Pharmaceutical manufacturing encyclopedia 2ed vol 1,2 sittig

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PHARMACEUTICAL MANUFACTURING ENCYCLOPEDIA

No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording or b y any informa- tion storage and retrieval system, without permission

in writing from the Publisher

Library of Congress Catalog Card Number: 87-31547

Printed in the United States

Published in the United States of America by

Foreword

The worldwide pharmaceutical industry has a dollar Sales volume greater than $100 billion with a number of individual drugs boasting sales volumes of over $100 million each Indeed some drugs have been called "blockbuster drugs"-those generating at least $300 million in new revenues each year The profit margins in drug manufacture are higher than the rest of the chemical industry and, of course, research expenditures are huge in order to maintain position and develop new drugs in this highly competitive industry

The presentday drug industry i s one of rapid change

Patents on current best-selling drugs are expiring It has been estimated that the top 100 products in the marketplace will all come off patent (that is, the basic patents will expire) in the period between 1973 and 1990

As patents expire, exclusivity of producing a trade-named product will pass and competitiveversions of the basic drug will be marketed under generic names (or

other new trade names) by new manufacturers It has been estimated that 40%

of t h e drugs on the market in 1990 will be generic drugs

New products will come on the market as

New products are developed through research

Products now marketed in Europe and Asia attain approved status

by the U S Food and Drug Administration (FDA) and enter the

huge and lucrative American market

Information on patented processes offers a number of commercial opportunities:

( 1 ) The patent expiration date (in the U.S usually 17 years after the patent

issuance date cited) offers the opportunity t o duplicate and practice the patented process without legal conflict after expiration

(2) The statement of ownership of the patents affords the opportunity to license the patent in question from the patent holder

(3) The definition of the patented process offers the opportunity to an in- novative chemist to develop a process which bypasses the original patent claims and offers a new legally clear route to an economically attractive product

This encyclopedic work gives details for the manufacture of 1295 pharmaceuticals, now being marketed as trade-named products somewhere in the world The pertinent process information has been obtained from examples given in the pertinent patent literature

(usually US patents and sometimes British patents)

In addition to the patentderived process information, references are also cited under each drug's entry to major pharmaceutical reference works where additional information can be obtained on synthesis methods and the pharmacology of the individual products

V

This work i s presented in two volumes The arrangement within the books is alphabetic by generic name The table of contents appears a t the beginning of Volume 1 There is also an index by trade names used in many of the countries in the world Another index lists the raw materials used in the manufacture of the various drugs, an index which should be com- mercially valuable t o suppliers of chemical raw materials to the pharmaceutical industry These indexes appear at the end of Volume 2

These volumes provide a handy first reference both t o manufacturing process and also to other reference sources where additional details on the product may be found

This handbook should be useful as an initial point of access to the commercial pharmaceuti- cal literature It can be consulted as a master source before using computerized retrieval even i f computer data on the pertinent literature are readily available

This work summarizes practical information available from the work of hundreds of phar- maceutical research laboratories and of thousands of chemists in those laboratories in de- veloping thousands of commercial products

Finally, it is hoped that these books will offer a sort of blueprint for entry into profitable generic drug manufacture Companies not now in the drug business but with some expertise

in fermentation processes and/or chemical synthesis may be able t o add a few technical peo- ple and make a relatively small investment to get themselves on the first rung of the ladder to being pharmaceutical producers Study of available technology, patent expiration dates and existing markets for particular trade-named drugs may well lead to routes to promising new ventures

NOTICE

To the best of the Publisher's knowledge the information con-

tained in this book i s accurate; however, the Publisher assumes

no responsibility nor liability for errors or any consequences

arising from the use of the information contained herein Final

determination of the suitability of any information, procedure,

or product for use contemplated by any user, and the manner

of that use, is the sole responsibility of the user The book i s in-

tended for informational purposes only Due caution should be

exercised in the use and handling of those raw materials that are

potentially hazardous Expert advice should be obtained a t a l l

times when manufacturing implementation i s being considered

In the case of personal use of any of the products included, the

manufacturer's medical instructions should be followed Men-

tion of trade names does not indicate endorsement by the

Author nor the Publisher

It should be noted that the manufacturing procedures described

are based on patented processes and that a proper license must

be obtained for the use of such processes, if the patent has not

expired

Contents

Introduction 1

Acebutolol 5

Aceclidine 6

Aceglutamide Aluminum - 8

Acemetacin 9

Acenocoumarol (Acenocoumarin) 10

Acetaminophen 11

Acetazolamide 15

Acetohexamide 16

Acetophenazine Dimaleate 18

Acetoxolone Aluminum Salt 19

Acetrizoate Sodium 20

Acetylcysteine 21

Acetyldigitoxin 22

Acetyl Sulfisoxazole 23

Aclarubicin 24

Aclatonium Napadisylate 26

Acyclovir 27

Adenosine Triphosphate 28

Afloqualone 29

Albendazole 30

Albuterol 31

Alcofenac 33

Alcuronium Chloride 34

Alfacalcidol 35

Alfaxalone 36

Alfentanil Hydrochloride 37

Algestone Acetophenide 38

Alibendol 39

Alizapride - 4 0 Alkofanone 41

Allopurinol 42

Alphaprodine Hydrochloride 44

Alprazolam 46

Alprenolol Hydrochloride 47

Altretamine - 4 9 Aluminum Nicotinate 50

Amantidine Hydrochloride 50

Ambenonium Chloride 52

Ambroxol 53

Ambuside 55

Amcinonide 55

Amezinium Methyl Sulfate 56

Ambuphylline 54

vii

Amikacin 57

Amiloride Hydrochloride 60

Amineptine Hydrochloride 61

Aminobenzoic Acid 62

Aminocaproic Acid 64

Aminoglutethimide 65

Aminometradine 66

Aminopentamide 67

Aminosalicylic Acid 68

Amiodarone Hydrochloride 69

Amisometradine 70

Amitriptyline Hydrochloride 71

Amitriptyline Oxide 73

Amixetrine Hydrochloride 74

Amodiaquin 75

Amoxapine 76

Amoxicillin 78

Amphetamine Phosphate 81

Amphomycin Calcium 82

Amphotericin B 83

Ampicillin 84

Ampicillin Trihydrate 88

Amrinone 90

Ancitabine Hydrochloride 91

Angiotensin Amide 92

Anileridine Dihydrochloride 93

Anisindione 94

Anisotropine Methylbromide 95

Antazoline Hydrochloride 96

Antrafenine 97

Apalcillin Sodium 98

Apazone 99

Aprindine Hydrochloride 101

Arginine Glutamate 102

Asparaginase 103

Aspartame 104

Aspirin 105

Astemizole 108

Atenolol 109

Atracurium Besylate 110

Auranofin 112

Aurothioglycanide 113

Azacyclonol 114

Azanidazole 115

Azapetine Phosphate 116

Azatadine Maleate 117

Azathioprine 118

Azidocillin 119

Azlocillin 121

Azosemide 122

Bacampicillin 124

Bacitracin 125

Baclofen 127

Barbexaclone 128

Batroxobin 129

Beclamide 129

Beclomethasone Dipropionate 130

Contents i x

Befunolol 132

Bokanamycin Sulfate 133

Benactyzine Hydrochloride 135

Benapryzine Hydrochloride 136

Bendacort 137

Bendazac 137

Bendroflumethiazide 138

Benfluorex Hydrochloride 140

Benfurodil Hemisuccinate 141

Benorylate 143

Benoxaprofen 144

Benoxinate Hydrochloride 145

Benperidol 147

Benproperine 147

Benserazide 148

Bentiromide 150

Benzbromarone 151

Benzethonium Chloride 152

Benzoctamine HCI 153

Benzonatate 154

Benzphetamine Hydrochloride 155

Benzpyrinium Bromide 156

Benzquinamide 157

Benzthiazide 159

Benztropine Mesylate 160

Bephenium Hydroxynaphthoate 161

Bepridil 162

Betamethasone 164

Betamethasone Acetate 165

Betamethasone Benzoate 166

Betamethasone Dipropionate 167

Betamethasone Valerate 169

Betaxolol Hydrochloride 170

Betazole 171

Bethanechol Chloride 172

Bialamicol 173

Bietaserpine 174

Bifonazole 175

Biperiden t 7 6 Bisacodyl 178

Bismuth Sodium Triglycollamate 180

Bretylium Tosylate 180

Bromazeparn 181

Bromelain 183

Bromhexine 184

Bromocriptine 186

Bromopride 187

Brompheniramine Maleate 188

Bronopol., 189

Brotizolam 190

Bucloxic Acid 191

Bucumolol Hydrochloride 192

Budralazine 193

Bufeniode 194

Bufetrol 195

Bufexamac 196

Buflomedil 197

Buformin HCI 198

Bumadizon 199

Bumetanide 200

Bunitrolol 202

Bupivacaine 203

Bupranolol 204

Busulfan 205

Butalamine Hydrochloride 206

Butamirate Citrate 207

Butethamine 208

Buthiazide 209

Butofilolol 210

Butorphanol 212

Butriptyline 213

Butropium Bromide 214

Cafaminol 215

Calcifediol 215

Calcitonin 217

Calcitriol 218

Calusterone 219

Camazepam 220

Candicidin 221

Canrenoate Potassium 223

Capreornycin Sulfate 224

Captodiamine 226

Captopril 227

Caramiphen Edisylate 229

Carazolol 230

Carbachol 231

Carbamazepine 232

Carbaspirin Calcium 233

Carbazochrome 234

Carbenicillin Disodium 235

Carbenicillin lndanyl Sodium 237

Carbenoxolone 238

Carbidopa 239

Carbinoxamine Maleate 241

Carbocysteine 242

Carbomycin 244

Carboquone 245

Carbuterol 245

Cargutocin 247

Carisoprodol 248

Carmofur 249

Carnitine 250

PCarotene 252

Caroxazone 253

Carphenazine Maleate 254

Carprofen 255

Carteolol 256

Carticaine 257

Cefaclor 258

Cefadroxil 259

Cefamandole Nafate Sodium S a l t 261

Cefatrizine 262

CefazolinSodium 263

Cefoperazone 266

Cefmenoxime 265

Contents x i

Cefotaxime Sodium 267

CefoxitinSodium 268

Cefroxadine 269

Cefsulodin 271

Ceftazidime., 272

Csftizoxime 273

Ceftriaxone Sodium 274

Cefuroxime 276

Celiprolol 277

CephacetrileSodium 278

Cephalexin 279

Cephaloglycin 282

Cephaloridine 283

Cephalothin Sodium 286

Cephapirin Sodium 287

Cephradine 289

Ceruletide 291

Cetiedil 292

Chenodiol 293

Chlophedianol 294

Chloral Betaine 295

C h I oram buci I 296

Chloramphenicol 297

Chloramphenicol Palmitate 301

Chlorcyclizine 302

Chlordantoin 303

Chlordiazepoxide Hydrochloride 304

Chlor hexidine 306

Chlorisondamine Chloride 307

Chlormerodrin 308

Chlormezanone 309

Chloroprocaine Hydrochloride 310

Chloroquine Phosphate 312

Chlorothiazide 313

Chlorotrianisene 314

4-Chloro-3.5-Xylenol 315

Chlorphenesin Carbamate 316

Chlorpheniramine Maleate 317

Chlorphenoxamine Hydrochloride 319

Chlorproethazine HCI 321

Chlorpromazine Hydrochloride 321

Chlorpropamide 323

Chlorprothixene 325

Chlorquinaldol 326

Chlortetracycline 327

Chlorthalidone 329

Chlorthenoxazine 331

Chlorzoxazone 332

Choline Dihydrogen Citrate 333

Choline Salicylate 334

Choline Theophyllinate 335

Chromonar Hydrochloride 336

Chymopapain 337

Ciclonicate 338

Ciclopiroxolamine 339

Cicloxilic Acid 340

Cimetidine 341

Cinepazet Maleate 343

Cinnarizine 343

Cinoxacin 345

Ciprofibrate 346

Citicoline 347

Citiolone 349

Clavulanic Acid 350

Clemastine Fumarate 351

Clemizole 353

Clenbuterol 354

Clidanac 355

Clidinium Bromide 356

Clindamycin Hydrochloride 357

Clinofibrate 358

Clobazam 359

Clobetasol 361

Clobutinol 361

Clocapramine 363

Clofezone 363

Clofibrate 364

Clofibride 367

Clofoctol 367

Clomiphene Dihydrogen Citrate 368

Clomipramine 369

Clonazepam 370

Clonidine Hydrochloride 372

Clopenthixol 374

Cloperastine 375

Cloprednol 376

Clorazepate Dipotassium 377

Clorexolone 378

Clorprenaline 380

Clortermine Hydrochloride 381

Clotiazepam 383

Clotrimazole 383

Cloxacillin 385

Cloxazolam 386

Clozapine 387

Colestipol 388

Cortisone Acetate 389

Cortivazol 390

Creatinolfosfate 392

Cromolyn Sodium 393

Crotamiton 395

Cryptenamine Tannates 395

Cyamemazine 397

Cyanocobalamin 398

Cyclacillin 401

Cyclamate Calcium 402

Cyclandelate 403

Cyclarbamate 405

Cyclizine 406

Cyclobenzaprine 407

Cyclobutyrol 407

Cyclofenil 409

Cyclomethycaine 410

Cyclopentamine Hydrochloride 411

Cyclopentolate Hydrochloride 413

Cyclophosphamide 414

Contents xiii

Cycloserine 415

Cyclosporin 416

Cyclothiazide 418

Cycrimine Hydrochloride 419

Cyproheptadine 420

Cyproterone Acetate 422

Cytarabine Hydrochloride 423

Dactinomycin 426

Danazol 427

Dantrolene Sodium 428

Dapsone 429

Daunorubicin 430

Deanol Acetamidobenzoate 432

Debrisoquin 433

Defosfamide 434

Demecarium Bromide 434

Demeclocycline Hydrochloride 436

Demegestone 438

Demexiptiline HCI 440

Deserpidine 441

Desipramine Hydrochloride 443

Desmopressin 444

Desogestrel 445

Desonide 446

Desoximetasone 447

Dexamethasone Acetate 449

Dexamethasone-21-Linoleate 450

Dexamethasone Phosphate 451

Dexbrompheniramine Maleate 453

Dexchlorpheniramine Maleate 454

Dexetimide 455

Dexpanthenol 456

Dextran 40 457

Dextroamphetamine Sulfate 458

Dextromethorphan Hydrobromide 459

Diamthazole Dihydrochloride 461

Diatrizoate Sodium 462

Diazepam 463

Diazoxide 467

Dibekacin 468

Dibenzepin Hydrochloride 470

Dibutoline Sulfate 471

Dichlorisone Acetate 472

Dichlorphenamide 473

Diclofenac Sodium 474

Dicloxacillin Sodium 476

Dicyclomine Hydrochloride 477

Dienestrol 479

Diethylcarbamazine Citrate 480

Diethylpropion HCI 481

Diethylstilbestrol 482

Diethylstilbestrol Diphosphate 484

Difenoxine 485

Diflorasone Diacetate 486

Diflucortolone Valerate 488

Diflunisal 489

Difluprednate 490

Dihydrostreptomycin Sulfate 491

Dihydrotachysterol 493

Dilazep Hydrochloride 494

Diltiazem Hydrochloride 495

Dimenhydrinate 496

Dimercaprol 498

Dimetacrine Tartrate 499

Dimethicone 500

Dimethindene Maleate 502

Dimethisoquin 503

Dimethisterone 504

Dimethoxanate 505

Dimethyl Sulfoxide 506

Dimethyl Tubocurarine Iodide 507

Dinoprost Tromethamine 508

Dinoprostone 509

Diosmin 510

Dioxyline Phosphate 512

Diphemanil Methylsulfate 514

Diphenadione 515

Diphenhydramine Hydrochloride 516

Diphenidol 518

Diphenoxylate Hydrochloride 519

Diphenpyramide 520

Diphenylpyraline Hydrochloride 521

Dipivefrin 522

Dipyridamole 523

Disopyramide Phosphate 525

Distigmine Bromide 526

Disulfiram 528

Ditazol 528

Dithiazanine Iodide 529

Dixyrazine 530

Dobesilate Calcium 531

Dobutamine 532

Docusate Calcium 534

Domiphen Bromide 534

Domperidone 535

Doxapram Hydrochloride 536

Doxepin Hydrochloride 538

Doxorubicin 539

Doxycycline 541

Dromostanolone Propionate 542

Droperidol 543

Droprenilamine HCI 545

Dyclonine Hydrochloride 545

Dydrogesterone 546

Dyphylline 547

Echothiopate Iodide 550

Econazole Nitrate 551

Ectylurea 552

Edetate Disodium 553

Edrophonium Chloride 554

Emylcamate 555

Endralazine 556

Enflurane 557

Enviomycin 559

Contents xv

Eperisone HCI 560

Epicillin 560

Epimestrol 562

Epinephryl Borate 563

Epirizole 563

Epitiostanol 565

Eprazinone HCI 565

Eprozinol 566

Erythromycin 568

Erythromycin Estolate 570

Erythromycin Gluceptate 571

Erythromycin Lactobionate 572

Erythromycin Stearate 573

Estazolam 574

Estradiol Cypionate 575

Estradiol Valerate 577

Estramustine.Phosphate 578

Estriol Succinate 580

Ethacrynic Acid 580

Ethambutol Hydrochloride 582

Ethamivan 584

Ethamsylate 585

Ethclnrvynol 585

Ethiazide 586

Ethinamate 587

Ethinylestradiol 588

Ethionamide 589

Ethoheptazine 591

Ethopropazine Hydrochloride 592

Ethosuximide 594

Ethotoin 595

Ethoxzolamide 595

Ethyl Biscoumacetate 596

Ethylestrenol 597

Ethynodiol Diacetate 598

EtidocaineHCI 599

Etidronate Disodium 600

Etifelmine 602

Etifoxine 603

Etilefrine Pivalate Hydrochloride 604

Etiroxate 605

Etodroxizine 605

Etofenamate 607

Etofibrate 607

Etofylline Clofibrate 608

Etomidate Hydrochloride 609

Etomidoline 611

Etozolin 612

Etretinate 613

Etryptamine 614

Exalamide 615

Exiproben 616

Fazidinium Bromide 617

Febantel 618

Febuprol 619

Felypressin., 619

Fenbendazole 621

Fenbufen 622

Fendiline Hydrochloride 623

FenethyllineHCI 624

Fenipentol 625

Fenofibrate 626

Fenoprofen 627

Fenoterol Hydrobromide 629

Fenoxedil 630

Fenproporex 631

Fenspiride 632

Fentanyl 633

Fentiazac 634

Fentonium Bromide 636

Feprazone 637

Ferrocholinate 638

Ferroglycine Sulfate 639

FerrousFumarate 639

Fibrinolysin 641

Flavoxate Hydrochloride 642

Flecainide 644

Floctafenine 645

Florantyrone 647

Floredil Hydrochloride 648

Floxacillin 649

Floxuridine 650

Fluazacort 651

Flubendazole 653

Flucloronide 654

Flucytosine 655

Fludiazepam Hydrochloride 657

Fludrocortisone Acetate 658

Flumequine 659

Flumethasone 660

Flumethiazide 661

FlunarizineHCI 662

Flunisolide 663

Flunitrazepam 664

Fluocinolone Acetonide 667

Fluocinonide 670

Fluocortin Butyl 671

Fluocortolone 673

Fluorometholone 674

Fluorouracil 676

Fluoxymesterone 678

Flupentixol 680

Fluphenazine Hydrochloride 681

Fluprednidene Acetate 683

Fluprednisolone 685

Flurandrenolide 686

Flurazepam 687

Flurbiprofen 689

Flurothyl 690

Fluroxene 691

Fluspirilene 692

Flutamide 693

Fluvoxamine Maleate 694

Folic Acid 695

FominobenHCI 697

Contents xvii

Fomocaine 699

Fonazine Mesylate 699

Formocortal Acetate 701

Fosfomycin 702

Fructose 703

Fumagillin 705

Furaltadone 706

Furazabol 707

Furazolidone 708

Furosemide 709

Fursultiamine 711

Furtrethonium Iodide 712

Fusafungine 713

Gallamine Triethiodide 717

Gemeprost 718

Gemfibrozil 719

Gentamicin Sulfate 720

Gepefrin 723

Glafenine 723

Glaucarubin 725

Glaziovine 726

Glibornuride 728

Gliclazide 729

Glipizide 730

Gliquidone 731

Glisoxepid 732

Glutethimide 733

Glybuzole 735

Glycopyrrolate 735

Glymidine 736

Gramicidin 738

Griseofulvin 739

Guaifenesin 740

Guanabenz 742

Guanadrel Sulfate 743

Guanethidine Sulfate 744

Guanfacine 745

Guanoxabenz Hydrochloride 746

Halazepam 748

Halcinonide 749

Haloperidol 750

Halopredone Acetate 751

Haloprogin 752

Halothane 753

Heparin 755

Hepronicate 756

Heptabarbital 757

Hetacillin Potassium 759

Hexachlorophene 760

Hexamethonium Bromide 761

Hexestrol 762

Hexetidine 763

Hexobendine 764

Hexocyclium Methyl Sulfate 765

Hexoprenaline 766

Glucagon 733

Hexylcaine Hydrochloride 768

Homofenazine 769

Hydralazine Hydrochloride 770

Hydrochlorothiazide 771

Hydrocortamate HCI 773

Hydrocortisone 775

Hydrocortisone Sodium Phosphate 778

Hydroflumethiazide 779

Hydroquinone 780

Hydroxocobalamin 781

Hydroxychloroquine Sulfate 783

Hydroxydione Sodium Succinate 785

Hydroxyphenamate 786

Hydroxyprogesterone Caproate 787

Hydroxypropyl Cellulose 788

Hydroxystilbamidine lsethionate 789

Hydroxytryptophan 791

Hydroxyurea 793

Hydroxyzine Hydrochloride 794

Ibuprofen 796

lbuproxam 798

ldoxuridine 799

lfenprodil Tartrate 801

lfosfamide 802

Imipramine Hydrochloride 803

lmprosulfan Tosylate 804

Indalpine 805

Indanazoline 806

lndapamide 807

Indenolol 808

Indomethacin 809

Indoprofen 812

Indoramin 813

Inosine 814

Inositol 816

Inositol Niacinate 817

Insulin 818

Insulin Isophane 820

Insulin Zinc Suspension 821

Interferon 822

lodamide 823

lodipamide 825

lodoalphionic Acid 826

loglycamic Acid 827

lopamidol 828

lopanoic Acid 829

lophendylate 831

IopronicAcid 832

lothahate Meglumine 833

lothiouracil 834

lotroxic Acid 835

lpratropium Bromide 836

Iproniazid 837

lpronidazole 838

lsaxonine Phosphate 839

lsoaminile 840

Isobornyl Thiocyanoacetate 841

Contents xix

lsocarboxazid 842

lsoconazole Nitrate 843

lsoflurane 844

Isoflurophate 844

Isometheptene 846

Isoniazid 846

lsopropamide Iodide 848

Isoproterenol Sulfate 849

lsosorbide Dinitrate 850

lsothipendyl HCI 852

lsoxicam., 853

lsoxsuprine Hydrochloride 854

Kanamycin Sulfate 856

Kebuzone 858

Ketamine Hydrochloride 859

Ketazolam 860

Ketoconazole 861

Ketoprofen 862

Ketotifen 864

Labetalol Hydrochloride 867

Lactulose 868

Letosteine 869

Levamisole Hydrochloride 870

Levodopa 871

Levothyroxine Sodium 873

Lidocaine 874

Lidoflazine 876

Lincomycin 877

Lindane 878

Liothyronine 879

Lofexidine Hydrochloride 881

Loflazepate Ethyl 882

Lonazolac 883

Loperamide Hydrochloride 884

Loprazolam 885

Lorazeparn 886

Lorcainide Hydrochloride 888

Lormetazepam 889

LoxaDine 890

Mafenide Acetate 892

Magaldrate 893

Malathion 894

Maltose., 895

Mannitol 896

Mazaticol Hydrochloride 897

Mazindol 898

Mebendazole 899

Mebeverine Hydrochloride 900

Mebutamate 902

Mecamylamine Hydrochloride 903

Mecillinam 905

Meclizine Hydrochloride 906

Meclofenamic Acid 907

Medazepam 908

Medigoxin 910

Medrogestone 911

Medroxyprogesterone Acetate 914

Medrysone 917

Mefenamic Acid 918

Mefenorex Hydrochloride 919

Mefruside 920

Megestrol Acetate 921

Melitracen 922

Melperone 923

Melphalan 924

Memantine 926

Menadiol Sodium Diphosphate 927

Menbutone 928

Mepazine 929

Mepenzolate Bromide 930

Meperidine Hydrochloride 931

Mephenesin 933

Mephenesin Carbamate 934

Mephenoxalone 935

Mephentermine 936

Mepindolol 938

Mepitiostane 939

Mepivacaine 940

Meprednisone 941

Meprobamate 942

Meptazinol 945

Mequitazine 946

Meralluride 947

Mercaptomerin Sodium 948

Mercaptopurine 949

Mesna 950

Mesoridazine Besylate 952

Mesterolone 953

Mestranol 954

Metampicillin Sodium 955

Metapramine 956

Metaproterenol Sulfate 957

Metaraminol 959

Metaxalone 960

Metergoline 961

Methacycline 962

Methadone Hydrochloride 964

Methallenestril 965

Methandrortenolone 967

Methapyrilene Hydrochloride 968

Methaqualone 969

Methazolarnide 971

Methdilazine Hydrochloride 972

Methenamine Hippurate 973

Methenolone Acetate 974

Methicillin Sodium 975

Methionine 976

Methitural 978

Methixene Hydrochloride 979

Methocarbamol 980

Methohexital Sodium 981

Methotrexate 984

Methotrimeprazine 985

Mepicycline 937

Contents xxi

Methoxamine Hydrochloride 986

Methoxsalen 987

Methoxyflurane 988

Methscopolamine Bromide 990

Methsuximide 991

Methyldopa 992

Methylergonovine Maleate 993

Methylhexaneamine Carbonate 995

Methylol Riboflavin 996

Methylphenidate Hydrochloride 997

Methylprednisolone 998

Methyltestosterone 1000

Methyprylon 1001

Methysergide Maleate 1002

Metiazinic Acid 1003

Metoclopramide HCI 1004

Metolazone 1006

Metoprolol Tartrate 1009

Metrizoic Acid 101 0 Metronidazole 101 1 Metyrapone 101 3 Metyrosine 1014

Mexenone 101 5 Mexiletine HCI 1016

Mezlocillin 1017

Mianserin 101 9 Miconazole Nitrate 1020

Micronomicin 1022

Midazolam Maleate 1024

Midecamycin 1025

Midodrine 1027

Minaprine 1028

Minocycline 1029

Minoxidil 1030

Mitobronitol 1031

Mitomycin 1032

Mitopodozide 1033

Molindone 1034

Mopidamol 1035

Morclofone 1036

Motretinide -1 037 Moxalactam Disodium 1039

Moxestrol 1040

Moxisylyte 1041

Muzolimine 1043

Nabilone 1045

Nadolol 1046

Nafcillin Sodium 1047

Nafiverine 1048

Nafronyl Oxalate 1049

Nalbuphine 1050

Nalidixic Acid 1051

Nalorphine 1053

Naloxone 1054

Nandrolone Decanoate 1056

Nandrolone Phenpropionate 1057

NaDhazoline 1058

Naproxen 1059

Natamycin 1061

Nefopam Hydrochloride 1062

Neomycin 1063

Netilmicin 1066

Nialamide 1067

Niaprazine 1068

Nicardipine -1 069 Nicergoline 1070

Niceritrol 1071

Niclosamide 1072

Nicomol 1073

Nicotinyl Alcohol 1074

Nifedipine 1076

Niflumic Acid 1077

Nifuratel 1078

Nifurfoline 1079

Nifuroxazide 1080

Nifurtoinol 1081

Nifurzide 1081

Nimetazepam 1082

Nimorazole 1083

Nimustine 1085

Nitrazepam 1086

Nitrofurantoin 1088

Nitrofurazone 1090

Nomifensine Maleate 1091

Nonoxynol 1092

Nordazepam 1092

Norethandrolone 1093

Norethindrone -1 094 Norethindrone Acetate 1096

Norethynodrel 1097

Norfenefrine 1098

Norfloxacin 1099

Norgestrel 1100

Nortriptyline 1101

Novobiocin 1102

Noxiptilin 1103

Noxytiolin 1105

Nylidrin 1105

Nystatin 1107

Octopamine Hydrochloride 1110

Oleandomycin 1111

Opipramol 1112

Orazarnide 1113

Orgotein 1114

Ornidazole 1115

Ornipressin 1116

Orphenadrine Citrate 1117

Oxaceprol 1118

Oxacillin Sodium 1119

Oxaflozane Hydrochloride 1122

Oxaflumazine Disuccinate 1123

Oxametacine 1124

Oxamniquine 1125

Oxandrolone 1127

Oxatomide 1128

Contents xxiii

Oxazepam 1129

Oxazolam 1130

Oxeladin 1131

Oxendolone 1133

Oxethazine 1134

Oxetorone Fumarate 1135

Oxiconazole Nitrate 1136

Oxitriptan 1137

Oxitropium Bromide 1138

Oxolinic Acid 1139

Oxomemazine 1141

Oxprenolol 1142

Oxybutynin Chloride 1143

Oxyfedrine 1144

Oxymetazoline Hydrochloride 1145

Oxymorphone 1146

Oxypendyl 1147

Oxyphenbutazone 1148

Oxyphencyclimine 1150

Oxyphenisatin Acetate -1 151 Oxytetracycline ': 1152

Oxytocin 1154

Pancuronium Bromide 1158

Papain 1159

Papaverine Monophosadenine 1160

Paramethadione 1162

Paramethasone Acetate 1163

Parapenzolate Bromide 1164

Pargyline Hydrochloride 1165

Paromomycin 1166

Pelargonic Acid 1168

Pemoline 1169

Penbutolol 1170

Penfluridol 1171

Penicillamine 1172

Penicillin G Benzathine 1174

Penicillin G Hydrabamine 1175

Penicillin G Procaine 1177

Penicillin 0 1178

Penicillin V 1179

Penicillin V Hydrabamine 1181

Pentaerythritol Tetranitrate 1182

Pentagastrin 1184

Pentapiperide Methosulfate 1185

Penthienate Bromide 1186

Pentobarbital Sodium 1187

Pen tox if y I I i ne 1188

Peplomycin Sulfate 1189

Perhexiline Maleate 1190

Perimethazine 1192

Perisoxal Citrate 1192

Perlapine 1194

Perphenazine 1195

Phenactropinium Chloride 1196

Phenaglycodol 1197

Phendimetrazine Tartrate 1199

Phenelzine Sulfate 1200

Phenethicillin Potassium 1201 Phenformin 1202 Phenindamine Tartrate 1203 Pheniprazine 1204 Pheniramine Maleate 1205 Phenmetrazine 1206 Phenoperidine Hydrochloride 1207 Phenoxybenzamine Hydrochloride 1208 Phenprocoumon 1210 Phensuximide 121 1 Phentermine Hydrochloride 1212 Phentolamine Hydrochloride 1214 Phenyl Aminosalicylate 1215 Phenylbutazone 1216 Phenylephrine Hydrochloride 1218 Phenylpropanolamine Hydrochloride 1220 Phenyltoloxamine 1222 Phenyramidol 1223 Phenytoin 1224 Phethenylate Sodium 1226 Phthalylsulfathiazole 1227 Phytate Sodium 1228 Phytonadione 1229 Picoperine 1230 Picosulfate Sodium 1231 Pifarnine 1233 Pimefylline Nicotinate 1234 Pimozide 1235 Pinazepam 1236 Pipamazine 1237 Pipamperone 1238 Pipazethate 1240 Pipebuzone 1241 Pipemidic Acid 1241 Pipenzolate Bromide 1243 Piperacillin Sodium 1244 Piperidolate 1245 Pipethanate Ethobromide 1246 Pipobroman 1247 Pipoxolan Hydrochloride 1248 Piprozolin 1249 Piracetam 1250 Pirbuterol 1251 Piretanide 1252 Piribedil 1253 Piritramide 1254 Piroheptine 1255 Piromidic Acid 1256 Pirozadil 1257 Pirprofen 1258 Pivampicillin 1259 Pivmecillinam 1261 Pixifenide 1262 Pizotyline Hydrochloride 1263 Poloxal kol 1265 Polyestradiol Phosphate 1266 Polymyxin 1267 Polythiazide 1268 Povidone.lodine 1270

Contents x x v

Practolol 1271 Prajmaline Bitartrate 1272 Pralidoxime Chloride 1273 Pramiverin 1274 Pramoxine Hydrochloride 1275 Pranoprofen 1276 Prazepam 1277 Praziquantel 1279 Prazosin 1281) Prednimustine 1281 Prednisolone 1283 Prednisolone Acetate 1285 Prednisolone Phosphate Sodium 1286 Prednisolone Stearoylglycolate 1288 Prednisolone Tebutate 1289 Prednisone 1289 Prenalterol 1292 Prenylamine 1292 Prilocaine Hydrochloride 1294 Primidone 1295 Probenecid 1296 Probucol 1297 Procarbazine Hydrochloride 1298 Procaterol 1300 Prochlorperazine 1301 Procyclidine Hydrochloride 1302 Proglumetacin Maleate 1303 Promazine Hydrochloride 1305 Promegestone 1306 Promethazine Hydrochloride 1307 Propafenone Hydrochloride 1308 Propanidid 1310 Propantheline Bromide 1310 Propiram Fumarate 1312 Propoxyphene Hydrochloride 1313 Propranolol Hydrochloride 1314 Propylhexedrine 1316 Proquazone 1317 Proscillaridin 1318 Prothipendyl Hydrochloride 1319 Protionamide -1 320 Protizinic Acid 1322 Protokylol 1323 Protriptyline 1324 Proxazole Citrate 1325 Proxibarbal 1326 Pyrantel Pamoate 1328 Pyrathiazine 1329 Pyrazinamide 1330 Pyridinol Carbamate 1331 Pyridostigmine Bromide 1332 Pyrilamine 1333 Pyrimethamine 1335 Pyrithyldione 1336 Pyritinol 1337 Pyrovalerone Hydrochloride 1338 Pyrrobutamine 1339 Pyrvinium Pamoate 1340

Quinestrol 1342 Quinethazone 1343 Quingestanol Acetate 1344 Quinidine Polygalacturonate -1345 Quinupramine 1346 Ranitidine 1348 Razoxane 1349 Relaxin 1350 Reproterol 1351 Rescimetol., 1352 Rescinnamine 1353 Reserpine 1354 Ribostamicin 1357 Rifarnpin 1358 Rimiterol 1359 Ritodrine 1360 Rociverine 1362 Rol i t e t racy cI i n e 1 363 Rosoxacin 1364 Salicylanilide 1366 Salicylic Acid 1366 Secnidazole 1368 Secobarbital Sodium 1369 Secretin 1371 Selegiline 1372 Selenium Sulfide 1372 Silymarin 1373 Simethicone 1374 Simfibrate -1 375 Sincalide 1376 Sisomicin 1377 Sobrerol 1379 Somatotropin 1380 Spectinomycin 1381 Spiperone 1383 Spiramycin 1384 Spironolactone 1385 Stallimycin Hydrochloride 1386 Stanolone 1388 Stanozolol 1389 Streptokinase 1390 Streptomycin 1391 Streptozocin 1393 Succinylsulfathiazole 1394 Sucralfate 1395 Sufentanil 1396 Sulbenicillin 1397 Sulfacetamide 1398 Sulfachlorpyridazine 1399 Sulfacytine 1400 Sulfadiazine 1401 Sulfadimethoxine 1403 Sulfadoxine 1404 Sulfaethidole 1405 Sulfaguanidine 1406 Sulfaguanol 1407

Tiapride 1477 Tiaprofenic Acid 1478 Tiaramide 1479 Tibezonium Iodide 1480 Ticarcillin Disodium 1481 Ticlopidine Hydrochloride 1482 Ticrynafen 1483 Tiemonium Iodide 1485 Tilidine Hydrochloride 1486 Timepidium Bromide 1487 Timolol Maleate 1489 Timonacic Sodium 1491 Tinidazole 1491 Tinoridine 1493 Tiocarlide 1493 Tioclomarol 1494 Tioconazole 1495 Tiopronin 1496 Tiratricol 1497 Tiropramide 1498 Tixocortol Pivalate 1499 Tocainide 1500 Tofenacin Hydrochloride 1501 Tofisopam 1502 Tolazamide 1503 Tolazoline 1505 Tolbutamide 1506 Tolciclate 1507 Tolmetin 1508 Tolnaftate 1509 Tolonidine Nitrate 1510 Tolonium Chloride 1512 Tramadol Hydrochloride 1513 Tranexamic Acid 1514 Tranilast 1515 Tranylcypromine Sulfate 1516 Trapidil 1518 Trazodone Hydrochloride 1518 Trenbolone Acetate 1520 Trepibutone 1521 Tretinoin 1522 Triacetin 1523 Triamcinolone 1524 Triamcinolone Acetonide 1526 Triamcinolone Diacetate 1528 Triamterene 1529 Triazolam 1530 Tribenoside 1531 Trichlormethiazide 1532 Triclobisonium Chloride 1533 Triclocarban 1534 Triclofos Sodium 1535 Tridihexethyl Iodide 1536 Triethylenemelamine 1537 Trifluoperazine 1538

LY.cY,LY Trifluorothyrnidine 1539 Triflupromazine 1540 Trihexyphenidyl Hydrochloride 1541

Contents xxix

Trilostane 1543 Trirneprazine 1544 Trimetazidine 1545 Trimethadione 1546 Trirnethobenzamide Hydrochloride 1547 Trimethoprim 1548 Trimetozine 1550 Trioxsalen -1 551 Triparanol 1552 Tripelennamine 1553 Triprolidine 1554 Trofosfamide 1556 Trornantidine Hydrochloride 1557 Tromethamine 1558 Tropicamide 1559 Tubocurarine Chloride 1560 Tybamate 1561 Tyloxapol 1562 Tyropanoate Sodium 1563 Ubidecarenone 1565 Uracil Mustard 1566 Urapidil 1567 Urokinase 1568 Valethamate Bromide 1571 Vancomycin 1572 Veralipride 1573 Verapamil 1574 Vidarabine 1575 Viloxazine Hydrochloride 1577 Virninol - 1 578

Vinbarbital Sodium 1579 Vinblastine Sulfate 1580 Vincamine 1582 Vincristine Sulfate 1584 Vindesine 1585 Viomycin 1586 Viquidil 1587 Visnadine 1588 Warfarin Sodium 1590 Xanthinol Niacinate 1592 Xibornol -1 593 Xipamid 1594 Xylornetazoline Hydrochloride 1596 Zeranol 1598 Zimelidine 1599 Zipeprol 1600 Zolirnidine 1601 Zomepirac 1602 Zotepine 1604 Zoxazolamine 1604 RAW MATERIALS INDEX 1606 Fermentation or Extraction 1606 Chemicals 1609 TRADE NAME INDEX 1669

INFORMATION SOURCES USED

A variety of sources were used to identify the patent associated with particular commercial products and to serve as a source of process information These include the following: Merck Index: followed by a citation of the entry number in the Tenth (1983)

Edition.' DFU: The periodical publication, Drugs of the Future,' published in Spain

DOT: The periodical publication, Drugs of Today,3 also published in Spain

Kleeman & The encyclopedic German work, Pharmazeutische W e r k ~ t o f f e , ~

Engel: second revised edition published in 1982

OCDS: The 3-volume reference series on the Organic Chemistry of Drug

The latest edition of Remington's Pharmaceutical Sciences.6

The biannual Swiss publication, Index Nominum.*

The guide to commercially available U.S drugs, the Physicians'

Desk R e f e r e n ~ e ~

Finally, earlier books by this author were drawn on to provide information for some entries These include:

The Pharmaceutical Manufacturing Encyclopedia, first edit ion.''

A book entitled, Manufacturing Processes for New Pharmaceuticals."

This book attempted to review processes for manufacturing drugs

s t i l l in the developmental stage-those which had attained generic

name status but not trade name status in most cases Many of these

have since fallen by the wayside

The Veterinary Drug Manufacturing Encyclopedia.12 The present

volume deals only in "people drugs" as did i t s predecessor volume1'

but some drugs find application in both areas

It should be emphasized again that this is simply a guide to manufacturing processes Under each generic named product a "Therapeutic Function" is indicated However, the reader i s

referred to the Merck Index' and to Remingtod as well as to Drugs of the Future,' Drugs

of Today,j and the Physicians'Desk Reference /PDRj9 for more information on the ma-

terial, i t s properties, i t s therapeutic use and i t s side effects The chemist who i s interested

in synthesis routes i s referred to Lednicer and Mitscher' as well as to Kleeman & EngeI4 for more information on routes to these products and to products having similar structures

1

2 Pharmaceutical Manufacturing Encyclopedia

SALES RANKINGS OF US D R U G S

In t h e preparation of the first edition of this volume, contact was made w i t h IMS, Inc of

Ambler,Pa.,a w e l l - k n o w n sourceof international statistics W i t h their help,a l i s t wasprepared

of the 100 top products based on U.S sales volume in 1976; t h a t list i s given in Table 1

Table 1 : - T h e Top 100 Generic Pharmaceuticals in the U.S in 1976

(67) Clindamycin Phosphate (68) Miconazole Nitrate (69) Chlorpheniramine Maleate (70) Theophylline

(71) Naproxen

(72) Kanamycin Sulfate (73) Pentaerythritol Tetranitrate (74) Meperidine

(75) Neomycin Sulfate (76) dxazepam (77) Guaiacol Glyceryl Ether

(78) Oxymetazoline (79) Tolazamide (80) Insulin Zinc Suspension (81) Metronidazole (82) Phentermine Resin (83) Erythromycin Stearate (84) Phenobarbital (85) Povidone.lodine (86) Quinidine Gluconate (87) Hydroflumethiazide (88) Imipramine Pamoate (89) Methyl Phenidate (90) Nitroglycerin (91) Albumin, Normal Human Serum (92) Cyclandelate

(93) Dicyclomine (94) Enflurane (95) Erythromycin Ethyl Succinate (96) Minocycline

(97) Carbendicillin Disodium (98) Hydroxyzine (99) Tobramycin Sulfate (100) Meprobamate

The t o p f o u r items o n t h e l i s t each h a d sales over $100 m i l l i o n ; b y coincidence t h e c u t o f f

p o i n t a t t h e end o f t h e 100 t o p generic products was a t t h e $10 m i l l i o n sales level; t h e t o t a l salesof t h e 1 0 0 p r o d u c t s l i s t e d wasabout $3 b i l l i o n Of thistotaI,some$600million w a s i n antiinfective products (penicillins, antibiotics, sulfa drugs, etc.), some $500 m i l l i o n in tran- quilizers and some $400 m i l l i o n in cardiovascular drugs These three categories represented half t h e dollar t o t a l o f t h e t o p 100 drugs sold i n t h e U.S Other major drug market areas are

i n a n t i a r t h r i t i c drugs and antiulcer drugs

Now, f o r this second edition, a n a t t e m p t was made t o l i s t t h e t o p prescription drugs i n t h e U.S.asof 1985-some t e n years later than t h e earlier tabulation This new listing wasdone b y

the author based o n his interpretation o f t h e sales l i s t b y trade name in t h e magazine American Druggist f o r February 1986; it gives approximate r a n k b y generic p r o d u c t as of t h e date o f manuscript preparation in 1986 See Table 2

Table 2: T h e T o p 100 Generic Pharmaceuticals in t h e U.S in 1985

4 Pharmaceutical Manufacturing Encyclopedia

TRENDS IN PATENT EXPIRATION

It has been estimated that patents on the top 100 drugs in the U.S market will expire in the period between 1973 and 1990

This will help to lead to a situation where genericallydesignated drugs are expected to account for 40% of the prescription drug market by 1990

BIBLIOGRAPHY

1, Windholz, M., editor, The Merck Index, 10th edition, Rahway, NJ, Merck & Co., Inc

2 Prous, J.R., editor, Drugs of the Future, Provenza 38587, Barcelona-13, Spain

3 Prous, J.R., editor, Drugs of Today, Provenza 385-87, Barcelona-13, Spain

4 Kleeman, A and Engel, J., Pharmazeutische Werkstoffe: Synthesen, Parente, Anwen-

5 Lednicer, D and Mitscher, L., The Organic Chemistry of Drug Synthesis, New York,

6 Philadelphia College of Pharmacy and Science, Remingron’s Pharmaceutical Sciences,

7 Paul de Haen International, Inc., Nonproprietary Name Index, Englewood, CO, Paul de

8 H.P Jasperson e t al, editors, Index Nominum, Zurich, Switzerland, Swiss Pharmaceu-

9 Barnhart, E.R., editor, Physicians Desk Reference, Oradell, NJ, Medical Economics Co.,

(1983)

dugen, Stuttgart, Germany, Georg Thieme Verlag (1982)

John Wiley and Sons, Vol 1 (1977); Vol 2 (1980); Vol 3 (1984)

Easton, PA, Mack Publishing Co., 17th edition (1985)

Haen International, Inc., 15th edition (1984)

10 Sittig, M Pharmaceutical Manufacturing Encyclopedia, Park Ridge, NJ, Noyes Data

11 Sittig, M., Manufacturing Processes for New Pharmaceuticals, Park Ridge, NJ, Noyes

12 Sittig, M., Veterinary Drug Manufacturing Encyclopedia, Park Ridge, NJ, Noyes Publi-

A

ACEBUTOLOL

Therapeutic Function: Cardiovascular betablocker

Chemical Name: N-[3-acetyl4-[2-hydroxy-3-[ (1 -methylethyl)sminol propoxyl phenyl] butanamide

Rhone Poulenc Rohm Pharma May & Baker Wyeth

W Germany

W Germany Switzerland Italy Italy Japan Italy Italy

-

- U.K

us

Epichlorohydrin Sodium Ethoxide lsopropylamine

Crude 5'-butyramido-2'-(2,3epoxypropoxy)acetophenone (1 6 g), isopropylamine (20 g) and

ethanol (100 ml) were heated together under reflux for 4 hours The reaction mixture was concentrated under reduced pressure and the residual oil was dissolved in N hydrochloric acid The acid solution was extracted with ethyl acetate, the ethyl acetate layers being discarded The acidic solution was brought t o pH 1 1 with 2 N aqueous sodium hydroxide solution and then extracted with chloroform The dried chloroform extracts were concentrated under re-

5

6 Pharmaceutical Manufacturing Encyclopedia

duced pressure to give an oil which was crystallized from a mixture of ethanol and diethyl

ether to give 5'-butyramido-2'-~2hydroxy-3-isopropylaminopropoxy~acetophenone (3 g),

MP 1 19°-1230C

Crude 5'-butyramido-2'-(2,3epoxypropoxy)acetophenone used as starting material was pre-

pared as follows: p-butyramidophenol (58 g; prepared according to Fierz-David and Kuster, Helv Chim Acta 1939,22821, acetyl chloride (25.4 g) and benzene (500 ml) were heated to- gether under reflux until a solution formed (12 hours) This solution was cooled and treated with water The benzene layer was separated and the aqueous layer was again extracted with benzene

The combined benzene extracts were dried and evaporated t o dryness under reduced pressure

to give p-butyramidophenyl acetate (38 g) as an off-white solid, MP 102°-1030C A mixture of p-butyramidophenyl acetate (38 g), aluminum chloride (80 g) and 1 ,I ,2,2-tetrachloroethane (250 ml) was heated a t 14OoC for 3 hours, The reaction mixture was cooled and treated with iced water The tetrachloroethane layer was separated and the aqueous layer was extracted with chloroform The combined organic layers were extracted with 2 N aqueous sodium hy- droxide and the alkaline solution was acidified to pH 5 with concentrated hydrochloric acid The acidified solution was extracted with chloroform and the chloroform extract was dried

and concentrated under reduced pressure to give 5'-butyramido-2'-hydroxyacetophenone

(15.6 g), MP 114°-1170C A solution of 5'-butyramido-2'hydroxyacetophenone (15.6 g) in

ethanol (100 ml) was added to an ethanolic solution of sodium ethoxide which was prepared from sodium (1.62 g) and ethanol (100 ml) The resulting solution was evaporated to dryness under reduced pressure and dimethylformamide (100 ml) was added to the solid residue Ap- proximately 10 ml of dimethylformamide was removed by distillation under reduced pres- sure Epichlorohydrin (25 ml) was added and the solution was heated at 100°C for 4 hours The solution was concentrated under reduced pressure to give a residual oil which was treated with water to give a solid The solid was dissolved in ethanol and the resulting solution was treated with charcoal, filtered and concentrated under reduced pressure to give crude 5'-butyr-

amido-2'-(2,3epoxypropoxy)acetophenone (16 g), MP 110°-1160C

The crude compound may be purified by recrystallization from ethyl acetate, after treat-

ment with decolourizing charcoal, to give pure 5'-butyramido4'-(2,3epoxypropoxy)aceto-

Therapeutic Function: Miotic, cholinomimetic

Chemical Name: l-Azabicyclo[2.2.21 octan-3-ol acetate

Common Name: 3-Quinuclidinol Acetate

ACECLIDINE

Structural Formula:

Chemicel Abstracts Registry No.: 827-61-2; 6109-70-2 (Hydrochloride)

Trade Name Manufacturer Country Year Introduced

Glacostat MSD-Chibret France 1966

Glaunorm Farmigea Italy 1969

A mixture of 274 g of methyl isonicotinate, 367 g of ethyl bromoacetate and 125 cc of ethyl

alcohol was stirred without heating for 4 hours in a flask equipped with a reflux condenser (The reaction was exothermic and precautions were taken to keep the temperature below

7OOC.l The reaction mixture was then left for 15 hours a t room temperature

The reaction product (1 carbethoxymethyl4carbornethoxy-pyridinium bromide) was ob-

tained in crystalline form (It formed prisms melting a t 166'-169'C after recrystallization from a mixture of isopropanol and acetone.) It was not necessary to isolate it For the follow- ing reduction step, the reaction mixture was brought into solution by the addition of about

1 liter of warm ethyl alcohol It was then hydrogenated at about 30 atm pressure in the pre-

sence of 2 g of platinum oxide The temperature rose during this reaction t o about 4OoC After the calculated amount of hydrogen had been absorbed, the catalyst was filtered off, the solution was concentrated in vacuo, and the residual syrup was dissolved in ice water Benzene was added and the mixture was made alkaline with an excess of concentrated ice cold potas- sium carbonate solution The temperature was kept low by continuous addition of ice, and the benzene layer was separated and dried with sodium sulfate The dried benzene solution was concentrated in vacuo and the residual oil was distilled in vacuo 8 P 30 mm = 175'-182"C,

'' = 1.4613-1.4628 During the reduction, partial alcoholysis occurred, and the product

;Elated was 1 carbethoxymethyl4"carbal koxy"-piperidine, wherein "carbal koxy" represents

a mixture of carbomethoxy and carbethoxy

100 g of potassium were pulverized in 200 cc of hot toluene in a heated three-neck flask equip-

ped with an efficient condenser, stirrer and dropping funnel To the refluxing potassium sus- pension were added in small portions 229 g of the product of the previous step and about

700 cc of toluene This addition had to be carried out very cautiously; the onset of the exo-

thermic reaction i s sometimesdelayed Theaddition was finished in about 1 hour To complete the reaction, the refluxing and stirring were continued for about 4 hours The reaction mix-

ture was then cooled to about +5OC and about 50 cc isopropanol were added to decompose unreacted potassium Then 2.5 liters of concentrated hydrochloric acid were added and the

mixture was refluxed for 15 hours,and then concentrated in vacuo to dryness To the residue

was added with cooling an excess of 50% potassium hydroxide Ether was then added and the

resulting mixture was filtered through a fritted glass funnel, thus removing the precipitated potassium chloride The ethereal and aqueous layers were separated, and the aqueous layer was extracted repeatedly with 500 cc portions of ether The organic solutions were combined, dried over sodium sulfate and concentrated in vacuo Aqueous hydrochloric acid was added to the residue until the solution becameacid The mixture was then diluted with distilled water

to about 300 cc, heated with decolorizing charcoa1,filtered and concentrated in vacuo to dry-

ness The residue was treated with isopropanol, and the precipitated crystalline product was filtered off The product was recrystallized from a mixture of water and isopropanol and was

8 Pharmaceutical Manufacturing Encyclopedia

identified as 1 azabicyclo[2.2.2] -3-octanone hydrochloride; prisms, MP 31 1°-3130C, with de- composition

A solution of 50 g of the above ketonehydrochloride in 30 cc of water was made alkaline by the addition of 30 g of potassium hydroxide After the alkali was dissolved, 35 g of granular potassium carbonate were added The free basic ketone was then extracted from the viscous mixture by shaking with 4 portions of hot benzene (300 cc in each portion) The benzene ex- tracts were decanted, filtered over sodium sulfate in order to remove any suspended alkali,

and concentrated in vacuo The residual lszabicyclo[2.2.21-3-octanone was purified by sub-

limation (5O0-7OoC/0.5 mm Hg); it can also be purified by recrystallization from petroleum ether It formed feathery crystals melting a t 147O-148OC

The product was reduced as follows:

A solution of 50 g of 1 azabicyclo[2.2.2] -3-octanone hydrochloride in 200 cc of water was hydrogenated a t room temperatureand 50atm pressurewith 1 gof platinum oxideascatalyst After the calculated amount of hydrogen had been absorbed, the mixture was filtered and concentrated in vacuo to dryness The residual product was recrystallized from a mixture of methanol and acetone and formed prisms melting above 30OoC It was identified as 1 szabicy- cl0[2.2.21 -3-octanol hydrochloride

A solution of 50 g of 1 szabicyclo[2.2.21-3~ctanol hydrochloride in 30 cc water was made alkaline with 30 g of potassium hydroxide After the alkali was dissolved 35 g of granular po- tassium carbonate were added The free basic alcohol was then extracted from the viscous mixture by shaking with four portions of boiling benzene (300 cc in each portion) The ben- zene extracts were decanted and filtered over anhydrous sodium sulfate, to remove any sus- pended alkali The combined benzene solutions were concentrated in vacuo The residue was recrystallized from benzene and identified as lszabicyclo[2.2.21-3-octanol, MP 22lo-223OC

T h e product can also be purified by recrystallization from acetone,or by sublimation in vacuo (12OoC/20 mm Hg) The alcohol was reacted with acetic anhydride to give the product ace-

Therapeutic Function: Antiulcer (free base as psychostimulant)

Chemical Name: Pentakis(N2-acetyl-Lglutaminato)tetrahydroxytrialuminum

Trade Name Manufacturer

Glumal Kyowa Hakko

Glumal Liade

Country Year Introduced Japan 1978

Spain - Raw Materials

N Acety I -L-GI utamine

Aluminum lsopropoxide

Manufacturing Process

A mixture of 37.6 g of N-acetyl-L3lutamine and 1,000 ml of water is heated to 40°C, and 900

ml of an isopropanol solution containing 4 0 8 g of aluminum isopropoxide i s added to the warm mixture with stirring The stirring is continued for 10 minutes.The reaction mixture is fil-

tered and the filtrate is concentrated under reduced pressure Isopropanol i s added to the aqueous solution and the salt precipitates in the solution The precipitatesare collected by fil- tration and upon drying, 48.5 g of the crystalline-like aluminum salt of N-acetyl-Lglutamine

Kagawa ,T ., Fuji , K ., Tanaka, M and Tanaka, H .; U .S Patent 3,787,466; Jan 22,1974; assigned

to Kyowa Hakko Kogyo Co., Ltd

ACEMETACIN

Therapeutic Function: Antiinflammatory

Chemical Name: 1 -(pChlorobenzoyl) dmethoxy-2methylindole-3acetoxyacetic acid

CommonName: -

Structural Formula:

Chemical Abstracts Registry No.: 5 3 1 6 4 0 5 8

Trade Name Manufacturer Country Year Introduced

Rantudil Bayer W Germany 1980

Rantudil Tropon W Germany -

Raw Materials

N-(pMethoxybenzyl) -p-Chlorobenzhydrazide HCI

Benzyl Levulinoyloxyacetate

Hydrogen

1 0 Phar maceut ical Manu fact u r i ng Encyclopedia

149.5°-150.50C (determined on the micro-Kofler bench); the yield was 19.4 g which corre-

sponds to 93% of the theoretical yield

The starting material for the above step may be prepared as follows: 5 g (0.016 mol) of N'-

(pmethoxypheny1)gchlorobenzhydrazide hydrochloride and 4.75 g (0.018 mol) of benzyl

levulinoyloxyacetate were heated in 25 ml of glacial acetic acid for 3 hours a t BOOC The sol-

vent was then evaporated off under vacuum The residue was taken up in chloroform and the solution was washed neutral by shaking with sodium bicarbonate solution and thereafter with water, After drying the chloroform solution, this was subjected t o chromatography on alumi- nium oxide, the eluate was concentrated by evaporation and the viscous oil remaining as residue was crystallized by adding ether The compound melted a t 94O-95"C The yield was 4.1 g which corresponds t o 50.7% of the theoretical yield

Boltze, K.H., Brendler, O., Dell, H.D and Jacobi, H.; US Patent 3,910,952; October 7,1945;

Boltze, K.H., Brendler,O., Dell, H.D.and Jacobi, H.; U.S Patent 3,966,956; June 29,1976;

assigned t o Tropenwerke Dinklage and Co

assigned to Tropenwerke Dinklage and Co

ACENOCOUMAROL (ACENOCOUMARIN)

Therapeutic Function: Anticoagulant, Vitamin K antagonist

Chemical Name: 3-(~-acetonyl~-nitrobenzyl)4-hydroxycoumarin

Common Name: Nicoumalone

Structural Formula:

on

Chemical Abstracts Registry No.: 152-72-7

Trade Name Manufacturer Country Year Introduced

Sintrom Geigy U.S 1957

Sintrom Geigy W Germany -

Sintrom Ciba Geigy Switz -

Sintrom CibaGeigy France 1959

Trade Name Manufacturer Country Year Introduced

NeoSintrom Geigy -

Ascumar Star Finland

Syncumar Egyt Hungary

Synthrome Geigy U.K

to a lye made up from 6 parts of sodium hydroxide in 400 parts of water while stirring and then the mixture is stirred for 30 minutes A littje animal charcoal is then added, the mixture is stirred for a further 15 minutes, 400 parts of water are added and the charcoal and undissolved components are separated by filtration under suction The clear solution

is made acid to Congo red paper with hydrochloric acid and the product which is precip- itated is filtered off under suction 3-[~~-(4'-nitrophenyl)-fl-acetyI ethyl] -4-hydroxycou- marin is obtained MP 196"-199'C

It should be noted that the process is akin to that for Warfarin except that 4-nitrobenzal- acetone replaces benzalacetone as a raw material

Therapeutic Function: Analgesic, antipyretic

Chemical Name: N-(4hydroxyphenyl)acetamide

Common Name: Paracetamol, AcetylpAminophenol, APAP

Structural Formula:

Chemical Abstracts Registry No.: 10340-2

Trade Name Manufacturer Country Year Introduced

12 Pharmaceutical Manufacturing Encyclopedia

Tilden Yates Mead Johnson

Am Pharm

Breon Westerfield Clwp Borden Dow

SK&F

Squibb ParkeDavis Central G&W

St Joseph Glenbrook Lederle AccuMed Buffington Dover Comatic Ferndale BristolMyers Winthrop Lannett First Texas Halsey Winthrop Win t h rop Johnson &

Johnson Geneva

Ph ilipsRoxane Car n r ic k

Webcon Bristol Myers AVP Winthrop Winthrop Parmed Robins Mallard Carnrick Delree ReidProvident Robins Otis Clapp Rekah Rekah lkapharm Streul i

Israel Japan Sweden

Marshalls Pharm

Prosana Sterwin-Espanola lsis

Winthrop Bayer B.M Labs UCB Zdravlje Weifa ICN Duncan Flockhart Trima

Adams Fisons Orion Knoll Atabay

Country U.K

Japan Austria Spain Canada Austria

W Germany U.K

Canada Australia U.K

Canada

W Germany Australia France

W Germany U.K

France

W Germany Canada U.K

Neth

Switz

Spain Israel Neth

Austria Israel U.K

Switz

W Germany U.K

Austria France Italy Switz

Israel Norway U.K

Australia Spain Yugoslavia U.K

W Germany U.K

Belgium Yugoslavia Norway Canada U.K

Israel Australia U.K

Finland Australia Turkey Stada W Germany

Year Introduced