Challenges in Low-Dose Tablet Development Using Direct Compression

3 CHALLENGES IN LOW-DOSE TABLET DEVELOPMENT USING DIRECT COMPRESSION 

If a low-dose dmg ( 1 mg per dose unit) is formulated as tablets or capsules, it can be very difficult to uniformly distribute a trace amount of dmg substance into a single unit dose, especially when direct compression is selected as the manufacturing platform. Major factors controlling the degree of homogeneity of the final blend are the mean particle size and the size distribution of dmg substance. It is often difficult to determine whether these factors are suitable for preparation of a low-dose dmg product.2 Generally, reduction of dmg substance particle size by milling or microni-zation is essential for a low-dose dmg product to meet the USP content uniformity criteria for tablets and capsules.3 

Several publications in the literature address the particle size of the dmg substance and USP content uniformity from a theoretical and statistical basis. In 1972, Johnson2 established an equation that predicts the expected variation in a unit dose when the particle size distribution of dmg substance is analyzed. This theoretical calculation 

The theoretical method can provide initial guidance in setting particle size specifications to avoid poor content uniformity of low-dose dmg products. These new modifications have made the theoretical model easier to use. However, those theoretical models do not take into account the particle size and size distribution of excipients used in a unit formula. Chapter 3 presents more detailed discussions of the theoretical consideration of the relationship between the dmg particle size and product content uniformity. 

Besides particle size and dmg concentration, particle shape and density of powders are also important factors for achieving a homogenous mixture. Powders with nearly spherical particles are easier to mix than those with irregularly shaped particles. Micronized, needle, or flat particles require longer blending time due to aggregate 

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