Formulation and Analytical Development for Low-Dose Oral Drug Products / Edition 1

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There are unique challenges in the formulation, manufacture, analytical chemistry, and regulatory requirements of low-dose drugs. This book provides an overview of this specialized field and combines formulation, analytical, and regulatory aspects of low-dose development into a single reference book. It describes analytical methodologies like dissolution testing, solid state NMR, Raman microscopy, and LC-MS and presents manufacturing techniques such as granulation, compaction, and compression. Complete with case studies and a discussion of regulatory requirements, this is a core reference for pharmaceutical scientists, regulators, and graduate students.

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Editorial Reviews

Doody's Review Service
Reviewer: Joseph Boullata, PharmD (University of Pennsylvania School of Nursing)
Description: This welcome addition to books on dosage formulations has as its focus the challenging issue of developing and bringing to market oral drug products containing a low dose (< 1 mg) of active ingredient. These include widely used products such as oral contraceptives and thyroid hormone replacement.
Purpose: The objective is to provide a concise review of the development of low-dose drug products from pharmaceutical, analytical, and regulatory perspectives.
Audience: This book is written primarily for formulation scientists, analytical scientists, and regulatory specialists who will deal with low-dose oral drug products in industry or academia, as well as graduate students and postdoctoral fellows preparing for the field.
Features: Following an excellent overview chapter by the editor, the book is divided into four sections. The first section on formulation development provides detailed information on strategies dealing with particle size and process methods issues. The second section discusses analytical methods for low dose products given the challenges of such low quantities of active ingredient. The third section has two chapters on technology for containment related to the potency of the active ingredient. The last section includes a final chapter on regulatory considerations. Among the book's outstanding features are 97 tables, 74 figures, some color plates, and dozens of equations. Numerous formulation case studies are provided. The referencing format is not consistent across the chapters, but the 7-page index appears to be adequate. The contributors come predominantly from industry, and it is unfortunate not to have more from academia and regulatory bodies.
Assessment: This book is unique in its depth of coverage of the topic.
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Product Details

  • ISBN-13: 9780470056097
  • Publisher: Wiley
  • Publication date: 1/27/2009
  • Edition description: New Edition
  • Edition number: 1
  • Pages: 465
  • Product dimensions: 6.50 (w) x 9.60 (h) x 0.90 (d)

Meet the Author

Jack Zheng, PhD, is Research Advisor and Team Leader in the Pharmaceutical Sciences R&D Division of Eli Lilly and Company and Adjunct Professor at Beijing University. Dr. Zheng is the author of more than thirty articles and several book chapters. He has been invited to present his work at numerous national and international scientific meetings. He was involved in more than ten new drug product development and regulatory filing with the Food and Drug Administration.

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Table of Contents




1. An Overview (Jack Y. Zheng).

1.1 The Drug Discovery and Development Process.

1.2 Challenges and Strategies in Development of Low-Dose DrugProducts.

1.3 Summary.




2. Challenges and Strategies in Formulation Development ofOral Solid Low-Dose Drug Products (Jack Y. Zheng).

2.1 Introduction.

2.2 Current Regulatory Environment and Its Impact on New DrugProduct Development.

2.3 Challenges in Developing Low-Dose Formulations.

2.4 Manufacturing Platforms for Low-Dose Drug Products.

2.5 Use of Experimental Design in Formulation and ProcessDevelopment.

2.6 Containments.

2.7 Summary.



3. Particle Size of Drug Substance and Product ContentUniformity - Theoretical Considerations (Kevin C. Johnson).

3.1 Introduction.

3.2 Concept of Ideal Mixing.

3.3 Ideal Mixing Model Comparison with the Yalkowsky and BoltonApproach.

3.4 Experimental Support of Model Assumptions.

3.5 Analytical and Practical Considerations.


4. Development of Low-Dose Formulations Using Fluidized BedGranulation (J. Joe Zhou and Ralph Lipp).

4.1 Introduction.

4.2 Granulation Fundamentals.

4.3 Theory of Fluidization.

4.4 Formulation Development.

4.5 Process Development.

4.6 Summay.


5. Development of Low-Dose Solid Oral Formulations Using WetGranulation (Ahmad Almaya).

5.1 Introduction.

5.2 Granulation Mechanisms.

5.3 General Considerations on Wet Granulation.

5.4 Advantages and Disadvantages of Wet Granulation.

5.5 Use of Wet Granulation for Low-Dose Formulations.

5.6 Process-Induced Form Changes in Wet Granulation.

5.7 Concluding Remarks.


6. Challenges in Development and Scale-Up of Low Dose DrugProducts by Dry Granulation: A Case Study (Mary T. Am Ende, DanielO. Blackwood, Daniel S. Gierer, and Christopher P. Neu).

6.1 Introduction.

6.2 Dry Granulation Process - Pros and Cons.

6.3 Overview of Dry Granulation Processes and EquipmentDesign.

6.4 Challenges for Low-Dose Product Development and theirAssessment Methods.

6.5 Case Study: Formulation Challenges for Low-DoseProducts.

6.6 Process Challenges During Dry Granulation Optimization forLow-Dose Products.

6.7 Conclusions.



7. Development of Low-Dose Solid Oral Tablets Using DirectCompression (Jack Y. Zheng and Robert L. Ternik).

7.1 Introduction.

7.2 Advantages of Direct Compression.

7.3 Challenges in Low-Dose Tablet Development Using DirectCompression.

7.4 Formulation Development for Low-Dose Drug Products UsingDirect Compression.

7.5 Manufacturing Process Development for Low-Dose DrugProducts.

7.6 Scale-Up for Blending Operation.

7.7 Formulation Examples for Direct Compression.

7.8 Conclusions.



8 Reduction of Particle Size of Drug Substance for Low-DoseDrug Products (Christopher L. Burcham, Paul C. Collins, Daniel J.Jarmer, and Kevin D. Seibert).

8.1 Introduction.

8.2 Reduction of Particle Size of Drug Substance by MillingTechnologies.

8.3 Reduction of Particle Size of Drug Substance UsingCrystallization Technologies.

8.4 Scale-Up Considerations.

8.5 Emerging Technologies and Future Directions.



9. Function, Quality, and Regulations of PharmaceuticalExcipients for Oral Solid Dosage Forms (Jack Y. Zheng).

9.1 Introduction.

9.2 Classification of Pharmaceutical Excipients in Solid DosageForms.

9.3 Physicochemical Attributes of Pharmaceutical Excipients.

9.4 Regulatory Status and Excipient Quality.

9.5 Summary.




10. Analytical Method Development: Challenges and Solutionsfor Low-Dose Oral Dosage Forms (Beverly Nickerson, Reena M. Joseph,Charles Palmer and Alex M. Opio and George H. Beresford).

10.1 Introduction.

10.2 Case Study 1: Drug Adsorption to Surfaces.

10.3 Case Study 2: Challenges Due to Nondrug-RelatedImpurities.

10.4 Case Study 3: HPLC Purity Method Development Challenges fora Fixed Combination Product Containing a Low-Dose Active Ingredientand a High-Dose Active Ingredient.

10.5 Case Study 4: Small Volume Dissolution Testing.

10.6 Summary.



11. In Vitro Dissolution Testing and Method Development(Vivian A. Gray Jack Y. Zheng and Norman N. Sesi).

11.1 Introduction.

11.2 Overview of Dissolution Testing.

11.3 Dissolution Method Development.

11.4 Dissolution Method Development for Low-Dose Oral DrugProducts.

11.5 Summary.


12. Analysis of Physical Transformation of API DuringManufacture and Storage (Gregory A. Stephenson).

12.1 Introduction.

12.2 Discussion of Solid-State Forms.

12.3 Monitoring Processing Steps.

12.4 Measuring Transitions and Solid-Form Transformations in theLow-Dose Tablet.

12.5 Common Methods Used for Examination of Solid Forms.

12.6 Conclusions.


13. Physical Characterization Tests for DrugSubstances Used in Low-Dose Formulations (Ronald G.Iacocca).

13.1 General Issues in the Physical Characterization ofMicronized Powders Used in Low-Dose Formulations.

13.2 Particle Size Analysis.

13.3 Specific Surface Area Analysis.

13.4 Summary.


14. An Excipient Library Approach to Analytical Developmentfor Low-Dose, Solid Oral Dosage Form Drug Products (Qing Chang,Lisheng Kang, Keri Varner, Joyce Bridges, Norman Sesi, and MargoPalmieri).

14.1 Introduction.

14.2 Importance of Excipient Absorbance Background to Low-DoseImpurity Analysis.

14.3 Factors Affecting Excipient Absorbance Background.

14.4 Use of Excipient Library.

14.5 Conclusions.



15. Cleaning Verification for Highly Potent Compounds (BrianW. Pack).

15.1 Introduction.

15.2 Cleaning Validation vs Cleaning Verification.

15.3 Acceptance Limit Calculations.

15.4 Analytical Method Validation.

15.5 General Analytical Techniques.

15.6 Analytical Techniques for Low-Dose Compounds.

15.7 Conclusions.




16 Containment Challenges and Strategies for Potent Compoundsin the Pharmaceutical Industry (Victoria Cathcart, Sarah Jones,Beverly Nickerson).

16.1 Introduction.

16.2 Safe Exposure Control Levels-Bands, Limits, and HandlingGuidance.

16.3 The Hierarchy of Workplace Controls.

16.4 Case Studies.

16.5 Summary.



17. Sample Handling and Containment in Analytical TestingLaboratories (David Pattavina, Nancy Sage, and BeverlyNickerson).

17.1 Introduction.

17.2 Sample Handling Considerations.

17.3 Handling Potent Compounds in Standard AnalyticalLaboratories.

17.4 Handling Potent Compounds in a Containment Laboratory.

17.5 Additional Considerations for Handling PotentMaterials.

17.6 Summary.




18. Regulatory Considerations in the Development of Low-DoseSolid Oral Drug Products (Ravi S. Harapanhalli).

18.1 Introduction and Overview.

18.2 Three-Pronged Approach to Low-Dose Formulations.

18.3 Pharmaceutical Development Report.

18.4 Facility Controls for Highly Potent Drugs.

18.5 Conclusion.



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