(379c) Polymorphism of D-Mannitol: Nucleation and Crystal Growth of the Metastable Polymorphs

Polymorphism of D-mannitol: Nucleation and Crystal Growth of the Metastable Polymorphs

Weiyi Su, Chunli Li, Honghai Wang, Jing Fang

School of Chemical Engineering, Hebei University of Technology, Tianjin 300130, PR China

Polymorphism has gained more and more attention in the field of pharmaceuticals[1] due to the discrepant functionality and bioavailability of different polymorphs. D- mannitol is a natural hexahydric alditol which has been widely used as a nephropathy treatment medicine and also an excipient in the formulation of various tablets and granulated powders[3]. It has been reported that there are three anhydrous polymorphs[4-6] and a hemihydrate[7] of mannitol. However the nomenclature of mannitol polymorphs is often diverse in different literatures[8, 9] in despite of similar unit cell parameters. Therefore a review of mannitol polymorphism is initially presented along with the crystal structure parameters. Then the influence of supersaturation on the polymorphic nucleation of mannitol is investigated in aqueous solutions and ethanol-water mixtures in order to prepare pure polymorphs. Moreover, a method reported by Kuldipkumar[10] was extended to determine the crystal growth of metastable δ mannitol, which is found to follow the 2D nucleation-mediated mechanism.

1. Polymorphs of D-mannitol

   It has been confirmed that there are only three pure anhydrous polymorphs of mannitol even though numerous names have been used[6, 8]. Hereby, for clarity and to avoid any confusion, the unite cell parameters of mannitol polymorphs in various literatures are summarized in Table 1. It is clear in Table 1 that the first six β references have a similar structure, which is named β in our work. While focusing on the polymorphs from the 7th to 9th in Table 1, the parameters were nearly the same disregarding what they were called in the original literature. So this form is referred to as α mannitol. Finally, the last three items are significantly distinct from the others, and they are referred to as the δ form of mannitol in this paper.

   Table 1. The review of unit cell parameters and nomenclature of D-mannitol anhydrous polymorphs in literatures

   
   

2. Nucleation of D-mannitol Polymorphs

   The cooling crystallization in water is firstly applied to produce mannitol polymorphs. Specifically the influence of the supersaturation on mannitol polymorphic nucleation is investigated, and the results are displayed in Figure 1 with a comparison to the solubility curves. As illustrated in Figure 1, it is quite interesting to find that the nucleation sequence is α, δ, β as the decrease of concentration while the solubility order is always δ > α > β at the temperature examined in this paper. This phenomenon reveals that the spontaneous nucleation of mannitol polymorphs is not only dependent on the thermodynamic properties but also the kinetic factors.

   
   

   
   

   Figure 1. Polymorphic nucleation results of mannitol (open symbols, labeled as “Nucleation”) at different initial concentrations and temperatures shown in aqueous solution with the solubility curves of the three polymorphs (solid symbols, labeled as “Solubility”).

   To clarify the nucleation zone for different polymorphs, the nucleation parameters (G*, r*, and n*) at various initial concentrations at 10 C are obtained as shown in Table 2 based on the measured induction time and supersaturation data with help of FBRM and Raman Spectroscopy. It is apparent that when the initial concentration is higher than 0.0305, the critical excess free energy forming the δ form nuclei is lower than that of the β form. It indicates that the kinetic properties play a more important role than the thermodynamic properties. While the concentration is lower than 0.0246, the supersaturation is the dominant factor compared with the kinetic factors, that is why β mannitol is easier to nucleate in this region.

   
   

   Table 2. Nucleation properties of two mannitol polymorphs at 10 C, the subscripts δ and β refer to the polymorph δ and β forms respectively while s stands for the supersaturation

   
   

   The values highlighted in italics in Table 2 show lower critical excess free energy values, smaller radius and molecular number of the critical nucleus for either the δ or β form at certain concentrations, leading to the preferential nucleation of this polymorph at those conditions. In this way, controlling to get the desired polymorphs can be fulfilled.

   A reverse anti-solvent crystallization of adding saturated mannitol solution into cold ethanol is also performed for polymorphs preparation of D-mannitol. The nucleation results at -10℃ are shown in Figure 2. It is similar to Figure 1 that high concentration favors the metastable α form and the least stable δ mannitol can only be obtained at relatively low concentration.

   
   

   Figure 2. Polymorphic nucleation results of mannitol (open symbols, labeled as “Nucleation”) at different concentrations in ethanol-water mixture shown with the solubility curves of the three polymorphs (solid symbols, labeled as “Solubility”).

   
   

3. Crystal growth

After nucleation, the nuclei should grow to be crystals with consuming supersaturation. But in bulk aqueous solution, the solvent-mediated polymorphic transformation is quite obvious for mannitol metastable forms, which makes it even more difficult to clarify the growth mechanism. In order to enlarge the acquaintance to the growth of δ mannitol, the induction time are used to provide the growth mechanism following a reported method by Kuldiplumar et al[10]. In this method, a function F(s) is defined for normal, spiral, and volume diffusion-controlled growth mechanisms:

Similarly for 2D nucleation-mediated growth, the function is defined as:

According to equation 1and 2, the calculated F(s) against 1/(ln2s) for the normal, spiral, and volume diffusion-controlled growth mechanism, as well as F(s) against 1/(lns) following the 2D nucleation-mediated growth mechanism are shown in Figure 3.

Figure 3. Plots of F(s) versus 1/ln2s for δ form of mannitol under the normal growth mechanism (a), the spiral growth mechanism (b), the volume diffusion controlled growth mechanism(c), and F(s) versus 1/lns under the 2D nucleation-mediated growth mechanism (d).

It is clear in Figure 3 that the largest R2 of 0.9912 appears when the data are fitted to the 2D nucleation-mediated mechanism. Therefore it is reasonable to believe that the growth mechanism of the metastable δ form of mannitol in aqueous solution should be 2D nucleation-mediated.

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