*3.1. Drug Excipient Compatibility Studies (ATR–FTIR Analysis)*

The methotrexate spectrum was compared with the spectrum of EC and HPMC polymers formulations at different concentrations.

The methotrexate ATR–FTIR spectrum shows its characteristic absorption band as a broad signal at 3450 cm−<sup>1</sup> (O–H being stretched from the carboxyl group overlaying with O–H being stretched from crystallized water). At 3080 cm−<sup>1</sup> (primary amine, N–H stretched), 1670–1600 cm−<sup>1</sup> is allocated to C=O stretching (–C=O stretched from the carboxylic group and C=O stretched from the amidic group (Figure 1). Hence, the C=O band is split into a double in the methotrexate sample). The corresponding N-H band from the amidic group appears in the spectral range of 1550–1500 cm−1. It is partly overlapped with the aromatic C=C stretching. The carboxylic group band appears in the range of 1400–1200 cm−1, corresponding to –C–O stretching. The molecular structure of the entire formulated patch of methotrexate indicates that it is in good agreement, which confirms its purity. The ATR–FTIR spectra of the physical mixture of methotrexate and polymers show major peaks. The FTIR spectrum of methotrexate with EC and HPMC polymers at different concentrations was compared with the methotrexate spectra. The major peaks of methotrexate and polymers were found preserved.
