Dosage Form Design Considerations

Volume I

• Publisher: Academic Press
• Year: 2018
• ISBN:
  9780128144244
• Topic: Medizin
• Subtopic: Pharmakologie

Dosage Form Design Parameters, Volume I, examines the history and current state of the field within the pharmaceutical sciences, presenting key developments. Content includes drug development issues, the scale up of formulations, regulatory issues, intellectual property, solid state properties and polymorphism. Written by experts in the field, this volume in the Advances in Pharmaceutical Product Development and Research series deepens our understanding of dosage form design parameters. Chapters delve into a particular aspect of this fundamental field, covering principles, methodologies and the technologies employed by pharmaceutical scientists. In addition, the book contains a comprehensive examination suitable for researchers and advanced students working in pharmaceuticals, cosmetics, biotechnology and related industries.

• Examines the history and recent developments in drug dosage forms for pharmaceutical sciences
• Focuses on physicochemical aspects, prefomulation solid state properties and polymorphism
• Contains extensive references for further discovery and learning that are appropriate for advanced undergraduates, graduate students and those interested in drug dosage design

Chapter 1

Preformulation in Drug Research and Pharmaceutical Product Development

Pratap Chandra Acharya^1,*, Saritha Shetty^2,*, Clara Fernandes^2,*, Divya Suares², Rahul Maheshwari³ and Rakesh K. Tekade^3,4, ¹Department of Pharmacy, Tripura University (A Central University), Suryamaninagar, Tripura, India, ²Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India, ³National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India, ⁴Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia

Abstract

A typical product lifecycle stage is fraught with challenges right from the inception, i.e., early drug discovery/lead optimization to product development. Challenge includes optimization of operation process, i.e., procurement and supply of bulk materials as well as production span to develop a final commercial product. The putative reasons attributed to failure to translation of product from conception to commercialization may include but not limited to subtherapeutic efficacy, toxicity issues, commercial viability, unforeseen operational issues, and so on. Together, these issues may culminate into failures of phase-II and phase-III clinical trials. Hence, to minimize all these formulation and delivery issues during the later stages of product development and registration, there is always a need for preformulation studies before the development stage. Preformulation studies are designed to provide insights of the essential physicochemical attributes of a new chemical entity, drug-excipient compatibility, to determine kinetic rate profile of the drug and the stability indicating assay method. However, the relation between preformulation and pharmacokinetics is also needed to be understood to utilize this concept in a better way. Apart from the general information on preformulation (importance, parameters, technologies, etc.), the chapter also covers a few recent case studies on the role of preformulation in development of dosage forms such as hydrogels, liposomes, and vaccines.

Keywords

Preformulation; drug discovery; stability; drug-excipient compatibility studies; preclinical

Outline

• 1.1 Introduction 2
  • 1.1.1 An Overview of Formulation Life Cycle and Management 3
  • 1.1.2 Need of Preformulation: First Stage of Formulation Development 4
  • 1.1.3 Major Hurdles Impeding Successful Product Development 5
  • 1.1.4 Role of Preformulation During Product Development 7
• 1.2 Parameters of Preformulation Studies 8
  • 1.2.1 Solubility 8
  • 1.2.2 The Permeability of the Drug 12
  • 1.2.3 Bulk Characterization: Physical, Analytical, and Physicochemical 14
  • 1.2.4 Inherent Properties: pH, pKa, Log P, Log D, and Intrinsic Dissolution 15
  • 1.2.5 Stability: The Solution, Solid State, & ICH Photostability 19
  • 1.2.6 Drug-Excipient Compatibility 25
  • 1.2.7 Particle Size and Distribution 27
  • 1.2.8 Thermal Properties 28
  • 1.2.9 Hygroscopicity 28
  • 1.2.10 Bulk Properties 30
  • 1.2.11 Mechanical Properties and Compatibility 30
  • 1.2.12 Crystallinity and Polymorphism 30
• 1.3 Role of Preformulation in Drug Discovery 31
  • 1.3.1 Material Properties in Lead Selection, High Throughput Preformulation Studies 32
  • 1.3.2 “Drugability” of New Chemical Entities 32
  • 1.3.3 Tools to Assist in Lead Selection 34
• 1.4 Role of Preformulation in Drug Development 35
  • 1.4.1 Identification of Challenges During Formulation Development: Pre-Assumptions 36
  • 1.4.2 The Dosage Form Specific Studies 36
• 1.5 Preformulation Studies of Proteins and Peptides 37
• 1.6 Preformulation in Vaccine Development: Critical Views 40
• 1.7 Preformulation Studies of Packaging Components 41
• 1.8 Preformulation in 21st Century: Technological Advancements 42
  • 1.8.1 Computerization and Aid of Software in the Preformulation Studies 42
  • 1.8.2 Artificial Neural Network Tool Used in the Factorial Design: An Optimization Approach 43
• 1.9 Case Studies on Preformulation of Dosage Forms 45
• 1.10 Pharmacokinetics and Preformulation: Point to Note 46
• 1.11 Rules and Regulations in Preformulation Studies: Role of Regulatory Bodies 47
• 1.12 Future Remarks and Conclusion 48
• Acknowledgment 48
• Abbreviations 48
• References 49
• Further Reading 53

Acknowledgment

Authors express their heartfelt thanks to NMIMS University, Mumbai for providing support for the research activities. Dr. Acharya also wishes to acknowledge UGC, New Delhi for the research grant [(F.30–376/2017 (BSR))] and CSIR, New Delhi for the extramural research grant [02(0329)/17/EMR] to work to work on chemo preventive measures of colon cancer. Dr. Acharya also expresses his heartfelt thanks to Tripura University (A Central University), Suryamaninagar, for providing all necessary research facilities. The authors would like to acknowledge Science and Engineering Research Board (Statutory Body Established Through an Act of Parliament: SERB Act 2008), Department of Science and Technology, Government of India for grant (Grant #ECR/2016/001964) allocated to Dr Tekade for research work on gene delivery and N-PDF funding to Dr. Maheshwari (PDF/2016/003329) for work on targeted cancer therapy in Dr. Tekade’s Laboaratory. The authors also acknowledge the support by Fundamental Research Grant (FRGS/1/2015/TK05/IMU/03/1) scheme of Ministry of Higher Education, Malaysia to support research on gene delivery.

Disclosures: There is no conflict of interest and disclosures associated with the manuscript.

1.1 Introduction

The pharmaceutical industry is playing a key role in contributing to global health science. The research and development team have unique responsibilities to develop new drugs, vaccines, medical devices, technologies, and so on, to improve patient compliance worldwide. This only becomes possible by adopting fundamental research into innovation. The success of any pharmaceutical company is based on its continuous innovation especially for preventing and treating the common, complex diseases, neglected diseases, and improving the existing treatments. From an industrial perspective, preformulation is often considered as a multidepartment activity which involves coordinated efforts between different skill domains such as analytical, formulation development, regulatory, and others throughout the development cycle.

1.1.1 An Overview of Formulation Life Cycle and Management

In any pharmaceutical company, the R&D team is at the forefront in generating newer concepts for furthering the brand development of the company. This department is responsible for identifying a new potential moiety amongst several screened compounds based on the physicochemical as well as biological activities for treatment of target maladies. This moiety is tested extensively for ensuring its safety and efficacy. This entire process is demanding, challenging and time-consuming, i.e., it can extend over a period of 10–15 years as shown in Fig. 1.1. For example, in 2015, 56 new medicaments were introduced, while currently, more than 7,000 composites are at various developmental phases globally.

Figure 1.1 Drug product life cycle.

Understanding the enormity of the task to generate one Investigational new drug (IND) application for a company, it becomes imperative to minimize the propensity of failure by conducting suitable and well-defined studies to predict the success of new chemical entities (NCEs). In this perspective, preformulation becomes an effective tool assisting researchers in generation of physicochemical and biopharmaceutical data for screening of lead compounds. Hence, this neces...