Abstract
Techniques enabling in situ monitoring of drug solubilization and changes in the solid-state of the drug during the digestion of milk and milk-based formulations are valuable for predicting the effectiveness of such formulations in improving the oral bioavailability of poorly water-soluble drugs. We have recently reported the use of low-frequency Raman scattering spectroscopy (region of analysis <200 cm–1) as an analytical approach to probe solubilization of drugs during digestion in milk using ferroquine (SSR97193) as the model compound. This study investigates the wider utilization of this technique to probe the solubilization behavior of other poorly water-soluble drugs (halofantrine, lumefantrine, and clofazimine) in not only milk but also infant formula in the absence or presence of bile salts during in vitro digestion. Multivariate analysis was used to interpret changes to the spectra related to the drug as a function of digestion time, through tracking changes in the principal component (PC) values characteristic to the drug signals. Characteristic low-frequency Raman bands for all of the drugs were evident after dispersing the solid drugs in suspension form in milk and infant formula. The drugs were generally solubilized during the digestion of the formulations as observed previously for ferroquine and correlated with behavior determined using small-angle X-ray scattering (SAXS). A greater extent of drug solubilization was also generally observed in the infant formula compared to milk. However, in the case of the drug clofazimine, the correlation between low-frequency Raman scattering and SAXS was not clear, which may arise due to background interference from clofazimine being an intense red dye, which highlights a potential limitation of this new approach. Overall, the in situ monitoring of drug solubilization in milk and milk-based formulations during digestion can be achieved using low-frequency Raman scattering spectroscopy, and the information obtained from studying this spectral region can provide better insights into drug solubilization compared to the mid-frequency Raman region.
Highlights
The dissolution of poorly water-soluble lipophilic drugs in the gastrointestinal (GI) tract is often the limitation of absorption that leads to poor and variable oral bioavailability.[1]
The solubilization of four basic model drugs in milk-based formulations was studied in real-time using lowfrequency Raman spectroscopy, and the behaviors were compared to synchrotron small-angle X-ray scattering (SAXS) and phase separation approaches
The disappearance of the distinct phonon modes in the low-frequency Raman region could be observed for ferroquine and halofantrine during digestion in milk and/or infant formula, and no changes were evident in tris buffer, where no fat was present, clearly linking the changes in the Raman spectrum to drug solubilization
Summary
The dissolution of poorly water-soluble lipophilic drugs in the gastrointestinal (GI) tract is often the limitation of absorption that leads to poor and variable oral bioavailability.[1] Lipid-based vehicles have received great interest as a formulation approach to overcome these challenges by maintaining the drug in a solubilized form during digestion.[2] These lipid-based formulations can range in composition from simple triglycerides to mixtures of glyceryl esters with fatty acids and surfactants or solvents. Full cream milk, having an average fat content of 3.8 w/v %, provides a natural source of triglycerides along with proteins and other micronutrients.[3] Ingestion of milk results in enzymatic lipolysis of triglycerides primarily in the intestinal region of the GI tract to form digestion products (diglycerides, monoglycerides, and fatty acids) that, due to the amphiphilic nature of the molecules, can self-assemble in aqueous solution to form a range of liquid crystalline structures.[4] These structures can potentially provide a favorable environment into which lipophilic drugs can partition, enabling their availability for absorption. Several studies have shown an enhanced oral bioavailability of poorly water-soluble drugs after coadministration with milk,[5,6] and an enhancement in drug solubilization during digestion was observed in in vitro studies.[7−9] The investigation of drug solubilization during digestion is critical to enable optimization of milk
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