Tablet Ingredients片剂处方（FMC）

1 Tablet Ingredients ........................................................................................................................1 Table of Contents ....................................................................................................................1 Excipients.... ................................................................................................................................3 Choice of Excipients ...............................................................................................................3 Direct-Compression Excipients...........................................................................................4 Directly Compressible Fillers-Binders-Disintegrants ......................................................4 Cellulose......................................................................................................................5 Avicel® PH Microcrystalline Cellulose NF, Ph. Eur., JP, BP.....................................5 Ceolus™ Microcrystalline Cellulose, NF, Ph. Eur., JP ..............................................6 Microfine Cellulose..................................................................................................6 Lactose........................................................................................................................7 Super-Tab™ Spray Dried Lactose Monohydrate NF, Ph. Eur., JP, BP .....................8 Alpha-Lactose Monohydrate...................................................................................8 Anhydrous Alpha-Lactose.......................................................................................8 Anhydrous Beta-Lactose ........................................................................................8 Agglomerated Lactose............................................................................................8 Other Sugars ...............................................................................................................9 Compressible Sugar NF..........................................................................................9 Dextrose Excipient NF ............................................................................................9 Dextrates NF ...........................................................................................................9 Starch and Starch Derivatives.....................................................................................9 Native Starches .......................................................................................................9 Pregelatinized Starch NF ........................................................................................9 Sodium Starch Glycolate NF ................................................................................10 Inorganic Salts...........................................................................................................10 Dibasic Calcium Phosphate USP .........................................................................10 Tribasic Calcium Phosphate NF............................................................................10 Calcium Sulfate NF ...............................................................................................11 Polyols.......................................................................................................................11 Mannitol USP ........................................................................................................11 Sorbitol NF ............................................................................................................11 Xylitol NF ...............................................................................................................11 Coprocessed Excipients ...........................................................................................11 Ludipress® .............................................................................................................12 Cellactose® ............................................................................................................12 Pharmatose® DCL 40 ............................................................................................12 Section 4 Tablet Ingredients By Dr. Zak T. Chowhan Table of Contents 2 Wet-Granulation Excipients.......................................................................................................12 Binders..... .............................................................................................................................12 Avicel® PH Microcrystalline Cellulose NF, Ph. Eur., JP, BP ...............................................12 Cellulose Derivatives .........................................................................................................13 Povidone USP ...................................................................................................................13 Copolyvidone ....................................................................................................................13 Gelatin NF .........................................................................................................................13 Natural Gums ....................................................................................................................13 Starch Paste......................................................................................................................13 Pregelatinized Starch NF...................................................................................................13 Sucrose NF........................................................................................................................13 Other Binders ....................................................................................................................14 Disintegrants .........................................................................................................................14 Ac-Di-Sol® Croscarmellose Sodium NF, Ph. Eur., JPE......................................................14 Sodium Starch Glycolate NF, Explotab®, Primojel®...........................................................14 Crospovidone NF ..............................................................................................................15 Lubricants..............................................................................................................................15 Magnesium Stearate .........................................................................................................16 Calcium Stearate...............................................................................................................16 Stearic Acid .......................................................................................................................16 Sodium Stearyl Fumarate..................................................................................................16 Hydrogenated Vegetable Oils............................................................................................16 Mineral Oil .........................................................................................................................16 Polyethylene Glycols .........................................................................................................16 Antiadherents ........................................................................................................................17 Glidants..... ............................................................................................................................17 Dry Granulation Excipients........................................................................................................18 Excipients Tablet ingredients consist of Active Pharmaceutical Ingredient(s) (API) and excipients. In order to deliver an accurate amount of a drug for its intended clinical use in a convenient unit dosage form, excipients perform very important functions, specifically as: • Fillers/Diluents • Binders • Disintegrants/Super Disintegrants • Lubricants • Antiadherents • Glidants • Wetting/Surface Active Agents • Colors/Pigments • Flavors • Sweeteners • Taste-Maskers The choice of excipients in a tablet formulation depends on the API, the type of tablet, the desired characteristics, and the manufacturing process used. Several types of tablets are available on the market. These include prompt release, from which the drug dissolves in a very short time (sublingual or buccal tablets), and immediate release and modified release, which include most of the orally administered tablets that are swallowed. Other types include chewable, effervescent, bilayer, multiple compressed, and topical tablets, and tablets for solution. The desired characteristics of a tablet may be achieved by adding colors, pigments, sweeteners, flavors, and a sugar or film coating. 3 Choice of Excipients The types of excipients selected for a formulation depend on the basic process used to manufacture the tablets. Compacted or compressed tablets are produced from granulations or powder mixtures made by the following general techniques: • Direct compression (dry mixing and blending) • Wet granulation (high shear, low shear) combined with tray drying or fluid-bed drying • Wet granulation and drying in the same equipment • Dry granulation by roller compaction or slugging Over the past four decades, improvements in the availability of excipients with consistent physical properties (including particle size and shape, and improved functionality such as compaction and flow), have revolutionized tablet production on a commercial scale. In addition, the availability of a diversity of equipment for the wet granulation process (including high-shear granulators, fluid-bed granulators and dryers, extrusion granulators, continuous granulators, and granulators with wet granulation and drying combined in the same equipment), have made tablet produc- tion more economical. However, tablet pro- duction by direct compression still remains the method of choice because it offers eco- nomic advantages by eliminating the wet granulation and drying steps. Specialized processes may be used for certain types of tablets, such as extrusion; a combination of extrusion, spheronization, and compaction; a coating for modified-release tablets; and freeze drying for prompt-release tablets. 4 The evolution in tablet film coating technology has made it a preferred method for taste- masking and trade-dressing, as well as for modifying release and allowing site-specific delivery of drug. The sugar-coating operation has also been refined over the years as a result of improvements made in the equipment and the process, and is still in use. In order to perform the intended functions, the delivered dose of the drug is the primary consideration in selecting the excipient type, grade, and concentration (level) in a formulation. The type of tableting process employed is also important. For high-dosage drugs, the tableting process of choice is generally the wet granulation process, unless mechanical properties of the API are better suited to the direct blending and compression process. Other considerations in the selection of excipients are the physical and chemical compatibility with the API. In general, the chemical and physical stability of the API is investigated in preformulation studies by mixing the API and individual excipients or combinations, and aging them under controlled storage conditions of heat and relative humidity. The effect on the stability of the API and excipients can be determined through this method. Direct-Compression Excipients The direct-compression process generally involves mixing an active pharmaceutical ingredient with excipients prior to com- paction. The selected excipients must meet all of the functionality requirements to pro- duce compacted tablets on a commercial scale. The basic functional requirements are compaction, flowability, lubrication, disintegration, and dissolution. When selecting excipients for direct compression, several factors must be considered: high compactibility; good flowability and blending properties without a potential for segregation of API and excipients (incompleteness of mixing); low lubricant sensitivity to compaction; good stability; enhancement of tablet disintegration and dissolution; non- interference with the biological availability of the active ingredient; batch-to-batch reproducibility of the physical and physical- mechanical properties; worldwide continuous availability and compendia! acceptability; and cost effectiveness. Some of these criteria are difficult to attain because they require universal consistency in the physical and chemical properties of the excipients to obtain reproducibility in the production of dosage forms. It is, therefore, important that the selected excipients in a formulation are manufactured by reputable manufacturers who can guarantee that the process and the in-process controls are identical in different plants around the world. Directly Compressible Fillers-Binders- Disintegrants The process of direct compression was revolutionized by the introduction of Avicel® PH microcrystalline cellulose (MCC), although spray-dried lactose had been introduced one year earlier. In combination, these two excipients are used in most direct- compression formulations. Other directly compressible excipients, commonly referred to as fillers-binders, have appeared in the pharmaceutical market over the past three decades. To improve the functionality of native starches, partially pregelatinized starch was introduced as a filler, binder, and disintegrant, and is successfully used in formulations to perform these functions. The inorganic excipients, such as dibasic calcium phosphate dihydrate (Emcompress®), calcium sulfate dihydrate (Compactrol®), and tricalcium phosphate (Tritab®), are directly 5 compressible and are to be used with caution because of their potential to slow down the in vitro dissolution of the drug after the tablet has aged. The most important excipients identified below are used as directly compressible fillers. Some grades of these classes of excipients are also used as fillers in the wetgranulation process. Cellulose Cellulose forms the backbone of many excipients used in marketed drug products. Pharmaceutical grades of cellulose are obtained by either mechanical or chemical processing, or through a combination of both. Pure cellulose can be ground mechanically or following additional treatment by hydrochloric acid. The resulting powder is cellulose powder, or microcrystalline cellulose. Powdered cellulose has lower compressibility when compared with microcrystalline cellulose, and is generally not used in directly compressible formulations. Avicel® PH Microcrystalline Cellulose NF, Ph. Eur., JP, BP Microcrystalline cellulose is described in the National Formulary (NF) as a purified, partially depolymerized cellulose prepared by treating alpha cellulose, which is obtained as a pulp from fibrous plant material with mineral acids. Of the celluloses, Avicel® PH microcrystalline cellulose (MCC) is the substance most often used in tableting as a filler, disintegrant, flow aid, and dry binder in directly compressed tablets. It has extremely good binding properties as a dry binder. During compression, Avicel® PH MCC is believed to undergo stress relief deformation by several mechanisms. It produces hard tablets at low compression forces and can be used alone or in combination with other directly compressible excipients, such as lactose, starches, etc. Strong binding properties are caused by hydrogen bonds between the hydroxyl groups on the plastically deformed, adjacent cellulose particles. The compressibility of Avicel® PH MCC depends on its moisture content. It has been suggested that, at its equilibrium moisture content of 5%, most of the water will be within the porous structure of microcrystalline cellulose, and a large portion of this bound moisture is expected to hydrogen-bond to small units of cellulose within the particle. In wet granulations, Avicel® PH MCC also acts as a binder and permits rapid addition of the granulation solution because of its ability to absorb water. It is the best spheronization excipient, and up to 70% of an API can be loaded in the formulation. The spheres that are produced have low friability and a good aspect ratio. Several grades of Avicel® PH MCC, which vary in particle size and moisture content (Table 1), are available for different applications. For APls that are water soluble, nonhygroscopic, and difficult to agglomerate, Avicel® PH MCC functions as a wet binder and helps in forming agglomerates that do not powder on dry milling. In direct-compression formulations, Avicel® PH-102 MCC can improve flow characteris- tics. The grades of larger particle size, such as PH-200, can be used in formulations having flow problems. This is attributed to the more rounded particle shape of PH-200, compared with PH-102 aggregates. The compaction properties of PH-102 and PH-200 are essentially identical. Table 2 gives typical values of particle size, bulk density, and loss on drying of commercial grades of Avicel® PH MCC. These grades are engineered for the 6 following specific applications: • PH-101 is one of the most widely used materials for direct compression and wet granulation applications • PH-102 has a larger particle size and may be valuable in improving flow • PH-105 has the smallest particle size with excellent compaction properties • PH-103, PH-112, and PH-113 have reduced moisture content and are ideal for moisture-sensitive, active pharmaceutical ingredients • PH-200 has a large particle size and offers increased flowability • PH-301 has a higher bulk density than its particle size equivalent (PH-101) and good flowability • PH-302 has a bulk density similar to PH-301, a particle size similar to PH-102, and offers better flowability Avicel® PH MCC has a high dilution potential, which is defined as “the ability of a given quantity of an excipient to bind a specified amount of an active ingredient to form an acceptable tablet.” This high dilution potential is attributed to low bulk density (which imparts high covering power), broad particle size distribution (which allows optimum packing density), and its superior binding properties. In addition to the compaction and binding properties, which result in the production of tablets with excellent hardness and low friability, Avicel® PH MCC has good lubrication and disintegration properties. A mixture of Avicel® PH MCC with up to 40% Super-Tab™ spray-dried lactose monohydrate NF can be compressed without the addition of a lubricant. The lubricating property is attributed to a very low coefficient of friction and very low residual die-wall pressure. The disintegrant properties of Avicel® PH MCC are attributed to penetration of water into the hydrophilic tablet matrix by means of capillary action of the pores, followed by a subsequent disruption of the hydrogen bonds, which holds the matrix together. Ceolus™ Microcrystalline Cellulose, NF, Ph. Eur., JP Ceolus™ is the newest highly specialized grade of microcrystalline cellulose offered by FMC. It exhibits superior compressibility and high dilution potential. Because of these properties, it is most suited for the formulation of small size tablets with a high content of active pharmaceutical ingredient. Microfine Cellulose Elcema® is a mechanically produced cellulose powder, which is supplied in a granular grade (G-250). It is the only grade that may be used in direct compression bec