Active pharmaceutical ingredient techniques

I hope that this chapter provides a fitting introduction to the complex task of active pharmaceutical ingredient product design through ciystallization, and most importantly that it will stimulate work and encourage further growth in the application of thermodynamic models and optimization techniques in this area. 

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. 

While this is a very positive boundary condition for the development of low-dose formulations, the major drawback of the low-dose formulation range is, as mentioned earlier, the potential exacerbation of chemical instability of active pharmaceutical ingredients. Thus, stabilization techniques are of high interest to the formulator dealing with this formulation space. Specifically, stabilizers from various classes of antioxidants have been applied.23,24 It is obvious that the specific knowledge of potential and actual degradation pathways of the drug will be crucial for the development of stable formulations. 

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

Based upon the advantages of the other techniques presented prior to LC-MS, large volume injection HPLC-UV, and HPLC-CAD, the decision to use electrochemical detection would be driven primarily by a unique analytical need, equipment availability and previous experience of the analytical chemist. A complex chemical matrix should not be of concern at most there could be some residual cleaning agent and residual excipients in addition to the active pharmaceutical ingredient. Since the matrix in cleaning verification is typically simple, electrochemical detection would not be the primary detection technique. However, the sensitivity afforded by ECD is excellent and can meet the most stringent of the acceptance limits outlined in Table 15.2. 

Final product isolation in a form suitable for further processing into the final dose form of the pharmaceutical, e.g., as a tablet or an injectable solution. Secondary production of this type is sometimes done in a separate facility, with the raw material referred to as the bulk product or, more recently, the active pharmaceutical ingredient. Examples of unit operations at this stage of processing include lyophilization, precipitation, or crystallization followed by solid isolation using filtration and drying techniques. In some cases, the final product must be produced in a sterile form, which introduces additional complications when selecting suitable process equipment. 

Although this is not a new method, several researchers have used this method for removal of solvent from other micronization techniques (e.g., Nanocrystals). Initially, spray drying was used for the removal of solvent from solutions, which caused rapid evaporation of the feed solution and precipitation of the dissolved Active Pharmaceutical Ingredient (API)/Stabilizers. This method. 

Solid-state nuclear magnetic resonance (SSNMR) spectroscopy is a powerful technique used in the analysis of solids, and is currently finding more and more applications, particularly in the analysis of pharmaceutical formulations. It is a non-destructive, non-invasive technique that can be employed to simultaneously examine the physical and chemical states of both the active pharmaceutical ingredient (API) and the excipients present as they exist within the formulation. It is also highly selective, as nuclei of the API often have different chemical shifts than do common excipients. 

Unstable compounds are problematic. A sample purified in the laboratory might have a short shelf-life and poor performance as a standard. Compounds altered by assays are also inconvenient. For example, substituted benzylic alcohols can dehydrate under acidic HPLC conditions, or carboxylic esters can hydrolyze in aqueous mobile phase. An impurity isolated from an active pharmaceutical ingredient as an organic salt of an organic compound poses two problems at once. The analyst must account for both the acid and the base. In the case of a toluenesulfonic acid salt of an aliphatic amine, two different methods of detection might be needed. The toluenesulfonic acid in a reverse-phase HPLC assay can by monitored by UV light, but the aliphatic amine, with no chromophore, must be measured by a different technique. 

We have embraced this relatively modem definition of PAT for the purposes of this chapter. In particular, PAT in this context includes any analytical technique that provides data in real time to manufacturing processes involved in making bulk active pharmaceutical ingredients (APIs) with the primary intent to ensure process control and thus product quality. 

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