Capsules - Lecture notes 1-4 PDF

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Lecture Notes of the capsule....

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CAPSULES Introduction 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. The basic idea of a capsule is to enclose the drug or active pharmaceutical ingredient (API) in an odorless, tasteless, elegant, easy-to-swallow, and easy-to-fill shell. Capsules are usually intended to be administered orally by swallowing them whole. Occasionally, capsules may be administered rectally or vaginally.

History •

Capsules were first patented for use in 1830 by Joseph Gerard Auguste Dublanc and Francois Achille.

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The first patented capsules were made from soft gelatin.

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In 1846 Jules Lehuby obtained a patent for two-piece hard capsules, such as those that are in use today. Since these capsules were made by hand, there was difficulty obtaining precision to get the two parts to fit together well.

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In 1931, Arthur Colton invented a machine to make both parts of hard capsules, so they fit together properly. The machines that make hard capsules today are based on Colton's invention

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Today there are two main types of capsules: the hard gelatin capsule (dry fills) and the soft gelatin capsule, often called soft shells.

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Advantages: The advantages of the capsules can be broadly categorized into three categories from patient point of view, from manufacturer point of view and from drug delivery point of view

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From patient point Neat and elegant in appearance. Smooth and slippery surface makes it easy to swallow Self medication is possible Tasteless shell to mask the unpleasant taste/odor of the drug increasing patient compliance. Capsules eliminate all contact between the drug and the mouth, which makes them tasteless and odorless, as most drugs have a bitter taste with an unpleasant aftertaste. The contents may be removed from the gelatin shell and employed as a pre measured medicinal powder, the capsule shell being use to contain a dose of the medicinal substance. Example: Theo-dur Sprinkle Commonly embossed or imprinted on their surface the manufacturer’s name and product code readily identified.

From manufacturers point of view Minimum excipients required. Packaged and shipped by manufacturers at lower cost less breakage than liquid forms. More stable and longer shelf life. The relative simplicity of capsule formulations can speed up the development process, especially for high-dose, poorly compressible drugs. Can be made one a time in a compounding pharmacy, in small-scale production for clinical studies, and all the way up to commercial production with machines that can make hundreds of thousands of capsules per hour. Convenient way to give powdered herbs because they conceal unpleasant tastes or textures. 2

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From the drug delivery aspects For immediate-release (IR) dosage forms, a key step is the breakdown of the capsule shell, which is analogous to disintegration in a tablet. The ready solubility of gelatin at gastric pH provides rapid release of medication in the stomach. And thus are ideally suited for immediate release delivery capsules can be used for other types of release profiles as well. In addition to dry powder fills, multi-particulate beads can be filled into capsules with multi-particulate beads, a mixture of beads with different release rates can be delivered thus providing with sustained and immediate release Multiple drugs can also be incorporated into capsule by formulating as beads of mini tablets

Disadvantages: •

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The capsule exposes the drug to the gastrointestinal (GI) tract and the GI tract to the drug. For example, some drugs when exposed to the GI tract can cause nausea, vomiting, and diarrhea. Other drugs such as iron in prenatal supplements and fish oil capsules have an unpleasant “burp back” effect, which reduces patient compliance Drugs that are readily degraded in the GI tract, either due to stomach acids or enzymatic degradation in the stomach and small intestine, don’t make good candidates for capsules. Capsule plugs are made with a lot less force than tablets, so for high-dose bulky materials such as botanical supplements, the dosage form size will be much bigger, and patients prefer smaller dosage forms. Capsules are not suitable for liquids that dissolve gelatin, such as aqueous or hydro alcoholic solutions. The concentrated solutions which require previous dilution are unsuitable for capsules because if administered as such lead to irritation into stomach. Not useful for efflorescent or deliquescent materials. Efflorescent cause capsules to soften & Deliquescent may dry the capsule shell to brittleness.

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Types of Capsules • •

Hard gelatin capsules Soft gelatin capsules

HARD GELATIN CAPSULES These are used for administration of solid medicaments. The capsule shell is prepared from gelatin. It consists of two parts i.e. body and cap. The powdered material is filled into the cylindrical body of the capsules and then the cap is placed over it. These are also known as dry fills

Constituents of Hard Gelatin Capsule Shell: CONSTITUENTS

EXAMPLES

GELATIN PLASTICIZERS

Type A, Type B Glycerine USP, glycerol (85% & 98%) Methyl paraben, Sorbic acid (0.2%) Oils TiO2(0.2-1.2%)

PRESERVATIVES SOLVENTS OPACIFYING AGENTS COLOURS

FLAVOURS SUGARS ACIDS THICKENING AGENTS WATER

FUNCTION

Veg. colours,FD&C D&C water soluble dyes, certified lakes Ethyl vanillin(0.1-2%) Sucrose( up to 5%) Fumaric acid(up to 1%) Methyl cellulose

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Imparts softness, Elasticity & hardness Retard growth of microorganisms Elegance Minimize transparency Gives pleasant appearance to the shells. Good flavour Sweet taste Lessen aldehydic tanning of gelatin Adjust viscosity of gelatin

Gelatin •

Gelatin is a protein derived by hydrolytic extraction of animal collagen. The animal collagen is obtained from animal bones, hide portions and frozen pork skin.

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Based on the type of hydrolytic extraction and its properties, gelatin can be divided into two types: Type A and Type B TYPE A

TYPE B

Acid treated precursor (obtained by acid Alkali treated precursor (obtained from hydrolysis) base hydrolysis) Isoelectric point at pH 9 Isoelectric point at pH 4.7 Obtained from pork skin Obtained from animal bones Forms plastic and clear film Forms tough, firm, brittle and hazy film Nowadays acid tried gelatin from animal bones (with isoelectric pH 5.5 to 6) and green bones (grass fed) are also used to manufacture gelatin

Manufacturing of gelatin

Type A

Type B

Animal Skin

Animal Splits/bones Wash

Wash Grind Grind

Liming (10% lime, 4-8 weeks)

Hydrolysis (1-5% acid, 10-30 hrs)

Wash

wash

Neutralize

Stage Extraction

Stage Extraction

Gelatin solution

Gelatin solution

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Properties of Gelatin 1) Bloom Strength It is the measure of the cohesive strength of cross linking that occurs between the gelatin molecules. It indicates the stability of gelatin. Bloom strength is directly proportional to the molecular weight of gelatin. It is defined as “weight in grams required by the plunger (0.5” diameter) to depress the surface of gelatin gel, at specified temperature, up to 4mm without breaking.” It is measured using Durameter. 6.67% gelatin solution previously maintained at 10°C for 17-18hrs is used for this test. The range of bloom strength for capsule shell formulation is 150-250 gm 2) Viscosity It gives an idea about the chain length and manufacturing characteristic of films. The ideal range is between 25-45 mPa 3) Iron content It is present in raw gelatin as well as water used in mfg. excess qty. of iron can effect FD &C & react with organic compounds. Hence, iron is used in the conc of not more than 15ppm. Other properties like pH, isoelectric point are also important.

Manufacturing of Hard Gelatin Capsule shell Hard gelatin capsule shell manufacturing is divided into seven steps. These are: 1) 2) 3) 4) 5) 6) 7) • • • • •

Dipping Spinning Drying Stripping Trimming Joining Polishing

The gelatin and hot demineralized water are mixed under vacuum in Stainless Steel Gelatin Melting System and dyes, opacifants, and any needed water are added to the gelatin in the feed tanks to complete the gelatin preparation procedure. From the feed tank, the gelatin is gravity fed to Dipper section. Dipping: Pairs of the stainless steel pins are dipped into the dipping solution to simultaneously form the caps and bodies for 12sec. The dipping solution is maintained at a temperature of about 50º C in a heated, jacketed dipping pan & pins are at 22ºC Spinning: The pins are rotated to distribute the gelatin over the pins uniformly and to avoid the formation of a bead at the capsule ends it is rotated 2½ times by moving upward. Drying: The gelatin is dried by a blast of cool air to form a hard shells. The pins are moved through a series of air drying kilns, Here gently moving air which is precisely controlled for volume, temperature, and humidity, removes the exact amount of moisture from the capsule halves.

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Stripping: A series of bronze jaws strip the cap and body portions of the capsules from the pins. Trimming and joining: The stripped cap and body portions are trimmed to the required length by stationary knives. The cap and body lengths are precisely trimmed to a ± 0.15 mm tolerance. After trimming to the right length, the cap and body portion are joined. Capsule quality is monitored throughout the production process including size, moisture content, single wall thickness, and color. Capsules are sorted and visually inspected on specially designed Inspection Stations and are imprinted with the client logo on high-speed

Capsule size For human use, empty capsules ranging in size from 000 the largest to 5 the smallest. The size 0 to 5 are used for human consumption whereas the 00 and 000 size are for veterinary purposes. Generally, hard gelatin capsule is used to encapsulate between 65 mg to 1 gram. The selection of the capsule size depends on the volume/amount of formulation to be filled into it

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Capsule size 000 00 0 1 2 3 4 5

Volume (ml) 1.37 0.95 0.68 0.50 0.37 0.30 0.21 0.13

Height (cm) 2.61 2.33 2.17 1.94 1.80 1.59 1.43 1.11

Diameter (cm) 0.99 0.85 0.76 0.69 0.63 0.58 0.53 0.49

Pre made shells have a moisture content between 12-15% Filling is ideally carried out between 30 to 45% RH and is generally done in Air Conditioner

Formulation aspects The API Solid or in powder form. If dose is less than 10 mg, then diluent maybe required after choosing of the right size of the capsule. Two major problems are seen regarding the formulation to be filled in the hard gelatin capsule shell 1) Physical incompatibility Physical incompatibility may be seen between the excipients and the drug, the drug and the gelatin of the shell and excipient and gelatin. Hence a through study needs to be done prior to selection of excipients for presence of any incompatibility. Incompatibility is check at different temperature and humidity to ascertain the stability during transportation and storage. 2) De-mixing During the storage and filling process due to constant vibrations, chances of de-mixing are possible. So care must be taken that adequate mixture delivered to the capsule at the time of filing. In order to prevent de-mixing from occurring, the particle size, size distribution and the density of the drug and all other ingredients need to be close to one another. Other than the drug, the following excipients are also present in the formulation: a) Diluent: it forms the bulk of the drug. The diluent must be so chosen that it provides characteristic flow as required by the machine. In case of free flowing/ gravity filling corn starch is used as diluent whereas in case of slug formation microcrystalline cellulose is preferred. Other examples include: bentonite, calcium carbonate, lactose, mannitol, silica gel, tapioca powder, talc etc The concentration of diluent depends on i) API concentration, ii) other excipient concentration and iii) the size of the capsule

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b) Disintegrating agents: if the formulation filled is in form of granules, pellets or tablets then required. Super disintegrants such as sodium starch glycolate, cross linked PVP, cross lined sodium CMC are used. Added in a concentration of less than 1% c) Lubricant: needed to provide a free flowing powder. Eg. Magnesium stearate, glycol esters, silicones, stearic acid, talc. Concentration 1.8 the shells are not able to retain their shape and size.

Typical shell hardness ratio and their use Hardness

Dry glycerine/dry gelatin

Use

Hard Medium Soft

0.4/1 0.6/1 0.8/1

Oral, oil based for hot humid area and shell softening products Oral, tube, vaginal, oil based/water miscible base Tube, vaginal, water miscible and shell hardening products and for use in dry areas

Shapes and size of soft gelatin capsules

The number represents the volume of the soft gelatin capsule in minims.

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Formulation of soft gelatin capsule • Soft gelatin capsules are generally filled with liquids, semi solids or soft mass. Sometimes even powders are also filled in soft gelatin capsules. • LIQUIDS: should not affect the moisture content of this range. pH of the liquid should be between 2.5 to 7.5. (pH 7.5 – tanning of gelatin ) Emulsion (o/w) are not filled as it affects the stability. Suspension containing only specific suspending agent such as PEG 4000 &6000 and oily vehicle such as beeswax 5%, paraffin wax 5% and animal stearate are used. • SEMISOLIDS: ointments and creams • SOFT MASS: Gels with lower water content. • Water immiscible, volatile or more likely volatile liquids such as vegetable oils, mineral oils, medium-chain triglycerides and acetylated glycerides are used as the vehicle for soft gelatin capsule formulation • Water miscible, nonvolatile liquids such as low molecular weight PEG (400,600) have come into use more recently because of their ability to mix with water readily and accelerate dissolution of dissolved or suspended drugs. • All liquids used for filling must flow by gravity at a temperature of 35°C or less & sealing temp. of gelatin films is 37-40 ° C.

Minimum capsule size determination In case of liquid formulation the size of the capsule to be used is determined based on the volume of the formulation and the specific gravity. For the filing of the semisolids, the Base Adsorption method is widely used for selection of the final size of the capsule. Base Adsorption of solids to be suspended: No of gm of liquid base required to produce a capsuleatable mixture when mixed with 1 gm of solid. Base adsorption depends on size, shape, crystallinity, density, moisture content and nature of the formulation. The solid must be completely wetted with liquid base. For oily base use soy lecithin (2 to 3%) as wetting agent.

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Method: 2 to 3% of soy lecithin by weight of oil is used as a wetting agent 40 g of solid is added into 100 g of base and mixed. Excess of base is slowly added till all the solids are coated with base. Here ointment like consistency is obtained. Addition of base is continued till the formulation starts to flow when held at 45 degree angle. The amount of base added is determined and based on that the size is decided. 𝑾𝒕. 𝒐𝒇&𝒃𝒂𝒔𝒆 = 𝑩𝒂𝒔𝒆&𝑨𝒅𝒔𝒐𝒓𝒑𝒕𝒊𝒐𝒏 𝑾𝒕&𝒐𝒇&𝒔𝒐𝒍𝒊𝒅

Using the base adsorption and employing the specific gravity of sample, the minim per gram factor (M/g) of solid can be determined. Minim per gram factor (M/g): is the volume of minims that is occupied by 1 gm of the solid (S) plus the weight of liquid base (BA) required to make a capsulateable mixture. (𝑩𝑨& + 𝑺) × 𝑽 𝑴 =...