3

STIROLBIOFARM BALTIKUM LTD Vitamin C Orange 500 mg chewable tablets Tabulettae Atussinum

3.2.PDRUG PRODUCT

3.2.P.1 Description and Composition of the Drug Product

3.2.P.1Description and Composition of the Drug Product

3.2.P.1.1Description

Finished product Vitamin Orange 500 mg chewable tablets is pink-orange biconvex tablets with break line and inscription C and 500 on one side, having orange flavour and sweet and sharp taste. On the surface white or bright orange inclusions are allowed; tablets may be with powder-like blush or slightly cogged.

3.2.P.1.2Composition

In the manufacturing process, per one tablet, the following materials are used:

IngredientQuantityFunction

%g

Active substances:

Sodium ascorbate (Ph. Eur.1)31.910.33800Active ingredient

(with reference to ascorbic acid)0.30050

Ascorbic acid, as granulate (95 %) (In-house)22.300.21000Active ingredient

(with reference to ascorbic acid)0.19950

Excipients:

Mannitol (Ph. Eur.)

23.550.20351Diluent

Compressible sugar (USP NF2)16.990.14000Sweetening agent

Sodium cyclamate (Ph. Eur.)0.710.00671Sweetening agent

Orange flavour30.030.00028Flavouring agent

Aspartame (Ph. Eur.)0.510.00580Sweetening agent

Stearic acid (In-house / Ph. Eur.) 2.040.01920 Binder

Yellow colorant 6 (In-house)0.410.00387Colouring agent

Magnesium stearate (In-house / USP NF / Ph. Eur.)1.020.00940Lubricant

Colloidal silicon dioxide0.530.00493Lubricant

Total:100.00.94170

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1 European Pharmacopoeia (Ph. Eur.) current edition

2 The United States Pharmacopeia National Formulary (USP NF) current edition

3 Orange flavouring agent contains the mixture of nature-identical flavouring substances,

maltodextrin and Arabic gum3.2.P.1.3Type of container used for dosage form

Finished product Vitamin C Orange 500 mg chewable tablets is packed as follows:

12 tablets are placed per polyvinylchloride (PVC) film / aluminium (Al) foil blister. 30 or 50 tablets are placed per plastic container.1 blister or 1 plastic container together with Patient Information Leaflet is placed into cardboard box.3.2.P.4 Control of Excipients

3.2.P.4Control of Excipients

For manufacturing of finished product Vitamin C Orange 500 mg chewable tablets the following starting materials, described in pharmacopoeias are used:

MannitolPh. Eur.

Sucrose compressible USP NF

Sodium cyclamatePh. Eur.

Flavouring agent orangeIn-house

AspartamePh. Eur.

Strearic acidIn-house / Ph. Eur.

Colouring agentIn-house

Magnesium stearate In-house / Ph. Eur./ USP NF

Silica, colloidal anhydrousIn-house / Ph. Eur.

Each batch of above mentioned ingredients is tested in accordance with pharmacopoeial requirements and corresponding Quality Specifications.

Company- manufacturer of magnesium stearate confirms that fatty acids, used for magnesium stearate producing, have completely vegetable origin. According to EC directive 1999/82 EEC the products, having vegetable origin, couldnt be the source of TSE risk.

In the manufacturing of product Vitamin C Orange 500 mg chewable tablets yellow colorant Spectracol Dual FD&C Yellow No 6 LK (Sunset yellow FCF, CAS No. 2783-94-0) is used. It is FDA certified colorant.

Also orange flavouring agent FD-9285-D-T, manufactured by company Givaudan Roure Flavours Ltd (Switzerland) is used in the manufacturing process of Vitamin C 500 mg chewable tablets. Company manufacturer of colouring agent declares that product complies with the requirements of the EEC Directive 78/25/EC Colouring Matter in Medicines, the EC Directive 95/45/EC, and the FAO/WHO Food Drug and Nutrition paper 52/1 and 2 as well as that its production facilities meet the requirements of the health Authorities of the country of origin of the product. Certificate of origin is attached to the documentation.The attached documentation includes:

1) company Stirolbiopharm Quality Specification for mannitol;

2) company Stirolbiopharm certificate of analysis for mannitol;

3) company-suppliers quality certificate for mannitol;

4) the copy of Ph. Eur. monograph Mannitol;

5) company Stirolbiopharm Quality Specification for sucrose compressible;

6) company Stirolbiopharm certificate of analysis for sucrose compressible;

7) company-suppliers quality certificate for sucrose compressible;

8) the copy of USP NF monograph Compressible Sugar;

9) company Stirolbiopharm Quality Specification for sodium cyclamate;

10) company Stirolbiopharm certificate of analysis for sodium cyclamate;

11) company-suppliers quality certificate for sodium cyclamate;

12) the copy of Ph. Eur. monograph Sodium cyclamate;

13) company Stirolbiopharm Quality Specification for flavouring agent;

14) company Stirolbiopharm certificate of analysis for flavouring agent;

15) company-suppliers quality certificate for flavouring agent;

16) company Stirolbiopharm Quality Specification for aspartame;

17) company Stirolbiopharm certificate of analysis for aspartame;

18) company-suppliers quality certificate for aspartame;

19) the copy of Ph. Eur. monograph Aspartame;

20) company Stirolbiopharm Quality Specification for stearic acid;

21) company Stirolbiopharm certificate of analysis for steariv acid;

22) company-suppliers quality certificate for stearic acid;

23) the copy of Ph. Eur. monograph Stearic acid;

24) company Stirolbiopharm Quality Specification for colouring agent;

25) company Stirolbiopharm certificate of analysis for colouring agent;

26) company-suppliers quality certificate for colouring agent;

27) company Stirolbiopharm Quality Specification and Analytical Procedures for magnesium stearate;

28) company Stirolbiopharm certificate of analysis for magnesium stearate;

29) company-suppliers quality certificate for magnesium stearate;

30) the copy of ph. Eur. monograph Magnesium stearate;

31) the copy of USP NF monograph Magnesium stearate;32) company Concern Stirol Quality Specification for silica colloidal;

33) company Concern Stirol certificate of analysis for silica colloidal;

34) company-suppliers quality certificate for colloidal silicon dioxide;

35) the copy of Ph. Eur. monograph Silica colloidal , anhydrous.3.2.P.4.1Specifications

All excipients, i.emannitol, sucrose compressible, sodium cyclamate, orange flavouring agent, aspartame, stearic acid, yellow colouring agent, magnesium stearate and silica colloidal used in the manufacture of Vitamin C Orange 500 mg chewable tablets are tested to conform to corresponding Quality Specification requirements. 3.2.P.4.2Analytical Procedures

All excipients are tested according to respective Quality Specification using pharmacopoeial methods.3.2.P.4.3Validation of Analytical Procedures

Not applicable

3.2.P.4.4Justification of Specifications

Specifications and established limits for all excipients are in accordance with manufacturers Quality Specification or corresponding pharmacopoeial monograph. So, any justification is not needed. 3.2.P.4.5Excipients of Human or Animal Origin

Not applicable3.2.P.4.6Novel Excipients

Not applicable

3.2.P.5 Control of Drug Product

3.2.P.5.1Specification(s)

All batches of the finished product Vitamin C Orange 500 mg chewable tablets are checked to conform to the requirements of Quality Specification developed according to general requirements of Ph. Eur. for solid dosage forms (tablets).

SpecificationsRequirementsMethods of analyses

DescriptionPink-orange biconvex tablets with break line and inscription C and 500 on one side, having orange flavour and sweet and sharp taste. On the surface white or bright orange inclusions are allowed; Tablets may be with powder-like blush or slightly cogged. Determine visually

IdentificationPasses tests A, B, C and DIn-house methods

Uniformity of mass0.9417 g 5.0 %Ph. Eur., 2.9.5

pHFrom 4.0 to 5.0Ph. Eur., 2.2.3

FriabilityNot more than 3.0 %Ph. Eur., 2.9.7

AerosilNot more than 0.5 % In-house method

Loss on dryingNot more than 0.5 %Ph. Eur., 2.2.32, method d

Microbial contamination:Ph. Eur., 2.6.12, 2.6.13 and 5.1.4

- bacteriaNot more than 1000/g

- fungiNot more than 100/g

- EnterobacteriaceaeAbsence

- Pseudomonas aeruginosaAbsence

- Staphylococcus aureusAbsence

Assay of ascorbic acid and sodium ascorbate, calculated to ascorbic acidFrom 0.475 g to 0.525 g

In-house method

Ascorbic acid tablets are described in BP and USP. Corresponding monographs are presented on the following pages.3.2.P.5.2Analytical Procedures

Generally the methods employed for finished product quality control are pharmacopoeial.DESCRIPTIONDescription of the tablets should comply with QS requirements. Determine visually. IDENTIFICATIONA. Dissolve 0.2 g of powdered tablets to be examined in 5 ml of water R, add 1 ml of silver nitrate solution R2 (17 g/l); a grey precipitate is formed (ascorbate).

B. Dissolve 0.02 g of powdered tablets to be examined in 10 ml of water R, drop sodium 2,6-dichlorophenolindophanolate solution: the blue colour of the last reagent immediately disappears (ascorbate). Preparation of sodium 2,6-dichlorophenolindophenolate solution: dissolve 0.25 g of sodium 2,6-dichlorophenolindophenolate in 500 ml of carbon dioxide-free water vigorously mixing and filter into 1000 ml volumetric flask through paper filter. Make to volume with carbon dioxide-free water and mix. The solution prepared is available for 7 days when stored in cold, dark place.C. Dissolve 0.2 g of powdered tablets to be examined in 5 ml of water; the solution obtained shows characteristic reaction of sodium (colourless flame upon introduction of the solution becomes yellow).

D. UV spectrophotometry. UV absorption spectrum of the test solution prepared under Assay test within the range 220 nm to 320 nm should have maximum of absorbance at 244 nm (ascorbic acid).DEVIATION FROM AVERAGE MASSIs determined according to Ph. Eur., 2.9.5. Not more than 2 individual masses deviate from the average mass by more than 5 % and none deviates by more than 10 %.FRIABILITYIs determined according to Ph. Eur., 2.9.7. Examine 10 tablets.Requirements: NMT 3.0 %.

pHIs determined according to Ph. Eur., 2.2.3. Dissolve one tablet in 50 ml of water and measure pH of the solution obtainedRequirements: from 4.0 to 5.0.

AEROSILTransfer accurately weighed about 1 g of powdered tablets to vessel and treat them with 200 ml of warm water; filtrate through ash-less paper filter; wash vessel with water. Wash the residue on filter with warm water (by 10 ml portions) until absence of visible residue on watch glass after evaporation. Dry the filter with residue and ignite it. Treat residue after ignition under heating with 30 ml of diluted hydrochloric acid, filtrate and wash residue on filter with warm water until absence of chlorides in washing water. Dry the filter and residue, ignite it and then weigh with precision 0.0001 g.

Requirements: NMT 0.5 %.

LOSS ON DRYINGIs determined according to Ph. Eur., 2.2.32, method d.

Requirements: NMT 0.5 %.

MICROBIAL CONTAMINATIONThe test is carried out according to Ph. Eur., 2.6.12 and 2.6.13 requirements.

Transfer 10 g of the powdered tablets to be examined to sterile 100 ml volumetric vessel, dissolve in sterile buffered sodium chloride-peptone solution pH 7.0, make to volume with the same solvent and mix well (sample A).

Transfer 10 g of the powdered tablets to be examined to sterile 100 ml volumetric vessel, dissolve in sterile buffered sodium chloride-peptone solution pH 7.0 containing polysorbate-80 (30 g/l), make to volume with the same solvent and mix well (sample B).

To determine total bacterial count add by pour-plate method 1 ml of the sample B to each of two Petri dishes containing agar medium No 1.

To determine total count of fungi add by pour-plate method 1 ml of the sample A to each of two Petri dishes containing dense agar medium No 2.

To detect bacteria belonging to the family of Enterobacteriaceae transfer 10 ml of the sample A to 100 ml of the broth medium No 3.

To determine Staphylococus aureus and Pseudomonas aeruginosa transfer 10 ml of sample B to 100 ml of nutrition medium No 8.

Specifications for microbial contamination for the preparation to be examined are stated according to Ph. Eur., 5.1.4, as for preparations of category 3 A.

Requirements:

Total viable aerobic count: not more than 1000 bacteria and not more than 100 fungi per 1 g of the preparation to be examined.

Absence of bacteria belonging to family of Enterobacteriaceae per 1 g.

Absence of Staphylococus aureus per 1 g.

Absence of Pseudomona aeruginosa per 1 g.

ASSAYAssay of ascorbic acid is determined by UV spectrometric method (Ph. Eur., 2.2.25). Requirements: from 0.475 g to 0.525 g.

Accurately weighed about 0.08 g of powdered tablets into to 100 ml volumetric flask, add 70 ml of water R, 1 ml of 0.1 M hydrochloric acid and shake vigorously for 10 min. Make to volume with water R, mix and filter rejecting the first 10 ml of the filtrate. Transfer 2 ml of the filtrate obtained to 100 ml volumetric flask; add 1 ml of 0.1 M hydrochloric acid, make to volume with water R and mix well.

Measure the absorbance of the solution prepared at the wavelength 244 nm in 10 mm cell, using 0.001 M hydrochloric acid as the compensation liquid.

Measure the absorbance of the ascorbic acid CRS standard solution in parallel.

The content of ascorbic acid (X), per one tablet, in g is calculated as follows:

X =A1 x m0 x 100 x 100 x 2 x b x C=

A1 x m0 x b x C

A0 x 200 x 100 x 10 x m1 x 2 x 100A0 x m1 x 200

Where: A1 absorbance of the test solution;

A0 absorbance of ascorbic acid CRS standard solution;

m0 mass of ascorbic acid CRS, g;

m1 mass of tablets powdered sample, g;

C assay of ascorbic acid in CRS, %;

b average mass of one tablet, g.

The content of C6H8O6 (ascorbic acid) and of C6H7NaO6 (sodium ascorbate) in one tablet should be from 0.475 g to 0.525 g, calculating with reference to average tablet mass.Preparation of the solutionsAscorbic acid CRS standard solution. Accurately weighed about 0.08 g of ascorbic acid R transfer to 200 ml volumetric flask, add 150 ml of water R, 2 ml of 0.1 M hydrochloric acid solution, make to volume with water R and mix well.The solution is available for 6 h.

Transfer 2 ml of the solution prepared to 100 ml volumetric flask, add 70 ml of water R, 1 ml of 0.1 M hydrochloric acid solution, make to volume with water R and mix well.

The solution is available for 4 h.

0.001 M hydrochloric acid solution. Transfer 1 ml of 0.1 M hydrochloric acid solution to 100 ml volumetric flask, make to volume with water R and mix well.The solution is available for 1 month.

Note. All reagents, volumetric solutions and indicators are described in Ph. Eur. corresponding chapters.

3.2.P.5.3Validation of Analytical Procedures

Generally all methods of analyses are pharmacopoeial. Description of the tablets is checked according to Ph. Eur. requirements.

Pink-orange biconvex tablets with break line and inscription C and 500 on one side, having orange flavour and sweet and sharp taste. On the surface white or bright orange inclusions are allowed; tablets may be with powder-like blush or slightly cogged.For identification of active substances four specific methods are used:A. It reduces silver nitrate solution R2 (17 g/l); producing a grey precipitate (ascorbate).

B. Dissolve 0.02 g of powdered tablets to be examined in 10 ml of water R, drop sodium 2,6-dichlorophenolindophenolate solution: the blue colour of the last reagent immediately disappears (ascorbate).

C. Dissolve 0.2 g of powdered tablets to be examined in 5 ml of water; the solution obtained shows characteristic reaction of sodium (colourless flame upon introduction of the solution becomes yellow).

D. UV spectrophotometry. UV absorption spectrum of the test solution prepared under Assay test within the range 220 nm to 320 nm should have maximum of absorbance at 244 nm (ascorbic acid).pH, friability, loss on drying are determined according to Ph. Eur. requirements.

Average mass is determined according to Ph. Eur. requirements. 20 tablets are weighed with precision 0.0001 g. Average mass should be within ( 5 % from nominal value.

Aerosil is performed according to In-house method.Microbial contamination is determined according to Ph. Eur. requirements. The requirements are as follows: total bacteria NMT 103/g and fungi NMT 102/g, absence of Enterobacteriaceae, Pseudomonas aeruginosa and Staphylococcus aureus.

Assay of C6H8O6 (ascorbic acid) and of C6H7NaO6 (sodium ascorbate), calculated with reference to ascorbic acid, is determined by UV spectrophotometric method developed. Appropriate validation of UV spectrophotometric method, used for identification and for assay determination was performed. Method was shown to be specific, linear (r = 0.9981) within used interval (80 120 %), precise and accurate. Validation Report, including validation plane and results, is presented on the following pages.3.2.P.5.4Batch Analyses

The analytical analysis results for 3 batches of Vitamin C Orange 500 mg chewable tablets are tabulated below.

Quality certificates for corresponding batches No 840708, 850708 and 890708 are presented on the following pages.

Tests RequirementsBatch

No 840708Batch

No 850708Batch

No 890708

DescriptionPink-orange biconvex tablets with break line and inscription C and 500 on one side, having orange flavour and sweet and sharp taste. On the surface white or bright orange inclusions are allowed; Tablets may be with powder-like blush or slightly cogged. CompliesCompliesComplies

IdentificationPasses tests A, B, C and DPasses testsPasses testsPasses tests

Uniformity of mass0.9417 g 5.0 %0.9264 g

3.2 %0.9267 g

3.6 %0.9322 g

1.8 %

pHFrom 4.0 to 5.04.394.314.32

FriabilityNot more than 3.0 %1.50 %1.94 %1.76 %

AerosilNot more than 0.5 % 0.24 %0.24 %0.35 %

Loss on dryingNot more than 0.5 %0.32 %0.33 %0.22 %

Microbial contamination:

- bacteriaNot more than 1000/gLess than 10Less than 10Less than 10

- fungiNot more than 100/gLess than 10Less than 10Less than 10

- EnterobacteriaceaeAbsenceNot detectedNot detectedNot detected

- Pseudomonas aeruginosaAbsenceNot detectedNot detectedNot detected

- Staphylococcus aureusAbsenceNot detectedNot detectedNot detected

Assay of ascorbic acid and sodium ascorbate, calculated to ascorbic acidFrom 0.475 g to 0.525 g

0.504 g0.514 g0.487 g

3.2.P.5.5Characterisation of Impurities

Not applicable3.2.P.5.6Justification of Specification

All specifications and established limits for Vitamin C Orange 500 mg chewable tablets are in accordance with the Ph. Eur. general requirements for tablets. Description

The external appearance of the tablets remains unchanged during the whole products life.

Determine visually.

This test is performed in every batch.

Identification

The identification is carried out by four specific methods:

a) reducing of silver nitrate solution (prove of ascorbate ion);

b) discoloration of 2,6-dichlorophenolindophenolate solution (prove of ascorbate ion);

c) characteristic reaction of sodium;d) comparison of the test solution absorption maxima versus the standard.

All above mentioned methods are specific methods and, therefore, appropriate for a selective identification.

These tests are performed in every batch.

Average mass and uniformity of massThe test is performed according to the established by ph. Eur. specification and acceptance criterion. This test is performed in every batch.

Friability

The test is performed according to the established by Ph. Eur. specification and acceptance criterion. This test is performed in every batch.

pHThe test is performed according to the established by manufacturer specification and acceptance criterion. This test is performed in every batch.

AerosilThe test is performed according to the established by manufacturer specification and acceptance criterion. This test is performed in every batch.

Loss on dryingThe test is performed according to the established by manufacturer specification and acceptance criterion. This test is performed in every batch.

Microbial contamination

The test is carried out according to the required criteria of Ph. Eur. for preparations for oral administration.

Assay

According to ICH Guidelines the content deviation for ascorbic acid in tablet is ( 5.0 %. Assay requirements: from 0.475 to 0.525 g.

For this reason there is not necessary further justification.

This test will be performed in every batch.

In conclusion, the specification, analytical methods and limits set for quality control of the finished product Vitamin C Orange 500 mg chewable tablets are found to be acceptable.

3.2.P.6 Reference Standards or Materials

3.2.P.6Reference Standards or Materials

Ascorbic acid CRS In-house standard is used as reference substance assay determination by UV spectrophotometric method. No other reference standards are needed in the routine analysis.3.2.P.7 Container Closure System

3.2.P.7Container Closure System

3.2.P.7.1Primary Packaging

Finished product Vitamin C Orange 500 mg chewable tablets are packed in blisters, formed according to internal standard OCT 64-074-91, from aluminium foil, manufactured by company Alupak (Slovenia), and polyvinylchloride film, manufactured by company TBP (Slovenia). Also the finished product Vitamin C 500 mg chewable tablets is packed in plastic containers.The quality of the packaging materials is tested according to the corresponding internal normative documentation.To the documentation attached:

1) quality specification for aluminium foil used in Klckner blistering equipment and its

translation in English;

2) quality specification for aluminium foil used in NOACK blistering equipment and its

translation in English;

3) method 1 for analysis of aluminium foil and its translation in English;

4) quality specification for polyvinylchloride film used in Klckner blistering equipment and

its translation in English;

5) quality specification for polyvinylchloride film used in NOACK blistering equipment and

its translation in English;

6) method 2 for analysis of polyvinylchloride film and its translation in English;

7) quality specification for plastic container 75 ml;8) quality specification for plastic container 90 ml;

9) quality certificate for plastic containers.3.2.P.7.2Secondary Packaging

One blister or plastic container together with Patient Information Leaflet is packed in cardboard box. Cardboard boxes for blisters are tested according to internal standard 12301-81 or 12303-80.

3.2.P.8 Stability

3.2.P.8Stability

3.2.P.8.1Stability Summary and Conclusion

3.2.P.8.1.1Long-term stability studies

Long-term stability studies are carried out to identify characteristics of a product that may change under defined conditions. This type of study is for the stability assessment of a product under normal conditions.

Studies are designed to establish appropriate expiration periods and product storage requirements.

Summary

Long- term stability studies for Vitamin C Orange 500 mg chewable tablets were carried out for batches, packed in blisters as well as in plastic containers. The packaging is the same as that of the marketed product.The product was manufactured according to the proposed formulation on equipment that is entirely representative of full-scale production.

Batches tested

010197, 020197, 0300197, 040197 and 050197 packed in PVC/Al blisters.

060197, 070197, 0800197, 090197 and 100197 packed in plastic containers.

210304, 220304 and 230304 - packed in PVC/Al blisters (according to current Quality

Specification for the finished product).Tests performed

Tests checked were description, identification, uniformity of tablet mass, pH, aerosol, friability, loss on drying, microbial contamination and assay.

Test methods

The validated analytical methods employed in the stability tests for Vitamin C Orange 500 mg chewable tablets are the same as for freshly prepared product. Storage conditions

All stability batches were stored protected from light at (25 ( 2) (C/ (60 ( 5)% RH under controlled conditions.

Frequency of analysis

0; 6; 12, 18; 24; 30 and 33 months

Results

Stability test results obtained after 33 months storage at (25 ( 2) (C/ (60(5)% RH demonstrate conformance of the product Vitamin C Orange 500 mg chewable tablets to the quality specification requirements.

3.2.P.8.1.2Accelerated stability studies

Not applicable

Conclusion

Finished product Vitamin C Orange 500 mg chewable tablets when properly stored is a stable product. On the basis of stability testing results, the 3 years shelf life for Vitamin C Orange 500 mg chewable tablets is established.3.2.P.8.2Post-approval Stability Protocol and Stability Commitment

Stability studies are ongoing and will be continued. Upon approval, at least one batch of manufactured finished product Vitamin C Orange 500 mg chewable tablets will be incorporated annually into a programme of ongoing stability trials. All batches included in the stability program will be tested according to the protocol (long-term).3.2.P.8.3Stability Data

The analytical methods employed in the stability tests for Vitamin C Orange 500 mg chewable tablets are those used for the freshly prepared finished product analyses.

The results of stability tests are summarized in the table format and presented on the following pages.

3.2.AAPPENDICES

3.2.AAppendices

3.2.A.1Facilities and Equipment

3.2.A.2Adventitious Agents Safety Evaluation

3.2.A.3Excipients

Not applicable

3.2.R REGIONAL INFORMATION

3.2.RRegional information

Company DSM Nutritional Products Ltd. has been granted Certificate of Suitability of monographs of European Pharmacopoeia No R1-CEP 1996-078-Rev 01 for the active substance Ascorbic Acid. Certificate of Suitability is presented on the following pages.Company DSM Nutritional Products Ltd. has been granted Certificate of Suitability of monographs of European Pharmacopoeia No R0-CEP 2002-254-Rev 00 for the active substance Sodium Ascorbate. Certificate of Suitability is presented on the following pages.3.3. LITERATURE REFERENCES

Literature1. J.E.F. Reynolds. Martindale. The Extra Pharmacopoeia. London: The Pharmaceutical Press, 1989.

2. Rote Liste 2003.

3. Remingtons Pharmaceutical Sciences. Easton, Pennsylvania 18042: Mack Publishing Company, 1990.

4. Raymond C. Rowe, Paul J. Sheskey, Paul J. Weller. Handbook of Pharmaceutical Excipients, Fourth Edition. London, Chicago: Pharmaceutical Press, 2003.

5. Russian Pharmacopoeia XI edition ( XI).6. Ukrainian State Pharmacopoeia ().7. European Pharmacopoeia current edition.

8. The United States Pharmacopeia current edition.9. The British Pharmacopoeia current edition._1157201354.unknown