Essential Chemistry for Formulators of Semisolid and Liquid Dosages

Vitthal S. Kulkarni, Charles Shaw

• Publisher: Academic Press
• Year: 2015
• ISBN:
  9780128010723
• Topic: Physical Sciences
• Subtopic: Chemistry
• Index: Chemistry

A needed resource for pharmaceutical scientists and cosmetic chemists, Essential Chemistry for Formulators of Semisolid and Liquid Dosages provides insight into the basic chemistry of mixing different phases and test methods for the stability study of nonsolid formulations. The book covers foundational surface/colloid chemistry, which forms the necessary background for making emulsions, suspensions, solutions, and nano drug delivery systems, and the chemistry of mixing, which is critical for further formulation of drug delivery systems into semisolid (gels, creams, lotions, and ointments) or liquid final dosages. Expanding on these foundational principles, this useful guide explores stability testing methods, such as particle size, rheological/viscosity, microscopy, and chemical, and closes with a valuable discussion of regulatory issues. Essential Chemistry for Formulators of Semisolid and Liquid Dosages offers scientists and students the foundation and practical guidance to make and analyze semisolid and liquid formulations.

• 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

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; Surfa...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Preface
• Chapter 1. Introduction
• Chapter 2. Surfactants, Lipids, and Surface Chemistry
• Chapter 3. Drug Delivery Vehicles
• Chapter 4. Formulating Creams, Gels, Lotions, and Suspensions
• Chapter 5. Use of Polymers and Thickeners in Semisolid and Liquid Formulations
• Chapter 6. Aerosols and Nasal Sprays
• Chapter 7. Preparation and Stability Testing
• Chapter 8. Particle Size Analysis: An Overview of Commonly Applied Methods for Drug Materials and Products
• Chapter 9. Rheological Studies
• Chapter 10. Microscopy Techniques
• Chapter 11. Miscellaneous Physical, Chemical, and Microbiological Test Methods
• Chapter 12. An Overview of Regulatory Aspects for Pharmaceutical Semisolid Dosages
• Index