Резюме
Половко Н.П. Вивчення стабільності гелю клотрімазолу.
Досліджено кількісний вміст клотрімазолу за критичних умов зберігання протягом 27 місяців при температурі від 2 до 40°С та рН від 5 до 7.  Проведено вивчення фізико-хімічних властивостей гелю клотрімазолу під час зберігання в тубах протягом 27 місяців при температурі +(8÷15)°С та +(15÷25)°С. Встановлено термін придатності гелю - 2 роки при зберіганні від 15°С до 25°С у пластикових тубах.
Ключові слова: гель, клотрімазол, стабільність, термін придатності.
Резюме
Половко Н.П. Изучение стабильности геля клотримазола.
Исследовано количественное содержание клотримазола при критических условиях хранения в течение 27 месяцев при температуре от 2 до 40° С и рН от 5 до 7. Проведено изучение физико-химических свойств геля клотримазола при хранении в тубах в течение 27 месяцев при температуре (8 ÷ 15) ° С и (15 ÷ 25) ° С. Установлен срок годности геля при хранении в пластиковых тубах при температуре от 15 ° С до 25 ° С - 2 года.
Ключевые слова: гель, клотримазол, стабильность, срок годности.
Summary
Polovko N.P. The study of the stability of the gel clotrimazole.
Investigated the quantitative content of clotrimazole for critical storage of conditions during 27 months by temperatures from 2 to 40 ° C and a pH of 5 to 7. The study of the physicochemical properties of clotrimazole gel during storage in tubes for 27 months at (8 ÷ 15) ° C and (15 ÷ 25) ° C. Established shelf life of the gel during storage in plastic tubes at a temperature of 15 ° C to 25 ° C - 2 years.
Key words: gel, clotrimazole, stability and shelf life.
Рецензент: д.фарм.н., І.І. Баранова

УДК 615.454.1:54.061/.062

Національний фармацевтичний університет (Харків)

Национальный фармацевтический университет (Харьков)

National University of Pharmacy (Kharkov)

polovko.nat@mail.ru

Introduction. Widespread fungal infections among people of different age groups, long and often chronic diseases, even some resistance to cutting-edge treatments determine the relevance of search for new antifungal agents, the development and improvement of technology antifungal drugs [3]. Effective antifungal agents for external use are drugs of azoles (clotrimazole, ketoconazole, bifonazol et al.). They are characterized by high activity, a high level of penetration into the stratum corneum of the epidermis , relatively low toxicity, lack of resistance [4]. According to the results of previous studies has been developed structure and technology of drug clotrimazole in gel form, the basis of which contains carbomer complex and hydrophilic non-aqueous solvents [7].

One of the stages of introduction of drugs is their standardization, including determining the conditions and shelf life. Given the above, the purpose is to study the physical and chemical properties of the gel and determine its stability during storage.

Materials and methods

To study the stability of the gel was used methods of physical, chemical and microbiological tests as required by generally accepted methods of SPU. description, pH, uniformity, weight content of container , etc. [ 3]. Identification of clotrimazole and propylenglycol was performed by TLC by the appearance of spots on the chromatogram, which by position and size correspond chromatogram comparator (Rf 0,8 and 0,7, respectively) [9]. Ethanol, glycerol and PEO-400 identified by qualitative reactions. For the quantitative determination of clotrimazole used a variety of methods: Titrimetric, HPLC, UV-spectrophotometry, etc. [8, 10]. Quantitative determination of clotrimazole was carried out after a preliminary selection chloroform titration with sodium lauryl to change the color of the chloroform layer lemon-yellow to orange-pink.

Quantitative determination of hydrophilic non-aqueous solvents - glycerol, ethanol and propylene glycol in the formulation developed "Clotrimazolum-gel" was performed by gas chromatography [1, 2]. Determination of viscosity indexes , as required HFC, conducted on a rotary viscometer HB BROOKFIELD DV-ΙΙ PRO (USA) 20 rev/min. in the temperature range from 2 to 40^oC [1]. The required temperature provided by ultratermostat included in the kit viscometer.

Results and discussion.

To set the expiration date of the gel studied its stability for 27 months when stored in tubes with a multilayer polymeric material at two temperatures (8 – 15, 15 – 25⁰C).

Stability control preparation was performed in all specific characteristics: description, color, odor, homogeneity, pH, average weight content of container identification and quantitative content of clotrimazole and excipients, microbiological purity also measured viscosity values.

Stability studies of qualitative and quantitative characteristics of the gel during storage was based primarily on the dependence of the properties of drug substances and gel bases on various factors. Clotrimazole molecule can break down in acidic medium under the influence of temperature [5]. The mechanism of degradation of clotrimazole is shown in figure 1.

Figure. Destruction of clotrimazole in acidic medium

To determine the optimal storage conditions and critical drug was kept for 27 months at temperatures of 2, 10, 15, 25 and 40° C. Determination of the stability of clotrimazole in the developed formulation was carried out during storage at selected temperature conditions at pH 6 and 7 of the gel. The pH of the test specimens regulate the necessary number of TEA or citric acid.
The results are presented in table 1.

Table 1

The analysis of clotrimazole gel during storage

The results indicate that the storage of anhydrous samples clotrimazole gels at temperatures not exceeding 25 ° C is no significant degradation of clotrimazole and content of drug substance during storage shelf life is at least 95% of the original. At a temperature of 40 ° C observed a significant degree of degradation of clotrimazole.

Results of rheological studies are presented in table 2 showed that the developed gel for 2 years and 3 months of storage as a stable colloidal disperse system at 2 ° C to 40 ° C change in temperature does not result in any significant effect on the viscosity of the developed gel.

Table 2

The value of structural viscosity gel clotrimazole during storage

(Р=95%; t=2,78; ^–Х; n=5)

Quality of the processed gel during storage was studied by physicochemical and pharmaco-technological parameters. Consistency with specific parameters gel was run for 27 months storage at a temperature of + (8 ÷ 15) ° C and + (15 ÷ 25) ° C in tubes of 50.0 g [6].

Results of experimental studies are presented in Table 3 show that during storage at a temperature of from 8 to 25 ° C sample gels on organoleptic, physico-chemical parameters and microbiological purity meet regulatory documentation and SPU. The analysis of five pilot scale batches of the drug pH during storage no tendency to increase or decrease. When storing the pH did not reach the maximum and minimum value, which is especially important for gel clotrimazole. The quantitative content of drug substance varies within acceptable limits.

Conclusions

1. The influence of storage conditions on the stability of the drug "Clotrimazolum-gel." The established stable physical and chemical properties of the gel during storage in tubes at temperatures between 8 ° C to 25 ° C.

2. Established shelf life of the gel - 2 years when stored in plastic tubes at a temperature of 15 ° C to 25 ° C.

Література

1. Державна Фармакопея України / Держ. п-во «Науково-експертний центр». – [1-е вид.]. – Харків: РІРЕГ, 2001. – 556 с.
2. Державна Фармакопея України. Допов. 1. / Держ. п-во «Науково-експертний центр». – [1-е вид.]. – Харків: РІРЕГ, 2004. – 520 с.
3. Кулага В.В. Грибковые болезни и их осложнения: рук-во для врачей / В.В. Кулага, И.М. Романенко. – Луганск, 2006. – 520 с.
4. Коляденко В.Г. Протигрибкові засоби: сучасне та майбутнє / В.Г. Коляденко, В.В. Короленко, В.В. Бондур // Укр. журн. дерматології, венерології, косметології. – 2004. – № 3 (14). – С. 49–57.
5. Папазова Н.А. Разработка состава и технологи геля клотримазола и геля кетоконазола: дис. …канд. фармац. наук: спец. 15.00.01 «Технология лекарств и организация фармацевтического дела» / Н.А. Папазова. – СПб., 2004. – 189 с.
6. Половко Н.П. Визначення умов зберігання антимікотичних гелів з похідними імідазолу / Н.П. Половко // Фармацевтична наука: історичні аспекти формування та шляхи вдосконалення: зб. тез. VІ Регіональної наук.-практ. конф. молодих вчених та студентів, Луганськ, 29 квіт. 2010 р. – Луганськ, 2010. – С. 43-44.
7. Половко Н.П. Розробка технології та дослідження гелю з клотрімазолом/ Н.П. Половко, О.Г. Башура // Фармац. часопис. – 2010. – № 1 (10). – С.41-44.
8. Abdel-Moety E.M. Simultaneous determination of Clotrimazole and Betamethasone dipropionate by coupled TLC-Densitometry, HPLC, and Derivative UV-Spectrophotometry / E.M. Abdel-Moety, K.O. Kelani, A.M. Abou-Al Alamein // Saudi Pharmaceutical Journal. – 2002. – Vol. 10, № 1. – Р. 44–53.
9. European Pharmacopoeia. – [6thed.] – Strasbourg: European Department for the Quality of Medicines, 2007. – 3308 p.
10. Valenta C. Analysis of clotrimazole in ointments by high-performance liquid chromatography / C. Valenta, A. Lexer, P.Spiegl // Pharmazie. – 1992. – Vol. 47, № 6. – Р.641-642.