Innovative Dosage Forms

Design and Development at Early Stage

Yogeshwar Bachhav, Raimund Mannhold, Helmut Buschmann, Jörg Holenz

• Publisher: Wiley-VCH
• Year: 2019
• Print ISBN: 9783527343966
• eBook ISBN: 9783527812189
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Organic Chemistry

Teaches future and current drug developers the latest innovations in drug formulation design and optimization

This highly accessible, practice-oriented book examines current approaches in the development of drug formulations for preclinical and clinical studies, including the use of functional excipients to enhance solubility and stability. It covers oral, intravenous, topical, and parenteral administration routes. The book also discusses safety aspects of drugs and excipients, as well as regulatory issues relevant to formulation.

Innovative Dosage Forms: Design and Development at Early Stage starts with a look at the impact of the polymorphic form of drugs on the preformulation and formulation development. It then offers readers reliable strategies for the formulation development of poorly soluble drugs. The book also studies the role of reactive impurities from the excipients on the formulation shelf life; preclinical formulation assessment of new chemical entities; and regulatory aspects for formulation design. Other chapters cover innovative formulations for special indications, including oncology injectables, delayed release and depot formulations; accessing pharmacokinetics of various dosage forms; physical characterization techniques to assess amorphous nature; novel formulations for protein oral dosage; and more.

-Provides information that is essential for the drug development effort
-Presents the latest advances in the field and describes in detail innovative formulations, such as nanosuspensions, micelles, and cocrystals
-Describes current approaches in early pre-formulation to achieve the best in vivo results
-Addresses regulatory and safety aspects, which are key considerations for pharmaceutical companies
-Includes case studies from recent drug development programs to illustrate the practical challenges of preformulation design

Innovative Dosage Forms: Design and Development at Early Stage provides valuable benefits to interdisciplinary drug discovery teams working in industry and academia and will appeal to medicinal chemists, pharmaceutical chemists, and pharmacologists.

1
Impact of the Polymorphic Form of Drugs/NCEs on Preformulation and Formulation Development

MHD Bashir Alsirawan and Anant Paradkar

Center for Pharmaceutical Engineering Sciences, University of Bradford, Richmond Road, Bradford, BD7 1DP, UK

1.1 Introduction

Polymorphism is a well‐established phenomenon which describes the ability of a solid‐state molecular structure to be repetitively positioned in at least two different arrangements in three‐dimensional space. These different arrangements can result in different sets of physicochemical properties of the same molecular structure, which can significantly affect material behavior during handling, processing, and storing. Hence, polymorphism is crucial for many applications, including the pharmaceutical industry. Most drugs, whether already produced or newly discovered candidates, and usually referred to as new chemical entities (NCEs), are found as solids under normal conditions of temperature and pressure. Eighty‐five percent of active pharmaceutical ingredients (APIs) display pseudopolymorphism, including 50% having real polymorphism [1]. In addition, Cruz‐Cabeza et al. have listed polymorphic incidence of single‐component NCEs from the Cambridge Structure Database (CSD), European Pharmacopeia, and data from the extensive screening procedures performed in Roche and Lilly (Table 1.1) [2].

Table 1.1 Polymorphism incidence for single‐component NCE from several data source.

Source	Number of single NCEs	Polymorphism occurrence (%)
CSD	5941	37
European Pharmacopeia 2004	598	42
Roche	68	53
Lilly	68	66

Consequently, polymorphism must be taken into consideration during every processing stage starting from early steps such as preformulation and formulation development, passing through processing, manufacturing, and storage, and eventually until consumption in humans.

1.1.1 Background

Polymorphism has been discussed and investigated by many reports [3–7]. Moreover, several definitions were made depending on the researcher or the field of research; McCrone (1965) defined polymorphism thus: “Polymorph is a solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of the molecule of that compound in the solid state.” Buerger defined polymorphism of a crystal as “molecular arrangements having different properties.” The definition by Purojit and Venugopalan states it is the “ability of a substance to exist as two or more crystalline phases that have different arrangements or conformations of the molecules in the crystal lattice” [3]. IUPAC defined the phase transition between polymorphs as the “reversible transition of a solid crystalline phase at a certain temperature and pressure (the inversion point) to another phase of the same chemical composition with a different crystal structure” [8]. Other definitions were similar to those previously mentioned, such as different crystal arrangements for the same chemical composition [9], or crystal systems of same elemental structure but with unlike unit cells [4]. Desiraju has debated the experimentality of McCrone's definition depending on previous observations of polymorphism cases where coexistence of two polymorphs within the same crystal is found with no distinctive phase separation or, in other cases, where two structures are very similar with a barely identified difference (divergence). Desiraju has suggested setting criteria to differentiate whether two arrangements are genuine polymorphs or belong to the same solid phase [6].

The first reported polymorphism event was discovered with calcium carbonate in 1788 by Kalporoth. In 1832, benzamide was the first organic molecule the polymorphism of which was observed by Wöhler and Liebig [10]. The first crystal structure of polymorphic form determined by X‐ray diffraction was for resorcinol in 1938 [11].

Although the term polymorphism seems specific, there is confusion around designating different structures as polymorphs. Moreover, reports follow different terminology rules depending on the fields of interest and background. To mitigate this confusion, other terms have arisen such as pseudopolymorphism or solvatomorphism. However, several reports do not encourage using these terms as it may create further confusion [7,12].

1.1.2 Types of Polymorphism

If we stick to the pure definition of polymorphism and exclude chemically nonsimilar structures, there are two primary types of polymorphism, conformational and packing polymorphism.

1.1.2.1 Conformational Polymorphism

This type of polymorphism resulted in molecules having flexible moieties which, in turn, have rotatable bonding. The rotational movement of a single bond in the molecular structure leads to a symmetry change and produces a new configuration, and, subsequently, a change in lattice packing [13]. A typical example of conformational polymorphism is ranitidine hydrochloride, which has two polymorphs, form 1 and form 2. Both phases are monoclinic, with the same space group but with only...

Table of contents

• Cover
• Table of Contents
• Preface
• 1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation and Formulation Development
• 2 Strategies for the Formulation Development of Poorly Soluble Drugs via Oral Route
• 3 Effect of Residual Reactive Impurities in Excipients on the Stability of Pharmaceutical Products
• 4 Preclinical Formulation Assessment of NCEs
• 5 Regulatory Aspects for Formulation Design – with Focus on the Solid State
• 6 Insight into Innovative Applications of Parenteral Formulations
• 7 Assessing Pharmacokinetics of Various Dosage Forms at Early Stage
• 8 Transdermal Medical Devices: Formulation Aspects
• 9 Physical Characterization Techniques to Access Amorphous Nature
• 10 Design and Development of Ocular Formulations for Preclinical and Clinical Trials
• 11 Preclinical Safety Aspects for Excipients: Oral, IV, and Topical Routes
• 12 Formulation of Therapeutic Proteins: Strategies for Developing Oral Protein Formulations
• Index
• End User License Agreement