Development of atorvastatin

Roth, B. D., The discovery and development of atorvastatin, a potent novel hypolipidemic agent. Prog. Med. Chem., 2002, 40, 1-22 and references cited therein. 

The development of atorvastatin 32 demonstrated the parallel approach used in chemical development. The production of the first kilos of material used modifications of the medicinal chemistry synthesis enabling the process to be carried out in the pilot plant. At the same time, process research designed, developed, and piloted a commercial process wUch was then transferred to manufacturing. 

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. 

A summary of the industrial-scale process development for the nitrilase-catalyzed [93] route to ethyl (/ )-4-cyano-3-hydroxy-butyrate, an intermediate in the synthesis of Atorvastatin (Pfizer Lipitor) from epichlorohydrin via 3-hydroxyglutaronitrile (3-HGN) was recently reported (Figure 8.15) [94], The reaction conditions were further optimized to operate at 3 m (330 gL ) substrate, pH 7.5 and 27 °C. Under these conditions, 100% conversion and product ee of 99% was obtained in 16 h reaction time with a crude enzyme loading of 6% (based on total protein, 0.1 U mg-1). It is noted that at pH < 6.0 the reaction stalled at <50% conversion and at alkaline pH a slowing in reaction rate was observed. Since the starting material is of low cost and the nitrilase can be effectively expressed in the Pfenex (Pseudomonas) expression system at low cost, introduction of the critical stereogenic center... 

It has been found that the 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) inhibitors statins (atorvastatin, pravastatin, and cerivastatin), widely prescribed cholesterol-lowering agents, are able to inhibit phorbol ester-stimulated superoxide formation in endothelial-intact segments of the rat aorta [64] and suppress angiotensin II-mediated free radical production [65]. Delbose et al. [66] found that statins inhibited NADPH oxidase-catalyzed PMA-induced superoxide production by monocytes. It was suggested that statins can prevent or limit the involvement of superoxide in the development of atherosclerosis. It is important that statin... 

For the synthesis of atorvastatin we developed an efficient process that allows for direct cyanation of lactone 2 [21] to cyanomethyl lactone 3 to finally afford the well known atorvastatin precursor 5 (Scheme 6.3) [22]. It is worth pointing out that the two synthetic routes to the advanced statin intermediates 5 and 6 described here avoid ultra-low temperature chemistry, heavy metal catalysts, metal-organic species, and chromatographic purification steps. The DERA-catalyzed chemistry to form the six-carbon chiral unit is cost competitive and operated on a commercial scale. 

Since 2000, atorvastatin (1) has been the world s top selling prescription drug, with sales in the 12 months to June 2008 of 13.8 billion [4]. The conversion of the chloro alcohol 2 to the key atorvastatin intermediate hydroxy nitrile 3 (Scheme 11.1) provides a good case history for the development of a continuous process, as it demonstrates... 

In a comparison of atorvastatin with pravastatin, of 224 patients taking atorvastatin, two had clinically significant increases in alanine transaminase activity (32). They recovered during the next 4 months, one after withdrawal of atorvastatin and the other after a dosage reduction. Withdrawals due to adverse effects were similar in the two groups. One patient developed hepatitis while taking atorvastatin, but was able to tolerate simvastatin (33). The authors concluded that this adverse effect was not a class effect. Eosinophils in a liver-biopsy specimen pointed to an immunological mechanism. 

FIGURE 1.16 pH-Solubility profile of atorvastatin calcium, as predicted using the advanced chemistry development program. 

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. 

Md.K. Pasha, S. Muzeeb, S.J.S. Basha, D. Shashikumar, R. Mullangi, N.R. Srinivas, Analysis of five HMG-CoA reductase inhibitors—atorvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin pharmacological, pharmacokinetic and analytical overview and development of a new method for use in pharmaceutical formulations analysis and in vitro metabolism studies, Biomed. Chromatogr. 20 (2006) 282-293. 

R. Petkovska, C. Cornett, A. Dimitrovska, Development and validation of rapid resolution RP-HPLC method for simultaneous determination of atorvastatin and related compounds by use of chemometrics, Anal. Lett. 41 (2008) 992-1009. 

D.A. Shah, K.K. Bhatt, R.S. Mehta, M.B. Shankar, S.L. Baldania, T.R. Gandhi, Development and validation of a RP-HPLC method for determination of atorvastatin calcium and aspirin in a capsule dosage form, Indian J. Pharm. Sci. 69 (2007) 546-547. 

N. Jain, R. Raghuwanshi, D. Jain, Development and validation of RP-HPLC method for simultaneous estimation of atorvastatin calcium and fenofibrate in tablet dosage forms, Indian J. Pharm. Sd. 70 (2008) 263-265. 

Research on the pathway of cholesterol biosynthesis led to the development of a new class of drugs called statins. All statins, including atorvastatin (Lipitor, 2.22) and rosuvastatin (Crestor, 2.23), are inhibitors of the enzyme HMG-CoA reductase (Figure 2.6). Structurally, the acid side chain found on statin drugs closely resembles mevalonic acid (2.18). The side chain plays an important role in the binding of statins to HMG-CoA reductase. 

The above process has been improved and optimized. An almost 400-fold increase in volumetric productivity relative to the published enzymic reaction conditions has been achieved, resulting in a attractive process that has been run on up to 100-g scale in a single batch at a rate of 30.6 g/L/hr. The catalyst load has been improved by 10-fold as well, from 20 to 2.0 wt % DERA. These improvements were achieved by a combination of the discovery of a DERA with improved activity and reaction optimization to overcome substrate inhibition. The two stereogenic centers are set by DERA, with an ee of >99.9% and a diastereomeric excess of 96.6%. In addition, downstream chemical processes have been developed to convert the enzymic product efficiently to versatile intermediates applicable to the preparation of atorvastatin and rosuvastatin (Greenberg et al., 2004). 

Medications in this class include delavirdine, efa-virenz, and nevirapine. Similar to the NRTls, these agents bind to viral reverse transcriptase and block DNA polymerase activity. A key difference is that NNRTIs do not require intracellular phosphorylation and are not incorporated into viral DNA. Clinically significant kidney toxicities or specific fluid-electrolyte complications have not been reported with this class of agents. In the rat model, efavirenz was associated wifh a species specific dependent kidney toxicity which occurred secondary to the development of a unique glutathione conjugate produced as a metabolite of efavirenz associated with renal tubular epifhelial cell necrosis [125-126]. This toxicity has not been observed in humans. One patient was recently reported to have reversible nephrotic-range proteinuria attributed to efavirenz use, in which a kidney biopsy showed diffuse podocyte foot process effacement [127]. Another report noted the development of rhabdomyolysis and acute tubular necrosis as a result of a drug interaction between delavirdine and atorvastatin [128]. Kidney toxicity due to nevirapine has not been reported. 

The development and validation of the bioanalysis of atorvastatin, its two hydroxy metabolites, and their lactone forms in human serum was reported, using a [Zljl-ILIS [51], Samples were extracted at pH 5.0 with MTBE. The analytes were separated on a 50x2-mm-lD YMC Basic column (5 pm) and an aqueous formic acid-methanol gradient, and analysed in positive-ion ESI-MS in SRM mode. The LOQ was 0.5 ng/ml. 

Cerivastatin is administered in its acid form. It forms seven acid and lactone biotransformation products. The simultaneous bioanalysis of all eight components in human scram was reported using [Djl-ILIS for cerivastatin and its lactone [52]. The method was similar to the method developed for atorvastatin [51], described above. The LOQ was 0.01 ng/ml for cerivastatin and its lactone, and between 0.05 and 0.5 ng/ml for the other biotransformation products. The method was validated. 

Biocatalysis is often used to prepare molecules with two or more chiral centers or to prepare intermediates from simple precursors when selective chemical transformations would be difficult [55]. Molecules with one chiral center are generally prepared by classical chemical resolution or by transferring chirality into achiral starting materials using chiral reagents. The launch of atorvastatin was initially carried out by classical conversion of 39 to the chiral diol 40 (Figure 3.27), and a biocatalyzed preparation of 40 was also developed [56]. The biocatalyzed route may now be the preferred route for preparing 40 [55]. 

Zeller, J., Atorvastatin A Case Study in the Development of a Commercial Process. Published notes from contributed talk at The Third International Conference on Process Development Chemistry, March 28,1997. 

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