Chapter 5 Capsules 2007.1.28

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 capsules orally (whole or mixed with food or drink after opening capsules)

Introduction – Advantages of capsules for oral administration 1. conveniently carried 2. readily identified 3. easily taken 4. prescribing flexibility 5. Efficiently and productively manufactured 6. Packaged and shipped at lower cost and with less breakage 7. More stable and have a longer shelf-life 8. 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.

Introduction - Dosage forms that must be left intact Dosage forms that must be left intact include: enteric coated tablets extended/controlled release dosage forms sublingual or buccal tablets In 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.

Types of capsules Gelatin capsule shells may be hard or soft depending on their composition. Hard gelatin capsules Soft gelatin capsules

Hard gelatin capsules The application of hard gelatin capsules used to manufacture most medicated agents employed in clinical trials used in the extemporaneous compounding The empty capsule shells consist of gelatin, sugar, water, colorants (various dyes), and opaquants遮光剂 (titanium dioxide).

Hard gelatin capsules The main quality control item of gelatin (continuned) viscosity degradation (粘度下降) moisture (水分) transparency (透明度) ash (灰分) pH value Iron: Its concentration depends on the iron content of the water used in its manufacture. ≤15ppm for gelatin used in soft gelatin capsules.

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 shape lose their contained moisture: become brittle and crumble when handled desiccant (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.

Two methods used to track the passage of capsules and tablets through the gastrointestinal tract Gamma scintigraphy(闪烁照相) Heidelberg capsule

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) → joining a) The thickness of the gelatin walls must be strictly controlled. b) The caps are slightly larger in diameter than the bodies.

The manufacture of hard gelatin capsule shells Some improvements to hard gelatin capsule shells capsule-making pegs (body-making or cap-making pegs): general rounded shape pegs → tapered pegs tapered 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

The manufacture of hard gelatin capsule shells Tamper-evident sealing and imprinting Tamper-evident sealing (显窃启密封): through various capsule sealing techniques Imprinting which signals will be imprinted on finished capsules? a) names and monograms of the manufacturer b) the assigned national drug code (NDC) number c) other markings making the product identifiable and distinguishable from other products

Capsule sizes How to select capsule size? 1) the amount of fill material to be encapsulated 2) the density and compressibility of the fill 3) The final determination largely may be the result of trial. The sizes of empty capsules For human use: 000(the largest), 00, 0, 1, 2, 3, 4, 5 (the smallest) For veterinary use: Larger capsules are available.

Preparation of filled hard gelatin capsules The general steps of preparation 1) 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.

Developing the formulation and selection of capsule size The goal of developing a capsule formulation is to prepare a capsule with How to get to the goal? 1) pharmaceutical processing(工艺) 2) pharmaceutical excipient(辅料)

Developing the formulation and selection of capsule size The pharmaceutical processing in the preparation of filled hard gelatin capsules 1) blending: → uniform powder mix, uniform drug distribution 2) 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

Developing the formulation and selection of capsule size The pharmaceutical excipient in the preparation of filled hard gelatin capsules 1) diluent/filler: to produce the proper capsule fill volume; to provide cohesion to the powders, e.g. lactose, microcrystalline cellulose and starch 2) disintegrants/disintegration agents: to assist the break-up and distribution of the capsule contents e.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)

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 mix e.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 absorption 4) wetting agents: to facilitate wetting of the dry powder e.g. surfactants, as sodium lauryl sulfate

Developing the formulation and selection of capsule size The form of filling material in capsules: 1) powder or granulate 2) pellet mixture 3) paste or wetted mass: the mixture of liquid and an inert powder 4) capsule 5) tablet 4 and 5 are employed to separate chemically incompatible agents or to add premeasured (as tablets) amounts of potent drug substances 6) 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

Developing the formulation and selection of capsule size The selection of capsule size For a commercial product: during the product development stage In the extemporaneous compounding of prescriptions

Developing the formulation and selection of capsule size Examples of filled hard gelatin capsules 1) Tetracycline capsules Active ingredient: Tetracycline hydrochloride, 250 mg Filler: Lactose Lubricant/glidant: Magnesium stearate Capsule colorants: omitted Capsule opaquant: Titanium dioxide

Filling hard capsule shells 1. The “punch” method suitable for filling a small number of capsules in the pharmacy 1) placing the powder on paper 2) forming the powder mix into a cake 3) punching the empty capsule body into the powder cake 1) nonpotent drugs: The first filled capsules should be weighed. The other capsules should be weighed periodically. 2) potent drugs: Each capsules should be weighed.

Filling hard capsule shells 2. The pouring method suitable for filling a small number of capsules in the pharmacy suitable for granular material

Filling hard capsule shells 3. Hand-operated capsule filling machines consist of a couple of plates

Filling hard capsule shells 4. Machines for industrial use The 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 capsules 165,000 capsules per hour SCF-10半自动胶囊充填机

Capsule sealing make the capsules tamper-evident (显窃启) 1) sealing with a colored band of gelatin 2) heat welding 3) Thermally bonding at 40-45℃ with the help of a melting-point-lowering liquid wetting agent 4) extemporaneously, by lightly coating the inner surface of the cap with a warm gelatin solution

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

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 capsules 1) pharmaceutically elegant 2) easily swallowed by the patient Turn to 34 Turn to 35

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Soft gelatin capsules The pharmaceutical applications of soft gelatin capsules are 1) as an oral dosage form 2) as a suppository dosage form 3) as a specialty package in tube form, for human and veterinary single dose application of topical, ophthalmic, and otic preparations, and rectal ointments.

Soft gelatin capsules The components of soft gelatin capsules 2) glycerin or polyhydric alcohol 3) water/moisture 4) preservative 5) colorant 6) markings 7) opaquants 8) Flavors may be added and up to 5% sucrose may be included for its sweetness and to produce a chewable shell.

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 plate 2) pouring the liquid-containing medications 3) placing the second sheet of gelatin 4) putting the top plate of the mold into place 5) pressing the mold to form, fill, and seal the capsules simultaneously 6) removing and washing the capsule Today, this equipment can no longer be purchased.

Preparation of soft gelatin capsules 2. The rotary die process(旋转模压法 1933, R. P. Scherer) more efficient and productive 1) Liquid gelatin is formed into two ribbons 2) The two ribbons are brought together 3) Metered fill material is injected between the ribbons 4) These pockets of fill-containing gelatin are sealed

Rotary die soft capsule machine The dies for production of soft capsule

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.

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)

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

The nature of soft gelatin capsule shell 2) Plasticizers glycerin or sorbitol or combinations of these The ratio by weight of dry plasticizer to dry gelatin determines the “hardness” of the gelatin shell. 0.4/1 hard 0.6/1 medium 0.8/1 soft The ratio by weight of water to dry gelatin can vary from 0.7-1.3 to 1.0. 3) The color of the gelatin shell

The fill material of soft gelatin capsules 1) liquids a) water-immiscible volatile and nonvolatile liquids b) water-miscible, nonvolatile liquids c) water-miscible and relatively nonvolatile liquids e.g. propylene glycol, isopropyl alcohol d) Liquids that can easily migrate through the capsule shell cannot be encapsulated into soft gelatin capsules 2) solids (solutions, suspensions, pasty mass, dry powders, granules, pellets, or small tablets.)

Compendial requirements for capsules The requirements for added substances 1) are harmless in the quantities used 2) do not exceed the maximum amounts required to provide their intended effect 3) do not impair the product’s bioavailability, therapeutic efficacy or safety 4) do not interfere with requisite compendial assays and tests

The container and preservation condition described in USP containers 1) 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 conditions 1) Freezer: -25 ~ -10 ℃; 2) Cold: <8 ℃; 3) 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)

Compendial requirements for capsules Disintegration test for capsules 1) Method The 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.

Compendial requirements for capsules Dissolution test for capsules 1) 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.

Compendial requirements for capsules Weight variation and content uniformity show the uniformity of dosage units. Weight variation Wcapsule – Wemptied shell = Wcontent 10 capsules labeled 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 moisture Content uniformity The 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.

Compendial requirements for capsules Other requirements: 1) content labeling: the quantity of each active ingredient 2) stability testing method: long-term stability testing, accelerated stability test aim: storage condition, shelf life 3) moisture permeation test: unit dose container

Inspecting, counting, packaging, and storing capsules visual or electronic inspection → uniform in appearance 2) Counting a) counting tray; b) counting and filling machines 3) Packaging unit dose and strip packaging (sanitary, identifiable, safe) 4) Storing in tightly capped container in a cool, dry place