Oral Drug Delivery for Modified Release Formulations

Cover
Title Page
Copyright Page
Contents
Preface
List of Contributors
Part I Understanding of Physiology and Anatomy – Factors Influencing Drug Release and Absorption from MR Formulations
	Chapter 1a Composition of Gastric Fluids Under Fasting and Fed Conditions
		1a.1  Gastric Volume
		1a.2  Gastric Acid
		1a.3  Buffer Capacity
		1a.4  Mucus/Viscosity
		1a.5  Enzymes
		1a.6  Surface Tension
		1a.7  Osmolality
		1a.8  Duodenogastric Reflux
		References
	Chapter 1b Composition of the Small Intestinal Contents Under Fasting and Fed Conditions
		1b.1  Small Intestinal Volume
		1b.2  pH Profile Along the Small Intestine
		1b.3  Composition of the Luminal Contents
			1b.3.1 Bile
			1b.3.2 Phospholipids
			1b.3.3 Monoglycerides and Free Fatty Acids
		1b.4  Other Characteristics of Small Intestinal Fluids
			1b.4.1 Buffer Capacity
			1b.4.2 Osmolality
			1b.4.3 Surface Tension
			1b.4.4 Ionic Strength
			1b.4.5 Viscosity
		1b.5  Influence of Age, Gender, and Disease on the Small Intestinal Composition
		References
	Chapter 1c The Luminal Environment in the Proximal Colon
		1c.1  Volume of Luminal Contents
			1c.1.1 Liquid Contents
			1c.1.2 Aspirated Contents and Liquid Fractions
		1c.2  Luminal pH Values
			1c.2.1 Data Collected with Telemetric Capsules
			1c.2.2 Data Collected with Aspirated Samples
		1c.3  Buffer Capacity
		1c.4  Characteristics of Liquid Fraction of Contents
		1c.5  Concluding Remarks
		References
	Chapter 2 Gastrointestinal Transit and Hydrodynamics Under Fasting and Fed Conditions
		2.1 Introduction
		2.2 Imaging Techniques Used for Assessment of Transit Times and Hydrodynamics
		2.3 Oral Cavity and Esophagus
		2.4 Stomach
		2.5 Small Intestine
		2.6 Large Intestine
		2.7 Whole Gut Transit Time
		2.8 Therapy-Related Effects on GI Transit
		2.9 Motility Disorders Affecting the GI Transit of Oral Dosage Forms
		2.10 Patient-Related Effects on GI Transit
			2.10.1 Age
			2.10.2 Gender
			2.10.3 Dietary and Smoking Habits
		2.11 Conclusion
		References
	Chapter 3 Intestinal Epithelium and Drug Transporters
		3.1 Introduction: Oral Drug Absorption General Mechanisms and Influencing Factors
		3.2 Expression of Drug Transporters in the Intestinal Epithelium
		3.3 Uptake Transporters Present at the Intestinal Level
		3.4 Regional Distribution of Uptake Transporters
		3.5 Efflux Transporters at the Intestinal Level
		3.6 Regional Distribution of Efflux Transporters
		3.7 Impact of the Regional Distribution of Enzymes and Transporters in the Intestine on the Enzyme/Transporter Interplay
		3.8 Species Differences in Regional Expression of Uptake and Efflux Transporters
		3.9 Models for Regional Assessment of Intestinal Permeability
		3.10 Use of PBPK to Integrate Formulation and Permeation Knowledge
		3.11 Impact of Regional Solubility and Permeability Along the Intestine
		3.12 Formulation Excipients and Their Potential Modulatory Effects on Transporters
		3.13 Other Confounding Factors Affecting Drug Intestinal Absorption
		3.14 Drug–Drug Interactions
		3.15 Conclusion and Future Challenges
		References
	Chapter 4 The Interplay Between Drug Release and Intestinal Gut-Wall Metabolism
		4.1 The Role of Gut Wall Metabolism in Determining Oral Bioavailability
			4.1.1 Cytochrome P450’s (CYPs)
			4.1.2 Uridine 5-Diphosphate Glucuronosyltransferases (UGTs)
			4.1.3 Sulfotransferases (SULTs)
			4.1.4 Other Drug-Metabolizing Enzymes in the Gut-Wall
			4.1.5 Luminal Degradation in the Gut
		4.2 Factors Affecting Gut Wall Metabolism
			4.2.1 Absorption
			4.2.2 Mucosal Blood Flow
			4.2.3 Protein Binding
			4.2.4 Metabolic Drug–Drug Interactions
			4.2.5 Intestinal Transporter-Metabolism Interplay
		4.3 Preclinical and Clinical In Vivo and In Situ Models for Studying Intestinal Metabolism
		4.4 In Vitro Assays for Studying Intestinal Metabolism
		4.5 Models for Studying Bacterial Degradation
		4.6 In Vitro–In Vivo Extrapolation of Metabolic Clearance and In Silico Models for Predicting In Vivo Gut Wall Metabolism
		4.7 Oral Extended-Release Formulations and Gut Wall Metabolism
		4.8 Excipient Effects on Gut Wall Metabolism
		4.9 Considerations for Intestinal Metabolism in Special Populations
		4.10 Summary
		References
Part II Design of MR Formulations – Considerations, Mechanisms and Technologies
	Chapter 5 Preformulation Considerations for Design of Oral Modified-Release Products
		5.1 Introduction
		5.2 Purpose of MR Formulations
		5.3 Means to Obtain MR Drug Products
			5.3.1 Physicochemical Characterization of the Drug Substance and its Impact on the Design of Modified-release Dosage Forms
		5.4 Ionization Constant – pKa
		5.5 Lipophilicity
		5.6 Solubility
		5.7 Chemical Stability
		5.8 Solid State Characterization
		5.9 Compatibility with Excipients
		5.10 Permeability and Metabolism
			5.10.1 Additional Early Drug Substance Testing
		5.11 Regional Absorption
		5.12 Microbial Stability
			5.12.1 Early Performance Testing of Formulations
		5.13 Quality by Design (QbD) for MR formulations
		5.14 Conclusions
		References
	Chapter 6 The Application of Biopharmaceutics Classification Systems to Modified-Release Formulations
		6.1 Introduction
		6.2 The Use of Biopharmaceutics Classification Systems in Oral Drug Development
		6.3 The Application of Classification Systems to MR Drug Product Development – An Evidence-Based Approach
			6.3.1 Test Sets Used
			6.3.2 Where Do Successfully Marketed Modified-Release Products Fit in Solubility/Permeability Classification Systems?
			6.3.3 Classification System Categorization and Relative Colonic Bioavailability Data
			6.3.4 The Significance of Dissolution Rate and Solubility in the Colon
			6.3.5 Does Ionization State Matter?
			6.3.6 Managing Low Solubility (DCS IIA/IIB)
			6.3.7 Managing Low Permeability (DCS III/IV)
			6.3.8 Beyond Permeability and Solubility: Other Factors Affecting MR Feasibility
				6.3.8.1 Time-period for Drug Release and Absorption
				6.3.8.2 Bacterial Metabolism in the Colon
				6.3.8.3 Uptake Transporters
				6.3.8.4 Gut Wall First-Pass Metabolism
				6.3.8.5 Efflux Transporters
			6.3.9 Relative Bioavailability in the Colon (FrelColon) as a Guide to Extended-Release Formulation Feasibility
			6.3.10 The Properties of Drugs for Delayed-Release (Gastro Protection)
			6.3.11 The Properties of Drugs for Targeting Local Release in the Lower GI Tract
		6.4 Summary
		References
	Chapter 7 Technologies and Mechanisms for Oral Modified Release by Monolithic and Multiparticulate Delivery Systems
		7.1 Introduction
		7.2 Mechanism of Drug Release
		7.3 Manufacturing Processes
			7.3.1 Pelletization Processes
				7.3.1.1 Extrusion–spheronization
				7.3.1.2 Layering Techniques
				7.3.1.3 Direct Pelletization from Powders (Wet Granulation)
			7.3.2 Particulate Production from Liquid Systems (Globulation Methods)
				7.3.2.1 Pelletization Methods Utilizing Melts
				7.3.2.2 Spray Drying and Spray Congealing
				7.3.2.3 Jet Cutting (Prilling)
			7.3.3 Compression Methods
		7.4 Formulation Screening and Characterization
		7.5 Conclusions and Perspectives
		References
	Chapter 8 Lipid-based Formulations
		8.1 Introduction
		8.2 Mechanisms of Lipid-mediated Improvements in Bioavailability
			8.2.1 Increased Drug Solubilization and Dissolution in the GIT
			8.2.2 Increased Intestinal Permeability, Reduced First-pass Metabolism, and Intestinal Efflux
			8.2.3 Promotion of Intestinal Lipid Absorption and Lymphatic Uptake
		8.3 Lipid-based Formulations for Controlled Release
			8.3.1 Solid Lipid Excipient Matrices
			8.3.2 Solid Lipid Nanoparticles
		8.4 Design of Lipid-based Formulations
			8.4.1 Excipient Type and Selection
			8.4.2 Drug Loading
			8.4.3 Formulation Types and the Lipid Formulation Classification System
		8.5 Formulation Screening and Characterization
			8.5.1 Drug Solubility in Lipid-based Formulations
			8.5.2 Self-emulsification and the Effect of Dispersion
			8.5.3 Impact of Digestion
			8.5.4 Assessing Supersaturation and Precipitation
			8.5.5 Identifying Formulation Limiting Factors and the Lipid Formulation Performance Classification System (LF-PCS)
			8.5.6 Characterization of Nanoparticulate Lipid-based Formulations
			8.5.7 Preclinical to Clinical Dose Scaling and Developing In Vitro and In Vivo Correlations
		8.6 Industrial Considerations on LBF
		8.7 Emerging Applications of Lipid-based Formulations
		8.8 Conclusions
		References
	Chapter 9 Strategies for MR Formulation Development: Mesoporous Silica
		9.1 Introduction
		9.2 Technologies
			9.2.1 The Template Method in Synthesis of Mesoporous Silica
				9.2.1.1 M41S Mesoporous Materials
				9.2.1.2 SBA Mesoporous Materials
			9.2.2 Factors Affecting Drug Loading
		9.3 Characterization
		9.4 Stability of Drug Carrier
		9.5 Silica-based Materials for the Modified Release of Poorly Soluble Drugs – In Vitro/In Vivo Applications
			9.5.1 pH-sensitive Silica-based Systems
			9.5.2 Surface-modification of Silica-based Materials
			9.5.3 Lipid Formulations of Silica-based Materials
		9.6 Toxicological Assessment
			9.6.1 In vitro Toxicity
		9.7 Conclusions and Future Directions
		References
	Chapter 10 Hot-Melt Extrusion Technology for Modified-Release (MR) Formulation Development
		10.1 Introduction
		10.2 HME Technology Overview
			10.2.1 Feeding of Raw Materials
				10.2.1.1 Single-screw Extruders: Flood Feeding
				10.2.1.2 Twin-screw Extruders: Starve Feeding
			10.2.2 Conveying and Melting
			10.2.3 Mixing
				10.2.3.1 Dispersive Mixing
				10.2.3.2 Distributive Mixing
			10.2.4 Venting
			10.2.5 Die Pressurization
			10.2.6 Pumping and Shaping
			10.2.7 Postprocessing
			10.2.8 Process Monitoring and Statistical Process Controls
		10.3 General Considerations in Developing MR Dosage Forms Using HME Processing
		10.4 Material Considerations for MR-HME Application
		10.5 Dosage Form Design and Case Studies
			10.5.1 Powder/Granules/Multiparticulates
			10.5.2 Compressed Tablets
		10.6 Characterization of HME Products
			10.6.1 Rheological Techniques
			10.6.2 Use of Diffraction-Based Methods
			10.6.3 Spectroscopic Methods
			10.6.4 Thermal Methods
			10.6.5 Microscopic Techniques
			10.6.6 Chemical Properties
			10.6.7 In Vitro Dissolution/Release Properties
		10.7 Summary
		References
	Chapter 11 Gattefosse: Strategies for MR Formulation Development – Lipids
		11.1 Introduction
		11.2 Lipids Used in SR Matrix
			11.2.1 Names and Structures
			11.2.2 Physicochemical Properties
			11.2.3 Physiological Properties
		11.3 Processing Lipid SR Matrix
			11.3.1 Direct Compression (DC)
				11.3.1.1 Impact of Dual Hydrophilic/Hydrophobic Matrix
				11.3.1.2 Impact of Filler
				11.3.1.3 Impact of Tablet Size
				11.3.1.4 Comparison with Polymer Matrices
			11.3.2 Granulation
			11.3.3 Melt and Mix Methods
			11.3.4 Hot Melt Coating
		11.4 Understanding Drug Release from Lipid Matrix
			11.4.1 Drug Release Mechanism
			11.4.2 Optimizing Drug Release with Formulation and Process Parameter Adjustments
			11.4.3 Drug Release Prediction
		11.5 Characterizing Lipid SR Matrix
			11.5.1 In Vitro Characterization
			11.5.2 In Vivo–In Vitro Correlation (IVIVC)
			11.5.3 Resistance and Alcohol
			11.5.4 Stability
		11.6 Conclusions
		References
	Chapter 12 Polymethacrylates for Modified-Release Formulations
		12.1 Introduction
		12.2 Polymethacrylate Polymers and Their Application in Modified-Release Dosage Forms
		12.3 Protective Coatings
		12.4 Gastro-Resistant Coatings
		12.5 EUDRACAP™ Functional Ready-To-Fill Capsules for Fast Track Development of Sensitive Drugs
		12.6 Modified-Release Technology
		12.7 Modified-Release Formulations for Gastrointestinal Targeting
			12.7.1 Duodenal Drug Release
			12.7.2 Colonic Drug Release
			12.7.3 Modulated Drug Release
		12.8 Matrix Tablets as an Alternative to Modified-Release Multiparticulate Dosage Forms
		12.9 Alcohol-Resistant Formulation Concepts with EUDRAGIT® Polymers
		12.10 Conclusion
		References
	Chapter 13 Strategies for Modified Release Oral Formulation Development
		13.1 Introduction
		13.2 Controlled-Release Drug Delivery Systems
			13.2.1 Osmotic Tablets
				13.2.1.1 Formulation, Characterization, and Evaluation
				13.2.1.2 Manufacturing and Process Considerations
			13.2.2 Multiparticulate Systems
				13.2.2.1 Formulation, Characterization, and Evaluation of Spray-Layered Multiparticulates
				13.2.2.2 Manufacturing and Process Considerations of Spray-Layered Multiparticulates
				13.2.2.3 Formulation, Characterization, and Evaluation of Lipid-Based Multiparticulates
				13.2.2.4 Manufacturing and Process Considerations of Lipid-Based Multiparticulates
		13.3 Dual-Release Drug Delivery Systems and Fixed-Dose Combination
			13.3.1 DuoCap™ Capsule-in-Capsule Technology
				13.3.1.1 Formulation, Characterization, and Evaluation
				13.3.1.2 Manufacturing and Process Considerations
		13.4 Site-Specific Drug Delivery Systems
			13.4.1 Postgastric-Targeted Release
				13.4.1.1 Delayed-Release Acid-Resistant Capsules (DRcaps®)
				13.4.1.2 Enteric Drug Delivery Capsules (enTRinsic™)
			13.4.2 Encode™ Colonic Drug Delivery System
				13.4.2.1 Formulation, Characterization, and Evaluation
				13.4.2.2 Manufacturing and Process Considerations
		13.5 Conclusion/Future Perspectives
		References
Part III Evaluation of MR Formulations
	Chapter 14 Dissolution Equipment and Hydrodynamic Considerations for Evaluating Modified-Release Behavior
		14.1 Introduction
		14.2 Compendial Dissolution Equipment
			14.2.1 USP Apparatus 1 – Basket Apparatus
			14.2.2 USP Apparatus 2 – Paddle Apparatus
			14.2.3 USP Apparatus 3 – Reciprocating Cylinder
			14.2.4 USP Apparatus 4 – Flow-Through Cell
		14.3 USP Apparatus 7 – Reciprocating Holder
		14.4 Noncompendial Dissolution Equipment
			14.4.1 Dynamic Monocompartmental Models
				14.4.1.1 Rotating Beaker Apparatus
				14.4.1.2 Apparatus for Simulating GI Forces Acting on a Dosage Form
				14.4.1.3 Dynamic Gastric Model
				14.4.1.4 Dynamic Colon Model
			14.4.2 Dynamic Multicompartmental Models
				14.4.2.1 Dissolution Stress Test Device
				14.4.2.2 In Vitro Gastrointestinal Model (TIM)
		14.5 Summary and Conclusion
		References
	Chapter 15 The Role and Applications of Dissolution Media for the Investigation of Modified-Release Formulations
		15.1 Introduction
		15.2 Compendial Media
		15.3 Biorelevant Media
			15.3.1 Concept of Different Levels of Complexity for Dissolution Media
			15.3.2 Case Example Level I Media
			15.3.3 Case Example Level II Media
			15.3.4 Case Example Level III Media
			15.3.5 Application of Levels Concept
			15.3.6 Bicarbonate Buffer
		15.4 Biphasic Dissolution Media
		15.5 Summary and Outlook
		References
	Chapter 16 Biorelevant Dissolution Testing to Forecast the In Vivo Performance of Modified-Release Formulations
		16.1 Introduction
		16.2 Factors Affecting the In Vivo Performance of MR Products
			16.2.1 Physiological Aspects
		16.3 Drug-Related Aspects
		16.4 Formulation-Related Aspects
		16.5 Biorelevant In Vitro Dissolution Test Methods
		16.6 General Remarks on Dissolution Media
		16.7 General Remarks on Dissolution Test Devices
		16.8 Dissolution Test Methods for the Simulation of Regional Transit Conditions
			16.8.1 Simulation of Fasted State Administration of Oral MR Products
			16.8.2 Simulation of Fed State Administration of Oral MR Products
		16.9 Criteria for the Selection of a Suitable Biorelevant In Vitro Dissolution Method
		16.10 Conclusion
		References
	Chapter 17 In Vitro and Ex Vivo Dissolution Tests for Considering Dissolution in the Lower Intestine
		17.1 Introduction
		17.2 Dissolution Tests for pH-responsive Delivery Systems
			17.2.1 Dissolution Tests Using Compendial Apparatuses
			17.2.2 Dissolution Tests Using Noncompendial Apparatuses
		17.3 Dissolution Tests for Enzyme-triggered Delivery Systems
			17.3.1 Dissolution Tests Using Enzyme-supplemented Compendial Media
			17.3.2 Dissolution Tests Using Rat Cecal Contents
			17.3.3 Dissolution Tests Using Human Fecal Contents
			17.3.4 Dissolution Tests Using Bacteria-containing Media
		17.4 Conclusion
		References
	Chapter 18 Preclinical Evaluation – Animal Models to Evaluate MR Formulations
		18.1 Introduction
		18.2 When to Use Nonclinical Models in the Development of Modified-release Formulations
		18.3 Physiological Factors in Animals Used to Investigate Modified-release Formulations
			18.3.1 The Stomach
			18.3.2 The Small Intestine
			18.3.3 The Large Intestine
		18.4 Intestinal Site-specific Administration in Animals
		18.5 Evaluation of Modified-release Formulations in Animal Models
			18.5.1 Rodents – Rats
			18.5.2 Dogs
			18.5.3 Pigs and Mini-Pigs
			18.5.4 Monkeys
		18.6 Conclusions
		References
	Chapter 19 In Vitro–In Vivo Correlations for Modified Release Formulations
		19.1 Introduction
		19.2 Definitions of IVIVC
		19.3 Correlation Levels
		19.4 Considerations in IVIVC Development
			19.4.1 In Vivo Absorption
			19.4.2 In Vitro Dissolution Methodology
		19.5 IVIVC Models
		19.6 Predictability of IVIVC
		19.7 Use of IVIVC
			19.7.1 Setting In Vitro Dissolution Limits
			19.7.2 Optimization of Formulations
			19.7.3 Dissolution and IVIVC as a Surrogate for In Vivo Data
		19.8 Limitations of an IVIVC
		19.9 Conclusion
		Acknowledgment
		References
	Chapter 20 Application of the Simcyp Population-based PBPK Simulator to the Modelling of MR Formulations
		20.1 Introduction
		20.2 The ADAM Oral Absorption Model
		20.3 Handling of Modified Release Formulations
		20.4 System Information
		20.5 MR Case Studies/Examples
			20.5.1 Introduction
			20.5.2 Bottom-up Methods
			20.5.3 Virtual Bioequivalence, Biowaivers, and Setting Dissolution Specifications
			20.5.4 Physiologically Based IVIVC
		20.6 Conclusion
		References
	Chapter 21 PK-Sim® for Modeling Oral Drug Delivery of Modified-Release Formulations
		21.1 General Introduction on PK-Sim® and MoBi®
		21.2 Gastrointestinal Transit and Absorption Model
		21.3 Formulations Available in PK-Sim®
		21.4 Dissolved Form
		21.5 Zero and First-order Release and Lint80 Release
		21.6 Weibull
		21.7 Particle Dissolution
			21.7.1 Direct Use of MR In Vitro Release Profiles
		21.8 Dissolution Media and Transit Times
		21.9 Case Studies
			21.9.1 Use of a Fitted In Vitro Dissolution Function as a Direct Drug Input
			21.9.2 Prediction of Plasma Concentration After Administration of an Enteric-coated Tablet
		21.10 Outlook
		References
	Chapter 22 Clinical Evaluation – In Vivo Bioequivalence Assessment of MR Formulations
		22.1 Introduction/Historical Background
		22.2 Clinical Evaluation of New and Generic Modified-Release Formulations
			22.2.1 Pharmacokinetic Studies
			22.2.2 The Modified-Release Formulations in the Milieu of the Gastrointestinal Tract
			22.2.3 Influence of Drug Properties
			22.2.4 Influence of Physiological Factors
			22.2.5 Food Effect and Drug Interactions
			22.2.6 The Use of In Vitro/In Vivo Correlations (IVIVC) in Clinical Evaluation of Controlled-Release Formulations
			22.2.7 Bioequivalence of MR Products: An Ever-Evolving Field
			22.2.8 Approaches and Metrics Associated with the Modified-Release Bioequivalence Assessment
			22.2.9 Current Regulatory Requirements for the Demonstration of Bioequivalence of MR Formulations
		22.3 Summary
		References
	Chapter 23 US Regulatory Considerations for Modified Release Products
		23.1 Introduction
		23.2 Clinical Development Programs for Nongeneric MR Dosage Forms
			23.2.1 Clinical Development Programs for Obtaining Efficacy and Safety Information
				23.2.1.1 Bioequivalence Trials
				23.2.1.2 Bioavailability Trials in Combination with PK/PD Trials or with Clinical Efficacy and Safety Trials
			23.2.2 Clinical Development Program for Product Characterization
				23.2.2.1 In Vivo Evaluation of Multiple Strengths
				23.2.2 Clinical Development Program for Product Characterization
				23.2.2.3 Assessment of Alcohol Effect
				23.2.2.4 Dosage Instructions in Patients with Changed Clearance
			23.2.3 Modeling and Simulations to Support Product Development
		23.3 Considerations for Clinical Development Programs for Generic MR Products
		23.4 Studies to Support Postapproval Changes for MR Products
			23.4.1 Different Levels of Postapproval Changes
			23.4.2 Additional In Vitro Dissolution Evaluations
			23.4.3 In vitro/In Vivo Correlations (IVIVC)
		23.5 Summary
		Disclaimer
		References
	Chapter 24 Regulatory Assessment, European Perspective
		24.1 Introduction
		24.2 Quality of Oral Extended-Release Products
			24.2.1 Pharmaceutical Development
				24.2.1.1 Quality Target Product Profile and Critical Quality Attributes
				24.2.1.2 Manufacturing Process
				24.2.1.3 Dissolution Method and Discriminatory Power
				24.2.1.4 Bioavailability Studies
			24.2.2 In Vitro–In Vivo Correlation
			24.2.3 Setting Specifications
				24.2.3.1 Case (A) Level A IVIVC is Established
				24.2.3.2 Case (B) No IVIVC is Established
			24.2.4 Control Strategy
		24.3 Quality by Design in Pharmaceutical Development
			24.3.1 Risk Assessment
			24.3.2 Design Space
			24.3.3 Control Strategy
		24.4 Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms
			24.4.1 Rationale for Development
			24.4.1.1 Pharmacokinetic Studies
			24.4.1.2 Prolonged Residence Time in the Stomach
			24.4.1.3 Clinical Studies
			24.4.1.4 Generic Modified Release Formulations
		24.5 Concluding Remarks
		References
	Chapter 25 Industry Perspectives for the Evaluation of MR Formulations
		25.1 Introduction
		25.2 Commercially Marketed MR Products – Historical Trends and Emerging Themes
		25.3 Early-stage MR Product Development
		25.4 Current Themes for Industrial MR Product Evaluation: (1) Dissolution Acceleration
		25.5 Current Themes for Industrial MR Product Evaluation: (2) Hydro-ethanolic Studies
		25.6 Conclusion
		References
Index
EULA