Hard Gelatin Capsules

• Capsules are oral unit dosage forms typically made of gelatin and filled with medication.
• There are two main types: hard and soft gelatin capsules.

Hard Gelatin Capsules

• Consist of two cylindrical pieces: a shorter "cap" that fits over the longer "body".
• Empty capsules contain water, acting as a plasticizer essential for function.
• Low humidity can cause capsules to lose moisture and become brittle.
• High humidity can cause capsules to gain moisture and soften.
• Proper storage in sealed containers at an even temperature is crucial.
• Capsules are readily soluble in water at 37°C, with solubility decreasing at lower temperatures.
• Standard human medicine sizes range from 0-4.
• Size 0 has a body volume of 0.67 ml.
• Size 1 has a body volume of 0.48 ml.
• Size 2 has a body volume of 0.37 ml.
• Size 3 has a body volume of 0.28 ml.
• Size 4 has a body volume of 0.20 ml.
• Powder for filling must not react with gelatin.
• Powder must not contain high levels of free moisture.
• The unit dose volume must not exceed the capsule size.

Capsule Filling Machines

• At bench-scale, empty capsules are manually loaded, bodies are locked, and caps removed.
• Powder is spread into the bodies using a spatula, with uniformity dependent on powder flow.
• The cap plate is repositioned, and capsules are rejoined manually, filling 30-100 capsules of a specific size.
• Industrial-scale machines fill 5,000-15,000 capsules per hour, varying from semi to fully automatic.
• Dependent dosing systems use the capsule body for powder measurement, requiring complete filling for uniformity.
• Independent dosing systems measure powder separately, allowing for partial filling and better weight uniformity.

Formulation Requirements

• Formulations must fill uniformly to provide a stable product.
• Active ingredients must be released in a form available for absorption.
• Compliance with pharmacopeias and regulatory authorities, such as dissolution tests, is essential.

Powder Formulation Excipients

• Excipient selection depends on active ingredient properties, dose, solubility, particle size, and capsule size.
• Diluents (e.g., lactose, starch, microcrystalline cellulose) provide plug-forming properties.
• Lubricants (e.g., Mg stearate) reduce powder-metal adhesion.
• Glidants improve powder flow.
• Wetting agents (e.g., surfactants) enhance water penetration.
• Disintegrants (e.g., sodium starch glycolate, croscarmellose) facilitate active ingredient release.
• Stabilizers improve product stability.
• Good flow, no adhesion, and good cohesion are necessary for uniform filling and a homogenous product.

Soft Gelatin Capsules

• Softgels consist of a liquid or semisolid matrix within a one-piece gelatin shell.
• The drug can be in solution or suspension within the fill matrix.
• Fill matrices can be hydrophilic (e.g., polyethylene glycol) or hydrophobic (e.g., triglyceride vegetable oils) or a mixture.
• Improved drug absorption, patient compliance, and safety are advantages of softgels.
• They can overcome manufacturing problems, ensure dose uniformity for low-dose drugs and enhance product stability.

Softgel Formulation

• Gelatin shell choice depends on the fill matrix's nature.
• Plasticizers (e.g., glycerol, sorbitol, propylene glycol) make the shell elastic.
• Water is essential for processing and encapsulation; excess is removed through controlled drying.
• The final water content should be 5-8% w/w for physical stability.
• Colorants and opacifiers (e.g., titanium dioxide) are used in low concentrations.

Soft Gelatin Shell Properties

• It provides a good barrier against oxygen diffusion.
• Oxygen permeability decreases with higher relative humidity and glycerol content.
• For maximum oxygen protection, the shell should be dry and contain 30-40% glycerol.
• Low residual water content is important for stability.

Experimental Capsule Filling

• Fill capsule shells with diluents alone (non-medicated) to determine insufficient fill amount.
• Weigh the drug and insufficient diluent amount and mix them.
• Add the mixture to the empty capsule, adding extra diluents to complete the volume if needed.
• Weigh the filled (medicated) capsule.
• Calculate complementary diluents (CD) = Weight of medicated capsule – Weight of drug.
• Calculate the weight of displaced diluents = Weight of non-medicated capsule – Weight of complementary diluents.
• Calculate the bulk density factor = Weight of drug/weight of displaced diluents.
• Calculate displaced value = 1/bulk density factor.

Quality Control of Capsules

• Capsules are solid dosage forms with medicinal and inert ingredients enclosed in a gelatin shell.
• Advantages include taste masking, ease of swallowing, fewer adjuncts required, and physiological inertness.
• Disadvantages include unsuitability for hygroscopic drugs or concentrated solutions.
• Quality control tests include physical, disintegration, weight variation, chemical, dissolution, assay, content uniformity, stability, and moisture permeation tests.
• Physical tests involve diameter and color sorting.
• Diameter sorters allow capsules within ±0.020 inch of the theoretical diameter to pass.
• Color sorters discard capsules that do not conform to the reference color standard.

Disintegration Test

• Determines if capsules disintegrate within a prescribed time in a liquid medium.
• Introduce one capsule into each tube and suspend in a beaker containing 60ml water at 37°C.
• Operate the apparatus for 30 minutes, then remove the assembly.
• The capsule passes if no residue remains on the screen or if the residue consists of fragments or a soft mass.

Weight Variation (Hard Capsules)

• Weigh 20 capsules individually and determine the average weight.
• Individual weights should be within 90-110% of the average weight.
• Remove and weigh the contents of each capsule.
• Net weight of contents individually = Gross weight – Shell weight.
• Determine the average net content and the difference between each net content and average net content.
• Limits: Not more than 2 differences exceed 10% of the average net content, and no difference exceeds 25%.

Chemical Tests

• A dissolution test is carried out using the apparatus official in both the U.S.P and I.P.
• The capsule is placed in a basket immersed in a dissolution medium at 37°C ± 0.5°C.
• Stirrer speed and medium are specified in the monograph.
• Six capsules are tested and accepted if each is not less than the monograph's specification (p + 5%).

Dissolution Profile Factors

• Dissolution is a function of shell dissolution rate, medium penetration, powder mass deaggregation, and nature of primary drug particles.
• Shells typically rupture and dissolve within 4 minutes, first at the thinnest shoulder area.
• Liquid penetration and deaggregation cause formulations to spill out of the ends.

Content Uniformity

• 10 capsules are tested, with 9 within ±15% (85-115%) and all within ±25% (75-125%).

Capsule Physical Stability and Packaging

• Unprotected soft gelatin capsules equilibrate with atmospheric conditions rapidly.
• Stability depends on water pickup or loss by the shell.
• Capsules should be packed in well-closed glass or plastic containers and stored in a cool place.
• Desiccants like silica gel can be added to prevent moisture absorption.
• Strip packaging provides sanitary handling.
• Other packaging options include plastic bottles with screw caps, blister packs, and plastic pouches.