BPT 311.24 Lecture Notes: Tableting and Encapsulation PDF

BPT 311.2024.EOS 1 Course Outline Course Information: Course Title: Tableting and Encapsulation Course Code: BPT 311 Credits: 4 Academic Year: First Semester (2023/2024) Lecturer’s Name: Prof. E. Omari-Siaw Office: Head of Dept, Pharmaceutical Sciences, 3rd Floor MPC Block Office Hours: Tuesdays (3 pm – 5 pm) Contact: +233 549 557 888 Email: [email protected] Course Description Solid dosage formulations namely tablets, and capsules are the most common dosage forms for pharmaceuticals. Preparation of solid dosage forms utilizes a wide range of excipients and active pharmaceutical ingredients. This course provides requisite knowledge and skills on the formulation of solid dosage forms. Course Objectives: This course is aimed at equipping students with the knowledge and skill in the manufacture of tablets as well as capsules. It is also expected to address packaging containers for the packaging and storage of pharmaceutical products. Course Content Week 1 Course Outline Week 2 Tablet – Types, Ingredients, Week 3 Granulation Technology, Week 4 Tablet Press and Compression, Quiz 1 Week 5 Tablet coating Week 6 Flow Properties Particle Size Analysis, Powder Rheology Week 7 Capsules – Types Week 8 Encapsulation Techniques 1 BPT 311.2024.EOS 2 Week 8 Mid-Semester Examinations Week 10 Pharmaceutical Packaging and Closures Week 11 General overview – Quiz 2 Week 12 Group Work and Presentation Week 13 Tutorial Class Week 14-16 End of Semester Examinations Course Presentation and Assessments Lectures shall be in the form of face to face interactions, online presentations using the Virtual Learning Platform, class and group discussions as well as any appropriate mode which could promote clarity and understanding of the topic. The assessment of students shall be based on: (A) Class work (40%) -computed from marks obtained from group presentations, assignments, quizzes as well as mid-semester examination; and (B) End of Semester Examination (60%). Students are encouraged to: ✓ Be present and punctual at all scheduled classes; ✓ Participate actively in all class sessions or group assignments; ✓ Have an exercise book to jot down points during lecture periods; ✓ Do extensive reading and research on related topics; and ✓ Ask relevant questions or make contributions during class sessions. Recommended Books Aulton, M.E. Pharmaceutics: the science of dosage forms Pharmaceutical Practice Ancel, Pharmaceutical Dosage Forms and Drug Delivery Systems Remington Thompson, J.E. (1998) A practical guide to Contemporary Pharmacy Practice Alfred N. Martin, Physical Pharmacy 2 BPT 311.2024.EOS 3 GENERAL OVERVIEW OF SOLID DOSAGE FORMS The development of novel drug delivery systems that target drugs more effectively to their therapeutic site have gained a lot of attention in recent years. In spite of this, oral solid dosage forms such as powders, tablets and hard gelatin capsules, which have been in existence since the nineteenth century, remain the most frequently used dosage forms. Advantages of Solid Dosage forms over liquid dosage forms Drugs and chemicals are most stable as dry solids Allows easy packaging, transportation, administration and storage Allows concealment of undesirable/objectionable taste Accurate dosing is easier to achieve tablets, capsules and divided powders Controlled release is much easier to achieve than with liquids. AN OVERVIEW OF POWDERS Learning Objectives: At the end of the topic, students should be able to: a. Define Powders b. Differentiate powders from granules; c. State the advantages and disadvantages of powders compared to liquid dosage forms; d. Explain the types of powders with examples; and e. Explain the general principles of compounding powders. Powders are intimate mixtures of dry, finely divided drugs and/or chemicals that may be intended for internal (oral Powders) or external (topical powders) use. Powders agglomerated to produce larger free-flowing particles are called granules. It can serve as a dosage form (simple powder or compound powder) or primary ingredient for other delivery systems such as dentifrices, products for reconstitution, insufflations, aerosols and other miscellaneous products. Types of Powders Topical bulk powders (dusting powders) are applied to the skin for local effect. Powders for internal use: Mostly made up of Active ingredient + excipients (diluents, sweeteners, dispersing agents). Undivided (bulk) powders 3 BPT 311.2024.EOS 4 Applicable to non potent, bulky drugs with a large dose, dry powders more stable than its liquid form. It reduces transport and packaging cost. Can be used to prepare liquid mixtures by addition of a specific volume of water. Stored in wide-mouth containers. Dose is measured volumetrically by the patient or care-giver. Limited by inaccuracies in measuring the dose; and inconvenient to carry. E.g. Antacids, bulk laxatives and antidiarrhoeal medication. Divided powders (chartula or chartulae) Dispensed in the form of individual doses. Mostly associated potent drugs (accuracy is important); wrapped separately in packet or polyethylene bags; Useful when a solid dosage form is desired but the medication is not manufactured in the required volume or when the patients has difficulty in swallowing capsule or tablets. PRINCIPLES OF COMPOUNDING FOR POWDERS A. General Principles a. Particle size reduction is essential in nearly all compounding situations b. The properties of a given solid must be understood and considered to properly handle and manipulate the material when formulating a particular solid dosage form of during incorporation. Fine powders need no further manipulation Fine powders agglomerated on storage need to be broken down to primary particles Chemicals or drugs available as crystals can be crushed using standard compounding technique such as trituration Special techniques such as pulverization by intervention could be applied on waxy substances, or hard crystals materials which are not easy to pulverize. c. When two or more solids are being combined into a mixture, homogenous blending of the powders is needed. B. Particle Size Reduction The reduction in particle size of a solid is accompanied by a great increase in the specific surface area of that substance. Communition is the process of reducing the particle size of a solid substance to a finer state of subdivision. This can be achieved by: - Trituration: It is the continuous rubbing of a solid in a mortar with a pestle to reduce the size of the solid particles to a desirable degree of fineness. - Sieving (sieves) - Levigation: It is the process of reducing the particle size of a solid by triturating it in a mortar or spatulating it on an ointment slab with a small amount of a liquid in which the solid is not soluble. - Pulverization by intervention - Mills and pulverivers (on a large scale) 4 BPT 311.2024.EOS 5 C. Blending Powders When two or more substances are to be combined to form a uniform powder mixture, it is best to reduce the particle size of each individually before weighing and blending. The goal of blending is to create a homogenous mixture. Depending upon the nature of ingredients, the amount of powder to prepare and the equipment available, powders may be blended by: Spatulation is a method by which small amounts of powders may be blended by the movement of a pharmaceutical spatula through the powders on a sheet of paper or an ointment tile. Trituration: Triturating is a preferred method because: It mixes powders more intimately than other methods. It is ideal when making mixtures that contain small quantities of potent drugs. It accomplishes two processes at the same time – Particle size reduction and blending. It saves time when powders of unequal particle sizes are being combined. Sifting: Powders may also be mixed by passing them through sifters like the type used in the kitchen to sift flour. Tumbling: The powder is enclosed in a large container which rotates generally by motorized process. Special powder blenders have been devised and mix powders by tumbling motion. The mixing is thorough and widely used in industry. Ingredients of powders should be mixed thoroughly using the technique of doubling up (geometric dilution) PARTICLE SIZE ANALYSIS Particle Size of a powder, described using standard descriptions given in the official compendia (British or United States Pharmacopoeia). The USP employs certain descriptive terms such as: Very coarse powder: All particles pass through a No. 8 sieve and not more than 20% through No. 60 sieve. Coarse powder: All particles pass through No. 20 sieve and not more than 40% through No. 60. Moderately coarse powder: All particles pass through No. 40 sieve and not more than 40% through a No. 80 sieve. Fine: All particles pass through a No. 60 sieve and not more than 40% pass through a No. 100. Very fine: All particles pass through a No. 80 sieve. There is no limit as to greater fineness. Granules typically fall within the range of 4- to 12- sieve size. 5 BPT 311.2024.EOS 6 These terms are related to the proportion of powder that is capable of passing through the openings (aperture) of standardized sieves of varying dimensions in a specified time period under shaking, generally in a mechanical sieve shaker. The purpose of particle size analysis in pharmacy is to obtain quantitative data on the size, distribution and shapes of drug and non-drug components to be used in pharmaceutical formulations. Particle size can influence a variety of important factors in tableting uniform distribution of drug substance in a powder mixture or solid dosage form. Methods of Determining Particle Size - Sieving - Microscopy - Sedimentation - Light energy diffraction - Laser holography - Cascade impaction Particle size determinations are complicated by the fact that the particles are non-uniform in shape. 6 BPT 311.2024.EOS 7 Topic 1: TABLETS Learning Objectives: At the end of the topic, students should be able to: a. Describe the types and quality of tablets; b. Discus ingredients necessary for the preparation of Tablets c. Identify and understand the various granulation techniques; d. Describe the steps involved in wet granulation techniques e. Discus the types and application of Tablet machines in tablet compression. f. Discus tablet coating DESCRIPTION OF TABLETS Tablets are solid preparations each containing a single dose of one or more active/therapeutic ingredients usually prepared with the aid of suitable pharmaceutical adjunct(s)/additives (excipients). Tablets may vary in characteristics such as size, shape, weight, hardness, disintegration time, depending on the intended use and method of manufacture. They are simple to manufacture and can be kept for a long time. Tablets may be intended for oral, sublingual, buccal or vaginal administration. The tablets for oral use are the commonest and can be presented in various types. Que: Enumerate the advantages of tablets over other dosage forms. TYPES OF TABLETS Buccal and Sublingual tablets Buccal tablets are generally flat, oval soluble tablets that are placed into a cheek (bucca in Latin) pouch to dissolve slowly. Sublingual tablets are placed under the tongue. In both buccal and sublingual tablets, the drug is absorbed directly into the bloodstream through the lining of the mouth (oral mucosa). Example of sublingual tablets include nitroglycerin for angina attacks or buprenorphine for opioid addiction treatment. Figure 1.1 A sublingual tablet Chewable tablets and lozenges 7 BPT 311.2024.EOS 8 These tablets contain active ingredients that are intended to have an effect in the throat or that can be absorbed through the lining of the mouth. These tablets are either chewed or sucked on in the mouth. Example: Strepsils. Fizzy (effervescent or carbon) tablets Prepared by compressing granular effervescent salts or other materials having the capacity to release gas when in contact with water. These tablets are dissolved in a glass of water before administering and can have a faster effect than the compressed tablet since the medication exists in solution by the time it arrives in the stomach. They are useful for patients who have difficulty in swallowing whole tablets. Figure 1.2 Effervescent tablets Compressed tablets (Tablets without coating) Compressed tablets are prepared by single compression of the medicinal substance(s) and excipients. Multiple compressed tablets are also prepared by subjecting a tablet to more than a single compression resulting in a multiple-layered tablet or a tablet-within-a-tablet. In such cases, the inner tablet is considered as the core and the outer portion the shell. Coated tablets (sugar-coated or film-coated tablets) Tablets can be covered with a layer to protect them against external influences, such as dampness or bacteria. Coated tablets are smooth (making swallowing easy), coloured, and often shiny. Coated tablets are not to be crushed or chewed because then they will no longer be protected by the coating. i. Sugar-coated tablets Compressed tablets may be coated with a coloured or uncoloured sugar which is water soluble and quickly dissolved after swallowing. Such sugar coating may offer protection to the drug from air and humidity; provide a taste or a smell barrier to drugs with objectional taste or smell; and enhance the appearance and smoothness. ii. Film-coated tablet 8 BPT 311.2024.EOS 9 Compressed tablets coated with a thin layer of a water-insoluble or water-soluble polymer capable of forming a film over the tablet. The coating ruptures in the gastrointestinal tract. The film is generally coloured and offers more durability, less bulkiness and less time-consuming advantages over sugar-coatings. iii. Enteric-coated Tablets Tablets with a coating that resist dissolution or disruption in the stomach but not in the intestines. It allows the tablet to transit through the stomach into the intestines before disintegration, dissolution and absorption of the drug. Employed in instances where the drug substance is destroyed by gastric acid; irritating to the gastric mucosa or when absorption is significant in the intestines. Controlled/modified release tablets There are instances when the release of the active ingredient in the formulation is carefully controlled or modified leading to delayed onset of action or extended/ prolonged duration of action. i. Delayed release tablet aims at protecting the drug from an unfavourable environment in the gastrointestinal tract (GIT). For example, to protect the GIT from high local concentration of an irritating drug compound or target a specific region of absorption or action. Delayed release products are typically enteric-coated or targeted to the colon. ii. Extended-release products aim at releasing the drug continuously at a predetermined rate in order to increase the patient compliance due to reduced frequency of administration and also to prevent high concentration, locally or systematically. Ways of achieving prolonged drug release include: 1. Use of ion exchange resins 2. pH- independent formulations 3. Prodrugs 4. Barrier – coating 5. Embedment in hydrophilic 6. Plastic or slowly eroding matrices 7. Repeat action 8. Polymer resin beads 9. Drop complex formation 10. Bio adhesives 9 BPT 311.2024.EOS 10 Tablet quality attributes Tablet quality attributes are the characteristics that affect the safety, efficacy, performance, and usability of the drug product. These factors are controlled within the production of a batch of tablets as well as inter-batch productions to assure both outward appearance and therapeutic efficacy. Appearance (Physical Features): Standardization of some physical features of tablets help ensure high quality of the tablets. Tablets may be characterized based on shape, degree of flatness, thickness, scores, and colour as shown in Figure 1.3. For instance: i. Shape: Tablets are normally round, oblong, triangular, or circular. ii. Flatness: Depending on varying degrees of convexity tablets are either flat or biconvex faces. This is usually determined by the die and punches used for the compression of the tablet. iii. Thickness: How thick or thin a tablet depends on the amount of fill permitted to enter the die and the amount of pressure applied during compression. Figure 1.3 Tablet features iv. Score: Tablets can be scored or grooved in halves, thirds or quadrants to permit a fairly accurate breaking of the tablets when partial amounts are required. v. Colour: Different colours to make distinction of tablets easy. vi. Engraved with a symbol of the manufacturer to denote the company, the product or both. Punches having raised impressions will produce recessed impression on the tablets; punches having recessed etchings will produce raised impression. Tablets must meet other physical specifications such as tablet weight, tablet thickness, tablet hardness, tablet disintegration, content uniformity and drug dissolution. These factors must be controlled within the production of a batch of tablets as well as inter production batches to assure both outward appearance and therapeutic efficacy. 10 BPT 311.2024.EOS 11 Tablet hardness: This is the ability of the tablet to withstand mechanical stress without breaking or crumbling. It is measured using a hardness tester. The desired hardness of the tablet relatively depends on the type of drug, the route of administration, and the intended use of the tablet, among others. The hardness of the tablet can affect the bioavailability and therapeutic efficacy of the drug. Weight variation: This is the variation in weight among different tablets in a particular batch. It is important to ensure that the weight variation is within the desired range to ensure dosing accuracy and consistency. Friability: This is the tendency of the tablet to break or crumble when subjected to mechanical shocks, such as handling and transportation. It is measured using a friability tester or a friabilator and is expressed as a percentage of weight loss. The lower the friability, the better the tablet quality. Content uniformity: This is the degree of uniformity of the drug substance in each tablet. It is assessed by testing a sample of tablets for drug concentration in each tablet. The content uniformity of the tablets should be within the specified limits to ensure that each tablet delivers the same amount of drug. Tablet disintegration: This ensures that the tablet breaks down rapidly and consistently into smaller particles when exposed to aqueous fluids. This rapid disintegration facilitates the dissolution and release of the active pharmaceutical ingredient (API) into the gastrointestinal tract, enabling absorption and systemic distribution of the drug. It is measured using a disintegration apparatus. Dissolution rate: This is the rate at which the tablet dissolves in a specified medium under specified conditions. It is measured using a dissolution apparatus and is expressed as a percentage of drug dissolved in a given time. The dissolution rate of the tablet can affect the absorption and bioavailability of the drug. 11 BPT 311.2024.EOS 12 TABLET INGREDIENTS Ingredients for oral solid dosage forms can be categorized mainly into two namely: i) Active Pharmaceutical Ingredient(s) (API) – The medicinal substance(s) or primary drug(s) in the formulation that provide(s) the intended therapeutic action; and ii) Excipients also known as pharmaceutical adjunct(s)/additives – inactive substances that serve various functions in the formulation. Active ingredients used for preparing oral solid dosage forms The European Medicines Agency, the United States Food and Drug Authority, and the International Conference on Harmonisation (Q7) all adopt the same definition of API as "any substance or mixture of substances intended to be used in the manufacture of drug (medicinal) products, and that, when used in the production of drug, becomes an active ingredient of the drug product". Key characteristics of active pharmaceutical ingredients include: Biological Activity: Active pharmaceutical ingredients (APIs) which are the most important component of a medication. They are the chemical-based and biologically active compounds that are used for pharmacological activity in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or function of the body. Sources: APIs can be produced from natural or synthetic, chemical, biological, mineral, and other sources of raw materials with a specified strength and chemical concentration. APIs can be derived from a variety of sources, including plants, animals, or synthesized through chemical processes. They undergo comprehensive scientific, regulatory, and manufacturing processes to ensure their safety, quality, and efficacy. Safety: The quality and purity of APIs in a drug product are critical for the safety and efficacy of the drug. APIs are carefully synthesized and purified to meet strict specifications, and they are subject to rigorous testing to ensure their identity, strength, purity, and stability. 12 BPT 311.2024.EOS 13 Chemical structure: APIs have defined chemical structures, which are crucial for understanding their pharmacokinetics, mechanisms of action, metabolism, and potential interactions within the body. Formulation: They are used to formulate various pharmaceutical dosage forms such as tablets, capsules, solutions, etc. The amount of API in a drug product is typically expressed in milligrams (mg) or micrograms (mcg). APIs need to be compatible with various excipients and other components in the formulation process to ensure stability, solubility, and bioavailability in the final dosage form. Some common active ingredients include but not limited to Acetaminophen, Ibuprofen, Metformin, Diclofenac, Nifedipine Manufacture: Manufacturing APIs often involve complex processes such as synthesis, extraction, purification, and crystallization. These processes require adherence to strict quality control measures to produce APIs of high purity and consistency. Regulation: APIs are subject to stringent regulatory oversight by health authorities globally to ensure their safety, quality, and efficacy. These regulations govern aspects such as manufacturing practices, labeling, and documentation related to the production of APIs. Excipients Used For Preparing Oral Solid Dosage Forms Excipients (pharmaceutical adjunct(s)/additives) are inactive substances employed to help in the delivery of APIs in the body system as well as to aid the formulation of oral solid dosage forms. The excipients may be classified according to the role they play in the finished tablet. The first group include those which help to impart satisfactory processing and compression characteristics to the formulation. These include diluents, binders or adhesives, antiadherents, glidants and lubricants or lubricating agents. The second group of added substances help to give additional desirable physical characteristics to the finished tablets. These include disintegrants/disintegrators (disintegrating agents), colorants/colours. In the case of chewable Tablets, sweetening and flavoring agents; polymers or waxes as well as solubility-retarding materials for controlled-release tablets. 13 BPT 311.2024.EOS 14 Thus, while some excipients help to impart satisfactory processing and compression characteristics to the formulation others help to give additional desirable physical characteristics to the finished product. Common excipients employed in the formulation of most oral solid dosage forms include diluents, binders or adhesives, disintegrants, lubricants, glidants, colouring agents, flavouring agents and sweetening agents. Different excipients are used in various suitable formulation. The common types and their specific roles are discussed as follows: In a suitable formulation a number of different excipients are used. The common types used are: Diluents - to produce a unit dose weight of suitable size; Disintegrating agents, which are added to aid the break-up of the granule when it reaches a liquid medium, e.g. on ingestion by the patient. Binders (Adhesives) may also be added. - The primary role of binders is to provide the cohesiveness essential for the bonding of the solid particles under compaction to form a tablet. Refer to BPT 311 Practical Manual for notes on common types of excipients and their specific roles. Assignment: Identify the main categories of tablets ingredients, their roles as well as examples. 14 BPT 311.2024.EOS 15 MANUFACTURE OF TABLETS (GRANULATION TECHNOLOGY) Granulation is one of the most important unit operations in the production of pharmaceutical oral dosage forms. The compression of medicinal materials into tablets is normally carried out by means of a tablet machine that stamps out the tablets in a die between punches. To achieve this, it is necessary to prepare the materials in the form of small granules to enhance uniform flow of the materials from the hopper to the die. Granulation may be defined as the size enlargement process which converts fine or coarse particles into physically stronger and larger agglomerates (1 to 2 mm in diameter) having good flow property, better compression characteristics and uniformity. The art and science for process and production of granules is known as Granulation Technology. Reasons for granulation Parameter Fine powders Granules Flowability Do not normally flow freely from Flow and pack down easily results the hopper into the die, resulting in in less variation in tablet weight. uneven tablets. Segregation of A powder containing two or more Granules are of uniform size and ingredients components may segregate. The composition if properly prepare. denser components or those of Segregation is not serious, although smaller particle size may separate a certain proportion of the fine to the bottom of the hopper, the materials cannot be avoided This effect often aggravated by the does not exceed 15%. vibration of the tablet machine. Pressure Pressure transmission through a Granules pack down rapidly and transmission powder masss is very poor due to readily transmit the compression low packing density. Materials do forces. Bond to form a strong tablet. not ‘knit’ together, unless special methods are employed. 15 BPT 311.2024.EOS 16 Blowing out and Fine powders tend to blow out of The granules being heavier do not seeping the die at the top and to seep blow out of the die and do not clog downwards round the stem of the the lower punch. lower punch, causing sticking The granulation of toxic materials will reduce the hazard associated with the generation of toxic dust that may arise when handling powders. Suitable precautions must be taken to ensure that such dust is not a hazard during the granulation process. Thus, granules should be non-friable and have a suitable mechanical strength. Materials which are slightly hygroscopic may adhere and form a cake if stored as a powder. Granulation may reduce this hazard, as the granules will be able to absorb some moisture and yet retain their flowability because of their size. Granules, being denser than the parent powder mix, occupy less volume per unit weight. They are therefore more convenient for storage or shipment. The effectiveness of granulation depends on the following properties: ✓ Particle size of the drug and excipients ✓ Type of binder (strong or weak) ✓ Volume of binder (less or more) ✓ Wet massing time (less or more) ✓ Amount of shear applied ✓ Drying rate (Hydrate formation and polymorphism) Methods of Granulation There are three basic methods of granulation namely: Dry granulation Wet (moist) granulation, and Direct compression (granulation by preliminary compression). Dry Granulation (precompression or the double-compression method) Employed in instances where the tablet ingredients are: Sensitive to moisture; Thermolabile; and Have sufficient inherent binding or cohesive properties. 16 BPT 311.2024.EOS 17 In dry granulation, process the powder mixture is compressed without the use of heat and solvent. It is the least desirable of all methods of granulation. The two basic procedures are to form a compact of material by compression and then to mill the compact to obtain granules. In the dry methods of granulation, the primary powder particles are aggregated under high pressure. There are two main processes. Either a large tablet (known as a ‘slug’) is produced in a heavy-duty tableting press (a process known as ‘slugging’) or the powder is squeezed between two rollers to produce a sheet of material (‘roller compaction’) i.e. To pre-compress the powder with pressure rolls using a machine such as Chilsonator. In both cases, these intermediate products are broken using a suitable milling technique to produce granular material, which is usually sieved to separate the desired size fraction. Steps involved in dry granulation process are 1. Milling of drugs and excipients 2. Mixing of milled powders 3. Compression into large, hard tablets to make slug 4. Screening of slugs 5. Mixing with lubricant 6. Tablet compression Advantages of dry Granulation: It uses less equipment and space. It eliminates the need for binder solution, heavy mixing equipment as well as the costly and time consuming drying step required for wet granulation. Slugging can be advantages for moisture and heat sensitive materials and improved disintegration since powder particles are not bonded together by a binder. Disadvantages of dry granulation It requires a specialized heavy-duty tablet press to form slug. It does not permit uniform color distribution as can be achieved with wet granulation where the dye can be incorporated into binder liquid. The process tends to create more dust than wet granulation, increasing the potential contamination. Direct Compression Direct compression consists of compressing tablets directly from powdered material without modifying the physical nature of the material itself. Usually employed for a small group of crystalline chemicals such as potassium salts (chlorate, chloride, bromide, iodide, nitrate, 17 BPT 311.2024.EOS 18 permanganate), ammonium chloride and methenamine) which possess cohesive and flow properties. Direct compression for tablets containing 25% or less of drug substances would require a suitable diluent which acts as carrier or vehicle for the drug. Good flow and compressible characteristics of direct compression vehicles or carriers can be imparted to them by a preprocessing step such as wet granulation, slugging, spray drying, spheronization or crystallization. In some cases, require greater sophistication in blending and compression equipment. Direct compression equipment are expensive. Wet Granulation Wet granulation involves the massing of a mix of dry primary powder particles using a granulating fluid. The fluid contains a solvent which must be volatile so that it can be removed by drying, and be non-toxic. Typical liquids include water, ethanol and isopropanol, either alone or in combination. The granulation liquid may be used alone or, more usually, as a solvent containing a dissolved adhesive (also referred to as a binder or binding agent) which is used to ensure particle adhesion once the granule is dry. Water is commonly used for economical and ecological reasons. Its disadvantage is, solvents may adversely affect drug stability, causing hydrolysis of susceptible products, and it needs a longer drying time than do organic solvents. This increases the length of the process and again may affect stability because of the extended exposure to heat. The primary advantage of water is that it is non- flammable, which means that expensive safety precautions such as the use of flameproof equipment need not be taken. Organic solvents are used when water-sensitive drugs are processed, as an alternative to dry granulation, or when a rapid drying time is required It is the most widely employed method for the production of granules due to the greater probability that the granulation will meet all the physical requirements for the compression of a good tablet. It is also applicable to most powdered materials. However, wet granulation is limited by the number of separate steps involved as well as the extensive time and labour consumed to carry out the procedure, especially on the large scale. The basic steps involved are: - Weighing and blending (mixing) the ingredients - Preparing the wet granulation - Screening the damp mass into pellets or granules - Drying - Dry screening - Lubrication - Compression 18 BPT 311.2024.EOS 19 Limitations of wet granulation: ✓ The greatest disadvantage of wet granulation is its cost. It is an expensive process because of labor, time, equipment, energy and space requirements. ✓ Loss of material during various stages of processing. ✓ Stability may be major concern for moisture sensitive or thermo labile drugs. ✓ Multiple processing steps add complexity and make validation and control difficult ✓ An inherent limitation of wet granulation is that any incompatibility Four major techniques which are used for wet granulation process: ✓ Single pot granulation ✓ High shear mixture granulation ✓ Fluid bed granulation ✓ Extrusion-Spheronization Advanced Granulation Techniques Over a period of time, due to technological advancements and in an attempt to improve commercial output various, newer granulation technologies have been evolved such as, ✓ Steam Granulation ✓ Melt Granulation Technology ✓ Moisture Activated Dry Granulation (MADG) ✓ Moist Granulation Technique (MGT) ✓ Thermal Adhesion Granulation Process (TAGP) ✓ Foamed Binder Technologies (FBT) ✓ Pneumatic Dry Granulation (PDG) ✓ Freeze granulation Technology TABLET MACHINES AND SEQUENCE OF COMPRESSION After the preparation of granules (in case of wet granulation) or slugs (in case of dry granulation) or mixing of ingredients (in case of direct compression), they are compressed to get final product. The compression is done either by single punch machine (stamping press) or by multi station machine (rotary press). The tablet press is a high-speed mechanical device which 'squeezes' the ingredients into the required tablet shape with extreme precision. Each tablet is made by pressing the granules inside a die, made up of hardened steel. The die is a disc shape with a hole cut through its centre. The powder is compressed in the centre of the die by 19 BPT 311.2024.EOS 20 two hardened steel punches that fit into the top and bottom of the die. This determines the weight of the tablet. The punches and dies are fixed to a turret that spins round. As it spins, the punches are driven together by two fixed cams (an upper cam and lower cam). The top of the upper punch (the punch head) sits on the upper cam edge. The bottom of the lower punch sits on the lower cam edge. Types of compression machines There are 2 types of compression machines namely: a. Single punch/single station or eccentric press Single station press, also referred to as stamping process, is the simplest machine for tablet manufacturing which uses an easy-to-use single set of station tooling (a die and a pair of punches (upper and lower punches). The compaction force on the fill material is exerted by only the upper punch while the lower punch is static. This press usually produces about 60 - 85 tablets/min and can manufacture odd-shaped products with a diameter of up to 20 mm. The single punch structure is rational and small and operates at a high utilization ratio. It is ideal for development of tablets and small batch production. The single tablet press utilizes a high amount of pressure which reduces weight variations between tablets while maintaining a low noise level at the same time. Parts of a single punch tablet press i) Hopper: It is used to hold the granules (powder mix) to be compressed and supply the material to the die and removes the tablet after its compression. ii) Die: Die defines the shape and the size of the tablet by allowing the lower and upper punch to come close together to compress the material. 20 BPT 311.2024.EOS 21 iii) Punches (Lower and upper punches): These are used for compressing of the materials (drug or the drug with excipients/ granules) within the die. iv) Cam track: This is the component used for guiding the movement of the punches. v) Capacity regulator: It adjusts the position of the lower punch to accommodate the required quantity of materials by the die. vi) Ejection regulator: To adjust the position of the lower punch, so that its highest position is at par with the surface of the die. vii) Driving wheel: It helps in the movement of the lower punch, the upper punch and hopper shoe and also checks their movement. Working cycle of a single punch machine The working cycle of a single punch is as follows as shown in Figure 2.11. i) Filling: Upper punch is withdrawn from the die by the upper cam, lower punch is lowered in the die, so the powder falls in through the hole and fill the die. ii) Weight adjustment: Lower punch moves up to adjust the powder/granule weight. It raises and expel the extra powder/granules. iii) Compression: Upper punch is driven into the die by upper cam. Lower punch is raised by lower cam. Both punch heads pass between the heavy rollers to compress the tablet. iv) Ejection: Upper punch is withdrawn by the upper cam. Lower punch is pushed up and expels the tablets. Tablet is removed from the die surface by the surface plate. Figure 2.11 sequence of compression 21 BPT 311.2024.EOS 22 Examples of single punch tableting machine The different series of the single punch tableting machine include but not limited to Automatic Single Punch Tableting Machine, C&C600B Series, TDP - Benchtop Model, TDP-1 Benchtop Model, TDP-5 Benchtop Model, and TDP-30 Benchtop Model Single Punch Tablet Presses. Automatic Single Punch Tableting Machine is the most popular unit. This is a bench-top, semi- portable, motor-driven unit but can also be hand-driven for adjustment and testing purposes. It is designed for pressing tablets from a variety of granular materials for Research & Development and small-scale production. It is adjustable, operator friendly, easy to maintain, compact and light weight. C&C600B Series Single Punch Tablet Press is an advanced machine with new structure. It is a continuous, automatic tablet machine used in many departments such as pharmacy, laboratory which needs to make powder, and granular raw material into tablets. b. Multi-Station/Rotary Presses Multi-station press is a mechanical device that unlike the single punch tablet press has several tooling stations which rotate to compress granules/powder mixture into tablets of uniform size, shape (depending on the punch design) and uniform weight. It increases the output of tablets of between 9000 – 234000 tab/hour. In rotary press, the compaction force on the fill material is exerted by both the upper and lower punches leaving the powder granules to be compressed in the middle. This is known as accordion type of compression. The capacity of a rotary tablet press is determined by the rotation speed of the turret and the number of stations on the press. Multi-station press increases high productivity with a minimal amount of labour while saving cost and meets up with the high demand of tablet dosage form. The powder filled cavity can be automatically managed by a moving feeder. The machine allows independent control of both weight and hardness. 22 BPT 311.2024.EOS 23 Main parts of a rotary press The main parts of a rotary press include hopper, feeder system, punches, die system, turret, cam tracks, tablet press filling station and weight control, compression rollers, ejection cam, take-off blade and discharge chute, touch screen control panel, sealing system, electric motors, gears and belts, lubrication system and hydraulic pump unit. Figure 2.13 Parts of the rotary tablet press PROBLEMS THAT COULD ARISE DURING COMPRESSION PROCESS OF TABLETS Binding: It is the adhesion of the granules to the die walls due to insufficient lubrication and it causes the resistance of the tablets to eject from the die. Tablets produced are usually with rough and vertical score marks on the edges. It could be corrected by increasing lubrication and its distribution as well as the improving the moisture content in the granulation. Sticking: Adhesion of the whole tablet surface to the punch faces due to the improperly dried or lubricated granules. This leads to tablets with dull, scratched or rough faces. Picking: A form of sticking in which a small portion of granules sticks to the punch face leaving a portion of the tablet missing. 23 BPT 311.2024.EOS 24 Filming: a slow form of sticking and is largely due to excess moisture in the granulation. Capping: Occurs when the upper segment of the tablet separates from the main portion of the tablet and comes off as a cap. Attributable to compression of air entrapped in the granules which then expands when the pressure is released. Other contributing factors include: Large amount of fines and lack of sufficient clearance between the punches and the die wall; too much or too little lubricant of excessive moisture. Can be solved by increasing binder; decreasing the upper punch diameter or adding binder as dry powder. Lamination: Tablet splits at the sides into two or more parts. This could be solved by increasing binder; decreasing the upper punch diameter or adding binder as dry powder. Mottling: unequal distribution of colour on the surface of the tablet. Other problems include weight variation, poor flow, cracking, etc. PC (e) Discuss tablet coating Tablet coating is a process by which an essentially dry, outer layer of coating material (a sugar or polymeric coat) is applied to the surface of a dosage form in order to confer specific benefits over the uncoated variety. The reasons for tablet coating include: a. To mask the disagreeable odour, colour or taste of the tablet. b. To offer a physical and/or chemical protection to the drug. c. To modify, control and sustain the release of the drug from the dosage form. d. To incorporate another drug which create incompatibility problems. e. To protect an acid-labile drug from the gastric environment. f. Increasing the mechanical strength of the dosage form. Coating equipment A coating pan is a device used to coat tablets, pills, capsules, or other pharmaceutical products with a thin layer of material. The main components of a coating pan (Figure 2.16) include: i. Pan: It is the heart of the coating pan and typically made of stainless steel. It is usually cylindrical or conical in shape and is mounted at an angle of 30-45 degrees to facilitate the movement of the tablets or pellets. 24 BPT 311.2024.EOS 25 ii. Spray system: The spray system is responsible for applying the coating material to the tablets or pellets. It consists of a spray gun, nozzle, and pump. The spray gun is positioned above the pan and the nozzle is positioned to atomize the coating material into a fine mist. The pump is used to regulate the flow of coating material to the nozzle. iii. Air handling unit: The air handling unit is responsible for drying the coating material and removing excess moisture from the pan. It consists of a blower, heater, and exhaust system. The blower draws air through the pan, the heater heats the air, and the exhaust system removes the moisture-laden air. iv. Control panel: The control panel is used to monitor and control the operation of the coating pan. It typically includes a temperature controller, a timer, and a speed controller. v. Other parts include Dust collector, Loading system, and Discharge system. Figure 2.16 Tablet coating pan Coating Process Various techniques have been designed for the application of the coating on the tablet surface. Generally, the coating solutions are sprayed onto the uncoated tablets as the tablets are being agitated in a pan, fluid bed, etc. As the solution is being applied, a thin film is formed which sticks to each tablet. The liquid portion of the coating solution is then evaporated by passing air over the surface of the tumbling pans. The coating may be formed either by a single application or may be developed in layers through the use of multiple spraying cycles. The choice of coating method 25 BPT 311.2024.EOS 26 depends on the substrate material, coating material, desired coating properties, and production scale. Tablet coating techniques There are several techniques for tablet coating such as sugar coating, film coating and enteric coating. a. Sugar Coating This technique involves tablet coating developed originally from the use of sugar to mask the taste and provide an attractive appearance. The process of sugar coating consists of several steps: i. Sealing: A seal coat is applied over the tablet to prevent moisture penetration into the tablet core. Zein (a corn protein derivative) is a sealant in use now. Shellac is no longer in use as a sealant due to polymerization problems. ii. Sub coating: This step is done to round the edges and increase the tablet weight. iii. Syrup Coating: The imperfections in tablet surface are covered up and the predetermined size is achieved. This step requires the maximum skill. iv. Colouring: Gives the tablet its final colour. v. Polishing: Powdered wax (beeswax or carnauba) is applied to provide a desired luster. Sugar coating process is very time consuming and is dependent on the skills of the coating operator. Time and expertise required by the process and increase in the size and weight of the compressed tablets tend to limit its application in the manufacture of tablets. Sugar coated tablets may be 50% larger or heavier than the original uncoated tablet. b. Film Coating Film coating technology involves spraying of a solution of polymer, pigments and plasticizer onto a rotating tablet bed to form a thin, uniform film on the tablet surface. The choice of polymer mainly depends on the desired site of drug release (stomach/intestine), or on the desired drug release rate. 26 BPT 311.2024.EOS 27 Some of the non-enteric coating polymers are Hydroxyproply methyl cellulose (HPMC), Methyl hydroxyethyl cellulose, Ethylcellulose, Povidone, etc. On the other, commonly used enteric coating polymers include Cellulose acetate phthalate, Acrylate polymers (Eudragit L& Eudragit S), and HPMC phthalate. Generally, an ideal film coating material should possess the following characteristics: i. It should be soluble in a solvent of choice. ii. It must produce an elegant coat. iii. It should be stable in presence of heat, light or moisture. iv. It should not possess disagreeable colour, taste or odour. v. It should be non-toxic and pharmacologically inert; and vi. It should be compatible with other coating additives. Film-coating solutions may be non-aqueous or aqueous. The nonaqueous solutions contain the following types of materials to provide the desired coating to the tablets: i. A film former capable of producing smooth, thin films reproducible under conventional coating conditions and applicable to a variety of tablet shapes. Example: Cellulose acetate phthalate ii. An alloying substance providing water solubility or permeability to the film to ensure penetration by body fluids and therapeutic availability of the drug. Example: Polyethylene glycol iii. A plasticizer to produce flexibility and elasticity of the coating and thus provide durability. Example: Castor oil iv. A surfactant to enhance spreadability of the film during application. Example: Polyoxyethylene sorbitan derivatives v. Opaquants and colorants to make the appearance of the coated tablets handsome and distinctive. Examples: opaquant, titanium dioxide; colorant, FD&C or D&C dyes vi. Sweeteners, flavours, and aromas to enhance the acceptability of the tablet by the patient. Examples: sweeteners, saccharin; flavours and aromas, vanillin 27 BPT 311.2024.EOS 28 vii. A glossant to provide luster to the tablets without a separate polishing operation. Example: beeswax viii. A volatile solvent to allow the spread of the other components over the tablets while allowing rapid evaporation to permit an effective yet speedy operation. Example: alcohol mixed with acetone Defects arising from Tablet coating. i. Picking and sticking: This is when the coating removes a piece of the tablet from the core. It is caused by over-wetting the tablets, under-drying, or poor tablet quality. ii. Bridging: This occurs when the coating fills in the lettering or logo on the tablet typically caused by excess application of the solution, poor design of the tablet embossing, high coating viscosity, high percentage of solids in the solution, or improper atomization pressure. iii. Erosion: This can be the result of soft tablets, an over-wetted tablet surface, inadequate drying, or lack of tablet surface strength. iv. Twinning: It is the sticking together of two tablets during coating. It can be corrected by increasing the pan speed and lowering the spray rate. v. Peeling and frosting: This is a defect where the coating peels away from the tablet surface in a sheet. Peeling indicates that the coating solution did not lock into the tablet surface due to a defect in the coating solution, over-wetting, or high moisture content in the tablet core. vi. Blistering: Arising from too rapid evaporation of solvent from the coated tablets and the effect of high temperature on the strength and elasticity of the film. vii. Mottled colour: This can happen when the coating solution is improperly prepared, the actual spray rate differs from the target rate, the tablet cores are cold, or the drying rate is out of spec. viii. Orange peel: Coating texture that resembles the surface of an orange. It is usually the result of high atomization pressure in combination with spray rates that are too high. 28 BPT 311.2024.EOS 29 Quality Evaluation of Coated Tablet Determination of the quality of a tablet coat involves studying of the film and the film-tablet interactions using any of the following test methods: i. Adhesion test with tensile strength testers to measure the force needed to peel the film from the tablet surface. ii. Diametric crushing strength of the coated tablets to measure the tablet hardness. iii. Rate of coated tablet disintegration and dissolution should also be studied. iv. Stability studies on coated tablets to verify whether temperature and humidity changes would result in film defects. v. measurement of tablet weight gain after exposure to elevated humidity provide relative information on the protection provided by the film. 29 BPT 311.2024.EOS 30 TOPIC 2: POWDER RHEOLOGY Learning Objectives: At the end of the topic, students should be able to: a. Identify factors that could influence flow properties of granules; b. Calculate parameters such as true volume, void, porosity, apparent density and bulkiness. c. Explain interparticulate forces using angle of repose and Hausner ratio values. The study of the flow and deformation of powders is the science of powder rheology. Factors that influence the rheological properties of a powder mass may include size, shape and distribution. Poor flow properties may be due to the following reasons: Surface forces existing between the particles causing cohesion (powders adhering to the surface of the container). Such forces include Van de Waals, surface tension and electrostatic forces; Appreciable interparticulate friction if the particles surface are rough and pitted; Particles may interlock causing ‘bridging’ and ‘arching’ for irregular shaped particles. The cohesion of a powder bed increase as the bed packs down and consolidates due to particle rearrangement. This rearrangement happens if the bed is vibrated or tapped. Some feature influencing cohesion of powders include: ✓ Average Particle Size ✓ Parking density ✓ Nature of the surface Packing of spheres Rhombus/triangle packing where the angles of 60o and 120o are common. The closest packing and the space between the particles, the void, is about 0.26, resulting in a porosity of about 26%. Cubical packing where cubes are packed at 90o to each other, results in void of about 0.47 or a porosity of about 47%. This is the most open type of packing. If particles are not uniform, the smaller particles will slip into the void spaces between the larger particles and decrease the void areas. Packing and flow is important because it can impact the: Size of container required for packaging, Flow of granulations; Efficiency of the filling apparatus during the tableting and encapsulation process; and Ease of working with the powders. A number of characteristics can be used to describe powders: ✓ Porosity ✓ True Volume 30 BPT 311.2024.EOS 31 ✓ Bulk Volume ✓ Apparent density ✓ True density ✓ Bulkiness The fraction of a powder bed that consist of free space is known as the porosity. (Porosity is void × 100) This value can be determine experimentally by measuring the volume occupied by a selected weight of a powder. This volume is called the initial volume (Vo or Vbulk). The true (Tapped/Consolidated or Final) volume (V or Vf) of a powder is the space occupied by the powder exclusive of the spaces greater than the intramolecular space. Void can be defined as Vbulk – V or 1 – V/Vo Vbulk Porosity = Void × 100 Is Porosity the same as carr’s index? Bulk volume is True volume + porosity Initial density ≡ Apparent Density/bulk density (ρa) True density ≡ consolidated/Tapped density (ρ) Bulkiness (B) is the reciprocal of the apparent density. B = 1/ρa Powders with a low apparent density and a large bulk volume are “light” powders and those with high apparent density and a small bulk volume are “heavy” powders. Que: A selected powder has a true density of 3.5 g/ml. Experimentally 2.5 g of the powder measures 40 ml in a measuring cylinder. Calculate the true volume, void, porosity, apparent density and bulkiness. Que: Use your knowledge on micromeritics to distinguish light powders from heavy powders. Predicting Powder Flow Flowability is defined as the ability of particles to move relative to neighboring particles or along walls. When examining the flow properties of a powder, it is useful to be able to quantify the type of behavior. 31 BPT 311.2024.EOS 32 Many methods have been described, either directly using dynamic or kinetic methods like Hooper flow rate methods and Recording flow meter methods, or indirectly, generally by measurements carried out on static beds. The indirect methods include: Angle of repose measurements, Shear cell determinations, Bulk density measurements (Hausner ratio and percentage compressibility). Angle of Repose (AoR) Angles of repose have been used as indirect method of quantifying powder flowability, because of their relationship with interparticle cohesion. The AoR is considered a characteristic parameter of powder flowability because the heap angle is affected by the ability of particles to slide along the heap surface. It is the most commonly observed and measured angular property of granular solids. An object such as a particle will begin to slide when the angle of inclination is large enough to overcome frictional forces. Conversely, an object in motion will stop sliding when the angle of inclination is below that required to overcome adhesion and cohesion. This balance of forces causes a powder or granules poured from a container onto a horizontal surface to form a heap. Initially, the particles stack until they approach an angle after which subsequent addition of particles causes the stack to slip and roll over each other until the gravitational forces balance the interparticle frictional forces. The sides of the heap formed in this way make an angle with the horizontal, which is called the Angle of repose and is characteristic of the internal friction or cohesion of the particles. The value will be high if the powder is cohesive and low if non-cohesive. Is a relatively simple technique for estimating the flowability of a powder. Powder with low angle of repose will flow freely (excellent) and powder with high angle of repose will flow poorly. Experimentally determined by allowing a powder to flow through a funnel and fall freely on to a surface. The height and diameter of the resulting cone is measured and using the equation below: tan θ = h/r Where h is the height of the powder cone and r is the radius of the powder cone Eg. A powder was powdered through the funnel and resulted in a cone that was 3.3 cm and 9cm in diameter. What is the angle of repose? tan ɵ = h/r 3.3/4.5 = 0.73 θ = tan-1 0.73 = 36.25 32 BPT 311.2024.EOS 33 1. MICROMERITICS Learning Objectives: At the end of the topic, students should be able to: a. Understand the usefulness of micromeritics in tablets compression and drug formulation; b. Determine particle size of particles using the sieving method; and c. Calculate statistical mean diameters using the Hatch and Choate Equations. MICROMERITICS - Micromeritics is the science of small particles. Micromeritics includes a number of characteristics: particle size, particle size distribution, particle shape, Angle of repose, porosity, true volume, bulk volume, apparent density and bulkiness. A particle is any unit of matter having defined physical dimension. The purpose of particle size analysis in pharmacy is to obtain quantitative data on the size distribution and shapes of drug and non drug components to be used in pharmaceutical formulations. Particle size can influence a variety of important factors: a. Dissolution rate of particles intended to dissolve; b. Suspendability of particles; c. Uniform distribution (in powder mixture or solid dosage form); d. Penetrability (intended to be inhaled 1-5 mm); and e. Non grittiness of solids in dermal ointment/cream ophthalmic preparations Particle size determination Several techniques can be used to determine particle size and particle size distribution. 1) Microscopic method: counting not less than 200 particles in a single plane using a calibrated ocular on a microscope. 2) Sieving method involves using a set of US Standard sieves in the size range desired. Standardized Sieves for pharmaceutical tests and measurement are generally made of wire cloth woven from brass, bronze or other suitable wire (not coated or plated). Standard sieve numbers and sieve openings in each, expressed in millimeters and in micrometer (microns). 33 BPT 311.2024.EOS 34 Sieve Number Aperture Size (Sieve Sieve Number Aperture size (Sieve opening) opening) 2 9.5 mm 60 250 µm 3.5 5.6 mm 80 212 µm 4 4.75 mm 100 180 µm 8 2.36 mm 120 150 µm 10 2.00 mm 200 75 µm 20 850 µm 230 63 µm 30 600 µm 270 53 µm 40 425 µm 325 45 µm 50 300 µm 400 38 µm Adapted from USP23-NF18 A stack of sieves is arranged in order, the powder is placed in the top sieve, the stack is shaken, and the quantity of powder resting on each sieve is weighed. The cumulative percent by weight of powder retained is plotted on a probability scale against the logarithm of the arithmetic mean size of the opening of each of the two successive screens (sieves). Table 3.0 A sample data and the relevant features for log probability plot Sieve Aperture Range (mm) Mid Point Weight % Weight Cumulative No. (mm) (mm) Retained (g) Retained % Weight retained 20 0.850 ≥ 0.850 0 0 0 60 0.250 0.250 – 0.850 0.550 45.0 71.1 71.1 80 0.180 0.180 – 0.250 0.214 18.3 28.9 100 Referring to a Sample log probability graph plot Two important statistical parameters namely Geometric mean diameter (d'g) and Geometric standard deviation (σg) can be obtained. ✓ The Geometric mean diameter (d'g) is the size corresponding to the 50% on the cumulative percentage axis; while ✓ Geometric standard deviation (σg) is the quotient of the ratio of (84% size)/(50% size) or (50% size)/(16% size). Using appropriate formulae developed by Hatch and Choate the statistical diameters for particles separated into weight fractions can be obtained as follows: 34 BPT 311.2024.EOS 35 Table 4.0 Diameter Weight Distribution Equation Mean Diameter (dav) log dav = log d'g – 5.757 log2 σg Mean surface diameter (ds) log ds = log d'g – 4.605 log2 σg Mean volume diameter (dv) log dv = log d'g – 3.454 log2 σg Mean volume surface diameter (dvs) log dvs = log d'g – 1.151 log2 σg Sample calculations: where d'g is extrapolated from the graph as 96.0 µ and 84% size = 90. Arithmetic mean diameter: log dav = log d'g – 5.757 log2 σg σg = (84% size)/(50% size) = 90/96 = 0.9375 log dav = log d'g – 5.757 log2 σg = 1.982 – 5.757 (-0.028)2 dav = 95.0 µ 35 BPT 311.2024.EOS 36 2. CAPSULES Learning Objectives: At the end of the topic, students should be able to: a. Define capsule? b. Distinguish between Hard gelatin and Soft gelatin capsules; and c. Application of soft gelatin capsules. Capsules Capsules are solid dosage forms in which one or more medicinal and/or inert substances are enclosed within a small shell or container generally prepared from a suitable form of gelatin, cellulose or other polymers. Capsules vary in size, depending on the amount of drug to be administered, and have distinctive shapes and colours when produced commercially. The choice of capsule type depends on various factors including the physicochemical properties of the drug substance, the desired drug release profile, and the target site of action. Types of pharmaceutical capsules: 1. Hard-shelled capsules Hard-shelled capsules also called “two pieces” are made of two pieces of gelatin or hydroxypropyl methylcellulose (HPMC) that are sealed together. The two pieces are presented in the form of small cylinders closed at one end. The shorter piece is called the “cap” which fits over the open end of the longer piece, called the “body” as shown in Figure 1.1. Figure 1.1. Hard-shelled capsule They are typically used for dry solids such as powders, pellets, granules or tablets; semi-solids like suspensions or pastes; as well as non-aqueous liquids. Hard-shelled capsules are easy to manufacture and fill, and they are relatively inexpensive. They are also tasteless and odourless, making them a good choice for medications that have an unpleasant taste or smell. Hard gelatin capsules are the most common type used by pharmaceutical manufacturers in the preparation of the majority of capsule products. The basic empty gelatin capsule shells are made 36 BPT 311.2024.EOS 37 from a mixture of gelatin, sugar, and water. They are mostly clear and may be coloured with combinations of colorants such as dyes and opaquants like titanium dioxide to make the caps and bodies distinctive. Gelatin is stable in air when dry but is subject to microbic decomposition when it becomes moist or when it is maintained in aqueous solution. Normally, hard gelatin capsules contain between 13 to 16% of moisture. However, if stored in an environment of high humidity, additional moisture is absorbed by the capsule and may become distorted and lose their rigid shape. In extreme dry environment, some of the moisture normally present may be lost and the capsule becomes brittle and may crumble when handled. This could affect hygroscopic or deliquescent materials enclosed within capsules. Capsules should be generally stored in areas of low humidity. Gelatin is insoluble in cold water, but softens through the absorption of up to ten times its weight of the water. Gelatin is soluble in hot water, and in warm gastric fluid. Gelatin, being a protein, is digested and absorbed. Plant-based capsules are also a type of hard-shelled capsules made from vegetable-derived polymers, such as hydroxypropyl methylcellulose (HPMC), offering a vegetarian alternative to gelatin capsules which are derived from animal. Plant-based capsules offer advantages in terms of biocompatibility and sustainability. 2. Soft-shelled capsules Soft-shelled capsules, also known as softgels or “one piece”, are made of a single piece of gelatin that is filled with a liquid or semi-liquid substance as shown in Figure 1.2. They are typically used for oils and for active ingredients that are dissolved or suspended in oil. Soft-shelled capsules are more expensive than hard-shelled capsules, but they offer several advantages. They are easier to swallow than hard-shelled capsules, and they allow for a more precise dosing of the medication. Additionally, soft-shelled capsules can protect the medication from degradation by the stomach acid. Figure 1.2 Softgels 37 BPT 311.2024.EOS 38 Soft gelatin capsules are prepared from shells of gelatin to which glycerin or a polyhydric alcohol such as sorbitol has been added to render the gelatin elastic or plastic-like. A soft gel (a soft gelatin capsule) is a solid capsule (outer shell) surrounding a liquid or semi-solid center (inner fill). These capsules may be oblong, elliptical or spherical in shape, and may be employed to contain liquids, suspensions, pasty materials, or dry powders. An active ingredient can be incorporated into the outer shell, the inner fill, or both. Soft gelatin capsules are usually prepared, filled and sealed in a continuous operation using specialized equipment. Application of soft gelatin capsules. Soft gelatin capsules may be used to contain a variety of liquids and dry fills. Liquids which may be encapsulated into soft gelatin capsules include: a. Water immiscible, volatile and non-volatile liquids e.g. vegetable and aromatic oils, aromatic and aliphatic hydrocarbons, chlorinated hydrocarbons, ethers, esters, alcohols, and organic acids. b. Water miscible, non-volatile liquids such as polyethylene glycols, and non-ionic surface active agents as polysorbate 80. c. Water miscible and relatively non-volatile compounds as propylene glycol and isopropyl alcohol depending on the concentration used and packaging conditions. Extended/Modified release capsules The release of hard-shelled capsules can be modified like tablets. Capsules can also be coated or designed to release their medication over a prolonged period or to targeted sites. i. Enteric Capsules: These capsules are designed to resist disintegration in the stomach and release their medication in the small intestine. This is achieved by coating the capsule with an enteric polymer that dissolves at a higher pH level. Enteric capsules are useful for medications that are unstable in stomach acid or that need to be targeted to the lower gastrointestinal tract. ii. Extended-Release Capsules: Extended-release capsules are designed to release their medication over a prolonged period, typically several hours. This is achieved by incorporating mechanisms such as matrix systems, osmotic pumps, or controlled-release polymers into the capsule formulation. Extended-release capsules are beneficial for medications that require sustained release to maintain therapeutic blood levels. iii. Targeted-release capsules are designed to deliver medication to specific sites in the body, such as lungs, tumours or diseased tissues. This is achieved by incorporating targeting ligands or nanocarriers into the capsule formulation. Targeted-release capsules can improve drug efficacy and minimize systemic side effects. 38 BPT 311.2024.EOS 39 Encapsulation equipment Encapsulation equipment are machines designed to encapsulate active pharmaceutical ingredients (APIs) within a protective shell, typically made of gelatin, cellulose, or other polymers. Types of Encapsulation Equipment: 1. Hard Gelatin Capsule Filling Machines These machines are used to produce hard gelatin as well as plant-based capsules, for various medications. They typically employ a dipping pin method, where pins are immersed in gelatin solution to form the capsule shells, which are then filled and sealed. Capsule shell filling In practice hand operated and electrically operated hard gelatin capsule filling machines are available for filling capsules. However, for small and quick dispensing, hand operated machines are quite economical. A hand operated gelatin capsule filling machine consists of the following parts as shown in Figure 1.3. a. A bed with 200-300 holes. b. A capsule loading tray c. A powder tray d. A pin plate having 200 or 300 pins corresponding to the number of holes in the bed and capsule loading tray. e. A lever f. A handle g. A plate fitted with rubber top. 39 BPT 311.2024.EOS 40 Figure 1.3b Parts of the hand operated capsule filing machine Automated encapsulation equipment An automated encapsulation equipment may have the following components: a. Capsule Shell Feeder: This mechanism feeds preformed capsule shells into the encapsulation process, ensuring proper alignment and orientation for filling and sealing. b. Powder or Granule Filling System: This system accurately dispenses the API-excipient mixture into the capsule shells, ensuring consistent dosing per capsule. c. Sealing Mechanism: This mechanism seals the filled capsule shells together under pressure, forming complete capsules. d. Drying Chamber: This chamber removes residual moisture from the formed capsules to ensure their stability and maintain their shape. e. Polishing System: This system polishes the capsules to enhance their appearance and remove any imperfections. f. Control Panel: This interface allows operators to control various machine parameters, such as filling volume, sealing pressure, and drying time. 40 BPT 311.2024.EOS 41 2. Soft Gelatin Capsule Filling Machines: These are specifically designed for soft gelatin capsules, which offer faster drug release and are suitable for oily or liquid medications. They utilize a rotary die or reciprocating die mechanism to form the capsule bodies and caps simultaneously, filling the capsules with the API in the process. In the rotary die process, two gelatin ribbons are continuously fed between twin rotating dies. The dies have carefully shaped pockets that form the capsules. The fill material is injected into the pockets, and the gelatin ribbons are sealed together, forming the capsules. The capsules are then cut from the ribbons and transferred to the next step as shown in Figure 1.5. Figure 1.5 Soft gelatin capsule machine (rotary die process) Selection of Encapsulation Equipment: The choice of encapsulation equipment depends on several factors, including: 1. Capsule Type: The type of capsules being produced, whether hard gelatin, soft gelatin, or plant-based, determines the specific equipment design. 2. Production Capacity: The desired production volume dictates the machine's capacity and speed. 3. Dosage Accuracy: The required level of dosing accuracy influences the machine's filling system precision. 4. Budgetary Constraints: The available budget plays a role in selecting equipment that meets both performance and cost requirements. 41 BPT 311.2024.EOS 42 5. Regulatory Compliance: The equipment must adhere to relevant regulatory standards and cGMP guidelines. Encapsulation process The process to enclose active pharmaceutical ingredients (APIs) and other excipients within a protective shell, typically made of gelatin, cellulose, or other polymers is known as encapsulation. 1. Encapsulation of hard gelatin capsule The preparation of filled hard gelatin capsules may be divided into the following steps: a. Formulation Preparation: The API is mixed with excipients, such as fillers, binders, and lubricants, to create a uniform powder or granule mixture through granulation. b. Encapsulation Machine Setup: The encapsulation machine is calibrated and adjusted to the desired capsule size, filling volume, and sealing pressure. c. Capsule Shell Preparation: Preformed capsule shells are selected and loaded into the machine, while ensuring proper alignment and orientation. d. Powder or Granule Filling: The API-excipient mixture is accurately filled into the capsule shells, ensuring consistent dosing per capsule. e. Capsule Sealing: The capsule shells are sealed together under pressure to form complete capsules. f. Drying and Finishing: The formed capsules undergo drying to remove residual moisture and may be polished to enhance their appearance. g. Quality Control: Capsules are subjected to various quality control tests, including visual inspection, weight and content uniformity, and dissolution testing, to ensure compliance with specifications. 2. Encapsulation of soft gelatin capsule The soft gelatin capsule filling process is a complex one that involves a continuous process. There are two main methods of encapsulation for soft gelatin capsule namely the rotary die, and plate process. The rotary die process involves the following steps: a. Gelatin preparation: At this stage, gelatin is first dissolved in water and other additives to create a solution with the desired viscosity and elasticity. This solution is then carefully filtered to remove any impurities. b. Fill material preparation: The fill material, such as a liquid, paste, or suspension, is carefully prepared to ensure to the desired viscosity. c. Encapsulation: Achieved through the rotary die process. d. Drying: The encapsulated softgels are transferred to a carefully controlled drying chamber to remove excess moisture from the gelatin shell. 42 BPT 311.2024.EOS 43 e. Inspection and packaging: The dried softgels are then inspected for defects, such as tears, wrinkles, or inconsistencies in size or shape. Defective capsules are removed, and the remaining capsules are packaged for distribution. Quality attributes of tablets Capsule quality attributes are the characteristics that define the acceptability and performance of capsules as a dosage form for delivering medications. These attributes help maintain appearance, integrity, stability, content uniformity, and enhanced release profiles of the capsules. These attributes include: 1. Appearance: a. Capsules should have a consistent and uniform shape and size according to the specified dimensions. b. The capsule surface should be smooth, free from cracks, splits, or other imperfections. c. The capsule colour should be uniform and consistent throughout the batch. 2. Integrity: a. The capsule seal should be intact to prevent leakage of the drug substance or contamination from external factors. b. The capsule shell should have a consistent thickness to ensure adequate protection of the drug substance and maintain capsule integrity. c. Capsules should be friable (able to withstand a certain level of physical stress without breaking or chipping). d. The capsule packaging should maintain its integrity throughout the distribution chain to protect the capsules from damage, contamination, or moisture exposure. 3. Content Uniformity, dissolution and drug release: a. The amount of drug content per capsule should be consistent within a specified range to ensure consistent dosing. b. Capsules should meet acceptable impurity limits to ensure patient safety and avoid adverse effects. c. The capsules should dissolve at a controlled rate in the appropriate dissolution medium to facilitate drug absorption from the gastrointestinal tract. d. The drug substance should be released from the capsules in a consistent and reproducible manner to achieve the desired therapeutic effect. 4. Stability: Capsules should maintain their physical integrity and appearance throughout their shelf life under specified storage conditions. The drug substance within the capsules should maintain its chemical stability and potency throughout the shelf life. Common defects of capsules include: 43 BPT 311.2024.EOS 44 a. Cracks or splits in the capsule shell b. Missing or incomplete caps or bodies c. Non-uniform shape or size d. Discoloration or staining e. Foreign particles or contamination f. Visible signs of leakage or damage Capsule sizes Manufactured in varying sizes, length, diameter and capacity. Size selected based on amount of material to be encapsulated. Since the density and compressibility of a powder or powder mixture will largely determine to what extent it may be packed into a capsule shell there are no strict rules for predicting the proper capsule size for a given powder or formulation. For human use empty capsules ranging in size from 000, the largest, to 5, the smallest are commercially available, plain or coloured. Comparison of capsules and tablets Capsules are versatile oral dosage form for oral medications, offering several advantages over tablets, such as faster drug release, better taste masking, and suitability for hygroscopic drugs. There are several types of capsules, each with its own unique characteristics and applications. Tablets on the other hand have some uniqueness over capsules namely ease of compression, scoring as well as controlled release. Table 1.0 provides some comparison of capsules and tablets. 44 BPT 311.2024.EOS 45 Table 1.0 Comparison of Capsules and tablets Comparing Capsules Tablets Parameter Manufacturing Produced by filling preformed Typically produced by Process shells with the drug substance and compression, where a powdered excipients. The shells can be made mixture of drug substance and from various materials, including excipients is forced through a mold hard gelatin, soft gelatin, or plant- under high pressure based alternatives. Rate of Capsule production may be slower Tablet compression is faster and Manufacturing and more complex. simple. Flexibility Capsules can be filled with a variety Tablets can be manufactured in of excipients, such as powders, various shapes and sizes, allowing pellets, liquid or oily drug for precise dosing and extended- substances providing flexibility in release formulations. formulation design. Durability Capsules are less durable and more Tablets are generally more durable susceptible to damage during and less susceptible to damage storage and transportation. during storage and transportation. Storage Capsules may require specific Tablets may require room storage conditions to maintain their temperature conditions to maintain integrity, such as protection from their integrity. moisture and temperature extremes. Potential for Soft gelatin capsules may leak if Tablets can be more susceptible to leakage or punctured or exposed to extreme breakage, especially during breakage temperatures. handling or transportation. Size limitations Capsules can be produced in There may be limitations in varying sizes producing very small or very large tablets. Desired release Capsules typically offer faster drug Drug release from tablets are profile release compared to tablets, making relatively slower than capsules them suitable for medications that require quick absorption. 45 BPT 311.2024.EOS 46 3. PARKAGING MATERIALS Packaging can be defined as an economical means of providing presentation, protection, identification/information, containment, convenience, carriage and display until a time that the product is used by or administered to the consumer. This time frame must be within the shelf-life of the product, which is controlled by the selection of the right combination of product and pack. A Pharmaceutical Package container is an article or device which contains the pharmaceutical product. The container may or may not in direct contact with the product. The container which is designed for pharmaceutical purpose must be stable. Ideal Qualities of a Pharmaceutical Package It should have sufficient mechanical strength so as to withstand handling, filling, closing and transportation. It should not react with the contents stored in it. It should be of such shape that can be elegant and also the contents can be easily drawn from it. It should not leach alkali in the contents. The container should not support mould growth. The container must bear the heat when it is to be sterilized. The contents of container should not be absorbed by the container. The material used for making the container should be neutral or inert. Any part of the container or closure should not react with each other. Closure should be of non toxic nature and chemically stable with container contents. It should provide desired degree of protection from environmental hazards. [2, 3] Advancements in science and technology and changing trends in product has caused a distinct move from for example, the use of unpleasant oral liquids to the solid dosage form such as delayed or sustained release products. Such changes can have a positive influence on the type of pack used such as shown by the increasing application of blister and strip packing. Both sustained-release and the unit – type packs offer obvious patient convenience, as a selected number of units can be readily detached and carried around as a day’s treatment. This leads to improved patient compliance. Packaging such as blister packs need relatively little storage space, compared to bottles. Other examples of packs offering patient convenience include unit-dose presentations that permit immediate disposal after use; metered dose aerosols, and nasal sprays which combine convenience with dosage control, squeeze eye packs instead of the earlier dropper and teat assembly. THE ROLE OF THE PACK 46 BPT 311.2024.EOS 47 The shelf-life of all pharmaceutical products largely depends on certain functions of the packaging. The pack must be economical and, therefore, contribute to overall profitability; It must also provide protection from climatic, biological, physical and chemical hazards. It must provide an acceptable presentation which will contribute to or enhance product confidence, which at the same time, maintains adequate identification and information on the drug. Packaging must also contribute to convenience and patient compliance. Each of these aspects, has to be considered against the total shelf life of the product, which involves periods of storage (static), carriage (motion), possible display and finally use or administration, directly by a patient or indirectly by a health professional. In certain cases, the pack may form part of the administration system, as seen with aerosols, metered dose nasal pumps, prefilled syringes etc. The external image of the pack must compliment product confidence, provides clear and concise product identification, adequate information related to the contents, the route of administration, storage conditions, batch number, expiry date, manufacturer name and address and product license number, it must also assist the patient to comply with his medication. Producing an aesthetically acceptable design is therefore a requirement in good packaging. Majority of packaging factors are however associated with its functions. THE PACK AS A PROTECTION Although, each function of the pack is important, protection is the most critical factor, as it controls the total shelf-life of the product. Possible hazards include: Mechanical, Climatic, Biological and Chemical factors. MECHANICAL FACTORS Mechanical or physical damage may occur due to the following: Stock or impact damage: This implies rough handling where rapid deceleration occur (drops, impacts). Stock can normally be reduced or overcome by various forms of cushioning, restriction of movement, more careful handling etc. However, it should be pack or packaging material before it reaches the stage of a packed product. A. Compression Top pressure or loading can crush a pack and damage the product inside. The crushing of a carton can make a product difficult to sell, even though no damage may have occurred to the contents. Although this is most likely to occur during stacking in the warehouse, or in transit, where vibration adds a further hazard, compression of the pack can occur in other situations (eg. Capping on a production line). 47 BPT 311.2024.EOS 48 B. Vibration Vibration consists of two variables - frequency and amplitude. These can vary enormously. E.g. A load on a truck may bounce up and down say 50 mm, up to about 120 times per minute, whereas vibration from aircraft or ship engines may have low amplitude, but very high frequency. Each extreme may produce different forms of damage to products or packs. Components of products may separate, screw caps may loosen, labels or decorations may abrade, etc. C. Abrasion This results from both regular and irregular forms of vibrations. Abrasion can affect the visual appearance of the product or package. E.g. A

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