Nose Temperature and Anticorrelation between Recrystallization Kinetics and Molecular Relaxation Dynamics in Amorphous Morniflumate at High Pressure

Abstract

We probe the dielectric response of the supercooled liquid phase of Morniflumate, an active principle with anti-inflammatory and antipyretic properties, studying in particular the pressure and temperature dependence of the relaxation dynamics, glass transition temperature Tg, and recrystallization kinetics. Tg increases by roughly 20 K every 100 MPa at low applied pressure, where the ratio Tg/Tm has a constant value of ∼ 0.8 (Tm = melting point). Liquid Morniflumate displays two dielectric relaxations: the structural α relaxation associated with the collective reorientational motions which become arrested at Tg, and a secondary relaxation likely corresponding to an intramolecular dynamics. The relaxation times of both processes scale approximately with the inverse reduced temperature Tg/T. Near room temperature and under an applied pressure of 50 MPa, supercooled Morniflumate recrystallizes in a characteristic time of few hours, with an Avrami exponent of 1.15. Under these conditions, the recrystallization rate is a nonmonotonic function of temperature, displaying a maximum around 298 K, which can be taken to be the optimum crystal growth temperature Tnose. The β relaxation becomes kinetically frozen at ambient temperature under an applied hydrostatic pressure higher than 320 MPa, suggesting that the Morniflumate glass should be kinetically stable under these conditions.

Comparative Physical Study of Three Pharmaceutically Active Benzodiazepine Derivatives: Crystalline versus Amorphous State and Crystallization Tendency

“…Here, n is the Avrami exponent and Z is a constant from which the recrystallization rate in s −1 can be obtained 9,74 as k = Z 1/n . According to eq 8, the quantity ln(−ln(1 − ε n )) should be linearly proportional to the logarithm of the time elapsed since the onset of recrystallization, t − t o .…”

“…Here n is the Avrami exponent and Z is a constant from which the recrystallization rate in s -1 can be obtained 9,74 as k = Z 1/n . According to Eq.…”

“…These aspects are extremely important for the pharmaceutical industry, as polymorphism or the possible stability of an amorphous (glass and supercooled liquid) phase can have a strong impact on the viable protocols for the preparation of suitable formulations for the administration of APIs. 8,9 Drug derivatization also affects the glass transition temperature and the kinetic stability of the amorphous form of the drug. It is well known that amorphous pharmaceuticals have better dissolution and thus better bioavailability properties than their crystalline counterparts, 10,11 and a few amorphous drugs have appeared on the market in recent years.…”

“…[14][15][16] Despite their advantage in terms of solubility, however, amorphous drugs are not thermodynamically stable and are thus prone to recrystallization into the lower-solubility crystalline form. 9,[17][18][19] A better understanding of the amorphous state is needed to advance in the formulation of amorphous drugs. In the context of drug modification strategies, it would be extremely useful to be able to predict how different drug derivatives behave in terms of kinetic stability and tendency towards recrystallization of the amorphous form, both in the case of amorphous API phases formed spontaneously or purposefully during formulation of a medicament.…”

“…The chemical modification may, for example, determine a modified crystal structure of the resulting drug and have an impact also on the possible polymorphism and relative stability of different crystalline forms, which is of relevance for API storage prior to industrial processing. These aspects are extremely important for the pharmaceutical industry, as polymorphism or the possible stability of an amorphous (glass and supercooled liquid) phase can have a strong impact on the viable protocols for the preparation of suitable formulations for the administration of APIs. , …”