Table of Contents

Cover

Title Page

List of Contributors

Chapter 1: Excipient Characterization

1.1 Introduction
1.2 Chemical and Physical Properties
1.3 Compendial Characterization Methods and Excipient Performance
1.4 Novel Characterization Techniques
1.5 Excipient Impurities and Implications to Drug Product Stability (Drug–Excipient Interactions)
1.6 Excipient Impurities and their Sources
1.7 Guidance on Excipient Impurity and Interactions
1.8 Analytical Methods for Determining Trace Reactive Excipient Impurities
1.9 Conclusion
References

Chapter 2: Excipients for Conventional Oral Solid Dosage Forms

2.1 Introduction
2.2 Diluents/Fillers
2.3 Binders
2.4 Disintegrants
2.5 Lubricants
2.6 Coating-Related Excipients
2.7 Colorants
2.8 pH Modifiers
2.9 Anticaking Agents
2.10 Antioxidants
2.11 Coprocessed Excipients
2.12 Future Directions
References

Chapter 3: Excipients and their Functionality for Enabling Technologies in Oral Dosage Forms

3.1 Pharmaceutical Excipients
3.2 Solid Dispersions
3.3 Lipid-based Systems
3.4 Nanocrystals
3.5 Oral Modified Release Dosage Forms
3.6 Orodispersible Tablets
3.7 Future Directions
References

Chapter 4: Excipients used in Biotechnology Products

4.1 Unique Challenges in the Formulation Development of Biotechnology Products
4.2 Degradation Pathways of Proteins
4.3 Common Classes of Excipients Used for Biotechnology Products
4.4 Excipients Used in Solid Dosage Forms of Biopharmaceuticals
4.5 Conclusion and Future Outlooks
References

Chapter 5: Excipient Standards and Harmonization

5.1 Introduction
5.2 The Excipient Life Cycle
5.3 Excipient Composition
5.4 Excipient Performance
5.5 Excipient Specifications
5.6 Pharmacopeias and other Compendia
5.7 Harmonization
5.8 The Future
5.9 Conclusion
References

Chapter 6: Regulatory Information for Excipients

6.1 Introduction
6.2 Regulation of Excipients in the United States
6.3 Color Additives and Flavors
6.4 Introduction to IPEC
6.5 Excipient Information for Drug Product Applications
6.6 Drug Master Files
6.7 Supporting Regulatory Information Necessary for Excipients
6.8 New Developments in the United States Affecting Excipients
6.9 Safety Evaluation of Excipients
6.10 The IPEC New Excipient Safety Evaluation Procedure
6.11 Total Excipient Control System
6.12 Excipient Composition: Additives and Processing AIDS
References

Chapter 7: Development of New Excipients

7.1 Introduction
7.2 Development of Novel Excipients
7.3 Development of Coprocessed Excipients
7.4 Development of Modified Excipients
7.5 Summary
References

Chapter 8: PATability of Excipients

8.1 Introduction
8.2 Elucidating Raw Material Variability with Pat Tools
8.3 Pat for Excipients: Case Studies by Unit Operations
8.4 Case Study: Magnesium Stearate Blend Uniformity by NIR
8.5 Conclusion
8.6 Acknowledgments
References

Index

End User License Agreement

List of Illustrations

Chapter 1: Excipient Characterization

Figure 1.1 Classification of USP/NF compendial testing methods specified for excipients. Universal tests cover required testing of ID, assay, and impurities. Specific tests are additional methods to better describe and control excipient chemical and physical properties. Most commonly utilized methods for excipients intended for oral solid formulations are noted in bold text.
Figure 1.2 Harmonization status of general compendial analytical testing methods and excipient monographs. Listing includes the stage of review and publication (1–6) and the agency leading the harmonization process. Status indicated reflects public announcement for July 2013.
Figure 1.3 (a) Initial and (b) aged tablets containing drug substance sensitive to local pH environment provided by a minor excipient (<10 wt%). The aged tablet was exposed to 40 °C and 40% RH for 2 weeks.
Figure 1.4 Chemical imaging of drug product stability showing (a) surface-enhanced Raman chemical imaging of between 0.025% and 0.2% 4-aminophenol (degradant/impurity) versus the pixel position in tablets of acetaminophen and PVP. Images were obtained from plotting the median intensity of the principal band of 4-aminophenol normalized butanethiol peak.
Figure 1.5 FTIR images and histograms of HPMC ibuprofen tablets using blends stored at two RH conditions and compressed at two forces: (a) 60% RH blend compressed at 80 cN m; (b) 80% RH blend compressed at 120 cN m.
Figure 1.6 Dispersion of magnesium stearate (MS) lubricant particles in physical blends analyzed by Raman chemical imaging. Quantification of domain size, number, and localization is provided. Blending time increases from 2 to 60 minutes from the top to bottom tablet images.
Figure 1.7 ¹H–¹³C CPMAS solid-state NMR spectra of lactose (a) from different vendors; Kerry-1320016404 (top) and DFE Pharma-42312-7356 [587] (bottom). (b) Zoomed region of Kerry-1320016404 showing five different phases.
Figure 1.8 (a) Low-field NMR analysis of HPMC matrix tablets providing time course images of the darker dry tablet core and lighter gel layer in a static aqueous buffer solution (SEMS, T_r = 1800 ms, NS = 2, T_e = 6 ms) and (b) corresponding area of the dry tablet core over 8 hours in aqueous media.
Figure 1.9 AFM measurements of dicalcium phosphate dihydrate in contact with aspirin (100) surface (a) image 30 minutes after contact demonstrating pits and new crystalline grown on aspirin surface and (b) and (c) force–displacement curves for low and high RH condition, respectively.
Figure 1.10 Number of documents containing the keyword process analytical technology in pharmacy and engineering journals between 1980 and 2014 in Scopus database. The number of documents per year is indicated in (a) and the top contributing US institutions are listed in (b).
Figure 1.11 Fluid bed drying curves for ibuprofen granulation monitored by in-line NIR measurement of the moisture content.
Figure 1.12 Formaldehyde/formic acid formation from oxidation and breakdown of polyethylene glycol and polysorbates.
Figure 1.13 Chemical interaction between BMS-204352 and formaldehyde.
Figure 1.14 Proposed mechanism of degradation of Irbesartan by formaldehyde.
Figure 1.15 Reaction of haloperidol with HMF to form a condensation product.
Figure 1.16 Piperazine reaction with hydrogen peroxide to form N-oxide.
Figure 1.17 Sites susceptible for oxidation.
Figure 1.18 SN2 reaction between API and monochloroacetate impurity.
Figure 1.19 Chemical structure of magnesium stearate and other metallic salts (calcium and zinc) of stearic acids.

Chapter 2: Excipients for Conventional Oral Solid Dosage Forms

Figure 2.1 Crushing strength of tablets of spray-dried lactose samples with varying particle size, compressed at a compaction pressure of 75 MPa and containing 6% water content. From top to bottom () 1–8 µm, (•) 8–16 µm, () 16–24 µm, () 24–32 µm and () 32–45 µm.
Figure 2.2 The effect of moisture content on the tensile strength of binder films. () Gelatin; () methylhydroxyethylcellulose; (•) starch; () acacia; () PVP. The vertical error bar shows limits of error of the means at P = 0.95.
Figure 2.3 Volume median diameter of different disintegrants in different media.
Figure 2.4 The impact of tablet aging on the effectiveness of disintegrants on tablet dissolution.
Figure 2.5 PXRD and SEM images of magnesium stearate from three different vendors.
Figure 2.6 Increase in the concentration of Z-isomer in uncoated 10 mg potency sorivudine tablets containing no colorant (•); tablets without iron oxide but with 11% w/w coating of Opadry^® white (o); 0.2% w/w yellow iron oxide () or () 0.2% w/w red iron oxide after 14-day exposure to fluorescent room light (110-ft candle light).

Chapter 3: Excipients and their Functionality for Enabling Technologies in Oral Dosage Forms

Figure 3.1 Classification of solid dispersions.
Figure 3.2 Methods of preparation for SDs.
Figure 3.3 Classification of lipid-based formulations.
Figure 3.4 Classification of modified release dosage form.
Figure 3.5 Classification of matrix MR systems.

Chapter 4: Excipients used in Biotechnology Products

Figure 4.1 Overview of the chemical and physical instability processes observed in biopharmaceuticals and their consequences on the drug product.
Figure Scheme 4.1 Lumry–Eyring framework of protein aggregation.
Figure 4.2 Schematic reaction coordinate diagram of protein aggregation depicted in Scheme 4.1 on an arbitrary free energy scale. Curved lines indicate kinetic energy barriers. Used with permission from Chi et al. [8, 9].
Figure 4.3 The effect of conformational stability on the aggregation rates of (a) recombinant human interferon-g (rhIFN-g) [43, 49] and (b) recombinant human granulocyte colony stimulating factor (rhGCSF) [10]. Increasing the free energy of unfolding (G_unf) by the addition of sucrose decreased protein aggregation rates. Used with permission from Chi et al. [8, 9].
Figure 4.4 Possible physical degradation pathways and aggregate forms of proteins caused by interfaces, foreign particulates, and leachables. The Figure shows a vial as an example. These aggregation processes may also occur in other upstream operations and in other containers, closures, and delivery devices. Used with permission from Bee et al. [82].
Figure 4.5 Structures of commonly used nonionic surfactants in biopharmaceutical formulations.

Chapter 5: Excipient Standards and Harmonization

Figure 5.1 Sources of potential excipient components. From Ref. [3]; with permission.
Figure 5.2 The components of a pharmaceutical formulation.
Figure 5.3 Components of pharmaceutical product variability.

Chapter 6: Regulatory Information for Excipients

Figure 6.1 IPEC excipient master file guide format.
Figure 6.2 Level of supporting data needed based on the type of new excipient.
Figure 6.3 Three main areas of control within the total excipient control system.

Chapter 7: Development of New Excipients

Figure 7.1 Development chart of new excipients.
Figure 7.2 Development organization and structure.
Figure 7.3 Steps and milestones in product development.
Figure 7.4 Monomers and polymerization techniques.
Figure 7.5 Optimization helix.
Figure 7.6 Analytical characterization of a new excipient.
Figure 7.7 Toxicological studies required for pharmaceutical excipients for oral applications.
Figure 7.8 Relationship between excipient supplier, pharmaceutical company, and health authority.
Figure 7.9 Synthesis of Kollicoat IR.
Figure 7.10 Structure of Kollicoat IR.
Figure 7.11 Comparison of most relevant properties of immediate release coatings: Kollicoat IR versus market standard.
Figure 7.12 LCCC–SEC analysis of Kollicoat IR.
Figure 7.13 Regulatory aspects of Kollicoat IR.
Figure 7.14 Particle structure of Ludiflash (SEM photo).
Figure 7.15 Hardness–disintegration time–compression force profile of Ludiflash (comparison of different tablet presses).
Figure 7.16 Relationship between volume and projected area of spheres.
Figure 7.17 Impact of particle size on binding properties.
Figure 7.18 SEM photos of Kollidon VA 64 Fine.
Figure 7.19 Hardness–compression force profile of vitamin C tablets.

Chapter 8: PATability of Excipients

Figure 8.1 NIR spectra of L-(+) lactic acid (1), stearic acid (2), hydroxypropyl cellulose LF (3), crospovidone NF (4) and magnesium stearate (5).
Figure 8.2 NIR spectra of MCC PH 102 (1), lactose anhydrous DC NF (2), sodium starch glycolate (3) and sodium citrate dihydrate FCC USP (4).
Figure 8.3 Raman spectra of corn starch (1), lactose monohydrate (2), xylitol (3) and magnesium stearate (4).
Figure 8.4 Raman spectra of crospovidone (1), MCC PH 102 (2), MCC PH 200 (3), MCC PH 101 (4) and croscarmellose sodium (5).
Figure 8.5 NIR spectra of calibration blends during fluid bed drying showing the main absorption bands at 1470–1408 nm and 1960–1890 nm.
Figure 8.6 % w/w water versus time for three different batches of a wet granulated product and LOD reference values.
Figure 8.7 (a) Representative preprocessed calibration spectra covering the range for the model generation (b) Calibration curve showing the regression of % w/w magnesium stearate values (gravimetric weight) to the NIR-predicted values.
Figure 8.8 Typical blending profile of magnesium stearate in PB (: Batch 1, : Batch 2) and FB (: Batch 1, : Batch 2).
Figure 8.9 %RSD vs. time for magnesium stearate in PB (: Batch 1, : Batch 2) and FB (: Batch 1, : Batch 2).
Figure 8.10 NIR spectrum of FB (1) pure magnesium stearate (2), and lump found in FB (3).

List of Tables

Chapter 1: Excipient Characterization

Table 1.1 Examples of Excipients with Indication of Chemical Classification, Key Common Compendia Tests, and Other Specific Tests That Can Be Utilized by Manufacturers and Formulation Scientists
Table 1.2 Revised Default Concentration Limits for Heavy Metal Impurities in Excipients and Drug Substances in Monograph <232>
Table 1.3 Molar Phase Composition of Lactose Batches from Vendors Kerry and DFE Pharma
Table 1.4 A Sample of Drug Incompatibility with Excipient Impurities
Table 1.5 Reported Trace Organic Acids Impurities in Pharmaceutical Excipients
Table 1.6 Profiling of Reactive Impurities in Selected Lots of Pharmaceutical Excipients

Chapter 2: Excipients for Conventional Oral Solid Dosage Forms

Table 2.1 Properties of Various Klucel-EF and HPC-L Lots Sourced from Hercules and Nippon Soda
Table 2.2 Functionality-Related Characteristics of a Binder That Could Impact the Manufacturing and Performance of an Oral Solid Dosage Form
Table 2.3 Functionality-Related Characteristics of Disintegrants and Their Potential Impact in an Oral Solid Dosage Form
Table 2.4 Functionality-Related Characteristics of Magnesium Stearate That Could Impact the Manufacturing and Performance of an Oral Solid Dosage Form
Table 2.5 Dissolution of 40 mg Potency Capsules Hand Filled with Granules Containing 1% w/w Magnesium Stearate at Various Time Points During Capsule Filling Showing Impact of Overmixing
Table 2.6 Details of Marketed Coprocessed Excipients and Their Claimed Benefits

Chapter 3: Excipients and their Functionality for Enabling Technologies in Oral Dosage Forms

Table 3.1 Examples of FRCs and Their Testing Methods [3]
Table 3.2 Excipients Used in SDs [17]
Table 3.3 FRCs and FRTs of Excipients Used in SDs
Table 3.4 Excipients Used in LBFs
Table 3.5 FRCs and FRTs for Excipients Used in LBFs
Table 3.6 Methods of Preparation of Nanocrystals
Table 3.7 List of Stabilizers Used for Nanocrystals
Table 3.8 FRCs and FRTs of Excipients Used
Table 3.9 Excipients Used in MR Systems
Table 3.10 Excipients Used in Hydrophobic Matrices
Table 3.11 Excipients Used in Lipid Matrices [17, 44]
Table 3.12 FRCs and FRTs of Polymers Used in Hydrophilic Matrix Systems [3, 40, 49, 50]
Table 3.13 Osmotic Agents Used in Osmotic Pumps [17, 52]
Table 3.14 FRCs and FRTs of Semipermeable Membranes Used in Osmotic Pumps [17, 52]
Table 3.15 Excipients Used as Wicking Agents [17, 53]
Table 3.16 Excipients Used as Pore Formers [17, 52]
Table 3.17 Excipients Used as Flux Regulators [17, 53]
Table 3.18 Excipients Used as Plasticizers [17, 53]
Table 3.19 FRCs and FRTs of Excipients Used in Osmotic Pumps [3]
Table 3.20 Comparison of Multiparticulate Systems with Single-Unit Dosage Forms [58]
Table 3.21 Excipients Used in ODTs [17]
Table 3.22 FRCs and FRTs of Excipients Used in ODTs [65]

Chapter 4: Excipients used in Biotechnology Products

Table 4.1 Factors that Influence Protein Adsorption to Surfaces and Interfaces
Table 4.2 Summary of Excipients Used in Biopharmaceutical Formulations and Their Effects
Table 4.3 Common Excipients Used in Lyophilized Biopharmaceutical Products

Chapter 5: Excipient Standards and Harmonization

Table 5.1 The “Tally” of Known Deaths Due to Ethylene Glycol/Diethylene Glycol Either Being Used in or Determined to Be an Adulterant of Medicines for Human Use
Table 5.2 ICH Guidelines Relevant to Pharmaceutical Excipients
Table 5.3 Excipients Included in the PDG Harmonization Process (as of June 06, 2012)
Table 5.4
Table 5.5 The PDG Harmonization Process [19]

Chapter 6: Regulatory Information for Excipients

Table 6.1 Section P.4 of the CTD, Control of Excipients
Table 6.2 ICH Testing Guidance
Table 6.3 List of IPEC Guidelines and White Papers

Chapter 7: Development of New Excipients

Table 7.1 Main Categories and Examples of New Excipients
Table 7.2 Types of Excipient Developments
Table 7.3 Content of a Type IV Drug Master File and of Proposed Content for a “Regulatory Information File”
Table 7.4 Development of Coprocessed Excipients
Table 7.5 Particle Characteristics of Ludiflash

Chapter 8: PATability of Excipients

Table 8.1 NIR PAT Tools and Conditions Used to Monitor Pharmaceutical Excipients in Blends
Table 8.2 NIR PAT Tools and Conditions to Monitor in Tablets
Table 8.3 NIR Instrument Parameters
Table 8.4 NIR Method Validation Parameters and Results

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Title: Pharmaceutical excipients : properties, functionality, and applications in research and industry / edited by Otilia M Y Koo.

Description: Hoboken, New Jersey : John Wiley & Sons, Inc., [2017] | Includes bibliographical references and index.

Identifiers: LCCN 2016022475| ISBN 9781118145647 (cloth) | ISBN 9781118992418 (PDF) | ISBN 9781118992425 (ePub)

Subjects: | MESH: Excipients | Dosage Forms | Technology, Pharmaceutical–methods

Classification: LCC RS201.E87 | NLM QV 800 | DDC 615.1/9–dc23 LC record available at https://lccn.loc.gov/2016022475

List of Contributors

Arvind Kumar Bansal
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India

Eva Y. Chi
Department of Chemical and Biological Engineering and Center for Biomedical Engineering, University of New Mexico, Albuquerque, NM, USA

Claudia Corredor
Pharmaceutical Development, Bristol-Myers Squibb Company, New Brunswick, NJ, USA

Christopher C. DeMerlis
Global Regulatory Affairs, Colorcon, Inc., West Point, PA, USA

Divyakant Desai
Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, NJ, USA

David Good
Drug Product Science and Technology, Bristol-Myers Squibb Company, New Jersey, USA

Felicitas Guth
BASF SE, Global Research & Formulation Nutrition & Health, Ludwigshafen, Germany

Umesh Kestur
Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, NJ, USA

Sakshi Khurana
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India

Karl Kolter
BASF SE, Global Research & Formulation Nutrition & Health, Ludwigshafen, Germany

R. Christian Moreton
FinnBrit Consulting, Waltham, MA, USA

David R. Schoneker
Global Regulatory Affairs, Colorcon, Inc., West Point, PA, USA

Kunnal Sharma
Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India

Alexa Smith
Global Regulatory Affairs, Colorcon, Inc., West Point, PA, USA

Shreya Thakkar
Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India

Yongmei Wu
Drug Product Science and Technology, Bristol-Myers Squibb Company, New Jersey, USA

Properties, Functionality, and Applications in Research and Industry