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Theme: Analysis of quality of inorganic drugs of Magnesium, Calcium, Zinc, Bismuth, Copper

June 19, 2024

Theme: Analysis of metal-containing compounds of Calcium, Magnesium, Zinc, Copper and Bismuth.

Inorganic drugs of Calcium

Distribution to the nature

In a free condition does not meet (alkaline-earth metal).

1. Minerals:

Carbonates: СаСО₃ – calcite (deposits of a chalk, limestone, marble); dolomite – CaCO₃×MgCO₃;

Sulphates: СаSО₄×2Н₂O – plaster, СаSО₄ – anhydrite;

Phosphates: 3Са₃(РО₄)₂×Са(OH)₂ – phosphorites,

3Са₃(РО₄)₂×СаF₂ – fluor apatite;

Fluorides: CaF₂ – fluoride or fluor-spar.

2. Living organisms. Calcium – is a macrocell. Са₃(РО₄)₂ – in structure of bones, a tooth tissue, muscles, a nervous tissue, blood.

Biological action and medical application

Са²⁺-ions formation of bone and tooth tissue; strengthen ability to live of cages; promote reduction of skeletal muscles and heart muscles; curlings of blood necessary for improvement.

Calcium preparations:

1. Calcium oxide (Calcii oxydum) CaО – for preparation of limy water (Aqua calcis).

2. Plaster medical (Calcii sulfas) 2СаSО₄×Н₂O – for surgery.

3. Calcium carbonate (Calcii carbonas) СаСО₃ – at the calcium insufficiency in the form of Calcium Carbonate Chewable Tablets and at the raised acidity of gastric juice (Calcii carbonas praecipitatus).

4. Calcium chloride (dihydrate and hexahydrate).

5. Organic preparations of Calcium (calcium lactate, calcium gluconate, calcium glycerophosphate) will be considered in following lectures.

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Calcium Chloride Dihydrate

Calcium Chloride Dihydrate

General Notices

(Ph Eur monograph 0015)

Calcii chloridum dihydricum

Calcium chloratum

CaCl₂,2H₂Oээ

147.0ээ 10035-04-8

DEFINITION

Content

97.0 per cent to 103.0 per cent of CaCl2,2H2O.

CHARACTERS

Appearance

White or almost white, crystalline powder, hygroscopic.

Solubility

Freely soluble in water, soluble in ethanol (96 per cent).

IDENTIFICATION – the same as Calcium Chloride Hexahydrate. (see CaCl₂,6H₂O). ээ

эA. Solution S (see Tests) gives reaction (a) of chlorides (2.3.1) .

эB. It gives the reactions of calcium (2.3.1) .

C. Put some drops of hydrochloric acid on the sample of CaCI₂, 2H₂O. The flame is tinged with red (Ca²⁺).

эC. It complies with the limits of the assay.

TESTS– the same as Calcium Chloride Hexahydrate

Solution S

Dissolve 10.0 g in carbon dioxide-free water R prepared from distilled water R and dilute to

100 ml with the same solvent.

Appearance of solution

Solution S is clear (2.2.1) and not more intensely coloured than reference solution Y6 (2.2.2, Method II).

Acidity or alkalinity

To 10 ml of freshly prepared solution S add 0.1 ml of phenolphthalein solution R . If the

solution is red, not more than 0.2 ml of 0.01 M hydrochloric acid is required to discharge the colour and if the solution is colourless, not more than 0.2 ml of 0.01 M sodium hydroxide is required to turn it red.

Sulphates (2.4.13)

Maximum 300 ppm.

Dilute 5 ml of solution S to 15 ml with distilled water R .

Aluminium – inadmissible impurity.

To 10 ml of solution S add 2 ml of ammonium chloride solution R and 1 ml of dilute ammonia R1 . Heat to boiling. No turbidity or precipitate is formed. If intended for use in the manufacture of dialysis solutions, the above test is replaced by the following test for aluminium (2.4.17): maximum 1 ppm. Prescribed solutionэ Dissolve 6 g in 100 ml of water R and add 10 ml of acetate buffer solution pH 6.0 R . Reference solutionэ Mix 2 ml of aluminium standard solution (2 ppm Al) R, 10 ml of acetate buffer solution pH 6.0 R and 98 ml of water R . Blank solutionэ Mix 10 ml of acetate buffer solution pH 6.0 R and 100 ml of water R.

Barium– inadmissible impurity.

To 10 ml of solution S add 1 ml of calcium sulphate solution R . After at least 15 min, any

opalescence in the solution is not more intense than that in a mixture of 1 ml of distilled water R and 10 ml of solution S.

Iron (2.4.9)

Maximum 10 ppm, determined on solution S.

Magnesium and alkali metals

Maximum 0.5 per cent.

To a mixture of 20 ml of solution S and 80 ml of water R add 2 g of ammonium chloride R and 2 ml of dilute ammonia R1 , heat to boiling and pour into the boiling solution a hot solution of 5 g of ammonium oxalate R in 75 ml of water R . Allow to stand for 4 h, dilute to 200 ml with water R and filter through a suitable filter. To 100 ml of the filtrate add 0.5 ml of sulphuric acid R . Evaporate to dryness on a water-bath and ignite to constant mass at 600 ± 50 °C. The residue weighs a maximum of 5 mg.

Heavy metals (2.4.8)

Maximum 20 ppm.

12 ml of solution S complies with test A. Prepare the reference solution using lead standard solution (2 ppm Pb) R .

ASSAY– the same as Calcium Chloride Hexahydrate

(BrPh, SPU, add. 1). Chelatometry, direct titration. Dissolve 0.280 g in 100 ml of water R and carry out the complexometric titration of calcium (2.5.11).

1 ml of 0.1 M sodium edetate is equivalent to 14.70 mg of CaCl2,2H2O.

LABELLING

The label states, where applicable, that the substance is suitable for use in the manufactureof dialysis solutions.

STORAGE

In an airtight container .

Ph Eur

Action and use. Antiallergic, use in treatment of calcium deficiency.

Another preparations of Calcium: Calcium gluconate Tablets; Effervescent calcium gluconate Tablets; Calcium hydroxide solution; Calcium lactate Tablets.

Preparations

Calcium Chloride Injection

Compound Sodium Lactate Intravenous Infusion

Ph Eur

Chelatomerty in the pharmaceutical analysis (SPU)

Titrant – sodium EDTA (disodium salt of ethylenediaminetetraacetate acid) (Na2-EDТА)

Test ion

Conditions of carrying out of experiment

Indicator mix

Colouring change

Bi^{3 +}

Solution NH3 conc. before clouding occurrence, then HNO3 before disappearance of clouding,

t° = 70 °C

Xylenol orange

(1 part. + 99 parts of KNO3)

With pink-violet to yellow

Ca^{2 +}

Solution NаОH conc.

calconcarbonic acid

(1 part + 99 parts of NaCl)

Violet in dark blue

Mg^{2 +}

Ammoniac buffer solution

pН 10,0, t = 40 °C

Eriochrome black

(1 part + 99 parts of NaCl)

Violet in dark blue

Pb^{2 +}

hexamethylenetetramine (the alkaline medium) pH~7,8–8,2

Xylenol orange

(1 part + 99 parts of NaCl)

Violet-red in the yellow

Zn^{2 +}

hexamethylenetetramine (the alkaline medium) pH~7,8–8,2

Xylenol orange

(1 part. + 99 parts of KNO3)

Violet-red in the yellow

Al^{3 +}

Back chelatometry, excess Na2-EDТА titrate of standart solution of Pb (NO3) 2

Xylenol orange

(1 part. + 99 parts of KNO3)

pink-violet

Hg^{2 +}

Back chelatometry, excess Na2-EDТА titrate of standart solution of ZnSO4

Eriochrome black

(1 part + 99 parts of NaCl)

The violet

Medical preparations of Magnesium

Distribution in the nature

Magnesium is the most widespread element in the nature. In the earth crust it content is to 0,2 %.

Basic minerals: magnesite – MgCO₃, dolomite – CaCO₃×MgCO₃, carnallite – KCl×MgCl₂×6H₂O, kainite – KCl×MgSO₄×3H₂O, kieserite – MgSO₄×H₂O або MgSO₄×7H₂O, talc – 3MgО×4SiО₂×H₂O.

Use in the medical practice

BrPh, SPU – Heavy Magnesium Oxide, Light Magnesium Oxide (MgO).

BrPh, SPU, add. 1 – Heavy Magnesium Carbonate, Light Magnesium Carbonate (MgCO₃); Magnesium Sulphate Heptahydrate (MgSO₄, 7H₂O), Dried Magnesium Sulphate; Magnesium Chloride Hexahydrate (MgCl₂, 6H₂O).

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Heavy Magnesium Oxide

Heavy Magnesium Oxide

General Notices

(Ph Eur monograph 0041)

Magnesii oxydum ponderosum

MgOээ

40.30ээ1309-48-4

DEFINITION

Content

98.0 per cent to 100.5 per cent of MgO (ignited substance).

OBTAINING

Thermal processing of magnesium carbonate basic t 250–300 °C:

3MgCO₃×Mg(OH)₂×3H₂O 4MgО + 3CO₂ + 4H₂O

CHARACTERS

Appearance

Fine, white or almost white powder.

Solubility

Practically insoluble in water. It dissolves in dilute acids with at most slight effervescence.

IDENTIFICATION

эA. (BrPh, SPU). Bulk volume. 15 g has an apparent volume (2.9.15) before settling of not more than 60 ml.

эB. (BrPh, SPU). It gives the reactions of magnesium after substance dissolution in the dilute nitric acid and the next neutralization by dilute sodium hydroxide solution

Dissolve about 15 mg in 2 ml of dilute nitric acid R and neutralise with dilute sodium hydroxide solution R. The solution gives the reaction of magnesium (2.3.1).

MgО + 2HNO₃ = Mg(NO₃)₂ + H₂O

Magnesium and Magnesium Salts

(BrPh, SPU). Reaction with disodium hydrogen phosphate solution in the presence of dilute ammonia and ammonium chloride solution. Dissolve about 15 mg of the substance to be examined in 2 ml of water R or use 2 ml of the prescribed solution. Add 1 ml of dilute ammonia R1. A white precipitate is formed that dissolves on addition of 1 ml of ammonium chloride solution R. Add 1 ml of disodium hydrogen phosphate solution R. A white crystalline precipitate is formed.

Mg²⁺ + HPO₄^2– + NH₄ОН NH₄MgPO₄¯ + Н₂О

white precipitate

эC. (BrPh). Loss on ignition (see Tests).

OTHER REACTIONS:

1. Reaction with 8-oxyquinoline in the medium of an ammoniac buffer solution; the yellow- green crystalline precipitate of magnesium 8-oxyquinoline is formed:

yellow- green crystalline precipitate

2. Reaction with quinalizarin alcoholic solution and sodium hydroxide solution; at addition sodium hydroxide solution to quinalizarin alcoholic solution is formed blue-violet reagent. In the presence of Mg²⁺-ions complex compound with cornflower blue colour is formed:

quinalizarin complex compound

with cornflower blue colour

TESTS

Solution S

Dissolve 5.0 g in a mixture of 30 ml of distilled water R and 70 ml of acetic acid R, boil for 2 min, cool and dilute to 100 ml with dilute acetic acid R. Filter, if necessary, through a

previously ignited and tared porcelain or silica filter crucible of suitable porosity to give a clear filtrate.

Appearance of solution

Solution S is not more intensely coloured than reference solution B3 (2.2.2, Method II).

Soluble substances

Maximum 2.0 per cent.

To 2.00 g add 100 ml of water R and boil for 5 min. Filter whilst hot through a sintered-glass filter (40) (2.1.2), allow to cool and dilute to 100 ml with water R. Evaporate 50 ml of the filtrate to dryness and dry at 100-105 °C. The residue weighs a maximum of 20 mg.

Substances insoluble in acetic acid

Maximum 0.1 per cent.

Any residue obtained during the preparation of solution S, washed, dried, and ignited at 600 ± 50 °C, weighs a maximum of 5 mg.

Chlorides (2.4.4)

Maximum 0.1 per cent.

Dilute 1 ml of solution S to 15 ml with water R.

Sulphates (2.4.13)

Maximum 1.0 per cent.

Dilute 0.3 ml of solution S to 15 ml with distilled water R.

Arsenic (2.4.2, Method A)

Maximum 4 ppm, determined on 5 ml of solution S.

Calcium (2.4.3)

Maximum 1.5 per cent.

Dilute 1.3 ml of solution S to 150 ml with distilled water R. 15 ml of the solution complies with the test.

Iron (2.4.9)

Maximum 0.07 per cent.

Dissolve 0.15 g in 5 ml of dilute hydrochloric acid R and dilute to 10 ml with water R. Dilute 1 ml of the solution to 10 ml with water R.

Heavy metals (2.4.8)

Maximum 30 ppm.

To 20 ml of solution S add 15 ml of hydrochloric acid R1 and shake with 25 ml of methyl

isobutyl ketone R for 2 min. Allow to stand, then separate and evaporate the aqueous layer to dryness. Dissolve the residue in 1 ml of acetic acid R and dilute to 30 ml with water R. 12 ml of the solution complies with test A. Prepare the reference solution using lead standard solution (1 ppm Pb) R.

Loss on ignition

Maximum 8.0 per cent, determined on 1.00 g at 900 ± 25 °C.

ASSAY

Dissolve 0.320 g in 20 ml of dilute hydrochloric acid R and dilute to 100.0 ml with water R

MgO + 2HCl = MgCl₂ + H₂O

test solution

Using 20.0 ml of the (test) solution, carry out the complexometric titration of magnesium (2.5.11).

1 ml of 0.1 M sodium edetate is equivalent to 4.030 mg of MgO.

Ph Eur

Magnesium

(BrPh, SPU). Chelatometry, direct titration. (see table).

Introduce the prescribed solution into a 500 ml conical flask and dilute to 300 ml with water R. Add 10 ml of ammonium chloride buffer solution pH 10.0 R and about 50 mg of mordant black 11 triturate R. Heat to about 40 °C then titrate at this temperature with 0.1 M sodium edetate until the colour changes from violet to full blue.

1 ml of 0.1 M sodium edetate is equivalent to 2.431 mg of Mg.

At titration Magnesium salt with 0.01 M sodium edetate a very strong colourless, soluble in water, complexes is formed:

H₂Ind +Mg²⁺ ® MgInd + 2H⁺

blue violet

Excess drop of sodium edetate destroys complex MeInd and complex H₂Ind is formed again and the full blue colour is again obtained.

Em (MgО) = М m.

OTHER METHOD OF ASSAY:

The acid-base titration, back titration.

Additional titrant – standard solution of HCl.

Basic titrant – standard solution of NaOH.

Indicator – methyl orange.

Titrate with NaOH until the colour changes from pink to yellow.

1MgО + 2HCl = MgCl₂ + H₂O

excess

2HCl + 2NaOH = 2NaCl + 2H₂O

rest

1 mol MgО ® 2 mol (2 equivalent) HCl ® 2 mol (2 equiv.) NaOH

Therefore Em (MgO) = М m./2

Action and use

Antacid; osmotic laxative.

Ph Eur

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Light Magnesium Oxide

Light Magnesium Oxide

General Notices

Light Magnesia

(Ph Eur monograph 0040)

Magnesii oxydum leve

MgOэ

э40.30ээ1309-48-4

DEFINITION

Content

98.0 per cent to 100.5 per cent of MgO (ignited substance).

CHARACTERS

Appearance

Fine, white or almost white, amorphous powder.

Solubility

Practically insoluble in water. It dissolves in dilute acids with at most slight effervescence.

IDENTIFICATION– the same as Heavy Magnesium Oxide.

эA. 15 g has an apparent volume (2.9.15) before settling of at least 100 ml.

эB. Dissolve about 15 mg in 2 ml of dilute nitric acid R and neutralise with dilute sodium

hydroxide solution R. The solution gives the reaction of magnesium (2.3.1).

эC. Loss on ignition (see Tests).

TESTS– the same as Heavy Magnesium Oxide.

Solution S

Dissolve 5.0 g in a mixture of 30 ml of distilled water R and 70 ml of acetic acid R, boil for 2min, cool and dilute to 100 ml with dilute acetic acid R. Filter, if necessary, through a

previously ignited and tared porcelain or silica filter crucible of a suitable porosity to give a clear filtrate.

Appearance of solution

Solution S is not more intensely coloured than reference solution B2 (2.2.2, Method II).

Soluble substances

Maximum 2.0 per cent.

Substances insoluble in acetic acid

Maximum 0.1 per cent.

Any residue obtained during the preparation of solution S, washed, dried, and ignited at 600 ±50 °C, weighs a maximum of 5 mg.

Chlorides (2.4.4)

Maximum 0.15 per cent.

Dilute 0.7 ml of solution S to 15 ml with water R.

Sulphates (2.4.13)

Maximum 1.0 per cent.

Dilute 0.3 ml of solution S to 15 ml with distilled water R.

Arsenic (2.4.2, Method A)

Maximum 4 ppm, determined on 5 ml of solution S.

Calcium (2.4.3)

Maximum 1.5 per cent.

Dilute 1.3 ml of solution S to 150 ml with distilled water R. 15 ml of the solution complies with the test.

Iron (2.4.9)

Maximum 0.1 per cent.

Dissolve 50 mg in 5 ml of dilute hydrochloric acid R and dilute to 10 ml with water R. Dilute 2 ml of t his solution to 10 ml with water R.

Heavy metals (2.4.8)

Maximum 30 ppm.

To 20 ml of solution S add 15 ml of hydrochloric acid R1 and shake with 25 ml of methyl

isobutyl ketone R for 2 min. Allow to stand, then separate and evaporate the aqueous layer to dryness. Dissolve the residue in 1.5 ml of acetic acid R and dilute to 30 ml with water R. 12 ml of the solution complies with test A. Prepare the reference solution using lead standard solution (1 ppm Pb) R.

Loss on ignition

Maximum 8.0 per cent, determined on 1.00 g at 900 ± 25 °C.

ASSAY– the same as Heavy Magnesium Oxide.

Dissolve 0.320 g in 20 ml of dilute hydrochloric acid R and dilute to 100.0 ml with water R.

Using 20.0 ml of the solution, carry out the complexometric titration of magnesium (2.5.11).

1 ml of 0.1 M sodium edetate is equivalent to 4.030 mg of MgO.

Ph Eur

Action and use

Antacid; osmotic laxative.

Preparation

Magnesium Hydroxide Mixture

Ph Eur

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Heavy Magnesium Carbonate

Heavy Magnesium Carbonate

General Notices

(Ph Eur monograph 0043)

Magnesii subcarbonas ponderosus

MgCO₃

ээээ546-93-0

DEFINITION

Hydrated basic magnesium carbonate.

Content

40.0 per cent to 45.0 per cent, calculated as MgO (Mr 40.30).

CHARACTERS

Appearance

White or almost white powder.

Solubility

Practically insoluble in water. It dissolves in dilute acids with effervescence.

IDENTIFICATION

эA. (BrPh). Bulk density (2.9.34): minimum 0.25 g/ml.

(SPU, add. 1). Bulk volume. 15 g has an apparent volume before settling of not more than 30 ml.

B. (BrPh, SPU, add. 1). It gives the reaction of carbonates (2.3.1).

Carbonates and Bicarbonates

(BrPh, SPU, add. 1). Reaction with mineral acids. Introduce into a test-tube 0.1 g of the substance to be examined and suspend in 2 ml of water R or use 2 ml of the prescribed solution. Add 3 ml of dilute acetic acid R. Close the tube immediately using a stopper fitted with a glass tube bent twice at right angles. The solution or the suspension becomes effervescent and gives off a colourless and odourless gas. Heat gently and collect the gas in 5 ml of barium hydroxide solution R. A white precipitate is formed that dissolves on addition of an excess of hydrochloric acid R1.

СО₃^2– + 2СН₃СООН = 2СН₃СОО^– + Н₂О + СО₂

colourless and

odourless gas

СО₂ + Ва(ОН)₂ = ВаСО₃¯ + Н₂О

white precipitate

ВаСО₃¯ + 2HCl = BaCl₂

excess solution

Other reaction:

SPU, N. Reaction with saturated solution of magnesium sulphate

At addition saturated solution of magnesium sulphate to water solution of substance with СО₃^2––anions at room temperature white precipitate of magnesium carbonate is formed (unlike hydrogencarbonates, which formed precipitate only at boiling):

CO₃^2– + Mg²⁺ = MgCO₃¯

white precipitate

C. (BrPh, SPU). Reactions of magnesium after substance dissolution in the dilute nitric acid and and neutralise with dilute sodium hydroxide solution. Dissolve about 15 mg in 2 ml of dilute nitric acid R and neutralise with dilute sodium hydroxide solution R. The solution gives the reaction of magnesium (2.3.1).

MgCО₃ + 2HNO₃ = Mg(NO₃)₂ + H₂O + CO₂

solution

Magnesium and Magnesium Salts

(BrPh, SPU). Reaction with disodium hydrogen phosphate solution in the

presence of dilute ammonia and ammonium chloride solution. Dissolve about 15 mg of the substance to be examined in 2 ml of water R or use 2 ml of the prescribed solution. Add 1 ml of dilute ammonia R1. A white precipitate is formed that dissolves on addition of 1 ml of ammonium chloride solution R. Add 1 ml of disodium hydrogen phosphate solution R. A white crystalline precipitate is formed.

Mg²⁺ + HPO₄^2– + NH₄ОН NH₄MgPO₄¯ + Н₂О

white precipitate

TESTS

Solution S

Dissolve 5.0 g in 100 ml of dilute acetic acid R. When the effervescence has ceased, boil for 2 min, allow to cool and dilute to 100 ml with dilute acetic acid R. Filter, if necessary, through a previously ignited and tared porcelain or silica filter crucible of suitable porosity to give a clear filtrate.

Appearance of solution

Solution S is not more intensely coloured than reference solution B4 (2.2.2, Method II).

Soluble substances

Maximum 1.0 per cent.

Mix 2.00 g with 100 ml of water R and boil for 5 min. Filter whilst hot through a sintered-glass filter (40) (2.1.2), allow to cool and dilute to 100 ml with water R. Evaporate 50 ml of the filtrate to dryness and dry at 100-105 °C. The residue weighs not more than 10 mg.

Substances insoluble in acetic acid

Maximum 0.05 per cent.

Any residue obtained during the preparation of solution S, washed, dried, and ignited at 600 ± 50 °C, weighs not more than 2.5 mg.

Chlorides (2.4.4)

Maximum 700 ppm.

Dilute 1.5 ml of solution S to 15 ml with water R.

Sulphates (2.4.13)

Maximum 0.6 per cent.

Dilute 0.5 ml of solution S to 15 ml with distilled water R.

Arsenic (2.4.2, Method A)

Maximum 2 ppm, determined on 10 ml of solution S.

Calcium (2.4.3)

Maximum 0.75 per cent.

Dilute 2.6 ml of solution S to 150 ml with distilled water R. 15 ml of the solution complies with the test.

Iron (2.4.9)

Maximum 400 ppm.

Dissolve 0.1 g in 3 ml of dilute hydrochloric acid R and dilute to 10 ml with water R. Dilute 2.5 ml of the solution to 10 ml with water R.

Heavy metals (2.4.8)

Maximum 20 ppm.

To 20 ml of solution S add 15 ml of hydrochloric acid R1 and shake with 25 ml of methyl

isobutyl ketone R for 2 min. Allow to stand, separate the aqueous lower layer and evaporate to dryness. Dissolve the residue in 1 ml of acetic acid R and dilute to 20 ml with water R. 12 ml of the solution complies with test A. Prepare the reference solution using lead standard solution (1 ppm Pb) R.

ASSAY

(BrPh, SPU, add. 1). Chelatometry, direct titration. (see table). Dissolve 0.150 g in a mixture of 2 ml of dilute hydrochloric acid R and 20 ml of water R. Carry out the complexometric titration of magnesium (2.5.11).

1 ml of 0.1 M sodium edetate is equivalent to 4.030 mg of MgO.

E_m (MgО) = М. m.

OTHER METHODS OF ASSAY:

1. The acid-base titration, back titration

(similarly magnesium oxide).

Em (MgО) = М m./2

2. Gravimetric (weight) method

Shot of magnesium carbonate alkaline 3MgCO₃×Mg (OH)₂×3H₂O dry up , calcinate to constant weight and weigh (weight or gravimetric form – MgО):

3MgCO₃×Mg(OH)₂×3H₂O 4MgО + 3СО₂ + 4Н₂О

Calculate the maintenance of magnesium oxide MgО in a preparation under the formula:

Where F – gravimetric factor, which calculate under the formula:

Maintenance МgO should be less than 40,0 % and no more than 45 %.

Action and use

Antacid; osmotic laxative.

Ph Eur

FUNCTIONALITY-RELATED CHARACTERISTICS

This section provides information on characteristics that are recognised as being relevant

control parameters for one or more functions of the substance when used as an excipient

(see chapter 5.15). This section is a non-mandatory part of the monograph and it is not

necessary to verify the characteristics to demonstrate compliance. Control of these

characteristics can however contribute to the quality of a medicinal product by improving the

consistency of the manufacturing process and the performance of the medicinal product

during use. Where control methods are cited, they are recognised as being suitable for the

purpose, but other methods can also be used. Wherever results for a particular characteristic

are reported, the control method must be indicated.The following characteristics may be

relevant for heavy magnesium carbonate used as a filler in tablets.

Particle-size distribution (2.9.31 or 2.9.38).

Bulk and tapped density (2.9.34).

Ph Eur

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Light Magnesium Carbonate

Light Magnesium Carbonate

General Notices

(Ph Eur monograph 0042)

Magnesii subcarbonas levis

ээээ546-93-0

DEFINITION

Hydrated basic magnesium carbonate.

Content

40.0 per cent to 45.0 per cent, calculated as MgO (Mr 40.30).

CHARACTERS

Appearance

White or almost white powder.

Solubility

Practically insoluble in water. It dissolves in dilute acids with effervescence.

IDENTIFICATION (BrPh, SPU, add. 1) – the same as Heavy Magnesium Carbonate.

эA. Bulk volume. 15 g has an apparent volume (2.9.15) before settling of at least 100 ml.

(Ph. Eur. method 2.9.15)

The test for apparent volume is intended to determine under defined conditions the apparent volumes, before and after settling, the ability to settle and the apparent densities of divided solids (for example, powders, granules).

Apparatus

The apparatus (see Figure 2.9.15.-1) consists of the following:

—a settling apparatus capable of producing in 1 min 250 ± 15 taps from a height of 3 ± 0.2 mm. The support for the graduated cylinder, with its holder, has a mass of 450 ± 5 g;

—a 250 ml graduated cylinder (2 ml intervals) with a mass of 220 ± 40 g.

Method

Into the dry cylinder, introduce without compacting 100.0 g (m g) of the substance to be examined. If this is not possible, select a test sample with an apparent volume between 50 ml and 250 ml and specify the mass in the expression of results. Secure the cylinder in its holder. Read the unsettled apparent volume V₀ to the nearest millilitre. Carry out 10, 500 and 1250 taps and read the corresponding volumes V₁₀, V₅₀₀ and V₁₂₅₀, to the nearest millilitre. If the difference between V₅₀₀ and V₁₂₅₀ is greater than 2 ml, carry out another 1250 taps.

Expression of the results

a) Apparent volumes:

—apparent volume before settling or bulk volume: V₀ ml.

—apparent volume after settling or settled volume: V₁₂₅₀ ml or V₂₅₀₀ ml.

b) Ability to settle: difference V₁₀ ml – V₅₀₀ ml.

c) Apparent densities:

The apparent densities are expressed as follows:

—apparent density before settling or density of bulk product: m/V₀ (grams per millilitre) (poured density).

—apparent density after settling or density of settled product: m/V₁₂₅₀ or m/V₂₅₀₀ (grams per millilitre) (tapped density).

эB. It gives the reaction of carbonates (2.3.1).

C. Dissolve about 15 mg in 2 ml of dilute nitric acid R and neutralise with dilute sodium

hydroxide solution R. The solution gives the reaction of magnesium (2.3.1).

TESTS – the same as Heavy Magnesium Carbonate.

Solution S

Appearance of solution

Solution S is not more intensely coloured than reference solution B4 (2.2.2, Method II).

Soluble substances

Maximum 1.0 per cent.

Mix 2.00 g with 100 ml of water R and boil for 5 min. Filter whilst hot through a sintered-glass filter (40) (2.1.2), allow to cool and dilute to 100 ml with water R. Evaporate 50 ml of the filtrate to dryness and dry at 100-105 °C. The residue weighs a maximum of 10 mg.

Substances insoluble in acetic acid

Maximum 0.05 per cent.

Any residue obtained during the preparation of solution S, washed, dried and ignited at 600 ±50 °C, weighs a maximum of 2.5 mg.

Chlorides (2.4.4)

Maximum 700 ppm.

Dilute 1.5 ml of solution S to 15 ml with water R.

Sulphates (2.4.13)

Maximum 0.3 per cent.

Dilute 1 ml of solution S to 15 ml with distilled water R.

Arsenic (2.4.2, Method A)

Maximum 2 ppm, determined on 10 ml of solution S.

Calcium (2.4.3)

Maximum 0.75 per cent.

Dilute 2.6 ml of solution S to 150 ml with distilled water R. 15 ml of the solution complies with the test.

Iron (2.4.9)

Maximum 400 ppm.

Dissolve 0.1 g in 3 ml of dilute hydrochloric acid R and dilute to 10 ml with water R. Dilute 2.5 ml of the solution to 10 ml with water R.

Heavy metals (2.4.8)

Maximum 20 ppm.

To 20 ml of solution S add 15 ml of hydrochloric acid R1 and shake with 25 ml of methyl

isobutyl ketone R for 2 min. Allow to stand, separate the aqueous lower layer and evaporate to dryness. Dissolve the residue in 1 ml of acetic acid R and dilute to 20 ml with water R. 12

ml of the solution complies with test A. Prepare the reference solution using lead standard solution (1 ppm Pb) R.

ASSAY – the same as Heavy Magnesium Carbonate.(see table).

Dissolve 0.150 g in a mixture of 2 ml of dilute hydrochloric acid R and 20 ml of water R. Carry out the complexometric titration of magnesium (2.5.11).

1 ml of 0.1 M sodium edetate is equivalent to 4.030 mg of MgO.

Ph Eur

E_m (MgО) = М. m.

Action and use

Antacid; osmotic laxative.

Preparation

Aromatic Magnesium Carbonate Mixture

Ph Eur

In the SPU is drug – Basic Magnesium Carbonate, N

Magnesii subcarbonas

Magnesia alba

Magnesium subcarbonicum

3MgCO₃×Mg(OH)₂×3H₂O

Magnesium Sulphate Heptahydrate

MgSO₄,7H₂O

246.5

10034-99-8

Magnesium Sulphate Heptahydrate complies with the requirements of the 3rd edition of the European Pharmacopoeia [0044]. These requirements are reproduced after the heading ‘Definition’ below.

Action and use Osmotic laxative; used in treatment of electrolyte deficiency.

Preparations

Magnesium Sulphate Injection

Magnesium Sulphate Mixture

When magnesium sulphate is prescribed or demanded, Magnesium Sulphate Heptahydrate shall be dispensed or supplied.

DEFINITION

Magnesium sulphate heptahydrate contains not less than 99.0 per cent and not more than the equivalent of 100.5 per cent of MgSO₄, calculated with reference to the dried substance.

CHARACTERS

A white, crystalline powder or brilliant, colourless crystals, freely soluble in water, very soluble in boiling water, practically insoluble in alcohol.

IDENTIFICATION

A. It gives the reactions of sulphates (2.3.1).

B. It gives the reaction of magnesium (2.3.1).

TESTS

Solution S Dissolve 5.0 g in water R and dilute to 50 ml with the same solvent.

Appearance of solution Solution S is clear (2.2.1) and colourless (Method II, 2.2.2).

Acidity or alkalinity To 10 ml of solution S add 0.05 ml of phenol red solution R. Not more than 0.2 ml of 0.01M hydrochloric acid or 0.01M sodium hydroxide is required to change the colour of the indicator.

Chlorides (2.4.4). 1.7 ml of solution S diluted to 15 ml with water R complies with the limit test for chlorides (300 ppm).

Arsenic (2.4.2). 0.5 g complies with limit test A for arsenic (2 ppm).

Heavy metals (2.4.8). 12 ml of solution S complies with limit test A for heavy metals (10 ppm). Prepare the standard using lead standard solution (1 ppm Pb) R.

Iron (2.4.9). 5 ml of solution S diluted to 10 ml with water R complies with the limit test for iron (20 ppm).

Loss on drying (2.2.32). 48.0 per cent to 52.0 per cent, determined on 0.500 g by drying in an oven at 110°C to 120°C for 1 h and then at 400°C to constant mass.

ASSAY

Dissolve 0.450 g in 100 ml of water R and carry out the complexometric titration of magnesium (2.5.11).

1 ml of 0.1M sodium edetate is equivalent to 12.04 mg of MgSO₄.

Dried Magnesium sulphate (dried Epsom Salts)

Definition. Contains not less than 62% and not more than 70% of MgSO₄.

Preparations. Magnesium Sulphate Paste.

Magnesium Trisilicate (is a hydrated magnesium silicate of the approximate composition 2MgO,3SiO₂, xH₂O)

Preparations. Magnesium Trisilicate Mixture, Compound Magnesium Trisilicate Oral Powder, Compound Magnesium Trisilicate Tablets.

Action and use. Antacid.

Light Magnesium Carbonate (is hydrated basic magnesium carbonate. It contains the equivalent of not less than 40% and not more than 45% of MgCO₃)

Preparations. Aromatic Magnesium Carbonate Mixture.

Action and use. Antacid; osmotic laxative.

Magnesium Chloride (MgCl₂,6H₂O) – used in dialysis solutions.

Magnesium Oxide (MgO) – antacid; osmotic laxative.

Inorganical drugs of Zinc

Distribution in the nature. Basic minerals of Zinc: blende – ZnS; zinc spar – ZnCO₃; calamite – Zn₄(Si₂O₇)(OH)₂×H₂O.

Biological function

Zinc – is necessary microelement, it plats important role in the organism activity. In the organism of adult person is approximately 2 g of Zinc (in the muscles, teeth, nervous tissue, is the part of insulin, is the vitamins synergetic.

Zinc deficiency is at diseases of intestinal, nephroses, liver, blood, psoriasis, neoplasm. It is accompany with immunity weakening, sense dropping, relish and appetite dropping, dermatitis.

Application oin the medical practice

In the big doseage of Zinc is a toxic, then its use for local application compounds of Zinc has astringent action. At peroral using its makes vomiting.

Using of Zinc compounds is based (similar to other heavy metals) on protein–binding with albuminates formation.

In the medical practice use such inorganic drugs of Zinc: – Zinc Oxide ZnО, Zinc Sulphate Heptahydrate ZnSO₄×7H₂O (BrPh, SPU, add. 1), Zinc Sulphate Hexahydrate ZnSO₄×6H₂O, Zinc Sulphate Monohydrate ZnSO₄×H₂O (BrPh) and Zinc Chloride ZnCl₂(BrPh, SPU, add. 1).

Browse: British Pharmacopoeia 2009 SPU, add. 1

British Pharmacopoeia Volume I & II

Monographs: Medicinal and Pharmaceutical Substances

Zinc Oxide

Zinc Oxide

General Notices

(Ph Eur monograph 0252)

Zinci oxydum

Zincum oxydatum

Flores Zinci

Lana philosophica

ZnOээ

81.4ээ 1341-13-2

DEFINITION

Content

99.0 per cent to 100.5 per cent (ignited substance).

OBTAINING

1. Tempering of zinc spar ZnCO₃:

ZnCO₃ ZnО + CO₂

2. Tempering of zinc hydroxide Zn(OH)₂. Zinc hydroxide obtained by addition some excess of ammonium hydroxide solution NH₄OH to 10 % zinc nitrate solution Zn(NO₃)₂:

Zn(NO₃)₂ + 2NH₄OH = Zn(OH)₂¯ + 2NH₄NO₃

Zn(OH)₂ wash by decantation, filtrate and wash in the filter by water to disappearance reaction for ammonium cations NH₄⁺(with Nessler reagent). The precipitate after desiccation fry in the porcelain incineration dish at t 400 °С:

Zn(OH)₂ ZnО + H₂O

CHARACTERS

Appearance

Soft, white or faintly yellowish-white, amorphous powder, free from gritty particles.

Solubility

Practically insoluble in water and in ethanol (96 per cent). It dissolves in dilute mineral acids.

Chemical properties. Zinc oxide has amphoteric properties, therefore it is soluble in:

а) mineral acids and acetic acid with salts formation:

ZnО + 2HCl = ZnCl₂ + H₂O;

б) alkali solution NaOH with hydroxocomplex formation:

ZnО + 2NaOH + H₂O = Na₂[Zn(OH)₄];

в) ammonia solution NH₃with ammonia complex formation:

ZnО + 4NH₃ + H₂O = [Zn(NH₃)₄](OH)₂.

IDENTIFICATION

эA. (BrPh, SPU, add. 1). Substance heating with the next cooling. It becomes yellow when strongly heated; the yellow colour disappears on cooling.

эB. (BrPh, SPU, add. 1). Dissolve 0.1 g in 1.5 ml of dilute hydrochloric acid R and dilute to 5 ml with water R. The solution gives the reaction of zinc (2.3.1).

Zinc and Zinc Salts

Reaction with sodium hydroxide and sodium sulphide solutions. Dissolve 0.1 g of the substance to be examined in 5 ml of water R or use 5 ml of the prescribed solution. Add 0.2 ml of strong sodium hydroxide solution R. A white precipitate is formed. Add a further 2 ml of strong sodium hydroxide solution R. The precipitate dissolves. Add 10 ml of ammonium chloride solution R. The solution remains clear. Add 0.1 ml of sodium sulphide solution R. A flocculent white precipitate is formed.

ZnCl₂ + 2NaOH = Zn(OH)₂¯ + 2NaCl

white precipitate

Zn(OH)₂ + 2NaOH = Na₂[Zn(OH)₄]

precipitate dissolves

Na₂[Zn(OH)₄] + 4NН₄Cl = ZnCl₂+ 2NaCl + 4NH₄OH

solution remains clear

ZnCl₂ + Na₂S = ZnS¯ + 4NaCl

white precipitate

OTHER REACTION:

SPU, add. 1, _N. Reaction with potassium ferrocyanide:

3ZnCl₂ + 2K₄[Fe(CN)₆] = K₂Zn₃[Fe(CN)₆]₂¯ + 6KCl

white precipitate

2K⁺ + 3Zn²⁺ + 2[Fe(CN)₆]^4–® K₂Zn₃[Fe(CN)₆]₂¯

TESTS

Alkalinity

Shake 1.0 g with 10 ml of boiling water R. Add 0.1 ml of phenolphthalein solution R and filter. If the filtrate is red, not more than 0.3 ml of 0.1 M hydrochloric acid is required to change the

colour of the indicator.

Carbonates and substances insoluble in acids

Dissolve 1.0 g in 15 ml of dilute hydrochloric acid R. It dissolves without effervescence and the solution is not more opalescent than reference suspension II (2.2.1) and is colourless (2.2.2, Method II).

Arsenic (2.4.2, Method A)

Maximum 5 ppm, determined on 0.2 g.

Cadmium

Maximum 10.0 ppm.

Atomic absorption spectrometry (2.2.23, Method II).

Test solutionэDissolve 2.0 g in 14 ml of a mixture of equal volumes of water R and cadmium-and lead-free nitric acid R, boil for 1 min, cool and dilute to 100.0 ml with water R.

Reference solutionsэPrepare the reference solutions using cadmium standard solution (0.1

per cent Cd) R and diluting with a 3.5 per cent V/V solution of cadmium- and lead-free nitric

acid R. SourceэCadmium hollow-cathode lamp.

Wavelengthэ228.8 nm.

Atomisation deviceэAir-acetylene or air-propane flame.

Iron (2.4.9)

Maximum 200 ppm.

Dissolve 50 mg in 1 ml of dilute hydrochloric acid R and dilute to 10 ml with water R. Use in this test 0.5 ml of thioglycollic acid R.

Lead

Maximum 50.0 ppm.

Atomic absorption spectrometry (2.2.23, Method II).

Test solutionэDissolve 5.0 g in 24 ml of a mixture of equal volumes of water R and cadmium-and lead-free nitric acid R, boil for 1 min, cool and dilute to 100.0 ml with water R. Reference solutionsэPrepare the reference solutions using lead standard solution (0.1 per cent Pb) R and diluting with a 3.5 per cent V/V solution of cadmium- and lead-free nitric acid R.

SourceэLead hollow-cathode lamp.

Wavelengthэ283.3 nm; 217.0 nm may be used depending on the apparatus.

Atomisation deviceэAir-acetylene flame.

Loss on ignition

Maximum 1.0 per cent, determined on 1.00 g by ignition to constant mass at 500±50°C.

ASSAY

(BrPh, SPU, add. 1). Chelatometry, direct titration (after dissolution in the dilute acetic acid). Dissolve 0.150 g in 10 ml of dilute acetic acid R. Carry out the complexometric titration of zinc (2.5.11). 1 ml of 0.1 M sodium edetate is equivalent to 8.14 mg of ZnO.

Zinc (2.5.11).

Introduce the prescribed solution into a 500 ml conical flask and dilute to 200 ml with water R. Add about 50 mg of xylenol orange triturate R and hexamethylenetetramine R until the solution becomes violet-pink. Add 2 g of hexamethylenetetramine R in excess. Titrate with 0.1 M sodium edetate until the violet-pink colour changes to yellow.

1 ml of 0.1 M sodium edetate is equivalent to 6.54 mg of Zn.

Ph Eur

ZnО + 2CH₃COOH = Zn(CН₃СОО)₂ + H₂O

dissolution

Zn(CН₃СОО)₂ + H₂Ind = ZnInd + 2CН₃СОО

violet-pink

Na₂Н₂–EDTA + ZnCl₂ ® Na₂Zn-EDTA + 2НCl

Na₂Н₂–EDTA + ZnInd ® Na₂Zn-EDTA + H₂Ind

yellow

E_m (ZnО) = М. m.

Action and use

Mild astringent.

Preparations

Zinc Cream

Coal Tar and Zinc Ointment

Zinc Ointment

Zinc and Castor Oil Ointment

Compound Zinc Paste

Zinc and Salicylic Acid Paste

Zinc and Coal Tar Paste

Ph Eur

Zinc Sulphate

ZnSO₄*7H₂O

287.5 7446-20-0

Zinc Sulphate complies with the requirements of the 3rd edition of the European Pharmacopoeia [0111]. These requirements are reproduced after the heading ‘Definition’ below.

Action and use Astringent.

Preparations

DEFINITION

Zinc sulphate contains not less than 99.0 per cent and not more than the equivalent of 104.0 per cent of ZnSO₄,7H₂ 0.

CHARACTERS

A white, crystalline powder or colourless, transparent crystals, efflorescent, very soluble in water, practically insoluble in alcohol.

IDENTIFICATION

A. Solution S (see Tests) gives the reactions of sulphates (2.3.1).

B. Solution S gives the reaction of zinc (2.3.1).

1. The reaction of precipitation of zinc ions as a Zinc Sulphide (white precipitate). The Zinc Sulphide is soluble in dilute hydrochloric acid and insoluble in acetic acid.

2. The solution of zinc salt reacts with hexacyanoferate(II) solution to give the white precipitate, which is soluble in bases and insoluble in dilute acids.

TESTS

Solution S Dissolve 2.5 g in carbon dioxide-free water R and dilute to 50 ml with the same solvent.

Appearance of solution Solution S is clear (2.2.1) and colourless (Method II, 2.2.2).

pH (2.2.3). The pH of solution S is 4.4 to 5.6.

Chlorides (2.4.4). 3.3 ml of solution S diluted to 15 ml with water R complies with the limit test for chlorides (300 ppm).

Iron (2.4.9). 2 ml of solution S diluted to 10 ml with water R complies with the limit test for iron (100 ppm). Use in this test 0.5 ml of thioglycollic acid R.

ASSAY

Dissolve 0.500 g in 5 ml of dilute acetic acid R. Carry out the complexometric titration of zinc (2.5.11).

1 ml of 0.1M sodium edetate is equivalent to 28.75 mg of ZnSO₄*7H₂O.

Zinc chloride

(Ph Eur monograph 0110)

ZnCl₂

136.3

7646-85-7

Ph Eur

DEFINITION

Zinc chloride contains not less than 95.0 per cent and not more than the equivalent of 100.5 per cent of ZnCl₂.

CHARACTERS

A white, crystalline powder or cast in white sticks, deliquescent, very soluble in water, freely soluble in alcohol and in glycerol.

IDENTIFICATION

A. Dissolve 0.5 g in dilute nitric acid R and dilute to 10 ml with the same acid. The solution gives reaction (a) of chlorides (2.3.1).

B. 5 ml of solution S (see Tests) gives the reaction of zinc (2.3.1).

TESTS

Solution S

To 2.0 g add 38 ml of carbon dioxide-free water R prepared from distilled water R and add dilute hydrochloric acid R dropwise until dissolution is complete. Dilute to 40 ml with carbon dioxide-free water R prepared from distilled water R.

pH (2.2.3)

Dissolve 1.0 g in 9 ml of carbon dioxide-free water R, ignoring any slight turbidity. The pH of the solution is 4.6 to 5.5.

Oxychlorides

Dissolve 1.5 g in 1.5 ml of carbon dioxide-free water R. The solution is not more opalescent than reference suspension II (2.2.1). Add 7.5 ml of alcohol R. The solution may become cloudy within 10 min. Any cloudiness disappears on the addition of 0.2 ml of dilute hydrochloric acid R.

Sulphates (2.4.13)

5 ml of solution S diluted to 15 ml with distilled water R complies with the limit test for sulphates (200 ppm). Prepare the standard using a mixture of 5 ml of sulphate standard solution (10 ppm SO₄) R and 10 ml of distilled water R.

Aluminium, calcium, heavy metals, iron, magnesium

To 8 ml of solution S add 2 ml of concentrated ammonia R and shake. The solution is clear (2.2.1) and colourless (2.2.2, Method II). Add 1 ml of disodium hydrogen phosphate solution R. The solution remains clear for at least 5 min. Add 0.2 ml of sodium sulphide solution R. A white precipitate is formed and the supernatant liquid remains colourless.

Ammonium (2.4.1)

0.5 ml of solution S diluted to 15 ml with water R complies with the limit test for ammonium (400 ppm).

ASSAY

Dissolve 0.250 g in 5 ml of dilute acetic acid R. Carry out the complexometric titration of zinc (2.5.11).

1 ml of 0.1 M sodium edetate is equivalent to 13.63 mg of ZnCl₂.

STORAGE

Store in a non-metallic container.

Ph Eur

Inorganic drugs of Copper

Distribution in the nature

Copper is slow-acting metal. In the nature Copper is in the form of:

а) native element;

б) compounds (one of component many ores and minerals): CuFeS₂ – yellow copper ore, Cu₂O – tough-pitch copper, (CuOH)₂CO₃ – green copper ore, etc.

For drugs obtaining use Copper, which obtained from ores.

Biological function

Copper is organism microelement. It has important function in the metabolic process. It is in the blood (Він міститься в крові (in the erythrocytes) and is an Iron activator at hemoglobin formation.

Application in the medical practice

For the medical purpose use only Copper(ІІ) compounds, in particular in the British and SPU (add. 1) Pharmacopoeias are a monographies for and Anhydrous Copper Sulphate CuSO₄ and Copper Sulphate Pentahydrate CuSO₄×5H₂O.

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Anhydrous Copper Sulphate

Anhydrous Copper Sulphate

General Notices

(Ph Eur monograph 0893)

Cupri sulfas anhydricus

CuSO₄

ээ159.6ээ7758-98-7

DEFINITION

Content

99.0 per cent to 101.0 per cent (dried substance).

OBTAINING

Interaction in the presence of oxygen a hot sulphatic acid solution with copper prompt industrial scraps:

2Сu + O₂ = 2CuО

CuО + H₂SO₄ = CuSO₄ + H₂O

Clearing of obtained salt makes by recrystallization.

CHARACTERS

Appearance

Greenish-grey powder, very hygroscopic.

Solubility

Freely soluble in water, slightly soluble in methanol, practically insoluble in ethanol (96 per cent).

IDENTIFICATION

эA. (Reaction for Copper-ions):

(BrPh, SPU, add. 1). Reaction with dilute ammonia solution. Add several drops of dilute ammonia R2 to 1 ml of solution S (see Tests). A blue precipitate is formed. On further addition of dilute ammonia R2 the precipitate dissolves and a dark blue colour is produced.

2CuSO₄ + 2NH₄OH = (CuOH)₂SO₄¯ + (NH₄)₂SO₄

blue precipitate

(NH₄)₂SO₄ + (CuOH)₂SO₄ + 6NH₄OH = 2[Cu(NH₃)₄]SO₄ + 8H₂O

precipitate dissolves and a dark blue colour is produced

OTHER REACTIONS for Copper-ions:

1. Action metallic iron to test solution

Solution of copper sulphate (1:20) cover a red scurf of metallic copper a iron strand:

CuSO₄ + Fe = FeSO₄ + Cu

2. Interaction with sulphides solutions:

Cu²⁺ + S^2–® CuS¯

black precipitate

3CuS + 14HNO₃ = 3Cu(NO₃)₂ + 3H₂SO₄ + 8NO + 4H₂O

dissolution

3. Reaction with potassium ferrocyanide:

2Cu²⁺ + [Fe(CN)₆]^4–® Cu₂[Fe(CN)₆]¯

red-brown precipitate

4. Reaction with potassium iodide

До розчину купрум сульфату додають розчин калій йодиду KI; утворюється білий осад Cu₂I₂і спостерігається поява жовтого забарвлення (за рахунок утворення йоду I₂):

CuSO₄ + 2KI = CuI₂ + K₂SO₄

2CuI₂ ® Cu₂I₂¯ + I₂_{(yellow solution)}

white precipitate

2CuSO₄ + 4KI = Cu₂I₂¯ + I₂ + 2K₂SO₄

white precipitate (yellow solution)

5. Interaction with polyatomic alcohols (for example, glycerine), amino- and oxoacids ( for example, gluconic acid, etc.) in the alkaline medium

At interaction alkaline solution of copper sulphate (Feling reagent) with з glycerine chelate compound of dark blue colour if formed:

CuSO₄ + 2NaOH = Cu(OH)₂¯ + Na₂SO₄

chelate compound

of dark blue colour

эB. (BrPh). Loss on drying (see Tests).

эC. (BrPh, SPU, add. 1). Dilute 1 ml of solution S to 5 ml with water R. The solution gives reaction (a) of sulphates (2.3.1).

Sulphates

A. (BrPh, SPU, add. 1). Reaction with barium chloride solution in the hydrochloric-acid medium. Dissolve about 45 mg of the substance to be examined in 5 ml of water R or use 5 ml of the prescribed solution. Add 1 ml of dilute hydrochloric acid R and 1 ml of barium chloride solution R1. A white precipitate is formed.

CuSO₄ + BaCl₂ = BaSO₄¯ + CuCl₂

SO₄^2–+ Ва²⁺ ® ВаSO₄¯

white precipitate

B. (SPU, add. 1). To the suspension obtained during reaction (a), add 0.1 ml of 0.05 M iodine. The suspension remains yellow (distinction from sulphites and dithionites), but is decolorised by adding dropwise stannous chloride solution R (distinction from iodates). Boil the mixture. No coloured precipitate is formed (distinction from selenates and tungstates).

SO₄^2– + I₂ ¹ (suspension remains yellow – iodine is not decolorised)

I₂ + SnCl₂ + 4HCl = 2HI + H₂[SnCl₆] (is decolorised)

TESTS

Solution S

Dissolve 1.6 g in water R and dilute to 50 ml with the same solvent.

Appearance of solution

Solution S is clear (2.2.1).

Chlorides (2.4.4)

Maximum 150 ppm.

Dilute 10 ml of solution S to 15 ml with water R.

Iron

Maximum 1.50 . 102 ppm.

Atomic absorption spectrometry (2.2.23, Method I).

Test solutionэDissolve 0.32 g in 10 ml of water R, add 2.5 ml of lead-free nitric acid R and dilute to 25.0 ml with water R.

Reference solutionsэPrepare the reference solutions using iron standard solution (20 ppm Fe) R, adding 2.5 ml of lead-free nitric acid R and diluting to 25.0 ml with water R.

SourceэIron hollow-cathode lamp.

Wavelengthэ248.3 nm.

Atomisation deviceэAir-acetylene flame.

Copper may form explosive acetylides with acetylene. Therefore, clean the burner thoroughly before any residues become dry.

Lead

Maximum 80.0 ppm.

Atomic absorption spectrometry (2.2.23, Method I).

Test solutionэDissolve 1.6 g in 10 ml of water R, add 2.5 ml of lead-free nitric acid R and dilute to 25.0 ml with water R.

Reference solutionsэPrepare the reference solutions using lead standard solution (100 ppm Pb) R, adding 2.5 ml of lead-free nitric acid R and diluting to 25.0 ml with water R.

SourceэLead hollow-cathode lamp.

Wavelengthэ217.0 nm.

Atomisation deviceэAir-acetylene flame.

Copper may form explosive acetylides with acetylene. Therefore, clean the burner thoroughly before any residues become dry.

Loss on drying (2.2.32)

Maximum 1.0 per cent, determined on 0.500 g by drying in an oven at 250 ± 10 °C.

ASSAY

(BrPh, SPU, add. 1). Iodometry, substitute titration. Dissolve 0.125 g in 50 ml of water R. Add 2 ml of sulphuric acid R and 3 g of potassium iodide R. Titrate with 0.1 M sodium thiosulphate, using 1 ml of starch solution R, added towards the end of the titration. (Titrate until disappearance a blue colour).

1 ml of 0.1 M sodium thiosulphate is equivalent to 15.96 mg of CuSO4.

2CuSO₄ + 4KI = Cu₂I₂ + I₂ + 2K₂SO₄

2Cu²⁺ + 4I^– = Cu₂I₂ + I₂

I₂ + 2Na₂S₂O₃ = 2NaI + Na₂S₄O₆

I₂ + 2е ® 2I^–

2S₂O₃^2– – 2е ® S₄O₆^2–

E_m(CuSO₄) = М. m.

E_m(Na₂S₂O₃) = М. m. ; k(Na₂S₂O₃) = 1

STORAGE

In an airtight container .

Action and use

Used in treatment of copper deficiency.

Ph Eur

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British Pharmacopoeia Volume I & II

Monographs: Medicinal and Pharmaceutical Substances

Copper Sulphate Pentahydrate

Copper Sulphate Pentahydrate

General Notices

Copper Sulphate

(Ph Eur monograph 0894)

Cupri sulfas pentahydricus

Cuprum sulfuricum

CuSO₄,5H₂Oэ

э249.7ээ7758-99-8

DEFINITION

Content

99.0 per cent to 101.0 per cent.

OBTAINING

Dissolution clear metallic copper in the hot sulphatic acid concentrated in the presence of nitric acid concentrated (for reaction acceleration):

3Cu + 3H₂SO₄ + 2HNO₃ = 3CuSO₄ + 2NO + 4H₂O

Obtained solution evaporate to dryness (evaporated water, excess H₂SO₄ and HNO₃, NO), rest dissolve in the water and CuSO₄×5H₂O is crystallized. This crystals centrifuge and recrystallize from water.

CHARACTERS

Appearance

Blue, crystalline powder or transparent, blue crystals.

Solubility

Freely soluble in water, soluble in methanol, practically insoluble in ethanol (96 per cent).

IDENTIFICATION the same as Anhydrous Copper Sulphate.

эA. (Reaction for Copper-ions):

(BrPh, SPU, add. 1). Reaction with dilute ammonia solution. Add several drops of dilute ammonia R2 to 1 ml of solution S (see Tests). A blue precipitate is formed. On further addition of dilute ammonia R2 the precipitate dissolves and a dark blue colour is produced.

2CuSO₄ + 2NH₄OH = (CuOH)₂SO₄¯ + (NH₄)₂SO₄

blue precipitate

(NH₄)₂SO₄ + (CuOH)₂SO₄ + 6NH₄OH = 2[Cu(NH₃)₄]SO₄ + 8H₂O

precipitate dissolves and a dark blue colour is produced

эB. (BrPh). Loss on drying (see Tests).

C. (BrPh, SPU, add. 1). Dilute 1 ml of solution S to 5 ml with water R. The solution gives reaction (a) of sulphates (2.3.1).

Sulphates

CuSO₄ + BaCl₂ = BaSO₄¯ + CuCl₂

SO₄^2–+ Ва²⁺ ® ВаSO₄¯

white precipitate

TESTS the same as Anhydrous Copper Sulphate.

Solution S

Dissolve 5 g in water R and dilute to 100 ml with the same solvent.

Appearance of solution

Solution S is clear (2.2.1).

Chlorides (2.4.4)

Maximum 100 ppm.

Dilute 10 ml of solution S to 15 ml with water R.

Iron

Maximum 1.00 . 102 ppm.

Atomic absorption spectrometry (2.2.23, Method I).

Test solutionэDissolve 0.5 g in 10 ml of water R, add 2.5 ml of lead-free nitric acid R and dilute to 25.0 ml with water R.

Reference solutionsэPrepare the reference solutions using iron standard solution (20 ppm Fe) R, adding 2.5 ml of lead-free nitric acid R and diluting to 25.0 ml with water R.

SourceэIron hollow-cathode lamp.

Wavelengthэ248.3 nm.

Atomisation deviceэAir-acetylene flame.

Copper may form explosive acetylides with acetylene. Therefore, clean the burner thoroughly before any residues become dry.

Lead

Maximum 50.0 ppm.

Atomic absorption spectrometry (2.2.23, Method I).

Test solutionэDissolve 2.5 g in 10 ml of water R, add 2.5 ml of lead-free nitric acid R and dilute to 25.0 ml with water R.

Reference solutionsэPrepare the reference solutions using lead standard solution (100 ppm Pb) R, adding 2.5 ml of lead-free nitric acid R and diluting to 25.0 ml with water R.

SourceэLead hollow-cathode lamp.

Wavelengthэ217.0 nm.

Atomisation deviceэAir-acetylene flame.

Copper may form explosive acetylides with acetylene. Therefore, clean the burner thoroughly before any residues become dry.

Loss on drying (2.2.32)

35.0 per cent to 36.5 per cent, determined on 0.500 g by drying in an oven at 250±10°C.

ASSAY the same as Anhydrous Copper Sulphate.

(BrPh, SPU, add. 1). Iodometry, substitute titration. Dissolve 0.200 g in 50 ml of water R. Add 2 ml of sulphuric acid R and 3 g of potassium iodide R. Titrate with 0.1 M sodium thiosulphate, adding 1 ml of starch solution R towards the end of the titration.

1 ml 0.1 M sodium thiosulphate is equivalent to 24.97 mg of CuSO4,5H2O.

2CuSO₄ + 4KI = Cu₂I₂ + I₂ + 2K₂SO₄

2Cu²⁺ + 4I^– = Cu₂I₂ + I₂

I₂ + 2Na₂S₂O₃ = 2NaI + Na₂S₄O₆

I₂ + 2е ® 2I^–

2S₂O₃^2– – 2е ® S₄O₆^2–

E_m(CuSO₄×5H₂O) = М. m.

E_m(Na₂S₂O₃) = М. m. ; k(Na₂S₂O₃) = 1

Action and use

Used in treatment of copper deficiency.

Ph Eur

Inorganic drugs of Bismuth:

1. Bismuth subcarbonate (bismuth carbonate) (BrPh).

2. Heavy Bismuth Subnitrate (BrPh, SP X).

Browse: British Pharmacopoeia 2009 SP X

British Pharmacopoeia Volume I & II

Monographs: Medicinal and Pharmaceutical Substances

Heavy Bismuth Subnitrate

Heavy Bismuth Subnitrate

General Notices

(Ph Eur monograph 1494)

Bismuthi subnitras

Bismuthum nitricum basicum

Bismuthum subnitricum

Magisterium bismuthi

4[BiNO₃(OH)₂],BiO(OH)ээ

1462ээ1304-85-4

Ph Eur

DEFINITION

Content

71.0 per cent to 74.0 per cent of Bi (Ar 209.0) (dried substance).

OBTAINING

Джерелом для одержання препарату є бісмутові руди, зокрема бісмутова охра Ві₂О₃.

1. Frying of bismuth ore with coal and the next acid treatment:

Ві₂О₃+ С 2Ві + 3СО (reduction Ві³⁺ ® Ві⁰)

Bi + 4HNO₃ = Bi(NO₃)₃ + NO + 2H₂O (oxidution Ві⁰ ® Ві³⁺)

Hydrolysis Bi(NO₃)₃:

a) Вi(NO₃)₃ + HOH « ВiОН(NO₃)₂ ® BiОNO₃¯ + НNO₃

white

Bi³⁺ + HOH « ВiОН²⁺ + H⁺

b) ВiОН(NO₃)₂ + HOH « НNO₃ + Вi(ОН)₂NO₃ ® BiОNO₃¯ + Н₂О

BiОН²⁺ + HOH « Вi(ОН)₂⁺ + H⁺

c) Вi(ОН)₂NO₃ + HOH « НNO₃ + Вi(ОН)₃® BiО(ОН)¯ + Н₂О

Bi(ОН)₂⁺ + HOH « Вi(ОН)₃ + H⁺

General reaction of hydrolysis:

CHARACTERS

Appearance

White or almost white powder.

Solubility

Practically insoluble in water and in ethanol (96 per cent). It dissolves in mineral acids with

decomposition.

IDENTIFICATION

эA. (BrPh, SP X). Reaction with potassium iodide solution after dissolution in the nitric acid (in the SP X – dissolution in the sulphatic acid). Dilute 1 ml of solution S1 (see Tests – Solution S1: shake 5.0 g by gently heating in 10 ml of water R and add 20 ml of nitric acid R. Heat until dissolution, cool and dilute to 100 ml with water R) to 5 ml with water R and add 0.3 ml of potassium iodide solution R. A black precipitate is formed which dissolves into an orange solution with the addition of 2 ml of potassium iodide solution R.

Bi₂O₃ + 6HNO₃ ® 2Bi(NO₃)₃ + 3H₂O

dissolution in the acid

Bi₂(SO₄)₃ + 6KI = 2BiI₃¯ + 3K₂SO₄

black precipitate

BiI₃ + KI = K[BiI₄]

complex salt

orange solution

эB. (BrPh, SP X). It gives reaction (b) of bismuth (2.3.1).

Bismuth and Bismuth Compounds

A. (SP X). Reaction with sodium sulphide solution in the hydrochloric acid medium. To 0.5 g of the substance to be examined add 10 ml of dilute hydrochloric acid R or use 10 ml of the prescribed solution. Heat to boiling for 1 min. Cool and filter if necessary. To 1 ml of the solution obtained add 20 ml of water R. A white or slightly yellow precipitate is formed which on addition of 0.05 ml to 0.1 ml of sodium sulphide solution R turns brown.

brown precipitate

B. (BrPh, SP X).Reaction with thiourea in the nitric-acid medium. To about 45 mg of the substance to be examined add 10 ml of dilute nitric acid R or use 10 ml of the prescribed solution. Boil for 1 min. Allow to cool and filter if necessary. To 5 ml of the solution obtained add 2 ml of a 100 g/l solution of thiourea R. A yellowish-orange colour or an orange precipitate is formed. Add 4 ml of a 25 g/l solution of sodium fluoride R. The solution is not decolorised within 30 min.

yellowish-orange colour or

an orange precipitate

C. (BrPh, SP X). It gives the reaction of nitrates (2.3.1).

Nitrates

(BrPh). Reaction with nitrobenzene in the presence of sulphuric acid. To a mixture of 0.1 ml of nitrobenzene R and 0.2 ml of sulphuric acid R, add a quantity of the powdered substance equivalent to about 1 mg of nitrate (NO₃^–) or the prescribed quantity. Allow to stand for 5 min. Cool in iced water and add slowly and with mixing 5 ml of water R, then 5 ml of strong sodium hydroxide solution R. Add 5 ml of acetone R. Shake and allow to stand. The upper layer is coloured deep violet.

Not pharmacopoeial reactions:

1. Interaction with diphenylamine in the acid medium (conc. H₂SO₄) with formation organic dye dark blue colour (analogical to Nitrites-ions, see NaNO₂):

diphenylbenzidine

sulphoimmonium salt of diphenylbenzidine (dye with dark blue colour)

SP Х. Drug decomposition at heating

0,5 г бісмуту нітрату основного поміщають у фарфоровий тигель і прожарюють; утворюються жовто-бурі пари (NO₂) і залишок яскраво-жовтого кольору (Bi₂O₃):

yellow precipitate yellow-brown steam

эD. (BrPh). pH (2.2.3): maximum 2.0 for solution S2 (see Tests).

(Ph. Eur. method 2.2.3 –Determination of pH Values)

The pH is a number which represents conventionally the hydrogen ion concentration of an aqueous solution. For practical purposes, its definition is an experimental one. The pH of a solution to be examined is related to that of a reference solution (pH_s) by the following equation:

in which E is the potential, expressed in volts, of the cell containing the solution to be examined and E_s is the potential, expressed in volts, of the cell containing the solution of known pH (pH_s), k is the change in potential per unit change in pH expressed in volts, and calculated from the Nernst equation.

The potentiometric determination of pH is made by measuring the potential difference between 2 appropriate electrodes immersed in the solution to be examined: 1 of these electrodes is sensitive to hydrogen ions (usually a glass electrode) and the other is the reference electrode (for example, a saturated calomel electrode).

Apparatus The measuring apparatus is a voltmeter with an input resistance at least 100 times that of the electrodes used. It is normally graduated in pH units and has a sensitivity such that discrimination of at least 0.05 pH unit or at least 0.003 V may be achieved. [Suitable glass electrodes and pH meters of both the analogue and digital type are described in British Standards 2586:1979 and 3145:1978.]

Method Unless otherwise prescribed in the monograph, all measurements are made at the same temperature (20-25 °C). Table 2.2.3.-2 shows the variation of pH with respect to temperature of a number of reference buffer solutions used for calibration. For the temperature correction, wheecessary, follow the manufacturer’s instructions. The apparatus is calibrated with the buffer solution of potassium hydrogen phthalate (primary standard) and 1 other buffer solution of different pH (preferably one shown in Table 2.2.3.-2). The pH of a third buffer solution of intermediate pH read off on the scale must not differ by more than 0.05 pH unit from the value corresponding to this solution. Immerse the electrodes in the solution to be examined and take the reading in the same conditions as for the buffer solutions.

When the apparatus is in frequent use, checks must be carried out regularly. If not, such checks should be carried out before each measurement.

All solutions to be examined and the reference buffer solutions must be prepared using carbon dioxide-free water R.

Preparation of reference buffer solutions

Potassium Tetraoxalate 0.05 M Dissolve 12.61 g of C₄H₃KO₈,2H₂O in carbon dioxide-free water R and dilute to 1000.0 ml with the same solvent.

Potassium Hydrogen Tartrate, Saturated at 25 °C Shake an excess of C₄H₅KO₆ vigorously with carbon dioxide-free water R at 25 °C. Filter or decant. Prepare immediately before use.

Potassium Dihydrogen Citrate 0.05M Dissolve 11.41 g of C₆H₇KO₇ in carbon dioxide-free water R and dilute to 1000.0 ml with the same solvent. Prepare immediately before use.

Potassium Hydrogen Phthalate 0.05M Dissolve 10.13 g of C₈H₅KO₄, previously dried for 1 h at 110 ± 2 °C, in carbon dioxide-free water R and dilute to 1000.0 ml with the same solvent.

Potassium Dihydrogen Phosphate 0.025M + Disodium Hydrogen Phosphate 0.025M Dissolve 3.39 g of KH₂PO₄ and 3.53 g of Na₂HPO₄, both previously dried for 2 h at 120 ± 2 °C, in carbon dioxide-free water R and dilute to 1000.0 ml with the same solvent.

Potassium Dihydrogen Phosphate 0.0087M + Disodium Hydrogen Phosphate 0.0303M Dissolve 1.18 g of KH₂PO₄ and 4.30 g of Na₂HPO₄, both previously dried for 2 h at 120 ± 2 °C, in carbon dioxide-free water R and dilute to 1000.0 ml with the same solvent.

Disodium Tetraborate 0.01M Dissolve 3.80 g of Na₂B₄O₇,10H₂O in carbon dioxide-free water R and dilute to 1000.0 ml with the same solvent. Store protected from atmospheric carbon dioxide.

Sodium Carbonate 0.025M + Sodium Hydrogen Carbonate 0.025M Dissolve 2.64 g of Na₂CO₃ and 2.09 g of NaHCO₃ in carbon dioxide-free water R and dilute to 1000.0 ml with the same solvent. Store protected from atmospheric carbon dioxide.

Calcium Hydroxide, Saturated at 25 °C Shake an excess of calcium hydroxide R with carbon dioxide-free water R and decant at 25 °C. Store protected from atmospheric carbon dioxide.

Storage

Store buffer solutions in suitable chemically resistant, tight containers, such as type I glass bottles or plastic containers suitable for aqueous solutions.

TESTS

Solution S1

Shake 5.0 g by gently heating in 10 ml of water R and add 20 ml of nitric acid R. Heat until dissolution, cool and dilute to 100 ml with water R.

Solution S2

Place 1.00 g in a 20 ml volumetric flask and add 2.0 ml of lead-free nitric acid R. Allow acid attack to take place without heating and if necessary warm slightly at the end to completely dissolve the test sample. Add 10 ml of water R, shake and add, in small fractions, 4.5 ml of lead-free ammonia R; shake and allow to cool. Dilute to 20.0 ml with water R, shake again and allow the solids to settle. The clear supernatant solution is solution S2.

Acidity

Suspend 1.0 g in 15 ml of water R and shake several times. Allow to stand for 5 min and filter. To 10 ml of the filtrate, add 0.5 ml of phenolphthalein solution R1. Not more than 0.5 ml of 0.1 M sodium hydroxide is required to change the colour of the indicator to pink.

Chlorides (2.4.4)

Maximum 200 ppm.

To 5.0 ml of solution S1, add 3 ml of nitric acid R and dilute to 15 ml with water R.

Copper

Maximum 50.0 ppm.

Atomic absorption spectrometry (2.2.23, Method I).

Test solutionэSolution S2.

Reference solutionsэPrepare the reference solutions using copper standard solution (10 ppm Cu) R and diluting with a 37 per cent V/V solution of lead-free nitric acid R.

SourceэCopper hollow-cathode lamp.

Wavelengthэ324.7 nm.

Atomisation deviceэAir-acetylene flame.

Lead

Maximum 20.0 ppm.

Atomic absorption spectrometry (2.2.23, Method II).

Test solutionэSolution S2.

Reference solutionsэPrepare the reference solutions using lead standard solution (10 ppm Pb) R and diluting with a 37 per cent V/V solution of lead-free nitric acid R.

SourceэLead hollow-cathode lamp.

Wavelengthэ283.3 nm (depending on the apparatus, the line at 217.0 nm may be used).

Atomisation deviceэAir-acetylene flame.

Silver

Maximum 25.0 ppm.

Atomic absorption spectrometry (2.2.23, Method I).

Test solutionэSolution S2.

Reference solutionsэPrepare the reference solutions using silver standard solution (5 ppm Ag) R and diluting with a 37 per cent V/V solution of lead-free nitric acid R.

SourceэSilver hollow-cathode lamp.

Wavelengthэ328.1 nm.

Atomisation deviceэAir-acetylene flame.

Substances not precipitated by ammonia

Maximum 1.0 per cent.

To 20 ml of solution S1, add concentrated ammonia R until an alkaline reaction is produced and filter. Wash the residue with water R, and evaporate the combined filtrate and washings to dryness on a water-bath. To the residue, add 0.3 ml of dilute sulphuric acid R and ignite.

The residue weighs a maximum of 10 mg.

Loss on drying (2.2.32)

Maximum 3.0 per cent, determined on 1.000 g by drying in an oven at 105 °C.

ASSAY

(BrPh, SP X). Chelatometry, direct titration (after dissolution in the acid). Dissolve with heating 0.250 g in 10 ml of a mixture of 2 volumes of perchloric acid R and 5 volumes of water R. To the hot solution, add 200 ml of water R and 50 mg of xylenol orange triturate R. Titrate with 0.1 M sodium edetate until a yellow colour is obtained.