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Polymorphism in Simvastatin: Twinning, Disorder, and Enantiotropic Phase Transitions
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-09-19 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00818 Ricardo G. Simões 1 , Carlos E. S. Bernardes 1 , Abhinav Joseph 1 , M. Fátima M. Piedade 1, 2 , Werner Kraus 3 , Franziska Emmerling 3 , Hermíno P. Diogo 2 , Manuel E. Minas da Piedade 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-09-19 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00818 Ricardo G. Simões 1 , Carlos E. S. Bernardes 1 , Abhinav Joseph 1 , M. Fátima M. Piedade 1, 2 , Werner Kraus 3 , Franziska Emmerling 3 , Hermíno P. Diogo 2 , Manuel E. Minas da Piedade 1
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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 (P212121, Z′/Z = 1/4) and form III was monoclinic (P21, 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–1 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.
中文翻译：
辛伐他汀的多态性：孪生，无序和对映相变
辛伐他汀是用于治疗高脂血症的最广泛使用的活性药物成分之一。由于该化合物在药物制剂中以固体形式使用，因此应特别注意不同多晶型物的表征，其稳定域以及与它们相关的相变的性质。在这项工作中，基于单晶X射线衍射（SCXRD），热台显微镜（HSM）和微分法，从结构，能量学和动力学的角度研究了界定三种先前报道的辛伐他汀形式的稳定域的相变。扫描量热（DSC）实验（常规扫描和热容量测量），并辅以分子动力学（MD）模拟。先前指定的晶型已由SCXRD确认：P 2 1 2 1 2 1，Z '/ Z = 1/4），晶型III是单斜晶（P 2 1，Z '/ Z = 2/4）。获得的结果进一步表明：（i）在以10 K min进行的DSC运行中，观察到不同形式之间的转变分别为235.9±0.1 K（形式III→形式II）和275.2±0.2 K（形式II→形式I）。–1当使用其他类型的技术（例如HSM）时，则接近这些值。（ii）它们是对映体的（即，在熔融之前存在两个相关的转变温度，在该温度下稳定性顺序颠倒了），快速，可逆，在加热和冷却模式之间的磁滞很小，并且在单晶至单晶下发生晶体条件。（iii）似乎遵循了成核和生长机制，因为在单晶上进行的HSM实验证明了界面的传播，并伴随着双折射和晶体收缩或膨胀的变化（在形式III→形式II的情况下更为微妙），当触发相变时。（iv）符合相变的可逆性和小滞后性，SCXRD结果表明，分子堆积在所有形式上都非常相似，主要的结构差异与“酯尾”的构象变化有关。（v）MD模拟进一步表明，尾部在III→II转变温度以下的两个构象中基本上“冻结”，在形式II的整个稳定域中受阻逐渐减少，并且在II→I之上具有较大的构象自由度过渡。最后，发现这些转变是快速且可逆的，这表明多晶型对于采用结晶辛伐他汀的药物制剂而言不太可能成为问题，因为如果存在，III和II形式将在环境温度下容易转化为I形式。
更新日期：2018-09-19
中文翻译：
辛伐他汀的多态性：孪生，无序和对映相变
辛伐他汀是用于治疗高脂血症的最广泛使用的活性药物成分之一。由于该化合物在药物制剂中以固体形式使用，因此应特别注意不同多晶型物的表征，其稳定域以及与它们相关的相变的性质。在这项工作中，基于单晶X射线衍射（SCXRD），热台显微镜（HSM）和微分法，从结构，能量学和动力学的角度研究了界定三种先前报道的辛伐他汀形式的稳定域的相变。扫描量热（DSC）实验（常规扫描和热容量测量），并辅以分子动力学（MD）模拟。先前指定的晶型已由SCXRD确认：P 2 1 2 1 2 1，Z '/ Z = 1/4），晶型III是单斜晶（P 2 1，Z '/ Z = 2/4）。获得的结果进一步表明：（i）在以10 K min进行的DSC运行中，观察到不同形式之间的转变分别为235.9±0.1 K（形式III→形式II）和275.2±0.2 K（形式II→形式I）。–1当使用其他类型的技术（例如HSM）时，则接近这些值。（ii）它们是对映体的（即，在熔融之前存在两个相关的转变温度，在该温度下稳定性顺序颠倒了），快速，可逆，在加热和冷却模式之间的磁滞很小，并且在单晶至单晶下发生晶体条件。（iii）似乎遵循了成核和生长机制，因为在单晶上进行的HSM实验证明了界面的传播，并伴随着双折射和晶体收缩或膨胀的变化（在形式III→形式II的情况下更为微妙），当触发相变时。（iv）符合相变的可逆性和小滞后性，SCXRD结果表明，分子堆积在所有形式上都非常相似，主要的结构差异与“酯尾”的构象变化有关。（v）MD模拟进一步表明，尾部在III→II转变温度以下的两个构象中基本上“冻结”，在形式II的整个稳定域中受阻逐渐减少，并且在II→I之上具有较大的构象自由度过渡。最后，发现这些转变是快速且可逆的，这表明多晶型对于采用结晶辛伐他汀的药物制剂而言不太可能成为问题，因为如果存在，III和II形式将在环境温度下容易转化为I形式。
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