(684e) Polymorphism of D-Mannitol: Selective Nucleation and Crystal Growth Mechanism

Polymorphism
of D-mannitol: Selective Nucleation and Crystal Growth Mechanism

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].
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 these
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. Moreover, a
method reported by Kuldipkumar^[10] was extended to determine the
crystal growth of metastable ¦Ä mannitol, which was 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 ¦Â references have a similar structure, which
is named ¦Â 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 ¦Á
mannitol. Finally, the last three items are significantly distinct from the
others, and they are referred to as the ¦Ä form of mannitol in this
paper.

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

* volume per molecule, and others are volume per
unit cell. 

¡è the author also mentioned the ¦Â form they
obtained was in agreement with Marwick¡¯s result.

2. Selective Nucleation
of D-mannitol Polymorphs

The influence of the
supersaturation on mannitol polymorphic nucleation is investigated in cooling
crystallization, 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 ¦Á, ¦Ä,
¦Â as the decrease of concentration while the solubility order is
always ¦Ä > ¦Á > ¦Â along with
temperature.

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 (DG*, r*,
and n*) at various initial concentrations at 10 ¡ãC are
obtained as shown in Table 2 based on the measured induction time and
supersaturation data. It is apparent
that when the initial concentration is higher than
0.0305, the critical excess free energy forming the ¦Ä form nuclei is
lower than that of the ¦Â 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, that is why ¦Â
mannitol is easier
to nucleate in this region.

Table 2.
Nucleation properties of two mannitol polymorphs at 10 ¡ãC,
the subscripts ¦Ä and ¦Â refer to the
polymorph ¦Ä and ¦Â 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 ¦Ä or
¦Â form at certain concentrations, leading to the selective 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. The nucleation results at
-10¡æ
are shown in Figure 2. It is similar to Figure 1
that high concentration favors the metastable ¦Á form and the least stable ¦Ä
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 by 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 ¦Ä 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:

       
                     (1)

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

 
            (2)

According to
equation 1 and 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 ¦Ä 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 ¦Ä form
of mannitol in
aqueous solution should be 2D nucleation-mediated.

Reference

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Bernstein, Polymorphism in molecular crystals, Oxford University Press, USA,
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Datta, D.J.W. Grant, Nat. Rev. Drug Discov. 3 (2004) 42-57.

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