(T1530-06-34) Seeing is Believing: A Microscopic “Google Earth” View of Extended-Release Claritin Formulation

Purpose: An estimated 10–30% of the global population is affected by allergic rhinitis associated with histamine release triggered by immune response to allergens with hallmark symptoms of sinus congestion, runny nose, watery/itchy eyes, etc..¹ A combination of antihistamine and nasal decongestant active pharmaceutical ingredients (APIs) has proven effective in temporarily relieving these symptoms but often requires several doses throughout a 24-hour period to maintain efficacy. Claritin D formulations are modified-release oral solid dosage compositions comprising loratadine (antihistamine) and pseudoephedrine (nasal decongestant) and employs a hydrophilic polymer matrix technology to provide extended relief from these symptoms for 12-24 hours. Modified-release drug delivery systems allow for control of the rate and site of drug release and present several clear advantages over conventional dosage forms including improved efficacy, performance, and patient compliance. Given their nature as complex multi-particulate mixtures of drug and excipients, modified release systems demand an unprecedented understanding of the microstructure and ingredient distribution fundamental to critical quality attributes that determine product performance and quality. Several imaging and spectroscopy techniques may be utilized to interrogate the microstructure of modified-release formulations. One novel imaging technique that may be employed for this purpose is mosaic field of view scanning electron microscopy (MFV-SEM). MFV-SEM allows for ultra-high-resolution imaging of large representative two-dimensional surfaces. MFV-SEM also affords the opportunity for Energy Dispersive Spectroscopy (EDS) chemical characterization for correlative phase confirmation. Employing innovative microstructure imaging and spectroscopy techniques, this study reveals the complex microstructure and spatial arrangement of ingredients in modified-release Claritin D formulations and provides insights into how those features are related to performance properties.

Methods: Over-the-counter Claritin D12 tablets (Bayer AG, Germany) were purchased and analyzed. Optical images were collected of the intact tablet before the tablet was mechanically sectioned with a diamond knife revealing a flat cross-section. An approximately 7mm x 2mm region near the center of the cross-section was imaged via MFV-SEM at 100 nm resolution. In order to remove surface debris and further polish the surface, argon beam flat milling was employed and an optical image of the milled cross-section was collected. A second MFV-SEM image of half of the milled cross-section (approximately 7mm x 5mm) was collected at 100 nm resolution. Two regions of interest (ROI) were selected for EDS elemental mapping to quantify ingredient distribution. The first ROI focused on the innermost core and a portion of the intermediate layer. The second ROI focused on the outer coating and a portion of the intermediate layer. Composite and individual elemental maps were generated for both ROIs and evaluated utilizing the elemental composition of the known tablet ingredients.

Results: The mosaic SEM images allows for the construction of a “Google Earth” view, with a hierarchical image data structure, supporting macroscale to nanoscale observation of the cross-section prior to argon milling. After manual sectioning the tablet cross-section was observed to have distinct layers with a bright white inner core, off white intermediate layer, and a thin opaque white outer coating. After Argon beam flat milling, these distinct tablet layers became fully evident after MFV-SEM where grayscale contrast distinguished three layers with decided interfaces and distinct domains within each layer. Fractures and porosity represented by the darkest grayscale intensity are clearly elucidated. Elemental mapping proved to be invaluable in revealing the location of the APIs in this tablet. Based on EDS chlorine mapping, it was made clear loratadine was completely dispersed within the tablet coating. Sulfur mapping further revealed pseudoephedrine sulfate was distributed throughout both the inner core as well as the outer coating.

Conclusion: Pharmaceutical development intrinsically relies on microstructures of various components and processing stages of the drug products or intermediates to achieve specific therapeutic goals. Researchers are relying increasingly on high sensitivity tools to inform critical product development decisions. While nanoscale resolution can be realized with other imaging techniques/modalities much of their utility is forfeited in the absence of the broader macroscopic information the sample can provide. Using Claritin 12-hour formulation as an example, MFV-SEM has been shown here to be a novel approach in investigating the complex microstructure and spatial arrangement of oral solid dosage forms. From macroscale observation of coating layers to highly magnified nanoscale observation of individual ingredients, MVF-SEM has been demonstrated as a critical imaging technique to inform formulation decisions. EDS elemental maps acquired directly from the tablet cross-section also provided direst spatial information invaluable in determining the size and location of both APIs. This technique can be broadly applied to formulation development, quality control and assurance, microstructure bioequivalence, forensic analysis, reverse engineering, stability assessment, and regulatory support. More data, analysis, and comparison with other Claritin formulations are work in progress.

References: 1. Schmidt CW. Pollen Overload: Seasonal Allergies in a Changing Climate. Environ Health Perspect. 2016;124(4):A70-A75. doi:10.1289/ehp.124-A70

Acknowledgements:

Funding: This study was internally funded by DigiM Solution LLC.
Disclosures: The author declares that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Fig. 1: MFV-SEM workflow. (a) optical image of intact tablet highlighting how tablet was sectioned and polished. (b1) optical image of polished tablet cross-section highlighting field of view of initial MFV-SEM imaging. (b2) optical image of argon beam flat milled tablet cross-section highlighting field of view of final MFV-SEM imaging. (c1) full field of view of MFV-SEM of cross-section prior to flat milling (scale bar = 500 µm) with a magnified view of the region highlighted by the blue box (scale bar = 500 µm). (c2) full field of view of MFV-SEM image of flat milled cross-section (scale bar = 1 mm) with a magnified view of the same region of the cross-section magnified in c1 (pre-milling) highlighted by the gold box (scale bar = 50 µm).


Fig. 2: EDS elemental mapping/chemical characterization. (a) full field of view MFV-SEM of polished argon beam flat milled tablet cross-section with tablet layers denoted (scale bar = 1 mm). (b) table of listed ingredients and corresponding elemental composition of each ingredient with elements unique to an ingredient in red text. (c) sulfur map revealing Pseudoephedrine Sulfate API in the inner core. (d), chlorine map revealing Loratadine API inside the coating. (e) sulfur map revealing Pseudoephedrine Sulfate API in the coating.