Drug candidates APIs

Telescoping, selecting reagents, and reaction optimization can afford significant decreases in the COG. The process route initially used to prepare 200 kg of the API intermediate acid 44 involved seven steps, four solvents, bromination, diazotization, and reaction with CO at 120°C, and produced the drug candidate in 20% yield. The optimized route shown in Scheme 2.12 was operationally simpler (using the same vessel for every... 

In the following section, taking diabetic drug candidates 1 and 2 [8, 9] as case studies (Figure 9.3), the purification and chirality control issues of peptide-hke API manufacturing are considered from a Green Chemistry perspective. 

Toxicology batches (drug candidate) Meeting deadline is primary concern, to reach go/no go decision points during API development. Note that animals may be grown in advance of such studies. Invest time to determine and prepare desired final form (salt, polymorph). Prepare high-quality material, but not ultra-pure. If tox studies are conducted on material of an unrealistically high purity, subsequent tox studies will be needed to qualify batches of lower quality. 

Computational assessment of the likelihoods of occurrence and the relative stabilities of polymorphs is not necessarily more effective than the experimental approach. Whilst great advances have been made in the field of ab initio crystal structure prediction (CSP), as documented in five international blind tests spanning the years 1999-2010 [5], it is still not routinely possible to predict whether a molecule is likely to be polymorphic or to confirm whether the most thermodynamically stable structure has been found experimentally, especially for molecules of the complexity of a typical drug. It is possible to compute the polymorph landscape for a specific flexible molecule, but the calculations require considerable expertise, and the timescales and computing resources can render CSP impractical for application to even a limited portfolio of candidate APIs. 

Multicomponent crystalline pharmaceutical solids, as for example, ionic complexes or salts, are usually developed to improve the pharmaceutical profile of a single organic molecule in terms of solubility, stability, bioavailability and organoleptic properties. A better understanding of the solid-state interactions in these complexes may lead to a rational design of crystalline APIs to rapidly advance a drug candidate through development to the launch of a product. 

Alternatively, a parallel screening approach with different screening methods (solvent-casting, melt-fusion and coprecipitation) can also be adopted in case (1) ASD with high solubility and stability is required (2) drug candidates are amendable for different ASD processing (3) API supply is not the limiting factor. 

Although therapeutic efficacy is the primary concern for an active pharmaceutical ingredient (API), the solid state form i.e., the crystalline or amorphous form) of an API can be critical to its pharmacological properties, such as bioavailability, and to its development as a viable drug candidate. Recently,... 

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