Abstract
We have recently shown that real-time monitoring of drug solubilization and changes to solid state of the drug during digestion of milk can be achieved using synchrotron small-angle X-ray scattering. A complementary laboratory-based method to explore such changes is low-frequency Raman spectroscopy, which has been increasingly used to characterize crystalline drugs and their polymorphs in powders and suspensions. This study investigates the use of this technique to monitor in situ drug solubilization in milk during the process of digestion, using a lipolysis model/flow-through configuration identical to that used previously for in situ synchrotron small-angle X-ray scattering studies. An antimalarial drug, ferroquine (SSR97193), was used as the model drug for this study. The Raman spectra were processed using multivariate analysis to extract the drug signals from the milk digestion background. The results showed disappearance of the ferroquine peaks in the low-frequency Raman region (<200 cm–1) after approximately 15–20 min of digestion when milk fat was present in the system, which indicated drug solubilization and was in good agreement with the in situ small-angle X-ray scattering measurements. This proof-of-concept study therefore suggests that low-frequency Raman spectroscopy can be used to monitor drug solubilization in a complex digesting milk medium because of the unique vibrational modes of the drug crystal lattices.
Highlights
Letter necessary sensitivity and time resolution to conduct such studies and is not amenable to routine use in formulation development and screening
Ferroquine was dispersed in milk or buffer as a suspension (186 mg granules in 2.75 mL of water and 17.5 mL of milk, which is approximately equivalent to a clinical dose in a glass of milk).[14]
The fat content of the full-cream milk used for the Raman studies was slightly lower than that for the equivalent X-ray scattering studies (3.3% vs 3.8%, due to differences in the fat content of commercially available milk in New Zealand and Australia, respectively), the results obtained from the analysis of the low-frequency Raman spectra were in good agreement with the small-angle X-ray scattering (SAXS) data where diffraction peaks associated with crystalline ferroquine disappeared after about 15−20 min of digestion (Figure 3d)
Summary
Necessary sensitivity and time resolution to conduct such studies and is not amenable to routine use in formulation development and screening. The fat content of the full-cream milk used for the Raman studies was slightly lower than that for the equivalent X-ray scattering studies (3.3% vs 3.8%, due to differences in the fat content of commercially available milk in New Zealand and Australia, respectively), the results obtained from the analysis of the low-frequency Raman spectra were in good agreement with the SAXS data where diffraction peaks associated with crystalline ferroquine disappeared after about 15−20 min of digestion (Figure 3d) This signifies that 0.58 g of milk fat (17.5 mL of 3.3% milk fat) is sufficient to provide complete solubilization of 93 mg of ferroquine API (equivalent to 186 mg of ferroquine granules), as verified by the SAXS measurements. It is worth noting that the PC1 values in the tris/ferroquine sample stayed relatively constant throughout the digestion, a slight decrease in the PC1 value was observed after lipase injection, which could arise because of the slight dilution of the ferroquine as lipase suspension contributed ∼10% of the total digestion volume
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