(527d) Crystal Growth Kinetics of Stable and Metastable Polymorphs of Piracetam in Organic Solvents

Crystal growth kinetics of stable and metastable polymorphs
of Piracetam in organic solvents

R.
Soto¹, Å. Rasmuson*^1,2,

¹Synthesis
and Solid State Pharmaceutical Centre (SSPC), Bernal Institute, Department of
Chemical and Environmental Science, University of Limerick. Limerick V94 T9PX,
Ireland.

²Department
of Chemical Engineering and Technology, KTH Royal Institute of Technology,
SE-100 44 Stockholm, Sweden

*emails: rodrigo.soto@ul.ie ; ake.rasmuson@ul.ie

The
relevance of crystallization from solution as unit operation in the
pharmaceutical industry is of utmost importance since the performance of
crystallizers determine the required up- and downstream handling and processing operations.
Polymorphism, is the ability of a substance to exist in more than one solid
form and it is crucial due to its influence on the final drugs physicochemical
properties, e.g. dissolution rates, bioavailability and morphology. Besides,
the solvent used in the crystallization process also influences the solid form
obtained and its physicochemical and morphological properties. In this sense,
research on the nucleation and growth of active pharmaceutical ingredients is
essential due to its immediate industrial application and its direct impact on
society.

Piracetam (PCM) is a polymorphic
compound used as a nootropic agent for the enhancement of
memory in human beings. Its effectiveness in the treatment of ischemia,
cognitive impairment, stroke, and dementia without causing sedation or
stimulation is recognized widely. Up to date, five different polymorphs of PCM have
been reported being only two of them stable at room temperature in it solid
forms II (mestastable) and III (stable) [1]. The solubility of FII and FIII of
PCM has been studied in a range of organic solvents as well as their solution
mediated polymorphic transformations [2,3]. However, to the best to our knowledge
there is a lack of information on the kinetics of the crystal growth of the
different PCM polymorphs. The aim of the present work is to study the crystal
growth of FII and FII polymorphs of PCM in organic solvents. The modeling of
the experimental data to empirical equations and mechanistic ones based on the Burton-Cabrera-Frank
(BCF) and Birth and Spread (B+S) theories also constitutes an important goal.

Isothermal
seeded desupersaturation experiments were carried out in a 250 mL jacketed
batch glass crystallizer equipped with an accurate control of temperature. The
liquid concentration and the number of counts during the runs were monitored in-situ
by IR and FBRM probes (both from Mettler Toledo), respectively. The solvents
studied were ethanol (EtOH) and isopropanol (IPrOH). The range of temperature
explored 283-308 K and the initial supersaturation ratio was always below 1.2. The
seeds were prepared by cooling crystallization, the correct polymorphic forms were
characterized by PXRD and SEM and eventually, they were sieved to a particle
size 100-180 µm.  The harvested crystals
after growth experiments were analyzed by PXRD to ensure that growth was undertaken
by the desired polymorph. Principal component analysis was used to treat the
raw IR spectra from the experiments and to establish their relation with the liquid
concentration at any instant within the crystallizer.

Experimental
desupersaturation data or driving force obtained was fitted to power law
empirical equations by solving the differential equation derived from the crystal
growth rate definition.  Thereby,
calculated driving forces were computed and the involved kinetic parameters
were estimated by non-linear regression using a specially designed Matlab
script. An example of the fitting results is given and of the derived crystal
growth rates is given in Figure 1. Using an analogous methodology, experimental
desupersaturation evolutions were fitted to classical BCF and B+S theories. The
goodness of the fitting was remarkably good for both, empirical and
mechanistic-based growth models.

Figure 1. (a) Fitting of power-law
equation to the experimental desupersaturation data in terms of (S-1) for form
II of piracetam in EtOH at different temperatures. (b) Comparison of crystal
growth rates calculated from the experimental driving forces and those
predicted by the fitting power law equation for form II of piracetam in EtOH at
different temperatures.

The estimated
activation energies for the main four systems studied, polymorphs FII and FIII
in EtOH and IPrOH, were in the range 55-71 kJ/mol, indicating that the growth
process was controlled by the surface integration rather than by diffusion in
all cases. The growth rates in terms of m/s were found to be dependent on the
polymorph and the solvent studied and to increase in the order: IPrOH-FIII <
IPrOH-FII < EtOH-FIII < EtOH-FII. Therefore, the metastable polymorph
growth faster in both EtOH and IPrOH and the growth is also faster in EtOH than
in IPrOH. The solid liquid interfacial energies estimated from B+S model ranged
1.75­­­–2.11 mJ/m², indicating that there is smooth difference
within the polymorphs in the solvents studied.

[1] A. Maher, C. C. Seaton, S. Hudson, D. M. Croker, Å. C.
Rasmuson, and B. K. Hodnett, “Investigation of the solid-state polymorphic
transformations of piracetam,” Cryst. Growth Des., vol. 12, no. 12, pp.
6223–6233, 2012.

[2] A. Maher, Å. C.
Rasmuson, D. M. Croker, and B. K. Hodnett, “Solubility of the metastable
polymorph of piracetam (Form II) in a range of solvents,” J. Chem. Eng. Data,
vol. 57, no. 12, pp. 3525–3531, 2012.

[3] A. Maher, D. M.
Croker, Å. C. Rasmuson, and B. K. Hodnett, “Solution mediated polymorphic
transformation: Form II to lIII piracetam in ethanol,” Cryst. Growth Des.,
vol. 12, no. 12, pp. 6151–6157, 2012.