With the advent of the Food and Drug Administration initiatives to investigate and encourage the use of process analytical technologies, laser-induced breakdown spectroscopy (LIBS) is considered an excellent analytical tool to understand the processability of solid dosage form. In this article, the feasibility of the LIBS system for quantitation of active drug within a solid dosage form, as well as the effects of various physical parameters on its signal, is investigated. A model drug containing chlorine and sulfur was used. The examination of the specificity and reproducibility of the measurements led to the use of chlorine and carbon as the internal standard. An overall relative SD of 1.1% for the signal was found. For quantitation purposes, calibration curves using compound-X in formulated tablets were generated. It was found that curves generated from roller-compaction tablets generally gave higher LIBS signal than those generated using direct-compressed (DC) process. To investigate these differences, effect of LIBS signals from several physical properties of the tablets were examined. It was found that unmilled compound-X used in the manufacture of the tablets gave a LIBS signal 30% lower than when milled compound-X was used. However, by using multiple crushing-recompression DC process of the milled compound-X, the LIBS results were comparable with those found from both processed tablets using milled compound-X. Other physical parameters, such as wide ranges of granule size and tablet hardness found in the typical manufacturing process, had limited effect on the LIBS signal. From these results, it was noted that for accurate quantitation, it is necessary to use the same physical properties of compound-X and the same manufacturing process in the calibration standards as the actual samples.