CONTENTS SECTION I ESSENTIALS OF DOSAGE FORM DESIGN SECTION II SOLID DOSAGE FORMS CHAPTER 1 PREFORMULATION STUDIES CHAPTER 2 TABLETS.

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1 Contents (9) CONTENTS Preface... (v) Acknowledgement... (vii) SECTION I ESSENTIALS OF DOSAGE FORM DESIGN CHAPTER 1 PREFORMULATION STUDIES Introduction... 3 Organoleptic Properties... 5 Purity and Impurity... 5 Particle Size, Shape and Surface Area... 7 Solubility... 8 Determination of Solubility... 9 ph and Solubility... 9 Particle Size and Solubility pk a and Solubility Salt Formation Ionization Constant Partition Coefficient Permeation through Biological Membrane Polymorphism and Crystal Properties.. 16 Crystal Characteristics and Bioavailability Crystal Characteristics and Chemical Stability Crystal Property and Physical Stability. 18 Dissolution Factors Affecting Dissolution Intrinsic Dissolution Biopharmaceutics Classification System (BCS) Determination of Solubility (Limits of Solubility Term) Determination of Permeability (Limits of Permeability Term Particulate Dissolution Stability Solid State Stability Effect of Temperature on Stability Effect of Humidity on Stability Effect of Light Effect of Air (Oxygen) Solution State Stability Drug Excipient Compatibility Studies Chromatographic Method Differential Thermal Analysis Diffuse Reflectance Spectroscopy Miscellaneous Properties Density Flowability Compactibility or Compressibility Wettability Model Questions References SECTION II SOLID DOSAGE FORMS CHAPTER 2 TABLETS Introduction Preformulation/Formulation Development Studies (ix)

2 (x) Contents Systematic Approach to Design A Tablet Dosage Form Tablet Components Active Ingredient (Drug) Excipients Manufacture of Tablet Methods of Manufacture Direct Compression Excipients Water Soluble Diluents (Filler binders) Water Insoluble Fillers Co processed Excipients Factors Influencing Direct Compression Formulation Compressibility Flowability Lubrication Morphology of Particles Co processed Active Ingredients Manufacturing Process Granulation Characterization of Granules Surface Shape Factor Granule Density and Packing Principle of Wet Granulation Excipients Diluents Binders Lubricants Glidants Disintegrants Other Polymers Super Disintegrants High Shear Granulation Flow Process Dry Granulation Flow Process Compression Coated Tablet Application of the Method Excipients Factors affecting Drug Release Effect of Core Formulation Effect of the Type of Polymer Effect of Particle Size of Polymer Effect of Porosity of the Coat Effect of Core Coat Ratio Effect of Compression Force Effect of Position of Core in Coated Layer Effect of Compressibility of Materials 100 Effect of Drug Coat Interaction Method of Manufacture Equipments Effervescent Tablets Formulation Ingredients Active Ingredient Excipients Effervescing Components Other Effervescent Materials Binders Diluents Lubricants Other Ingredients Method of Manufacture Wet Granulation Method Dry Granulation Method Fluidized Bed Granulation Method Chewable Tablets Factors Influencing Formulation Excipients

3 Contents (xi) Organoleptic Agents (Sweetner, Flavor, and Color) Manufacturing Considerations Buccal Tablets Advantages of Buccal Drug Delivery Manufacturing Considerations Sublingual Tablets Manufacturing Considerations Vaginal Tablets Manufacturing Considerations Rectal Tablets Advantages of Rectal Drug Delivery Dispensing Tablets Tablet Coating Characteristics of Tablets Types of Coating Sugar Coating Film Coating Coating Process Defects in Coating Evaluation of Tablets Physical Characteristics Mouth Dissolving Tablets Introduction Advantages Ideal Characteristics of MDTs Disadvantages Characteristics of Drugs Suitable for MDT Principles Involved in MDT Formulation Techniques/Methods used for MDT Formulation Freeze Drying or Lyophilization Molding Direct Compression (DC) Effervescent Agents Cotton Candy Process Spray Drying Sublimation Mass Extrusion Nanonization Fast Dissolving Films Model Questions References CHAPTER 3 CAPSULES Introduction Advantages Disadvantages Gelatin Capsule Physical Property of Gelatin Preparation of Gelatin Hard Gelatin Capsules Manufacture of Hard Gelatin Capsule Shells Filling of Powders in Capsules Excipients used in the Formulation Formulation Parameters Compatibility with Gelatin Doses Solubility Shape of the Particle Particle Size Hygroscopic Compounds Adhesion Wetting Properties Moisture Sensitivity of the Drug Lubrication Formulation

4 (xii) Contents Hard Gelatin Capsule for Multiple Units Hard Gelatin Capsule for Semi Solid and Liquid Preparation Excipients Filling and Sealing Modification of Capsule Shell Property Soft Gelatin Capsule Advantages Disadvantages Size and Shape of Soft Gelatin Capsule Manufacture of Soft Gelatin Capsule. 175 Preparation of Gelatin Melt Composition of Soft Gel Shell Preparation of Fill Material Encapsulation Drying Inspection In process Control Finished Product Testing Polishing Packaging Model Questions References CHAPTER 4 SUPPOSITORIES Rectal and Vaginal Drug Delivery System Introduction Anatomy and Physiology of the Rectum Absorption of Drugs from the Rectum Physiological Factors Formulation Considerations Drug Physical State Bulk Density and Surface Properties Solubility and Partition Coefficient pk a Amount of the Drug Additives Suppository Base Desired Characteristics of Suppository Base Classification of Suppository Base Natural Bases Synthetic Bases Semisynthetic Bases Hydrogels Criteria for Selection of Bases Melting Temperature Range Iodine Value Hydroxyl Index Method of Manufacture Fusion Method Compression Method Injection Molding Calibration of Moulds Use of Displacement Value In process Quality Control Evaluation of Suppositories Physical Tests Chemical Tests Some Manufacturing Problems and their Solutions

5 Contents (xiii) Bioavailability of Drug from Suppositories Other Rectal Formulations Vaginal Drug Delivery Applications Model Questions References SECTION III SEMISOLID DOSAGE FORMS CHAPTER 5 SEMISOLIDS Introduction Types of Semisolid Dosage Forms Advantages Disadvantages Factors Influencing Drug Absorption from Topical Formulation Permeation through Skin Skin Microflora Skin Temperature Penetration/Permeation Enhancers Formulation Ingredients Drugs Base Preservative Chelating Agent Humectants Antioxidants Emulsifying Agents Perfumes Creams Formulation Considerations Manufacture of Cream Instability of Creams Ointment Formulation Consideration Selection of Ointment Base Classification of Ointment Bases Oleaginous Base Absorption Base Water Removable Base or Emulsion Base Water soluble Bases Manufacture of Ointments Fusion Method Trituration Method Chemical Method Emulsification Method Packaging Glass Containers Plastic Containers Evaluation of Semisolid Preparations 242 Rheological Properties Model Questions References CHAPTER 6 GELS Introduction Characteristics of Gel Uses Classification of Gels Structure Swelling Syneresis Rheology Gelling Agents Natural Gums Tragacanth

6 (xiv) Contents Alginates Carrageenan Xanthan Gum Pectin Guar Gum Gelatin Agar Chitosan Cellulose Derivatives Carboxymethyl Cellulose Ethyl Cellulose Hydroxypropyl Cellulose Polyethylene Acrylic Polymers Dispersible Colloidal Solids Microcrystalline Cellulose Clays Microcrystalline Silica Surfactants Manufacture of Gel Thermal Changes Chemical Reaction Flocculation Stability Evaluation of Gel ph Viscosity Homogeneity Grittiness Spreadability Extrudability Skin Irritation Drug Content In vitro Diffusion In vivo Studies Model Questions References SECTION IV LIQUID DOSAGE FORMS CHAPTER 7 SUSPENSIONS Introduction Types of Suspensions Oral Suspensions Topical Suspensions Parenteral Suspensions Ophthalmic Suspensions Development of Suspensions Characteristics of a well Formulated Suspension Formulation Considerations Interfacial Properties Wetting of Particles Zeta Potential Crystal Growth Aggregation and Caking Sedimentation Flocculated Suspension Prefomulation Crystal Properties and Polymorphism 281 Particle Size and Surface Area Dissolution Rheology (Flow property) Drug Excipient Compatibility Formulation Excipients Dispersing Agents Wetting Agents Deflocculating Agents Protective Colloids Electrolytes Suspending Agents Cellulose Derivatives Polysaccharides and Gums

7 Contents (xv) Synthetic Polymers Buffers Humectants and Cosolvents Preservatives Antioxidants Colors Flavors or Fragrances Sweetening Agents Manufacturing Process Processing Equipments Preparation of Suspension Dispersion of Drug Particles Preparation of Structured Vehicle Addition of Formulation Excipients Incorporation of Drug Dispersion Deaeration and Volume Make up Homogenization Stability Studies Microbial Stability Kinetics of Drug Degradation Evaluation Toxicity (Safety) Test Model Questions References CHAPTER 8 EMULSIONS Introduction Advantages of Emulsions Theory of Emulsification Surface Tension Theory Harkin s Oriented Wedge Theory Plastic or Interfacial Film Theory Viscosity Theory Formulation Ingredients Immiscible Phases Emulsifiers Emulsion Stabilizers Preservatives Antioxidants Formulation of Emulsions Optimization of Formulation Processing Parameters Methods of Preparation Equipments for Emulsification Methods of Manufacture of Emulsions in the Laboratory Continental or Dry Gum Method Wet Gum Method Forbes Bottle Method In Situ Soap Method Pilot Plant Scale Up Stability of Emulsion Creaming Flocculation Coalescence Chemical Stability Stability Studies and Shelf Life Physical Parameters Visual and Microscopic Examination. 339 Globule Size Analysis Change of Viscosity Electrophoretic Behavior Electrical Conductivity Chemical Parameters Oxidation and Hydrolysis Adverse Temperature Centrifugation Agitation Bioavailability from Oral Emulsions Model Questions References

8 (xvi) Contents CHAPTER 9 MICROEMULSIONS Introduction Advantages Disadvantages Properties of Microemulsion Uses Types of Microemulsion Phase Inversion Temperature (PIT) Theory of Microemulsion Thermodynamic Theory Formulation Consideration Conditions Necessary to Produce Microemulsions Phase Diagrams Dynamic behavior of Microemulsion. 356 Experimental Designing Solubilization of Drug Molecules in Microemulsions Characteristics of Microemulsion Biocompatibility Solubility and Stability R ratio Methods of Drug Delivery Oral Delivery Parenteral Delivery Topical Delivery Preparation of Microemulsion Phase Titration Method Phase Inversion Method Evaluation of Microemulsion In vitro Drug Release Studies Model Questions References CHAPTER 10 SOLUTIONS Introduction Advantages Limitations Formulation Parameters Solubility Solubilization ph Buffer Cosolvent Dielectric Constant Surface Active Agents Complexing Agents Hydrotrophy Chemical Modification Particle Size Reduction Solvents for Aqueous Preparations Water Potable/Drinking Water Purified Water Reverse Osmosis Water for Injections Other Grades of Water Alcohol Diluted Alcohol Polyhydric Alcohol Solvents for Nonaqueous Preparations Oils Mineral oil (Liquid paraffin) Dimethylsulphoxide (DMSO) Other Solvents Formulation Excipients Viscosity Enhancer Buffers

9 Contents (xvii) Preservatives Density Modifiers Isotonicity Modifiers Antioxidants Sweetening Agents Flavors and Perfumes Colors Types of Solution Formulations Manufacture of Solution Raw Materials Mixing Equipments Clarification/Filtration Gravity Filtration Vacuum Filtration Pressure Filtration Meta Filter Stability Studies Physical Stability Chemical Stability Packaging Containers and Closures Model Questions References SECTION V GASEOUS DOSAGE FORMS CHAPTER 11 AEROSOLS Introduction Types of Aerosol Products Advantages Disadvantages Basic Components of Aerosol or Pressure Pack Product Concentrate Propellants Liquefied Gas Propellant Coding of Propellants Mixture of Liquefied and Compressed Gases Two phase System Three phase System Containers Tinplate Containers Aluminium Containers Stainless Steel Containers Glass Containers Plastic Containers Valves Actuators Foam Valve Metering Valve Types of Aerosol System Water based System (Aerosol) Solution System Dispersion/Suspension System Intranasal Aerosol Manufacture of Pharmaceutical Aerosol Preparation of Product Concentrate. 435 Filling of Product Concentrate Filling of Propellant Pressure Filling Cold Filling Pressure Filling Quality Control of Pharmaceutical Aerosol Propellants Valve, Actuator and Dip Tube Method Interpretation Containers Weight Variation

10 (xviii) Contents Leak Test Spray Test Evaluation of Aerosol Stability Studies Product Concentrate and Propellant Container Valve Assembly Advancement in Aerosol Technology Model Questions References SECTION VI STERILE PRODUCTS CHAPTER 12 STERILE PRODUCTS Introduction Preparative Steps Planning, Scheduling and Control Materials Management Personnel Management Documentation Standard Operating Procedures Master File Environmental Records Validation Records Material Records Distribution Records Complaint File Preparation of Facilities and Equipments Environment Air Control Personnel Equipments Materials Environmental Control Air Handling Unit Ventilation Filtration of Air Testing of HEPA Filter Test for Efficiency (Hot DOP Test) Integrity Testing Evaluation of Air Filter System Evaluation of Airflow Resistance Evaluation of Filter Efficiency Evaluation of Service Life Evaluation of Arrestance Temperature and Humidity Control Control of Airborne Contamination Packaging Materials Rubber Components Elastomeric Closures Washing Siliconization Sterilization Glass Components Washing Sterilization of Containers Sterilization of Plastic Containers Moist Heat Sterilization Radiation Sterilization Gas Sterilization Model Questions References CHAPTER 13 STERILIZATION Introduction Pyrogens Microbial Death Kinetics Selection of Sterilization Process

11 Contents (xix) Thermal Sterilization Dry Heat Sterilization Types of Sterilizer Natural Convection Type (Hot Air Oven) Forced Convection Type Oven Dry Heat Tunnels Effect of Higher Temperature on Materials Moist Heat Sterilization Steam Sterilization Advantages Disadvantages Factors Influencing Sterilization Cycle Chemical Cold Sterilization Ethylene Oxide Hydrogen Peroxide Hydrogen Peroxide and Steam Chlorine Dioxide Ozone Chlorine Bleach Formaldehyde Other Sterilizing Agents Radiation Sterilization Gamma Radiation ( radiation) Electron Accelerators Filtration Types of Filters and Filtration Mechanism Screen Filtration Depth Filtration Cake Filtration Membrane Filtration Validation of Sterilization Process Model Questions References CHAPTER 14 SMALL VOLUME PARENTERALS Introduction Formulation Considerations Route of Administration Vehicle Types of Vehicle Water for Injection Cosolvents Nonaqueous solvent Solubilization Effect of Additives Buffers Antioxidants Preservatives Tonicity Effect of Containers Glass Rubber Closures Manufacture of the Product Preparation of Parenteral Solution Preparation of Parenteral Suspension Preparation of Freeze Dried Powder Injectables Preparation of Sterile Dry Fill Powders Lyophillization Stability Studies Model Questions References CHAPTER 15 LARGE VOLUME PARENTERALS Introduction Formulation Consideration Physiological Physicochemical

12 (xx) Contents Physical Packaging Materials Stabilization Raw Materials Types of Formulation Solutions Electrolyte Solutions Carbohydrate Solutions Fat Emulsions Total Parenteral Nutrition Nutritional Content Complications Intravenous Admixture Parenteral Incompatibility Model Questions References CHAPTER 16 OPHTHALMIC PRODUCTS Introduction Anatomy of Eye Absorption of Drug from the Eye Therapeutic Classification of Ophthalmic Products Formulation Consideration Development of Ophthalmic Formulation Excipients Wetting Agents Buffer Systems Viscosity Enhancing Agent Antioxidants Preservatives Tonicity (Osmolarity) Adjusting Agent Ophthalmic Solutions Factors Influencing Formulation Method of Manufacturing Ophthalmic Solution does not Contain any Gum Ophthalmic Solution Containing a Gum Ophthalmic Suspensions Preservatives Method of Manufacturing Ophthalmic Ointments Method of Manufacture Ophthalmic Gel Method of Manufacture Irrigating Solutions Method of Manufacture Model Questions References CHAPTER 17 CONTACT LENSES Introduction Soft Contact Lens Advantages of Contact Lens Manufacturing Process Molding Method Lathe Process Finishing Problems Associated with Contact Lens Quality Control Contact Lens Care Products Wetting Solutions Cleaning Solutions Soaking Solution Model Questions References

13 Contents (xxi) SECTION VII PHARMACEUTICAL PACKAGING CHAPTER 18 PACKAGING MATERIAL Functions of Packaging Protective Function Physical Protection Storage Function Loading and Transport Function Identification Mechanical Protection Environmental Protection Chemical Protection Biological Protection Containment Transfer of Information Marketing Convenience Security Cost Aseptic Packaging Systems Fill and Seal Erect, Fill, and Seal Form, Fill, and Seal Thermoform, Fill, and Seal Blow Mold, Fill, and Seal Bulk Storage and Packaging Selection of Packaging Materials Product Distribution System Market Manufacturing Facility Types of Packaging Materials Packaging Components Paper and Board Glass Types of Glass Type I or Borosilicate Glass Type II or Treated Soda Lime Glass Type III or Regular Soda Lime Glass Type NP or General Soda Lime Glass. 618 Manufacture of Glass Types of Glass Containers Ampoule Bottles, Vials, and Syringes Plastic Packaging Components Polyethylene Polypropylene Polyvinyl Chloride (PVC) Polystyrene Nylon (Polyamide) Polycarbonate Acrylic Multi polymers (Nitrile Polymers) Polyethylene Terephthalate (PET) Plastic Containers Interaction between Plastic and Product Permeation Leaching Sorption Change in Physicochemical Properties Chemical Reaction Closures Types of Closures Threaded Screw Cap Continuous Threaded (CT) Closures CT Plugs Combination Closure Crown Cap Roll on Type Friction Fit Closures Lug Style Closures

14 (xxii) Contents Snap Fit Closures Press on Vacuum Caps Vial and Bottle Stoppers Rubber Stoppers Performance of Elastomeric Closure. 635 Flanged Plug Elastomeric Stoppers Flanged Hollow Elastomeric Plug with Cutouts Metal Closure with an Elastomeric Disk Tube Closures Special Closures Dispensing Closures and Closure with Applicators Fitment Closure Spray and Pump Dispensers Precise Dose Dispensing Closure Single Dose Closures Liner less Closures Child Resistant (CR) Closures Aerosol Closures Closure Liners Selection of Closure Liner Composition of Closure Liners Non Reclosable Packages Pouches Peelable Seals Collapsible Tubes Metal Tubes Tin Aluminium Lead Plastic Tubes Tamper Resistant Packaging Film Wrapping End Folded Wrapping Fin Seal Wrapping Shrink Wrapping Blister Packing Bubble Packing Shrink Banding Secondary Packaging Materials Boards Evaluation of Packaging Materials Glass Containers Water Attack Test Powdered Glass Test Preparation of Sample Plastic Containers Physicochemical Test Elastomeric Closures Secondary Packaging Materials Coding in Pharmaceutical Packaging. 661 Symbology Current Trends in Packaging Types of Packaging Machines Model Questions References SECTION VIII VALIDATION OF PHARMACEUTICAL PROCESSES CHAPTER 19 VALIDATION OF PHARMACEUTICAL PROCESSES Introduction Situations need Pharmaceutical Validation Advantages of Validation Major Phases of Validation Protocols of Validation

15 Contents (xxiii) Types of Validation Validation Master Plan Content of Validation Master Plan Validation of Analytical Methods Strategy for Methods Validation Types of Procedures to be Validated. 679 Validation Report Equipment Validation/Qualification The Pharmaceutical Process Equipment Design Qualification (DQ) Installation Qualification (IQ) Operation Qualification (OQ) Performance Qualification (PQ) Environmental Considerations Cleaning and Clean Room Standards. 685 Process Validation Pre requisites for Process Validation. 686 Priority of Process Validation Sterile Products and their Processes Nonsterile Products and their Processes Approaches to Validation Process Types of Process Validation Prospective Validation Formulation Development Process Development Retrospective Validation Concurrent Validation Revalidation Stages of Process Validation Process Design (Stage I) Process Qualification (Stage II) Continued Process Verification (Stage III) Expert Evaluation The Validation Report Validation of Cleaning Process Type of Contamination Validation of Cleaning Process Model Questions References CHAPTER 20 ICH GUIDELINES Quality Guidelines Efficacy Guidelines Safety Guidelines Finalized Guidelines (Step 4) Multidisciplinary Guidelines New Codification as per November Stability Testing of New Drug Substances and Products, [Q1A (R2)] 709 Climatic Zones Significant Change Testing Frequency Stability Testing Photostability Testing of New Drug Substances and Products [Q1b] Source of Light Decision on Results Stability Testing for New Dosage Forms [Q1C] Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (Q1D) Evaluation of Stability Data (Q1E) Stability Data Package for Registration Applications in Climatic Zones III and IV, (Q1F)

16 (xxiv) Contents General Case Validation of Analytical Procedures [Q2 (R1)] Text and Methodology Types of Analytical Procedures to be Validated Validation of Analytical Methodology 724 Identification Assay and Impurity Test(s) Impurities in New Drug Substances, [Q3A (R2)] Classification of Impurities Impurities in New Drug Products, Q3B (R2) Impurities: Guideline for Residual Solvents, Q3C(R5) Classification of Residual Solvents by Risk Assessment Pharmaceutical Development, ICH Q Pharmaceutical Quality System, ICH Q Elements of Pharmaceutical Quality System Knowledge Management Quality Risk Management Design and Content Consideration Quality Manual Quality Policy Management Responsibility Quality Planning Resource Management Internal Communication Management Review Model Questions References Index