Abstract:Understanding the polymorphic behavior of active pharmaceutical ingredients is important for formulation purposes and for regulatory reasons. Metacetamol is an isomer of paracetamol and it similarly exhibits polymorphism. In the present paper, it has been found that one of the polymorphs of metacetamol is only stable under increased pressure, which has led to the conclusion that metacetamol like paracetamol is a monotropic system under ordinary (= laboratory) conditions and that it becomes enantiotropic under … Show more
“…As when comparing the relative thermodynamic stabilities of glycine polymorphs at ambient pressure, a reliable answer on the relative stabilities at high pressures could be given by high-pressure calorimetry. Examples of such studies for several compounds are known, [117][118][119][120][121][122][123][124][125][126] but not for glycine (yet? ).…”
Section: Relative Stabilities and Transformation At High Pressuresmentioning
Glycine is a small molecule. It cannot change its conformation and is achiral. Despite the apparent simplicity, glycine shows endless diversity in its behavior over many phenomena. It was the first amino acid for which polymorphism was reported, first on crystallization and then on hydrostatic compression. The polymorphs differ in their physical properties and their biological activity. Glycine clusters persist in solution, leading to "solution memory". Phenomena at interfaces are critically important for crystal growth, dissolution, and for physical properties, which can be at times unexpected, like polarity in centrosymmetric αpolymorph. It is a great pleasure to remind of these remarkable phenomena in a special issue honoring professors Meir Lahav and Leslie Leiserowitz, who pioneered the study of the behavior of this unique molecule in many respects, and showed how complex and non-trivial phenomena can be at interfaces: between phases and between research fields.
“…As when comparing the relative thermodynamic stabilities of glycine polymorphs at ambient pressure, a reliable answer on the relative stabilities at high pressures could be given by high-pressure calorimetry. Examples of such studies for several compounds are known, [117][118][119][120][121][122][123][124][125][126] but not for glycine (yet? ).…”
Section: Relative Stabilities and Transformation At High Pressuresmentioning
Glycine is a small molecule. It cannot change its conformation and is achiral. Despite the apparent simplicity, glycine shows endless diversity in its behavior over many phenomena. It was the first amino acid for which polymorphism was reported, first on crystallization and then on hydrostatic compression. The polymorphs differ in their physical properties and their biological activity. Glycine clusters persist in solution, leading to "solution memory". Phenomena at interfaces are critically important for crystal growth, dissolution, and for physical properties, which can be at times unexpected, like polarity in centrosymmetric αpolymorph. It is a great pleasure to remind of these remarkable phenomena in a special issue honoring professors Meir Lahav and Leslie Leiserowitz, who pioneered the study of the behavior of this unique molecule in many respects, and showed how complex and non-trivial phenomena can be at interfaces: between phases and between research fields.
“…12 Fortunately, many polymorphic forms only exist under conditions far from equilibrium, such as extremes of temperature, 13 pressure, 14−16 or their combination. 17 In many other cases, polymorphic forms can be generated at, or recovered to, ambient conditions. 18−21 These cases are troublesome for industry, particularly where a metastable polymorphic form is isolated under ambient conditions as a result of the processing conditions.…”
Section: ■ Introductionmentioning
confidence: 99%
“…This follows from the critical dependence of physical properties (e.g., electronic and thermal conductivity, compressibility, and solubility) on the atomic arrangements and intermolecular interactions within the solid structure. − As nearly all molecular materials exhibit polymorphism, , including multicomponent molecular materials, this phenomenon has dominated much of the solid state research . Fortunately, many polymorphic forms only exist under conditions far from equilibrium, such as extremes of temperature, pressure, − or their combination . In many other cases, polymorphic forms can be generated at, or recovered to, ambient conditions. − These cases are troublesome for industry, particularly where a metastable polymorphic form is isolated under ambient conditions as a result of the processing conditions. , In such cases, aging of the structure can lead to spontaneous polymorphic transformations, and as in the case of Ritonavir, have potentially detrimental effects on its function .…”
Mechanochemistry
has become a valuable method for the synthesis
of new materials and molecules, with a particular strength for screening
and preparing multicomponent crystals. In this work, two novel cocrystals
of pyrazinamide (PZA) with pimelic acid (PA) were prepared mechanochemically.
Their formation was monitored in real time by in situ synchrotron
powder X-ray diffraction. Control over the polymorphic form was obtained
through the selective choice of liquid additive via liquid assisted
grinding. Slurry experiments and dispersion-corrected density functional
theory calculations suggest that Form I is the thermodynamically stable
form under ambient conditions. Upon aging, Form II converts to Form
I. The stability of Form II upon aging was found to depend strongly
on the milling duration, intensity, and material of the milling vessels.
Longer or higher energy milling drastically increased the lifetime
of the Form II product. For the first time, this work also demonstrates
that the choice of milling jar can have a decisive effect on the aging
stability of a bulk polymorphic powder. In contrast to material prepared
in steel milling vessels, the preparation of Form II in Perspex (PMMA)
vessels increased its lifetime 3-fold. These findings offer a new
dimension to garnering control over mechanochemical cocrystallization
and demonstrate the critical importance of the careful and timely
ex situ screening of ball mill grinding reactions. This will be of
importance for potential industrial applications of mechanochemical
cocrystallization where understanding polymorph longevity is crucial
for the development of a robust preparative protocol.
“…This type of phase diagram is an example of the third case of the four possible cases of dimorphism formerly proposed by Bakhuis Roozeboom 6 , 23 , in which a monotropic system turns enantiotropic under pressure. Examples of such systems are paracetamol 16 , progesterone 21 , and ritonavir 19 ; however, the particularity of the benzophenone system, which it shares with metacetamol 62 , bicalutamide 63 , and fluoxetine nitrate 64 , is that a lower density phase only possesses a stable domain under pressure and at high temperature. Figure 3 Topological pressure–temperature phase diagram for the dimorphism of benzophenone.…”
For over a century, it was thought that the crystalline polymorph II of benzophenone does not possess a stable domain in the pressure–temperature phase diagram. With a combination of new experimental results and literature data, this case of crystalline dimorphism has finally been solved and it is shown that form II possesses a stable domain at high pressure and high temperature, even though its density is lower than that of form I, the stable form under ordinary pressure and temperature conditions. The phase diagram of benzophenone is a clear demonstration of the fact that to understand the phase behaviour of a chemical substance both the exchange of heat (due to the change in intermolecular interactions) and work (due to the change of volume at a given pressure) need to be taken into account.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
