Degradation of atorvastatin: (1R,2S,4S,5S)-4-(4-fluoro­phen­yl)-2-hydro­peroxy-4-hydr­oxy-2-isopropyl-N,5-diphenyl-3,6-dioxabicyclo­[3.1.0]hexane-1-carboxamide

Muhammad Ashfaq; Muhammad Nawaz Tahir; Islam Ullah Khan; Mohammad S Iqbal; Muhammad Nadeem Arshad

doi:10.1107/S1600536808022265

. 2008 Jul 19;64(Pt 8):o1548. doi: 10.1107/S1600536808022265

Degradation of atorvastatin: (1R,2S,4S,5S)-4-(4-fluorophenyl)-2-hydroperoxy-4-hydroxy-2-isopropyl-N,5-diphenyl-3,6-dioxabicyclo[3.1.0]hexane-1-carboxamide

Muhammad Ashfaq ^a, Muhammad Nawaz Tahir ^b,^*, Islam Ullah Khan ^a, Mohammad S Iqbal ^a, Muhammad Nadeem Arshad ^a

PMCID: PMC2962052 PMID: 21203252

Abstract

The degradation of atorvastatin calcium in methanol and hydrogen peroxide results in the crystallization of the title compound, C₂₆H₂₄FNO₆, which shows several differences compared with the starting compound. In the crystal structure of the title compound, intra- and intermolecular hydrogen bonding is found.

Related literature

For related literature, see: Cremer & Pople (1975 ▶); Rouleau (2005 ▶); United States Pharmacopeia (2007 ▶).

Experimental

Crystal data

C₂₆H₂₄FNO₆
M _r = 465.46
Monoclinic,
a = 11.7560 (6) Å
b = 11.7489 (6) Å
c = 17.0889 (9) Å
β = 94.438 (2)°
V = 2353.2 (2) Å³
Z = 4
Mo Kα radiation radiation
μ = 0.10 mm⁻¹
T = 296 (2) K
0.25 × 0.18 × 0.15 mm

Data collection

Bruker Kappa APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2005 ▶) T _min = 0.975, T _max = 0.980
14754 measured reflections
5340 independent reflections
3008 reflections with I > 2σ(I)
R _int = 0.040

Refinement

R[F ² > 2σ(F ²)] = 0.049
wR(F ²) = 0.136
S = 1.02
5340 reflections
318 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.34 e Å⁻³
Δρ_min = −0.28 e Å⁻³

Data collection: APEX2 (Bruker, 2007 ▶); cell refinement: APEX2; data reduction: SAINT (Bruker, 2007 ▶); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ▶) and PLATON (Spek, 2003 ▶); software used to prepare material for publication: WinGX (Farrugia, 1999 ▶) and PLATON.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536808022265/nc2108sup1.cif

e-64-o1548-sup1.cif^{(25.7KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808022265/nc2108Isup2.hkl

e-64-o1548-Isup2.hkl^{(256.2KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯O3	0.86 (2)	2.36 (2)	2.780 (2)	110.8 (17)
N1—H1⋯O2ⁱ	0.86 (2)	2.37 (2)	3.216 (2)	168.0 (18)
O2—H2⋯O5	0.84 (2)	2.15 (2)	2.920 (2)	152 (2)
O2—H2⋯O3ⁱⁱ	0.84 (2)	2.35 (2)	2.8188 (18)	116.1 (18)
O5—H5⋯O6	0.82	1.99	2.655 (2)	138

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Symmetry codes: (i) Inline graphic ; (ii) .

Acknowledgments

MA gratefully acknowledges the Higher Education Commision, Islamabad, Pakistan, for providing him with a scholaship under the Indigenous PhD Program (PIN 042-120556-PS2-275).

supplementary crystallographic information

Comment

Atorvastatin calcium is widly used as synthetic lipid-lowering agent (Rouleau, 2005). The medicinal organic compounds are affected by the environment in which they are stored and produce degradation products through reactions with moisture (humidity) and oxygen in air (oxidation) or due to thermal shocks. Thus, all the drug substances are given an expiration date which is the time at which 10% of the initial amount of a drug is transformed to various degradation products (United States Pharmacopeia, 2007). Thus it is a standard practice to study the stability profile of a drug substance under stress. In order to simulate the air oxidation under accelerated conditions the products are subjected to the reaction with hydrogen peroxide. The purpose of this study was to see the reaction of atorvastatin calcium towards hydrogen peroxide. In this example, the title compound crystallized after the reaction at ambient temperature.

In the structure of the title compound, the central five-membered ring (O1/C1–C4) is in an envelope conformation, with the C1–C4 atoms in the plane (Fig. 1). The puckering parameters (Cremer & Pople, 1975) are Q = 0.9737 (16)Å, θ = 115.69 (10)° and φ = 0.10 (13)°. The dihedral angles between this ring and benzene rings C6–C11, C12–C17 and C18–C23 are 88.71 (11), 66.85 (11) and 64.39 (12)°, respectively. There is intramolecular O—H···O and N—H···O hydrogen bonding between N1 and O3, between O2 and O5 and between O5 and O6 (Fig. 1 and Table 1). In the crystal structure, the molecules are connected via intermolecular O—H···O and N—H···O hydrogen bonding (Table 1).

Experimental

Atorvastatin calcium (100 mg) was dissolved in methanol (25 ml) at room temperature. A separate solution (10 ml) of hydrogen peroxide (5%) was prepared in distilled water. Both the solutions were mixed togather and set aside for 2 months. The crystals suitable for x-ray diffraction of the title compound (I) were obtained by filteration.