Analytical Characterization of an Orally-Delivered Peptide Pharmaceutical Product

Abstract

The characterization of orally-delivered peptide pharmaceuticals presents several challenges to analytical methods in comparison to characterization of conventional small-molecule drugs. These challenges include the analysis and characterization of difficult-to-separate impurities, secondary structure, the amorphous solid-state form, and the integrity of enteric-coated drug delivery systems. This work presents the multidisciplinary analytical characterization of a parathyroid hormone (PTH) peptide active pharmaceutical ingredient (API) and an oral formulation of this API within enteric-coated sucrose spheres. The analysis of impurities and degradation products in API and formulated drug product was facilitated by the development of an ultrahigh-performance liquid chromatography (UHPLC) method for analysis by high-resolution mass spectrometry (MS). The use of UHPLC allowed for additional resolution needed to detect impurities and degradation products of interest. The secondary structure was probed using a combination of solution-state NMR, infrared, and circular dichroism spectroscopic methods. Solid-state NMR is used to detect amorphous API in a nondestructive manner directly within the coated sucrose sphere formulation. Fluorescence and Raman microscopy were used in conjunction with Raman mapping to show enteric coating integrity and observe the distribution of API beneath the enteric-coating on the sucrose spheres. The methods are combined in a multidisciplinary approach to characterize the quality of the enteric-coated peptide product.

Hyperspectral Raman Line Mapping as an Effective Tool To Monitor the Coating Thickness of Pharmaceutical Tablets

“…Vibrational spectroscopy has been extensively evaluated as a promising candidate for process analytical technology (PAT), thereby enabling fast and nondestructive quality evaluation in diverse pharmaceutical areas such as the measurement of tablet-coating thickness, − the determination of mixing homogeneity, − and verification of the concentrations of active pharmaceutical ingredients (APIs). − This is because it provides rich chemical and structural information on the constituents of a sample, and measurements with it are easy to expand for online analysis. In most of the applications, spectroscopic information obtained from a sample is directly indicative of target properties such as API concentration and crystallinity, and so, building multivariate or univariate models using the respective spectra to determine these properties is rather straightforward.…”

Chapter 2. Solid‐State NMR in Drug Discovery and Development

“…For example, 2D 1 H-13 C HETCOR and 13 C CP-TOSS experiments have been used to probe secondary structure in an amorphous 3.7 kDa peptide API and also to detect the amorphous drug in a formulation. 210 The measurement of 1 H T 1r relaxation is a sensitive probe of molecular dynamics in the kHz range in amorphous drugs. 211 Differential scanning calorimetry (DSC) and modulated temperature DSC are commonly used to measure the glass transition temperature (T g ) of amorphous drugs, which is used as a predictor of physical stability, because the amorphous glassy solid transitions to a rubbery state above T g that has greater potential for recrystallization or chemical degradation.…”

Confocal UV and Resonance Raman Microscopic Imaging of Pharmaceutical Products

“…This study evaluates the performance of confocal UV Raman microscopy and imaging through four applications to pharmaceutical formulations: (1) imaging of the distribution of an active ingredient in a commercial vitamin tablet at the 0.2% w/w level via a resonance Raman enhancement, (2) imaging of the distribution of a small molecule drug candidate at a similar level as well as a number of excipients in a direct compression tablet formulation, (3) imaging of another small molecule drug candidate at 1% w/w in an amorphous solid dispersion in a polymer, and (4) imaging of a peptide drug candidate within an enteric-coated formulation that has been previously studied using conventional Raman microscopy with a 785 nm laser to avoid fluorescence . The applications to tablets and an amorphous solid dispersion containing a low dose of an active ingredient were chosen to illustrate the applications of confocal UV Raman microscopy to formulations of high-potency actives that are frequently encountered in drug development. − Excipient mapping over a wide range of concentrations is also demonstrated.…”