Thermal Stability of Simvastatin under Different Atmospheres

Simões, Ricardo G.; Diogo, Hermı́nio P.; Dias, Ana; Oliveira, M. Conceição; Cordeiro, Carlos; Bernardes, Carlos E. S.; Piedade, Manuel E. Minas da

doi:10.1002/jps.23787

Cited by 9 publications

(5 citation statements)

References 25 publications

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“…As it could be expected in thermal degradation, the temperature has biggest impact. This kind of effect was expected because it is known that kinetic constants have exponential dependency with reaction temperature (Arrhenius law) and this has also been reported by other authors [ 22 ].…”

Section: Resultssupporting

confidence: 62%

Comprehensive Assessment of Degradation Behavior of Simvastatin by UHPLC/MS Method, Employing Experimental Design Methodology

Gigovska¹,

Petkovska²,

Acevska

et al. 2018

International Journal of Analytical Chemistry

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This manuscript describes comprehensive approach for assessment of degradation behavior of simvastatin employing experimental design methodology as scientific multifactorial strategy. Experimental design methodology was used for sample preparation and UHPLC method development and optimization. Simvastatin was subjected to stress conditions of oxidative, acid, base, hydrolytic, thermal, and photolytic degradation. Using 2n full factorial design degradation conditions were optimized to obtain targeted level of degradation. Screening for optimal chromatographic condition was made by Plackett–Burman design and optimization chromatographic experiments were conducted according to Box-Behnken design. Successful separation of simvastatin from the impurities and degradation products was achieved on Poroshell 120 EC C18 50 × 3.0 mm 2.7 μm, using solutions of 20 mM ammonium formate pH 4.0 and acetonitrile as the mobile phase in gradient mode. The proposed method was validated according to International Conference on Harmonization (ICH) guidelines. Validation results have shown that the proposed method is selective, linear, sensitive, accurate, and robust and it is suitable for quantitative determination of simvastatin and its impurities. Afterwards, the degradation products were confirmed by a direct hyphenation of liquid chromatograph to ion-trap mass spectrometer with heated electrospray ionization interface. This study highlights the multiple benefits of implementing experimental design, which provides a better understanding of significant factors responsible for degradation and ensures successful way to achieve degradation and can replace the trial and error approach used in conventional forced degradation studies.

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Section: Resultssupporting

confidence: 62%

Comprehensive Assessment of Degradation Behavior of Simvastatin by UHPLC/MS Method, Employing Experimental Design Methodology

Gigovska¹,

Petkovska²,

Acevska

et al. 2018

International Journal of Analytical Chemistry

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“…Indeed, the III and II forms are metastable at ambient temperature and, if present, will readily convert to form I, whose stability domain extends up to the fusion temperature. It should, nevertheless, be bear in mind that melting and quench cooling can lead to persistent amorphous phases, , or to chemical degradation, if the process is not carried out under inert atmosphere. The possibility of chemical degradation will be particularly critical if, for example, strategies to improve the solubility of simvastatin involving melting are considered.…”

Section: Discussionmentioning

confidence: 99%

Polymorphism in Simvastatin: Twinning, Disorder, and Enantiotropic Phase Transitions

et al. 2018

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Simvastatin is one of the most widely used active pharmaceutical ingredients for the treatment of hyperlipidemias. Because the compound is employed as a solid in drug formulations, particular attention should be given to the characterization of different polymorphs, their stability domains, and the nature of the phase transitions that relate them. In this work, the phase transitions delimiting the stability domains of three previously reported simvastatin forms were investigated from structural, energetics, and dynamical points of view based on single crystal X-ray diffraction (SCXRD), hot stage microscopy (HSM), and differential scanning calorimetry (DSC) experiments (conventional scans and heat capacity measurements), complemented with molecular dynamics (MD) simulations. Previous assignments of the crystal forms were confirmed by SCXRD: forms I and II were found to be orthorhombic ( P222, Z'/ Z = 1/4) and form III was monoclinic ( P2, Z'/ Z = 2/4). The obtained results further indicated that (i) the transitions between different forms are observed at 235.9 ± 0.1 K (form III → form II) and at 275.2 ± 0.2 K (form II → form I) in DSC runs carried out at 10 K min and close to these values when other types of techniques are used (e.g., HSM). (ii) They are enantiotropic (i.e., there is a transition temperature relating the two phases before fusion at which the stability order is reversed), fast, reversible, with very little hysteresis between heating and cooling modes, and occur under single crystal to single crystal conditions. (iii) A nucleation and growth mechanism seems to be followed since HSM experiments on single crystals evidenced the propagation of an interface, accompanied by a change of birefringence and crystal contraction or expansion (more subtle in the case of form III → form II), when the phase transitions are triggered. (iv) Consistent with the reversible and small hysteresis nature of the phase transitions, the SCXRD results indicated that the molecular packing is very similar in all forms and the main structural differences are associated with conformational changes of the "ester tail". (v) The MD simulations further suggested that the tail is essentially "frozen" in two conformations below the III → II transition temperature, becomes progressively less hindered throughout the stability domain of form II, and acquires a large conformational freedom above the II → I transition. Finally, the fact that these transitions were found to be fast and reversible suggests that polymorphism is unlikely to be a problem for pharmaceutical formulations employing crystalline simvastatin because, if present, the III and II forms will readily convert to form I at ambient temperature.

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“…The amorphous sample for ss-NMR studies was obtained by the melting and quench-cooling method: simvastatin as received was heated at ca. 10 K·min –1 up to 423 K (∼10 degrees above the melting temperature) for approximately 3 min, under inert atmosphere, and the melt was cooled down to room temperature . The glassy sample was gently powdered in a mortar and placed in the solid-state NMR sample holder.…”

Section: Experimental Sectionmentioning

confidence: 99%

A Stable Amorphous Statin: Solid-State NMR and Dielectric Studies on Dynamic Heterogeneity of Simvastatin

Nunes¹,

Viciosa²,

Correia

et al. 2014

Mol. Pharmaceutics

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Statins have been widely used as cholesterol-lowering agents. However, low aqueous solubility of crystalline statins and, consequently, reduced biovailability require seeking for alternative forms and formulations to ensure an accurate therapeutic window. The objective of the present study was to evaluate the stability of amorphous simvastatin by probing molecular dynamics using two nondestructive techniques: solid-state NMR and dielectric relaxation spectroscopy. Glassy simvastatin was obtained by the melt quench technique. (13)C cross-polarization/magic-angle-spinning (CP/MAS) NMR spectra and (1)H MAS NMR spectra were obtained from 293 K up to 333 K (Tg ≈ 302 K). The (13)C spin-lattice relaxation times in the rotating frame, T1ρ, were measured as a function of temperature, and the correlation time and activation energy data obtained for local motions in different frequency scales revealed strong dynamic heterogeneity, which appears to be essential for the stability of the amorphous form of simvastatin. In addition, the (1)H MAS measurements presented evidence for mobility of the hydrogen atoms in hydroxyl groups which was assigned to noncooperative secondary relaxations. The complex dielectric permittivity of simvastatin was monitored in isochronal mode at five frequencies (from 0.1 to 1000 kHz), by carrying out a heating/cooling cycle allowing to obtain simvastatin in the supercooled and glassy states. The results showed that no dipolar moment was lost due to immobilization, thus confirming that no crystallization had taken place. Complementarily, the present study focused on the thermal stability of simvastatin using thermogravimetric analysis while the thermal events were followed up by differential scanning calorimetry and dielectric relaxation spectroscopy. Overall, the results confirm that the simvastatin in the glass form reveals a potential use in the solid phase formulation on the pharmaceutical industry.

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Thermal Stability of Simvastatin under Different Atmospheres

Cited by 9 publications

References 25 publications

Comprehensive Assessment of Degradation Behavior of Simvastatin by UHPLC/MS Method, Employing Experimental Design Methodology

Comprehensive Assessment of Degradation Behavior of Simvastatin by UHPLC/MS Method, Employing Experimental Design Methodology

Polymorphism in Simvastatin: Twinning, Disorder, and Enantiotropic Phase Transitions

A Stable Amorphous Statin: Solid-State NMR and Dielectric Studies on Dynamic Heterogeneity of Simvastatin

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