Activity pharmaceutically

Lipase-catalyzed kinetic resolutions are often practical for the preparation of optically active pharmaceuticals (61). For example, suprofen [40828-46-4] (45), which is a nonsteroidal antiinflamatory dmg, can be resolved by Candida glindracea]i 2Lse in >95% ee at 49% conversion (61). Moreover, hpase-based processes for the resolution of naproxen [22204-53-1] and ibuprofen [15687-27-1] (61) have also been developed. 

These and other FDA policy decisions launched the pharmaceutical industry and academia into a new era of developing stereoselective processes for the manufacture of enantiopure active pharmaceutical ingredients (APIs). 

Although in many cases an enantiopure drug can be safer than the racemate, the advantages are clear. The final formulation of the drug product could be reduced inhalf, potential side effects could be minimized, and the resulting pharmokinetic and pharmacodynamic studies could clearly determine the efficacy of the active pharmaceutical ingredient (API) [21]. 

Draft Guidance for Industry on Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients Availability Notice, Fed Regist. Docket No. 98-0193, 1998. 

Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients... 

Annex 18 Good manufacturing practice for active pharmaceutical ingredients (The ICH Guide) Annex 19 Reference and Retention Samples... 

The resolution of racemic esters via selective hydrolysis catalyzed by hydrolases is a practical way to prepare optically active pharmaceutical intermediates as shown in Figure 6.8 [53,54]. 

Prashad M (2004) Palladium-Catalyzed Heck Arylations in the Synthesis of Active Pharmaceutical Ingredients. 6 181-204 Pretraszuk C, see Marciniec B (2004) 11 197-248... 

Thomas, P.W. and Ramsay, A. (2004) Continuous manufacturing of a bulk active pharmaceutical ingredient. Presented at Switching from Batch to Continuous Processing Conference,... 

However, compared with the traditional analytical methods, the adoption of chromatographic methods represented a signihcant improvement in pharmaceutical analysis. This was because chromatographic methods had the advantages of method specihcity, the ability to separate and detect low-level impurities. Specihcity is especially important for methods intended for early-phase drug development when the chemical and physical properties of the active pharmaceutical ingredient (API) are not fully understood and the synthetic processes are not fully developed. Therefore the assurance of safety in clinical trials of an API relies heavily on the ability of analytical methods to detect and quantitate unknown impurities that may pose safety concerns. This task was not easily performed or simply could not be carried out by classic wet chemistry methods. Therefore, slowly, HPLC and GC established their places as the mainstream analytical methods in pharmaceutical analysis. 

The authors optimised conditions for the general reaction of 1,1-diphenylethylene and piperidine (Scheme 9.5). They obtained the highest TOF (288 h" ) and all linear product for this specific reaction when using complex 31 and 5 1 H iCO at 125°C for 24 h. An important note here is that the sterics of the substrate, 1,1-diarylethyl-enes, are responsible for generation of only linear products instead of the catalyst. With a one-pot method, the authors procured the active pharmaceuticals prozapine, fendilline, milverine, and diisopromine in 85%, 91%, 35% and 88% yield, respectively. The catalyst activities compare well to the established Rh-Xantphos system [33]. 

PIC, 1987, Guidelines for the Manufacture of Active Pharmaceutical Ingredients (Bulk Drug Substances) (Document PH 2/87). 

The use of palladium as a catalyst is common in the development and synthesis of active pharmaceutical ingredients (APIs). Palladium is an expensive metal and has no known biological function. Therefore, there is a need to recover spent palladium, which is driven both by cost and by government regulations requiring residual palladium in APIs to be <5 ppm (1). Thus, much research has been conducted with the aim of heterogenizing active palladium that can then be removed via simple filtration and hopefully reused without significant loss of activity. 

Although most fluorine-containing biologically active pharmaceutical and agrochemical compounds make use of the substituents that have been discussed in the previous three chapters, there are also numerous examples of more highly fluorinated bioactive compounds, the efficacy of which should encourage more examples to be sought. 

The preferred and easiest intake of medicines is by oral ingestion in the form of tablets. Tablets today contain a combination of an active pharmaceutical ingredient and a (polymer) excipient-the inactive ingredient that delivers the pharmaceutical active... 

Garrett, C.E. and Prasad, K. (2004) The art of meeting palladium specifications in active pharmaceutical ingredients produced by Pd-catalyzed reactions. Advanced Synthesis and Catalysis, 346 (8), 889-900. 

Tao, J., Zhao, L. and Ran, N. (2007) Recent advances in developing chemoenzymatic processes for active pharmaceutical ingredients. Organic Process Research Development, 11, 259-267. 

Octonol is an intermediate for the production of several optically active pharmaceuticals, such as steroids and vitamins. The asymmetric reduction of 2-octanone to (5)-2-octonol by baker s yeast was inhibited severely by substrate and product concentration of 10 him and 6 mM respectively. Whole-cell biotransformation of 2-octanone in a water-ra-dodecane biphasic system yielded a high product concentration of 106him with 89% ee in 96h [37],... 

Synthesis and scale-up production of active pharmaceutical ingredient (API)... 

Tab. 14.1 The role ofGMP (good manufacturing practice) in the production and processing of APIs (active pharmaceutical ingredients) from difference sources. It is not yet clear how biotechnology-derived plants fit into this scheme. Modified from the Good Manufacturing Practice Guide for Active Pharmacuetical Ingreedients, ICH (2000).

The majority of active pharmaceutical agents are administered as tablets, and as a result the characterization of compact species is of great interest to formulators. During the compression step, a variety of particle-particle interactions take place, which ultimately lead to the formation of a stable entity. One may envision that the compaction process results in such consolidation of the input solids that the final density of the tablet approaches the true density of the component materials. 

To get a better idea of the complexity of a real application scenario in these industries it makes sense to, once, exemplarily depict the planning processes in a typical production of active pharmaceutical ingredients (API production). Most pharmaceutical companies are looking at planning scenarios in which several hundred individual resources or facilities have to be accounted for, with demands and orders for some thousand final products. The planning horizon is often set to 2-5 years. Next to single equipment, there are facility pools, with one pool consisting of several individual units. 

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