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Oral solid dosage forms that contain APIs in the amorphous state have become commonplace because of many drug substances exhibiting poor water solubility, which negatively impacts their absorption in the human GI tract. While micronization, solvent spray-drying, and hot-melt extrusion can address solubility issues, spray coating of the APIs onto beads and tablets offers another option for producing amorphous drug products. High-level comparisons between bead and tablet coating technologies have the potential for simpler equipment and operation that can reduce the cost of development and manufacturing. However, spray coating directly onto tablets is not without challenges, especially with respect to meeting uniformity acceptance value ( AV ) criteria, comprising accuracy (mean) and precision (variance) objectives. The feasibility of meeting AV criteria is examined, based on mathematical models for accuracy and precision. The results indicate that the main difficulty in manufacturing satisfactory drug-layered tablets by spray coating is caused by the practical limitations of achieving the necessary coating precision. Despite this limitation, it is shown that AV criteria can be consistently met by appropriate materials monitoring and control as well as processing equipment setup, operation, and maintenance.

Raman spectroscopy has proven valuable for determining the composition of manufactured drug products, as well as identifying counterfeit drugs. Here we present a simple method to determine the active pharmaceutical ingredient (API) mass percent in a sample that does not require knowledge of the identities or relative mass percents of the inactive pharmaceutical ingredients (excipients). And further, we demonstrated the ability of the method to pass or fail a manufactured drug product batch based on a calculated acceptance value in accordance with the US Pharmacopeia method for content uniformity. The method was developed by fitting the Raman spectra of 30 Claritin ® tablets with weighted percentages of the Raman spectrum of its API, loratadine, and a composite spectrum of the known excipients. The mean loratadine mass of 9.79 ± 40 mg per 100 mg tablet compared favorably to the 10.21 ± 0.63 mg per 100 mg tablet determined using high-performance liquid chromatography, both of which met the acceptance value to pass the 10 mg API product as labelled. The method was then applied to a generic version of the Claritin product that employed different excipients of unknown mass percents. A Raman spectrum representative of all excipients was created by subtracting the API Raman spectrum from the product spectrum. The Raman spectra of the 30 generic tablets were then fit with weighted percents of the pure loratadine spectrum and the created excipient spectrum, and used to determine a mean API mass for the tablets of 10.12 ± 40 mg, again meeting the acceptance value for the 10 mg API product. The data suggest that this simple method could be used to pass or fail manufactured drug product batches in accordance with the US Pharmacopeia method for content uniformity, without knowledge of the excipients.

Novel mathematical models were developed to predict inter-tablet coating uniformity in terms of coefficients of variation (CV) and acceptance values (AV) for cylindrical tablet pan coaters, operating in batch and continuous modes. The models, based on binomial coating spray and tablet movement distribution functions and on bed geometry, yielded equations and results that are in good agreement with previously reported experimental data, most empirical expressions, and more computationally intensive models. The new model equations are readily useable for process analysis, optimization, scale-up, and manufacturing design and control.

A novel sampler device for flowing powders was tested to quantify drug concentrations as low as 0.76% w/w in pharmaceutical powder blends. The sampler device was developed based on the powder flow behavior within a tablet press feed frame, following the principles laid down in the Theory of Sampling. Two Near-Infrared (NIR) spectroscopic calibration models were developed with powder blends that varied from 0.52 to 2.52% w/w and 1.51-4.52% w/w. The calibration models were able to determine caffeine concentration in test set blends with root mean square error of predictions and bias below 0.1% w/w. Samples were collected from the sampler device and analyzed by ultraviolet-visible (UV-Vis) to determine the caffeine concentration. A high agreement between the in-line NIR predictions and the sampled UV-Vis results was found. The paddle wheel speed in the sampler can be varied up to ±10% without affecting NIR predictions; however, the models did not respond adequately to a 25% increase in this speed. Variographic analysis showed that the sampler device may quantify low drug concentrations with nugget effects below 0.0050 (%w/w) 2 . This study demonstrate that the sampler device may handle throughputs up to 45 kg/h, without significantly affecting the physical properties of powder blends., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)