Article pubs.acs.org/crystal
Solution-Mediated Polymorphic Transformation: Form II to Form III Piracetam in Organic Solvents Anthony Maher, Denise M. Croker,* Colin C. Seaton, Åke C. Rasmuson, and Benjamin K. Hodnett Solid State Pharmaceuticals Cluster, Materials and Surface Science Institute, Department of Chemical and Environmental Sciences, University of Limerick, Limerick, Ireland ABSTRACT: The solution-mediated polymorphic transformation from Form II to Form III 2-oxo-1-pyrrolidine acetamide (piracetam) was investigated in seven organic solvents over the temperature range of 5− 50 °C. The transformation rate increased as a function of temperature, agitation, and the solubility of piracetam in the host solvent. However, this trend was reversed in 2-propanol. Molecular modeling demonstrated that 2-propanol forms interactions with piracetam molecules in solution stronger than those formed by other solvents, thereby retarding the nucleation and growth of FIII(6.525) during the transformation in this solvent.
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⎡ 16πγ 3v 2 Φ ⎤ J = A × exp⎢ − 3 3 ⎥ ⎣ 3k T (ln S)2 ⎦
INTRODUCTION The crystal structures of five polymorphic forms of piracetam (Figure 1) have been published and collected in the Cambridge
where A is the pre-exponential or collision factor, v is the molecular volume, Φ is the heterogeneous nucleation factor, and k is the Boltzmann constant. Numerous studies of the effect of temperature on solution-mediated polymorphic transformations have been conducted. In general, higher temperatures increase the nucleation and growth kinetics through an increasing molecular thermal activity, caused by an increasing solute concentration and a decreasing interfacial energy.6,9,10,13,14 The supersaturation, which is governed by the free energy difference (ΔG in Scheme 1) between the polymorphs, represents the thermodynamic driving force for the transformation and is independent of solvent.10 Because the solubility difference between the polymorphs is very small,2,3 so too is the driving force for the transformation. On the other hand, the kinetic activation energy barrier for nucleation of FIII(6.525) during the transformation, Ea, is dependent on numerous parameters, one being solvent.9 Employing a manipulation of the Arrhenius equation, the nucleation rate can be expressed as
Figure 1. Molecular structure of piracetam.
Structural Database (CSD) under the reference code BISMEV.1 Because of inconsistencies in the literature, the system used for naming polymorphs in this work is outlined by Maher et al.,2,3 so that Form II is termed FII(6.403) below and Form III is termed FIII(6.525). FII(6.403) is the metastable polymorph of piracetam and is known to transform to the stable FIII(6.525) in numerous organic solvents.4−7 Previous studies found nucleation and growth of FIII(6.525) to be the limiting steps of the transformation, over the dissolution of FII(6.403), and that nucleation is likely to take place on the surface of the metastable form.8 Before the growth phase in the transformation, nucleation of stable FIII(6.525) must occur, making it the key step. The nucleation rate (J) equation (eq 1) is governed by three main variables: degree of supersaturation (S), temperature (T), and interfacial energy (γ):6,9 © 2014 American Chemical Society
(1)
⎛E ⎞ ln(J ) = −⎜ a ⎟ + ln(A) ⎝ RT ⎠
(2)
where R is the gas constant. Therefore, a plot of ln(J) versus T−1, under constant supersaturation, should give a straight line with a slope of −Ea/R, giving an estimation of the activation energy in each solvent. Received: April 23, 2014 Revised: July 11, 2014 Published: July 15, 2014 3967
dx.doi.org/10.1021/cg500565u | Cryst. Growth Des. 2014, 14, 3967−3974
Crystal Growth & Design
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Scheme 1. Qualitative Illustration of the Free Energy Diagram for the Solution-Mediated Polymorphic Transformation from FII(6.403) to FIII(6.525) Piracetam
EXPERIMENTAL SECTION
FII(6.403), produced as previously outlined,3 was employed to examine the effect of solvent on the solution-mediated polymorphic transformation to FIII(6.525) in seven solvents on a 25 g scale. Dissolution studies were conducted on a larger scale (130 g), allowing incorporation of an Fourier transform infrared probe to monitor the solution concentration. Computational modeling was employed to gain an understanding of the interactions between the piracetam molecules and respective solvent molecules. Materials. Piracetam was supplied by UCB Pharma SA and complies with European Pharmacopoeia 6.5 quality and purity standards. (CAS Registry Number 7491-74-9, Batch Number 09G06-B93. The certificate of analysis states that the batch complies with infrared, high-performance liquid chromatography, and solution appearance tests. It also complies with a heavy metal limit of
