(705e) Self-Aggregation of Gabapentin Under Confinement of Primary Particle By Smpt

1.  Introduction Solution-mediated phase transformation (SMPT) is one of the most common manufacturing methods used in pharmaceutical industry to control of the microstructure and the properties of the APIs [1-4]. In the traditional SMPT process, the crystal size and shape of stable form are uncontrolled by that of metastable form and is affected by the crystallization dynamics in the whole process. But now we can obtain the well-defined shape and size of stable form particles. The particles have a self-aggregation process under confinement of primary methastable particles during the phase transformation.

Gabapentin (GBP) is known to exist as a zwitterion in three solvent-free forms: II, III and IV, with form II being the most stable and form IV the least stable [5]. In practical production process, preparing of form I is the first step and then recrystallize to obtain form II. Form I can transform to form II through SMPT in organic solvent. The object is research the self- aggregation of GBP under confinement of primary particles. 2. Materials and methods

Form I and form II powder of GBP, with mass purity of 99%, were supplied by Zhejiang Chiral Medicine Chemicals Co., Ltd., China. Methanol, ethanol, propanol, acetone, acetonitrile and ethyl acetate were purchased from Tianjin Kewei Chemical Technology Co., Ltd., China.

The phase transformation was investigated in the form II saturated solution. It can also reduce the impact of dissolving process of form I. Excess amount of form II powder were dissolved in 150 mL of methanol, ethanol, propanol, acetone, acetonitrile and ethyl acetate, respectively. For each experiment, 110 mL saturated solution was filtered and added to 150 mL scale crystallizer, then 4.4 g form I was added to the solution. A Raman spectrometer and Fourier transformed infrared spectroscopy were used to monitor the process.

3. Results

3.1 Morphology characterization of the product

The SEM of the solid products reveals that the crystal habit of form II is diversity in different solvent (Figure 1). The particle obtained from methanol, ethanol or propanol has a good dispersion, and the particles have slightly aggregate in methanol. The form II nucleated by homogeneous primary nucleation from saturated solution. The form II particles grew significantly at the expense of disappearing of form I.

The result in acetone, acetonitrile and ethyl acetate is totally different from that in alcohols. The products are all aggregates and the morphology of the aggregates is plate-like shape, which is same with form I particles. Some breakage is due to the stirring or the sample preparation for test. It is apparently, the morphology and size of the aggregates are startlingly close to that of form I particle. We speculate that the predecessor of one aggregate is one particle of form I (Figure 1).

3.3 Non-directional self-aggregation under confinement of primary particle and the mechanism of the SMPT. Take the case in acetone as an example. The results of intermittent sampling analysis in acetone indicate that there was no obvious dissolution after the form I particles added into the solution (Figure 2). we analyzed the water content of the suspended solid at different time. When the form I particles was suspended in acetone, there is an obvious dehydration process, especially in the first 5 hours. This causes the self-cleaving in the particle and produces many small lamellae (Fig. 3B). The rough surface and defects provide many nucleation sites for stable form. Few hours later, a large number of nucleuses appear on these small lamellae (Fig. 2C). Owing to the very low solubility, the particles do not dissolve and there are almost no molecules of GBP spread into the solution. These nucleuses only can grow along the lamellae, and the molecules of GBP transfer from the lamellae to the nucleuses. Due to the various locations of the nucleuses and the stable form crystals have a variety of growth direction. The whole process advances slowly. After it is completely over, the product is an aggregate composed by a large number of need-like crystals .

The individual crystallites in the aggregate have no specific directional and they can aggregate only in the limited space – the space of the original particle. We call this process is non-directional self-aggregation under confinement of original particle during phase transformation. We have proposed a solvent penetration mediated phase transformation mechanism[6].

 4. Conclusion

The phase transformation of gabapentin from form I to the stable form II in methanol, ethanol, propanol, acetone, acetonitrile and ethyl acetate were studied. Form II nucleation is most likely homogeneous primary nucleation from saturated solution in methanol, ethanol and propanol. Due to the very low solubility of GBP in acetone, acetonitrile and ethyl acetate, there is no dissolution process of metastable form. A self-cleaving phenomenon appears on the original particle because of the extremely low water activity in these organic solvents. The hydrate is not stable and the water molecules need escape from the structure. The dehydration causes many defects on the particle and contributes to heterogeneous nucleation of stable form. The growth of these new nucleuses is confined by the original particles. Non-oriented self-aggregation phenomenon is observed during this phase transformation process. So the concept of non-directional self-aggregation under confinement in desolvation mediated phase transformation is proposed. The products of the stable form are aggregates, but the shape and size of these aggregates coincide exactly with that of the metastable particles. And the morphology of the individual crystallite can be needle-like, plate-like or even bulk shape.