Stability of the new tablet form of antibacterial action

The stability of the new tableted dosage form with antibacterial action on the basis of the FS-1 substance is investigated. In the process of storage under long-term tests is not revealed significant changes in the monitored parameters of quality. The compliance value of quality requirements of the specification stability allows establishing the expired date - 24 months.

Introduction. The FS-1 substance is a coordination compound of molecular iodine with organic ligands and metal salts [1]. According to the results of full-scale investigations including the non-clinical and clinical trials, standardized FS-1 substance was registered as domestic drug "FS-1 solution for oral use", the registrаtion certificаte № RK-LS-3№021305.

Based on the experimental study results of the physico-chemical and technological properties of FS-1, good pharmaceutical development, the rational formulation and optimal technology of coated FS-1 tablets are defined. A method for producing tablets - the method of direct compression, tablet coating carried out by modern coаting AquаPolish® P Yellow, which is а combinаtion of hypromellose, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), macrogol 1500. This unique dry milled homogeneous mixture of film formers selected from cellulose ethers and plasticizing coloring additives ready to the use for applying a film coating to tablets using water as a solvent.

The finished product is a yellow film-coated tablets or almost yellow, round biconvex, containing 75 mg of active substance, and meet the requirements of the State Pharmacopoeia of the Republic of Kazakhstan, vol. 1, the general monograph for "Tablets".

The aim of this study - the study of the stability of the original drug in tablet form based on the FS-1 substance for 24 months during long storage under natural conditions (long-term / real time testing) [2-3]. The objectives of the tests are to establish long-term probation period of storage and use, as well as confirmation of the lack of impact of any changes in the composition of the drug and in the process on product stability [4-6].

Materials and methods. The dosage form is coated tablet, yellow or almost yellow color, round biconvex, diameter of 7 mm and a weight of 0.150 g. The investigated package for storage of tablets - plastic flask with screw cap with the control of the first opening. The number of tablets in the flask is 50.

To determine the stability and shelf life of the tablets FS-1 used a long-term tests in real time, which is sufficient research during their registration.

To determine the period of storage and storage conditions for the establishment were conducted long-term tests under natural conditions (long-term / real time testing) of three pilot sclae batches (table 1) which were obtained in experimental production of JSC “SCAID”, Almaty.

Table 1 - General characteristics of the pilot scale batches of the drug Tests of the drug to meet quality specifications for the following parameters: description, identification, average weight and uniformity of weight, content uniformity, friability, dissolution, disintegration, loss on drying, microbiological purity, quantitative determination of: - iodine - potassium iodide; using validated methods [7-10], in primary packaging - polymer bank with a screw cap with the control of the first opening, identical to the proposed storage and sales. The storage temperature of the drug - (25±2) °C and relative humidity (RH) - (60±5) %. Description of the quality indicators are presented in table 2.

Batch №

Batch size, pcs.

Production date

Schedule testing, months

210413

2 000

21.04.2013 г.

0, 3, 6, 9, 12, 18, 24

060513

2 000

06.05.2013 г.

0, 3, 6, 9, 12, 18, 24

140513

2 000

14.05.2013 г.

0, 3, 6, 9, 12, 18, 24

Quality parameters

Acceptability of criteria

Test methods

Description

Tablets coated yellow or almost yellow color, biconvex round with weight 0.150 g.

Visually, SP RK, v. 1, the general monograph for "Tablets"

Identification

Staining chloroform layer into a violet-red color.

IR spectrum must contain absorption band in the ranges:2959,2 ÷ 2888,5 см , 1658,0 ÷ 1642,2 см , 1336,9 ÷ 1323,9 см-1, 1259,2 ÷ 1229,5 см-1, 1156,0 ÷ 1147,8 см-1, 1106,9 ÷ 1102,2 см-1, 1070,1 ÷ 1081,4 см1, 1023,7 ÷ 1015,5 см-1, 529,1 ÷ 510,3 см-1.

UV spectrum should contain peaks in the ranges: 350 ÷ 353 нм, 286 ÷ 291 нм, 223 ÷ 226 нм

SP RK, v. 1, 2.3.1

The average weight and uniformity of weight

Deviation from the average weight of individual tablets is allowed in 18 of 20 tablets no more than ± 7,5 %, 2 of 20 tablets no more than ± 15 %.

SP RK, v. 1, 2.9.5

Uniformity of content

From 85% to 115%

EPh, edition 6, v. 1, 2.2.34

Friability

Not more than 1 %

SP RK, v. 2, 2.9.7

Dissolution

75% in 45 min in water P

SP RK, v. 2, 2.9.3, Temporary AND project, EPh, edition 6, v. 1, 2.2.34

Disintegration

Not more than 30 minutes in water P

SP RK, v. 1, 2.9.1

Loss on drying

Not more than 1 %

SP RK, v. 1, 2.2.32

Microbiological purity

The product should meet the requirements SP RK, volume 1, category 3A. In 1 g of the drug, a maximum of 103 aerobic bacteria, 102 yeasts and fungi (in total). Not allowed in 1 g product availability E.coli. (category 3A).

SP RK, v. 1, 2.6.12 and v. 2, 2.6.13

Quantitative determination of:

  • iodine
  • Potassium iodide

1,1-2,1 %

2,25-3,25 %

Temporary AND project, EPh, edition 6, v. 1, 2.2.34

of Table 2 -

Results and discussion. According to research prepared the report of stability studies in accordance with the requirements of "On approval of the rules of production and quality control and testing to establish stability and period of storage and remonitoring of medicines, medical devices and medical equipment" from 05.12.2011. The results are presented in table 3-5.

During the storage period under standard conditions the drug "FS-1, tablets of 75 mg", placed in the primary package, are characterized by a constant composition over time, and its qualitative and quantitative characteristics are within regulated standards. Packaging provides protection from external influences of the drug because of its microbiological characteristics during storage does not change, and fully comply with the requirements of pharmacopoeia.

The stability study results also show the optimal composition of the developing product, in which excipients are chosen according to the physico-chemical and technological characteristics of the active substance. The above data indicate indifference excipients, as they do not affect adversely the structure of the active substances and thereby facilitate the proper therapeutic effect of the drug.

By the studies can be concluded that the optimal composition of the drug "FS-1, 75 mg" created in the form of tablets, stable for 2 years and provides good physical, mechanical and biopharmaceutical parameters.

According to the results long-term stability testing can conclude the following:

  • for the control period (2 years) no significant changes in the quality of the drug "FS-1" was observed, which confirms its stability for 2 years;
  • according the results of the experiment the storage period the drug "FS-1" is 2 years;
  • the recommended storage conditions for the "FS-1" drug: "store in a dry dark place at a temperature no higher than 25 °C".

Thus, as a result of studies the stability of the drug “FS-1, 75 mg” in the form of tablets are investigated. During the storage under long-term testing did not reveal significant changes in the monitored parameters of quality. Compliance of quality values with specification stability requirements allows establishing storage period of 24 months.

Table 3 – The results of stability studies of the drug batches 210413

Storage requirements: t=25±2 °С, RH=60±5 %

Date of beginning and completion of testing: 21.04.2013 г. - 21.04.2015

Quality parameters

Month

1

3

6

9

12

18

24

Description

yes

yes

yes

yes

yes

yes

yes

Identification

yes

yes

yes

yes

yes

yes

yes

The average weight and

0,199±

0,197±

0,198±

0,200±

0,201±

0,203±

0,201±

uniformity of weight

0,010

0,020

0,030

0,010

0,040

0,044

0,065

Uniformity of content

yes

yes

yes

yes

yes

yes

yes

Friability

yes

yes

yes

yes

yes

yes

yes

Dissolution

85

87

88

84

85

83

85

Disintegration

6,4±0,6

6,0±0,45

7,5±0,75

7,0±0,78

9,5±0,8

10,0±0,9

8,5±0,9

Loss on drying

yes

yes

yes

yes

yes

yes

yes

Microbiological purity

yes

yes

yes

yes

yes

yes

yes

Quantitative determination:

  • iodine
  • Potassium iodide

1,66±0,45

1,6±0,55

1,56±0,6

1,54±0,55

1,55±0,65

1,5±0,45

1,48±0,5

 

2,74±0,6

2,69±0,5

2,7±0,6

2,74±0,6

2,74±0,6

2,74±0,6

2,74±0,6

Table 4 – The results of stability studies of the drug batches 060513

Storage requirements: t=25±2 °С, RH=60±5 %

Date of beginning and completion of testing: 06.05.2013 г. - 06.05.2015

Quality parameters

Month

1

3

6

9

12

18

24

Description

yes

yes

yes

yes

yes

yes

yes

Identification

yes

yes

yes

yes

yes

yes

yes

The average weight and

0,200±

0,205±

0,202±

0,212±

0,205±

0,213±

0,211±

uniformity of weight

0,030

0,150

0,065

0,250

0,080

0,230

0,165

Uniformity of content

yes

yes

yes

yes

yes

yes

yes

Friability

yes

yes

yes

yes

yes

yes

yes

Dissolution

90

88

87

85

88

86

89

Disintegration

7,5±0,8

7,0±0,55

7,9±0,80

8,0±0,89

7,5±0,67

9,0±0,8

7,5±0,9

Loss on drying

yes

yes

yes

yes

yes

yes

yes

Microbiological purity

yes

yes

yes

yes

yes

yes

yes

Quantitative determination:

  • iodine
  • Potassium iodide

1,7±0,55

1,8±0,67

1,56±0,35

1,58±0,40

1,6±0,5

1,27±0,45

1,2±0,55

 

2,90±0,70

2,95±0,6

2,85±0,7

2,89±0,7

2,8±0,5

2,54±0,45

2,54±0,6

Table 5 – The results of stability studies of the drug batches 140513

Storage requirements: t=25±2 °С, RH=60±5 %

Date of beginning and completion of testing: 14.05.2013 г. - 14.05.2015

Quality parameters

Month

1

3

6

9

12

18

24

Description

yes

yes

yes

yes

yes

yes

yes

 

Storage requirements: t=25±2 °С, RH=60±5 %

Date of beginning and completion of testing: 14.05.2013 г. - 14.05.2015

Quality parameters

Month

1

3

6

9

12

18

24

Identification

yes

yes

yes

yes

yes

yes

yes

The average weight and

0,202±

0,200±

0,199±

0,205±

0,198±

0,204±

0,199±

uniformity of weight

0,035

0,260

0,055

0,040

0,030

0,040

0,065

Uniformity of content

yes

yes

yes

yes

yes

yes

yes

Friability

yes

yes

yes

yes

yes

yes

yes

Dissolution

90

88

87

85

88

86

89

Disintegration

8,2±0,040

8,4±0,030

8,8±0,070

8,6±0,080

9,0±0,056

9,0±0,86

7,9±0,08

Loss on drying

yes

yes

yes

yes

yes

yes

yes

Microbiological purity

yes

yes

yes

yes

yes

yes

yes

Quantitative determination:

  • iodine
  • Potassium iodide

1,54±0,45

1,5±0,60

1,47±0,55

1,53±0,40

1,58±0,65

1,45±0,30

1,34±0,75

 

2,83±0,60

2,87±0,6

2,85±0,65

2,89±0,7

2,88±0,7

2,75±0,40

2,54±0,65

REFERENCES

  1. Ilin A.I., Kulmanov M.E. Patent Appl. № 2010/1816.1, Republic of Kazakhstan (30 December 2010).
  2. Barinov D.V., Kalykova A.S., Sakipova Z.B. Study of some physical and technological characteristics of the FS-1 substance. // II междунар. науч.-практ. конф. «Интеграция фармацевтической науки, образования и практики на современном этапе» КазНМУ им. С.Д. Асфендиярова. - Алматы: 2013. - C. 82-85.
  3. Kalykova A.S., Vetchy D., Sakipova Z.B. Development of tablet medical form containing substance FS-1. // Research Journal of Pharmaceutical, Biological and Chemical Sciences. - January-February 2015. - №6(1). Р. 1610-1615.
  4. Kalykova A.S., Barinov D.V., Sakipova Z.B., Vetchy D. Use of the direct compression method in the development of FS-1 tablets technology. // Матер. II междун. науч.-практ. конф. «Интеграция фармацевтической науки, образования и практики на современном этапе». КазНМУ им. С.Д. Асфендиярова. - Алматы: 2013. - С. 111-113.
  5. 4 ICH Q1A (R2): Stability Testing of New Drug Substances and Products, February 2003.
  6. Тулегенова А.У. Проведение испытаний стабильности и установление срока хранения и периода переконтроля лекарственных средств (методические рекомендации). - Астана: 2008. - 116 с.
  7. Государственная фармакопея Республики Казахстан. Т.1. - Алматы: Издательский дом «Жибек молы», 2008. - 259 с.
  8. Государственная фармакопея Республики Казахстан. Т.2. - Алматы: Издательский дом «Жибек жолы», 2009. - 318 с.
  9. Государственная фармакопея Республики Казахстан. Т.3. - Алматы: Издательский дом «Жибек жолы», 2014. - 451 с.
  10. European Pharmacopoeia. Council of Europe, Strasbourg 6.0. - 2007. - vol. 1. - 1129 р.
Year: 2015
City: Almaty
Category: Medicine