Manufacturing of Hard Gelatin Capsules.

Manufacturing: Hard Gelatin Capsules.

• Hard gelatin capsules are composed of two halves, termed the cap and the body.
• During manufacture of the dosage form, the formulation is filled into the body (using a range of different mechanical techniques) and the cap is pushed into place.
• The two halves of the capsule are joined, the cap overlapping with the body.
• Due to the tight fit between the two halves, separation of the cap and body does not normally occur under normal storage conditions or in clinical use.
• However, other capsule designs are available in which the two halves form a mechanical seal via indentations on the outside of the body and/or inside the cap
• Sealing of hard gelatin capsules may also be performed using two further methods:
• 1. Gelatin band sealing. In this method, a dilute solution of gelatin is applied to the center of the capsule (between the two halves) which, once dried, produces a hermetic seal.
• 2. Hydroalcoholic solvent seal. A hydroalcoholic solution (1:1 water/ethanol) is applied to the centre of the capsule (between the two halves).
• This softens the capsule and, following heating to 45C, the interface fuses to produce a seal.

The manufacture of hard gelatin capsules is performed using a dip-coating method.

• The various stages of this are as follows:
• Preparation of the gelatin solution Initially a concentrated solution of gelatin is prepared (circa 35–40% w/w) in demineralised hot water with stirring.
• Following dissolution of the polymer a vacuum is then applied to the mixing vessel to remove entrapped air.
• Incorporation of other constituents of the capsule Other excipients may be included within the heated gelatin solution,
• e.g.: ■ Colourants. Most frequently hard gelatin capsules are coloured to enhance the aesthetic properties and also to act as a means of identifying the product. For this purpose the chosen dye is added at the required concentration into the heated gelatin solution.
• ■ Wetting agents/lubricants. It is permissible to formulate hard gelatin capsules with sodium lauryl sulphate ( 0.15% w/w) as an included component to increase the wetting properties of the capsule shell following contact with an aqueous solution (and hence enhance the dissolution properties of the formulation contained within the capsule).
• Furthermore, the presence of sodium lauryl sulphate in the heated gelatin solution will also enhance the wetting of the (hydrophilic) gelatin solution on the metal pins during the manufacturing process.
• This leads to the production of gelatin capsules of uniform thickness.

Control of the viscosity of the gelatin solution:

Capsule Sizes

• Following the inclusion of all components within the heated gelatin solution, the viscosity of the solution is then modified (reduced).
• Control of the viscosity is important as this regulates the thickness of the capsule (generally circa 100 µm).
• As the viscosity is lowered the capsule thickness will decrease.

Dip-coating the gelatin solution onto metal pins (moulds):

• The machine used to manufacture capsules consists of two sets of bars, each containing a series of pins (aligned in columnar formation) that have been lubricated prior to use.
• The pins (one set for the production of the cap and one for the body of the capsule) are dipped into a pan that contains the heated gelatin solution (maintained at 35–45°C).
• Following adsorption of the gelatin solution onto the surface of the pins, the bar containing the pins is removed and rotated.
• The reduction in the temperature of the gelatin and the rotating action cause the gelatin to gel on the surface of the pins in a uniform manner.
• The pins are then advanced through a series of air dryers in which air of the required humidity is passed across the surface of the gelatin film.
• Following this, the (hardened) capsules are removed from the pins and cut to the appropriate size prior to joining the two halves of the final capsule.

Properties of the final capsule:

• The final capsules should exhibit a water content of 13–16% w/w.
• This is an important consideration in light of the effects of water content on the mechanical (and hence in-use) properties of the capsules.
• Water acts as a plasticizer for gelatin to ensure that the mechanical properties of the capsule are sufficiently robust so that the capsule does not either crack or permanently deform during manufacture, handling or storage.
• If the water content is lower than the above specification, the capsule shell will become brittle and will crack when exposed to the appropriate stress.
• Conversely, if the water content is excessive, the capsule will undergo plastic flow upon exposure to stress and will lose shape.
• It is therefore, important that the desired water concentration in the capsule is achieved within the drying phase of the manufacturing process.
• It is additionally preferable that capsules should be stored under conditions that do not adversely affect this parameter.
• A wide range of capsule sizes is available that can accommodate fill volumes between 0.20 and 0.67 ml.
• The production of coloured capsules requires the addition of the appropriate colour and opacifying agent (e.g. titanium dioxide) in the heated gelatin solution during the capsule-manufacturing process.

Formulation considerations for hard gelatin capsules:

• The fill for hard gelatin capsules may be formulated as either a powder (or granule) containing the required drug or as a liquid into which the drug is either dispersed or dissolved.
• The formulation considerations for both of these strategies are individually discussed below,
• Solid capsule fills As YOU will observe, many of the excipients used for the formulation of solid capsule fills for capsules are commonly used in tablet formulations for similar purposes.
• Therefore, to prevent repetition, only the basic details of the excipients (including their properties and rationale for use) will be described.

General properties of solid fills:

• There are several general properties of powders that should be recognized when formulating these as capsule fills, as follows:
• The particle size distributions, of the various components of the powder mix (including the therapeutic agent) should be similar both to ensure homogeneous mixing and to minimize segregation.
•  It is preferable that the particle size distribution of the powder blend is both monomodal and exhibits low polydispersity (low standard deviation) to ensure predictable and reproducible flow during the filling process.
• Conversely, multimodal and polydisperse powder mixes will exhibit a tendency to segregate, with resultant problems associated with the homogeneity of the mix and a gradual increase in fill mass as a function of filling time.
•  Problems may occur during the filling of particles with an irregular shape (e.g. needle shape).

Filling of hard gelatin capsules:

• There are two main methods by which powders are filled into hard gelatin capsules, termed dependent and independent methods.
• The design and operation of these are described below,

A) Dependent method (dosing system):

• In this method, the lower half of the capsule is placed into slots that are located within a revolving turntable.
• The upper part of the capsule is also housed in a similar turntable.
• The turntable containing the lower half of the capsule (which may be rotated at a range of speeds) is rotated under a hopper that contains the powder formulation and, as a result, the powder falls into the capsule.
• The flow of the powder through the hopper and the homogeneity of the powder mix are maintained by the circular movement of an auger.
• At the end of the operation the two capsule halves are brought together to form the finished dosage form.
• The mass of powder that is dispensed into each capsule is dependent on the length of time that the hopper spends above the capsule (which is itself dependent on the speed of rotation of the turntable).
• At the end of the filling process, the filled capsules are removed from the turntable.

Independent method (dosing system):

• The independent method of capsule-filling involves the physical transfer of a plug of powder from the mixed powder into the capsule.
• In this method, a tube, which contains a spring-loaded piston, is depressed into a powder bed enabling a volume (plug) of powder to enter the tube.
• The settings of the spring-loaded piston control the volume of powder that enters the tube.
• If required, the bonding between the particles within the plug may be enhanced by the application of a compression pressure.
• The tube (containing the plug of powder) is then elevated out of the powder bed, rotated and located above the lower half of the capsule and the plug of powder is dispensed into the capsule by the depression of the piston.

Formulation of the fill of hard gelatin capsules:

• As detailed above, there are three main classes of fill that are employed in hard gelatin capsules, namely powders and liquids/semisolids.
• The formulation considerations for these categories are considered separately in the following sections.

Powders

• In general, powder formulations for inclusion within hard gelatin capsules should exhibit the following properties:
• ■ Homogeneity of mix (described above).
• ■ Good flow properties. Filling of the capsules requires the reproducible flow of the powder from the powder bed, through the filling apparatus and into the capsule.
• As the filling is performed according to volume, it is important that the packing of the particles is also reproducible, as variations in this property will result in differences in the mass of powder filled into each capsule.
• Acceptable powder flow also requires that clumping of the powders does not occur.
• Finally, as the filling process may require plug formation (within the dossator), the powder bed should be compressible.
• Typically the flow properties and the packing properties of the powders are assessed using the following techniques: –
• Angle of repose (f).
• In this method powder is passed through a funnel until the angle of inclination of the powder is too small to overcome cohesive forces between the particles.
• The angle of repose is the angle that the powder makes with the horizontal plane.
• The technique provides an indication of the flow properties of the powder and, specifically, is a measure of cohesion within the powder mass.
• The tangent of the angle of repose is frequently referred to as a measure of the internal friction of the powder bed.
• If the measured angle exceeds 50, the flow properties of the powder are poor.
• Typically an angle of circa 25 is indicative of a powder that would be expected to exhibit suitable flow for manufacturing process.
• Powder that exhibit high angles of repose will require the addition of a glidant to reduce particle–particle cohesion.
• Torque rheometry.
• Torque rheometry is a rheological technique in which a stress is applied to the powder bed (by means of a mixing head) and the subsequent deformation (rate of shear) of the powder bed is determined.
• Powder beds that should demonstrate high cohesion will require greater shearing stresses to initiate and maintain flow.
• This technique is often applied to the characterisation of the wet granulation process and, in particular, to examine the mixing requirements and end-point of the granulation process.
• Tap density.
• Tap density measures the volume occupied by the powder bed, both before (ro) and following (rf ) the application of a consolidation stress (generally shaking at a defined rate and for a defined period).
• The ratio of the density of the powder bed before to that after shaking is referred to as a Hausner ratio.
• Generally, a Hausner ratio of circa 1.2 is acceptable whereas, when the Hausner ratio exceeds 1.6, the powder may be problematic to fill into capsules due to the unnecessarily high cohesive interactions between the particles.
• These cohesive properties may result in erratic filling due to arching and related phenomena.
• Compatibility between the formulation components and between the formulation components and the capsule.
• The excipients that are employed in the formulation of powder fills for hard gelatin capsules are similar to those employed for the formulation and manufacture of tablets.
• The following excipients are used for the formulation of powder fills: –
• Diluents:
• Diluents are employed to increase the working mass of the powder bed and thereby enhance the reproducibility of the filling process.
• In addition, the diluents may offer additional properties, most notably their flow properties and their ability to undergo compression.
• Examples of excipients that are employed in the formulation of powder fills include:
•  lactose (monohydrate)
• maize starch
• microcrystalline cellulose.
• Lubricants/glidants:
• Lubricants are used to reduce the interaction of the powders with the metal dossator and/or other metal components of the filling machine, whereas glidants are used to lower the interparticle attraction, thereby reducing clumping and aiding powder flow.
• The types of lubricants and glidants used in the formulation of powder fill capsules are identical to those employed for tablet manufacture and include:
• magnesium stearate (and other stearates) as a lubricant
• colloidal silicon dioxide as a glidant.
• Disintegrants.
• Disintegrants are employed (as before) to break up the powder mass following release into the stomach.
• Examples that are used for this purpose include:
• maize starch
• microcrystalline cellulose
• sodium starch glycolate
• crospovidone
•  crosscarmellose.
•  Surface-active agents (Surfactants).
• Surface-active agents are employed within powder fill hard gelatin capsules to increase the wetting properties of the powder bed following release within the gastrointestinal tract.
• Their inclusion is particularly important if the formulation contains significant concentrations of hydrophobic components, e.g. lubricants and glidants.
• To achieve rapid drug release the powder fill should be readily dispersed within the gastrointestinal contents, a feature that is enhanced by the presence of surface-active agents of high hydrophile–lipophile balance, e.g. sodium lauryl sulphate.
• In addition, the presence of sodium lauryl sulphate within the hard gelatin capsule shell is allowed and acts similarly to enhance the uptake of fluid into the capsule shell.

Liquids/semisolid fills for hard gelatin capsules:

• Liquid/semisolid fills for hard gelatin capsules may be subdivided into various categories:
• Lipophilic liquids/oils containing dissolved or dispersed therapeutic agent.
• Examples of the types of liquids that are commonly used in this category include: –
• vegetable oils (e.g. sunflower, arachis, olive)
•  fatty acid esters (e.g. glyceryl monostearate).
• Water-miscible liquids containing dissolved/dispersed therapeutic agent.
• Examples of the types of liquids that are commonly used in this category include: – polyethylene glycols (PEGs) that are solid at room temperature but will liquefy upon heating (e.g. highermolecular-weight PEGs) – liquid polyoxyethylene-polyoxypropylene block co-polymers (Pluronics).
• A major concern in the choice and hence formulation of solvents for liquid fill formulations is the effect of the formulation on the stability of the capsule.
• As stated previously, the equilibrium moisture content of hard gelatin capsules should be 13–16% to ensure that the capsule exhibits the optimal mechanical properties.
• Solvents that are hygroscopic when filled into hard gelatin capsules will enhance moisture uptake into and result in splitting of the capsule shell.
• The moisture uptake of lipophilic solvents, solid PEGs and Pluronics is low and therefore these solvents are preferred for liquid fill formulations for hard gelatin capsules.

To stabilize the liquid fill formulations for hard gelatin capsules, other excipients will be required, e.g.

• Surface-active agents.
• These are included in liquid fills for hard gelatin capsules to: – solubilise the therapeutic agent within the solvent – stabilise the suspended therapeutic agent – enhance the dissolution of poorly water-soluble therapeutic agents within the gastrointestinal tract.
•  Viscosity-modifying agents.
• These are included in liquid fills for hard gelatin capsules to: – stabilise the suspended therapeutic agent – modify the viscosity of the formulation to optimise filling of the capsule.
• Typically, viscosity values within the range of 0.1–25 Pa/s are considered to be acceptable as liquid fills for hard gelatin capsules.
• If the viscosity is lower than this range, there will be a loss in the capsule contents due to splashing of the liquid from the capsule during filling.
• Conversely, liquids of viscosities greater than 25 Pa/s may cause filling problems due to the inability of pumps to fill liquids of this (high) viscosity reproducibly. The coefficient of variation in the volume of liquid fills of high viscosity ( 25 Pa/s) will exceed 0.03.
• Stabilisers (e.g. antioxidants, colours).