Pharmaceutical Film Coating Catalog for Spectral Domain Optical Coherence Tomography

Optical coherence tomography (OCT) has recently been demonstrated to measure the ﬁ lm coating thickness of pharmaceutical tablets and pellets directly. The results enable the analysis of inter- and intra-tablet coating variability at an off-line and in-line setting. To date, only a few coating formulations have been tried and there is very little information on the applicability of OCT to other coatings. As it is well documented that optical methods including OCT are prone to scattering leading to limited pene- tration, some pharmaceutical coatings may not be measurable altogether. This study presents OCT measurements of 22 different common coatings for the assessment of OCT applicability. © 2017 The Authors. Published by Elsevier Inc. on behalf of the American Pharmacists Association ® . This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).


Introduction
Film coatings serve the very purpose of achieving color uniformity, light protection, and taste masking. Coatings are additionally used to modify the drug release or to incorporate an active pharmaceutical ingredient in the formulation. Coating quality can be studied either by numerical modeling 1 or by the aid of process analyzers. Various process analytical technology approaches have been demonstrated for characterizing pharmaceutical coating, which include near-infrared and Raman spectroscopy, 2-4 nuclear magnetic resonance imaging, 5 terahertz pulsed imaging (TPI), [6][7][8] and optical coherence tomography (OCT). [9][10][11][12][13][14][15] Among these methods, TPI and OCT are attractive because they offer a direct, calibration-free coating thickness measurement, where the only unknown is the coating refractive index that can be obtained as a one-off measurement with terahertz time-domain spectroscopy and spectroscopic ellipsometry, respectively. Comparing the two, TPI has limited resolution (i.e., a lateral spatial of 200 mm and axial [depth] resolution of 2 mm for coating thickness greater than 30-40 mm) and requires relatively long measurement times (in the range of 8 ms). OCT, in contrast, can achieve sub-mm resolutions for coating thickness greater than 10 mm and exploits an ms acquisition time leading to information on both inter-tablet and intra-tablet coating variation. Specifically, OCT has been demonstrated in an off-line 9-11 and in-line setting for characterizing pellets 12,13 and tablets. 14,15 However, OCT has limited penetration depth than TPI, and in some cases fails to image through coatings altogether. This limitation originates from a similar refractive index between the tablet core and coating leading to weaker reflections, and/or pronounced scattering encountered as the optical beam penetrates into the sample, resulting in substantial signal attenuation. These effects ultimately limit the resolvable coating thickness. There is currently very little information available in the literature on what coating materials can or cannot be imaged using OCT technology. This study therefore aims to examine the transparency of a range of coating formulations for OCT measurement at 840 nm.

Tablet Production
The samples used in the present work comprise 22 randomly selected tablets from 22 different batches where a different coating formulation was used for each of the batches. The coating product name, the corresponding alias, and photographs of the tablets are shown in Table 1. Coating materials were applied to bi-convex-shaped tablet cores that contained 50% lactose monohydrate and 50% microcrystalline cellulose. Film coating was performed with a 15 00 fully perforated Labcoat IIX (O'Hara Technologies Inc., Richmond Hill, ON) equipped with one spray nozzle (Model 970; Düsen-Schlick GmbH, Untersiemau, Germany). The coating pan has a diameter of 380 mm and a full volume of 4.5 L enabling a batch size of 500 g. Average thickness, diameter, and weight of the tablet cores (n ¼ 6) were 4.079 ± 0.018 mm, 10.069 ± 0.005 mm, and 321 ± 3 mg, respectively. For measurement comparisons, one side of the tablets was marked by a scratch mark to serve as a datum. Film coating thickness was estimated by measuring the physical dimensions of coated tablets with a micrometer gauge and subtracting it away from the average core thickness, assuming no dimensional changes to the cores in the coating process.

Spectral Domain Optical Coherence Tomographic Measurements
An in-house fiber-based spectral domain OCT system 16 was developed for B-scan measurements of the coated tablets. As shown in Figure 1, a superluminescent diode (EXALOS AG, Schlieren, Switzerland) centered at a wavelength of 840 nm with a full width at half maximum bandwidth of 55 nm was used as the light source. The light source provided a theoretical axial resolution of 5.7 mm in air. The collimated light beam was first coupled into the input port of a 2 Â 2 wideband single mode fiber coupler using a collimator. The light beam was subsequently split (50:50) into a reference and a probe beam. The reference beam was collimated by an adjustable collimator (CFC-2X-B; Thorlabs Inc., Newton, NJ) and reflected by a reference mirror. The probe beam was focused onto the tablet surface by another identical adjustable collimator. The focal length was 7 mm, which lead to a lateral resolution of 20 mm and a depth of field of 734 mm. The backscattered probe beam interfered with the reflected reference beam at the output port of the fiber coupler. The interferogram was collected by a high resolution spectrometer (Wasatch Photonics Inc., Logan, UT) consisting of 2048 pixels linear array CCD camera. In order to obtain a B-scan (cross-sectional image) across the tablet surface, a translation stage was used to move the tablet sample at a velocity of 1 mm/s by a motorized stage. The spectrometer was set to acquire a spectrum every 6 ms with an exposure time of 90 ms. In total, 1000 A-scans, which covered a length of 6 mm with an equivalent step size of 6 mm, were acquired for each tablet to generate a B-scan. The measured optical spot size on the tablet surface was approximately 20 mm. Measurements were performed perpendicular to the overall tablet surface plane at the tablet center as opposed to being perpendicular to the tablets' curved surface. 6,7 As such, only the coating thickness at the tablet central region can be accurately measured unless the tablet curvature is accounted for. 17 The coating thickness is proportional to the separation between adjacent reflection peaks in an A-scan and is determined using d ¼ Dtc/(2n), where d is the coating thickness, c the speed of light, Dt the peak separation, and n the coating refractive index.
The data acquisition time was 4 h and the image reconstruction took 0.5 h size for 433 slices of 1116 Â 1116 pixels. Figure 2 shows the acquired B-scans of the 22 coated tablets. Evidently, the coating-core interface for coatings 1, 2, 7, 8, 13, and 18 can be visibly observed. The level of contrast between the aircoating and coating-core interface in coatings 1, 4, and 13 may be enhanced with signal denoising. 16 It should be noted that in order to quantify the absolute coating thickness, a clear observation of the coating-core interface and knowledge of the coating refractive index is required. 16,17 As refractive index remains unknown in this study, coating thickness is not determined but instead, estimated using a micrometer gauge. As a quick check, we measured coating 9 using XmCT, sub-volume shown in Supplementary Figure S1, that yielded a thickness of 51.0 ± 6.2 mm(n ¼ 10) in agreement with the estimated thickness of 59 ± 10 mm. No thickness information could be derived with OCT in this instance due to an absence of the coating-core interface. Closer inspection of Supplementary Figure S1 also shows that some of the coating has fused into the tablet core, 18,19 which would have caused a gradual refractive index change leading to low contrast in OCT measurement. To better isolate the causes behind OCT opaqueness at 840 nm, the coating compositions for the respective coatings are listed in Table 2.I n coating compositions without pigments or colorants, generally the coating-core interface in B-scans is visible. Coatings 1 and 3, however, are notable exceptions because of the additional lactose and polydextrose, which may have increased scattering and reduced the refractive index contrast between the core and coating as the core also contained 50% lactose monohydrate. This would then reduce the reflected signal intensity from the coating-core interface, resulting in no clear observation of the coating-core interface on the B-scan. Assuming negligible optical absorption in the polymer binder, 20 for compositions containing pigments, in particular, titanium dioxide, the coating-core interface is not visible at all. This is due to the pigment particle size and a relatively high value of the effective refractive index that in turn increases reflection at the air-coating interface, meaning that only a fraction of incidence beam can actually penetrate into the coating. 20 As the remaining beam travels into the coating, more scattering is encountered leading to a further signal reduction for measurement. The scattering effect for yellow iron oxide compared to titanium dioxide is generally weaker at near-infrared wavelengths. 21 Despite this, coating 9 is still opaque to OCT because of the gradual refractive index change encountered because the coating dispersion has diffused into the core material. 18,19 On the contrary, 3% weight gain red coating (coating 18) is transparent to OCT largely due to a comparatively larger difference between the coating and core refractive index in spite of the increased air-coating reflection from the similar colored coating to the incident beam. 22 For another red coating (coating 20), the coating-core interface is not visible Figure 1. Schematic of an in-house spectral domain OCT system with a tablet placed in the perforated coating pan. C1 and C2, adjustable collimators; L1, L2, and L3, lens; BS, beam-splitter; SLD, superluminescent diode. due to the titanium dioxide used in a comparatively thicker coating (10% weight gain). Finally, it is interesting to note that where the coating contains only talc and dye in the colorant as in the case of coating 13, the coating-core interface is marginally visible in the OCT measurements.

Conclusion
With the emergence of OCT for the non-destructive evaluation of pharmaceutical coatings, it is important to know the limitations of the technique. We have presented OCT measurements for a range of pigments and formulations based on a popular immediate release coating platform used in the pharmaceutical industry today. Our findings show that coating transparency for OCT measurement ultimately depends on the pigment type, coating formulation, and the tablet core as well as the coating process itself. Our findings further show that where the coating material contains titanium dioxide, either alone or together with other pigments, OCT measurement becomes adversely affected by scattering resulting in a blurred coating-core interface that makes coating thickness quantification impossible. For coatings without titanium dioxide, coating transparency is not always guaranteed. In order to precisely explain our measurements, mechanistic modeling could be applied. We therefore envision that OCT might be best suited for process  The weight and tablet thickness were measured of 6 tablets per batch. The coating thickness and weight gain were calculated from the average weight and tablet thickness measurements of each batch and the tablet core. The standard deviation was calculated by applying the error propagation law. HPMC, hydroxypropyl methylcellulose; PEG, polyethylene glycol; PVA, poly(vinyl alcohol); CMC, carboxymethyl cellulose; SLS, sodium lauryl sulfate; HPC, hydroxypropyl cellulose.