Title: Polymorphic transformation monitoring and the influence of operating parameters Principal Focus: Raman Spectroscopy was applied to identify different polymorphs of D-mannitol, and the difference

of the spectra was distinct with the obvious characteristic peaks of each form [1]. To in-situ monitor the polymorphic

transformation of D-mannitol, Raman Spectroscopy, FBRM and PVM were used to track the transformation process

from the metastable α form to the stable β form. The effect of different parameters, such as temperature, solvent and

seed mass on transformation time were investigated in order to get a clear profile of the transformation mechanism.

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Figure 1: FBRM data and Raman intensity change during the polymorphic transformation.

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Figure 2: Effect of temperature and solvent composition on transformation time

Discussion: Experiments conducted with FBRM, PVM and Raman spectroscopy have shown how these in situ

techniques can track changes in particle dimension, morphology, and crystal structure. From Figure 1, the dissolution

of metastable form and crystallization of stable form are obvious, which are the two main steps so solution-mediated

transformation mechanism. And the transformation time reflected by FBRM and Raman is consistent. The operating

temperature and solvent composition had a dramatic impact on the transformation time of the polymorphs according to

Figure 2. In addition, the seed mass of α mannitol also has effect on the transformation time.

Future Work: As polymorphs may have different functionalities and physical properties, such as bioavailability,

solubility and stability [2]

, it is essential to investigate the appropriate conditions for each polymorph and the probability

of transition between them. In order to investigate the transformation kinetics from α to β form of mannitol

quantitatively, a useful model will be established for the dissolution and crystallization process. Some necessary

parameters, such as the solubility of the metastable form of mannitol, as well as the rate of nucleation and growth of the

stable form of mannitol should be obtained first for the modelling work.

[1] Geoff G.Z.Z.; Devalina L.; Eric A. S. Phase transformation considerations during process development and

manufacture of solid oral dosage forms, Advanced Drug Delivery Review, 2004, 56: p.371-390

Project 7: Crystal Transformations and

Crystallisation Methodologies Date: 21/08/10

Author: Weiyi Su

Strand: Particle Engineering

Institute: University College Dublin

Transformation Experimental:

1. Prepare a saturated solution with respect

to β mannitol in a 100 mL Mettler-Toledo

EasyMax system.

2. Put 4 g α mannitol which is obtained in

the lab to the solution to initiate the

transformation.

3. Start the in-situ tools (Raman

Spectroscopy, FBRM and PVM) to

monitor the changes of characteristic peak

height, crystal size and morphology.

Note: The characteristic peak of α

mannitol was chosen at 1355 cm-1, while

the peak 1365 cm-1 was used to denote β

form.

Parameters Influence Experimental:

1. Get saturated solution of β mannitol in

different conditions. (While changing

solvents, temperature maintains at 27 °C.

All the experiments proceed in water

when research the influence from

temperature.)

2. Add 4 g α mannitol seeds to the saturated

solution, and introduce the in-situ Raman

Spectroscopy to measure the

transformation time.

Note: The transformation time is defined as

the difference between seeding and ending

point.