reading

Chapter 1: Particle Engineering of Polymers into Multifunctional Interactive Excipients

1.4 Strategies for Improving Polymeric Filler-Binder Performance for Direct Compression

Chapter 3: Development of Microstructuring Technologies of Polycarbonate for Establishing Advanced Cell Cultivation Systems

Chapter 4: In-Situ Gelling Thermosensitive Hydrogels for Protein Delivery Applications

Chapter 5: Polymers as Formulation Excipients for Hot-Melt Extrusion Processing of Pharmaceuticals

Chapter 6: Poly Lactic-Co-Glycolic Acid (PLGA) Copolymer and Its Pharmaceutical Application

Chapter 8: Application of PVC in Construction of Ion-Selective Electrodes for Pharmaceutical Analysis: A Review of Polymer Electrodes for Nonsteroidal, Anti-Inflammatory Drugs

8.3 PVC Application and Properties in Construction of Potentiometric Sensors for Drug Detection

8.6 Application of Polymer-Based ISEs for Determination of Analgetic, Anti-Inflammatory and Antipyretic Drugs: Literature Review (2000–2014)

Chapter 9: Synthesis and Preservation of Polymer Nanoparticles for Pharmaceutical Applications

9.2 Production of Polymer Nanoparticles by Solvent Displacement Using Intensive Mixers

Chapter 11: Stimuli-Sensitive Polymeric Nanomedicines for Cancer Imaging and Therapy

Chapter 12: Artificial Intelligence Techniques Used for Modeling of Processes Involving Polymers for Pharmaceutical Applications

Chapter 13: Review of Current Pharmaceutical Applications of Polysiloxanes (Silicones)

Chapter 15: Polymer-Based Augmentation of Immunosuppressive Formulations: Application of Polymer Technology in Transplant Medicine

Publishers at Scrivener
Martin Scrivener(martin@scrivenerpublishing.com)
Phillip Carmical (pcarmical@scrivenerpublishing.com)

Co-published by John Wiley & Sons, Inc. Hoboken, New Jersey, and Scrivener Publishing LLC, Salem, Massachusetts.
Published simultaneously in Canada.

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The modern pharmaceutical market is under relentless pressure from slowing new drug product approvals, blockbuster drug patent expiry, price pressure and global competition. In addition, new opportunities exist due to an evolving patient population, numerous unmet medical needs and growing disease awareness. In order to sustain performance, the pharmaceutical industry must evolve and improve product development and processing efficiencies. Therefore, efficient and cost-effective product development and processing are continually being explored to meet the challenge of not only reducing cost, but also the risk of product recalls. In the last few decades, much importance has been given to the use of polymers in pharmaceutical systems. Huge opportunities in the design, synthesis and modification of the physical and chemical properties of polymers have made them the most rapidly growing group of materials with great importance and possible applications in pharmacy, medicine and cosmetology. Polymeric materials having biomedical applications can be classified into different groups depending upon the application. For example, they are generally divided into two major groups according to use: those employed in prosthetic devices such as cardiovascular and orthopedic prostheses; and those employed as therapeutic systems such as drug carriers. Among the prosthetic systems, polymeric materials can be used as coatings or as cemented prostheses. Some of the major advantages in using polymeric materials for biomedical applications are their flexibility, biocompatibility, the possibility of tailoring their mechanical properties and their ability to incorporate therapeutic agents into their matrix in order to allow drug administration at a specific site.

Both natural and man-made polymers have been widely utilized as tablet binders and filler-binders in the pharmaceutical industry. The physico-chemical and mechanical properties such as particle size, shape and deformation behavior of polymeric binders are key to their effective use. Polymeric membranes are also becoming increasingly important in the field of separation processes in the pharmaceutical industry and artificial organs. Some polymers are obtained from natural sources (natural polymer) and then chemically modified for various applications, while others are chemically synthesized (synthetic polymer). Polymeric membranes can be fabricated in different configurations, such as flat sheet, tubular hollow fibers, nanofibers, etc., via different techniques. Since the performance of the membrane is largely controlled by its surface (active layer), the design of membrane surface and its characterization, either by chemistry or morphology, are extremely important. Hence, emphasis is being placed on the membrane surface. Hot-melt extrusion (HME) technique is used to create a dispersion of the active pharmaceutical ingredient (API) in a polymer matrix in order to achieve solubility enhancement, release rate modulation, mask taste, or to develop a new dosage form. However, polymers must fulfill a number of requirements in order to be suitable for HME processing. The relatively recent introduction of HME in the pharmaceutical industry has opened new areas of applications for old and newly synthesized polymers, and enabled drug manufacturers to scale up the production of solid dispersions. A variety of chemically diverse polymers with different physico-chemical properties are available, which enable formulators to fine-tune the solid form of the extruded product by the selection of suitable polymer, drug-polymer ratio and operating conditions. Scientists in collaboration with pharmaceutical industries are extensively developing new classes of pharmaceutical materials. This second volume of Handbook of Polymers for Pharmaceutical Technologies is primarily focused on the pharmaceutical polymers and deals with the processing and applications of these polymers. Numerous critical issues and suggestions for future work are comprehensively discussed in this book with the hope that it will provide a deep insight into the state-of-art of pharmaceutical polymers. The prime topics extensively described in this book include: particle engineering of polymers into multifunctional interactive excipients; the art of making polymeric membranes; pharmaceutical applications of polymeric membranes; development of microstructuring technologies of polycarbonate for establishing advanced cell cultivation systems; in-situ gelling thermosensitive hydrogels for protein delivery applications; polymers as formulation excipients for the hot-melt extrusion processing of pharmaceuticals; poly lactic-co-glycolic acid (PLGA) copolymer and its pharmaceutical application; application of PVC in construction of ion-selective electrodes for pharmaceutical analysis; a review of polymer electrodes for nonsteroidal, anti-inflammatory drugs; synthesis and preservation of polymer nanoparticles for pharmaceutical applications; pharmaceutical applications of maleic anhydride/acid copolymers; stimuli-sensitive polymeric nanomedicines for cancer imaging and therapy; artificial intelligence techniques used for modeling of processes involving polymers for pharmaceutical applications; a review of current pharmaceutical applications of polysiloxanes (silicones); polymer-doped nano-optical sensors for pharmaceutical analysis; and finally, polymer-based augmentation of immunosuppressive formulations – application of polymer technology in transplant medicine.

Several critical issues and suggestions for future work are comprehensively discussed in this book with the hope that it will provide a deep insight into the state-of-art of processing and applications of pharmaceutical polymers. We would like to thank the publisher and Martin Scrivener for their invaluable help in the organization of the editing process. Finally, we would like to thank our parents for their continuous encouragement and support.

Manju Kumari Thakur, MSc, MPhil, PhD
Himachal Pradesh University, Shimla, India
May 2015

Dr. Vijay Kumar Thakur has been working as Research Faculty (staff scientist) in the School of Mechanical and Materials Engineering at Washington State University, USA, since September 2013. His former appointments include being a research scientist in Temasek Laboratories at Nanyang Technological University, Singapore, and a visiting research fellow in the Department of Chemical and Materials Engineering at LHU-Taiwan. His research interests include the synthesis and processing of biobased polymers, nanomaterials, polymer micro/nanocomposites, nanoelectronic materials, novel high dielectric constant materials, electrochromic materials for energy storage, green synthesis of nanomaterials, and surface functionalization of polymers/nanomaterials. He did his post doctorate in Materials Science at Iowa State University and his PhD in Polymer Science (2009) at the National Institute of Technology. In his academic career, he has published more than 80 SCI journal research articles in the field of polymers/materials science and holds one United States patent. He has also published 15 books and thirty book chapters on the advanced state-of-the-art of polymers/materials science with numerous publishers.

Dr. Manju Kumar Thakur has been working as an Assistant Professor of Chemistry at the Division of Chemistry, Govt. Degree College Sarkaghat Himachal Pradesh University, Shimla, India, since June 2010. She received her BSc in Chemistry, Botany and Zoology; MSc, MPhil in Organic Chemistry and PhD in Polymer Chemistry from the Chemistry Department at Himachal Pradesh University, Shimla, India. She has rich experience in the field of organic chemistry, biopolymers, composites/nanocomposites, hydrogels, applications of hydrogels in the removal of toxic heavy metal ions, drug delivery, etc. She has published more than 30 research papers in several international journals, co-authored five books and has also published 25 book chapters in the field of polymeric materials.

Chapter 1

Particle Engineering of Polymers into Multifunctional Interactive Excipients

Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia

Abstract

Both natural and man-made polymers are widely utilized as tablet binders and filler-binders. The physicochemical and mechanical properties such as particle size, shape and deformation behavior of polymeric binders are key in their effective use. Many such binders are applied as solution in a wet granulation process, which facilitate its facile distribution leading to improved effectiveness as a binder. Direct compression and dry granulation are recognized as routes with reduced process complexity and cost. These processes require a binder to be employed in a dry form and it can be more difficult to obtain a homogeneous distribution of a dry binder in a powder formulation. Therefore, these binders are required in high proportions to generate mechanically strong tablets. At lower proportions, they often are insufficient to create mechanically strong tablets. Recently, innovations in the generation of co-processed excipients have been proposed. Co-processing is a popular means of improving excipient functionalities, where two or more existing excipients are combined by some suitable means to generate new structures with improved and often combined functionalities as compared to the component excipients. Particle size reduction is known to improve the binder properties of an excipient, but also makes it highly cohesive and hard to blend. Via particle engineering, surface structure of smaller particles can be tailored to optimize the cohesive-adhesive balance (CAB) of the powder, allowing formation of interactive mixtures. This chapter reviews recent efforts to engineer surface-modified polymeric micro-excipient structures with the inherent ability to not only form an interactive mixture efficiently and provide flow enhancement, but also to create harder tablets at lower proportions. Hence, this approach represents a potential novel multifunctional prototype polymeric micro-excipient for direct compression and dry granulation processes.

Keywords: Particle engineering, powder technology, interactive mixtures, tablets, binder, multifunctional excipients

1.1 Introduction

The modern pharmaceutical market is under relentless pressure from slowing new product approvals, patent expiries and global competition. In addition, new opportunities exist with an evolving patient population, numerous unmet medical needs and growing disease awareness. The pharmaceutical industry must evolve and improve product developing and manufacturing efficiencies for sustainable performance. Efficient and cost-effective product development and manufacturing are continually being explored to meet the challenge of not only reducing cost but also reducing the risk of product recalls.

Tablets are the most commonly used pharmaceutical preparation, accounting for more than 80% of all dosage forms administered [1]. The principal reasons for their continued popularity include convenience of administration and patient preference, high-precision dosing, stability and cost effectiveness [2].

Tablets are typically manufactured by applying pressure to active pharmaceutical ingredient(s) (APIs) and excipients powder blends in a die using a punch, which compresses the powder into a coherent compact. Under compression, bonds are established between the particles, thus conferring a certain mechanical strength to the compact. A formulation must exhibit good flow and high compactability for an API to be transformed into tablets of satisfactory quality. Good flow is necessary to ascertain the rapid and reproducible filling of powder into the die to minimize weight variation; while high compactability is required to ensure that the tablets are sufficiently strong to withstand handling during manufacturing and transportation [3].

The majority of API(s) lack the requisite flow and compactability for direct tablet manufacturing [4]. Therefore, the flow and compactability of the API(s) need to be adjusted to ensure formation of high-quality tablets. Typically, the flow and compactability of a tablet formulation is improved by a granulation step (wet or dry granulation) in which the particles of API(s) and excipients are agglomerated into larger particulate structures referred to as granules. Wet granulation of the input materials can improve the flow properties for further processing and can create non-segregating blends of powder ingredients [5]. However, it involves multiple manufacturing steps, which can add significant time and cost to the process. Conversely, direct compression merely involves mixing of API(s) and excipients followed by immediate compression (Figure 1.1). Therefore, direct compression is an attractive manufacturing process, with fewer steps, for reducing cost and improving manufacturing output.

Figure 1.1 The various steps involved in wet granulation, dry granulation and direct compression tablet manufacturing.

Adapted and modified from [6].

1.2 Polymers as Excipients

Excipients form an integral part of any pharmaceutical tablet formulation. They play the fundamental role in creation of robust tablet formulations by carrying out an extensive range of functions such as fillers, binders, disintegrants, lubricants, glidants, coating agent and anti-adherents. Currently, a wide range of polymeric materials are used as excipients [6,7], and polymers are the largest overall consumed product segment for the global excipients market, accounting for over 30% [8]. The excipient market is expected to grow at an annual rate of 5.2% from 2013 to 2018, to reach around $7.35 billion by 2018 [8].

Polymers of natural, semi-synthetic and synthetic origin are used especially in the role of binder and filler-binder (see Table 1.1). Polymeric excipients are popular as they can be tailored for many applications by altering their chain length and by chemical functionalization. This can achieve new materials with various optimized physicochemical and mechanical properties for such specific applications.

Table 1.1 List of polymeric excipients, their source and functionalities. This table is compiled from the information given in the Handbook of Pharmaceutical Excipients [9].

In wet and dry granulation, the properties of the individual API and excipients particles are significantly altered by their agglomeration into granules. Such structures can hide the undesirable properties of individual components (of both API(s) and excipients) of the blend. In wet granulation, a binder can be sprayed into the powder as a solution, and so is easily distributed onto the particle interfaces, so facilitating the binding action. For dry granulation, a binder must be added in dry particulate form. Tablet formulations involving a granulation step can be less sensitive to binder excipient performance and variation than for direct compression. In direct compression, the original particle’s structure remains largely unaltered, so individual particle properties (API(s) and excipient) have a more critical and direct impact on formulation properties, such as flow and compactability, and decide the success or otherwise of tablet formation. Consequently, excipients, particularly filler-binders, which play a critical role in direct compression, can be very different in nature to the excipients used in wet/dry granulation. Therefore, there is a great interest in generating ready-made multifunctional filler-binders with improved flowability and binder activity (API uptake capacity) for robust tablet manufacturing using direct compression.

The main focus of this chapter is to examine the critical material properties that influence polymeric binder and filler-binder performance of directly compressible excipients, and how these material properties can be optimized and integrated with other functionalities via particle engineering.

1.3 Material Properties Affecting Binder Activity

The material properties such as particle size and deformation mechanism (elasticity-plasticity and fragmentation) and compressibility have been identified as affecting the ability of a binder to create strong tablets [10–14].

1.3.1 Particle Size

Previous studies have indicated that the optimal amount of binder corresponds to that providing a surface area ratio of unity to the corresponding API, i.e., the amount needed to form a monoparticulate layer of binder particles around the API particles [10]. This suggests that if the particle size of the binder and API is similar (as desirable in direct compression powder blends to avoid segregation), higher proportions will be required to achieve monoparticulate layer of binder around the API particles. However, if the binder particles are smaller than the API, lower proportions of binder particles can form a monoparticulate layer. This concept is illustrated in Figure 1.2. The limited efficacy of the binders in direct compression formulations (and also in dry granulation) may partly be attributed to this concept, i.e., that the binder added in its dry state can be more difficult to disperse homogeneously than when added as a solution [10]. Other physical material properties such as shape and surface energy have also been demonstrated to have a significant impact on the tableting performance of the excipients [15–18].

Figure 1.2 Effect of particle size on surface coverage of API particles with binder.

1.3.2 Deformation Mechanisms

Polymers are typically considered to be as excellent binders owing to their good bonding properties [6,7]. The polymers such as PVP and PEG are also available in a variety of molecular weights, and their deformation behavior under compression can be altered by altering their molecular weight [14]. However, the compaction of polymers is greatly affected by the speed of tableting. This has been attributed to the high elasticity of the excipients at high rates of strain [19]. Large stress relaxation yields porous and consequently weak tablets. Figure 1.3 schematically depicts relations between stress and strain for several materials. For a plastic solid, stress (σ) is directly proportional to deformation (strain, γ):

Figure 1.3 Stress-strain behavior of brittle, plastic and rubbers. The point Py indicates the yield point with corresponding yield strength.

Adapted and modified from [21].

The proportionality constant (E) is the elastic or Young’s modulus [20]. It is a measure of the stiffness or resistance against deformation. The material behaves elastically up to the yield point (P_y) at which the stress is called yield stress (σ_c). Beyond this point the material behaves as a plastic, rather than as an elastic solid. Brittle materials can be distinguished from plastic materials by the absence of the P_y: stress increases proportionally with strain until the material breaks.

1.3.3 Glass Transition Temperature (Tg)

The amount of energy stored during densification is manifested as the stress relaxation propensity of the material. Large stress relaxation yields porous and consequently weak tablets. At a high temperature difference (i.e., tableting temperature is much lower than the Tg), the polymer exhibits higher resistance to deformation and the amount of stored energy is large, resulting in highly porous and weak tablets. The Tg of amorphous polymeric materials appears to be a critical parameter with respect to mechanical properties (i.e., plastic/elastic character) of polymers [20]. At temperatures substantially below the Tg, an amorphous material is in the glassy state and its Young’s modulus is high, resulting in greater resistance to deformation. However, at temperature close to the Tg a material undergoes the change from a hard glassy form to a more plastic structure or a viscous fluid and the resistance against deformation decreases dramatically. This change is related to the onset of a certain degree of movement in the main chain and the rotation of side segments. Consequently, the performance of polymeric excipients during processes such as compaction strongly depends on their Tg [21].

It was reported that the compaction at a temperature of about 20 K under Tg yields circumstances for which the amount of stored energy has a minimum [21]. The Tg of the material depends on its chemical structure, the presence of a plasticizer and, in the case of polymers, on the molecular weight [22]. Therefore, it may be expected that using polymers with lower Tg (preferably near room temperature) would be advantageous for improved binder activity.

1.4 Strategies for Improving Polymeric Filler-Binder Performance for Direct Compression

The development of excipients of new chemical composition requires extensive toxicology tests. This is a costly preposition and so, in the last three decades, only a few such new excipients have been introduced in the market [23]. Therefore, improved filler-binders have mainly been generated via physical manipulation of existing excipient materials, i.e., as the physical mixture of GRAS (generally regarded as safe) materials [24].

Particle size manipulation is a commonly used strategy to modify polymeric filler-binder performance. For example, microcrystalline cellulose, one of the most commonly used polymeric multifunctional excipients, is commercially available in a variety of particle size ranges [25]. In addition, a wide range of multifunctional excipients are also available in different particle size grades (Table 1.2).

Table 1.2 Particle size and flow specification of common commercially available fine-grade polymer powder excipients.

The main objective of excipient engineering is to improve both flow and binder activity of the excipients. Flow and compactability both depend on particle size, and these characteristics often compete, making it difficult to achieve an optimum excipient performance [30]. For example, large particle size is typically associated with improved flow (Table 1.3). However, a smaller particle size is associated with improved compactability due to an increase in the surface area except for brittle materials (as shown in Figure 1.2) [31–33]. Hence there is a fundamental contradiction in designing a multifunctional excipient where particle size reduction improves binder activity but compromises the flow. There are a number of commercially available polymeric excipients with small particle size and better binder activity but these have relatively poor flow characteristics (Table 1.3).

Table 1.3 Particle size and flow specifications of typical commercially available directly compressible excipients.

Efforts have been made to engineer excipients which exhibit both good flow and compactability by co-processing materials. For example, combining excipients with brittle and plastic compression behavior prevents storage of excessive elastic energy during the compression (Table 1.4) [42], which results in a reduced stress relaxation and a reduced tendency of capping and lamination. The brittle property also facilitates fragmentation under compression to generate reduced particle sizes in situ. However, improvement in binder activity achieved using this approach is relatively limited and large proportions of such excipients are needed to create robust and mechanically stable tablets [43], so directly compressible excipients are only used where a low-dose of API is needed. At higher API loads (>500 mg), this may result in large tablets which are difficult to swallow. Therefore, tableting using these direct compression multifunctional excipients is only considered suitable for high/intermediate potency APIs.

Table 1.4 List of co-processed excipients created by combining plastic and fragmenting excipients.

Another key aspect of particle size relates to powder segregation. The particle size and size distribution of excipients should also be able to generate a homogeneous and segregation-resistant blend with the API(s). This can be achieved via matching the particle sizes of API and excipients. A number of product recalls identified excipient variability as a contributor to failure of the pharmaceutical product [44], indicating the lack of understanding and control over excipient manufacturing and functionality.

With the US Food and Drug Administration’s (US-FDA) Quality in the 21st Century initiative, which includes the quality by design (QbD) and process analytical technologies (PAT), it is becoming increasingly important to understand the impact of formulation process as well as material variability on the performance and manufacturability of new pharmaceutical products [45]. The variability in both APIs and excipients can have a significant impact on the critical quality attributes (CQAs), thereby the performance and manufacturability of the pharmaceutical product [23,46–51]. The intrinsic lot-to-lot variability within a single grade of each excipient in a given formulation is dictated by the degree of process control implemented by each excipient vendor. Managing excipient variability is an essential element in designing and manufacturing robust solid oral products and is an integral task when applying QbD principles. Tables 1.3 and 1.4 show excipients are provided with relatively wide particle size limits. In a QbD world such wide limits may not always be appropriate. This, therefore, presents an additional risk and cost to the overall product.

1.4.1 Interactive Mixing

It was proposed that the knowledge and understanding of interactive mixing may be applied to create improved excipients. We proposed that binder with appropriate particle size and surface properties can exhibit improved performance due to the ability to interactively blend with the API(s). Interactive mixing is a practical powder blending strategy to achieve the homogeneous distribution of small particles over relatively large particles. A fundamental principle of interactive mixing is that small particles with appropriate size and surface properties adhere to the coarse particles by interparticle interaction forces, which results in a uniform and segregation-resistant blend [52–55]. Such mixtures have wide application in the preparation of dosage forms containing relatively small doses of highly potent micronized API(s) in inhalation and tablet formulations [56–58]. As the particle becomes smaller their interactive ability increases and particles below 10 μm are considered to be highly interactive and tend to exhibit high degrees of adhesion to surfaces and cohesion to neighboring particles [59,60]. This is because the interparticle forces (cohesive forces arising from electrostatic, capillary or van der Waals interaction for particles in this larger size range) significantly exceed external forces such as gravity [61].

In an interactive mixture of components A (coarse) and B (fine), the interaction between fine particle and coarse particles (A-B) or between two fine particles (B-B) represents the typical particle-particle interactions (Figure 1.4). However, if the coarse particles are uniformly and sufficiently coated with fine particles, then the contacts between fine particles will represent the majority of particle-particle interactions. Thus, in such mixtures, the force of interparticle interactions between fine particles will determine the flow of the mixture. Since interparticle cohesion of fine particles depends heavily on their surface energy, it is also proposed that lowering the surface energy of fine particles may lower the overall forces of interparticle interaction and improve the flowability of an interactive mixture. However, this hypothesis is based on the assumption that the fine particles form a uniform surface coating regardless of the difference in their surface energy and interparticle cohesion. Thus, interactive excipients could also exert a flow additive action, as typically observed with benchmark flow aids such as silica [62,63]. We proposed that the interactive excipients with appropriate particle size and surface properties could be a practical solution to the complex problem of achieving excellent content uniformity, improved flow performance and high binder efficiency in directly compressible formulations.

Figure 1.4 Interparticle contact models in an interactive mixture.

1.4.2 Challenges to Interactive Mixing

To form an interactive mixture, mixing must overcome the cohesion forces acting between the individual components of an interactive mixture. Small particles (< 10 μm) are considered to be highly cohesive in nature, as the interparticle forces significantly exceed external forces such as gravity, resulting in agglomeration [55]. The ability of the mixing process to split agglomerates into individual particles decreases with increasing interparticle cohesion forces, which makes it difficult to break agglomerates of particles during the mixing process [64]. This may compromise the ability of smaller excipient particles to form interactive mixture with larger API particles, affecting its functional performance as excipient. Therefore, controlling interparticle cohesion is considered to be a key aspect of designing such excipients, to facilitate easy de-agglomeration of interactive excipient, and thereby preferential adhesion to larger API particles.

Micronized particles usually interact with coarse particles via van der Waals forces in interactive mixtures [65,66]. Other attractive forces, such as capillary and electrostatic forces may also operate; but in general, they are smaller than the omnipresent van der Waals force in dry powders [66]. The magnitude of van der Waals force depends on the properties of both the fine and coarse components of an interactive mixture. It has been demonstrated that factors such as particle size, shape [67], particle size distribution [68,69], roughness [70–72] and surface energy [72] affect the phenomenon of particle adhesion in an interactive mixture. A change in any of these factors can change the magnitude of the van der Waals forces and hence the cohesion and adhesion strength of the particles [65].

The work of adhesion, W_ad, is defined as the free energy required to separate unit areas of two different surfaces from contact to infinity in vacuum, whereas, the energy required to separate unit area of similar surfaces is referred to as the work of cohesion, W_co [65]. The adhesion between particles of different materials only occurs if the energy that is released during adhesion is larger than the energy that is required to break up the cohesion contacts of particles of individual material. Thus, adhesion will be an energetically favored phenomenon for such powders [60]. However, it only has importance for those powder mixtures which are classified as interactive, i.e., where one component is much smaller than the other. Also, this concept disregards the influence of other factors on adhesion such as surface roughness, hardness, elasticity, etc. Cohesion (i.e., agglomeration of fine micronized particles) can also be of energetic advantage and can explain why micronized powders are often heavily agglomerated. So, one can assume that the fine particles will only adhere to coarse particles when the energy of cohesion is lower than the energy of adhesion (Figure 1.5). Hence, the performance of interactive mixtures is a function of the relative magnitudes of cohesive and adhesive interparticulate forces.

Figure 1.5 Effect of cohesive and adhesive forces on particle distribution in interactive mixtures.

1.4.3 Controlling Interparticle Cohesion

Engineering surface properties has evolved as one of the main strategies for reducing the interparticle cohesion of fine particles. The surface-altering excipients act as lubricants between surfaces, thus reducing cohesion and improving dispersibility [73,74]. These techniques were mainly explored in the area of dry powder inhalers, where particles 1–5 µm with low cohesion and good dispersibility are desirable for their efficient delivery to the lungs [75,76]. Of these, the co-spraying with L-leucine has been previously employed as a remarkably effective strategy to improve the aerosolization of spray-dried micron-sized inhalation formulations [77–80]. In spray drying, the formation of a surface layer relies largely on the properties of excipient materials to accumulate at the air-solvent interface of droplets before drying takes place [81]. Therefore, a coating layer is formed during the drying of droplets and a uniform and coherent coating is easy to achieve [77].

1.5 Preparation and Characterization of Interactive Excipients

We spray dried PVP as a polymeric binder (6% w/v) with L-leucine (0.6 % w/v) as a surface modifying agent to control interparticle cohesion of fine spray-dried particles [82]. PVP was spray dried with and without L-leucine to generate small interactive excipients. The effect of L-leucine on the surface composition, surface energy and bulk cohesion of spray-dried formulation was assessed. The surface composition of these formulations was examined using state-of-the-art technique X-ray photoelectron spectroscopy (XPS). To then understand the bulk surface interactions, which may be influenced by molecular orientation at the surface, the surface energy was determined using inverse gas chromatography (IGC). The data obtained were used to explore how surface leucine concentration and molecular state affects morphology, surface energy, solid-state properties and the resulting change in bulk properties such as interparticle cohesion.

1.5.1 Particle Size and Size Distribution of Excipients

The particle size of spray-dried and commercial PVP was measured using a standard validated Malvern Mastersizer 2000 (Malvern Instruments Ltd., Worcestershire, UK) dry cell method. Table 1.5 shows the particle size and size distribution (span) of PVP, PVP-SD and PVP-Leu. The results indicated that PVP exhibited a particle size D₉₀ of 56.7 µm, whereas the spray-dried interactive excipients, i.e., PVP-SD and PVP-Leu, exhibited particle sizes D₉₀ of 4.3 and 5.6 µm, respectively. It was also noted that the particle size of PVP-SD and PVP-Leu was approximately the same, suggesting that L-Leucine does not significantly affect the particle size of spray formulation. The particle size distribution plots of each PVP, PVP-SD and PVP-Leu are represented in Figure 1.6 which shows that particle size distribution of PVP, PVP-SD and PVP is mono-modal in each case. The inability to tightly control particle size and size distribution is considered to be a potential source of excipient variability amongst batches. Therefore, controlling variation in particle size and size distribution could minimize the excipient related variations in the formulations. The results demonstrated that spray drying could be successfully employed to generate particles sizing < 10 μm with narrow particle size distribution.

Table 1.5 Particle size of PVP, PVP-SD, PVP-Leu and paracetamol. Adapted from Mangal et al., 2015 [82].

Figure 1.6 Particle size distribution plots of various excipients.

Adapted and modified from Mangal et al., 2015 [82].

1.5.2 Effect of L-leucine on Surface Morphology

The shape and surface morphology of the various excipients were visualized by scanning electron microscopy (SEM, Phenom, FEI Company, Hillsboro, Oregon, USA). From SEM images, the surface of PVP and PVP-SD particles was observed to be relatively smooth without visible wrinkles or corrugation. In contrast, PVP-Leu particles were more corrugated and wrinkly (Figure 1.7). The SEM image showed that PVP-SD appeared highly agglomerated, whereas, PVP-Leu appeared as more discrete individual particles, suggesting that L-leucine could potentially overcome the cohesive forces between PVP particles. However, this was further confirmed by the bulk cohesion and surface energy analysis of PVP-SD and PVP-Leu.

Figure 1.7 SEM images of PVP (a), PVP-SD (b) and PVP-Leu (c).

Polymeric Excipient	Source	Functionality
Natural
Zein	Extracted from corn gluten	Binder, Coating agent
Cellulose	Extracted from fibrous plant material	Diluent, Disintegrant
Alginic acid	Extracted from various species of brown seaweed	Binder, Disintegrant
Acacia	Exudate from the stems and branches of Acacia Senegal	Binder
Guar gum	Extracted from the endosperm of the Cyamopsis tetragonolobus	Binder, Disintegrant
Inulin	Extracted from the tubers of Dahlia variabilis, Helianthus	Binder
Chitosan	Extracted from shells of crustaceans such as shrimps and crabs	Binder, Coating agent
Semi-synthetic
Sodium alginate	By neutralized alginic acid with sodium bicarbonate	Binder, Disintegrant
Calcium alginate	By treating sodium alginate with calcium salts	Disintegrant
Methyl cellulose	By treating wood pulp with alkali followed by methylation	Binder, Disintegrant, Coating agent
Carboxymethyl cellulose sodium	By treating wood pulp with alkali followed by reaction with sodium monochloroacetate	Binder, Disintegrant
Carboxymethyl cellulose calcium	By treating wood pulp with alkali followed by methylation and then converting to calcium salt	Disintegrant
Cellulose acetate	By treating cellulose with acid catalysis and acetic anhydride	Diluent, Coating agent
Cellulose acetate phthalate	By reacting cellulose acetate with phthalic anhydride	Coating agent
Microcrystalline cellulose	By controlled hydrolysis of cellulose with mineral acid	Binder, Diluent, Disintegrant
Hydroxypropylmethyl cellulose	By treating alkali cellulose with chloromethane and propylene oxide	Binder, Coating agent
Hydroxypropylmethyl cellulose acetate succinate	By the esterification of hydroxypropylmethyl cellulose with acetic anhydride and succinic anhydride	Film coating, Enteric coating
Hydroxypropylmethyl cellulose phthalate	By the esterification of hydroxypropylmethyl cellulose with phthalic anhydride	Enteric coating
Ethylcellulose	By ethylation of the alkali cellulose with chloroethane	Binder, Diluent, Coating agent
Low substituted-hydroxypropyl cellulose	By reacting alkaline cellulose with propylene oxide	Binder, Disintegrant
Ethyl cellulose	By ethylation of the alkali cellulose with chloroethane	Binder, Diluent, Coating agent
Hydroxyethyl cellulose	By reacting alkali cellulose with ethylene oxide	Binder, Coating agent
Maltodextrin	By heating starch with acid and/or enzymes	Binder, Diluent, Coating agent
Sodium starch glycolate	By reacting starch with sodium chloroacetate followed by acidic neutralization	Disintegrant
Hydroxypropyl starch	By reacting starch with propylene oxide in the presence of alkali	Binder, Disintegrant
Dextrates	By controlled enzymatic hydrolysis of starch	Binder, Diluent
Dextrin	By the incomplete hydrolysis of starch	Binder, Diluent
Lactose monohydrate	By crystallization from supersaturated lactose solutions	Binder, Diluent
Spray-dried lactose	By spray drying a suspension of α-lactose monohydrate	Binder, Diluent
Pregelatinized starch	By heating an aqueous slurry of starch with salts or bases and surfactants	Binder, Diluent, Disintegrant
Synthetic
Poloxamer	By reacting propylene oxide with propylene glycol followed by addition of ethylene oxide	Lubricant
Polyethylene oxide	By polymerization of ethylene oxide	Binder, Coating agent
Polyethylene glycol	By reacting ethylene oxide and water under pressure	Coating agent
Polyvinyl acetate phthalate	By reacting phthalic anhydride, sodium acetate, and a partially hydrolyzed polyvinyl alcohol	Coating agent
Polyvinyl alcohol	By hydrolyzing of polyvinyl acetate	Coating agent, Lubricant
Polyvinylpyrrolidone (PVP)	By reacting acetylene and formaldehyde followed by hydrogenation to form butyrolactone and reacting it with ammonia	Binder, Disintegrant
Copovidone PVP/VA	By free-radical polymerization of vinylpyrrolidone and vinyl acetate in a ratio of 6 : 4	Binder
Crospovidone	By polymerizing vinylpyrrolidone	Disintegrant
Polymethcrylate	By the polymerization of acrylic and methacrylic acids	Binder, Diluent
Carbomer	By crosslinking acrylic acid	Binder

Excipient	Component ingredients
Excipient	Brittle excipient	Plastic excipient
Ludipress	α -Lactose monohydrate (93.4%)	PVP (Kollidon 30) (3.2 %) and Crospovidone (Kollidon CL) (3.4 %)
Cellactose	α -Lactose monohydrate (75 %)	Cellulose (25%)
Prosolv	Fumed colloidal silicon dioxide (2%)	Microcrystalline cellulose (98%)
Pharmatose	Anhydrous lactose (95%)	Lactitol (5%)
Xylitab	Xylitol (>96.5%)	Sodium caboxymethyl cellulose (<2 %)
Advantose	Fructose (95%)	Starch (5%)
Formaxx	Calcium carbonate (70 %)	Sorbitol (30 %)
Microcelac	Lactose (75 %)	Microcrystalline cellulose (25 %)

Chapter 1

Particle Engineering of Polymers into Multifunctional Interactive Excipients

Abstract

1.1 Introduction

1.2 Polymers as Excipients

1.3 Material Properties Affecting Binder Activity

1.3.1 Particle Size

1.3.2 Deformation Mechanisms

1.3.3 Glass Transition Temperature (Tg)

1.4 Strategies for Improving Polymeric Filler-Binder Performance for Direct Compression

1.4.1 Interactive Mixing

1.4.2 Challenges to Interactive Mixing

1.4.3 Controlling Interparticle Cohesion

1.5 Preparation and Characterization of Interactive Excipients

1.5.1 Particle Size and Size Distribution of Excipients

1.5.2 Effect of L-leucine on Surface Morphology

1.5.3 Effect of L-leucine on Surface Composition