Essential Chemistry for Formulators of Semisolid and Liquid Dosages
By Vitthal S. Kulkarni and Charles Shaw
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- Unique coverage of the underlying chemistry that makes possible stable dosages
- Quality content written by experienced experts from the drug development industry
- Valuable information for academic and industrial scientists developing topical and liquid dosage formulations for pharmaceutical as well as skin care and cosmetic products
Vitthal S. Kulkarni
Vitthal Kulkarni, Ph.D. is Scientific Advisor at DPT Laboratories San Antonio, Texas. After earning Ph.D. in Chemistry at National Chemical Laboratory, Pune, India in the area of surface/colloid chemistry, Dr. Kulkarni studied lipid monolayers, bilayers, self-assembled nano-structures, and protein electron crystallography at various institutions including Université de Provence, Marseille, France, JEOL Ltd., Tokyo, Japan, Vanderbilt University, Nashville, Tennessee, University of Minnesota, Austin, Minnesota and Yale University, New Haven, Connecticut before moving into industry. Dr. Kulkarni has been with DPT Laboratories since 2003. Dr. Kulkarni is experienced in developing and characterizing various non-invasive drug delivery systems including topical drug delivery systems comprised of liposomes, and nano-particles, emulsions and nasal spray products. He has published scientific research articles in peer reviewed journals, patents, book chapters, and edited a book titled Handbook of Non-Invasive Drug Delivery Systems: Science and Technology. He is a current member of American Association of Pharmaceutical Scientists.
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- Rating: 5 out of 5 stars5/5Excelente introduccion a los temas, es facil de entender y leer, lo compare en fisico para mi coleccion.
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Essential Chemistry for Formulators of Semisolid and Liquid Dosages - Vitthal S. Kulkarni
Essential Chemistry for Formulators of Semisolid and Liquid Dosages
Vitthal S. Kulkarni, Ph.D.
Scientific Advisor, Research and Development, DPT Laboratories, Ltd., San Antonio, TX, USA
Charles Shaw, Ph.D.
Scientific Advisor, Research and Development, DPT Laboratories, Ltd., San Antonio, TX, USA
Table of Contents
Cover image
Title page
Copyright
Preface
Chapter 1. Introduction
Chapter 2. Surfactants, Lipids, and Surface Chemistry
2.1. Introduction
2.2. Types of Surfactants
2.3. Natural Surfactants
2.4. The Role of Surfactants in Pharmaceutical Formulations
2.5. Surface Chemistry for Pharmaceutical Formulations
2.6. Conclusion
Chapter 3. Drug Delivery Vehicles
3.1. Introduction
3.2. Emulsion Drug Delivery Systems
3.3. Liposome Drug Delivery Systems
3.4. Other Nanodrug Delivery Systems
3.5. Conclusion
Chapter 4. Formulating Creams, Gels, Lotions, and Suspensions
4.1. Introduction
4.2. Creams and Lotions
4.3. Gels, Ointments, and Suspensions
4.4. Formulating with Liposomes
4.5. Excipients
4.6. Conclusion
Chapter 5. Use of Polymers and Thickeners in Semisolid and Liquid Formulations
Background
5.1. Polymers as Styling Agents
5.2. Polymers as Conditioning Agents
5.3. Polymers as Preservatives
5.4. Polymers as Penetration Enhancers
5.5. Polymers as Thickening and Suspending Agents
5.6. Characteristics of Commonly Used Thickening, Gelling, and Suspending Agents
Chapter 6. Aerosols and Nasal Sprays
6.1. Aerosols
6.2. Nasal Sprays
Chapter 7. Preparation and Stability Testing
7.1. How Formulations Are Put Together
7.2. Mixing Systems
7.3. Quality by Design (QbD) for Formulation and Process Development
7.4. Stability Testing
Chapter 8. Particle Size Analysis: An Overview of Commonly Applied Methods for Drug Materials and Products
8.1. Introduction
8.2. Laser Diffraction
8.3. Particle Size Evaluation by Microscopy
8.4. Conclusion
Chapter 9. Rheological Studies
9.1. General Terms and Definitions
9.2. Instruments and Measuring Geometries
9.3. Material Behavior
9.4. Rheological Studies
9.5. Practical Application of Rheological Data
Chapter 10. Microscopy Techniques
10.1. Introduction
10.2. Optical Microscopy
10.3. Scanning Electron Microscopy
10.4. Transmission Electron Microscopy
10.5. Atomic Force Microscopy
10.6. Conclusion
Chapter 11. Miscellaneous Physical, Chemical, and Microbiological Test Methods
11.1. General Physical Tests
11.2. General Chemical Tests
11.3. General Microbiological Tests
11.4. Product-Specific Tests
Chapter 12. An Overview of Regulatory Aspects for Pharmaceutical Semisolid Dosages
12.1. Quality Data
12.2. Types of Regulatory Submissions
12.3. Resources—ICH
12.4. Resources—FDA
12.5. Resources—WHO
Index
Copyright
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Preface
The focus of this book is the formulation, product development, testing, and stability of semisolid and liquid dosage forms. Formulations of this type are important throughout the industry, and are an essential vehicle for delivering pharmaceuticals safely and effectively to their intended target. Understanding the chemistry of surfactants and surface phenomena is key to successfully formulating complex multicomponent formulations.
The formulation of semisolid dosages requires mixing several ingredients to produce a uniform, homogeneous, stable product that can be filled into suitable containers for the end user. This is also applicable to some liquid formulations that are multicomponent systems. The mixing of various ingredients that may be mutually immiscible liquids containing partially soluble or insoluble materials to form a uniform, stable system requires a thorough knowledge of chemistry. The required knowledge of physical, organic, and analytical chemistry that is essential for pharmaceutical formulation development is well documented in various books and research publications. The purpose of this book is not to give fundamental details of the chemistry, but to draw attention to the chemical principles underlying the formulation development of complex mixtures. As some of the medications will be delivered through specialized devices, a basic knowledge of engineering and, to a certain extent, physics is also beneficial. Furthermore, an important aspect for any chemist or pharmacist involved in pharmaceutical drug product development is an awareness of the regulatory agency’s requirements, generally known as the Chemistry, Manufacturing, and Controls
part of a drug product regulatory filing. In this book we have focused on surfactants, thickeners, surface chemistry, drug delivery systems, methods used for characterization, and regulatory aspects of testing drug products.
We hope that this book will be helpful to scientists involved in the drug product development of semisolid and liquid dosage forms, and that it will give newcomers to this field a broad perspective of the chemistry involved in formulating and testing drug products.
The process of writing and reviewing chapters was very time-consuming and took many hours of personal time away from our families. We are thankful to our colleagues and friends who assisted us at various stages. We remain indebted to our wives Anuradha and Karen, and our family members who supported us throughout the long process.
Vitthal S. Kulkarni, and Charles Shaw
September 2015
Chapter 1
Introduction
Abstract
The field of pharmaceutical product development is very competitive with several New Drug Applications and Abbreviated New Drug Applications (generic products) being filed every year. Product development activities include aspects of preformulation development (i.e., the compatibility of the Active Pharmaceutical Ingredient with formulation excipients, and the compatibility of the ingredients and finished formulation with the manufacturing process, process parts, and container-closure system), as well as aspects of manufacturing and stability testing. These and the various drug delivery systems used are discussed. This chapter provides a brief outline of the formulation development topics covered in the book. Various terms, as defined by the US Food and Drug Administration, are provided.
Keywords
Active pharmaceutical ingredient (API); Drug product; Microscopy; Regulatory agency; Rheology; Surfactants; Testing
Every year, several new drug products based on either new drug substances or generics of existing drug products are approved and enter the market. In 2014, approximately 95 Abbreviated New Drug Applications (ANDAs, i.e., generic) and 106 New Drug Applications (NDAs) were approved by the Center for Drug Evaluation and Research (CDER), a division of the US Food and Drug Administration (FDA). This demonstrates that Research and Development within the pharmaceutical industry is a very competitive field. Achieving success in drug formulation development requires a combined knowledge of chemistry, chemical and process engineering, and the regulations. Drug product development activities include aspects of preformulation/formulation development (including compatibility of the API with formulation excipients, and the compatibility of the ingredients and finished formulation with the manufacturing process, process parts, and container-closure system), as well as aspects of manufacturing and stability testing.
Due to concerns relating to toxicity and possible side effects, very few drug substances can be directly administered to the body. Additionally, the amount of the drug substance administered (i.e., the maximum daily dose) is often in milligram or microgram quantities. As a result, it is necessary to mix the drug with other nondrug (inactive) ingredients in such a way that the drugs can be safely delivered to their target within the body.
The US FDA definitions for active ingredient, drug, and drug products are:
• Active Ingredient: any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or affects the structure or any function of the body of man or animal.
• Drug:
• A substance recognized by an official pharmacopeia or formulary.
• A substance intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease.
• A substance (other than food) intended to affect the structure or any function of the body.
• A substance intended for use as a component of medicine but not a device or a component, part, or accessory of a device.
Biological products are included within this definition and are generally covered by the same laws and regulations, but differences exist regarding their manufacturing process.
• Drug Product: a finished dosage form that contains an active drug ingredient, generally, but not necessarily, in association with other active or inactive ingredients.
As an example, a tablet of Ibuprofen of 200 mg strength may actually weigh 500 mg, indicating that to deliver 200 mg of the drug substance, 300 mg of inactive ingredients are added to help safely deliver the drug to its destination. The added inactive ingredients might also help to keep the drug stable for a finite period. Therefore, converting a drug substance into a safe and effective drug product is equally as important as inventing the drug itself. This process of making drug products by combining the drug substance (the API) and the necessary inactive ingredients (the excipients) is called the formulation process. When formulating a drug product, the goal is to make a safe and effective product that has an acceptable shelf life, which can be easily administered (to promote patient compliance).
Pharmaceutical formulations are mixtures of the pharmaceutically active ingredient and selected inactive ingredients. Solution formulations that are used for injectable dosage forms generally have fewer inactive ingredients—such as water, cosolvents, buffering agents, and pH-adjusting agents. As a result, they are much simpler to formulate compared to some of the semisolid formulations used for topical administration. The inactive ingredients used in semisolid formulations may include water, oil, surfactants, emulsifiers, stabilizers, chelators, preservatives, and pH-adjusting agents. These types of formulations tend to be complex due to interactions between the various ingredients and consequently require considerable development efforts during the formulation process. Furthermore, when formulating a generic version of an existing marketed product, reverse engineering of the reference drug product is often challenging for semisolids.
For all types of formulations, product development efforts require putting together all of the ingredients, testing their mutual compatibility (e.g., the drug substance with the inactive ingredients, and between one inactive ingredient and another), the solubility of the API in the formulation matrix, the chemical stability of each ingredient, and the physical stability of the formulation as a whole. Developing stability-indicating test methods is an inherent part of product development activities. The US Food and Drug Administration (FDA) recommend using a Quality by Design (QbD) approach when developing drug products, including generic products. When developing generics, three critical attributes are (1) the ingredients are the same as in the reference-listed drug (RLD); (2) the concentrations of the ingredients are the same as in the RLD; and (3) the microstructure (arrangement of matter) within the generic is the same as in the RLD.
Common types of dosage forms are solid, liquid, aerosol, suspension, and semisolid. Solids are typically administered either orally, by inhalation (e.g., dry powder inhalers), or applied topically (e.g., powders). Liquids can be injected, taken orally, applied topically, or administered via the nasal or pulmonary route (in the form of a spray). Semisolids can be administered topically (e.g., creams, lotions, ointments, gels), transdermally, injected subcutaneously (e.g., gels for subcutaneous administration), vaginally, or anally (e.g., suppositories).
In recent years, several medications have appeared on the market in which the drug product is delivered via a device in which the device is an integral part of the medication. The term Combination Products
is used when the medication is composed of any combination of drug and a device. Examples of combination products include pressurized metered-dose inhalers, nebulizers, dry-powder inhalers, transdermal patches that deliver drugs by iontophoresis or microneedle technology, and prefilled syringes. The definition of a combination product includes:
• A product comprising two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or mixed and produced as a single entity.
• Two or more separate products packaged together in a single package or as a unit and comprising drug and device products, device and biological products, or biological and drug products.
• A drug, device, or biological product packaged separately that, according to the investigational plan or proposed labeling, is intended for use only with an approved individually specified drug, device, or biological product in which both are required to achieve the intended use, indication, or effect and in which upon approval of the proposed product the labeling of the approved product would need to be changed.
• Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product in which both are required to achieve the intended use, indication, or effect.
Inactive ingredients that act in the formulation as surfactants, emulsifiers, thickeners, gelling agents, or stabilizers play critical roles in making stable semisolid formulations. To successfully design and develop stable drug products, it is critical to have a knowledge and understanding of surfactants and surface chemistry. Formulation development is not complete until the various ingredient compatibility aspects are studied and data are produced. These compatibility aspects include API and excipients, solubility of the API in the formulation matrix, and compatibility of the formulation with the intended primary container-closure system. If more than one API is to be incorporated in the formulation, the process becomes more complicated. Establishing processing compatibility at all stages of the product development life cycle is also a key aspect of formulation development—including scale-up, full-scale manufacture, and the filling process. To assess the risks and take appropriate measures to reduce them, the FDA recommends following a QbD approach for all stages of formulation and process development. A detailed discussion surrounding QbD and stability testing is provided in this book.
Chapters covering the rheology, particle size, microscopy, and miscellaneous physical and chemical test methods for semisolid and liquid dosage forms are included. Formulation topics such as the use of polymers, thickeners, other excipients, and methods of manufacturing are also covered. A chapter is also devoted to aerosol formulations, which is a rapidly growing area in terms of new products.
Finally, no drug product can be placed into the market without approval by regulatory agencies. Satisfying the regulatory requirements for new drug products or generics is essential. A full chapter is devoted to a review of the current regulatory landscape relating to semisolid and liquid dosage forms.
Chapter 2
Surfactants, Lipids, and Surface Chemistry
Abstract
This chapter provides an overview of surfactants and surface properties that play important roles in pharmaceutical formulations. Examples of ionic, nonionic, and zwitterionic surfactants are provided. Structures of different lipids and their applications as excipients or actives are discussed. A brief introduction to the HLB system is provided. Examples of drug products in the marketplace that use various surfactants and lipids are listed indicating the importance of surfactants and lipids in pharmaceutical formulations. Surface and interfacial tension measurement, and the significance of the role of surface tension and contact angle in designing the pharmaceutical formulations has been discussed.
Keywords
Amphiphiles; Contact angle; Critical micelle concentration; Emulsions; HLB numbers; Lipids; Surface chemistry; Surface tension; Surfactants
Contents
2.1 Introduction 5
2.2 Types of Surfactants 6
2.2.1 Surfactant Micelles 6
2.2.2 Anionic Surfactants 7
2.2.3 Cationic Surfactants 8
2.2.4 Nonionic Surfactants 8
2.3 Natural Surfactants 8
2.3.1 Lipids 10
2.4 The Role of Surfactants in Pharmaceutical Formulations 12
2.4.1 Skin Penetration Enhancers 12
2.4.2 Emulsifying Agents 14
2.4.2.1 Hydrophile–Lipophile Balance (HLB) System 15
2.4.3 Aerosol Formulations 15
2.4.4 Surfactant Gels 15
2.5 Surface Chemistry for Pharmaceutical Formulations 16
2.5.1 Surface and Interfacial Tension 16
2.5.2 Contact Angle 17
2.6 Conclusion 18
References 18
2.1. Introduction
This chapter presents an introduction to surface chemistry and surfactants in pharmaceutical formulations. The choice and quantity of surfactants are essential factors in the formation of stable and efficacious emulsions as pharmaceutical dosage forms (including oral, topical, and injectable/infusible dosage forms). Understanding the physical chemistry of surfactant molecules in aqueous systems and at the air–water or liquid–liquid interface is fundamental to designing drug delivery systems. Important parameters include surface tension, contact angle, and critical micelle concentration.
Surfactants are amphiphilic
molecules (or amphiphiles
), containing both hydrophilic and hydrophobic portions on the same molecule. They have been termed surface active agents
due to their activity at the air–water or water–oil interfaces, reducing surface tension and improving miscibility. They are also considered as chemicals that form new surfaces
(micelles, liposomes, etc.) in the presence of water [1]. Surfactants are a class of chemicals that has ubiquitous applications in industries; almost all industries need to use surfactants, including engineering, food, petrochemical, pharmaceutical, and consumer products.
Figure 2.1 Schematic representation of a surfactant molecule. The circle represents the hydrophilic part of the molecule (also known as the head group or polar group), and the long acyl chain represents the hydrophobic (lipophilic) part of the molecule.
2.2. Types of Surfactants
A schematic representation of a surfactant molecule is shown in Figure 2.1; the hydrophilic (water loving
) end of the surfactant molecule is referred to as the head group
or polar group, and the hydrophobic (water hating
) portion is referred to as the tail
(or lipophilic, oil-soluble end). Depending on the charge of the polar group, surfactants are generally classified as cationic, anionic, nonionic, or zwitterionic (amphoteric) surfactants. Surfactants can be water soluble or insoluble, natural or synthetic in origin, and their chemical structures could be simple or large molecules or polymeric. Surfactants that have polar groups at each end of a long acyl chain are sometimes known as bolaamphiphiles
[2].
When mixed in water, surfactants reduce the surface tension of the water. As the concentration of the surfactant is increased, the surface tension continues to drop. Above a certain concentration, the surfactant molecules spontaneously form micelles. When these micelles start forming, further additions of surfactant have no further effect on the surface tension of the water. This concentration, at which the surface tension remains constant, is called the Critical Micelle Concentration (CMC). A typical representation of surface tension versus surfactant concentration is shown in Figure 2.2.
2.2.1. Surfactant Micelles
Micelles are self-assembled microstructures formed by surfactants in aqueous systems. They can trap hydrophobic molecules in their hydrophobic core and thereby act as wetting agents or solubilizing agents. This behavior enables them to be effective cleansing agents. Depending on the structure of the surfactant molecules, micelles of different shapes (including spherical, cylindrical, hexagonal, cubic lamellar, inverted cylindrical, and inverted spherical) can be formed. The size of a micelle is related to the number of monomers per micelle (commonly called the aggregation number) or the molecular weight of the micelle.
Figure 2.2 A schematic representation of trend lines for surfactant physical properties such as surface tension, conductivity, turbidity, and detergency as a function of surfactant concentration. A change in trend is observed after Critical Micelle Concentration (CMC) is reached. Adapted from Barnes, G. and Gentle, I., Interfacial Science An Introduction, Oxford University Press, 2005.
Factors affecting the formation of micelles include:
• Chain length of the surfactant molecule: molecules with longer chain lengths are less soluble, and will form micelles at lower