Demand for modified-release products has grown in recent years due to favorable therapeutic qualities resulting from site-specific delivery and controlled release of an active pharmaceutical ingredient (API). A timed-release mechanism ensures stable levels of the drug delivery and lesser dosage frequency than instant-release formulations. Modified-release products include delayed-release products and extended- (controlled) release products. Typical modified-release systems use small beads encapsulating the drug at the core with a polymer coating or sandwiching the drug between an inert core and several polymer layers. In both cases, it is crucial that the bead coating is uniformly applied.
Effexor XR (Pfizer; New York, N.Y.) was the sixth most commonly prescribed antidepressant and the twelfth most prescribed drug overall in the US in 2007.1 Venlafaxine, the active ingredient in Effexor and associated generic brands, is delivered by a controlled-release (CR) mechanism. Consistent coating thickness is very important for consistent drug delivery.
Traditional analytical methods
The validation of the coating process can be achieved by surface analysis of coated bead cross-sections by scanning electron microscopy (SEM) or mass spectroscopy.2 Both of these analytical methods require special sample preparation and may not be sensitive to physico-chemical changes in the sample such as hydration or polymorphism.
In mass spectroscopy, the sample is evaporated and ionized by electron or chemical means, and then the chemical species are identified by mass-to-charge ratio of the molecular fragments. Matrix-assisted laser desorption/ionization source with a time-of-flight mass analyzer (MALDI-TOF) is commonly used in tissue imaging3 and can also be used to analyze bead cross-sections. It should be noted, however, that image spatial resolution for MALDI-TOF is relatively low, about 20 µm. SEM employs secondary or back-scattered electrons to produce nanometer-resolved surface images.4 Because the analysis is carried out in vacuum, a SEM specimen should be dry and conductive in order to achieve high-quality imagery. Nonconductive specimens may acquire a charge when scanned by the electron beam—resulting in image artifacts—therefore, most non-metal samples are coated with an ultra-thin layer of gold. Layer differentiation will depend on the distinct morphology of the layers as the elemental composition of organic compounds is similar.
Wide-Field raman chemical imaging
Raman spectroscopy is a laser-based vibrational spectroscopy technique that provides high specificity for determining the chemical composition and requires little to no sample preparation. Wide-field Raman chemical imaging (RCI) is a hyperspectral imaging method based on Raman spectroscopy. It provides exceptional value for a variety of applications including pharmaceutical research and development. Liquid crystal-based optical tunable filter technology enables the transmission of spatially and spectrally resolved wavelengths of light to a CCD detector. A full or partial Raman spectrum is captured for each pixel in the chemical image that corresponds to a spatial location on a sample. These pixels represent fields of view that can be arranged to form a three-dimensional montage image possessing X (spatial), Y (spatial), and wavelength (spectroscopic) dimensions.
RCI determines the chemical identity of individual components of a heterogeneous sample by combining the objectivity of Raman spectroscopy with the visual perception of digital imaging. Each chemical entity in the field of view can be identified by its distinctive spectral profile and correlated with an associated optical image. Specific Raman spectral planes are used for identification, placement, and sizing purposes. Advanced chemometric techniques may be used to isolate unique Raman signatures and separate multiple ingredients in complex systems.
In this study, RCI coupled with optical microscopy was applied to investigate coating integrity and thickness in commercial controlled-release beads.
Generic controlled-release beads were obtained from an out-of-specification batch rejected by quality assurance. The pure component materials included venlafaxine, ethyl cellulose, and sugar starch. The beads were cross-sectioned to expose the core and inner layers. A small amount of each pure component powder was prepared as bulk material. Raman spectra of the pure component materials were analyzed to construct a Raman spectral signature library for selecting an optimal spectral range for efficient discrimination of each constituent. All data was collected using a FALCON II Wide-Field Raman Chemical Imaging System (ChemImage Corporation) with 532 nm laser excitation. Brightfield reflectance and Raman chemical images were collected at 5x magnification over the fields of view sufficient to image an individual bead. Imaging data was processed and analyzed using the ChemImage Xpert software package.
Raman dispersive spectra of the pure components comprising generic Effexor beads were collected and analyzed for selecting an optimal spectral region for pure component discrimination. The CH spectral region (2700-3200 cm-1) was selected for differentiation of the three main components: venlafaxine, ethyl cellulose, and sugar starch core as illustrated in Figure 1.
A generic venlafaxine bead was cross-sectioned, and Raman chemical images were collected over 2840 – 3150 cm-1 in 5 cm-1 increments. The RCI processing steps included bias correction, cosmic ray removal, and baseline correction followed by vector normalization. For final ingredient discrimination, a spectral unmixing algorithm called spectral mixture resolution (SMR) was applied to the RCI data. SMR evaluates each pixel spectrum using a linear combination of the pure component spectra to achieve an overall spectral contribution. A false-color RCI image was generated from the resulting SMR data images and is presented in Figure 2 by the brightfield optical microscopy image. The RCI-derived ingredient images can be used to objectively measure the thickness of individual coating layers. The sugar core diameter was measured to be 520 ± 30 ?m. The venlafaxine drug layer is uniformly distributed around the core at a thickness of 220 ± 20 ?m. The outer coating of ethyl cellulose was of non-uniform thickness varying from 35 nm to 120 nm, which can contribute to API elution profile.
About the Author
Dr. Klueva was hired as a senior scientist at ChemImage in 2004 and is currently working on developing applications and marketing materials, with emphasis in characterization of nasal sprays. She received her PhD in physical chemistry from Boston University in 2002.
1. “Top 200 brand drugs by units in 2007.” Drug Topics, Feb 18, 2008. https://drugtopics.modernmedicine.com/drugtopics/PharmacyFactsAndFigures/ArticleStandard/article/detail/491210. Visited January 11, 2010.
2. Pickles C. “Manufacturing Problems.” Pharmaceutical Technology Europe, 2008, Nov 1. https://pharmtech.findpharma.com/pharmtech/packaging+and+labelling/Manufacturing-problems/ArticleStandard/Article/detail/566707. Visited on January 11, 2010.
3. McDonnell LA, Heeren RMA. “Imaging mass spectrometry.” Mass Spectrometry Reviews, 2007, 26(4), 606-643.
4. Goldstein G I, et al. (1981). Scanning electron microscopy and x-ray microanalysis. New York: Plenum Press. ISBN 030640768X.
This article was published in Drug Discovery & Development magazine: Vol. 13, No. 2, March 2010, pp. 22-23.
Filed Under: Drug Discovery