Polymorphism active pharmaceutical ingredients

Quantitative and/or qualitative XRPD methods have been reported to determine the polymorphic content of clopidogrel bisulfate samples, and these have been summarized in Table 2.3. Koradia et al. [16] reported the qualitative analysis of clopidogrel bisulfate in both active pharmaceutical ingredients and tablet dosage forms. Based on the interplanar distances (d-spacing) associated with each polymorph, it was concluded that the molecular packing in Form-I was more dense than that of Form-II, indicating that Form-II would be less stable relative to Form-I. This result was similar with that reported by Bousquet [9]. 

The topic of polymorphism is of tremendous and increasing academic and industrial importance in modern crystal chemistry and crystal engineering. The industrial interest stems from the pharmaceutical industry and has stimulated wide-ranging academic study. Legally, a molecule (termed an active pharmaceutical Ingredient, API) with particular biological activity in vivo can be patented as a new invention. Moreover, particular crystal forms of that molecule (polymorphs) can be separately patented as distinct inventions. If particular polymorphs are patented after the original API patent then upon the... 

Three polymorphic forms of a cocrystal containing two active pharmaceutical ingredients... 

Another advantage of SS-NMR is that the observed chemical shift differences between polymorphs can be related to particular molecular sites based on known assignments (see Figure 6). Site-specific mobility can also be determined by probing the relaxation properties of the compound. This is an important application, since mobility is usually related to polymorphic interconversions and solid-state reactions.94 Solid-state reactions between active pharmaceutical ingredients and excipients can also be followed by SS-NMR. The study of polymorphic transitions can be performed by variable temperature experiments. 

In cases where drug formulations containing more than one polymorph are marketed it is required that the composition is fixed in relation to each polymorphic form. The issue is complicated by the conversions between polymorphs in the solid state. It is clear that the conversion of a crystal structure in a more stable polymorph has to be inhibited, to preserve the composition of the drug formulation. In terms of morphological stability, the production of the more stable polymorph of an active pharmaceutical ingredient is the more convenient option however, other issues may play critical roles. 

Crystallization plays an important role in the synthesis, scale-up, processing, formulation, and stability of active pharmaceutical ingredients (API) (Rodriguez-Hornedo and Murphy, 1999 Shekunov and York, 2000 Rodriguez-Hornedo and Sinclair, 2002). Crystallization from solvent is a particularly important process, as this is the primary means of purihcation during the intermediate and hnal stages of drug synthesis. Moreover, solution crystallization determines the hnal solid-state modihcation of the API namely polymorphs, solvates, and hydrates. 

The last example is of conformational polymorphs and multiple Z in an active pharmaceutical ingredient, commonly referred to as API. Venlafaxine 10 is a serotonin-norepinephrine reuptake inhibitor dmg (SNRI) for treating anxiety and depression, and marketed as the hydrochloride salt formulation in forms 1 and/or 2. 

Polymorphism plays a crucial role in the preparation of active pharmaceutical ingredients (APIs), and the possibility to predict and control the crystallization of a specific polymorph is today of great interest for many applications in the pharmaceutical industry. Although identical in their chanical composition, different polymorphs often exhibit important differences in solnbility, dissolution rate, stability, melting point, density, and many other properties that significantly affect the efficacy, bioavailability, and safety of APIs (Llinas and Goodman 2008). 

T. Virtanen, S.L. Maunu, Quantitation of a polymorphic mixture of an active pharmaceutical ingredient with sohd state CPMAS NMR spectroscopy, Int. J. Pharm. 394 (1-2) (2010) 18-25. 

Lu J, Rohani S (2009) Polymorphism and crystallization of active pharmaceutical ingredients. Curr Med Chem 16 884-905 (APIs)... 

Pharmaceutical excipients are formally considered as substances that are included in the manufacturing process of a pharmaceutical product and that are not the pharmacologically active drug or prodrug [1]. In pharmaceutical dosage form they possess a wide variety of functional roles such as modulation of solubility and bioavailability of Active Pharmaceutical Ingredients (APIs), improvement of stability of API in dosage forms, maintenance of its polymorphic form and conformation, maintenance of pH and/or osmolarity of liquid formulations, antioxidant activity, emulsifier, propellant of... 

Understanding of intermolecular interactions in molecular crystals in terms of synthons forms the basis of crystal engineering . Crystallization of organic compounds can lead to different forms of solids such as polymorphs, hydrates, solvates, salts, and co-crystals. These different forms of solid exhibit variable physico-chemical properties such as stability, crystal shape, compressibility, and density without changing its intrinsic chemical structure. In the pharmaceutical industry, these various solid forms of active pharmaceutical ingredients (APIs) can be used to improve physico-chemical properties and... 

Li, W., et al.. Determination of polymorph conversion of an active pharmaceutical ingredient in wet granulation using NIR calibration models generated from the premix blends. J. Pharm. Set, 94 2800-2806 (2005). 

M. Hildebrand, H. Hamaed, A.M. Namespetra, J.M. Donohue, R. Fu, I. Hung, Z. Gan, R.W. Schurko, C1 Solid-state NMR of HCl salts of active pharmaceutical ingredients strucmral prediction, spectral fingerprinting and polymorph recognition, CrystEngComm 16 (2014) 7334-7356. 

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