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

Nunes, Teresa; Viciosa, María Teresa; Correia, Natália T.; Danède, Florence; Nunes, Rita G.; Diogo, Hermı́nio P.

doi:10.1021/mp400455r

Cited by 26 publications

(28 citation statements)

References 39 publications

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“…Furthermore, formulation stability increases with increasing T g values ( Li et al, 2015 ). This is partly due to molecular mobility being a driving force for recrystallization ( Nunes et al, 2014 ). The lower the molecular mobility, the higher the degree of intermolecular interactions and the more stable the formulation ( Sibik et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…The formulation has a high T g (i.e., 107 °C) because the KinetiSol process does not require plasticizers, which are known to decrease the system's T g ( DiNunzio et al, 2010 ). Recrystallization rates increase above the formulation's T g ; therefore, limiting molecular mobility promotes stability ( Nunes et al, 2014 ). Additionally, Keratichewanun et al reported that for homogenous samples (e.g., 59–4 and 59–5), the crystallization tendency is inversely proportional to the degree of drug–polymer interactions ( Keratichewanun et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

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Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity

Davis

Miller²,

Santitewagun

et al. 2021

International Journal of Pharmaceutics: X

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We seek to further addresss the questions posed by Moseson et al. regarding whether any residual crystal level, size, or characteristic is acceptable in an amorphous solid dispersion (ASD) such that its stability, enhanced dissolution, and increased bioavailability are not compromised. To address this highly relevant question, we study an interesting heat- and shear-labile drug in development, LY3009120. To study the effects of residual crystallinity and degradation in ASDs, we prepared three compositionally identical formulations (57–1, 59–4, and 59–5) using the KinetiSol process under various processing conditions to obtain samples with various levels of crystallinity (2.3%, 0.9%, and 0.1%, respectively) and degradation products (0.74%, 1.97%, and 3.12%, respectively). Samples with less than 1% crystallinity were placed on stability, and we observed no measurable change in the drug's crystallinity, dissolution profile or purity in the 59–4 and 59–5 formulations over four months of storage under closed conditions at 25 °C and 60% humidity. For formulations 57–1, 59–4, and 59–5, bioavailability studies in rats reveal a 44-fold, 55-fold, and 62-fold increase in mean AUC, respectively, compared to the physical mixture. This suggests that the presence of some residual crystals after processing can be acceptable and will not change the properties of the ASD over time.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity

Davis

Miller²,

Santitewagun

et al. 2021

International Journal of Pharmaceutics: X

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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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“…As pointed out (Wenz, 1994) substrates complexed with CD are in a very heterogeneous environment and complexed and free molecules may undergo fast exchange processes. Future work includes the evaluation of the stability of the ABZ:citrate-␤-CD inclusion complex as previously described for a cholesterol-lowering drug (Nunes et al, 2014). This study will be performed by probing mobility in the kHz frequency range through spin-lattice relaxation time in the rotating frame measurements as a function of temperature.…”

Section: Cyclodextrinmentioning

confidence: 99%

13C and 15N solid-state NMR studies on albendazole and cyclodextrin albendazole complexes

Ferreira

Garcı́a

Leonardi

et al. 2015

Carbohydrate Polymers

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

Cited by 26 publications

References 39 publications

Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity

Formulating a heat- and shear-labile drug in an amorphous solid dispersion: Balancing drug degradation and crystallinity

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

13C and 15N solid-state NMR studies on albendazole and cyclodextrin albendazole complexes

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