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Handbook of Pharmaceutical
Manufacturing Formulations
Volume Three, Liquid Products
Handbook of Pharmaceutical
Manufacturing Formulations,
Third Edition
Volume Three, Liquid Products

Sarfaraz K. Niazi
CRC Press
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 To August P. Lemberger
Dean August P. Lemberger passed away in 2010; he gave me my first teaching job at the University
of Illinois when I was still working on my thesis. He served as the dean at Illinois and Wisconsin.
Contents
Preface to the Series—Third Edition......................................................................................................................................... xxv
Preface to the Series—Second Edition....................................................................................................................................xxvii
Preface to the Series—First Edition.........................................................................................................................................xxxi
Preface to the Volume—First Edition................................................................................................................................... xxxiii
Author...................................................................................................................................................................................... xxxv

PART I Regulatory and Manufacturing Guidance

Chapter 1 Manufacturing Considerations in Liquid Formulations........................................................................................... 3

I. Introduction................................................................................................................................................... 3
II. Facilities........................................................................................................................................................ 3
III. Equipment...................................................................................................................................................... 4
IV. Raw Materials................................................................................................................................................ 4
V. Compounding................................................................................................................................................ 5
VI. Microbiological Quality................................................................................................................................ 5
VII. Oral Suspensions........................................................................................................................................... 6
VIII. Product Specifications................................................................................................................................... 6
IX. Process Validation......................................................................................................................................... 6
X. Stability......................................................................................................................................................... 6
XI. Packaging...................................................................................................................................................... 6

Chapter 2 Oral Solutions and Suspensions............................................................................................................................... 9

I. Introduction................................................................................................................................................... 9
II. Facilities........................................................................................................................................................ 9
III. Equipment...................................................................................................................................................... 9
IV. Raw Materials................................................................................................................................................ 9
V. Compounding................................................................................................................................................ 9
VI. Microbiological Quality.............................................................................................................................. 10
VII. Oral Suspension Uniformity........................................................................................................................ 10
VIII. Product Specifications................................................................................................................................. 10
IX. Process Validation....................................................................................................................................... 10
X. Stability....................................................................................................................................................... 11
XI. Packaging.................................................................................................................................................... 11

Chapter 3 The FDA Drug Product Surveillance Program...................................................................................................... 13

I. Background.................................................................................................................................................. 13
II. Implementation............................................................................................................................................ 13
A. Objectives............................................................................................................................................ 13
B. Strategy................................................................................................................................................ 13
1. Biennial Inspection of Manufacturing Sites................................................................................. 13
2. Inspection of Systems................................................................................................................... 14
3. A Scheme of Systems for the Manufacture of Drugs and Drug Products.................................... 14
III. Program Management Instructions............................................................................................................. 15
A. Definitions........................................................................................................................................... 15
1. Surveillance Inspections............................................................................................................... 15
2. Compliance Inspections................................................................................................................ 15
3. State of Control............................................................................................................................. 15

vii
viii Contents

4. Drug Process................................................................................................................................. 16
5. Drug Manufacturing Inspection................................................................................................... 16
B. Inspection Planning............................................................................................................................. 16
C. Profiles................................................................................................................................................. 16
IV. Inspectional Observations........................................................................................................................... 16
A. Investigational Operations................................................................................................................... 16
1. General���������������������������������������������������������������������������������������������������������������������������������������� 16
2. Inspection Approaches����������������������������������������������������������������������������������������������������������������� 17
3. System Inspection Coverage������������������������������������������������������������������������������������������������������� 17
4. Sampling�������������������������������������������������������������������������������������������������������������������������������������� 20
5. Inspection Teams������������������������������������������������������������������������������������������������������������������������� 20
6. Reporting������������������������������������������������������������������������������������������������������������������������������������� 20
V. Analytical Observations.............................................................................................................................. 21
A. Analyzing Laboratories....................................................................................................................... 21
B. Analysis............................................................................................................................................... 21
VI. Regulatory/Administrative Strategy............................................................................................................ 21

Chapter 4 Changes to Approved NDAs and aNDAs.............................................................................................................. 23

I. Introduction................................................................................................................................................. 23
II. Reporting Categories................................................................................................................................... 23
III. General Requirements................................................................................................................................. 23
IV. Assessing the Effect of Manufacturing Changes........................................................................................ 24
A. Assessment of the Effects of the Change............................................................................................ 24
1. Conformance to Specifications..................................................................................................... 24
2. Additional Testing......................................................................................................................... 24
B. Equivalence......................................................................................................................................... 24
C. Adverse Effect..................................................................................................................................... 25
V. Components and Composition..................................................................................................................... 25
VI. Manufacturing Sites.................................................................................................................................... 25
A. General Considerations....................................................................................................................... 25
B. Major Changes (Prior Approval Supplement)..................................................................................... 25
C. Moderate Changes (Supplement—Changes Being Effected)������������������������������������������������������������ 26
D. Minor Changes (Annual Report)......................................................................................................... 26
VII. Manufacturing Process................................................................................................................................ 26
A. General Considerations....................................................................................................................... 26
B. Major Changes (Prior Approval Supplement)..................................................................................... 27
C. Moderate Changes (Supplement—Changes Being Effected)............................................................. 27
D. Minor Changes (Annual Report)......................................................................................................... 28
VIII. Specifications............................................................................................................................................... 28
A. General Considerations....................................................................................................................... 28
B. Major Changes (Prior Approval Supplement)..................................................................................... 29
C. Moderate Changes (Supplement—Changes Being Effected)............................................................. 29
D. Minor Changes (Annual Report)......................................................................................................... 29
IX. Package........................................................................................................................................................ 30
A. General Considerations....................................................................................................................... 30
B. Major Changes (Prior Approval Supplement)..................................................................................... 30
C. Moderate Changes (Supplement—Changes Being Effected)............................................................. 30
D. Minor Changes (Annual Report)......................................................................................................... 31
X. Labeling....................................................................................................................................................... 31
A. General Considerations....................................................................................................................... 31
B. Major Changes (Prior Approval Supplement)..................................................................................... 31
C. Moderate Changes (Supplement—Changes Being Effected)............................................................. 32
D. Minor Changes (Annual Report)......................................................................................................... 32
Contents ix

XI. Miscellaneous Changes............................................................................................................................... 32

A. Major Changes (Prior Approval Supplement)..................................................................................... 32
B. Moderate Changes (Supplement—Changes Being Effected)............................................................. 32
C. Minor Changes (Annual Report).......................................................................................................... 32
XII. Multiple Related Changes......................................................................................................................... 33
Glossary.................................................................................................................................................................. 34

Chapter 5 Formulation Considerations of Liquid Products.................................................................................................... 35

I.  Solubility................................................................................................................................................... 35
II.   Chemical Modification.............................................................................................................................. 35
III.  Preservation............................................................................................................................................... 35
IV.   Sweetening Agents.................................................................................................................................... 36
V.  Flavors....................................................................................................................................................... 36
VI.  Viscosity.................................................................................................................................................... 36
VII.  Appearance................................................................................................................................................ 36
VIII.   Chemical Stability..................................................................................................................................... 36
IX.   Physical Stability....................................................................................................................................... 36
X.   Raw Material............................................................................................................................................. 36
XI.   Manufacturing Equipment........................................................................................................................ 37
XII.   Manufacturing Directions......................................................................................................................... 37
XIII.  Packaging.................................................................................................................................................. 37
XIV.   Particle Size and Shape............................................................................................................................. 37
XV.  Suspensions............................................................................................................................................... 38
XVI.  Emulsions.................................................................................................................................................. 38
  Emulsions.................................................................................................................................................. 38
XVII.   Powder for Reconstitution......................................................................................................................... 40
XVIII.   Nasal Spray Products................................................................................................................................. 40
  A. Inhalation Solutions and Suspensions............................................................................................... 41
   B. Inhalation Sprays............................................................................................................................... 41
  C. Pump Delivery of Nasal Products..................................................................................................... 41
  D. Spray Content Uniformity for Nasal Products.................................................................................. 42
  E. Spray Pattern and Plume Geometry of Nasal Products..................................................................... 42
  F. Droplet-Size Distribution in Nasal Products...................................................................................... 42
  G. Particle-Size Distribution for Nasal Suspensions.............................................................................. 43
XIX.   Emulsification and Solubilization.............................................................................................................. 43
XX.  Complexing............................................................................................................................................... 43
XXI.  Hydrophilization........................................................................................................................................ 43
XXII.  Stabilizing Suspensions............................................................................................................................. 43

Chapter 6 Container Closure Systems.................................................................................................................................... 45

I.  Introduction............................................................................................................................................... 45
  A. Definitions......................................................................................................................................... 45
  B. Current Good Manufacturing Practice, the Consumer Product Safety Commission, and
Requirements on Containers and Closures��������������������������������������������������������������������������������������� 45
   C. Additional Considerations................................................................................................................. 45
II.   Qualification and Quality Control of Packaging Components.................................................................. 46
  A. Description........................................................................................................................................ 49
  B. Information about Suitability............................................................................................................ 49
  C. Stability Data (Packaging Concerns)................................................................................................ 50
  D. Inhalation Drug Products.................................................................................................................. 50
  E. Injection and Ophthalmic Drug Products.......................................................................................... 50
  F.   Liquid-Based Oral and Topical Drug Products and Topical Delivery Systems................................ 51
x Contents

  G. Solid Oral Dosage Forms and Powders for Reconstitution............................................................... 52

1. Polyethylene Containers (USP <661>)...................................................................................... 53
2. Single-Unit Containers and Unit-Dose Containers for Capsules and Tablets (USP <671>)..............53
3. Multiple-Unit Containers for Capsules and Tablets (USP <671>)............................................. 53
  H. Other Dosage Forms......................................................................................................................... 53
III. Postapproval Packaging Changes.................................................................................................................. 53
IV. Type III Drug Master Files............................................................................................................................ 54
V. Bulk Containers............................................................................................................................................. 54
Bibliography........................................................................................................................................................... 55

Chapter 7 Material for Containers.......................................................................................................................................... 57

I. Glass Containers.......................................................................................................................................... 57
II. Nonplasticized Poly(Vinyl Chloride) for Containers for Noninjectable Aqueous Solutions...................... 58
III. Polyethylene Terephthalate for Containers for Preparations Not for Parenteral Use.................................. 58
IV. Nonplasticized Poly(Vinyl Chloride) for Containers for Dry Dosage Forms for Oral Administration...... 58
V. Plasticized Poly(Vinyl Chloride) for Containers for Aqueous Solutions for Intravenous Infusion............. 58
VI. Polyethylene Terephthalate for Containers for Preparations Not for Parenteral Use.................................. 58
VII. Polyolefins................................................................................................................................................... 58
VIII. Polyethylene with Additives for Containers for Parenteral Preparations and for Ophthalmic
Preparations................................................................................................................................................. 59
IX. Polypropylene for Containers and Closures for Parenteral Preparations and
Ophthalmic Preparations............................................................................................................................. 60
X. Poly(Ethylene/Vinyl Acetate) for Containers and Tubing for Total Parenteral Nutrition Preparations.............60
XI. Plastic Containers for Aqueous Solutions for Infusion............................................................................... 61
XII. Sterile Single-Use Plastic Syringes............................................................................................................. 61
XIII. Rubber Closures for Containers for Aqueous Parenteral Preparations, for Powders, and for
Freeze-Dried Powders................................................................................................................................. 62
XIV. Silicone Oil Used as a Lubricant................................................................................................................. 62
XV. Silicone Elastomer for Closures and Tubing............................................................................................... 62

Chapter 8 Stability Testing of New Drug Substances and Products....................................................................................... 63

I.  Introduction..................................................................................................................................................... 63
A. Objectives of the Guideline.................................................................................................................... 63
B. Scope of the Guideline............................................................................................................................ 63
C. General Principles................................................................................................................................... 63
II. Guidelines....................................................................................................................................................... 63
A. Drug Substance....................................................................................................................................... 63
1.  General������������������������������������������������������������������������������������������������������������������������������������������ 63
2.  Stress Testing................................................................................................................................. 63
3.  Selection of Batches....................................................................................................................... 63
4.  Container Closure System.............................................................................................................. 64
5.  Specification................................................................................................................................... 64
6.  Testing Frequency.......................................................................................................................... 64
7.  Storage Conditions......................................................................................................................... 64
8.  Stability Commitment.................................................................................................................... 65
9.  Evaluation������������������������������������������������������������������������������������������������������������������������������������� 65
10. Statements/Labeling....................................................................................................................... 65
B. Drug Product........................................................................................................................................... 66
1.  General������������������������������������������������������������������������������������������������������������������������������������������ 66
2.  Photostability Testing..................................................................................................................... 66
3.  Selection of Batches....................................................................................................................... 66
4.  Container Closure System.............................................................................................................. 66
5.  Specification................................................................................................................................... 66
6.  Testing Frequency.......................................................................................................................... 66
7.  Storage Conditions......................................................................................................................... 66
Contents xi

8.   Stability Commitment.................................................................................................................... 68

9.  Evaluation������������������������������������������������������������������������������������������������������������������������������������� 69
10. Statements/Labeling....................................................................................................................... 69
Glossary.................................................................................................................................................................. 69
Bibliography........................................................................................................................................................... 71

Chapter 9 Stability Testing: Photostability Testing of New Drug Substances and Products.................................................. 73
I. General............................................................................................................................................................ 73
A. Preamble................................................................................................................................................. 73
B. Light Sources.......................................................................................................................................... 73
C. Procedure................................................................................................................................................ 73
II. Drug Substance............................................................................................................................................... 74
A. Presentation of Samples.......................................................................................................................... 75
B. Analysis of Samples................................................................................................................................ 75
C. Judgement of Results.............................................................................................................................. 75
III. Drug Product.................................................................................................................................................. 75
A. Presentation of Samples.......................................................................................................................... 75
B. Analysis of Samples................................................................................................................................ 76
C. Judgement of Results.............................................................................................................................. 76
IV.  Annex............................................................................................................................................................. 76
A. Quinine Chemical Actinometry.............................................................................................................. 76

Chapter 10 Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products......................... 77
I. Introduction..................................................................................................................................................... 77
A. Objectives of the Guideline.................................................................................................................... 77
B. Background............................................................................................................................................. 77
C. Scope of the Guideline............................................................................................................................ 77
II. Guidelines....................................................................................................................................................... 77
A. General.................................................................................................................................................... 77
B. Applicability of Reduced Designs........................................................................................................... 77
C. Bracketing............................................................................................................................................... 77
1. Design Factors.................................................................................................................................. 77
2. Design Considerations and Potential Risks..................................................................................... 78
3. Design Example............................................................................................................................... 78
D. Matrixing................................................................................................................................................ 78
1. Design Factors.................................................................................................................................. 78
2. Design Considerations..................................................................................................................... 79
3. Design Examples.............................................................................................................................. 79
4. Applicability and Degree of Reduction............................................................................................ 79
5. Potential Risk................................................................................................................................... 80
E. Data Evaluation....................................................................................................................................... 80

Chapter 11 Evaluation of Stability Data................................................................................................................................... 81

I. Introduction..................................................................................................................................................... 81
A. Objectives of the Guideline.................................................................................................................... 81
B. Background............................................................................................................................................. 81
C. Scope of the Guideline............................................................................................................................ 81
II. Guidelines....................................................................................................................................................... 81
A. General Principles................................................................................................................................... 81
B. Data Presentation.................................................................................................................................... 82
C. Extrapolation........................................................................................................................................... 82
D. Data Evaluation for Retest Period or Shelf-Life Estimation for Drug Substances or Products
Intended for Room-Temperature Storage���������������������������������������������������������������������������������������������� 82
1. No Significant Change at Accelerated Condition............................................................................ 82
2. Significant Change at Accelerated Condition.................................................................................. 83
xii Contents

E. Data Evaluation for Retest Period or Shelf-Life Estimation for Drug Substances or Products
Intended for Storage below Room Temperature������������������������������������������������������������������������������������ 83
1. Drug Substances or Products Intended for Storage in a Refrigerator.............................................. 83
2. Drug Substances or Products Intended for Storage in a Freezer...................................................... 84
3. Drug Substances or Products Intended for Storage below −20°C................................................... 84
F. General Statistical Approaches................................................................................................................ 84
Appendices............................................................................................................................................................. 85
Appendix A: Decision Tree for Data Evaluation for Retest Period or Shelf-Life Estimation for Drug
Substances or Products (Excluding Frozen Products)....................................................................... 85
Appendix B: Examples of Statistical Approaches to Stability Data Analysis................................................ 86
B.1. Data Analysis for a Single Batch.................................................................................................. 86
B.2. Data Analysis for One-Factor, Full-Design Studies..................................................................... 87
B.3. Data Analysis for Multifactor, Full-Design Studies..................................................................... 88
B.4. Data Analysis for Bracketing Design Studies.............................................................................. 89
B.5. Data Analysis for Matrixing Design Studies................................................................................ 89
References.............................................................................................................................................................. 89

Chapter 12 Stability Data Package for Registration Applications in Climatic Zones III and IV............................................. 91
I. Introduction..................................................................................................................................................... 91
A. Objectives of the Guideline.................................................................................................................... 91
B. Background............................................................................................................................................. 91
C. Scope of the Guideline............................................................................................................................ 91
II. Guidelines....................................................................................................................................................... 91
A. Continuity with the Parent Guideline..................................................................................................... 91
B. Storage Conditions.................................................................................................................................. 91
1. General Case.................................................................................................................................... 91
2. Aqueous-Based Drug Products Packaged in Semipermeable Containers........................................ 92
3. Tests at Elevated Temperature and/or Extremes of Humidity.......................................................... 92
C. Additional Considerations....................................................................................................................... 92
References.............................................................................................................................................................. 92

Chapter 13 EU Guidelines to Good Manufacturing Practice Medicinal Products for

Human and Veterinary Use.................................................................................................................................... 93
I. Introduction...................................................................................................................................................... 93
Part I: Chapter 1: Quality Management.......................................................................................................... 94
Principle������������������������������������������������������������������������������������������������������������������������������������������������� 94
Quality Assurance................................................................................................................................... 94
Good Manufacturing Practice for Medicinal Products (GMP)............................................................... 94
Quality Control....................................................................................................................................... 95
Product Quality Review.......................................................................................................................... 95
Quality Risk Management...................................................................................................................... 96
Chapter 2: Personnel....................................................................................................................................... 96
Principle������������������������������������������������������������������������������������������������������������������������������������������������� 96
General��������������������������������������������������������������������������������������������������������������������������������������������������� 96
Key Personnel���������������������������������������������������������������������������������������������������������������������������������������� 96
Training�������������������������������������������������������������������������������������������������������������������������������������������������� 97
Personnel Hygiene.................................................................................................................................. 97
Chapter 3: Premises and Equipment............................................................................................................... 98
Principle������������������������������������������������������������������������������������������������������������������������������������������������� 98
Premises������������������������������������������������������������������������������������������������������������������������������������������������� 98
Production Area�������������������������������������������������������������������������������������������������������������������������������������� 98
Storage Areas����������������������������������������������������������������������������������������������������������������������������������������� 99
Quality Control Areas���������������������������������������������������������������������������������������������������������������������������� 99
Ancillary Areas�������������������������������������������������������������������������������������������������������������������������������������� 99
Equipment���������������������������������������������������������������������������������������������������������������������������������������������� 99
Contents xiii

Chapter 4: Documentation.............................................................................................................................. 99
Principle������������������������������������������������������������������������������������������������������������������������������������������������� 99
General��������������������������������������������������������������������������������������������������������������������������������������������������� 99
Specifications for Starting and Packaging Materials............................................................................ 100
Specifications for Intermediate and Bulk Products............................................................................... 100
Specifications for Finished Products..................................................................................................... 100
Manufacturing Formula and Processing Instructions........................................................................... 100
Packaging Instructions...........................................................................................................................101
Batch Processing Records......................................................................................................................101
Batch Packaging Records.......................................................................................................................101
Procedures and Records.........................................................................................................................101
Sampling���������������������������������������������������������������������������������������������������������������������������������������������� 102
Testing�������������������������������������������������������������������������������������������������������������������������������������������������� 102
Other����������������������������������������������������������������������������������������������������������������������������������������������������� 102
Chapter 5: Production................................................................................................................................... 102
Principle����������������������������������������������������������������������������������������������������������������������������������������������� 102
General������������������������������������������������������������������������������������������������������������������������������������������������� 102
Prevention of Cross-Contamination in Production������������������������������������������������������������������������������ 103
Validation��������������������������������������������������������������������������������������������������������������������������������������������� 103
Starting Materials��������������������������������������������������������������������������������������������������������������������������������� 103
Processing Operations: Intermediate and Bulk Products��������������������������������������������������������������������� 104
Packaging Materials����������������������������������������������������������������������������������������������������������������������������� 104
Packaging Operations��������������������������������������������������������������������������������������������������������������������������� 104
Finished Products��������������������������������������������������������������������������������������������������������������������������������� 104
Rejected, Recovered, and Returned Materials������������������������������������������������������������������������������������� 104
Chapter 6: Quality Control�������������������������������������������������������������������������������������������������������������������������� 105
Principle����������������������������������������������������������������������������������������������������������������������������������������������� 105
General������������������������������������������������������������������������������������������������������������������������������������������������� 105
Good Quality Control Laboratory Practice������������������������������������������������������������������������������������������ 105
Documentation������������������������������������������������������������������������������������������������������������������������������������� 105
Sampling���������������������������������������������������������������������������������������������������������������������������������������������� 106
Testing�������������������������������������������������������������������������������������������������������������������������������������������������� 106
Ongoing Stability Program������������������������������������������������������������������������������������������������������������������ 106
Chapter 7: Contract Manufacture and Analysis������������������������������������������������������������������������������������������� 107
Principle����������������������������������������������������������������������������������������������������������������������������������������������� 107
General������������������������������������������������������������������������������������������������������������������������������������������������� 107
The Contract Giver������������������������������������������������������������������������������������������������������������������������������� 107
The Contract Acceptor������������������������������������������������������������������������������������������������������������������������� 107
The Contract����������������������������������������������������������������������������������������������������������������������������������������� 108
Chapter 8: Complaints and Product Recall�������������������������������������������������������������������������������������������������� 108
Principle����������������������������������������������������������������������������������������������������������������������������������������������� 108
Complaints������������������������������������������������������������������������������������������������������������������������������������������� 108
Recalls�������������������������������������������������������������������������������������������������������������������������������������������������� 108

Chapter 14 Impurities: Guideline for Residual Solvents........................................................................................................ 109

I.    Introduction................................................................................................................................................. 109
II.   Scope of the Guideline................................................................................................................................ 109
III. General Principles....................................................................................................................................... 109
A. Classification of Residual Solvents by Risk Assessment.................................................................... 109
B. Methods for Establishing Exposure Limits..........................................................................................110
C. Options for Describing Limits of Class 2 Solvents..............................................................................110
D. Analytical Procedures...........................................................................................................................111
E. Reporting Levels of Residual Solvents.................................................................................................111
IV. Limits of Residual Solvents..........................................................................................................................112
A. Solvents to Be Avoided........................................................................................................................112
B. Solvents to Be Limited.........................................................................................................................112
xiv Contents

C. Solvents with Low Toxic Potential.......................................................................................................112

D. Solvents for Which No Adequate Toxicological Data Were Found.....................................................112
Glossary.................................................................................................................................................................112
Appendix 1 List of Solvents Included in the Guideline.....................................................................................113
Appendix 2 Additional Background...................................................................................................................115
A2.1 Environmental Regulation of Organic Volatile Solvents..................................................................115
A2.2 Residual Solvents in Pharmaceuticals..............................................................................................115
Appendix 3 Methods for Establishing Exposure Limits....................................................................................115

Chapter 15 Electronic Records and Signatures (CFR 21 Part 11 Compliance).......................................................................117

Sec. 11.2 Implementation..............................................................................................................................118
Sec. 11.3 Definitions......................................................................................................................................118
Subpart B: Electronic Records..............................................................................................................................118
Sec. 11.10 Controls for Closed Systems........................................................................................................118
Sec. 11.30 Controls for Open Systems..........................................................................................................119
Sec. 11.50 Signature Manifestations.............................................................................................................119
Sec. 11.70 Signature/Record Linking............................................................................................................119
Subpart C: Electronic Signatures..........................................................................................................................119
Sec. 11.100 General Requirements................................................................................................................119
Sec. 11.200 Electronic Signature Components and Controls........................................................................119
Sec. 11.300 Controls for Identification Codes/Passwords............................................................................ 120

Chapter 16 Product-Specific Bioequivalence Testing Protocols............................................................................................. 121

Chapter 17 Formulation Considerations................................................................................................................................. 125

1. Background................................................................................................................................................... 125
2. Ion Resin Complexes..................................................................................................................................... 125
3. Ion Exchange Resins..................................................................................................................................... 125
3.1 Drug Loading....................................................................................................................................... 126
3.2 Coating Drug–Resin Complexes......................................................................................................... 126
4. Cyclodextrins................................................................................................................................................. 127

Chapter 18 Pediatric Pharmaceutical EU Legislation............................................................................................................ 129

Background.......................................................................................................................................................... 129
The Main Points in the Regulation....................................................................................................................... 129
Implications.......................................................................................................................................................... 130

Chapter 19 Pediatric Formulations......................................................................................................................................... 133

Specific Considerations on Formulations for Neonates....................................................................................... 134
Collaboration on Pediatric Formulations............................................................................................................. 134
Conclusions.......................................................................................................................................................... 134
Bibliography......................................................................................................................................................... 135

Chapter 20 SOP and Specification to Establish Electronic Submission to Regulatory Agencies.......................................... 137
1. Purpose.......................................................................................................................................................... 137
2. Scope............................................................................................................................................................. 137
3. Definitions and Abbreviations....................................................................................................................... 137
4. Responsibilities............................................................................................................................................. 137
4.1 Information Technology...................................................................................................................... 137
4.2 Regulatory Affairs................................................................................................................................ 137
4.3 Publishing............................................................................................................................................ 137
Contents xv

5. Materials and Equipment.............................................................................................................................. 137

5.1 Materials.............................................................................................................................................. 137
5.2 Equipment............................................................................................................................................ 138
6. Health and Safety.......................................................................................................................................... 138
7. Procedure....................................................................................................................................................... 138
7.1 Secure E-mail Setup............................................................................................................................ 138
7.2 Requesting a Pre-Assigned Application Number................................................................................ 138
7.3 ESG Account Setup............................................................................................................................. 138
8. References..................................................................................................................................................... 138
9.    Exhibits........................................................................................................................................................ 139
  Exhibit I—Pre-Assigned Application Number Request.............................................................................. 139
  Exhibit II – Sample Letters of Non-Repudiation Agreement...................................................................... 139
10. Revision History.......................................................................................................................................... 139
11. ICH eCTD Specification............................................................................................................................. 139
11.1 Introduction...................................................................................................................................... 139
11.2 Background....................................................................................................................................... 139
11.3 Scope................................................................................................................................................ 139
11.4 Requirements.................................................................................................................................... 140
11.5 Change Control................................................................................................................................. 140
11.5.1 Introduction......................................................................................................................... 140
11.5.2 Process................................................................................................................................ 140
11.5.3 Procedure............................................................................................................................ 140
11.6 Approach to Documentation and Use of the eCTD Specification.....................................................141
Appendix 1: Overall Architecture...........................................................................................................................................143
Appendix 2: The eCTD Submission....................................................................................................................................... 145
Appendix 3: General Considerations for the CTD Modules............................................................................................... 149
Appendix 4: File Organization for the eCTD........................................................................................................................ 157
Appendix 5: Region-Specific Information Including Transmission and Receipt.............................................................. 201
Appendix 6: The eCTD XML Submission............................................................................................................................ 205
Appendix 7: Specification for Submission Formats.............................................................................................................. 213
Appendix 8: XML eCTD DTD................................................................................................................................................217
Appendix 9: Glossary.............................................................................................................................................................. 225
Appendix A: GMP Audit Template........................................................................................................................................ 227
Appendix B: Dissolution Testing............................................................................................................................................ 247
Appendix C: Excipients........................................................................................................................................................... 249

PART II MANUFACTURING FORMULATIONS

Liquid Formulations................................................................................................................................................................ 279

Abacavir Sulfate Oral Solution............................................................................................................................ 279
Acetaminophen, Chlorpheniramine, and Pseudoephedrine Syrup....................................................................... 279
Acetaminophen Drops.......................................................................................................................................... 280
Acetaminophen Oral Suspension......................................................................................................................... 280
Acetaminophen Rectal Solution........................................................................................................................... 281
Acetaminophen Suspension................................................................................................................................. 281
Acetaminophen Syrup.......................................................................................................................................... 281
Acetaminophen Syrup.......................................................................................................................................... 282
Acetaminophen Syrup for Children..................................................................................................................... 282
xvi Contents

Acetaminophen Syrup.......................................................................................................................................... 282

Acetaminophen Syrup.......................................................................................................................................... 283
Acne Scrub........................................................................................................................................................... 283
Acyclovir Oral Suspension (2% = 200 mg/10 mL).............................................................................................. 283
Acyclovir Oral Suspension................................................................................................................................... 284
Acyclovir Oral Suspension................................................................................................................................... 284
Adapalene Solution.............................................................................................................................................. 284
Albendazole Oral Suspension.............................................................................................................................. 284
Albendazole Suspension...................................................................................................................................... 285
Albuterol Inhalation Solution............................................................................................................................... 285
Albuterol Inhalation Solution............................................................................................................................... 285
Alginic Acid + Aluminum Hydroxide + Magnesium Silicate Tablets (500 mg + 100 mg + 25 mg)................... 286
Alpha-Bisabolol Aqueous Mouthwash Solution.................................................................................................. 286
Alpha-Bisabolol Buccal or Topical Solution........................................................................................................ 286
Alpha-Bisabolol Ethanolic Mouthwash Solution................................................................................................. 286
Alpha-Bisabolol Mouthwash Solution................................................................................................................. 286
Aluminum Hydroxide + Magnesium Silicate Chewable Tablets (120 mg + 250 mg)......................................... 287
Aluminum Chloride Solution............................................................................................................................... 287
Aluminum Hydroxide and Magnesium Carbonate Dry Syrup............................................................................. 287
Aluminum Hydroxide and Magnesium Hydroxide Antacid Suspension............................................................. 287
Aluminum Hydroxide and Magnesium Hydroxide Antacid Suspension............................................................. 288
Aluminum Hydroxide and Magnesium Hydroxide Suspension.......................................................................... 288
Aluminum Hydroxide and Magnesium Hydroxide Suspension.......................................................................... 289
Aluminum Hydroxide and Magnesium Hydroxide Suspension.......................................................................... 289
Aluminum Hydroxide and Magnesium Hydroxide Suspension.......................................................................... 289
Aluminum Hydroxide and Magnesium Hydroxide Suspension.......................................................................... 289
Aluminum Hydroxide and Magnesium Hydroxide Suspension.......................................................................... 290
Aluminum Hydroxide and Magnesium Hydroxide Suspension.......................................................................... 290
Aluminum Hydroxide and Magnesium Hydroxide Suspension.......................................................................... 291
Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Suspension................................................... 291
Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Suspension................................................... 291
Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Suspension................................................... 291
Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Suspension................................................... 292
Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Tablets.......................................................... 292
Aminacrine Hydrochloride Topical Solution....................................................................................................... 293
Amoxicillin Powder for Suspension..................................................................................................................... 293
Amoxicillin–Clavulanate Syrup........................................................................................................................... 293
Amoxicillin–Clavulanate Syrup........................................................................................................................... 294
Ampicillin Powder for Suspension....................................................................................................................... 294
Ampicillin Powder for Suspension....................................................................................................................... 294
Ampicillin and Cloxacillin Oily Suspension........................................................................................................ 295
Amprenavir Capsules........................................................................................................................................... 295
Amprenavir Capsules........................................................................................................................................... 295
Amprenavir Oral Solution.................................................................................................................................... 295
Anise Oil Solution................................................................................................................................................ 295
Antipyrine and Benzocaine Elixir........................................................................................................................ 295
Antiseptic Wet Wipes........................................................................................................................................... 296
Apraclonidine Hydrochloride Ophthalmic Solution............................................................................................ 296
Ascorbic Acid Solution........................................................................................................................................ 296
Atovaquone Suspension....................................................................................................................................... 296
Atovaquone Suspension....................................................................................................................................... 296
Azelastine Hydrochloride Nasal Spray................................................................................................................ 296
Azelastine Hydrochloride Nasal Spray................................................................................................................ 297
Azithromycin Suspension.................................................................................................................................... 297
Azithromycin Suspension.................................................................................................................................... 298
Azulene Solution.................................................................................................................................................. 298
Contents xvii

Azulene Solution (1%)......................................................................................................................................... 298

Barium Sulfate Oral Suspension.......................................................................................................................... 298
Beclomethasone Dipropionate Inhalation Aerosol............................................................................................... 298
Beclomethasone Dipropionate Inhalation Aerosol............................................................................................... 298
Beclomethasone Dipropionate and Salbutamol Sulfate Nasal Spray................................................................... 299
Benzethonium Chloride Solution......................................................................................................................... 299
Benzethonium Chloride and Benzocaine Topical Anesthetic.............................................................................. 299
Benzocaine and Tetracaine Topical Solution........................................................................................................ 299
Benzyl Benzoate Solution.................................................................................................................................... 299
Beta-Estradiol Vaginal Solution........................................................................................................................... 299
Betamethasone Syrup........................................................................................................................................... 300
Bismuth Carbonate Suspension............................................................................................................................ 300
Bismuth Subsalicylate Suspension....................................................................................................................... 300
Bromazepam Drops.............................................................................................................................................. 300
Bromhexine Hydrochloride Syrup....................................................................................................................... 301
Bromhexine Hydrochloride Syrup—Alcohol Free.............................................................................................. 301
Bromhexine Hydrochloride Syrup....................................................................................................................... 302
Budesonide Inhaler............................................................................................................................................... 302
Butamirate Citrate Syrup...................................................................................................................................... 303
Caffeine Citrate Oral Solution.............................................................................................................................. 303
Calcipotriene Solution.......................................................................................................................................... 303
Calcitonin Nasal Spray......................................................................................................................................... 303
Calcitonin Nasal Spray......................................................................................................................................... 303
Calcium Carbonate and Guar Gum Suspension................................................................................................... 303
Calcium Iodide and Ascorbic Acid Syrup............................................................................................................ 304
Carbamazepine Oral Suspension 2%................................................................................................................... 305
Carbetapentane Tannate and Chlorpheniramine Suspension............................................................................... 305
Carnitine and Coenzyme Q Solution.................................................................................................................... 305
Cefaclor Suspension............................................................................................................................................. 305
Cefadroxil Monohydrate Oral Suspension........................................................................................................... 305
Cefpodoxime Proxetil Oral Suspension............................................................................................................... 305
Cefpodoxime Proxetil Oral Suspension............................................................................................................... 306
Cefpodoxime Proxetil for Oral Suspension.......................................................................................................... 306
Cefuroxime Axetil Suspension............................................................................................................................. 306
Cetirizine Hydrochloride Syrup........................................................................................................................... 306
Chlophedianol, Ipecac, Ephedrine, Ammonium Chloride, Carbinoxamine, and Balsam Tolu Syrup................. 307
Chlophedianol, Ipecac, Ephedrine, Ammonium Chloride, Carbinoxamine, and Balsam Tolu Syrup................. 307
Chloramphenicol Palmitate Oral or Topical Emulsion (2.5% = 250 mg/10 mL)................................................ 308
Chloramphenicol Palmitate Oral or Topical Emulsion (5% = 500 mg/10 mL)................................................... 308
Chloramphenicol Ophthalmic Solution................................................................................................................ 308
Chloramphenicol Palmitate Oral or Topical Emulsion........................................................................................ 308
Chlorhexidine Gel................................................................................................................................................ 309
Chlorpheniramine Maleate Syrup........................................................................................................................ 309
Chloroxylenol Surgical Scrub.............................................................................................................................. 309
Ciclopirox Topical Solution................................................................................................................................. 309
Cimetidine Syrup...................................................................................................................................................310
Ciprofloxacin Hydrochloride and Hydrocortisone Otic Suspension.....................................................................310
Cisapride Suspension............................................................................................................................................311
Citalopram Hydrobromide Oral Solution..............................................................................................................311
Clarithromycin Suspension, 125 mg/5 ml reconstituted.......................................................................................311
Clindamycin Phosphate Topical Solution.............................................................................................................312
Clotrimazole Topical Solution...............................................................................................................................312
Clotrimazole Topical Solution (3%)......................................................................................................................312
Codeine Phosphate and Acetaminophen Elixir.....................................................................................................312
Colistin Sulfate, Neomycin, Thonzonium Bromide, and Hydrocortisone Otic Suspension.................................312
Cotrimoxazole Oral Suspension............................................................................................................................313
xviii Contents

Cromolyn Sodium Nasal Spray.............................................................................................................................313

Cromolyn Sodium Oral Concentrate.....................................................................................................................313
Crospovidone Oral Suspension (2000 mg/10 mL)................................................................................................314
Cyclosporin Oral Solution.....................................................................................................................................314
Cyclosporin Soft Gelatin Capsules.......................................................................................................................314
Desmopressin Acetate Nasal Spray.......................................................................................................................314
Dexamethasone Elixir...........................................................................................................................................314
Dextromethorphan and Chlorpheniramine Maleate Solution...............................................................................314
Dextromethorphan, Pseudoephedrine, and Chlorpheniramine Maleate Syrup.....................................................315
Dextromethorphan Liquid.....................................................................................................................................315
Dextromethorphan Liquid.....................................................................................................................................316
Dextromethorphan, Pseudoephedrine, and Chlorpheniramine Maleate Syrup.....................................................316
Dextromethorphan Solution..................................................................................................................................316
Diazepam Rectal Solution.....................................................................................................................................317
Diclofenac Oral Solution.......................................................................................................................................317
Didanosine for Oral Solution................................................................................................................................317
Digoxin Elixir Pediatric........................................................................................................................................317
Dihydroergotamine Mesylate Drops.....................................................................................................................317
Diphenhydramine and Ammonium Chloride Syrup..............................................................................................318
Diphenhydramine Hydrochloride Liquid..............................................................................................................318
Dornase-Alpha Inhalation Solution.......................................................................................................................319
Doxercalciferol Capsules......................................................................................................................................319
Dyphylline, Guaifenesin Elixir.............................................................................................................................319
Electrolyte Lavage Solution..................................................................................................................................319
Eplerenone Solution..............................................................................................................................................319
Erythromycin Drops..............................................................................................................................................319
Erythromycin Topical Solution............................................................................................................................ 320
Estradiol Nasal Spray........................................................................................................................................... 320
Ethchlorvynol Gelatin Capsule (200 mg)............................................................................................................. 321
Eucalyptol Solution.............................................................................................................................................. 321
Eucalyptol Solution (8%)..................................................................................................................................... 321
Eucalyptus and Mint Emulsion............................................................................................................................ 321
Fentanyl Citrate Nasal Spray................................................................................................................................ 321
Ferrous Sulfate Oral Solution............................................................................................................................... 322
Ferrous Sulfate Oral Syrup................................................................................................................................... 322
Fir Needle Oil Solution........................................................................................................................................ 322
Fluconazole Oral Suspension............................................................................................................................... 323
Flunisolide Spray.................................................................................................................................................. 323
Fluocinonide Topical Solution............................................................................................................................. 323
Fluorouracil Solution............................................................................................................................................ 323
Fluorouracil Topical Solution............................................................................................................................... 323
Fluticasone Suspension Spray.............................................................................................................................. 323
Foot Bath.............................................................................................................................................................. 323
Furosemide Syrup................................................................................................................................................ 323
Gabapentin Oral Solution..................................................................................................................................... 324
Galantamine Hydrobromide Oral Solution.......................................................................................................... 324
Glucose, Fructose, and Phosphoric Acid Antiemetic Solution............................................................................. 324
Glycol Foam, Nonaqueous................................................................................................................................... 324
Gramicidin Ophthalmic Solution......................................................................................................................... 324
Guaifenesin, Pseudoephedrine, Carbinoxamine, and Chlophedianol Drops....................................................... 324
Haloperidol Oral Liquid....................................................................................................................................... 325
Heparin Nasal Spray............................................................................................................................................. 325
Hydrocodone Bitartrate Elixir.............................................................................................................................. 325
Hydroxyzine Pamoate Oral Suspension............................................................................................................... 325
Hyoscine Butylbromide Syrup............................................................................................................................. 326
Hyoscyamine Sulfate Elixir.................................................................................................................................. 326
Contents xix

Ibuprofen Topical Solution................................................................................................................................... 326

Ibuprofen Pediatric Suspension............................................................................................................................ 326
Iron Infant Drops.................................................................................................................................................. 327
Iron Polystyrene and Vitamin C Syrup................................................................................................................. 327
Ibuprofen Solution................................................................................................................................................ 328
Ibuprofen Suspension........................................................................................................................................... 328
Ibuprofen Suspension, Sugar Free........................................................................................................................ 328
Ibuprofen and Domperidone Maleate Suspension............................................................................................... 329
Insulin Inhalation Spray....................................................................................................................................... 329
Ipratropium Bromide Inhalation Solution............................................................................................................ 329
Ipratropium Bromide Nasal Spray....................................................................................................................... 329
Isoproterenol Sulfate and Calcium Iodide Syrup................................................................................................. 330
Isotretinoin Capsules............................................................................................................................................ 330
Itraconazole Oral Solution................................................................................................................................... 330
Kaolin, Pectin, and Aluminum Hydroxide Suspension........................................................................................ 330
Kaolin–Pectin Suspension.....................................................................................................................................331
Kaolin–Pectin Suspension.....................................................................................................................................331
Ketoprofen Topical Solution................................................................................................................................ 332
Ketotifen Syrup.................................................................................................................................................... 332
Lamivudine Oral Solution.................................................................................................................................... 332
Levalbuterol Hydrochloride Inhalation Solution.................................................................................................. 332
Levocarnitine Oral Solution................................................................................................................................. 332
Linezolid for Oral Suspension.............................................................................................................................. 332
Lithium Carbonate Solution................................................................................................................................. 332
Lithium Citrate Syrup........................................................................................................................................... 333
Lomustine Nasal Spray........................................................................................................................................ 333
Loracarbef for Oral Suspension........................................................................................................................... 333
Loratadine Syrup.................................................................................................................................................. 333
Mafenide Acetate Topical Solution...................................................................................................................... 333
Magaldrate Instant Powder for Dry Syrup........................................................................................................... 333
Magaldrate Suspension........................................................................................................................................ 334
Magaldrate with Simethicone Suspension........................................................................................................... 334
Magaldrate with Simethicone Suspension........................................................................................................... 335
Mebendazole Oral Suspension............................................................................................................................. 335
Mebendazole Suspension..................................................................................................................................... 336
Megestrol Acetate Oral Suspension..................................................................................................................... 336
Menthol and Benzocaine Solution....................................................................................................................... 336
Menthol Mouthwash............................................................................................................................................ 337
Mesalamine Rectal Suspension Enema................................................................................................................ 337
Mesalamine Rectal Suspension............................................................................................................................ 337
Metformin Liquid................................................................................................................................................. 337
Metoclopramide Oral Solution............................................................................................................................. 337
Metoclopramide Syrup......................................................................................................................................... 338
Metronidazole Suspension................................................................................................................................... 339
Mineral and Multivitamin Syrup.......................................................................................................................... 339
Minoxidil Solution............................................................................................................................................... 340
Mint–Menthol Mouthwash................................................................................................................................... 340
Mint Oil Solution................................................................................................................................................. 341
Mometasone Furoate Nasal Spray........................................................................................................................ 341
Monosulfiram Solution......................................................................................................................................... 341
Multivitamin and Calcium Syrup......................................................................................................................... 341
Multivitamin and Mineral Syrup.......................................................................................................................... 342
Multivitamin Drops.............................................................................................................................................. 343
Multivitamin Infant Drops.................................................................................................................................... 343
Multivitamin Infant Drops.................................................................................................................................... 344
Multivitamin Mineral Syrup................................................................................................................................. 345
xx Contents

Multivitamin Syrup.............................................................................................................................................. 346

Multivitamin Syrup.............................................................................................................................................. 346
Multivitamin with Fluoride Infant Drops............................................................................................................. 347
Multivitamin Drops.............................................................................................................................................. 348
Multivitamin Syrup.............................................................................................................................................. 348
Multivitamin Syrup.............................................................................................................................................. 348
Multivitamin with Fluoride—Infant Drops.......................................................................................................... 349
Nafarelin Acetate Nasal Solution......................................................................................................................... 349
Naproxen Suspension........................................................................................................................................... 349
Nevirapine Suspension......................................................................................................................................... 350
Nicotine Spray...................................................................................................................................................... 350
Nimesulide Suspension........................................................................................................................................ 350
Nimodipine Capsules........................................................................................................................................... 350
Nitroglycerin Lingual Spray................................................................................................................................. 350
Norephedrine Syrup............................................................................................................................................. 350
Norephedrine Syrup..............................................................................................................................................351
Nystatin Oral Suspension......................................................................................................................................351
Nystatin Suspension..............................................................................................................................................351
Ofloxacin Otic Solution........................................................................................................................................ 352
Omeprazole Solution............................................................................................................................................ 352
Ondansetron Hydrochloride Dihydrate Oral Solution......................................................................................... 352
Orciprenaline Sulfate and Clobutinol Hydrochloride Syrup................................................................................ 352
Oxitropium and Formoterol Nasal Spray............................................................................................................. 353
Oxymetazoline Hydrochloride Nasal Solution.................................................................................................... 353
Oxymetazoline Moisturizing Nasal Spray........................................................................................................... 353
Oxymetazoline Nasal Spray................................................................................................................................. 353
Oxymetazoline Sinus Nasal Spray....................................................................................................................... 353
Oxymetazoline Nasal Solution............................................................................................................................. 354
Peptide Topical Liquid......................................................................................................................................... 354
Pheniramine Maleate Syrup................................................................................................................................. 354
Phenobarbital, Hyoscyamine Sulfate, Atropine Sulfate, and Scopolamine Hydrobromide Elixir....................... 354
Phenylephrine Tannate and Chlorpheniramine Tannate Pediatric Suspension..................................................... 354
Phenylephrine Tannate and Pyrilamine Tannate Suspension............................................................................... 354
Phenylpropanolamine, Chlorpheniramine, Dextromethorphan, and Vitamin C Syrup........................................ 355
Phenylpropanolamine, Chlorpheniramine, Dextromethorphan, and Vitamin C Syrup........................................ 356
Phenylpropanolamine Controlled-Release Capsules............................................................................................ 357
Phenytoin Suspension........................................................................................................................................... 357
Phenytoin Suspension........................................................................................................................................... 357
Pipenzolate Methyl Bromide and Phenobarbital Drops....................................................................................... 357
Podofilox Solution................................................................................................................................................ 357
Polidocanol Wound Spray.................................................................................................................................... 358
Polyvinylpyrrolidone–Iodine Gargle Solution..................................................................................................... 358
Polyvinylpyrrolidone–Iodine Gargle Solution Concentrate................................................................................. 358
Polyvinylpyrrolidone–Iodine Liquid Spray.......................................................................................................... 358
Polyvinylpyrrolidone–Iodine Mouthwash............................................................................................................ 359
Polyvinylpyrrolidone–Iodine Mouthwash and Gargle Solution Concentrate...................................................... 359
Polyvinylpyrrolidone–Iodine Scrub..................................................................................................................... 359
Polyvinylpyrrolidone–Iodine Solution................................................................................................................. 360
Polyvinylpyrrolidone–Iodine Solution................................................................................................................. 360
Polyvinylpyrrolidone–Iodine Solution................................................................................................................. 360
Polyvinylpyrrolidone–Iodine Solution................................................................................................................. 360
Polyvinylpyrrolidone–Iodine Solution................................................................................................................. 360
Polyvinylpyrrolidone–Iodine Surgical Scrub....................................................................................................... 361
Polyvinylpyrrolidone–Iodine Surgical Scrub....................................................................................................... 361
Polyvinylpyrrolidone–Iodine Vaginal Douche Concentrate................................................................................. 361
Polyvinylpyrrolidone–Iodine Viscous Solution.................................................................................................... 362
Contents xxi

Polyvinylpyrrolidone–Iodine Mouthwash............................................................................................................ 362

Povidone–Iodine Concentrates for Broilers and Cattle........................................................................................ 362
Povidone–Iodine Foam Spray.............................................................................................................................. 362
Povidone–Iodine Gargle....................................................................................................................................... 362
Povidone–Iodine Gargle Solution Concentrate.................................................................................................... 363
Povidone–Iodine Liquid Spray............................................................................................................................. 363
Povidone–Iodine Mouthwash and Gargle Solution Concentrate......................................................................... 363
Povidone–Iodine Powder Spray........................................................................................................................... 363
Povidone–Iodine Pump Spray.............................................................................................................................. 364
Povidone–Iodine Shampoo................................................................................................................................... 364
Povidone–Iodine Solution.................................................................................................................................... 364
Povidone–Iodine Solution.................................................................................................................................... 365
Povidone–Iodine Solution.................................................................................................................................... 365
Povidone–Iodine Solution.................................................................................................................................... 365
Povidone–Iodine Solution.................................................................................................................................... 365
Povidone–Iodine Scrub........................................................................................................................................ 365
Povidone–Iodine Surgical Scrub.......................................................................................................................... 366
Povidone–Iodine Surgical Scrub.......................................................................................................................... 366
Povidone–Iodine Vaginal Douche Concentrate.................................................................................................... 366
Povidone–Iodine Viscous Solution....................................................................................................................... 367
Prednisone Oral Solution..................................................................................................................................... 367
Prednisolone Sodium Phosphate Oral Solution................................................................................................... 367
Prednisolone Syrup.............................................................................................................................................. 367
Progesterone Capsules.......................................................................................................................................... 367
Promethazine and Codeine Syrup........................................................................................................................ 367
Promethazine and Dextromethorphan Syrup....................................................................................................... 367
Promethazine Hydrochloride Syrup..................................................................................................................... 367
Promethazine Hydrochloride Syrup..................................................................................................................... 368
Promethazine Rectal Solution.............................................................................................................................. 368
Promethazine Rectal Solution.............................................................................................................................. 368
Pseudoephedrine Hydrochloride Syrup................................................................................................................ 369
Pseudoephedrine Hydrochloride and Carbinoxamine Maleate Oral Drops......................................................... 369
Pseudoephedrine and Carbinoxamine Drops....................................................................................................... 370
Pseudoephedrine Hydrochloride Syrup................................................................................................................ 370
Ribavirin Inhalation Solution............................................................................................................................... 371
Risperidone Oral Solution.................................................................................................................................... 371
Ritonavir Capsules............................................................................................................................................... 371
Ritonavir Oral Solution........................................................................................................................................ 371
Ritonavir and Lopinavir Oral Solution................................................................................................................. 371
Rivastigmine Tartrate Oral Solution..................................................................................................................... 371
Salbutamol Aerosol.............................................................................................................................................. 371
Salbutamol Syrup Sugar Free............................................................................................................................... 372
Salbutamol Syrup................................................................................................................................................. 372
Salicylic Acid Collodion...................................................................................................................................... 372
Salmeterol Xinafoate Inhalation Aerosol............................................................................................................. 372
Salmeterol Xinafoate Inhalation Aerosol............................................................................................................. 373
Scopolamine Nasal Spray..................................................................................................................................... 373
Selenium Sulfide Shampoo with Conditioner...................................................................................................... 373
Sertraline Hydrochloride Oral Concentrate.......................................................................................................... 374
Sertraline Hydrochloride Solution....................................................................................................................... 374
Simethicone Drops............................................................................................................................................... 374
Sirolimus Solution................................................................................................................................................ 375
Sodium Chloride Nasal Drops.............................................................................................................................. 375
Stavudine for Oral Suspension............................................................................................................................. 375
Sucralfate Suspension........................................................................................................................................... 375
Sulfacetamide Sodium and Sulfur Cleanser and Suspension............................................................................... 375
xxii Contents

Sulfadiazine and Trimethoprim Veterinary Oral Suspension............................................................................... 376

Sulfamethoxazole and Trimethoprim Suspension................................................................................................ 376
Sulfamethoxazole and Trimethoprim Suspension................................................................................................ 377
Sulfathiazole Veterinary Oral Solution................................................................................................................. 377
Sulfidoxine Solution............................................................................................................................................. 377
Sulfidoxine and Pyrimethamine Suspension........................................................................................................ 377
Sumatriptan Nasal Spray...................................................................................................................................... 378
Terfenadine Oral Suspension................................................................................................................................ 378
Terfenadine Suspension........................................................................................................................................ 378
Theophylline Sodium Glycinate Elixir................................................................................................................ 379
Thiabendazole Suspension................................................................................................................................... 379
Thiothixene Oral Concentrate.............................................................................................................................. 379
Timolol Maleate Ophthalmic Drops..................................................................................................................... 379
Tolnaftate Foot Care Microemulsion.................................................................................................................... 379
Tolu Balsam Cough Syrup................................................................................................................................... 380
Tretinoin Solution (50 mg/100 g)......................................................................................................................... 381
Tretinoin Solution................................................................................................................................................. 381
Triamcinolone Acetonide Nasal Spray................................................................................................................. 381
Triclosan Oral Solution........................................................................................................................................ 382
Triprolidine and Pseudoephedrine Hydrochloride Syrup..................................................................................... 382
Tulobuterol Syrup................................................................................................................................................. 382
Tolnaftate Foot Care Microemulsion.................................................................................................................... 383
Triprolidine and Pseudoephedrine Hydrochloride Syrup..................................................................................... 383
Undecylenic Acid and Chloroxylenol Solution.................................................................................................... 383
Urea Peroxide Ear Drops...................................................................................................................................... 383
Valproic Acid Capsules........................................................................................................................................ 384
Valproic Acid Syrup............................................................................................................................................. 384
Vancomycin Hydrochloride Oral Solution........................................................................................................... 384
Vitamin A and Vitamin D Infant Drops................................................................................................................ 384
Vitamin A and D Infant Drops............................................................................................................................ 385
Vitamin A and Vitamin D3 Drops....................................................................................................................... 385
Vitamin A and Vitamin D3 Oral Solution........................................................................................................... 385
Vitamin A and Vitamin D3 Syrup....................................................................................................................... 386
Vitamin A and Vitamin E Drops......................................................................................................................... 386
Vitamin A and Vitamin E Drops......................................................................................................................... 386
Vitamin A and Vitamin E Drops......................................................................................................................... 386
Vitamin A Concentrate, Water-Miscible.............................................................................................................. 386
Vitamin A Drops.................................................................................................................................................. 387
Vitamin B Complex Syrup................................................................................................................................... 387
Vitamin B Complex Syrup................................................................................................................................... 387
Vitamin B Complex and Vitamin C Syrup.......................................................................................................... 388
Vitamin B Complex (without B12) Syrup............................................................................................................ 388
Vitamin B Complex, A, C, D, and Calcium Drops.............................................................................................. 389
Vitamin B Complex and Iron Syrup.................................................................................................................... 390
Vitamin B Complex and Vitamin C Syrup.......................................................................................................... 391
Vitamin B Complex, A, C, and D Syrup............................................................................................................. 391
Vitamin B Complex, Vitamin A, Vitamin C, Vitamin D, and Vitamin E Pediatric Drops................................ 392
Vitamin B Complex, Vitamin C, and Iron Syrup................................................................................................ 393
Vitamin C Drops.................................................................................................................................................. 393
Vitamin E and Benzocaine Solution.................................................................................................................... 394
Vitamin E Concentrate, Water-Miscible.............................................................................................................. 394
Vitamin E Drops.................................................................................................................................................. 394
Vitamin E Soft Gel Capsules............................................................................................................................... 394
Vitamin E Solution with Ethanol......................................................................................................................... 394
Contents xxiii

Xylometazoline Hydrochloride Nasal Solution.................................................................................................... 395

Xylometazoline Hydrochloride Children’s Nasal Solution.................................................................................. 395
Zinc Pyrithione Shampoo..................................................................................................................................... 395

PART III Commercial Pharmaceutical Products

Commercial Pharmaceutical Products.................................................................................................................................. 399

Index.......................................................................................................................................................................................... 407
Preface to the Series—Third Edition
I am humbled by the wide praise and acceptance of the last two semisolid product volume also includes details on chewing
editions of the Handbook of Pharmaceutical Formulations, a gum delivery systems.
six-volume series that found home in the R&D laboratories of The updating of formulations is always cumulative as
just about every pharmaceutical company, both generic and there is little need to remove any formulation provided previ-
branded, and in the classrooms of pharmaceutical technol- ously—if it was right then, it shall remain good now. However,
ogy; and the regulatory agencies used this treatise to compare a variety of new drug delivery systems have evolved since the
the quality of pharmaceutical products. In creating this work, second edition was published, so I have included more details
back in 2004, my primary objective was to provide a ready on these formulations, although some of these may not be
source of safe and scalable generic and new pharmaceutical available to practice due to possible limitations on the intel-
formulations that take a long time to develop and incur a sub- lectual property.
stantial cost, to enable the availability of affordable medicines. As always, I advise the formulators to be aware of any
Each of the six volumes in the series has a structured con- intellectual property infringements as I cannot provide a
tent. Part I includes regulatory guidance, formulation steps, guarantee to this effect.
references to active ingredients and excipients, and a self- Finally, I wish to acknowledge the leaders of the pharma-
audit guidance for cGMP compliance. Chapters of common ceutical world, to whom each of the volumes is dedicated.
interest to all volumes are distributed across the six volumes, I have made a few changes to those whom the volumes are
such as the formulations for coating solutions are presented in dedicated, to recognize those who have since passed away;
Volume 5 (OTC), though they are also pertinent to Volume 1 they provided a role model to me and thousands of leaders
(Compressed Dosage Forms), and global bioequivalence test- and students of pharmacy over the decades of their careers.
ing guidelines are provided in Volume 4 (Semisolids), though They are gone, but not without leaving an indelible mark on
they apply to all volumes. Part II includes scalable formula- the profession.
tions and Part III, where applicable, other general formula- I also consider myself fortunate to have the sponsorship
tions. The appendices include a listing of excipients used in and assistance of the great folks at the CRC Press, more
FDA approved products and a cGMP compliance self-testing particularly Jessica Poile and Hilary LaFoe. The teams at
tool. Whereas the main focus of the guidance provided in the the CRC Press were very kind to put up with my redun-
handbook pertains to compliance with FDA requirements, dant changes to the manuscript and were extremely gener-
these apply equally to EU requirements, and, as a result, to ous in their advice in balancing the scientific and practical
any global agency. knowledge and, above all, making sure that the book was
The third edition also gets several significant additions; framed and published in the highest professional presenta-
now each volume includes a self-audit template, several chap- tion. As always, I take responsibility for any mistakes and
ters advising how to stay cGMP compliant, including a listing errors in my writing, and I am always open to suggestions
of most common FDA citations to look out for in the audits, a by the readers to make future editions. I can be contacted at
global regulatory focus and an updated list of excipients and [email protected].
the level of their incorporation in the FDA-approved products.
The number of formulations is also increased, and the OTC Sarfaraz K. Niazi, Ph.D.
volume now contains several cosmetic formulations, and the Deerfield, Illinois, U.S.A.

xxv
Preface to the Series—Second Edition
The science and the art of pharmaceutical formulation keeps and this applies to all information contained in this
evolving as new materials, methods, and machines become book. The freedom of information act (FOIA) is an
readily available to produce more reliable, stable, and release- extremely useful conduit for reliable information and
controlled formulations. At the same time, globalization of manufacturers are strongly urged to make use of this
sourcing of raw and finished pharmaceuticals brings chal- information. Whereas this information is provided
lenges to regulatory authorities and results in more frequent free of charge, the process of obtaining the informa-
revisions to the current good manufacturing practices, regula- tion may be cumbersome, in which case, commercial
tory approval dossier requirements, and the growing need for sources of these databases can prove useful, particu-
cost optimization. Since the publication of the first edition of larly for the non-U.S. companies.
this book, a lot has changed in all of these areas of importance 6. Also included are the new Good Manufacturing
to pharmaceutical manufacturers. The second edition builds Guidelines (2007) with amendments (2008) for the
on the dynamic nature of the science and art of formulations United States and similar updates for European
and provides an evermore useful handbook that should be Union and WHO; it is strongly urged that the com-
highly welcomed by the industry, the regulatory authorities, panies discontinue using all old documents as there
as well as the teaching institutions. are significant changes in the revised form, and
The first edition of this book was a great success as it many of them are likely to reduce the cost of GMP
brought under one umbrella the myriad of choices available compliance.
to formulators. The readers were very responsive and com- 7. Details on design of clean rooms is a new entry that
municated with me frequently pointing out to the weaknesses will be of great use to sterile product manufactur-
as well as the strengths of the book. The second edition totally ers; whereas the design and flow of personnel and
revised attempts to achieve these by making major changes to material flow is of critical nature, regulatory agen-
the text, some of which include: cies view these differently and the manufacturer
is advised always to comply with most stringent
1. Complete, revised errors corrected and subject mat- requirements.
ter reorganized for easy reference. Whereas this 8. Addition of a self-auditing template in each volume
series has six volumes differentiated on the basis of of the series. While the cGMP compliance is a com-
the type of dosage form and a separate inclusion of plex issue and the requirements diversified across
the U.S. OTC products, ideally the entire collection the globe, the basic compliance remains universal. I
is needed to benefit from the myriad of topics relat- have chosen the European Union guidelines (as these
ing to formulations, regulatory compliance, and dos- are more in tune with the ICH) to prepare a self-audit
sier preparation. module that I recommend that every manufacturer
2. Total number of pages is increased from 1684 adopt as a routine to assure GMP compliance. In
to 2726. most instances reading the template by those respon-
3. Total number of formulations is expanded by about sible for compliance with keep them sensitive to the
30% with many newly approved formulations. needs of GMP.
4. Novel formulations are now provided for a variety 9. OTC products cross-referenced in other volumes
of drugs; these data are collected from the massive where appropriate. This was necessary since the
intellectual property data and suggest toward the regulatory authorities worldwide define this class of
future trend of formulations. While some of these drug differently. It is important to iterate that regard-
formulations may not have been approved in the less of the prescription or the OTC status of a prod-
United States or Europe, these do provide additional uct, the requirements for compliance with the cGMP
choices, particularly for the NDA preparation. As apply equally.
always, it is the responsibility of the manufacturer 10. OTC monograph status is a new section added to the
to assure that the intellectual property rights are not OTC volume and this should allow manufacturers to
violated. chose appropriate formulations that may not require
5. A significant change in this edition is the inclusion a filing with the regulatory agencies; it is important
of commercial products; while most of this informa- to iterate that an approved OTC monograph includes
tion is culled out from the open source such as the details of formulation including the types and quan-
FOIA (http://www.fda.gov/foi/default.htm), I have tities of active drug and excipients, labeling, and
made attempts to reconstruct the critical portions presentation. To qualify the exemption, the manufac-
of it based on what I call the generally acceptable turer must comply with the monograph in its entirety.
standards. The drug companies are advised to assure However, subtle modifications that are merely cos-
that any intellectual property rights are not violated metic in nature and where there is an evidence that

xxvii
xxviii Preface to the Series—Second Edition

the modification will not affect the safety and effi- therefore included, as an appendix to each volume,
cacy of the products can be made but require prior a list of all excipients that are currently approved by
approval of the regulatory agencies and generally the U.S. FDA along their appropriate levels. I suggest
these approvals are granted. that a formulator consult this table before deciding
11. Expanded discussion on critical factors in the man- on which level of excipient to use; it does not mean
ufacturing of formulations provided; from basic that the excipient cannot be used outside this range
shortcuts to smart modifications now extend to all but it obviates the need for a validation and lengthy
dosage forms. Pharmaceutical compounding is one justification studies in the submission of NDAs.
of the oldest professions and whereas the art of 14. Expanded section on bioequivalence submission
formulations has been relegated to more objective was required to highlight the recent changes in these
parameters, the art nevertheless remains. An expe- requirements. New entries include a comprehensive
rienced formulator, like an artist, would know what listing of bioequivalence protocols in abbreviated
goes with what and why; he avoids the pitfalls and form as approved by the U.S. FDA; these descrip-
stays with conservative choices. These sections of tions are provided in each volume where pertinent.
the book present advice that is time tested, although To receive approval for an ANDA, an applicant must
it may appear random at times; this is intended for generally demonstrate, among other things, equiva-
experienced formulators. lence of the active ingredient, dosage form, strength,
12. Expanded details on critical steps in the manufactur- route of administration and conditions of use as the
ing processes provided but to keep the size of the listed drug, and that the proposed drug product is
book manageable, and these are included for proto- bioequivalent to the reference listed drug [21 USC
type formulations. The reader is advised to browse 355(j)(2)(A); 21 CFR 314.94(a)]. Bioequivalent drug
through similar formulations to gain more insight. products show no significant difference in the rate
Where multiple formulations are provided for the and extent of absorption of the therapeutic ingredient
same drug, it intended to show the variety of pos- [21 U.S.C. 355(j)(8); 21 CFR 320.1(e)]. BE studies are
sibilities in formulating a drug and whereas it per- undertaken in support of ANDA submissions with
tains to a single drug, the basic formulation practices the goal of demonstrating BE between a proposed
can be extended to many drugs of same class or even generic drug product and its reference listed drug.
of diversified classes. Readers have often requested The regulations governing BE are provided at 21
that more details be provided in the Manufacturing CFR in part 320. The U.S. FDA has recently begun to
Direction sections. Whereas sufficient details are promulgate individual bioequivalence requirements.
provided, this is restricted to prototype formula- To streamline the process for making guidance
tions to keep the size of the book manageable and to available to the public on how to design product-
reduce redundancy. specific BE studies, the U.S. FDA will be issuing
13. Addition of a listing of approved excipients and the product-specific BE recommendations (www.fda.
level allowed by regulatory authorities. This new gov/cder/ogd/index.htm). To make this vital informa-
section allows formulators a clear choice on which tion available, an appendix to each volume includes
excipients to choose; the excipients are reported in a summary of all currently approved products by the
each volume pertaining to the formulation type cov- U.S. FDA where a recommendation on conducting
ered. The listing is drawn from the FDA-approved bioequivalence studies is made available by the U.S.
entities. For the developers of an ANDA, it is critical FDA. When filing an NDA or an ANDA, the filer is
that the level of excipients be kept within the range faced with the choice of defending the methods used
generally approved to avoid large expense in justi- to justify the bioavailability or bioequivalence data.
fying any unapproved level. The only category for The U.S. FDA now allows application for waiver of
which the listing is not provided separately is the bioequivalence requirement; a new chapter on this
OTC volume since it contains many dosage forms topic has been added along with details of the dis-
and the reader is referred to dosage form–specific solution tests, where applicable, approved for various
title of the series. The choice of excipients forms dosage forms.
keeps increasing with many new choices that can 15. Dissolution testing requirements are included for all
provide many special release characteristics to the dosage forms where this testing is required by the
dosage forms. Choosing correct excipients is thus FDA. Surrogate testing to prove efficacy and compli-
a tedious exercise and requires sophisticated multi- ance is getting more acceptance at regulatory agen-
variate statistical analysis. Whereas the formulator cies; in my experience, a well-designed dissolution
may choose any number of novel or classical compo- test is the best measure of continuous compliance.
nents, it is important to know the levels of excipients Coupled with chapters on waivers of bioequiva-
that are generally allowed in various formulations lence testing, this information on dissolution test-
to reduce the cost of redundant exercises; I have ing should be great value to all manufacturers; it is
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unnerved me in the contemplation of the House of Usher? It was a
mystery all insoluble; nor could I grapple with the shadowy fancies
that crowded upon me as I pondered. I was forced to fall back upon
the unsatisfactory conclusion that while, beyond doubt, there are
combinations of very simple natural objects which have the power of
thus affecting us, still the analysis of this power lies among
considerations beyond our depth. It was possible, I reflected, that a
mere different arrangement of the particulars of the scene, of the
details of the picture, would be sufficient to modify, or perhaps to
annihilate its capacity for sorrowful impression; and, acting upon this
idea, I reined my horse to the precipitous brink of a black and lurid
tarn that lay in unruffled lustre by the dwelling, and gazed down—but
with a shudder even more thrilling than before—upon the remodelled
and inverted images of the gray sedge, and the ghastly tree-stems,
and the vacant and eye-like windows.
Nevertheless, in this mansion of gloom I now proposed to myself
a sojourn of some weeks. Its proprietor, Roderick Usher, had been
one of my boon companions in boyhood; but many years had
elapsed since our last meeting. A letter, however, had lately reached
me in a distant part of the country—a letter from him—which, in its
wildly importunate nature, had admitted of no other than a personal
reply. The MS. gave evidence of nervous agitation. The writer spoke
of acute bodily illness, of a mental disorder which oppressed him,
and of an earnest desire to see me, as his best, and indeed his only
personal friend, with a view of attempting, by the cheerfulness of my
society, some alleviation of his malady. It was the manner in which all
this, and much more, was said—it was the apparent heart that went
with his request—which allowed me no room for hesitation; and I
accordingly obeyed forthwith what I still considered a very singular
summons.
Although, as boys, we had been even intimate associates, yet I
really knew little of my friend. His reserve had been always
excessive and habitual. I was aware, however, that his very ancient
family had been noted, time out of mind, for a peculiar sensibility of
temperament, displaying itself, through long ages, in many works of
exalted art, and manifested, of late, in repeated deeds of munificent,
yet unobtrusive charity, as well as in a passionate devotion to the
intricacies, perhaps even more than to the orthodox and easily
recognizable beauties, of musical science. I had learned, too, the
very remarkable fact that the stem of the Usher race, all time-
honored as it was, had put forth, at no period, any enduring branch;
in other words, that the entire family lay in the direct line of descent,
and had always, with very trifling and very temporary variation, so
lain. It was this deficiency, I considered, while running over in
thought the perfect keeping of the character of the premises with the
accredited character of the people, and while speculating upon the
possible influence which the one, in the long lapse of centuries,
might have exercised upon the other—it was this deficiency,
perhaps, of collateral issue, and the consequent undeviating
transmission, from sire to son, of the patrimony with the name, which
had, at length, so identified the two as to merge the original title of
the estate in the quaint and equivocal appellation of the “House of
Usher”—an appellation which seemed to include, in the minds of the
peasantry who used it, both the family and the family mansion.
I have said that the sole effect of my somewhat childish
experiment of looking down within the tarn had been to deepen the
first singular impression. There can be no doubt that the
consciousness of the rapid increase of my superstition—for why
should I not so term it?—served mainly to accelerate the increase
itself. Such, I have long known, is the paradoxical law of all
sentiments having terror as a basis. And it might have been for this
reason only, that, when I again uplifted my eyes to the house itself,
from its image in the pool, there grew in my mind a strange fancy—a
fancy so ridiculous, indeed, that I but mention it to show the vivid
force of the sensations which oppressed me. I had so worked upon
my imagination as really to believe that about the whole mansion
and domain there hung an atmosphere peculiar to themselves and
their immediate vicinity—an atmosphere which had no affinity with
the air of heaven, but which had reeked up from the decayed trees,
and the gray wall, and the silent tarn—a pestilent and mystic vapor,
dull, sluggish, faintly discernible, and leaden-hued.
 Shaking off from my spirit what must have been a dream, I
scanned more narrowly the real aspect of the building. Its principal
feature seemed to be that of an excessive antiquity. The
discoloration of ages had been great. Minute fungi overspread the
whole exterior, hanging in a fine, tangled web-work from the eaves.
Yet all this was apart from any extraordinary dilapidation. No portion
of the masonry had fallen; and there appeared to be a wild
inconsistency between its still perfect adaptation of parts, and the
crumbling condition of the individual stones. In this there was much
that reminded me of the specious totality of old wood-work which has
rotted for years in some neglected vault, with no disturbance from
the breath of the external air. Beyond this indication of extensive
decay, however, the fabric gave little token of instability. Perhaps the
eye of a scrutinizing observer might have discovered a barely
perceptible fissure, which, extending from the roof of the building in
front, made its way down the wall in a zigzag direction, until it
became lost in the sullen waters of the tarn.
Noticing these things, I rode over a short causeway to the house.
A servant in waiting took my horse, and I entered the Gothic archway
of the hall. A valet, of stealthy step, thence conducted me, in silence,
through many dark and intricate passages in my progress to the
studio of his master. Much that I encountered on the way
contributed, I know not how, to heighten the vague sentiments of
which I have already spoken. While the objects around me—while
the carvings of the ceilings, the sombre tapestries of the walls, the
ebon blackness of the floors, and the phantasmagoric armorial
trophies which rattled as I strode, were but matters to which, or to
such as which, I had been accustomed from my infancy—while I
hesitated not to acknowledge how familiar was all this—I still
wondered to find how unfamiliar were the fancies which ordinary
images were stirring up. On one of the staircases, I met the
physician of the family. His countenance, I thought, wore a mingled
expression of low cunning and perplexity. He accosted me with
trepidation and passed on. The valet now threw open a door and
ushered me into the presence of his master.
 The room in which I found myself was very large and lofty. The
windows were long, narrow, and pointed, and at so vast a distance
from the black oaken floor as to be altogether inaccessible from
within. Feeble gleams of encrimsoned light made their way through
the trelliced panes, and served to render sufficiently distinct the more
prominent objects around; the eye, however, struggled in vain to
reach the remoter angles of the chamber, or the recesses of the
vaulted and fretted ceiling. Dark draperies hung upon the walls. The
general furniture was profuse, comfortless, antique, and tattered.
Many books and musical instruments lay scattered about, but failed
to give any vitality to the scene. I felt that I breathed an atmosphere
of sorrow. An air of stern, deep, and irredeemable gloom hung over
and pervaded all.
Upon my entrance, Usher arose from a sofa on which he had
been lying at full length, and greeted me with a vivacious warmth
which had much in it, I at first thought, of an overdone cordiality—of
the constrained effort of the ennuyé man of the world. A glance,
however, at his countenance convinced me of his perfect sincerity.
We sat down; and for some moments, while he spoke not, I gazed
upon him with a feeling half of pity, half of awe. Surely, man had
never before so terribly altered, in so brief a period, as had Roderick
Usher! It was with difficulty that I could bring myself to admit the
identity of the wan being before me with the companion of my early
boyhood. Yet the character of his face had been at all times
remarkable. A cadaverousness of complexion; an eye large, liquid,
and luminous beyond comparison; lips somewhat thin and very
pallid, but of a surpassingly beautiful curve; a nose of a delicate
Hebrew model, but with a breadth of nostril unusual in similar
formations; a finely moulded chin, speaking, in its want of
prominence, of a want of moral energy; hair of a more than web-like
softness and tenuity; these features, with an inordinate expansion
above the regions of the temple, made up altogether a countenance
not easily to be forgotten. And now in the mere exaggeration of the
prevailing character of these features, and of the expression they
were wont to convey, lay so much of change that I doubted to whom
I spoke. The now ghastly pallor of the skin, and the now miraculous
lustre of the eye, above all things startled and even awed me. The
silken hair, too, had been suffered to grow all unheeded, and as, in
its wild gossamer texture, it floated rather than fell about the face, I
could not, even with effort, connect its arabesque expression with
any idea of simple humanity.
In the manner of my friend I was at once struck with an
incoherence—an inconsistency; and I soon found this to arise from a
series of feeble and futile struggles to overcome an habitual
trepidancy, an excessive nervous agitation. For something of this
nature I had indeed been prepared, no less by his letter than by
reminiscences of certain boyish traits, and by conclusions deduced
from his peculiar physical conformation and temperament. His action
was alternately vivacious and sullen. His voice varied rapidly from a
tremulous indecision (when the animal spirits seemed utterly in
abeyance) to that species of energetic concision—that abrupt,
weighty, unhurried, and hollow-sounding enunciation—that leaden,
self-balanced and perfectly modulated guttural utterance, which may
be observed in the lost drunkard, or the irreclaimable eater of opium,
during the periods of his most intense excitement.
It was thus that he spoke of the object of my visit, of his earnest
desire to see me, and of the solace he expected me to afford him.
He entered, at some length, into what he conceived to be the nature
of his malady. It was, he said, a constitutional and a family evil, and
one for which he despaired to find a remedy—a mere nervous
affection, he immediately added, which would undoubtedly soon
pass off. It displayed itself in a host of unnatural sensations. Some of
these, as he detailed them, interested and bewildered me; although,
perhaps, the terms and the general manner of the narration had their
weight. He suffered much from a morbid acuteness of the senses.
The most insipid food was alone endurable; he could wear only
garments of certain texture; the odors of all flowers were oppressive;
his eyes were tortured by even a faint light; and there were but
peculiar sounds, and these from stringed instruments, which did not
inspire him with horror.
To an anomalous species of terror I found him a bounden slave.
“I shall perish,” said he, “I must perish in this deplorable folly. Thus,
thus, and not otherwise, shall I be lost. I dread the events of the
future, not in themselves, but in their results. I shudder at the thought
of any, even the most trivial, incident, which may operate upon this
intolerable agitation of soul. I have, indeed, no abhorrence of danger,
except in its absolute effect—in terror. In this unnerved—in this
pitiable condition—I feel that the period will sooner or later arrive
when I must abandon life and reason together, in some struggle with
the grim phantasm, Fear.”
I learned, moreover, at intervals, and through broken and
equivocal hints, another singular feature of his mental condition. He
was enchained by certain superstitious impressions in regard to the
dwelling which he tenanted, and whence, for many years, he had
never ventured forth—in regard to an influence whose supposititious
force was conveyed in terms too shadowy here to be restated—an
influence which some peculiarities in the mere form and substance
of his family mansion, had, by dint of long sufferance, he said,
obtained over his spirit—an effect which the physique of the gray
walls and turrets, and of the dim tarn into which they all looked down,
had, at length, brought about upon the morale of his existence.
He admitted, however, although with hesitation, that much of the
peculiar gloom which thus afflicted him could be traced to a more
natural and far more palpable origin—to the severe and long-
continued illness—indeed to the evidently approaching dissolution—
of a tenderly beloved sister, his sole companion for long years, his
last and only relative on earth. “Her decease,” he said, with a
bitterness which I can never forget, “would leave him (him the
hopeless and the frail) the last of the ancient race of the Ushers.”
While he spoke, the lady Madeline (for so was she called) passed
slowly through a remote portion of the apartment, and, without
having noticed my presence, disappeared. I regarded her with an
40
utter astonishment not unmingled with dread; and yet I found it
impossible to account for such feelings. A sensation of stupor
oppressed me, as my eyes followed her retreating steps. When a
door, at length, closed upon her, my glance sought instinctively and
eagerly the countenance of the brother; but he had buried his face in
his hands, and I could only perceive that a far more than ordinary
wanness had overspread the emaciated fingers through which
trickled many passionate tears.
The disease of the lady Madeline had long baffled the skill of her
physicians. A settled apathy, a gradual wasting away of the person,
and frequent although transient affections of a partially cataleptical
character, were the unusual diagnosis. Hitherto she had steadily
borne up against the pressure of her malady, and had not betaken
herself finally to bed; but, on the closing in of the evening of my
arrival at the house, she succumbed (as her brother told me at night
with inexpressible agitation) to the prostrating power of the
destroyer; and I learned that the glimpse I had obtained of her
person would thus probably be the last I should obtain—that the
lady, at least while living, would be seen by me no more.
For several days ensuing her name was unmentioned by either
Usher or myself; and during this period I was busied in earnest
endeavors to alleviate the melancholy of my friend. We painted and
read together; or I listened, as if in a dream, to the wild
improvisations of his speaking guitar. And thus, as a closer and still
closer intimacy admitted me more unreservedly into the recesses of
his spirit, the more bitterly did I perceive the futility of all attempt at
cheering a mind from which darkness, as if an inherent positive
quality, poured forth upon all objects of the moral and physical
universe, in one unceasing radiation of gloom.
I shall ever bear about me a memory of the many solemn hours I
thus spent alone with the master of the House of Usher. Yet I should
fail in any attempt to convey an idea of the exact character of the
studies, or of the occupations in which he involved me, or led me the
way. An excited and highly distempered ideality threw a sulphurous
lustre over all. His long improvised dirges will ring forever in my ears.
Among other things, I hold painfully in mind a certain singular
perversion and amplification of the wild air of the last waltz of Von
Weber. From the paintings over which his elaborate fancy brooded,
and which grew, touch by touch, into vaguenesses at which I
shuddered the more thrillingly because I shuddered knowing not
why;—from these paintings (vivid as their images now are before
me) I would in vain endeavor to educe more than a small portion
which should lie within the compass of merely written words. By the
utter simplicity, by the nakedness of his designs, he arrested and
overawed attention. If ever mortal painted an idea, that mortal was
Roderick Usher. For me at least, in the circumstances then
surrounding me, there arose out of the pure abstractions which the
hypochondriac contrived to throw upon his canvas, an intensity of
intolerable awe, no shadow of which felt I ever yet in the
contemplation of the certainly glowing yet too concrete reveries of
Fuseli.
One of the phantasmagoric conceptions of my friend, partaking
not so rigidly of the spirit of abstraction, may be shadowed forth,
although feebly, in words. A small picture presented the interior of an
immensely long and rectangular vault or tunnel, with low walls,
smooth, white, and without interruption or device. Certain accessory
points of the design served well to convey the idea that this
excavation lay at an exceeding depth below the surface of the earth.
No outlet was observed in any portion of its vast extent, and no
torch, or other artificial source of light was discernible; yet a flood of
intense rays rolled throughout, and bathed the whole in a ghastly
and inappropriate splendor.
I have just spoken of that morbid condition of the auditory nerve
which rendered all music intolerable to the sufferer, with the
exception of certain effects of stringed instruments. It was, perhaps,
the narrow limits to which he thus confined himself upon the guitar,
which gave birth, in great measure, to the fantastic character of his
performances. But the fervid facility of his impromptus could not be
so accounted for. They must have been, and were, in the notes, as
well as in the words of his wild fantasias (for he not unfrequently
accompanied himself with rhymed verbal improvisations), the result
of that intense mental collectedness and concentration to which I
have previously alluded as observable only in particular moments of
the highest artificial excitement. The words of one of these
rhapsodies I have easily remembered. I was, perhaps, the more
forcibly impressed with it, as he gave it, because, in the under or
mystic current of its meaning, I fancied that I perceived, and for the
first time, a full consciousness on the part of Usher, of the tottering of
his lofty reason upon her throne. The verses, which were entitled
“The Haunted Palace,” ran very nearly, if not accurately, thus:

I.
In the greenest of our valleys,
By good angels tenanted,
Once a fair and stately palace—
Radiant palace—reared its head.
In the monarch Thought’s dominion—
It stood there!
Never seraph spread a pinion
Over fabric half so fair.

II.
Banners yellow, glorious, golden,
On its roof did float and flow;
(This—all this—was in the olden
Time long ago)
And every gentle air that dallied,
In that sweet day,
Along the ramparts plumed and pallid,
A winged odor went away.

III.
Wanderers in that happy valley
Through two luminous windows saw
Spirits moving musically
To a lute’s well-tunèd law,
Round about a throne, where sitting
(Porphyrogene!)
In state his glory well befitting,
The ruler of the realm was seen.
 IV.
And all with pearl and ruby glowing
Was the fair palace door,
Through which came flowing, flowing, flowing,
And sparkling evermore,
A troop of Echoes whose sweet duty
Was but to sing,
In voices of surpassing beauty,
The wit and wisdom of their king.

V.
But evil things, in robes of sorrow,
Assailed the monarch’s high estate
(Ah, let us mourn, for never morrow
Shall dawn upon him, desolate!);
And, round about his home, the glory
That blushed and bloomed
Is but a dim-remembered story
Of the old time entombed.

VI.
And travellers now within that valley,
Through the red-litten windows, see
Vast forms that move fantastically
To a discordant melody;
While, like a rapid ghastly river,
Through the pale door,
A hideous throng rush out forever,
And laugh—but smile no more.

I well remember that suggestions arising from this ballad led us

into a train of thought wherein there became manifest an opinion of
Usher’s which I mention not so much on account of its novelty (for
 41
other men I have thought thus) as on account of the pertinacity
with which he maintained it. This opinion, in its general form, was
that of the sentience of all vegetable things. But, in his disordered
fancy, the idea had assumed a more daring character, and
trespassed, under certain conditions, upon the kingdom of
inorganization. I lack words to express the full extent or the earnest
abandon of his persuasion. The belief, however, was connected (as I
have previously hinted) with the gray stones of the home of his
forefathers. The conditions of the sentience had been here, he
imagined, fulfilled in the method of collocation of these stones—in
the order of their arrangement, as well as in that of the many fungi
which overspread them, and of the decayed trees which stood
around—above all, in the long undisturbed endurance of this
arrangement, and in its reduplication in the still waters of the tarn. Its
evidence—the evidence of the sentience—was to be seen, he said,
(and I here started as he spoke), in the gradual yet certain
condensation of an atmosphere of their own about the waters and
the walls. The result was discoverable, he added, in that silent, yet
importunate and terrible influence which for centuries had moulded
the destinies of his family, and which made him what I now saw him
—what he was. Such opinions need no comment, and I will make
none.
Our books—the books, which, for years, had formed no small
portion of the mental existence of the invalid—were, as might be
supposed, in strict keeping with this character of phantasm. We
pored together over such works as the Ververt et Chartreuse of
Gresset; the Belphegor of Machiavelli; the Heaven and Hell of
Swedenborg; the Subterranean Voyage of Nicholas Klimm by
Holberg; the Chiromancy of Robert Flud, of Jean D’Indaginé, and of
De la Chambre; the Journey into the Blue Distance of Tieck; and the
City of the Sun of Campanella. One favorite volume was a small
octavo edition of the Directorium Inquisitorium, by the Dominican
Eymeric de Gironne; and there were passages in Pomponius Mela,
about the old African Satyrs and Œgipans, over which Usher would
sit dreaming for hours. His chief delight, however, was found in the
perusal of an exceedingly rare and curious book in quarto Gothic—
the manual of a forgotten church—the Vigiliæ Mortuorum secundum
Chorum Ecclesiæ Maguntinæ.
I could not help thinking of the wild ritual of this work, and of its
probable influence upon the hypochondriac, when, one evening,
having informed me abruptly that the lady Madeline was no more, he
stated his intention of preserving her corpse for a fortnight
(previously to its final interment) in one of the numerous vaults within
the main walls of the building. The worldly reason, however,
assigned for this singular proceeding was one which I did not feel at
liberty to dispute. The brother had been led to his resolution, so he
told me, by consideration of the unusual character of the malady of
the deceased, of certain obtrusive and eager inquiries on the part of
her medical men, and of the remote and exposed situation of the
burial-ground of the family. I will not deny that when I called to mind
the sinister countenance of the person whom I met upon the
staircase, on the day of my arrival at the house, I had no desire to
oppose what I regarded as at best but a harmless, and by no means
an unnatural, precaution.
At the request of Usher, I personally aided him in the
arrangements for the temporary entombment. The body having been
encoffined, we two alone bore it to its rest. The vault in which we
placed it (and which had been so long unopened that our torches,
half smothered in its oppressive atmosphere, gave us little
opportunity for investigation) was small, damp, and entirely without
means of admission for light; lying, at great depth, immediately
beneath that portion of the building in which was my own sleeping
apartment. It had been used, apparently, in remote feudal times, for
the worst purposes of a donjon-keep, and, in later days, as a place
of deposit for powder, or some other highly combustible substance,
as a portion of its floor, and the whole interior of a long archway
through which we reached it, were carefully sheathed with copper.
The door, of massive iron, had been, also, similarly protected. Its
immense weight caused an unusually sharp grating sound, as it
moved upon its hinges.
Having deposited our mournful burden upon tressels within this
region of horror, we partially turned aside the yet unscrewed lid of
the coffin, and looked upon the face of the tenant. A striking
similitude between the brother and sister now first arrested my
attention; and Usher, divining, perhaps, my thoughts, murmured out
some few words from which I learned that the deceased and himself
had been twins, and that sympathies of a scarcely intelligible nature
had always existed between them. Our glances, however, rested not
long upon the dead—for we could not regard her unawed. The
disease which had thus entombed the lady in the maturity of youth,
had left, as usual in all maladies of a strictly cataleptical character,
the mockery of a faint blush upon the bosom and the face, and that
suspiciously lingering smile upon the lip which is so terrible in death.
We replaced and screwed down the lid, and, having secured the
door of iron, made our way, with toil, into the scarcely less gloomy
apartments of the upper portion of the house.
And now, some days of bitter grief having elapsed, an
observable change came over the features of the mental disorder of
my friend. His ordinary manner had vanished. His ordinary
occupations were neglected or forgotten. He roamed from chamber
to chamber with hurried, unequal, and objectless step. The pallor of
his countenance had assumed, if possible, a more ghastly hue—but
the luminousness of his eye had utterly gone out. The once
occasional huskiness of his tone was heard no more; and a
tremulous quaver, as if of extreme terror, habitually characterized his
utterance. There were times, indeed, when I thought his unceasingly
agitated mind was laboring with some oppressive secret, to divulge
which he struggled for the necessary courage. At times, again, I was
obliged to resolve all into the mere inexplicable vagaries of madness;
for I beheld him gazing upon vacancy for long hours, in an attitude of
the profoundest attention, as if listening to some imaginary sound. It
was no wonder that his condition terrified—that it infected me. I felt
creeping upon me, by slow yet certain degrees, the wild influence of
his own fantastic yet impressive superstitions.
It was, especially, upon retiring to bed late in the night of the
seventh or eighth day after the placing of the lady Madeline within
the donjon, that I experienced the full power of such feelings. Sleep
came not near my couch, while the hours waned and waned away. I
struggled to reason off the nervousness which had dominion over
me. I endeavored to believe that much, if not all of what I felt, was
due to the bewildering influence of the gloomy furniture of the room
—of the dark and tattered draperies, which, tortured into motion by
the breath of a rising tempest, swayed fitfully to and fro upon the
walls, and rustled uneasily about the decorations of the bed. But my
efforts were fruitless. An irrepressible tremor gradually pervaded my
frame; and, at length, there sat upon my very heart an incubus of
utterly causeless alarm. Shaking this off with a gasp and a struggle, I
uplifted myself upon the pillows, and, peering earnestly within the
intense darkness of the chamber, harkened—I know not why, except
that an instinctive spirit prompted me—to certain low and indefinite
sounds which came, through the pauses of the storm, at long
intervals, I knew not whence. Overpowered by an intense sentiment
of horror, unaccountable yet unendurable, I threw on my clothes with
haste (for I felt that I should sleep no more during the night), and
endeavored to arouse myself from the pitiable condition into which I
had fallen, by pacing rapidly to and fro through the apartment.
I had taken but few turns in this manner, when a light step on an
adjoining staircase arrested my attention. I presently recognized it as
that of Usher. In an instant afterward he rapped, with a gentle touch,
at my door, and entered, bearing a lamp. His countenance was, as
usual, cadaverously wan—but, moreover, there was a species of
mad hilarity in his eyes—and evidently restrained hysteria in his
whole demeanor. His air appalled me—but anything was preferable
to the solitude which I had so long endured, and I even welcomed
his presence as a relief.
“And you have not seen it?” he said abruptly, after having stared
about him for some moments in silence—“you have not then seen it?
—but stay! you shall.” Thus speaking, and having carefully shaded
his lamp, he hurried to one of the casements, and threw it freely
open to the storm.
The impetuous fury of the entering gust nearly lifted us from our
feet. It was, indeed, a tempestuous yet sternly beautiful night, and
one wildly singular in its terror and its beauty. A whirlwind had
apparently collected its force in our vicinity; for there were frequent
and violent alterations in the direction of the wind; and the exceeding
density of the clouds (which hung so low as to press upon the turrets
of the house) did not prevent our perceiving the life-like velocity with
which they flew careering from all points against each other, without
passing away into the distance. I say that even their exceeding
density did not prevent our perceiving this—yet we had no glimpse of
the moon or stars—nor was there any flashing forth of the lightning.
But the under surfaces of the huge masses of agitated vapor, as well
as all terrestrial objects immediately around us, were glowing in the
unnatural light of a faintly luminous and distinctly visible gaseous
exhalation which hung about and enshrouded the mansion.
“You must not—you shall not behold this!” said I, shudderingly, to
Usher, as I led him, with a gentle violence, from the window to a
seat. “These appearances, which bewilder you, are merely electrical
phenomena not uncommon—or it may be that they have their
ghastly origin in the rank miasma of the tarn. Let us close this
casement—the air is chilling and dangerous to your frame. Here is
one of your favorite romances. I will read, and you shall listen;—and
so we will pass away this terrible night together.”
The antique volume which I had taken up was the Mad Trist of
Sir Launcelot Canning; but I had called it a favorite of Usher’s more
in sad jest than in earnest; for, in truth, there is little in its uncouth
and unimaginative prolixity which could have had interest for the lofty
and spiritual ideality of my friend. It was, however, the only book
immediately at hand; and I indulged a vague hope that the
excitement which now agitated the hypochondriac, might find relief
(for the history of mental disorder is full of similar anomalies) even in
the extremeness of the folly which I should read. Could I have
judged, indeed, by the wild, overstrained air of vivacity with which he
harkened, or apparently harkened, to the words of the tale, I might
well have congratulated myself upon the success of my design.
I had arrived at that well-known portion of the story where
Ethelred, the hero of the Trist, having sought in vain for peaceable
admission into the dwelling of the hermit, proceeds to make good an
entrance by force. Here, it will be remembered, the words of the
narrative run thus:
 “And Ethelred, who was by nature of a doughty heart, and who
was now mighty withal, on account of the powerfulness of the wine
which he had drunken, waited no longer to hold parley with the
hermit, who, in sooth, was of an obstinate and maliceful turn; but,
feeling the rain upon his shoulders, and fearing the rising of the
tempest, uplifted his mace outright, and, with blows, made quickly
room in the plankings of the door for his gauntleted hand; and now
pulling therewith sturdily, he so cracked, and ripped, and tore all
asunder, that the noise of the dry and hollow-sounding wood
alarummed and reverberated throughout the forest.”
At the termination of this sentence I started, and for a moment
paused; for it appeared to me (although I at once concluded that my
excited fancy had deceived me)—it appeared to me that, from some
very remote portion of the mansion, there came, indistinctly, to my
ears what might have been, in its exact similarity of character, the
echo (but a stifled and dull one certainly) of the very cracking and
ripping sound which Sir Launcelot had so particularly described. It
was, beyond doubt, the coincidence alone which had arrested my
attention; for, amid the rattling of the sashes of the casements, and
the ordinary commingled noises of the still increasing storm, the
sound, in itself, had nothing, surely, which should have interested or
disturbed me. I continued the story:
“But the good champion Ethelred, now entering within the door,
was sore enraged and amazed to perceive no signal of the maliceful
hermit; but, in the stead thereof, a dragon of a scaly and prodigious
demeanor, and of a fiery tongue, which sate in guard before a palace
of gold, with a floor of silver; and upon the wall there hung a shield of
shining brass with this legend enwritten—

Who entereth herein, a conqueror hath bin;

Who slayeth the dragon, the shield he shall win;

And Ethelred uplifted his mace, and struck upon the head of the
dragon, which fell before him, and gave up his pesty breath, with a
shriek so horrid and harsh, and withal so piercing, that Ethelred had
fain to close his ears with his hands against the dreadful noise of it,
the like whereof was never before heard.”
Here again I paused abruptly, and now with a feeling of wild
amazement—for there could be no doubt whatever that, in this
instance, I did actually hear (although from what direction it
proceeded I found it impossible to say) a low and apparently distant,
but harsh, protracted, and most unusual screaming or grating sound
—the exact counterpart of what my fancy had already conjured up
for the dragon’s unnatural shriek as described by the romancer.
Oppressed, as I certainly was, upon the occurrence of this
second and most extraordinary coincidence, by a thousand
conflicting sensations, in which wonder and extreme terror were
predominant, I still retained sufficient presence of mind to avoid
exciting, by any observation, the sensitive nervousness of my
companion. I was by no means certain that he had noticed the
sounds in question; although, assuredly, a strange alteration had,
during the last few minutes, taken place in his demeanor. From a
position fronting my own, he had gradually brought round his chair,
so as to sit with his face to the door of the chamber; and thus I could
but partially perceive his features, although I saw that his lips
trembled as if he were murmuring inaudibly. His head had dropped
upon his breast—yet I knew that he was not asleep, from the wide
and rigid opening of the eye as I caught a glance of it in profile. The
motion of his body, too, was at variance with this idea—for he rocked
from side to side with a gentle yet constant and uniform sway.
Having rapidly taken notice of all this, I resumed the narrative of Sir
Launcelot, which thus proceeded:
“And now the champion, having escaped from the terrible fury of
the dragon, bethinking himself of the brazen shield, and of the
breaking up of the enchantment which was upon it, removed the
carcass from out of the way before him, and approached valorously
over the silver pavement of the castle to where the shield was upon
the wall; which in sooth tarried not for his full coming, but fell down at
his feet upon the silver floor, with a mighty great and terrible ringing
sound.”
 No sooner had these syllables passed my lips, than—as if a
shield of brass had indeed, at the moment, fallen heavily upon a floor
of silver—I became aware of a distinct, hollow, metallic and
clangorous, yet apparently muffled reverberation. Completely
unnerved, I leaped to my feet; but the measured rocking movement
of Usher was undisturbed. I rushed to the chair in which he sat. His
eyes were bent fixedly before him, and throughout his whole
countenance there reigned a stony rigidity. But, as I placed my hand
upon his shoulder, there came a strong shudder over his whole
person; a sickly smile quivered about his lips; and I saw that he
spoke in a low, hurried, and gibbering murmur, as if unconscious of
my presence. Bending closely over him, I at length drank in the
hideous import of his words.
“Not hear it?—yes, I hear it, and have heard it. Long—long—
long—many minutes, many hours, many days, have I heard it—yet I
dared not—oh pity me, miserable wretch that I am!—I dared not—I
dared not speak! We have put her living in the tomb! Said I not that
my senses were acute? I now tell you that I heard her first feeble
movements in the hollow coffin. I heard them—many, many days ago
—yet I dared not—I dared not speak! And now—to-night—Ethelred
—ha! ha!—the breaking of the hermit’s door, and the death-cry of the
dragon, and the clangor of the shield!—say, rather, the rending of her
coffin, and the grating of the iron hinges of her prison, and her
struggles within the coppered archway of the vault! Oh whither shall I
fly? Will she not be here anon? Is she not hurrying to upbraid me for
my haste? Have I not heard her footstep on the stair? Do I not
distinguish that heavy and horrible beating of her heart? Madman!”—
here he sprang furiously to his feet, and shrieked out his syllables,
as if in the effort he were giving up his soul—“Madman! I tell you that
she now stands without the door!”
As if in the superhuman energy of his utterance there had been
found the potency of a spell—the huge antique pannels to which the
speaker pointed threw slowly back, upon the instant, their ponderous
and ebony jaws. It was the work of the rushing gust—but then
without those doors there did stand the lofty and enshrouded figure
of the lady Madeline of Usher. There was blood upon her white
robes, and the evidence of some bitter struggle upon every portion of
her emaciated frame. For a moment she remained trembling and
reeling to and fro upon the threshold—then, with a low, moaning cry,
fell heavily inward upon the person of her brother, and in her violent
and now final death-agonies, bore him to the floor a corpse, and a
victim to the terrors he had anticipated.
From that chamber, and from that mansion, I fled aghast. The
storm was still abroad in all its wrath as I found myself crossing the
old causeway. Suddenly there shot along the path a wild light, and I
turned to see whence a gleam so unusual could have issued; for the
vast house and its shadows were alone behind me. The radiance
was that of the full, setting, and blood-red moon, which now shone
vividly through that once barely-discernible fissure, of which I have
before spoken as extending from the roof of the building, in a zigzag
direction, to the base. While I gazed, this fissure rapidly widened—
there came a fierce breath of the whirlwind—the entire orb of the
satellite burst at once upon my sight—my brain reeled as I saw the
mighty walls rushing asunder—there was a long tumultuous shouting
sound like the voice of a thousand waters—and the deep and dank
tarn at my feet closed sullenly and silently over the fragments of the
“House of Usher.”
 NATHANIEL PARKER WILLIS
1806–1867

Town talk sums up much of Willis, both what he was and what he wrote. He lived
in the public eye; he wrote of the hour, for the hour. Naturally, therefore, his work
was dying while he was yet alive. Now he is hardly more than a name. Of Andover
and Yale what little impress he received was soon rubbed away by a life in which
the daily cultivation of eminent society was industriously made to yield the daily
crop of journalism. Indeed, a man so quick to take every new impression was
hardly the man to bear the marks of many old ones. And of course the happy
fluency that gave him even in youth a current popularity could dispense with that
other and more deliberate merit of form. Form, since he had no native sense of it,
and could get on swimmingly without it, he never seriously pursued. Few story-
writers have spoiled so many good plots. Not only is he chatty, digressive,
episodic, but he rarely has any clear solution and he never culminates. Such merit
as The Inlet of Peach Blossoms has in this aspect is quite exceptional. Piquant,
even vivid sometimes, in sketchy description, he has no composition. This,
doubtless, is why of the hundred tales that pleased his public not one is read by
ours.
Pencillings by the Way were supplied from Paris and London in the early ’30’s
to the New York Mirror, and in collective form entertained both Britons and
Americans. The characteristic title would serve as well for his subsequent
collections. A list is appended to the biography in the American Men of Letters
series by Professor Beers, who has also edited a volume of selections. A New
York editor for many years, Willis touched at so many points the literary life of his
time that this biography has been made admirably significant of its main social
aspects. In fact, the life of Willis has more enduring interest than his works.