Raman spectroscopy is a physical characterization technique that is extensively used in the pharmaceutical industry. Raman spectroscopy is specifically used to identify various polymorphic forms.
Additionally, the chemical and physical performance of drugs, packaging materials and excipients depend on the presence and interaction of/with water vapor. Raman spectroscopy, in combination with vapor sorption techniques, provides a detailed understanding of vapor-solid interactions of pharmaceutical materials, as it correlates with the structural properties.
This article explores the in-situ monitoring of a moisture-induced polymorphic transformation using a combined Raman-vapor sorption technique.
Under specific controlled conditions, β D-mannitol was recrystallized to achieve pure a form and δ form of D-mannitol. Mannitol exists in at least three polymorphic forms — alpha, beta and delta, of which beta is considered the most stable form . Humidity converts the less stable delta form to the beta form .
Figure 1. Molecular structure of D-mannitol
Dynamic Gravimetric Vapor Sorption (DVS) Combined with In-Situ Raman Spectroscopy
The real-time transformation from δ D-mannitol to β D-mannitol was monitored by a unique combination of a fiber optic Raman probe with Dynamic gravimetric Vapor Sorption (DVS), as shown in Figure 2.
Earlier, Raman-vapor sorption experiments had been traditionally conducted on other systems , but not for monitoring polymorphic transformations.
Figure 2. Schematic of dynamic vapor sorption (a.) and the DVS stand with Raman adaptor (b.).
Stable β D-mannitol with water at 25 °C
Stable D-mannitol polymorph (Figure 3) did not show any irreversible change upon sorption of moisture. During the sorption and desorption cycle of water vapor, Raman spectra were collected which also proved that the sample remained unchanged.
No irreversible change was shown by the mixture of a form and δ form of D-mannitol upon moisture sorption. Raman spectra that were collected during the water vapor sorption and desorption cycle also confirmed that the sample remained unaffected (Figure 4).
Figure 3. DVS water sorption and desorption cycle (a.) and Raman spectra (b.) for β D-mannitol.
Figure 4. DVS water sorption and desorption cycle (a.) and Raman spectra (b.) for β and a D-mannitol.
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Unstable δ D-mannitol with Water at 95% RH at 25 °C
Under 95% RH (Figure 5), the unstable δ D-mannitol polymorph displayed very slow change over a period of 65 hours, as demonstrated in the DVS sorption data. This is in contrast to a complete conversion of the β polymorph within one day, as previously reported .
Raman spectra collected during this period showed only little conversion in 65 hours.
Figure 5. DVS water sorption at 95% RH (a.) and Raman spectra (b.) taken at 5-hour intervals for δ D-mannitol.
Unstable δ D-mannitol with Ethanol at 95% P/P0 at 45 °C
The unstable δ D-mannitol polymorph, under 95% P/P0 at 45 °C, showed quicker conversion, as demonstrated in the Raman spectra and the DVS data (Figure 6). While a complete conversion is not obtained, the intensity of peaks attributing to the β polymorph increased over a span of 24 hours.
Figure 6. DVS ethanol at 95% P/P0 at 45 °C (a.) and Raman spectra (b.) taken at 2-hour ntervals for δ D-mannitol.
This article has shown how the unique combination of Raman spectroscopy and gravimetric vapor sorption allows the real-time monitoring of the vapor-induced polymorphic transformation of D-mannitol polymorphs.
The combination of these two methods provides a better understanding of vapor-induced structural changes of pharmaceutical ingredients.
The authors gratefully acknowledge past and present colleagues especially Dr. Raimundo Ho (Abbott Laboratories, Chicago, USA) for their contributions to this work.
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