2 Introduction - The definition of capsules Capsules are solid dosage forms in which medicinal agents and/or inert substances are enclosed within a small shell of gelatin. Gelatin capsule shells may be hard or soft depending on their composition.Administration route of capsulesorally (whole or mixed with food or drink after opening capsules)
3 Introduction – Advantages of capsules for oral administration 1. conveniently carried2. readily identified3. easily taken4. prescribing flexibility5. Efficiently and productively manufactured6. Packaged and shipped at lower cost and with less breakage7. More stable and have a longer shelf-life8. Empty hard gelatin capsules are often used in the extemporaneous compounding of prescriptions.9. Tablets and capsules are sometimes used as the source of a medicinal agent when it is not otherwise available.
4 Introduction - Dosage forms that must be left intact Dosage forms that must be left intact include:enteric coated tabletsextended/controlled release dosage formssublingual or buccal tabletsIn instances in which a patient is unable to swallow an intact solid dosage form, an alternative product may be employed, such as chewable tablet, instant dissolving tablet, oral liquid, suppository or injection.
5 Types of capsulesGelatin capsule shells may be hard or soft depending on their composition.Hard gelatin capsulesSoft gelatin capsules
6 Hard gelatin capsules The application of hard gelatin capsules used to manufacture most medicated agentsemployed in clinical trialsused in the extemporaneous compoundingThe empty capsule shells consist ofgelatin, sugar, water, colorants (various dyes), and opaquants遮光剂 (titanium dioxide).
7 Hard gelatin capsulesThe main quality control item of gelatin (continuned)viscosity degradation (粘度下降)moisture (水分)transparency (透明度)ash (灰分)pH valueIron: Its concentration depends on the iron content of the water used in its manufacture. ≤15ppm for gelatin used in soft gelatin capsules.
8 Hard gelatin capsules The solubility property of gelatin: Normally, hard gelatin capsules contain between 13 to 16% of moisture.additional moisture is absorbed: become distorted and lose their rigid shapelose their contained moisture: become brittle and crumble when handleddesiccant (dried silica gel, clay, and activated carbon)→in vitro dissolution→bioavailability.The solubility property of gelatin:Insoluble in cold water, soften through the absorption of up to ten times its weight of water; soluble in hot water and in warm gastric fluid.Gelatin, being a protein, is digested by proteolytic enzymes.
9 Two methods used to track the passage of capsules and tablets through the gastrointestinal tract Gamma scintigraphy(闪烁照相)Heidelberg capsule
10 The manufacture of hard gelatin capsule shells The shell consists of two parts, the capsule body(囊体) and the capsule cap(囊帽).The process of capsule shell production with the peg/pin method:dipping(蘸胶) → drying → stripping(脱模) → trimming(截割) → joininga) The thickness of the gelatin walls must be strictly controlled.b) The caps are slightly larger in diameter than the bodies.
11 The manufacture of hard gelatin capsule shells Some improvements to hard gelatin capsule shellscapsule-making pegs (body-making or cap-making pegs):general rounded shape pegs → tapered pegstapered rims, indentations and locking grooves:straight-walled capsule shell → tapered rim capsule shell with indentations and locking grooves (see page 25)a) The tapered rims avoid splitting;b) The indentations prevent premature opening;c) The grooves lock the two capsule parts together after the capsule has been filled.extension capsule cap (CONI-SNAP SUPRO) (see page 26)increase the security of the contents and the integrity of the capsule
12 The manufacture of hard gelatin capsule shells Tamper-evident sealing and imprintingTamper-evident sealing (显窃启密封): through various capsule sealing techniquesImprintingwhich signals will be imprinted on finished capsules?a) names and monograms of the manufacturerb) the assigned national drug code (NDC) numberc) other markings making the product identifiable and distinguishable from other products
13 Capsule sizes How to select capsule size? 1) the amount of fill material to be encapsulated2) the density and compressibility of the fill3) The final determination largely may be the result of trial.The sizes of empty capsulesFor human use: 000(the largest), 00, 0, 1, 2, 3, 4, 5 (the smallest)For veterinary use: Larger capsules are available.
14 Preparation of filled hard gelatin capsules The general steps of preparation1) developing and preparing the formulation and selecting the size of capsule.2) filling the capsule shells.3) capsule sealing (optional).4) cleansing and polishing the filled capsules.
15 Developing the formulation and selection of capsule size The goal of developing a capsule formulation is to prepare a capsule withHow to get to the goal?1) pharmaceutical processing(工艺)2) pharmaceutical excipient(辅料)
16 Developing the formulation and selection of capsule size The pharmaceutical processing in the preparation of filled hard gelatin capsules1) blending: → uniform powder mix, uniform drug distribution2) comminution/milling: 50~100 microns, suitable for a drug of low dose (10mg or greater)3) micronization: 10~20 microns, suitable for drugs of lower dose
17 Developing the formulation and selection of capsule size The pharmaceutical excipient in the preparation of filled hard gelatin capsules1) diluent/filler: to produce the proper capsule fill volume; to provide cohesion to the powders,e.g. lactose, microcrystalline cellulose and starch2) disintegrants/disintegration agents: to assist the break-up and distribution of the capsule contentse.g. pregelatinized starch (预胶化淀粉), croscarmellose (交联羧甲基纤维素) , and sodium starch glycolate (羟基乙酸淀粉钠)
18 Developing the formulation and selection of capsule size The pharmaceutical excipient in the preparation of filled hard gelatin capsules (continued)3) lubricant or glidant: to enhance the flow properties of the powder mixe.g. fumed silicon dioxide, magnesium stearate, calcium stearate, stearic acid, or talc#: magnesium stearate, water-proofing characteristics, retard penetration of the GI fluids, delay drug dissolution and absorption4) wetting agents: to facilitate wetting of the dry powdere.g. surfactants, as sodium lauryl sulfate
19 Developing the formulation and selection of capsule size The form of filling material in capsules:1) powder or granulate2) pellet mixture3) paste or wetted mass: the mixture of liquid and an inert powder4) capsule5) tablet4 and 5 are employed to separate chemically incompatible agents or to add premeasured (as tablets) amounts of potent drug substances6) liquids: fixed or volatile oils (locking or sealed gelatin capsules)7) eutectic mixtures: mixed with a diluent or absorbent to separate the interacting agents and to absorb any liquefied material
20 Developing the formulation and selection of capsule size The selection of capsule sizeFor a commercial product: during the product development stageIn the extemporaneous compounding of prescriptions
21 Developing the formulation and selection of capsule size Examples of filled hard gelatin capsules1) Tetracycline capsulesActive ingredient: Tetracycline hydrochloride, 250 mgFiller: LactoseLubricant/glidant: Magnesium stearateCapsule colorants: omittedCapsule opaquant: Titanium dioxide
22 Filling hard capsule shells 1. The “punch” methodsuitable for filling a small number of capsules in the pharmacy1) placing the powder on paper2) forming the powder mix into a cake3) punching the empty capsule body into the powder cake1) nonpotent drugs: The first filled capsules should be weighed. The other capsules should be weighed periodically.2) potent drugs: Each capsules should be weighed.
23 Filling hard capsule shells 2. The pouring methodsuitable for filling a small number of capsules in the pharmacysuitable for granular material
24 Filling hard capsule shells 3. Hand-operated capsule filling machinesconsist of a couple of plates
25 Filling hard capsule shells 4. Machines for industrial useThe process of working:separating the caps from empty capsules → filling the bodies → scraping the excess powder → replacing the caps → sealing the capsules → cleaning the outside of the filled capsules165,000 capsules per hourSCF-10半自动胶囊充填机
26 Capsule sealing make the capsules tamper-evident (显窃启) 1) sealing with a colored band of gelatin2) heat welding3) Thermally bonding at 40-45℃ with the help of a melting-point-lowering liquid wetting agent4) extemporaneously, by lightly coating the inner surface of the cap with a warm gelatin solution
27 Cleaning and polishing capsules Small amount of powder may adhere to the outside of capsules after filling.1) On a small scale, cleaning with a clean gauze or cloth.2) On a large scale, cleaning vacuum
28 Soft gelatin capsules The definition of soft gelatin capsules Soft gelatin capsules are made of gelatin, glycerin (or a polyhydric alcohol such as sorbitol) and water etc. to hermetically seal and encapsulate liquids, suspensions, pasty materials, dry powders and even preformed granules, pellets, tablets. They may be manufactured to be oblong, oval or round in shape.The advantages of soft gelatin capsules1) pharmaceutically elegant2) easily swallowed by the patientTurn to 34Turn to 35
30 Soft gelatin capsulesThe pharmaceutical applications of soft gelatin capsules are1) as an oral dosage form2) as a suppository dosage form3) as a specialty package in tube form, for human and veterinary single dose application of topical, ophthalmic, and otic preparations, and rectal ointments.
31 Soft gelatin capsules The components of soft gelatin capsules 2) glycerin or polyhydric alcohol3) water/moisture4) preservative5) colorant6) markings7) opaquants8) Flavors may be added and up to 5% sucrose may be includedfor its sweetness and to produce a chewable shell.
32 Preparation of soft gelatin capsules 1. The plate process钢板模压法 (using a set of molds)The plates contain die pockets.1) placing a warm sheet of gelatin on the bottom plate2) pouring the liquid-containing medications3) placing the second sheet of gelatin4) putting the top plate of the mold into place5) pressing the mold to form, fill, and seal the capsules simultaneously6) removing and washing the capsuleToday, this equipment can no longer be purchased.
33 Preparation of soft gelatin capsules 2. The rotary die process(旋转模压法 1933, R. P. Scherer)more efficient and productive1) Liquid gelatin is formed into two ribbons2) The two ribbons are brought together3) Metered fill material is injected between the ribbons4) These pockets of fill-containing gelatin are sealed
35 Rotary die soft capsule machine The dies for production of soft capsule
36 Preparation of soft gelatin capsules 3. The reciprocating die process (往复模压法 1949, Norton company)is similar to the rotary process in that ribbons of gelatin are formed and used to encapsulate the fill, but it differs in the actual encapsulating process.1) A set of vertical dies continually open and close to form rows of pockets in the gelatin ribbons.2) These pockets are filled with the medication and are sealed, shaped, and cut out of the film.3) The capsules fall into refrigerated tanks which prevent the capsules from adhering to one another.
37 Preparation of soft gelatin capsules 4. The Accogel machine (1949, Cyanamid comcany)This equipment is unique in that it is the only equipment that accurately fills powdered dry solids.5. Dripping method(滴制法)
38 The nature of soft gelatin capsule shell 1) The gelatin is pharmacopoeial grade with additional specifications required by the capsule manufacturer.a) Bloom strength:b) viscosity:Generally, 25 to 45 millipoise is acceptable.c) iron: ≤15ppm
39 The nature of soft gelatin capsule shell 2) Plasticizersglycerin or sorbitol or combinations of theseThe ratio by weight of dry plasticizer to dry gelatin determines the “hardness” of the gelatin shell.0.4/1 hard0.6/1 medium0.8/1 softThe ratio by weight of water to dry gelatin can vary from to 1.0.3) The color of the gelatin shell
40 The fill material of soft gelatin capsules 1) liquidsa) water-immiscible volatile and nonvolatile liquidsb) water-miscible, nonvolatile liquidsc) water-miscible and relatively nonvolatile liquidse.g. propylene glycol, isopropyl alcohold) Liquids that can easily migrate through the capsule shell cannot be encapsulated into soft gelatin capsules2) solids (solutions, suspensions, pasty mass, dry powders, granules, pellets, or small tablets.)
41 Compendial requirements for capsules The requirements for added substances1) are harmless in the quantities used2) do not exceed the maximum amounts required to provide their intended effect3) do not impair the product’s bioavailability, therapeutic efficacy or safety4) do not interfere with requisite compendial assays and tests
42 The container and preservation condition described in USP containers1) light resistant container(避光):2) well-closed container(密闭):3) tight container(密封):4) Hermetic Container (熔封或严封):Preservation conditions1) Freezer: -25 ~ -10 ℃; ) Cold: <8 ℃; ) Cool: 8 ~ 15 ℃;4) Room Temperature: The temperature prevailing in a working area.5) Controlled Room Temperature: 20 ~ 25 ℃; 6) Warm: 30 ~ 40 ℃;7) Excessive Heat: >40 ℃;8) Protection from Freezing: (breakage of the container, loss of strength or potency, destructive alteration of its characteristics)
43 Compendial requirements for capsules Disintegration test for capsules1) MethodThe capsules are placed in the basket-rack assembly, which is repeatedly immersed 30 times per minute into a thermostatically controlled fluid at 37 ℃ and observed over the time described in the individual monograph.2) To fully satisfy the test, the capsules disintegrate completely into a soft mass having no palpably firm core, and only some fragments of the gelatin shell.
44 Compendial requirements for capsules Dissolution test for capsules1) The apparatus, dissolution media and test is the same as that for uncoated and plain coated tablets.2) Generally, when a dissolution test is applied to an existing capsule product, the disintegration test is unnecessary.
45 Compendial requirements for capsules Weight variation and content uniformity show the uniformity of dosage units.Weight variationWcapsule – Wemptied shell = Wcontent 10 capsuleslabeled amount or average amount, ±10%1) For hard capsules#1: Wcapsule should match Wemptied shell.2) For soft capsules#1: evaporating the washing solvent over 30 mins#2: avoid uptake or loss of moistureContent uniformityThe amount of active ingredient should be within the range of 85% to 115% of the label amount for 9 of 10 capsules, with no unit outside the range of 70% to 125% of label amount.
46 Compendial requirements for capsules Other requirements:1) content labeling: the quantity of each active ingredient2) stability testingmethod: long-term stability testing, accelerated stability testaim: storage condition, shelf life3) moisture permeation test: unit dose container
47 Inspecting, counting, packaging, and storing capsules visual or electronic inspection → uniform in appearance2) Countinga) counting tray;b) counting and filling machines3) Packagingunit dose and strip packaging (sanitary, identifiable, safe)4) Storingin tightly capped container in a cool, dry place