Barrio, María

Ceolin, René

Lloveras, Pol

Rietveld, Ivo B.

Tamarit, Josep-Lluis

English

Archive Ouverte en Sciences de l'Information et de la Communication

EHPRG 2019 - Abstracts 
 
 
Deducing high-pressure behavior for chemically fragile systems: the 
polymorphism of spironolactone 
 
I.B. Rietveld1,2*, Maria Barrio3, Pol Lloveras3, René Céolin4 and Josep-Lluís Tamarit3 
 
1Normandie Université, Lab. SMS-EA3233, Université de Rouen, 76821 Mont Saint Aignan, France 
2Fac. de Pharmacie, Université Paris Descartes, 4 av. de l’observatoire, 75006 Paris, France 
3Grup de Caracterització de Materials, Departament de Física – Barcelona Research Center in Multiscale Science and Engineering, 
Universitat Politècnica de Catalunya, EEBE, Campus Diagonal-Besòs, Av. Eduard Maristany 10-14, 08019 Barcelona, Spain 
4LETIAM, EA7357, IUT Orsay, Université Paris Sud, rue Noetzlin, 91405 Orsay, France 
 
Keywords: active pharmaceutical ingredient, topological method, crystalline polymorphism 
 
*e-mail: ivo.rietveld@univ-rouen.fr 
 
In the case that different crystalline polymorphs of 
active pharmaceutical ingredients (API i.e. drug 
molecules) have been observed, the study of their stability 
ranking becomes important, because they risk being prone 
to changes in the formulation and bioavailability due to a 
sudden polymorph transformation. In the case of 
spironolactone, an aldosterone agonist used as a diuretic, 
the melting points of the two polymorphs are more than 
70 degrees apart, which is very rare as can be seen in the 
graph representing a major part of molecular 
(pharmaceutical) polymorphs observed in the last 50 years 
(Figure 1). 
 
Figure 1. Differences in the melting points between the highest 
melting polymorph and other observed polymorphs for over 
200 pairs 
 
Form I, which has a melting point of 408 K compared 
to the melting point of form II of 480 K, possesses the 
highest density making it likely the more stable form 
under pressure. However, spironolactone is chemically 
not very stable under pressure and it is therefore difficult 
to obtain reliable pressure data on the phase behaviour. It 
is however still possible to construct a pressure-
temperature phase diagram based on data that has been 
obtained by calorimetry and X-ray diffraction as a 
function of temperature. 
By calorimetry, it has been found that the melting point 
of form II is 479.6 ±0.6 K with an enthalpy of 54.0 ±1.5 J 
g-1. The melting point of form I is 408 ±3 K, however, the 
melting enthalpy for form I is inaccessible, because the 
melt recrystallises instantly into form II. Some samples of 
spironolactone convert from form I into form II before 
melting at a temperature of around 375 K leading to an 
enthalpy between the two polymorphs of -6.9 ±0.3 J g-1 
(exothermic). In addition, the specific volume of both 
polymorphs as a function of the temperature from 100 K 
up to the melting point have been obtained. 
The fact that form II melts at a higher temperature and 
the observation that form I turns into form II with an 
exothermic transition clearly indicates, through the Le 
Chatelier principle, that form I does not possess a stable 
temperature domain under atmospheric pressure; 
however, pharmaceutical processing may include pressure 
changes and because form I is denser it is important to 
have a clear estimate of the position of the possible II-I 
equilibrium under pressure. Using the Clapeyron 
equation, the Le Chatelier principle and the fact that state 
functions do not depend on the path taken, i.e. the 
topological method, a relatively reliable estimate of the 
position of the I-II equilibrium can be obtained. It can be 
shown that at least in terms of phase behaviour a stable I-
II equilibrium exists, which has a negative slope, 
indicating that form I tends to get more stable with 
increasing temperature (Figure 2). Nevertheless, it can 
also be shown that the triple point, where both solids melt 
at the same temperature and pressure conditions can be 
found at 760 MPa, which is far beyond the reach of any 
pharmaceutical process. 
To conclude, it is interesting to see that a crystalline 
polymorph, which has a melting point that is 70 degrees 
lower than that of the stable polymorph does in fact 
possess a stable pressure-temperature domain that in terms 
of physical pressure conditions is very low (< 1 GPa) and 
it is most likely the relatively close proximity of this stable 
domain that causes the appearance of the metastable form 
I in the first place [1]. 
 
 
Figure 2. Schematic phase diagram of spironolactone 
dimorphism based on the Le Chatelier principle 
 
[1] I.B. Rietveld, M. Barrio, P. Lloveras, R. Céolin and J.-Ll. 
Tamarit, Int. J. Pharm. Sci. 552, 193 (2018). 


Deducing high pressure behavior for chemically fragile systems: the polymorphism of spironolactone

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Deducing high pressure behavior for chemically fragile systems: the polymorphism of spironolactone

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