloride was found, ensuring a clear determination of the equivalence point even in the presence of other mixture components. The influence of pH on the titration results was evaluated; it was shown that in the pH range of 4-8 the shape of titration curves and potential values remained constant, confirming the robustness of the method. The accuracy, precision, linearity (within 80–120% of the nominal content of the analyte), and the reproducibility of the method were characterized.
It has been experimentally demonstrated that the potentiometric method proposed is accurate, selective, and reproducible for the quantitative determination of chondroitin sodium sulfate both in pure form and in combined medicinal products. The results obtained confirm the analytical suitability of the method developed and the prospects of its implementation in the pharmaceutical analysis practice for the quality control of substances and combined medicinal products of small-scale and industrial production. |
| doi_str_mv | 10.24959/ophcj.25.350114 |
| first_indexed | 2026-03-12T15:49:16Z |
| format | Article |
| fulltext |
ISSN 2308-8303 (Print) / 2518-1548 (Online) 3
Original Research
http://ophcj.nuph.edu.ua
UDC 615.074:615.28:543.42
A. S. Koptielov1, V. I. Plyska2, O. V. Bevz1, O. V. Rudakova3, N. Yu. Bevz1, Ya. I. Studenyak2
1 National University of Pharmacy of the Ministry of Health of Ukraine,
53 Hryhorii Skovoroda str., 61002 Kharkiv, Ukraine
2 State University “Uzhhorod National University”, 3 Narodna Square, 88000 Uzhhorod, Ukraine
3 The Professional College of the National University of Pharmacy of the Ministry of Health of Ukraine,
18 Zaikivska str., 61140 Kharkiv, Ukraine
The Potentiometric Quantification of Chondroitin Sodium
Sulfate Using Ion-Selective Electrodes
Abstract
Chondroitin sodium sulfate is an anionic polysaccharide widely used in pharmaceutical practice as an active ingredient of mono-
and multicomponent medicinal products, and its quantitative determination is an essential stage of the quality control. It has
been found that the application of potentiometric titration with ion-selective electrodes can increase the accuracy and
objectivity of the quantitative analysis, which is of great importance for ensuring the quality and safety of medicines.
The aim of the study was to develop and validate a potentiometric method for the quantitative determination of chondroitin
sodium sulfate in the substance and in a combined medicinal product in the form of the sachet powder.
The study objects were chondroitin sodium sulfate substance and a combined medicinal product containing chondroitin sodium
sulfate in combination with D-glucosamine sodium sulfate, methylsulfonylmethane, sodium hyaluronate, ascorbic and citric
acids, and sorbitol. The conditions of the potentiometric titration with 0.001 M solution of cetylpyridinium chloride were
studied using an ion-selective electrode based on cetylpyridinium ionic associates with some lipophilic anions. The titrant
was standardized using sodium dodecyl sulfate as a primary standard, as well as the substance itself. The equivalence point was
determined from the titration curve and its mathematically processed forms (differential curve, first derivative, and Gran functions).
It has been found that the plasticized membrane ion-selective electrodes based on cetylpyridinium associates with dodecyl
sulfate and tetraphenylborate anions are characterized by a stable near-Nernstian response in the operating range of cetyl-
pyridinium concentrations of 10–3 – 10–6 mol L–1. The analytical characteristics of the electrodes remained stable for at least
30 consecutive titrations. The selectivity of the reaction between chondroitin sodium sulfate and cetylpyridinium chloride
was found, ensuring a clear determination of the equivalence point even in the presence of other mixture components.
The influence of pH on the titration results was evaluated; it was shown that in the pH range of 4 – 8 the shape of titration
curves and potential values remained constant, confirming the robustness of the method. The accuracy, precision, linearity
(within 80 – 120 % of the nominal content of the analyte), and the reproducibility of the method were characterized.
It has been experimentally demonstrated that the potentiometric method proposed is accurate, selective, and reproducible
for the quantitative determination of chondroitin sodium sulfate both in pure form and in combined medicinal products.
The results obtained confirm the analytical suitability of the method developed and the prospects of its implementation in
the pharmaceutical analysis practice for the quality control of substances and combined medicinal products of small-scale
and industrial production.
Keywords: chondroitin sodium sulfate; potentiometry; quality control; method validation; pharmaceutical analysis; small-
scale production
А. C. Коптєлов1, В. І. Плиска2, О. В. Бевз1, О. В. Рудакова3, Н. Ю. Бевз1, Я. І. Студеняк2
1 Національний фармацевтичний університет Міністерства охорони здоров’я України,
вул. Григорія Сковороди, 53, м. Харків, 61002, Україна
2 ДВНЗ «Ужгородський національний університет», пл. Народна, 3, м. Ужгород, 88000, Україна
3 Фаховий коледж Національного фармацевтичного університету Міністерства охорони здоров’я
України, вул. Заїківська, 18, Харків, 61140, Україна
Потенціометричне кількісне визначення хондроїтин натрію сульфату з використанням іон-
селективних електродів
Анотація
Хондроїтин натрію сульфат є аніонним полісахаридом, який широко застосовують у фармацевтичній практиці як ак-
тивний інгредієнт моно- та багатокомпонентних лікарських засобів і кількісне визначення якого є важливим етапом
ISSN 2308-8303 (Print) / 2518-1548 (Online) 4
Журнал органічної та фармацевтичної хімії 2025, 23 (4)
контролю якості. З’ясовано, що застосування потенціометричного титрування з іон-селективними електродами до-
зволяє підвищити точність і об’єктивність кількісного аналізу, що має важливе значення для забезпечення якості та
безпеки лікарських засобів.
Метою роботи були розробка та валідація методики кількісного потенціометричного визначення хондроїтин натрію
сульфату в субстанції та у складі комбінованого лікарського засобу у формі порошку в саше-пакетах.
Об’єктами дослідження були субстанція хондроїтин натрію сульфату та комбінований лікарський засіб, що містить
хондроїтин натрію сульфат у поєднанні з D-глюкозаміну натрію сульфатом, метилсульфонілметаном, натрію гіалуро-
натом, аскорбіновою та лимонною кислотами, а також сорбітолом. Розглянуто умови потенціометричного титрування
0,001 М розчином цетилпіридинію хлориду з використанням іон-селективного електрода на основі іонних асоціатів
цетилпіридинію з деякими ліпофільними аніонами. Стандартизацію титранту здійснювали із застосуванням додецил-
сульфату натрію як первинного стандарту, а також із використанням субстанції. Точку еквівалентності визначали за
кривою титрування та її математично обробленими формами (диференційна крива, перша похідна та функції Грана).
З’ясовано, що досліджувані пластифіковані мембранні іон-селективні електроди на основі асоціатів цетилпіридинію
з додецилсульфат- та тетрафенілборат-аніонами характеризуються стабільним відгуком, близьким до нернстівського,
у робочому діапазоні концентрацій цетилпіридинію 10–3 – 10–6 моль л–1. Аналітичні характеристики електродів зали-
шалися стабільними протягом щонайменше 30 послідовних титрувань. Виявлено селективність реакції між хондроїтин
натрію сульфатом та цетилпіридинію хлоридом, що забезпечує чітке визначення точки еквівалентності навіть у при-
сутності інших компонентів суміші. Оцінено вплив рН середовища на результати титрування; з’ясовано, що в діапазоні
рН 4 – 8 форма кривих титрування та значення потенціалу залишаються сталими, що підтверджує робастність мето-
дики. Схарактеризовано точність, прецизійність, лінійність (у межах 80 – 120 % від номінального вмісту аналіту) та
відтворюваність методики.
Експериментально продемонстровано, що запропонована потенціометрична методика є точною, селективною та від-
творюваною для кількісного визначення хондроїтин натрію сульфату як у чистому вигляді, так і у складі комбінованих
лікарських засобів. Отримані результати підтверджують аналітичну придатність розробленої методики й перспектив-
ність її впровадження в практику фармацевтичного аналізу для контролю якості субстанцій і комбінованих лікарських
засобів малосерійного та промислового виробництва.
Ключові слова: хондроїтин натрій сульфат; титрування; контроль якості; валідація методу; фармацевтичний аналіз;
малосерійне виробництво
Citation: Koptielov, A. S.; Plyska, V. I.; Bevz, O. V.; Rudakova, O. V.; Bevz, N. Yu.; Studenyak, Ya. I. The Potentiometric Quantification
of Chondroitin Sodium Sulfate Using Ion-Selective Electrodes. Journal of Organic and Pharmaceutical Chemistry 2025, 23 (4), 3 – 11.
https://doi.org/10.24959/ophcj.25.350114
Received: 4 September 2025; Revised: 2 November 2025; Accepted: 10 November 2025
Copyright© 2025, A. S. Koptielov, V. I. Plyska, O. V. Bevz, O. V. Rudakova, N. Yu. Bevz, Ya. I. Studenyak. This is an open access article under
the CC BY license (http://creativecommons.org/licenses/by/4.0).
Funding: The authors received no specific funding for this work.
Conflict of interests: The authors have no conflict of interests to declare.
■ Introduction
Chondroitin sodium sulfate (CS) is a sulfated
glycosaminoglycan widely used in pharmaceuti-
cal practice as an active pharmaceutical ingre-
dient in both mono- and combination medicinal
products for the treatment of degenerative disor-
ders of the musculoskeletal system, particularly
osteoarthritis. The pharmacological activity of CS
largely depends on its structural characteristics,
degree of sulfation, and molecular weight, which
necessitates a strict quality control at all stages
of the drug production [1].
In recent years, the pharmaceutical market
has shown a growing number of combined pro-
ducts containing CS together with glucosamine,
methylsulfonylmethane, ascorbic acid, and other
biologically active components. Such combinations
are aimed at enhancing the anti-inflammatory
and chondroprotective effects of these prepara-
tions [2]. Therefore, a medicinal product in the
form of powder in sachets was selected as the
object of this study. Its composition includes glu-
cosamine sodium sulfate (1500 mg), chondroitin
sodium sulfate (500 mg), methylsulfonylmetha-
ne (400 mg), vitamin C (80 mg), sodium hyalu-
ronate (30 mg), and excipients, such as sorbitol
and citric acid [3].
At the same time, the multicomponent compo-
sition significantly complicates the pharmaceu-
tical quality control since the presence of poly-
electrolytes and surfactants may affect the selec-
tivity and accuracy of the quantitative determina-
tion of CS. Recent studies indicate the substan-
tial variability in the qualitative and quantita-
tive composition of chondroitin sodium sulfate,
especially in combined medicinal products where
impurities of other polysaccharides or excipients
may be present [4]. In this regard, the implemen-
tation of reliable, selective, and reproducible ana-
lytical methods capable of providing an objective
quantitative determination of chondroitin sodium
ISSN 2308-8303 (Print) / 2518-1548 (Online) 5
Journal of Organic and Pharmaceutical Chemistry 2025, 23 (4)
sulfate in multicomponent systems is an urgent
task.
Scientific studies confirm that pharmacopoeial
methods may be insufficiently sensitive for the
detection and quantitative assessment of combi-
ned medicinal products of industrial and small-
scale production, which necessitates the develop-
ment and introduction of new analytical appro-
aches [5].
The ability of chondroitin sodium sulfate to
form poorly soluble complexes with cetylpyridi-
nium chloride (CPC) is used for the quantitative
analysis of CS in the substance. Indicator-based
and photometric titration methods regulated by
leading pharmacopoeias consist of two stages:
the titration with 4.000 g L–1 CPC solution with
the visual or instrumental endpoint detection, or
the photometric titration with 1.000 g L–1 CPC
solution [6, 7]. The non-indicator photometric-
turbidimetric titration using Mettler-Toledo pho-
totrodes is also widely applied [8, 9].
The disadvantages of these methods include
the practical impossibility of performing titration
in the presence of certain colored substances and
colloidal systems, which usually leads to a sig-
nificant increase in the analytical uncertainty.
For example, it has been reported [10] that this
method provides satisfactory results for the de-
termination of CS in chewable tablets only when
the effect of the excipient xanthan gum is com-
pensated by adding the same amount to the stan-
dard CS solution as contained in the tablets.
Similar problems associated with the titration
of CS with CPC solutions using the photometric
endpoint detection were reported by other au-
thors [11, 12], which partly motivated the present
study.
When developing a titrimetric method, it is es-
sential to evaluate validation characteristics, in-
cluding the method uncertainty, which depends
on the titrant standardization approach (prima-
ry or secondary) and, in some cases, on the labo-
ratory temperature, burette accuracy, purity of
reference standards, and other factors.
In this way, we aimed to develop and validate
a potentiometric method for the quantitative de-
termination of chondroitin sodium sulfate in the
substance and in a combined medicinal product
in the form of the sachet powder.
■ Materials and methods
Reagents and Materials. The study objects in-
cluded sodium chondroitin sulfate (Bioiberica, S.A.U.,
R.M. Barcelona, Spain, batch F0932, 100.0 % API
content, loss on drying – 6.3 %) and a novel com-
bined pharmaceutical powder formulation in sa-
chets, containing, in addition to sodium chondroi-
tin sulfate, sodium glucosamine sulfate (Shandong
Xiwang Sugar Industry, China, batch XWAC003),
ascorbic acid (SD LUWEI Pharmaceutical Co. Ltd,
China, batch 201404197), methylsulfonylmetha-
ne (Shijiazhuang Jirong Pharmaceutical, China,
batch 101-1303006), sodium hyaluronate (Nippon
Rica, Japan, batch 5992-143), sorbitol (Evonic In-
dustries, Germany, batch 2111240201), and cit-
ric acid monohydrate (Shandong Ensing Indus-
try Co., Ltd, China, batch 3МТ2504023).
For titration, cetylpyridinium chloride (CPC)
solutions with concentrations of 0.001 – 0.01 M
were used. Sodium dodecyl sulfate (SDS, analy-
tical grade) served as the primary standard for
the titrant standardization. All solutions were
prepared using purified water.
Equipment. Potentiometric titrations were
conducted at 20 ± 5 °C using a cetylpyridinium-
selective indicator electrode, with potential read-
ings recorded by a Radelkis OP-208/1 potentio-
meter equipped with an analog-to-digital conver-
ter (ADC ADA-1406, HOLIT DataSystems, Ukrai-
ne) under constant stirring on a magnetic stirrer.
The measurement scheme: Ag, AgCl/KCl sat./
Test solution // Membrane // 10–3 M CPC/AgCl, Ag.
Standardization of 0.001 M CPC solution.
A 0.2884 g sample of SDS (288.38 g mol–1) was
dissolved in distilled water, and the solution was
diluted to the volume of 1000 mL in a volumet-
ric flask at 20 °C. Then, 1.0 mL of the result-
ing 0.01000 M solution or 10.0 mL of the diluted
0.00100 M solution was transferred to a titration
cell equipped with the ion-selective electrode,
a reference electrode, and a magnetic stirrer.
20 – 40 mL of water was added, and the solution
was titrated with 0.0010 M CPC in 0.5 mL in-
crements, while recording the potential changes
of the indicator system. The CPC concentration
was calculated as the mean of at least two titra-
tions using the formula:
C(CPC) = (SDS)С ×
V(SDS)
V(CPC)
[ ]mol L
–1
Preparation of titration solutions. 0.100 g of so-
dium chondroitin sulfate or an equivalent amount
of the pharmaceutical powder (corresponding to
0.100 g of sodium chondroitin sulfate) was placed
in a 100 mL volumetric flask, dissolved in 50 mL
of water, and diluted to the volume with water.
ISSN 2308-8303 (Print) / 2518-1548 (Online) 6
Журнал органічної та фармацевтичної хімії 2025, 23 (4)
The pH of the solution was adjusted to 4.0 using
0.01 M sodium hydroxide. 2.0 mL of this solution
was transferred to a titration cell, 20 – 40 mL of
water was added, and the titration was perfor-
med potentiometrically with 0.001 M CPC. 1 mL
of 0.001 M CPC is equivalent to 0.35 mg of CS.
Potentiometric Titration Conditions.
Standard 0.001 M or 0.01 M CPC solutions were
added in 0.5 mL increments, and the potential
changes (E, mV) were recorded, or the titration
was continued until a predetermined potential
of the indicator system was reached. Testing the
response of the ion-selective electrodes to the
cetylpyridinium cation demonstrated the near-
Nernstian behavior for a monovalent cation (58 ±
± 3 mV/pC) in the CPC concentration range from
10–3 to 10–6 mol L–1.
Systematic titration errors were minimized
by the primary standardization of the titrant and
careful determination of the titration endpoint
of the test sample, maintaining a temperature
of 20 ± 5 °C and using ISO Class A volumetric
glassware [13].
Determination of the CS content. The content
of chondroitin sulfate in the substance and phar-
maceutical preparation was calculated using the
formula:
X =
V K T V (m )· · · · 100
v.fl. av
m
n
· V
pip.
where: V – is the volume of 0.001 M CPC solu-
tion used for titration, mL;
K – is the titration correction factor;
T – is the mass of the analyte equivalent to 1 mL
of the titrant of the nominal concentration;
m – is the mass of the sample, g;
mav – is the average sample mass, g.
Data processing. The statistical analysis of
the results was performed according to the State
Pharmacopoeia of Ukraine (SPhU) 5.3.N.1 “Sta-
tistical Analysis of Chemical Experiment Re-
sults” [13] using Microsoft Excel. The analysis
included calculation of the mean of three deter-
minations, the standard deviation of the mean,
and the relative standard deviation. No additional
statistical methods were applied as the study had
an analytical focus.
■ Results and discussion
The development of a potentiometric titrimet-
ric method for the quantitative determination
of CS in a mixture with D-glucosamine sodium
sulfate, methylsulfonylmethane, ascorbic acid,
sodium hyaluronate, citric acid, and sorbitol in-
volved the following steps:
• the selection of an ion-selective electrode;
• the determination of optimal conditions
for the potentiometric titration;
• the standardization of the CPC solution;
• testing the method for the quantitative
determination of chondroitin sodium sul-
fate in the presence of other mixture com-
ponents;
• the determination of the quantitative con-
tent of chondroitin sodium sulfate in the
combined medicinal product using the ti-
trimetric method proposed.
Cetylpyridinium chloride belongs to the group
of cationic surfactants and is widely used for the
potentiometric titration of anionic surfactants.
Sodium chondroitin sulfate, due to the presence
of carboxyl and sulfate groups in its structure,
is a negatively charged polysaccharide. This fea-
ture ensures its interaction with CPC cations and
provides selectivity of the titrimetric reaction and
the determination of the titration end-point us-
ing a CPC-selective electrode [14].
The development of the potentiometric titri-
metric method for the quantitative determina-
tion of sodium chondroitin sulfate in the mixture
using the CPC solution began with the selection
of an ion-selective electrode. According to the de-
scribed modified method [15], an ionic associate
[16] was obtained by the interaction of aqueous
0.01 M solutions of cetylpyridinium chloride with
sodium dodecyl sulfate or sodium tetraphenyl-
borate in the ratio of 1:1. Upon the formation of
the corresponding ionic associates, ion-selective
membranes were prepared using polyvinyl chlo-
ride grade 6602 and Fluka. The PVC electrodes
contained approximately 1 % of the associate and
73 ± 3 % of a plasticizer, which was one of the
phthalic acid diesters (octyl, nonyl) or o-nitro-
phenyl octyl ether.
The stability of the prepared ion-selective elec-
trodes based on CPC ionic associates with dode-
cyl sulfate and tetraphenylborate [17], plastici-
zed with phthalates or o-nitrophenyl octyl ether,
was tested over 30 consecutive titrations (over
the period of 6 months). No significant differenc-
es were observed in the titration volume when
potentiometrically determining the titration end-
point.
To select the optimal titration conditions, the
behavior of potentiometric systems with different
electrodes was studied, including the method
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Journal of Organic and Pharmaceutical Chemistry 2025, 23 (4)
selectivity, the effect of pH, linearity, and repro-
ducibility of the method on the substance, model
mixture, medicinal product, and placebo.
During the potentiometric titration of CS with
0.001 M or 0.01 M CPC solutions, a typical titra-
tion curve was observed. Two examples for diffe-
rent electrodes are shown in Figure 1, present-
ing one of the differential dependencies. On the
titration curve with 0.001 M CPC solution, a ti-
tration jump of more than 60 mV was observed.
This allows reliable determination of the titra-
tion end-point with the minimal influence from
the nature of the ion-selective electrode (Figure 1).
Due to the asymmetry of titration curves for
reactions with stoichiometry different from 1:1
and the frequent heterogeneity of monomer units
of natural polyelectrolytes, an important issue
arises regarding the correct determination of the
equivalence point and the calculation of analyti-
cal results. To clarify the uncertainty of such ana-
lysis, the behavior of titrimetric systems and me-
thods for processing/calculating titration results
were experimentally studied over the period of
two years. First of all, the method for the titrant
standardization was selected, and the use of so-
dium dodecyl sulfate as a primary standard proved
to be the most appropriate, with control of the re-
sults performed using the CS substance standard.
Figure 2 presents the typical data obtained
during the titrant standardization using SDS and
CS, along with the corresponding methods for
processing the experimental data.
As can be seen from the dependences, the titra-
tion jump for CS is significantly smaller compared
to that for SDS; however, it allows the determi-
nation of CS at concentrations in the titrated so-
lution ranging from 0.02 to 10 mg mL–1 at the
corresponding titrant concentration (with a ti-
ter of 0.35 – 3.50 mg mL–1).
The titrant (CPC) volume corresponding to
the equivalence point was determined using va-
rious approaches, namely: the titration to a con-
stant potential corresponding to the equivalence
point (E_end), processing of EMF dependences
f(t) by the Gran method, and the calculation of
derivatives (Figure 2). It has been found that
the most reliable method in terms of selectivity
and accuracy is titration to a predetermined E_end
value previously determined based on the stan-
dardization data and the CS substance titration.
Due to the asymmetry of the chondroitin titra-
tion curve caused by interaction coefficients dif-
fering from unity, this approach makes it pos-
sible to obtain reliable results.
During the titrant (CPC) standardization using
SDS, any of the listed methods for determining
the titration end-point may be applied, which,
in contrast to the CS titration, yield practically
identical results (Figure 2B). It should be noted
that differential processing of curves is sensitive
to the titrant portion volume interval ΔVCPC in-
troduced during the titration and, accordingly,
may be characterized by higher uncertainty.
The presence of foreign interferents forming
more stable/less soluble ionic associates with ce-
tylpyridinium leads, under conventional titration
conditions, to positive systematic errors in the de-
termination of chondroitin sulfate. However, when
0
60
120
0 1 2 3 4 5 6 7 8 9 10 11
ΔE/ VΔ
V
CPC
, mL
DDS-CPC ISE
LABSA-CPC ISE
Differential
60 mV
E, mV
Figure 1. Original (classical) and differential titration curves of the chondroitin sodium sulfate sample titrated with 0.01 M CPC solution
using two different ion-selective electrodes
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Журнал органічної та фармацевтичної хімії 2025, 23 (4)
this effect is taken into account by constructing
differential curves, such influences can be par-
tially considered and compensated (Figure 3).
Nevertheless, it should be taken into account
that the differential form indicates the inflec-
tion point of the titration curve, which does not
coincide with the equivalence point when the ti-
tration stoichiometry differs from 1:1. This will
play a certain role when titrating minimal
amounts of CS.
If the titration is performed in the presence
of foreign polyelectrolytes forming less stable/
more soluble ionic associates, such as hyaluro-
nate, the systematic error can be eliminated by
the titration to a specific potential correspond-
ing to the equivalence point of the chondroitin–
cetylpyridinium interaction reaction (Figure 4).
Thus, when titrating CS in the presence of
foreign interferents, for example, hyaluronic
acid, reliable results are obtained only when the
А В
-240
-180
-120
-60
0
60
120
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
E, mV
E end.
1
2
60 mV y = –7.7274x + 78.41
R = 0.9975²
y = 9.7242x – 98.722
R = 0.9986²
-5
0
5
10
15
20
25
30
35
40
45
50
5 6 7 8 9 10 11 12 13 14 15
G
V
eq
V
CPC
, mL
V
CPC
, mL
Figure 2. Potentiometric titration curves obtained with 0.001 M CPC solution for the standard SDS solution (2) and the chondroitin
sodium sulfate substance solution (1) using a TPhB–CPC electrode (A), and processing of the SDS titration curve by the Gran method (B):
G = (Vtotal + VCPC) × 10(k ± E)S–1
A B
360 00.
300 00.
240 00.
180,00
120 00.
60,00
0 2 4 6 8 10 12 14 16
60 mV
Eend
0
30
60
90
0 2 4 6 8 10 12 14 16
ΔE/ VΔ
V
CPC
, mL
E, mV
ChS
ChS+DDS
V
CPC
, mL
ChS
ChS+DDS
Figure 3. Titration curves obtained with 0.001 M CPC solution: A) glucosamine (ChS) and a mixture of glucosamine with sodium dodecyl
sulfate (SDS); B) corresponding differential dependences
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Journal of Organic and Pharmaceutical Chemistry 2025, 23 (4)
titration is performed to a constant potential
value (Eend).
The titration to a constant Eend value is con-
venient for automation of titration using autoti-
trators. The Gran function applied to the data
obtained after the equivalence point does not al-
low correct results to be obtained in the presence
of anionic interferents capable of interacting with
CPC to form ionic associates of lower stability/
higher solubility compared to CPC–CS associates.
Taking into account the stability of CS ionic as-
sociates compared to SDS associates, and under
satisfactory performance of the ion-selective in-
dicator electrode, the titration end-point poten-
tial (Eend) can be selected based on the end-point
potential of the SDS titration with CPC solutions,
which in the case of 0.001 M titrant solution will
be 60 – 70 mV more positive.
The linearity of the method was studied by ti-
trating different sample volumes of the chondroi-
tin sodium sulfate solution with different data
processing approaches (Figure 4B). The linearity
of the quantitative potentiometric determination
of chondroitin sodium sulfate in the mixture was
studied within ± 5 % acceptance limits relative
to the nominal concentration of the active com-
pound in the range from 80 % to 120 % according
to the method, and a calibration plot in normal-
ized coordinates was constructed (Table 1) [13].
The study of the dependence of the electro-
analytical properties of the ion-selective electro-
de on the solution acidity showed that the elec-
trode response and the shape of titration curves
remained constant within the pH range of 4 – 8.
The study of dependence of the electroanaly-
tical properties of the ion-selective electrode on
the medium acidity demonstrated that in the pH
range of 4 – 8, the electrode response and the shape
of potentiometric titration curves remained stable.
The results obtained indicate the absence of a sig-
nificant pH effect on the course of the titrimetric
reaction, confirming the robustness of the method
developed and the possibility of its application
over a wide range of analytical conditions.
The results of the quantitative determination
of chondroitin sodium sulfate in the substance
and in the combined medicinal product are pre-
sented in Table 2.
It was found that the actual content of the
active substance agreed with the declared value.
The relative standard deviation (RSD) did not
exceed 3.0 % in any determination, meeting the
А В
-60
0
60
120
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
ChS+GA
ChS-HA
60 mV
Eend
y = 0,3607x + 0,0572
R = 0,9887²
y = 0,398x + 0,2
R = 0,9916²
0
1
2
3
4
5
6
7
8
9
0 5 10 15 20 25
E, mV
V
CPC
, mL
V
CPC
, mL
V( ), mLsample
Figure 4. Titration curves of chondroitin sulfate obtained with 0.001 M CPC solution in the presence of an eight-fold excess of
glucosamine and, respectively, a ten-fold excess of sodium hyaluronate (A), and plots of the titrant volume versus the sample volume
using different methods for the end-point determination (B)
Table 1. Validated method parameters
Parameter Result
Number of determinations 27 (9 × 3 aliquots)
Concentration range 80 – 120 % (80.0 – 120.0 mg)
a 0.200
b 0.398
r² 0.9916
Complies
Mean value of Z % 100.09
The lack of statistically significant
the systematic error: δ ≤ 1.89
0.5523 ≤ 1.89
Complies
The practical insignificance of
the systematic error: δ ≤ 1.0667
0.09 ≤ 1.0667
Complies
The overall conclusion on
precision and accuracy Complies
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Журнал органічної та фармацевтичної хімії 2025, 23 (4)
pharmacopoeial requirements for analytical me-
thods. The data obtained confirm the accuracy and
practical applicability of the method proposed for
the quality control of finished medicinal products.
The approach proposed can be integrated into
routine quality control without the use of expen-
sive equipment, which makes it attractive for la-
boratories of small and medium-sized pharma-
ceutical enterprises.
■ Conclusions
A potentiometric method for the quantitative
determination of chondroitin sodium sulfate using
a cetylpyridinium-selective electrode has been de-
veloped and validated. The method is characte-
rized by the simple sample preparation and the
total analysis time of no more than 15 – 20 min
per sample.
The effect of other active pharmaceutical in-
gredients and excipients of the medicinal pro-
duct has been studied, and it has been shown
they do not to have a statistically significant ef-
fect on the analytical results (p > 0.05), confirm-
ing the specificity of the method.
The method is characterized by linearity, ac-
curacy, and reproducibility, complying with the
pharmacopoeial requirements and ICH recom-
mendations.
The results obtained allow recommending the
application of the method developed not only in
scientific research, but also in practical activities
of large pharmaceutical enterprises and pharma-
cies engaged in small-scale production, including
control of the incoming raw material and fini-
shed medicinal products of chondroitin sodium
sulfate of both small-scale and industrial manu-
facture.
■ References
1. Shen, Q.; Guo, Y.; Wang, K.; Zhang, C.; Ma, Y. A Review of Chondroitin Sulfate’s Preparation, Properties, Functions, and Applications.
Molecules 2023, 28 (20), 7093. https://doi.org/10.3390/molecules28207093.
2. Li, H.; Zeng, C.; Wei, J.; Yang, T.; Gao, S. G.; Li, Y. S.; Lei, G. H. Associations between Dietary Antioxidants Intake and Radiographic Knee
Osteoarthritis. Clin. Rheumatol. 2016, 35 (6), 1585 – 1592. https://doi.org/10.1007/s10067-016-3177-1.
3. Koptielov, A. S.; Deyneka, A. S.; Bevz, N. Yu.; Kuchtenko, O. S. Vyznachennia farmakotekhnolohichnykh pokaznykiv aktyvnykh far-
matsevtychnykh inhrediientiv pry rozrobtsi khondroprotektornoho likarskoho zasobu [Determination of pharmacotechnological indi-
cators of active pharmaceutical ingredients during the development of a chondroprotective drug, in Ukrainian]. Health 2024, 1, 13.
https://doi.org/10.32782/health-2024.1.13.
4. Restaino, O. F.; Finamore, R.; Diana, P.; et al. Evaluation of commercial chondroitin sulfate samples. Carbohydr. Polym. 2019, 222,
114998. https://doi.org/10.1016/j.carbpol.2019.114998.
5. Patil, R. N.; Deore, B. L.; Gurav, D. G. Analytical method development and validation. Indian Journal of Pharmacy and Drug Studies
2024, 3 (4), 1 – 7.
6. European Pharmacopoeia, 11th ed.; Council of Europe: Strasbourg, 2023. 4370 p.
7. State Pharmacopoeia of Ukraine. 2nd ed. Vol. 3. State Enterprise “Ukrainian Scientific Pharmacopoeial Center for Quality of Medi-
cines”. Kharkiv; 2014. 732 p.
8. Caro, C. A. D. Analysis of Dietary Supplements: Turbidimetric Titration of Chondroitin Sulfate. UserCom Anal. Chem. 2005, No. 10, Publica-
tion ME 51724437 (access https://www.researchgate.net/publication/311517550_Analysis_of_dietary_supplements_Turbidimetric_titration_of_
chondroitin_sulfate_UserCom_Analytical_Chemistry_No_10_Mettler-Toledo_Publication_ME-51724437_September_2005).
9. Metrohm Application Note AN-T-083. Turbidimetric Titration of Chondroitin Sulfate. https://www.metrohm.com/en/applications/
application-notes/aa-t-001-100/an-t-083.html (accessed 2025-06-17).
10. Liang, Z.; Bonneville, C.; Senez, T.; Henderson, T. Development and Validation of a Photometric Titration Method for the Quan-
titation of Sodium Chondroitin Sulfate in Cosequin® DS Chewable Tablet. J. Pharm. Biomed. Anal. 2002, 28 (2), 245 – 249.
https://doi.org/10.1016/S0731-7085(01)00563-5.
11. Burns, D. T.; Walker, M. J.; Mussell, C. Chondroitin Sulfate: A Critical Review of Generic and Specific Problems in Its Characterization and
Determination. J. AOAC Int. 2018, 101 (1), 196 – 202. https://doi.org/10.5740/jaoacint.17-0213.
12. Restaino, O. F.; Schiraldi, C. Chondroitin Sulfate: Are the Purity and the Structural Features Well Assessed? Carbohydr. Polym. 2022,
292, 119690. https://doi.org/10.1016/j.carbpol.2022.119690.
13. State Pharmacopoeia of Ukraine. 2nd ed., Suppl. 7, Vol. 2. Kharkiv: State Enterprise “Ukrainian Scientific Pharmacopoeial Center for
Quality of Medicines. Kharkiv; 2024. 242 p.
14. (a) Khaled, E.; Aboul-Enein, H. Y. Surfactants. In Environmental Analysis by Electrochemical Sensors and Biosensors; Elsevier, 2015;
pp 905 – 930. (b) Müller, W.; Déjugnat, C.; Zemb, T.; Dufrêche, J.-F.; Diat, O. How Do Anions Affect Self-Assembly and Solubility of Ce-
tylpyridinium Surfactants in Water. The Journal of Physical Chemistry B 2013, 117 (5), 1345 – 1356. https://doi.org/10.1021/jp3093622.
15. Fizer, O.; Fizer, M.; Sidey, V.; Studenyak, Y. Predicting the end point potential break values: a case of potentiometric titration of lipophilic
anions with cetylpyridinium chloride. Microchem. J. 2021, 160, 105758. https://doi.org/10.1016/j.microc.2020.105758.
Table 2. The results of the CS determination in the substance and the medicinal product
Test object Declared content Found content SD RSD Conclusion
Substance 100.0 % 100.13 % 0.2628 0.26 Complies
Medicinal product 500.0 mg 500.36 mg 1.3106 0.26 Complies
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Journal of Organic and Pharmaceutical Chemistry 2025, 23 (4)
16. Hajduković, M.; Samardžić, M.; Galović, O.; Széchenyi, A.; Sak-Bosnar, M. A Functionalized Nanomaterial-Based Solid-State Cationic-
Surfactant-Selective Sensor. Sens. Actuators B Chem. 2017, 251, 795 – 803. https://doi.org/10.1016/j.snb.2017.05.067.
17. Fizer, O.; Fizer, M.; Filep, M.; Studenyak, Y.; Mariychuk, R. Deciphering the Structural and Functional Peculiarities of Cetylpyridinium
Tetraphenylborate. J. Mol. Liq. 2025, 127858. https://doi.org/10.1016/j.molliq.2025.127858.
Information about the authors:
Andrii S. Koptielov, PhD student, Department of Pharmaceutical Chemistry, National University of Pharmacy of the Ministry of Health
of Ukraine; https://orcid.org/0000-0001-7512-7426.
Vitaliia I. Plyska, PhD student, Department of Analytical Chemistry, Uzhhorod National University, https://orcid.org/0000-0003-3937-7086.
Olena V. Bevz (corresponding author), PhD in Pharmacy, Associate Professor, Department of Pharmaceutical Chemistry,
National University of Pharmacy of the Ministry of Health of Ukraine; https://orcid.org/0000-0002-7695-3612;
e-mail for correspondence: bevz.helen@gmail.com.
Olha V. Rudakova, PhD in Pharmacy, Lecturer at the Cyclic Committee of Pharmaceutical Chemistry and Pharmacognosy,
Professional College of National University of Pharmacy of the Ministry of Health of Ukraine; https://orcid.org/0000-0003-4216-0590.
Nataliia Yu. Bevz, PhD in Pharmacy, Associate Professor, Department of Pharmaceutical Chemistry, National University of Pharmacy
of the Ministry of Health of Ukraine; http://orcid.org/0000-0002-7259-8908.
Yaroslav I. Studenyak, PhD in Chemistry, Associate Professor, Head of Department of Analytical Chemistry, Uzhhorod National University;
https://orcid.org/0000-0002-8970-2222.
|
| id | oai:ojs.journals.uran.ua:article-350114 |
| institution | Journal of Organic and Pharmaceutical Chemistry |
| issn | 2518-1548 |
| keywords_txt_mv | |
| language | English |
| last_indexed | 2026-08-23T01:00:42Z |
| publishDate | 2026 |
| publisher | National University of Pharmacy |
| record_format | ojs |
| resource_txt_mv | ophcjnupheduua/fa/a4b3e5423bbe0881446c40d8bdab24fa.pdf |
| spelling | oai:ojs.journals.uran.ua:article-3501142026-08-22T19:01:53Z The Potentiometric Quantification of Chondroitin Sodium Sulfate Using Ion-Selective Electrodes Потенціометричне кількісне визначення хондроїтин натрію сульфату з використанням іонселективних електродів Koptielov, Andrii S. Plyska, Vitaliia I. Bevz, Olena V. Rudakova, Olha V. Bevz, Nataliia Yu. Studenyak, Yaroslav I. хондроїтин натрій сульфат титрування контроль якості валідація методу фармацевтичний аналіз малосерійне виробництво chondroitin sodium sulfate potentiometry quality control method validation pharmaceutical analysis small-scale production Chondroitin sodium sulfate is an anionic polysaccharide widely used in pharmaceutical practice as an active ingredient of mono- and multicomponent medicinal products, and its quantitative determination is an essential stage of the quality control. It has been found that the application of potentiometric titration with ion-selective electrodes can increase the accuracy and objectivity of the quantitative analysis, which is of great importance for ensuring the quality and safety of medicines. The aim of the study was to develop and validate a potentiometric method for the quantitative determination of chondroitin sodium sulfate in the substance and in a combined medicinal product in the form of the sachet powder. The study objects were chondroitin sodium sulfate substance and a combined medicinal product containing chondroitin sodium sulfate in combination with D-glucosamine sodium sulfate, methylsulfonylmethane, sodium hyaluronate, ascorbic and citric acids, and sorbitol. The conditions of the potentiometric titration with 0.001 M solution of cetylpyridinium chloride were studied using an ion-selective electrode based on cetylpyridinium ionic associates with some lipophilic anions. The titrant was standardized using sodium dodecyl sulfate as a primary standard, as well as the substance itself. The equivalence point was determined from the titration curve and its mathematically processed forms (differential curve, first derivative, and Gran functions). It has been found that the plasticized membrane ion-selective electrodes based on cetylpyridinium associates with dodecyl sulfate and tetraphenylborate anions are characterized by a stable near-Nernstian response in the operating range of cetylpyridinium concentrations of 10-3-10-6 mol L-1. The analytical characteristics of the electrodes remained stable for at least 30 consecutive titrations. The selectivity of the reaction between chondroitin sodium sulfate and cetylpyridinium chloride was found, ensuring a clear determination of the equivalence point even in the presence of other mixture components. The influence of pH on the titration results was evaluated; it was shown that in the pH range of 4-8 the shape of titration curves and potential values remained constant, confirming the robustness of the method. The accuracy, precision, linearity (within 80–120% of the nominal content of the analyte), and the reproducibility of the method were characterized. It has been experimentally demonstrated that the potentiometric method proposed is accurate, selective, and reproducible for the quantitative determination of chondroitin sodium sulfate both in pure form and in combined medicinal products. The results obtained confirm the analytical suitability of the method developed and the prospects of its implementation in the pharmaceutical analysis practice for the quality control of substances and combined medicinal products of small-scale and industrial production. Хондроїтин натрію сульфат є аніонним полісахаридом, який широко застосовують у фармацевтичній практиці як активний інгредієнт моно- та багатокомпонентних лікарських засобів і кількісне визначення якого є важливим етапом контролю якості. З’ясовано, що застосування потенціометричного титрування з іон-селективними електродами дозволяє підвищити точність і об’єктивність кількісного аналізу, що має важливе значення для забезпечення якості та безпеки лікарських засобів. Метою роботи були розробка та валідація методики кількісного потенціометричного визначення хондроїтин натрію сульфату в субстанції та у складі комбінованого лікарського засобу у формі порошку в саше-пакетах. Об’єктами дослідження були субстанція хондроїтин натрію сульфату та комбінований лікарський засіб, що містить хондроїтин натрію сульфат у поєднанні з D-глюкозаміну натрію сульфатом, метилсульфонілметаном, натрію гіалуронатом, аскорбіновою та лимонною кислотами, а також сорбітолом. Розглянуто умови потенціометричного титрування 0,001 М розчином цетилпіридинію хлориду з використанням іон-селективного електрода на основі іонних асоціатів цетилпіридинію з деякими ліпофільними аніонами. Стандартизацію титранту здійснювали із застосуванням додецилсульфату натрію як первинного стандарту, а також із використанням субстанції. Точку еквівалентності визначали за кривою титрування та її математично обробленими формами (диференційна крива, перша похідна та функції Грана). З’ясовано, що досліджувані пластифіковані мембранні іон-селективні електроди на основі асоціатів цетилпіридинію з додецилсульфат- та тетрафенілборат-аніонами характеризуються стабільним відгуком, близьким до нернстівського, у робочому діапазоні концентрацій цетилпіридинію 10-3-10-6 моль л-1. Аналітичні характеристики електродів залишалися стабільними протягом щонайменше 30 послідовних титрувань. Виявлено селективність реакції між хондроїтин натрію сульфатом та цетилпіридинію хлоридом, що забезпечує чітке визначення точки еквівалентності навіть у присутності інших компонентів суміші. Оцінено вплив рН середовища на результати титрування; з’ясовано, що в діапазоні рН 4-8 форма кривих титрування та значення потенціалу залишаються сталими, що підтверджує робастність методики. Схарактеризовано точність, прецизійність, лінійність (у межах 80–120 % від номінального вмісту аналіту) та відтворюваність методики. Експериментально продемонстровано, що запропонована потенціометрична методика є точною, селективною та відтворюваною для кількісного визначення хондроїтин натрію сульфату як у чистому вигляді, так і у складі комбінованих лікарських засобів. Отримані результати підтверджують аналітичну придатність розробленої методики й перспективність її впровадження в практику фармацевтичного аналізу для контролю якості субстанцій і комбінованих лікарських засобів малосерійного та промислового виробництва. National University of Pharmacy 2026-01-10 Article Article application/pdf https://ophcj.nuph.edu.ua/article/view/350114 10.24959/ophcj.25.350114 Journal of Organic and Pharmaceutical Chemistry; Vol. 23 No. 4 (2025); 3-11 Журнал органической и фармацевтической химии; Том 23 № 4 (2025); 3-11 Журнал органічної та фармацевтичної хімії; Том 23 № 4 (2025); 3-11 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/350114/340518 Copyright (c) 2026 Andrii S. Koptielov, Vitaliia I. Plyska, Olena V. Bevz, Olha V. Rudakova, Nataliia Yu. Bevz, Yaroslav I. Studenyak http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | хондроїтин натрій сульфат титрування контроль якості валідація методу фармацевтичний аналіз малосерійне виробництво Koptielov, Andrii S. Plyska, Vitaliia I. Bevz, Olena V. Rudakova, Olha V. Bevz, Nataliia Yu. Studenyak, Yaroslav I. Потенціометричне кількісне визначення хондроїтин натрію сульфату з використанням іонселективних електродів |
| title | Потенціометричне кількісне визначення хондроїтин натрію сульфату з використанням іонселективних електродів |
| title_alt | The Potentiometric Quantification of Chondroitin Sodium Sulfate Using Ion-Selective Electrodes |
| title_full | Потенціометричне кількісне визначення хондроїтин натрію сульфату з використанням іонселективних електродів |
| title_fullStr | Потенціометричне кількісне визначення хондроїтин натрію сульфату з використанням іонселективних електродів |
| title_full_unstemmed | Потенціометричне кількісне визначення хондроїтин натрію сульфату з використанням іонселективних електродів |
| title_short | Потенціометричне кількісне визначення хондроїтин натрію сульфату з використанням іонселективних електродів |
| title_sort | потенціометричне кількісне визначення хондроїтин натрію сульфату з використанням іонселективних електродів |
| topic | хондроїтин натрій сульфат титрування контроль якості валідація методу фармацевтичний аналіз малосерійне виробництво |
| topic_facet | хондроїтин натрій сульфат титрування контроль якості валідація методу фармацевтичний аналіз малосерійне виробництво chondroitin sodium sulfate potentiometry quality control method validation pharmaceutical analysis small-scale production |
| url | https://ophcj.nuph.edu.ua/article/view/350114 |
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