Drug substances particle size distribution

The impact of the drug substance particle size distribution was also evaluated. No significant effect on compact hardness is observed, as shown in Figure 7. 

The target drug substance particle size specifications for Drugs A and B were set based on a theoretical model and experimental data generated from studies performed to determine the effect of drug substance particle size distribution on the content uniformity of the tablets. 

To assess the impact of drug substance particle size and size distribution on a formulation, prepare two to three batches of drug substance with different mean particle sizes for formulation and process evaluation. This helps establish a specification to control particle size and size distribution of the drug substance. 

Early data collection of prototype-blend experiments could be an invaluable tool to successful scale-up. Physical characteristics such as particle size distribution, bulk and tapped density, and flowability and functional characteristics (mainly compactability) are key indicators of possible downsteam scale-up problems. If, for example, the active drug substance has a mean particle diameter... 

Change in particle size distribution of the drug substance, if the drug is in suspension. 

How do you design the physical properties of the API For the development of low-dose formulations, the design of the solid-state form of the drug substance is of utmost importance. Careful selection of a suitable salt form, co-crystal or clathrate (if applicable), crystal modification, habit, particle size and particle size distribution is of utmost importance. 

Generally, when developing a direct compression formulation, efforts to match particle size distribution and density of drug substance to the major excipients help minimize segregation. Meanwhile, the particle size distribution should be relatively narrow (100 im range) to ensure a satisfactory flow for the blend. The commonly used excipients for preparing direct compression blends can be categorized by the... 

These practical issues of particle shape and dispersion are not intended to cast aspersions on the laser diffraction technique rather, these factors have been discussed to bring awareness around the analytical results that are obtained when these factors are present. Laser diffraction has proven itself to be a reliable, robust technique for particle size analysis. When the assumption of nonaggregated spherical particles is violated, there are clear manifestations in the calculated particle size distribution. When analyzing drug substances that are used in low-dose solid oral formulations, the impact of these manifestations can be particularly impactful as there is often a limited number of API lots to be used for method development. Therefore, the analyst must be aware of these issues prior to the commencement of method development to avoid these pitfalls. In addition to the information contained in ISO 13320, Snorek et al. have written a summary around the general practices of laser diffraction measurements in the pharmaceutical industry.19... 

Each of the aforementioned techniques is capable of measuring powder that would be used in low-dose, solid oral dosage formulations. The technique must be compatible with the drug substance, and must be capable of producing the information that is needed. For example, if the particle size distribution is needed to ensure dose content uniformity, photon correlation spectroscopy can only provide an average particle size. In this instance, laser diffraction or image analysis would be more suitable techniques. Table 13.1 contains a comparison of the techniques that have been discussed. 

This technology can produce narrow particle size distributions with a controlled surface area and is finding utilization for final bulk drug substances. Control of particle size has the added benefit of eliminating the need for milling for particle size reduction and control. In addition, scale-up can be achieved to production scale by operation at the same local conditions in the same (or only approximately two times larger) size jets that are mn for longer times. See Examples 9-5 and 9-6. 

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