Capsules as a Technology Platform 1421 Capsule Sizes Materials and Properties

Different design options exist for HC capsules, depending on the active ingredient (API) and fill composition. They may accommodate solids such as powder, granules, pellets, mini-tablets, or combinations thereof in standard two-piece capsules (e.g. ConiSnap® capsules: Fig. 14.1). Liquid, semisolid, or formulations comprising liquid and solid (e.g. pellets, capsules) can be contained using capsules designed for liquid fillings (e.g. Licaps capsule) and readily sealed by microspray technology (e.g. LEMS sealing) or band sealed with gelatin.

Units of appropriate volume are used to accommodate the required drug dose (Table 14.1). Dose can be adjusted by altering fill weight, as in the case of individualized medicines or where different doses of a novel entity are being evaluated in a blinded clinical trial.

Two-piece HC were traditionally manufactured from gelatin due to its unique gelling and film-forming properties within a very narrow temperature window.

More recently, capsules made from hypromellose (hydroxypropyl-methylcellulose, HPMC) became available. "First-generation" HPMC units also contained a gelling agent [gellan gum (e.g. Vcaps® capsules) or carrageenan (QualiV® capsules) and a

Tapered rim of the body engages easily with the cap for problem-free closure

Six elongated dimples maintain precise round capsule diameter, improving filling machine performance

Six elongated dimples maintain precise round capsule diameter, improving filling machine performance

BODY

T^lf

BODY

Two aerodynamic air vents allow air to escape from the cap; critical when operating high speed filling machines

Rounded, hemispherical ends are mechanically stronger and more resistant to deformation

Closely-matched locking rings provide full-circumference leak-free closure

Fig. 14.1 ConiSnap® capsules gel promoter (e.g. potassium chloride or potassium acetate)]. The gelling systems were found to affect drug delivery as capsule shell dissolution depended on pH and ionic strength of the dissolution medium.

A "second generation" of hypromellose capsules has also been developed. These comprise a "hypromellose-only" capsule (e.g. Vcaps Plus® capsules). Capsule shell dissolution is independent of pH and ionic strength providing the same predictability of release as gelatin capsules.

Table 14.2 summarizes the characteristics and properties of two-piece capsules.

Gelatin capsules have an equilibrium water content of 13-16% at 35-60% rh and 15-25°C. Capsules can be dried to below 13% water content if beneficial for moisture-sensitive drugs but decreasing water content can lead to brittle shells that may crack during product manufacture. Generally however, reduction in shell moisture to about 12% water does not cause excessive brittleness. Hypromellose capsules have an equilibrium moisture content of 4-9% under normal processing conditions. Such capsules can be dried to <1% water content if beneficial for moisture-sensitive drugs without losing their mechanical properties. Figure 14.2 compares equilibrium moisture contents for gelatin and hypromellose capsules. It is evident that both materials have comparable propensity at each specific relative humidity to donate moisture to materials with lower equilibrium relative humidity, less would be transferred in the case of HPMC because of its lower equilibrium moisture content.

Hypromellose, unlike gelatin does not interact with aldehyde residues that may be present in some drugs and excipients.

Table 14.1 Capsule sizes (in millimeter) and capsules volumes (in milliliter)

Size

000

OOel

00

Oel

0

lei

1

2el

2

3

4el

4

5

Volume

1.37

1.02

0.91

0.78

0.68

0.54

0.50

0.41

0.37

0.30

0.25

0.21

0.13

Closed length

1.029

0.995

0.917

0.953

0.854

0.804

0.765

0.760

0.709

0.626

0.621

0.563

0.437

External

0.390

0.336

0.336

0.301

0.300

0.272

0.272

0.250

0.250

0.229

0.209

0.209

0.193

diameter diameter

Table 14.2 Characteristics of two-piece capsules made of gelatin, hypromellose with gelling system (first generation) and pure hypromellose (second generation)

HPMC

HPMC

Polymer

Gelatin

First generation

Second generation

Material

Protein

Cellulose

Cellulose

Origin

Animal derived

Plant derived

Plant derived

Pharmacopoeial inclusion

EP, USP/NF, JP

EP, USP/NF, JP

EP, USP/NF, JP

Moisture content

13-16%

4-9%

4-9%

Oxygen permeability

Low

High

High

Cross-linking Propensity

Yes

No

No

pH-independent dissolution

Yes

Depends on the

Yes

co-gelling agent

Hygroscopicity at 22°C +/- 2°C -■-Com-Snap gelatin capsule Vcaps Plus

Hygroscopicity at 22°C +/- 2°C -■-Com-Snap gelatin capsule Vcaps Plus

% RH

Fig. 14.2 Equilibrated moisture content of gelatin and hypromellose capsules after 1 week at different RH [1]

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