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Preface Downloaded by 148.251.232.83 on May 1, 2018 https://pubs.acs.

1 Preface Downloaded by on May 1, American Viscose Corporation (AVC) was a subsidiary of Courtaulds, when it was established as the first North American producer of rayon fiber (regenerated cellulose). The first factory was constructed at Marcus Hook, Pennsylvania, in "Avisco" was the AVC trademark and it was the origin of the trademark Avicel known today as the most widely used excipient in the pharmaceutical industry. Avicel is made from hydrolyzed native cellulose fibers, usually chemical grade wood pulps. The HCl hydrolysis conditions used to convert pulp fibers to Avicel powder removes about 5-10% by weight of non-crystalline pulp and after neutralization and washing the resultant fine powder, hydrocellulose, is about 80% crystalline. The treatment greatly diminishes the molecular weight, down to a degree of polymerization (DP) of 230 (i.e., about 1/25 of the native cellulose value. Nevertheless Avicel is completely water insoluble and is often referred to as microcrystalline cellulose (MCC). Originally intended as a low-calorie food (e.g. as an additive to be used by the baking industries), its use as an excipient was unexpected. Hydrocellulose itself was known as far back as 1854, having been reported by a French scientist, Girard (1-3). The discovery was not far behind the seminal paper by Anselme Payen (4,5) in which he showed the polyglucan structure of cellulose without providing the famous name: "cellulose" which was coined by the reviewers. A second version of the hydrolyzed cellulose is a colloidal grade used in wet applications for foods. AVC like many of the manufacturers of cellulose-based fibers and plastics (e.g., Dupont, Celanese, Hercules, and Eastman-Kodak) had extensive analytical facilities for development of tests related to the dissolving grade pulps. These were used in the production of cellulose derivatives such as cellulose acetate, cellulose nitrate, carboxymethyl cellulose, and cellulose xanthate that are used in the film fiber and plastics industries based on chemical grade cellulose. One such test was referred to as "level-off DP", which probably inspired the HCl hydrolysis conditions used for making Avicel. xi

Orlando Battista was head of analytical testing at AVC and patented the process (6) for making Avicel with its numerous examples of food applications.

2 Orlando Battista was head of analytical testing at AVC and patented the process (6) for making Avicel with its numerous examples of food applications. Studies involving puddings, whipped cream, bread, and ice cream for example, all with low-cal properties etc. did not convert to successful marketing results. The Avicel powder could be pressed into disks to which nails and screws could be fixed. The compressed disks were also resistant to the flame of an oxyacetylene torch. Clearly, these observations were the intellectual seeds that led to excipient applications especially when the tablet-size disks were found to rapidly redisperse when placed in water. This brief historical review of the origin of Avicel is to set the stage for the written account of numerous polysaccharide-based excipients, many of which derive from the Avicel success. The latter is constantly studied and improved as an excipient, for example a typical pharmaceutical formulation today is MCC + colloidal silicone dioxide + magnesium stearate + iron oxides + titanium dioxide + hydroxypropyl methylcellulose. The compositional adjustments take into account properties relating to tablet stability and powder flow into the high speed tableting machines. However, in keeping with the extensive know-how in cellulose derivatization and the prototypical role of cellulose as a crystalline polysaccharide it is not surprising that cellulose derivatives are used as adjuvents with Avicel (e.g. cross-linked carboxymethyl cellulose), which controls the tablet dispersion speed. Many different polysaccharide excipients and adjuvents described in the following chapters of this book were chosen for a variety of reasons but most often to complement Avicel. In 1963 AVC was acquired by FMC Corporation and the patent portfolio of Avicel products relating to excipients and food additives was explored by O. A. Battista and his team. Today, many other polysaccharides are used and considered as excipients (e.g., alginate, beta (1-3) glucans, schitosan, hyaluronic acid, xanthan gum, starch). Even a polysaccharide drug such as heparin can be part of the excipient package. The collection of chapters in this book is a celebration of the diversity of polysaccharide platforms, which enable a variety of drug delivery systems and application platforms for pharmaceutical uses. This is also an occasion to salute the late Orlando Battista whose creative perseverance started it all. He received his graduate training at the Pulp and Paper Research Institute, McGill University and promptly joined the Avisco R&D group. In 1960 he was Chair of the Cellulose Division of the American Chemical Society. In recognition of his work xii

3 on Avicel he was awarded the Division's prestigious Anselme Payen Award. His innovative work on MCC is summarized in his well-known book Microcrystalline Polymer Science published in 1975 by McGraw- Hill Inc. The polysaccharides featured in this book, include MCC and starch that are commodity biopolymers. The former is the widely used hydrolyzed cellulose, which derived from Battista's discovery. Large pharmaceutical organizations dedicate considerable effort to exploring the many ways that MCC can be formulated to improve the tableting properties. Chapter 2 by Li and Mei of Boehringer Engelheim provides a survey of the physicochemical processing, called wet granulation, which is at the base of formulation for such pharmaceutical firms where approximately 80% of the products are in solid dosage form. Accordingly, drying, fine powder transport, mixing, and blending, coating, and large-scale manufacture of tablets and capsules are ongoing operations in pharmaceutical companies. The catalog of available and well-understood polysaccharides was the reason why this symposium was organized. A recent review in Orlando A. Battista xiii

4 Chemistry and Engineering News states that "Excipients are the cinderellas of the drug industry... they do all the work but get none of the glory... they are the inactive ingredients that deliver the active ingredient" (C&E News Nov. 22, 1999). Examples of new polysaccharides being considered for pharmaceuticals are Hyaluronic acid, a well known physiological material, chitin/chitosan, "a Jekyl and Hyde" material from seafood leftovers which is used for dermatology, arthritics, coacervate gels, etc. The writer is grateful for the patience of the contributors, the scholarship of the referees, and the support of my colleagues. The ongoing help of Dr. Grégory Chauve was essential to the completion of the book. Downloaded by on May 1, References 1. Girard, A. Comptes rendus 1875, 81, Girard, A. Comptes rendus 1879, 88, Girard, A. Ann. Chim. Phys. 1881, 24, Payen, A. Comptes rendus 1838, 7, Payen, A. Comptes rendus, : p Battista, O. A. Microcrystalline Polymer Science; McGraw-Hill Inc.: Orlando, FL, Robert H. Marchessault Emeritus Ε. Β. Eddy Professor Chemistry Department McGill University Montréal, Québec H3A 2A7 Canada xiv

Overview Downloaded by 148.251.232.83 on May 1, 2018 https://pubs.acs.org During the past decades, we have seen the pharmaceutical industry grow at a tremendous rate.

5 Overview Downloaded by on May 1, During the past decades, we have seen the pharmaceutical industry grow at a tremendous rate. Along with the discoveries of new drugs for various preventive and therapeutic treatments, the need for novel materials and methods to deliver them energized the field of drug delivery creating new opportunities for material scientists. Drug delivery companies have redefined the picture of the pharmaceutical industry as not only providing tools for the delivery of novel drugs but also as applying their technology to existing formulations available on the market. By doing so, already marketed drugs are given better bioavailability, easier administration, and fewer side effects while giving the patient an optimum treatment. Among those materials, the pharmaceutical industry has since the beginning relied on starch and cellulose, the most abundant natural polymers on earth. Because of the wide variety and range of physicochemical properties created by Mother Nature, and the possibility to perform a large number of specific modifications, polysaccharides are choice starting materials. Nowadays, many polysaccharides are used, modified and transformed to serve the ever evolving pharmaceutical needs either as excipients, surfactants, adhesives, carriers, protectors, or active substances themselves. This book covers several polysaccharides that are utilized in drug delivery, medical and pharmaceutical applications, together with their sources, properties, preparation, and mechanism of action. By bringing together key researchers in these diverse fields, new dialogues have been initiated for the next generation of drug delivery systems. François Ravenelle Manager, New Technologies, Labopharm, Inc. 480 Boulevard Armand-Frappier Laval, Québec H7V 4B4 Canada xv

7 Polysaccharides for Drug Delivery and Pharmaceutical Applications

New formulas for successful drug delivery Hot-melt extrusion for enhanced solubility and bioavailability

New formulas for successful drug delivery Hot-melt extrusion for enhanced solubility and bioavailability Andreas Gryczke, an enabler in excipients Pharma Ingredients & Services. Welcome to more opportunities.