Pharmaceutical Technology Chapter 4 PDF

PHARMACEUTICAL TECHNOLOGY CHAPTER 4 Hard Capsules Dr. Suhair Sunoqrot Dr. Nisrein Jaber Introduction The word ‘capsule’ is derived from the Latin capsula, meaning a small box. There are two types of capsule, ‘hard’ and ‘soft’ The hard capsule consists of two pieces...

PHARMACEUTICAL TECHNOLOGY CHAPTER 4 Hard Capsules Dr. Suhair Sunoqrot Dr. Nisrein Jaber Introduction The word ‘capsule’ is derived from the Latin capsula, meaning a small box. There are two types of capsule, ‘hard’ and ‘soft’ The hard capsule consists of two pieces in the form of cylinders closed at one end; the shorter piece, called the ‘cap’, fits over the open end of the longer piece, called the ‘body’. Raw materials used in capsules Gelatin (major component in both hard and soft capsules) Water Colorants Wetting agents Preservatives Gelatin Non-toxic, widely used in foodstuffs. Readily soluble in biological fluids at body temperature. Good film-forming material, producing a strong flexible film. Gelatin is prepared by the hydrolysis of collagen from animal skins and bones. There are two main types of gelatin: type A, which is produced by acid hydrolysis, and type B, which is produced by basic hydrolysis. The acid process takes about 7–10 days and is used mainly for porcine skins, because they require less pre-treatment than bones. The basic process takes about 10 times as long and is used mainly for bovine bones. Gelatin After hydrolysis, gelatin is extracted from the treated material using hot water to form a gel which are then dried in a fluidized-bed system. The properties of gelatin that are most important are: (1) Bloom strength and (2) viscosity. The Bloom strength is a measure of gel rigidity. It is determined by preparing a standard gel (6.66% w/ v) and maturing it at 10 °C. The load in grams required to push a standard plunger 4 mm into the gel is recorded as the Bloom strength. The gelatin used in hard capsule manufacture is of a higher Bloom strength (200–250 g) than that used for soft capsules (150 g). Colorants Water-soluble dyes or insoluble pigments. To make a range of colours; dyes and pigments are mixed together as solutions or suspensions. The dyes used are mostly synthetic in origin and can be subdivided into the azo dyes (those that have an –N=N– linkage) and the non-azo dyes. Most dyes used are non-azo: erythrosine (E127), indigo carmine (E132) and quinoline yellow (E104). Types of pigment are used: black, red and yellow iron oxides (E172) and titanium dioxide (E171), which is white and is used to make the capsule opaque. Wetting agents Surfactants such as sodium lauryl sulfate are used in hard gelatin capsule manufacture. They function as wetting agents, to ensure that the lubricated metal molds are uniformly covered when dipped into the gelatin solution. Preservatives in order to prevent microbiological contamination during manufacture. Preservatives Added as an in-process aid to prevent microbial contamination during manufacture Manufacturers operating according to GMP guidelines no longer use them, because moisture level is regulated to 13 – 16%, so water activity will not support microbial growth as water molecules are too strongly bound to gelatin molecules Manufacturing of hard capsules Concept: metal molds are dipped in a hot gelatin solution  gelatin undergoes sol-gel transition upon contact with colder molds The gelatin film is then dried, cut to the desired length and removed from the molds Nowadays the operation is completely automated and performed at specialized companies Preparation of raw materials 1. 35 – 40% w/v gelatin solution is prepared in demineralized water at 60 – 70 ºC under stirring. Vacuum is applied to remove air bubbles 2. Aliquots of this solution are dispensed into containers and mixed with the required amounts of dye/pigment 3. Viscosity is measured and adjusted by addition of hot water. Viscosity is important as it will determine the thickness of the capsule shell 4. The prepared mixes are then transferred to a heated holding hopper on the manufacturing machine Manufacturing steps The manufacturing machines consist of two halves that are mirror images of each other (one half for the capsule cap and the other for the body) The molds (50,000 per machine), called “pins” and made of stainless steel, are mounted in sets on metal strips (“bars”) Capsules are formed by dipping sets of molds which are at room temperature into a dip pan holding a fixed amount of gelatin solution kept at 45 – 55 ºC (fed from the holding hopper) A film is formed on the surface of each mold by gelling The molds are slowly withdrawn from the solution and allowed to air dry in the upper level of the machine The dried films are removed from the molds, cut to the correct length, and the two parts are joined together Manufacturing steps The assembled capsules are not fully closed at this stage and are in a ‘prelocked’ position, which prevents them falling apart before they reach the filling machine. The capsules now pass through a series of sorting and checking processes, which can be either mechanical or electronic, to remove as many defective ones as possible. Modern capsules are ‘self-locking’, developed to prevent content spill during manufacturing. These have a series of indentations on the inside of the cap and the outside of the body, which fit together to hold the two parts together. Empty capsule properties Empty gelatin capsules contain a significant amount of water that acts as a plasticizer for the film and is essential for their function. The standard moisture content specification for hard gelatin capsules is between 13% and 16% w/w. This value can vary depending upon the conditions to which they are exposed. Gelatin capsules are readily soluble in water at 37 °C. Their rate of dissolution decreases when the temperature falls below this. Below about 26 °C they are insoluble and simply absorb water, swell and distort. Capsule sizes Hard capsules are made in a range of sizes. The standard industrial ones in use today for human medicines range from size 0 to 4. To estimate the fill weight for a powder, the body volume is multiplied by the tapped density. The fill weight for liquids is calculated by multiplying the specific gravity of the liquid by the capsule body volume multiplied by 0.9. Elongated size capsules (extra 10% volume) Capsule filling Limitations in properties of materials for filling into capsules: Must not react with gelatin (e.g. formaldehyde causes cross-linking) Must not contain a high level of moisture (causes shell softening) Unit dose volume must not exceed the sizes of capsules available (e.g. low density formulations) Types of materials that can be filled into hard capsules: Dry solids (powders, granules, tablets) Semi-solids (thermo-softening and thixotropic mixtures, pastes) Liquids (nonaqueous) Filling of powder formulations 1. Bench-scale filling: ‘Feton’ device consists of sets of plastic plates with predrilled holes to take from 30 to 100 capsules of a specific size. Empty capsules are fed into the holes, either manually or with a simple loading device. The bodies are locked in their plate by means of a screw and the caps in their plate are removed. The bodies are released and drop below their plate surface, powder is placed onto this surface and is spread with a spatula so that it fills the bodies. The uniformity of fill weight is very dependent upon good flow properties of the powder. The cap plate is then repositioned over the body plate and the capsules are rejoined using manual pressure.  Filling of powder formulations A.With empty capsules in the loader tray, the tray is placed on top of the filler unit B.The loader inserts the capsules into the filling unit and is removed, and the top plate is lifted to separate the caps from the bodies C.The powder is placed on the unit and the capsule bodies are filled D.The top plate is returned to the unit and the caps are placed on filled capsule bodies. Filling of powder formulations 2. Industrial-scale filling: The machines (dosing systems) come in a variety of shapes and sizes, varying from semi- to fully automatic and ranging in output from 3000 to 150 000 per hour. Automatic machines can be either continuous in motion, like a rotary tablet press, or intermittent Filling of powder formulations The dosing systems can be divided into two types: 1. Dependent dosing systems: Use the capsule body directly to measure the powder. Uniformity of fill weight can only be achieved if the capsule is completely filled. Semi-automatic. Empty capsules are fed into a pair of ring holders, the caps being retained in one half and the bodies in another. The body holder is placed on a revolving turntable with variable speed and then the powder hopper is pulled on top Filling of powder formulations 2. Independent dosing systems: The powder is measured independently of the body in a special measuring device. Weight uniformity is not dependent on filling the body completely; with this system capsules can be partially filled. Fully automatic. Use a dosing mechanism that forms a powder plug which is then transferred to the capsule body. Plugs are soft compact formed at low compression forces Two types of plug-forming machines: 1. The ‘dosator’ system 2. The ‘tamping finger and dosing disc’ system Filling of powder formulations a) Dosator system A dosing tube inside which moves a spring- loaded piston, forming a variable-volume chamber in the bottom of the cylinder The tube is lowered open end first into a bed of powder As the powder enters the tube and fills the chamber, it forms the plug The assembly is then raised from the powder bed and positioned over the capsule body. The piston is lowered, ejecting the powder plug into the capsule body. Output can reach up to 150 000 capsule/h  https://www.youtube.com/watch?v=O_hBcz_LMXk https://www.youtube.com/watch?v=EbCHRoMvoqg Filling of powder formulations b) Tamping finger and dosing disc The dosing disc forms the bottom of a revolving powder hopper This disc has several sets of drilled holes in which powder plugs are formed by tamping fingers. At each position the fingers compress the material in the holes, building up a plug. As the disc rotates, material flows into the holes. At the last position, fingers push the plugs through the disc into capsule bodies. Powder fill weight can be varied by the amount of insertion of the fingers into the disc, by changing the thickness of the dosing disc, and by adjusting the amount of powder in the hopper.  https://www.youtube.com/shorts/FADerVQ-tPg Pellet filling Preparations formulated to give modified-release. They are filled using dosing system based on a chamber with a volume that can easily be changed. Pellets are not compressed in the process and may have to be held inside the measuring devices by mechanical means, e.g. applying suction to the dosing tube. Pellet size determines the fill weight (larger size occupies larger volume). Tablet filling Capsules can also be filled with tablets, which can be of use when preparing blinded clinical trial materials. Tablets are fed from a hopper into a chamber that simply releases one or more tablets into the capsule body as it passes underneath. The optimum formulation for capsule filling is a biconvex film-coated tablet, the film coating reducing abrasion and material loss. Semi-solid and liquid filling Liquids can easily be dosed into capsules using volumetric pumps. The problem after filling is to stop leakage from the closed capsule. This can be done in one of two ways, either by formulation (thermo-softening or thixotropic materials) or by sealing the capsule. Semi-solid mixtures can be liquefied for filling by either heating or by stirring. After filling, they cool and solidify or revert to their resting state in the capsule to form a solid plug. Both types of formulations are filled as liquids using volumetric pumps. Formulation All formulations for filling into capsules have to meet the same basic requirements: 1. They must be capable of being filled uniformly to give a stable product. 2. They must release their active contents in a form that is available for absorption by the patient. 3. They must comply with the requirements of the Pharmacopoeial and regulatory authorities, e.g. dissolution tests. Powder formulations The easiest active compounds to formulate are low-dose potent ones, which in the final formulation occupy only a small percentage of the total volume (