Handbook of Pharmaceutical Wet Granulation

Theory and Practice in a Quality by Design Paradigm

Ajit S. Narang, Sherif I.F. Badawy, Ajit S. Narang, Sherif I.F. Badawy

• Éditeur: Academic Press
• Année: 2018
• ISBN:
  9780323481038
• Sujet: Medicina
• Sous-sujet: Farmacologia

Handbook of Pharmaceutical Wet Granulation: Theory and Practice in a Quality by Design Paradigm offers a single and comprehensive reference dedicated to all aspects of pharmaceutical wet granulation, taking a holistic approach by combining introductory principles with practical solutions. Chapters are written by international experts across industry, academic and regulatory settings, and cover a wide spectrum of relevant and contemporary wet granulation topics, techniques and processes. The books' focus on process analytical technology, quality by design principles, granulation equipment, modeling, scale-up, control and real time release makes it a timely and valuable resource for all those involved in pharmaceutical wet granulation.

• Discusses fundamentals of theory and current industrial practice in the field of wet granulation, including product and process design and role of material properties in wet granulation
• Examines the modern evolution of wet granulation through current topics such as established and novel process analytical technologies (PATs), and product development and scale-up paradigms
• Written for scientists working within the pharmaceutical industry, as well as academics, regulatory officials and equipment vendors who provide PAT tools and granulation equipment

Part 1

Process Design and Product Quality Attributes

Chapter 1

Physicochemical Principles Governing Agglomeration and Growth Kinetics

Jonathan B. Wade Technical Services/Manufacturing Science Division, Eli Lilly & Company, Indianapolis, IN, United States

Abstract

This text provides perspectives on the physicochemical principles governing agglomeration and growth kinetics of granules, providing the theory describing granule growth in the context of the key granulation rate processes of wetting and nucleation, consolidation and coalescence, and breakage. This chapter describes quantitative models and dimensionless terms such as dimensionless spray flux, nucleation regime map, Stokes deformation number, and growth regime map used for process characterization and development. Provided are examples demonstrating the effect of formulation and process variables on granule growth and breakage. Considerations for characterization of important properties such as binder liquid viscosity and contact angle, measurement of granule porosity, and determination of Stokes deformation number are presented to facilitate practical use of the approaches described.

Keywords

Wet granulation; Nucleation; Consolidation; Breakage; Porosity; Liquid saturation; Stokes deformation number

1 General Introduction

1.1 Overview of Common Agglomeration Techniques

Wet granulation typically involves an initial dry blending of the powders, to give a homogeneous distribution, followed by the addition of a granulation liquid. Continued mixing ensures wetting of the powder surfaces and promotes agglomeration of the particles to form granules. Mixing is continued until the desired end point is reached. The end point could be defined by a number of parameters, including mixing time, quantity of binder liquid added, and power or torque reading on the mixing impeller. The wet granules then are passed through a coarse screen to break large lumps, dried to remove the binder liquid, and milled to produce granules of the desired particle size distribution. The milled granules often are blended with a lubricant, and potentially a portion of extra-granular binder and disintegrant, to form the final granule blend that is homogeneous, free flowing, and possesses sufficient compaction properties to form a suitable tablet under compression.

Wet granulation is used to reduce segregation potential and to enhance powder flowability, density, and compaction properties. Additionally, wet granulation offers the ability to increase the wettability of poorly soluble drugs. A surface active agent can be readily incorporated into the binder liquid, where it is brought into intimate contact with the surfaces of the drug particles during the granulation process, to enhance dissolution rate (Chowdary & Manjula, 1999; Grace, Latha, Shanthi, & Reddy, 2011). Approximately 40% of the world's top oral drugs are classified as Biopharmaceutics Classification System (BCS) class II (low solubility, high permeability) and IV (low solubility, low permeability) compounds (Amidon, Dahan, & Miller, 2009), and that the problem is considered even worse in drug discovery pipelines (Lipinski, 2002). Consequently, the use of wet granulation processes to simultaneously form granules of the desired physical properties and enhanced bioavailability remains a popular option.

1.2 Introduction to Wet Granulation

Wet granulation processes have been a topic of research for several decades with Newitt and Conway-Jones (1958) pioneering some of the earliest work in 1958, where they investigated the agglomeration behavior of sand in a drum granulator. Since then, a substantial volume of work has been published studying a wide range of materials, such as detergents, minerals, and pharmaceuticals, which have been granulated in a variety of equipment, including coffee grinders, food processors, rotating drums, fluidized beds, and high shear mixers. Several comprehensive review papers have been written to summarize the state of knowledge in the discipline; notably in the 1970s, when Kapur (1978) reviewed the “balling” process, the 1980s (Kristensen, 1988; Kristensen & Schaefer, 1987; Schubert, 1981) and 1990s (Ennis, 1996), when authors reviewed “agglomeration” and “size enlargement,” and the 2000s, when Iveson, Litster, Hapgood, and Ennis (2001) reviewed the “nucleation, growth, and breakage phenomena in agitated wet granulation processes.” These reviews provide the basis for the current understanding that wet agglomeration processes involve three simultaneous rate processes (Ennis & Litster, 1997) as shown in Fig. 1: wetting and nucleation; consolidation and coalescence; attrition and breakage. Each has received considerable attention in the literature and is discussed separately.

Fig. 1 Representation of wet granulation rate processes: (A) wetting and nucleation, (B) consolidation and coalescence, (C) attrition and breakage (Kristensen, 1988).

1.3 Wetting and Nucleation

Wetting is the process of displacing air from the powder surface with binder liquid. Nucleation is the process of bringing two or more surface wet particles into contact to form nuclei (Fig. 1A). The area where the binder liquid and powder surface come into contact to form initial nuclei is termed the nucleation zone. Nuclei formation and binder liquid dispersion are both important in the nucleation zone. The size of the binder liquid droplet relative to the powder particles onto which it is deposited will influence the nucleation mechanism. Two different nucleation mechanisms have been proposed (Schaefer & Mathiesen, 1996; Scott, Hounslow, & Instone, 2000). If the droplet is large compared to the particles, nucleation will occur by immersion of the smaller particles into the larger droplet to form nuclei with saturated pores. Alternatively, nucleation with relatively small droplets ...