Atorvastatin derivatives

A selective and sensitive spectrophotometric method for determination of atorvastatin and fluvastatin in tablets have been developed after derivatization with 9-chloromethylanthracene. Atorvastatin and fluvastatin were reacted with 9-chloromethylanthracene in hexane and then tetrabuthylammonium hydroxide for 20 at 90 °C. For spectrophotometric method the derivatives of atorvastatin and fluvastatin were measured at wavelengths, 301 and 303 nm, respectively. The developed method was applied to analyze the atorvastatin and fluvastatin contents in tablets. 

There are currently marketed four naturally derived statins (lovastatin, pravastatin, simvastatin, and rosuvas-tatin) and two synthetic statins (atorvastatin and fluvas-tatin). The structure of these statins is shown in Fig. 2. 

The monocarboxylic acid transporter family MCT (mostly MCT1) was investigated in the past decade for its involvement in intestinal, nondiffusional drug absorption. Typical studies have indicated that salicylic acid [150], tolbutamide [151], atorvastatin (a water-soluble derivative of coenzyme A) [152], and valproic acid [153] are probably uptaken, at least in part, by MCT into the bloodstream. 

As described in US patent 6,777,552, an atorvastatin ester derivative is converted to atorvastatin hemicalcium by mixing the ester derivative with more than 70% excess (molar basis) of calcium hydroxide (see Fig. 1.3). Calcium hydroxide functions as a basic catalyst for the hydrolysis of ester and also supplies calcium ion to form the hemi calcium salt. A significant advantage of this method is that the amount of calcium hydroxide does not have to be as carefully controlled in contrast to the amount of sodium hydroxide and calcium acetate generally controlled in other processes. 

The infrared absorption spectrum of atorvastatin calcium, Form-I, was obtained using a Nicolet FT-IR Impact 410 spectrophotometer equipped with deuterated triglycine sulfate detector, and using Omnic 5.1 a software. The sample was contained in a pressed KBr pellet, with each spectrum being derived from 16 single scans over the range of 4000-400 cm-1 at a... 

Erk developed a spectrophotometric procedure for the assay of atorvastatin, both for the bulk drug substance as well as for pharmaceutical formulations. The procedures are based on the reaction between the drug and bromocresol green, alizarin red, or bromophenol blue, which result in the production of ion-pair complexes (1 1). Beer s law was obeyed over the concentration ranges 5.0-53.0, 7.1-55.8, or 7.5-56.0 /ig/ml with bromocresol green, alizarin red, and bromophenol blue, respectively. The specific absorptivities, molar absorptivities, Sandell sensitivities, standard deviations, and the percent recoveries were evaluated. Atorvastatin was determined by measurement of its first derivative signal at 217.8 nm. 

The calibration curve was established for 4.2-69.0 fig/ml of atorvastatin by first derivative spectrophotometry, and the method showed no interference from the common pharmaceutical adjuvants [11]. 

Atorvastatin is extensively metabolized to its ortho- and para-hyd roxylated derivatives, and to various beta oxidation products. At least 70% of HMG-CoA reductase inhibitory activity has been attributed to the active metabolites of atorvastatin. 

In the case of atorvastatin, a lH-pyrrole ring system was selected [3], The synthetic 2-(4-fluoro-phenyl)-5-isopropyl derivative (Fig. 4.5) inhibited [uC]-acetate conversion to cholesterol in a crude rat liver homogenate. A optimization of its 3,4-disubstituted analogues resulted in atorvastatin. 

The first entirely synthetic derivative, fluvastatin (see Ref. [19]), and its subsequent derivative, atorvastatin, have a lipid solubility that is intermediate between pravastatin and the lactone prodrugs (see Tab. 4.2), and consequently their liver specificities are less expressed. In order to benefit from selective statin uptake mechanism into the liver cells and thereby decrease passive diffusion into other cell types, the recently introduced rosuvastatin molecule was purposefully made more hydrophilic by the introduction of a sulfonamide group. Indeed, the ratio of IC5 values measured in fibroblasts and hepatocyte cultures became considerable higher than that of atorvastatin (see Tab. 4.1). The pronounced differences of inhibitory potency, lipophilicity and the extent of active OATP-linked transport jointly... 

Statins. Statins, such as atorvastatin (Lipotor), simvastatin (Zocor) and lovastatin (Mevacor), are fungal-derived HMG-CoA reductase inhibitors. Treatment results in an increased cellular uptake of LDLs, since the intracellular synthesis of cholesterol is inhibited and cells are therefore dependent on extracellular sources of cholesterol. However, since mevalonate (the product of the HMG-CoA reductase reaction) is also required for the synthesis of other important isoprenoid compounds besides cholesterol, long-term treatments carry some risk of toxicity. 

Following the success of lovastatin, a number of other statins were developed (Figure 12.3). Simvastatin, a semisynthetic derivative of lovastatin, was first approved for marketing in Sweden in 1988 and then later worldwide. Pravastatin, isolated from Nocardia autotropica, was approved in 1991. The purely synthetic statins fluvastatin (1994), atorvastatin (1997), cerivastatin (1998), rosuvastatin (2003), and pitavastatin (2009) soon followed. Cerivastatin was subsequently pulled from the market in 2001 because of postmarketing surveillance reports which revealed 52 deaths that were attributed to rhabdomyolysis and resulting renal failure [61]. 

Figure 6-9 Chemical structures of atorvastatin and its metabolites derived from oxidative and conjugation pathways.

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