Formulation particle size requirement

The active pharmaceutical ingredient in a low-dose formulation is typically a small molecule, designed to meet a small particle size requirement for uniformity purposes, and can be susceptible to effects of static charge and segregation. The impact of static charge on the accuracy of blend uniformity measurements (i.e., sampling bias) is discussed in the next section. 

Siekmann and Westesen investigated the influence of the formulation procedure on the quality of tyloxapol- (1.5 w%) and soy lecithin- (1 w%) stabilized tripalmitin (3 w%) nanoparticles [27]. They demonstrated the principal possibility of obtaining size distributions in the range of 30 to 180 nm by ultrasonification. However, these small particle sizes required long sonication times (>15 min), which raises concerns about metal contamination of the product. Moreover, it is difficult to disperse higher... 

The particle size distribution of the API can affect the dissolution rate of the drug product and thus the bioavailability of the product. Once particle size requirements have been defined from formulation studies, the process must be capable of routinely meeting these requirements. One of the ways that particle size distribution can be controlled is by the conditions under which the product is... 

Pharmaceutical powder aerosols have more stringent requirements placed upon the formulation regarding moisture, particle size, and the valve. For metered-dose inhalers, the dispensed product must be deflvered as a spray having a relatively small (3—6 -lm) particle size so that the particles can be deposited at the proper site in the respiratory system. On the other hand, topical powders must be formulated to minimize the number of particles in the 3—6-p.m range because of the adverse effects on the body if these materials are accidently inhaled. 

Injection moulding compositions have a number of requirements with regard to granule flow and cure characteristics not always met by conventional formulations. For example, granules should be free-flowing (i.e. of a narrow particle size distribution and not too irregular in shape). There are also certain requirements in terms of viscosity. 

One of the most difficult parenteral dosage forms to formulate is a suspension. It requires a delicate balance of variables to formulate a product that is easily resuspended and can be ejected through an 18-to 21-gauge needle through its shelf life. To achieve these properties it is necessary to select and carefully maintain particle size distribution, zeta potential, and rheological properties, as well as the manufacturing steps that control wettability and surface tension. The requirements for, limitations in, and differences between the design of injectable suspensions and other suspensions have been previously summarized [17b, 18,19]. 

The formulation of this type of product usually employs a small number of ingredients and sometimes only the active ingredient. Particle size and particle size distribution, rugosity, and particle charge should be considered for all ingredients, and the specific grade of excipients should be stated. The excipients should be sourced from a single supplier (with data to demonstrate the suitability of different batches of material), but if multiple sources are used, additional data will be required to establish the suitability of different batches from each supplier. 

A number of factors must be considered in formulating a slurry propellant. The particle size of the solid powder must not be too large, or the residence time required to effect complete combustion could be too long, and inefficient energy release would result. On the other hand, if the particle size is extremely small, it may not be possible to formulate a slurry of the requisite solid content (25-50 vol. % ). 

When suspensions are formulated to provide a stable system, the particle size becomes critical. Flocculated suspensions also require careful particle size control either in the process of manufacturing or in the starting material. Equally important is the crystal habit — the outward appearance of an agglomeration of crystals. Crystal structure can be altered during the manufacturing process, particularly if the product is subject to temperature cycling, and this can alter the stability of suspensions. 

---