Compatibility with gelatin
Aldehydes. Incompatibilities are known to occur; with certain substances that contain reactive aldehydes. The aldehydes can react with the gelatin by forming crosslinks.

Cross-linking is not inevitable, but depends on several mechanisms. The main contributory factors are storage stress (high temperature, high humidity, excessive light exposure) and the presence of aldehydes, for example formaldehyde.

Water Content and Humidity. Incompatibility also occurs caused by the water content of the gelatin shell. If a substance is highly hygroscopic, it might absorb water from the capsule shell. This process can lead to brittleness of the shell, which might break under mechanical strain. If the drug substance in the capsule is sensitive to humidity the water content of the shell, which is normally between 13% and 16%, can lead to the degradation of the drug substances.


Doses
The dose of the drug active that is the main parameter for a suitable formulation.

Low dose active ingredient
For low doses in the milligram range, homogeneity of the substance within the powder has to be maintained. For doses in excess of 100 mg or in the smallest suitable capsule size, the properties of the active are of key importance, as the quantities of excipients are minimal.

High dose active ingredient
High concentrations of drug active usually lead to difficulties during the filing process. Problems at the stage can be prevented by choosing the suitable diluents and adequate quantities of lubricants.
For doses over 600 mg in powder form need more preparations. For instance, increasing the density of the formulation by granulation. Granulation usually leads to an improvement of parameters such as product flow. It’s also possible to improve the dissolution rate of substances by granulation, due to increased dispersion of the drug active in the granule.

Shape of Particle
To achieve the specification for content uniformity on filling machine, it is vital to have an adequate powder flow. Poor powder flow is characterized by the formation of a central cavity when flowing out of a cylinder, while the powder at the edge remains static.

Product flow is mainly defined by the shape of the particles as well as by inter-particulate cohesion and surface films (sorption water). The fluidity of anisometric particles such as needle-shaped, plate shaped or prismatic particles is peculiar, insofar as it not only follows the primary direction but also a secondary direction according to the orientation of the particles. This is the reason why anisometric particles result in significant differences in the bulk and tap density. The mechanical vibration is strong enough to allow the particles to gain a higher grade of order.

Isometric –for example, round-particles are already in highly compact order, forming the most dense shape. Hard gelatin capsules the drug substances and excipients should preferably be of isometric shapes. In the case of anisometric particles, grinding or granulation should be considered.

Solubility
Solubility of the drug active and the excipients is the major contributory factor in disintegration and dissolution. The more water soluble the formulation, the quicker it disintegrates and releases the substance. Disintegrants and diluents become the most influence factor for disintegration and releasing drug for substance that poorly soluble in water.

Particle Size
The particle size of the drug active is critically important to the homogeneity and fluidity of the powder. By decreasing the particle size the electrostatic charge increases. While leaving the filling funnel , this may lead to the formation of agglomerates, which hinder the flow during the filling process.

Minimum particle size for filing of hard gelatin capsule should be 10 um. If the particle size is more than 60 um, the fluidity of the powder starts to deteriorate, which leads to unwanted deviations of the filling weights. The size of particles should ideally measure between 10um and 150 um. Other excipients should be chosen in relation to the particle size of the drug active.

Continue to : Critical Parameters of Formulating Drug in Hard Gelatin Capsules (Part II)

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