2.2.3 LIMIT TEST FOR HEAVY METALS Draft revision for The …€¦ · 21/08/2018 · 55 Draft revision for The International Pharmacopoeia 56 2.2.3 LIMIT TEST FOR HEAVY METALS 57

Working document QAS/18.769

August 2018

Draft for comments

1 2

2.2.3 LIMIT TEST FOR HEAVY METALS 3

Draft revision for The International Pharmacopoeia 4

(August 2018) 5

DRAFT FOR COMMENTS 6

7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

© World Health Organization 2018 23 24 All rights reserved. 25 26 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft 27 may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any 28 form or by any means outside these individuals and organizations (including the organizations' concerned staff and member 29 organizations) without the permission of the World Health Organization. The draft should not be displayed on any website. 30 31 Please send any request for permission to: 32 33 Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies Standards and Norms, Regulation of Medicines and 34 other Health Technologies, Department of Essential Medicines and Health Products, World Health Organization, CH-1211 35 Geneva 27, Switzerland, fax: (41 22) 791 4856, email: [email protected]. 36 37 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 38 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its 39 authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines 40 for which there may not yet be full agreement. 41 42 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended 43 by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions 44 excepted, the names of proprietary products are distinguished by initial capital letters. 45 46 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. 47 However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility 48 for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for 49 damages arising from its use. 50 51 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 52

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Please send any comments you may have on the attached text to Dr Herbert Schmidt, Technical

Officer, Medicines Quality Assurance, Technologies Standards and Norms ([email protected]), with

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SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/18.769: 54



57

First draft prepared. November 2017

Discussion at informal consultation on new medicines, quality

control and laboratory standards. 2–4 May 2018

Preparation of a revised document based on feedback received at

the informal consultation June – July 2018

Draft revision sent out for public consultation. August – September 2018

Compilation of the feedback received October 2018

Presentation to WHO Expert Committee on Specifications for

Pharmaceutical Preparations. October 2018

Further follow-up action as required.

58

59

[Note from the Secretariat. Feedback is being sought in relation to the revision of the method of 60

analysis 2.2.3 Limit Test for Heavy Metals. It is proposed to change the provision as follows: 61

62

to add a note to provide users of The International Pharmacopoeia with the option to 63

apply ICH Q3D principles to control elemental impurities; 64

to add a new procedure for the preparation of the test solution: procedure 5, a closed-65

vessel microwave digestion that shall be used as an alternative, in particular, for 66

procedures 3 and 4 employing ignition techniques (in new and revised monographs, 67

procedure 5 shall be preferred to procedures 3 or 4); 68

to replace the reagent hydrogen sulfide R by thioacetamide R; and 69

to align parts of text to the corresponding text included in the European Pharmacopoeia 70

(2.4.8.), thereby keeping and further simplifying the structure of the existing text. 71


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72

The aim of the limit test for heavy metals is to control metal contaminants potentially emanating 73

from reagents, solvents, electrodes, reaction vessels, rubber seals, and so on. The test shall 74

serve as a screening tool indicating the overall quality of the production process, with limits 75

usually set at < 10 ppm or 20 ppm Pb. 76

77

The principle of the test is based on the precipitation of metal sulfides and assumes that all 78

metals behave in a similar manner to a lead standard with which samples are compared. As 79

investigations have shown, the test is effective for detecting Pb, Hg, Pd, Ag, V, Au and Cu which 80

give dark brown or black precipitates. The colour of other precipitates varies from pale yellow 81

to orange. 82

83

It is proposed to complement this document by a review of all tests for heavy metals currently 84

prescribed in The International Pharmacopoeia to evaluate the impact of the new provisions on 85

existing test descriptions. In addition, a document could be developed that provides guidance for 86

collaborating laboratories involved in the development of monographs for The International 87

Pharmacopoeia on how to elaborate and validate this limit test. 88

89

Comments are sought in particular on the Note added to the text providing users with the option 90

to assess and control elemental impurities according to ICH Q3D, for example, to accommodate 91

decisions of responsible national or regional authorities. 92

93

Parts of the text are reproduced from the European Pharmacopoeia with permission and with 94

appropriate editorial modifications. 95

96

Changes from the current monograph are indicated in the text by insert or delete.] 97

98

99


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102

Note. The Guideline for Elemental Impurities Q3D, published by the International Council for 103

Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), presents 104

a process to assess and control elemental impurities in finished pharmaceutical products using 105

the principles of risk assessment. It is within a regulatory authority’s remit to decide whether or 106

not they apply this guideline for the assessment of elemental impurities. If ICH Q3D is 107

implemented, compliance of pharmaceutical substances with the limit test for heavy metals will 108

no longer be required. 109

110

The limit test for heavy metals is provided to demonstrate that the content of metallic impurities 111

that are precipitated as coloured sulfides by thioacetamide does not exceed the heavy metals 112

limits given in the individual monographs in terms of micrograms of lead per gram of the test 113

substance. 114

115

The test consists of three consecutive operations: preparation of the test solutions (precedures 1 116

to 5), development of the coloured precipitate by reaction with thioacetamide, and comparison of 117

the colours thus obtained either by directly comparing the coloration of liquids in suitable 118

comparison tubes (Method A) or by comparing the intensity of coloured residues obtained by 119

filtering the liquid using an appropriate apparatus (Methods B or C). Method A is generally 120

applicable only when the amount of heavy metals in the weight of the test substance used 121

exceeds 5 μg; Methods B or C can also be used for amounts of 2 to 5 μg of heavy metals. 122

123

PREPARATION OF THE TEST SOLUTIONS 124

125

For the standard solution, unless otherwise specified, dilute lead PbTS containing 10 µg of lead 126

per mL solvent to obtain a solution containing 1 µg of lead per mL or 2 µg of lead per mL, 127

depending on the limit prescribed in the monograph. Use the solvent used to prepare the sample 128

solution. 129


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130

Procedure 1. For the sample solution, unless otherwise specified in the monograph, weigh the 131

quantity of the substance to be examined and dissolve it in 25 mL of water R. For the reference 132

solution, add 2 mL of the sample solution to 10 mL of the standard solution. For the blank 133

solution, add 2 mL of the sample solution to 10 mL of water R. 134

135

Procedure 2. For the sample solution , unless otherwise specified in the monograph, weigh the 136

quantity of the substance to be examined and dissolve it in about 25 mL of the organic solvent 137

specified in the monograph, containing a minimum percentage of water R (for example, dioxan 138

R containing 15% of water R or acetone R containing 15% of water R). For the reference 139

solution, add 2 mL of the sample solution to 10 mL of the standard solution. For the blank 140

solution, add 2 mL of the sample solution to 10 mL of the solvent used to prepare the sample 141

solution. 142

143

Procedure 3. For the sample solution, place the prescribed quantity (not more than 2 g) of the 144

substance to be examined in a silica crucible with 4 mL of a 250 g/L solution of magnesium 145

sulfate R in sulfuric acid (~98 g/L) TS. Mix using a fine glass rod. Heat cautiously. If the 146

mixture is liquid, evaporate gently to dryness on a water bath. Progressively heat to ignition and 147

continue heating until an almost white or, at most, greyish residue is obtained. Carry out the 148

ignition at a temperature not exceeding 800 °C. Allow to cool. Moisten the residue with a few 149

drops of sulfuric acid (~98 g/L) TS. Evaporate, ignite again and allow to cool. The total period 150

of ignition must not exceed two hours. Take up the residue in two quantities, each of 5 mL, of 151

hydrochloric acid (~70 g/L) TS. Add 0.1 mL of diluted phenolphthalein/ethanol TS, then 152

ammonia (~35 g/L) TS, until a pink colour is obtained. Cool, add anhydrous acetic acid R until 153

the solution is decolorized and add 0.5 mL in excess. Filter if necessary and wash the filter. 154

Dilute with water R to 20 mL. 155

156

For the reference solution, follow the procedure described for the sample solution, using the 157

prescribed volume of dilute lead PbTS containing 10 µg of lead per mL instead of the substance 158

to be examined. To 10 mL of the solution obtained, add 2 mL of the sample solution. 159

160


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For the monitor solution, follow the procedure described for the sample solution, adding to the 161

substance to be examined the volume of dilute lead PbTS prescribed for the preparation of the 162

reference solution. To 10 mL of the solution obtained add 2 mL of the sample solution. 163

164

For the blank solution, add 2 mL of the sample solution to 10 mL of water R. 165

166

Procedure 4. For the sample solution, unless otherwise specified in the monograph, mix 167

thoroughly in a silica crucible the prescribed quantity of the substance to be examined with 0.5 g 168

of magnesium oxide R1. Ignite to a dull redness until a homogeneous white or greyish-white 169

mass is obtained. If after 30 minutes of ignition the mixture remains coloured, allow to cool, mix 170

using a fine glass rod and repeat the ignition. If necessary, repeat the operation. Heat at 800 °C 171

for about one hour. Take up the residue in two quantities, each of 5 mL, of a mixture of equal 172

volumes of hydrochloric acid (~250 g/L) TS and water R. Add 0.1 mL of diluted 173

phenolphthalein/ethanol TS and then ammonia (~35 g/L) TS until a pink colour is obtained. 174

Cool, add anhydrous acetic acid R until the solution is decolorised, then add 0.5 mL in excess. 175

Filter if necessary and wash the filter. Dilute with water R to 20 mL. 176

177



to be examined and drying in an oven at 100 °C to105 °C. To 10 mL of the solution obtained, 180

add 2 mL of the sample solution. 181

182



reference solution and drying in an oven at 100 °C to105 °C. To 10 mL of the solution obtained 185

add 2 mL of the sample solution. 186

187

For the blank solution, add 2 mL of the sample solution to 10 mL of water R. 188

189

Procedure 5. For the sample solution, unless otherwise specified in the monograph, place the 190

prescribed amount of the substance to be examined (not more than 0.5 g) in a suitable, clean 191


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beaker. Add successively 2.7 mL of cadmium-free and lead-free sulfuric acid (~1760 g/L) TS, 192

3.3 mL of cadmium-free and lead-free nitric acid (~1000 g/L) TS, and 2.0 mL of hydrogen 193

peroxide (~330 g/L) TS using a magnetic stirrer. Allow the substance to react with the reagent 194

before adding the next one. Transfer the mixture to a dry high-pressure digestion vessels 195

(fluoropolymer or quartz glass). 196

197



to be examined. 200

201



reference solution. 204

205

For the blank solution, prepare the solution as described for the sample solution, omitting the 206

substance to be examined. 207

208

CAUTION. When using high-pressure digestion vessels, the safety precautions and operating 209

instructions given by the manufacturer must be followed. The digestion cycles have to be 210

elaborated depending on the type of microwave oven to be used (for example, energy-controlled 211

microwave ovens, temperature-controlled microwave ovens or high-pressure ovens). The cycle 212

must conform to the manufacturer′s instructions. The digestion cycle is suitable if a clear 213

solution is obtained. 214

215

Close the vessels and place them in a laboratory microwave oven. Digest using a sequence of 216

two separate suitable programmes. Design the programmes in several steps in order to control 217

the reaction, monitoring pressure, temperature or energy depending on the type of microwave 218

oven available. After the first programme, allow the digestion vessels to cool before opening. 219

220

Add to each vessel 2.0 mL of hydrogen peroxide (~330 g/L) TS and digest using the second 221

programme. After the second programme, allow the digestion vessels to cool before opening. If 222


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necessary to obtain a clear solution, repeat the addition of hydrogen peroxide (~330 g/L) TS and 223

the second digestion programme. 224

225

Cool, dilute cautiously with water R and rinse into a flask, ensuring that the total volume does 226

not exceed 25 mL. 227

228

Colour development and measurement 229

230

For Procedures 1 to 4 231

232

Method A. Use matched flat-bottomed comparison tubes of transparent glass with a uniform 233

internal diameter of 16 mm for the comparison of the colours. “Matched tubes" means tubes that 234

are matched as closely as possible in internal diameter and in all other respects. 235

236

Transfer 12 ml of each of the test solutions prepared as described under Preparations of the test 237

solutions to comparison tubes, add 2 mL of acetate buffer, pH 3.5, TS and mix. Add 1.2 mL of 238

freshly prepared thioacetamide reagent TS, mix and allow to stand for two minutes. 239

240

Compare the colours of the solutions by viewing down the vertical axis of the tube in diffused 241

light against a white or, if necessary, a black background, or by another suitable method. The 242

test is not valid unless the colour of the reference solution is more intense than the colour of the 243

blank solution. If the use of a monitor solution is prescribed, the colour of the monitor solution 244

is at least as intense as the colour of the reference solution. 245

246

The sample complies with the requirements of the test when the colour of the test solution is not 247

darker than the reference solution. 248

249

Method B. Transfer 12 ml of each of the test solutions prepared as described under Preparations 250

of the test solutions to a beaker, add 2 mL of acetate buffer, pH 3.5, TS and mix. Add 1.2 mL of 251

freshly prepared thioacetamide reagent TS, mix and allow to stand for two minutes. 252

253


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Filter the solutions through a suitable membrane filter (nominal pore size 0.45 µm). Carry out 254

the filtration slowly and uniformly, applying moderate and constant pressure to the piston. 255

256

Compare the intensity of the coloration of the residues obtained with the different test solutions 257

on the membrane filters. The test is not valid unless the coloured residue obtained with the 258

reference solution is more intense than the coloured residue obtained with the blank solution. If 259

the use of a monitor solution is prescribed, the coloured residue obtained with the monitor 260

solution is at least as intense as the coloured residue obtained with the reference solution. 261

262

The sample complies with the requirements of the test when the coloured residue obtained from 263

the test solution is not more intense than the coloured residue from the lead standard. 264

265

For Procedure 5: 266

267

Method C. Using short-range pH indicator paper, adjust the test solutions to pH 3.0-4.0 with 268

ammonia (~260 g/L) TS. (Ammonia (~100 g/L) TS may be used as the specified range is 269

approached). To avoid heating of the solutions, use an ice bath and a magnetic stirrer. Dilute to 270

40 mL with water R and mix. Add 2 mL of acetate buffer, pH 3.5, TS and mix. Add to 1.2 mL 271

of thioacetamide reagent R. Mix immediately. Dilute to 50 mL with water R, mix and allow to 272

stand for two minutes. Filter the solutions through a suitable membrane filter (nominal pore size 273

0.45 µm). Carry out the filtration slowly and uniformly, applying moderate and constant 274

pressure to the piston. 275

276

Compare the spots on the filters obtained with the different solutions. The test is not valid unless 277

the coloured residue obtained with the reference solution is more intense than the coloured 278

residue obtained with the blank solution. The coloured residue obtained with the monitor 279

solution is at least as intense as the coloured residue obtained with the reference solution. 280

281

The sample complies with the requirements of the test when the coloured residue obtained with 282

the sample solution is not more intense than the coloured residue obtained with the reference 283

solution. 284


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285

2.2.3 Limit test for heavy metals 286

287

The limit test for heavy metals is provided to demonstrate that the content of metallic impurities 288

that are coloured by hydrogen sulfide does not exceed the heavy metals limit given in the 289

individual monograph in terms of micrograms of lead per gram of the test substance. 290

291

The test consists of two consecutive operations: preparation of the test solution, and the colour 292

development by reaction with hydrogen sulfide, followed by comparison of the colour obtained 293

with that produced with standard lead solution. 294

295

The preparation of the test solution is carried out, as specified in the monograph, according to 296

procedures 1 to 4 described below. A blank is prepared in a similar manner. 297

298

The reaction with hydrogen sulfide is carried out by mixing the test solution with freshly 299

prepared hydrogen sulfide TS. The comparison of the colour thus obtained is carried out either 300

by directly comparing the coloration of the liquid in suitable comparison tubes (Method A) or by 301

comparing the intensity of coloration of spots obtained by filtering the liquid using an 302

appropriate apparatus (Method B). 303

304

Method A is generally applicable only when the amount of heavy metals in the weight of test 305

substance used exceeds 5 μg; for amounts of 2-5 μg of heavy metals Method B should be used. 306

307

The standard lead solution used in the test; dilute lead PbTS contains 10 μg of lead in 1 mL. 308

When 0.1 mL of this solution is employed to prepare the standard for comparison with a solution 309

of 1 g of the substance being tested, the standard solution thus prepared contains 1 μg of Pb and 310

represents the equivalent of 1 μg of lead per g of the substance tested. 311

312

Apparatus 313

314


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For determination of heavy metals by Method A carry out the test in matched flat-bottomed 315

comparison tubes of transparent glass of about 70 mL capacity and about 23 mm internal 316

diameter bearing a 40-mL and a 50-mL mark. Nessler cylinders complying with the above 317

dimensions are suitable. The expression "matched tubes" means tubes that are matched as closely 318

as possible in internal diameter and in all other respects. For mixing the solution use a stirring 319

rod preferably having a loop at the lower end. 320

321

For determination of heavy metals by Method B use a 50-mL syringe made of suitable material 322

(usually plastic) with a detachable plunger and a male Luer conical joint of 9 mm internal 323

diameter at the lower end (Millipore syringe XX 11 050 05 is suitable) to which an adaptor for 324

filtration is attached. 325

326

The adaptor is made of suitable material (a filtration adapter Millipore SX00 013 00 in 327

polypropylene is suitable) and has a female joint for connecting it with the syringe. It is devised 328

so as to be separable into two parts to permit the exchange of filters, the lower part containing a 329

support for membrane filters 13 mm in diameter. A suitable prefilter (Millipore prefilter AP 2001 330

300 is suitable) and a membrane filter made of mixed cellulose esters, 13 mm in diameter, with a 331

pore opening of 3 μm (a Millipore filter SSWP 013 00 is suitable) are used for the filtration. 332

333

Recommended procedure 334

335

Preparation of test solution 336

337

Procedure 1. Weigh the quantity of substance specified in the monograph, dissolve it in 25 mL of 338

water, adjust the pH of the solution to 3-4 with acetic acid (~60 g/l) PbTS, or with ammonia 339

(~100 g/l) PbTS, as necessary, then dilute to 40 mL with water and mix. 340

341

Procedure 2. Weigh the quantity of substance specified in the monograph, dissolve it in about 30 342

mL of solvent specified (ethanol (~750 g/l) TS, methanol R, acetone R, or dioxan R may be 343

used), add 0.5 mL of acetic acid (~300 g/l) TS, and dilute to 40 mL with the solvent. 344

345


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Procedure 3. Place the quantity of the substance specified in the monograph in a suitable crucible, 346

preferably made of silica, and carefully ignite at a low temperature until the contents are 347

thoroughly charred. The crucible may be loosely covered with a lid during the charring. Add to 348

the contents of the crucible 2 mL of nitric acid (~1000 g/l) TS and 5 drops of sulfuric acid 349

(~1760 g/l TS), and cautiously heat until white fumes are evolved, and then ignite, preferably in 350

a muffle furnace, at 500°C until all the carbon is burned off. Cool, add 2 mL of hydrochloric acid 351

(~250 g/l) TS, and slowly evaporate in a water-bath to dryness. Moisten the residue with 1 drop 352

of hydrochloric acid (~250 g/l) TS, add 10 mL of hot water, and digest for 2 minutes. Add, drop 353

by drop, ammonia (~100 g/l) PbTS, until the pH of the solution is between 8 and 8.5, then add, 354

drop by drop, acetic acid (~60 g/l) PbTS, to adjust the pH to between 3 and 4. Filter if necessary, 355

wash the crucible and the filter with about 10 mL of water, dilute with water to 40 mL, and mix. 356

357

Procedure 4. Place the quantity of substance specified in the monograph in a suitable crucible, 358

preferably made of silica, mix it well with about 0.5 g of magnesium oxide R and incinerate until 359

a homogeneous white mass is obtained. If after 15 minutes of incineration the residue is still 360

coloured, let the crucible cool, mix the contents well with a glass rod and resume heating. Next, 361

dissolve the residue in hydrochloric acid (~70 g/l) TS, add, drop by drop, a solution of ammonia 362

(~100 g/l) PbTS, until the pH of the solution is between 8 and 8.5, then add, also drop by drop, 363

acetic acid (~60 g/l) PbTS, to adjust the pH to 3-4, filter, dilute with water to 40 mL, and mix. 364

365

Colour development and measurement 366

367

Method A 368

369

To 40 mL of the liquid contained in the comparison tube add 10 mL of freshly prepared 370

hydrogen sulfide TS, mix and allow to stand for 5 minutes. 371

372

In another comparison tube place a volume of solution of dilute lead PbTS, containing the lead 373

equivalent of the heavy metals limit specified in the monograph, dilute with water, adjust the pH 374

with ammonia (~100 g/l) PbTS and acetic acid (~60 g/l) PbTS to 3-4; dilute with water or the 375


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solvent used to 40 mL, mix, add 10 mL of freshly prepared hydrogen sulfide TS, mix and allow 376

to stand for 5 minutes. 377

378

Compare the colours by viewing down the vertical axis of the tube in diffused light against a 379

white background, or by another suitable method. The colour of the test solution is not darker 380

than that of the lead standard. 381

382

Method B 383

384

Take the filtration syringe, arrange the prefilter and the membrane filter as indicated in the 385

diagram for prefiltration, remove the plunger from the syringe, place the test solution inside the 386

syringe, replace the plunger, and filter the test solution slowly by exerting a regular pressure on 387

the plunger. Collect the filtrate in a beaker or a test-tube. Open the adapter and check whether the 388

membrane filter is free from impurities. If not, replace it and repeat the operation in the same 389

manner. Then rearrange the prefilter and membrane filter as indicated in Fig. 4. Adjust the pH of 390

the filtrate with ammonia (~100 g/l) PbTS and acetic acid (~60 g/l) PbTS to 3-4, add 10 mL of 391

freshly prepared hydrogen sulfide TS, all the reagents previously filtered through a membrane 392

filter, mix, allow to stand for 5 minutes, take out the plunger, place the solution inside the 393

syringe, and filter it through the membrane filter by exerting slowly a regular and moderate 394

pressure on the plunger. Open the adaptor and take out the membrane filter. 395

396

FIG. 4. LIMIT TEST FOR HEAVY METALS: METHOD B 397

398


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399

400

Take a volume of solution of dilute lead PbTS containing the lead equivalent to the heavy metals 401

limit specified in the monograph, dilute with water, adjust the pH with ammonia (~100 g/l) PbTS 402

and acetic acid (~60 g/l) PbTS to 3-4, dilute with water to 40 mL, mix, and proceed as described 403

above. 404

405

Compare the intensity of the coloration of spots obtained on the membrane filters. The colour 406

obtained from the test solution is not more intense than that from the lead standard. 407

408

REAGENTS TO BE ADDED OR REVISED 409

410

Acetate buffer, pH 3.5, TS 411

Procedure. Dissolve 25.0 g of ammonium acetate R in 25 mL of water R and add 38.0 mL of 412

hydrochloric acid (~250 g/l) TS. Adjust the pH, if necessary, with hydrochloric acid (~70 g/L) 413

TS or ammonia (~100 g/L) TS. Dilute with water R to 100.0 mL. 414


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Magnesium oxide R1 415

Complies with the requirements prescribed for magnesium oxide R with the following 416

modifications: 417

Arsenic: maximum 2 ppm. 418

Heavy metals (2.2.3): maximum 10 ppm. 419

Iron: maximum 50 ppm. 420

421

Phenolphthalein/ethanol TS, diluted 422

Procedure. Dissolve 0.1 g of phenolphthalein R in sufficient ethanol (~750 g/L) TS to produce 423

100 mL. 424

Sensitivity test. To 0.1 mL of the phenolphthalein solution add 100 mL of carbon dioxide-free 425

water R. The solution is colourless. Not more than 0.2 mL of 0.02 M sodium hydroxide is 426

required to change the colour to pink. 427

Colour change: pH 8.2 (colourless) to pH 10.0 (red). 428

429

Thioacetamide R 430

C2H5NS = 75.13 (62-55-5). 431

General reagent grade of commerce. 432

White crystals or crystalline powder; melting point, about 113 °C. 433

434

Thioacetamide reagent TS 435

Add 1 mL of a mixture of 15 mL of 1m sodium hydroxide, 5 mL of water and 20 mL of glycerol 436

(85%) to 0.2 mL of thioacetamide solution, heat in a water bath for 20 seconds, cool and use 437

immediately. 438

439

Thioacetamide solution TS 440

A 4% w/v solution of thioacetamide R. 441

442

*** 443

Documents

2.2.3 LIMIT TEST FOR HEAVY METALS Draft revision for The …€¦ · 21/08/2018 · 55 Draft revision for The International Pharmacopoeia 56 2.2.3 LIMIT TEST FOR HEAVY METALS 57