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Inhibition of the Vapor-Mediated Phase Transition of the High Temperature Form of Pyrazinamide.
Crystal Growth & Design ( IF 3.2 ) Pub Date : 2017-12-28 , DOI: 10.1021/acs.cgd.7b01550
M M H Smets 1 , G Baaklini 2 , A Tijink 1 , L Sweers 1 , C H F Vossen 1 , C Brandel 2 , H Meekes 1 , H M Cuppen 1 , G Coquerel 2
Affiliation  

Tailor-made additives can prove an effective method to prolong the lifetime of metastable forms of pharmaceutical compounds by surface stabilization. Pyrazinamide (PZA) is a pharmaceutical compound with four polymorphic forms. The high temperature γ form, which can be produced by spray drying or sublimation growth, is metastable at room temperature and transforms within days when produced by spray drying, and within several months up to years for single crystals produced by sublimation. However, when PZA is cospray dried with 1,3-dimethylurea (DMU), it has been reported to remain in its γ form for several years. Scanning electron microscopy (SEM) images reveal that the phase transition from γ-PZA to the low temperature forms involves a vapor-mediated recrystallization, while the reverse phase transition upon heating is a nucleation-and-growth solid-solid phase transition. The lifetime-extending effect of DMU on spray-dried PZA has been investigated in more detail and compared with high-energy ball milling of sublimation-grown γ-PZA crystals. Co-ball milling of PZA and DMU is found to extend the lifetime of the high temperature form of PZA to a few months, while separate ball milling leads to an extension of merely a few weeks. DMU acts as an additive that most likely stabilizes the surface of γ-PZA, which would reduce the vapor pressure of PZA, thereby reducing the transition rate. Alternatively, DMU could prevent nucleation of low temperature forms of PZA.

中文翻译:

吡嗪酰胺高温形式的蒸汽介导相变的抑制。

量身定制的添加剂可以证明是通过表面稳定作用来延长亚稳形式药物化合物寿命的有效方法。吡嗪酰胺(PZA)是具有四种多晶型形式的药物化合物。可以通过喷雾干燥或升华生长产生的高温γ形式在室温下是亚稳态的,并且在通过喷雾干燥产生的几天内可以转化,对于通过升华产生的单晶在数月至数年内可以转化。然而,当将PZA与1,3-二甲基脲(DMU)共喷雾干燥时,据报道它以γ形式保留了数年。扫描电子显微镜(SEM)图像显示,从γ-PZA到低温形式的相变涉及气相介导的重结晶,加热时的逆相变是成核和生长的固-固相变。已经详细研究了DMU对喷雾干燥PZA的延长寿命的作用,并将其与升华生长的γ-PZA晶体的高能球磨进行了比较。发现PZA和DMU的共同球磨可以将PZA高温形式的寿命延长到几个月,而单独的球磨可以将球磨延长几个星期。DMU充当添加剂,最有可能稳定γ-PZA的表面,从而降低PZA的蒸气压,从而降低转变速率。或者,DMU可以防止低温形式的PZA成核。已经详细研究了DMU对喷雾干燥PZA的延长寿命的作用,并将其与升华生长的γ-PZA晶体的高能球磨进行了比较。发现PZA和DMU的共同球磨可以将PZA高温形式的寿命延长到几个月,而单独的球磨可以将球磨延长几个星期。DMU充当添加剂,最有可能稳定γ-PZA的表面,从而降低PZA的蒸气压,从而降低转变速率。或者,DMU可以防止低温形式的PZA成核。已经详细研究了DMU对喷雾干燥PZA的延长寿命的作用,并将其与升华生长的γ-PZA晶体的高能球磨进行了比较。发现PZA和DMU的共同球磨可以将PZA高温形式的寿命延长到几个月,而单独的球磨可以将球磨延长几个星期。DMU充当添加剂,最有可能稳定γ-PZA的表面,从而降低PZA的蒸气压,从而降低转变速率。或者,DMU可以防止低温形式的PZA成核。DMU充当添加剂,最有可能稳定γ-PZA的表面,从而降低PZA的蒸气压,从而降低转变速率。或者,DMU可以防止低温形式的PZA成核。DMU充当添加剂,最有可能稳定γ-PZA的表面,从而降低PZA的蒸气压,从而降低转变速率。或者,DMU可以防止低温形式的PZA成核。
更新日期:2018-01-19
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