Industrial Pharmacy Lec 2 PDF

Lec. 2: Excipients Mohammed Albarki, PhD  Tablet Excipients All "nondrug" materials of the formula are called excipients. Excipients are necessary for the following reasons: 1. Improve patient compliance such as color, flavor, and...

Lec. 2: Excipients Mohammed Albarki, PhD  Tablet Excipients All "nondrug" materials of the formula are called excipients. Excipients are necessary for the following reasons: 1. Improve patient compliance such as color, flavor, and sweeteners. 2. Increase dosage form stability such as antioxidants, and preservatives. 3. Increase dose accuracy such as diluent or fillers. 4. Act as a process aid such as binders and lubricants. 5. Improve and control drug release, such as disintegrant and coating agents. 2 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Types of Excipients The main excipients used in tablet formulation are: 1. Diluents (fillers) such as lactose, starch, and microcrystalline cellulose. 2. Binders (granulating agents) such as starch, acacia, and gelatin. 3. Disintegrants such as starch, and super disintegrant. 4. Lubricant, Antiadherent, Glidants such as magnesium stearate and stearic acid. Typical Tablet content 3 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Diluents (Fillers) Diluents are materials used to make up the required bulk of the tablet when the drug itself is inadequate to provide this bulk. Occasionally, the active ingredient has a large dose and good compressibility so that it does not need diluent, e.g., aspirin and some antibiotics. However, most tablets need a diluent. Round tablets are usually in the size range of 5-13 mm. Tablets below 5mm may be difficult for the elderly to handle and those larger than 13 mm become difficult to swallow. 1. Diluents are therefore used to formulate the tablets within the desired size range. 2. The diluent can also provide better tablet properties such as improved cohesion or promote flow. 4 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Lactose The most widely used diluent in tablet formulation because it does not react with most drugs. Three forms of lactose are available (anhydrous, hydrous, and spray- dried): 1. Anhydrous lactose has an advantage over the other two types; on aging, it does not undergo discoloration (brown discoloration, Maillard reaction) with amines and alkali compounds. 2. When exposed to elevated humidity, the anhydrous lactose may pick up moisture from the environment and convert to the hydrous form. èThese Tablets should be carefully packaged to prevent moisture exposure. 3. The hydrous form is usually used when wet granulation is used to produce tablets. 5 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Lactose In general, all lactose types show the following advantages: 1. Good drug release. 2. In granulations, granules are easily dried. 3. The disintegration time of lactose-containing tablets is not very sensitive to variations in tablet hardness. 4. Low cost. 5. Has no reaction with most drugs. Disadvantages: Hydrous form undergoes discoloration when used with alkali or amine-containing compounds 6 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Starch It may be derived from different sources such as corn, wheat, or potatoes. Great care should be taken when using starch in the formula because it can be used as diluent, binder, or disintegrant depending on: 1. Type of starch: the useful type for a particular formula can be known by experts. 2. The amount used: it is used as a diluent in the ratio of 50-60%, binder in the ratio of 2-10%, and disintegrant in the ratio of 5-20%. 3. Stage of addition: it is used as a diluent when added in the dry form at the beginning of the procedure (mixing step), a binder when used as a paste in the preparation of the wet mass step, and disintegrant when added finally after granulation as a dry form. 7 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Other Diluents Dextrose: It is available in two forms: hydrous and anhydrous. Dextrose is sometimes used in the formulas to replace some of the lactose to minimize the discoloration (when used with alkaline compounds). Mannitol: It is widely used in chewable and orodispersible tablets because of its sweet taste (sugar) pleasant feeling in the mouth (due to the negative heat of solution), and slow solubility. It is non-hygroscopic so can be used safely in water-sensitive formulations like vitamin formulations. However, it is somewhat expensive, has poor flow, and requires a high lubricant level. 8 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Diluents Microcrystalline cellulose: It is often referred to by the trade name Avicel®. It is a multipurpose excipient used as a diluent and disintegrant. Advantages: It is inert and can be used with alkaline or acidic substances (No discoloration). Has high purity and low moisture content. Avicel is a directly compressible diluent due to its good compressibility and flowability. Avicel-containing tablets are characterized by short disintegration time, high hardness, low friability, and low weight variation. (Why?) 9 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Binders (Granulating agent) They are substances that bind the particles together to form granules (in wet and dry granulation) or to promote the formation of cohesive compacts (in Direct compression). Below are some examples: Acacia and tragacanth: Natural gums. These materials are more effective when added as a solution than if they are used as powders. Disadvantages: They are variable in their composition (why?) and performance according to their origin. They are also easily contaminated by bacteria. Gelatin: Synthetic protein is preferred over acacia and tragacanth and is also easier to prepare in solution than the two gums. However, bacterial growth is also troublesome. 10 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Binders Starch: One of the most commonly used granulating agents (binder) and used as a paste. It is prepared by dispersing starch into water which is then heated for a certain time to induce starch hydrolysis into dextrin and glucose. A properly made paste is translucent rather than clear (which indicates complete conversion to glucose). 11 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Binders Modified Natural Polymers: Common and important binders. Alginates (e.g., sodium alginates) and cellulose derivatives (e.g., methylcellulose (MC), ethyl cellulose (EC), hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC)) are examples of these binders. Except for EC, all of the cellulose derivatives can be used as dry powders (in Direct compression and dry granulation) and as an aqueous solution (in wet granulation). HPC can also be used as an alcoholic solution, thus it is useful for water-sensitive drugs. EC is used only as an alcoholic solution because it is insoluble in water, therefore it may retard tablet disintegration. 12 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Disintegrants A disintegrant is a substance that facilitates the breakdown of the tablet into smaller fragments upon contact with GI fluids. (https://youtu.be/s5aGmUQIzSs ) The function of the disintegrant is to oppose the effect of the tablet binder and the physical force that is applied during the compression process. The disintegrants act by drawing water into the tablet, swelling and rupturing the tablet. This tablet fragmentation is critical to the drug's subsequent dissolution and achieving satisfactory bioavailability. Disintegrants may added at two stages: during the formation of granules (to give intragranular action) and at the second mixing stage during compaction of granules into tablets (extragranular). 13 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Disintegrants Starch The most commonly used disintegrants because of their low cost. It is used in the ratio of 5-20% of the tablet weight. Starch has the property of rapid water uptake and swelling that leads to the rupture of the tablet due to the increase in internal pressure. Super Disintegrant: They are so-called due to their powerful disintegrating action. Examples of these materials are sodium starch glycolate (Explotab®), croscarmellose sodium, and crospovidone (Kollidon CL). They are very potent if compared with the classic disintegrants. For example, croscarmellose sodium swells to 900% of its original volume in acidic media while starch swells to 25% only in the same media. They are used when rapid disintegration is required such as in orodispersible tablets. 14 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Lubricants, Antiadherent, and Glidants Lubricants: They are materials used to reduce the friction during tablet ejection between the tablet and the walls of the die cavity in which the tablet was formed. Antiadherents: Reduce sticking of tablet granules to the faces of the bunches or to the die wall Glidants: They are used to promote the flow of granules or powders by reducing the friction between the particles themselves. Glidants are thought to work by filling irregularities in granules making them more round and reducing friction between granules. 15 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Lubricants Advantages of lubricants 1. Facilitate tablets’ ejection and prevent their sticking in the die. 2. Prolong the life of the die. 3. Decrease the liberated heat (friction heat). Mechanism of action of the lubricants + 1. Fluid lubrication (Hydrodynamic (formation of thin film)): this +- Die wall mechanism is used to explain the action of liquid lubricants. In general, all liquids (especially oily ones) decrease the friction between +- two surfaces. Example: Mineral oils such as liquid paraffin have been applied on the +- granules as a fine spray. However, the problem with using this type of lubricant is the production - of oil spots. Another problem is that the particle surface will be hydrophobic and the tablet may have a slower dissolution rate è may alter bioavailability. 16 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Mechanisms of lubricants (continue): 2. Boundary lubrication: this mechanism is used for solid lubricants. In this type, the polar portion (such as –OH, –NH2) of the lubricant is attached to the metal and prevents the tablet from sticking to the die. The lubricants should be added in the last step (just before compression) since they must be present on the surface of the granules and not between them. 17 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Notes About Lubricants 1. The particle size of the lubricants is crucial; they should be 200 mesh in size or finer. As a general rule, as the particle size of the lubricants increases, their efficacy decreases. 2. The amount of the lubricant in the formula should not exceed 1% (for most lubricants) and this is due to the following problems that can happen with increasing lubricant amount: These materials are water-insoluble and present on the surface of the granules, thus retard water penetration and decrease dissolution rate and may alter bioavailability. 18 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Lubricants 3. The mixing time of the lubricant with the formula should be 2-5 min. Over-mixing decreases the lubricant efficacy because it causes the penetration of the lubricant from the surface to the core of the formula. 4. The mixing rate is also important; a high mixing rate causes the penetration of the lubricant inside the core of the formula and thus, decreases the lubricant’s efficacy. 19 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Lubricants and Glidants Examples of the commonly used lubricants: Magnesium or calcium stearate are the most widely used lubricants due to their efficacy. These lubricants should not be used with acidic drugs like aspirin (due to pH-induced hydrolysis ). Stearic acid is less effective than its magnesium and calcium salts. It should not be used with alkaline drugs. Zinc stearate is inert with good lubricating properties and small particle size. It is used effectively in direct compression. Talc may also be used as a lubricant. Problem: it does contain a trace amount of iron, so it should be applied carefully in any formulation containing a drug whose breakdown is catalyzed by the presence of iron. 20 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Tablet Design and Formulation Generally, tablet formulation consists of the following main processes: 1. Weighing. 2. Granulation. 3. Milling and mixing. 4. Compression. Three types of tablet manufacturing process: 1. Wet Granulation. 2. Dry Granulation. 3. Direct compression. 21 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Mixing A crucial step in the formulation of the pharmaceutical dosage form. 1. Mixing allows uniform distribution of tablet constituents throughout the formulation 2. Allows for adequate distribution of lubricants around tablet granules. Undermixing will probably lead to impaired content uniformity of tablet formulation and poor flow properties Over-mixing will lead to other tablet manufacturing problems such as poor flow properties due to lubricants entering into the tablet granules instead of staying on the surface. V- Shape Mixer 22 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Granulation Fine powder drug mostly has poor flow properties. Granules have: 1. Better flowability than individual ingredients 2. Better compressibility than individual ingredients. 3. It ensures the consistent spread of API in the formulation. 23 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Wet Granulation (used liquid binder) Most common; Contains more steps but is relatively easier to control and compress. Active ingredients plus excipients are mixed together then a binder (binding liquid) is added to a rapid mixer granulator (machine) Granules are then dried and milled to the required size range Then mix with lubricant and compress 24 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Dry Granulation 1. Used when there is a limitation for using a granulating solution such as the interaction between the active ingredient and the solution 2. Also in cases when the drug is sensitive to heat. Drug powder and inactive ingredients are mixed together and passed through a powder roller compactor machine to produce slugs. This process is called slugging Slugs undergo milling and screening to get the desired particle size Examples are vitamin formulations 25 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Direct Compression A special case of tablet formulation. No granulation step; only mixing ingredients and excipients and compressing directly. It requires certain properties of the active ingredients to be able to produce a good tablet: 1. Crystalline in nature. 2. Components are easy to compress. Sodium chloride, potassium salts of iodide, or chloride tablets can be done using this method. Limitation: Most materials have weak intermolecular interaction attraction that tends to hinder compaction. 26 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Direct Compression Advantages of Direct Compression: 1. Simple, low labor input and hence economic. 2. Being a dry process, the risk of deterioration of the active ingredient is decreased. 3. Tablets will disintegrate onto their primary particles rather than granular aggregates à the resultant increase in surface area available for dissolution should result in faster drug release. 27 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Compression The final step is tablet formulation. Required a set of variables to be evaluated which are beyond the scope of this class. 28 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form  Tablet Compression Machine 1. Hopper(s) for holding and feeding tablet components. 2. Dies that define the size and shape of the tablet. 3. Punches for compressing the granulation within the dies. 4. Cam tracks to guide the movement of the punches. Note: there are various auxiliary equipment designed to aid in tablet production such as automatic feeders, deduster (beyond the scope of this class) 29 College of Pharmacy- Industrial Pharmacy II- 5th stage- First Semester Tablet Dosage Form