SUPPLEMENTARY MATERIAL S3: Quality by design empowered development and optimisation of time-controlled pulsatile release platform formulation employing compression coating technology
Riddhish Patadia, ChintanVora, Karan Mittal, and RajashreeMashru#
Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Vadodara 390001, Gujarat, India
#Correspondingauthor: Dr. RajashreeMashru ()
Evaluation of nifedipineamorphous solid dispersion (ASD)
The results of DSC, PXRD, and FTIR analyses fordeveloped nifedipine ASD are displayed in Figure S18.
Figure S18DSC [x], PXRD [y] and FTIR [z] analyses of nifedipine (A), copovidone (B), nifedipine-copovidone physical mixture (C) and nifedipine-copovidone ASD (D).
As shown in Figure S18 [x], DSC thermogram of pure nifedipinedemonstrated crystalline nature of drug substance with sharp melting endotherm at about 172°C which was slightly broadened in nifedipine-copovidone physical mixture but completely absent in nifedipine ASD. Hence, it was anticipated that crystalline nifedipine would have converted into the amorphous form and molecularly dispersed inside the copovidone matrix. To confirm the same, PXRD study was further carried out.
The results of PXRD study is demonstrated in Figure S18 [y]. The PXRD spectra of pure nifedipineclearly demonstrated crystalline nature with presence of characteristic 2θ peaks1 which were also evident in nifedipine-copovidone physical mixture but not in nifedipine ASD. Hence, it was confirmed that the developedsolid dispersion did not contain crystalline portion and the drug was molecularly dispersed throughout the copovidone matrix. Next, FTIR study was performed to check bonding interaction between drug and carrier.
The overlaid FTIR spectra of nifedipine, copovidone, their physical mixture, and ASD are displayed in Figure S18 [z]. Here, prime noticeable change was the absence of characteristic 3331 cm-1 band (N-H stretching vibration of nifedipine1) in the spectra of nifedipine ASD which was apparent in the spectra of pure nifedipine as well as nifedipine-copovidone physical mixture. Absence of this vibration frequency indicates formation of hydrogen bond between drug and carrier; suggesting formulation of a stable ASD1.
The equilibrium solubility of crystalline nifedipine, nifedipine-copovidone physical mixture, and nifedipine ASD were determined in three aqueous media i.e. purified water, 0.1 N HCl and pH 6.8 phosphate buffer at 37±0.5°C; the results of which are demonstrated in Figure S19. In purified water, the solubility of crystalline nifedipine, nifedipine-copovidone physical mixture, and nifedipine ASD was respectively found to be 8.49±0.50, 12.56±0.74, and 65.58±1.13 µg/ml; and almost similar results were also obtained with other media. Thus, the prepared nifedipine ASD, which increased the aqueous solubility about 7-8 times, was further employed for preparation of core tablets.
Figure S19Solubility studies of crystalline nifedipine and nifedipine ASD in various aqueous media (mean±S.D.; n=3)
Evaluation of lornoxicam ASD
The results of DSC, PXRD, and FTIR studies for developed lornoxicam ASD are displayed in Figure S20.
Figure S20DSC [x], PXRD [y] and FTIR [z] analyses of lornoxicam (A), meglumine (B), HPMC E5 (C), lornoxicam-meglumine-HPMC E5physical mixture (D) and lornoxicam-meglumine-HPMC E5ASD (E)
The DSC thermograms of lornoxicam, meglumine, HPMC E5, their physical mixture, and ASD are displayed in Figure S20 [x]. As shown in the Figure, pure lornoxicam exhibited an exotherm at about 235°C due to melting with decomposition2. The thermogram of meglumine displayed a melting endotherm at 131°C whereas thermogram of HPMC did not show any sharp peak. The thermogram of lornoxicam-meglumine-HPMC physical mixture demonstrated slight shift/broadening of melting endotherm of meglumine but devoid of exotherm at 235°C which might be because of solubilisation of lornoxicam in previously molten meglumine. However, the thermogram of lornoxicam ASD did not display any endotherm corresponding to meglumine or exotherm corresponding to lornoxicam. Hence, it was anticipated that the prepared lornoxicam-meglumine-HPMC ternary system would be a molecularly dispersed amorphous system which was further confirmed through PXRD study.
The results of PXRD study are displayed in Figure S20 [y]. As shown in the Figure, pure lornoxicam as well as megluminewere evidently crystalline in nature whereas polymer HPMC was veritably amorphous. Importantly, the spectra of lornoxicam-meglumine-HPMC physical mixture exhibited crystalline nature whereas that of ASD demonstrated amorphous nature. Hence, it was confirmed that the developed solid dispersion was, in fact, a molecularly dispersed amorphous ternary system of lornoxicam-meglumine-HPMC E5.
The overlaid FTIR spectra of lornoxicam, meglumine, HPMC, their physical mixture, and ASD are displayed in Figure S20 [z]. The FTIR spectra of lornoxicam distinctly depicted the band at 3065 cm-1 correspondingto N-H stretching vibration of lornoxicam2. This band, which was absent in the spectra of meglumine as well as HPMC, was present in their physical mixture but not in the ASD. Hence, same as nifedipine ASD, the possibility of hydrogen bonding between drug and carrier was substantiated in this case also.
Further, the equilibrium solubility of crystalline lornoxicam and lornoxicam ASD were determined in three aqueous media at 37±0.5°C and the results are displayed in Figure S21. The study revealed that lornoxicampossesses sharp pH-dependent solubility which is lower in 0.1 N HCl. Hence, the focus was to improve solubility of lornoxicam mainly in the acidic medium which would thereby solve the solubility issue with other medium also. The solubility of crystalline lornoxicam, lornoxicam-meglumine-HPMC physical mixture, and lornoxicam ASD in 0.1 N HCl was respectively found to be 4.08±0.19, 4.57±0.21, and 17.11±0.72 µg/ml. Thus, formulation of ASD increased the solubility of lornoxicam approx 4 fold in 0.1 N HCl. Notably, the solubility of crystalline lornoxicam in purified water and pH 6.8 phosphate buffer were respectively found to be 17.67±0.69 and 89.64±3.25 µg/ml, whereas the same for ASD were respectively found to be 9.65±0.18 and 10.28±0.32 mg/ml. Such significant boostin solubility was the pooled effect of developed amorphous system and increase in pH of the medium due to simultaneous solubilisation of meglumine. However, with consideration of 4 fold solubility enhancement in 0.1 N HCl, the developed ASD was further employed for preparation of core tablets.
Figure S21Solubility studies of crystalline lornoxicam and lornoxicamASD in various aqueous media (mean± S.D.; n=3).
References
- Chutimaworapan S, Ritthidej G, Yonemochi E, Oguchi T, Yamamoto K. Effect of water-soluble carriers on dissolution characteristics of nifedipine solid dispersions. Drug Dev Ind Pharm.2000;26:1141-50.
- Ahmed MO, Al-Badr AA. Lornoxicam. In: Harry GB, editor. Profiles of Drug Substances, Excipients and Related Methodology. London: Academic Press; 2011. p. 205-39.
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