Particle size active pharmaceutical ingredients

Among several techniques possible to design process measurement tools, those based on spectroscopic techniques such as near-infrared (NIR), infrared (IR), Raman, terahertz (THz), fluorescence and UV-Vis absorption offer obvious advantages for PAT owing to their speed, compactness and versatility. Spectroscopic assessment yields chemical information such as content of active pharmaceutical ingredient (API) or of the relative concentration of different ingredients in a suspension, a blend, a composite preparation/formulation. However, physical information may also be obtained that is directly or indirectly related to, for example, particle size, porosity and density. Physical information is particularly valuable in characterisation of manufacturing processes and for reliable prediction of finished product properties. 

Recrystallization of an active pharmaceutical ingredient on a spinning disc, employing a solvent/antisolvent approach to induce rapid precipitation, results in the desired small particles (1-15 microns) and narrow particle size distribution (59). 

Pharmaceutical products such as tablets usually consist of active pharmaceutical ingredients. In the pharmaceutical industry, the API particle size has tended to become smaller in recent years and the needle shape has become very common. These small API particles usually belong to Group C according Geldart classification.2 3 It is well known that the needle-shaped Group C particles are very cohesive. They do not flow easily and mix poorly with other particles. 

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. 

TABLE 13.1 Comparison of Particle Sizing Techniques for Active Pharmaceutical Ingredients... 

Berry, J., Kline, L. C., Sherwood, J. K., et al. (2004), Influence of the size of micronized active pharmaceutical ingredient on the aerodynamic particle size and stability of a metered dose inhaler, Drug Dev. Ind. Pharm., 30,705-714. 

Felmet, K. Olsofsky, M. Robertson, S. Starbuck, C. Tom, J. Tung, H.-H. Wang, J. An evaluation of cavitation milling to achieve particle size reduction of active pharmaceutical ingredients. AIChE Annual Meeting, Reno, Nevada, November, 2001. 

During the early 1990s, crystallizations were considered more of an art than a science. During that time, process chemists would design a process that delivered an active pharmaceutical ingredient (API) with a certain particle size, and formulation chemists would use it to design a tablet or a capsule suitable for clinical trials or the marketplace. Since then, several events have changed that business model ... 

Raw materials for pharmaceutical preparations are either active substances (or active pharmaceutical ingredients APIs) or excipients. The choice of excipients and the quality of all raw materials determine the quality of a medicinal product. In addition to purity and content, physical properties such as particle size can influence the manufacturing process and the therapeutic effectiveness. Changes in quality can have unforeseen consequences. 

Some active pharmaceutical ingredients (API) for therapy of pulmonary disease are available as dry powder inhalant. The particles are only able to penetrate the lung if their diameter is less than d = 5 pm. Particles of this size are highly cohesive. Large... 

Tablets and other drug formulations often comprise the active pharmaceutical ingredient (API) and pharmacologically inert carrier substances, or excipients, which bind, stabilize, and assist absorption of the drug by the body, or simply add bulk to APIs in low dosages. Common excipients are inorganic phosphates and organic compounds such as lactose, cellulose, and polyethylene glycol. Particle size reduction by micronization or milling can provide the energy to transform an API into undesirable polymorphs or...

As reported later in Chapter 9.9 of this book, active-ingredient-containing polymeric micro-particles are widely used in technological and medical applications. For example, these particles are suitable as drug-delivery devices and can control the pharmaceutical release-rate over time. The particle size is absolutely important when dealing with drug-delivery devices. Very small particles can be inhaled, while larger ones can be injected into the blood stream. Therefore, it is important to control the microparticle size in the production. 

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