İkili Tadalafil Karışımlarında DSC, TGA ve FTIR Kullanılarak İlaç-Yardımcı Madde Geçimlilik Çalışmaları

Öz

Amaç: İlaç ön formülasyon çalışmaları sırasında, formülasyondaki aktif bileşik ile yardımcı maddeler arasındaki fiziksel veya kimyasal geçimliliklerini tespit etmek ve nihai ürünün güvenilirliğini ve/veya etkinliğini göstermek için, uygun bir formülasyon eldesinde termal analiz ve spektroskopik teknikler kullanılır. Erektil disfonksiyonda, seçici bir siklik guanozin monofosfata özgü fosfodiesteraz tip 5 inhibitörlerinin geliştirilmesi ile devrim yaratmıştır. Tadalafil de bu inhibitörlerden bir tanesidir. Yardımcı maddeler, üretim, emilim veya uygulamaya yardımcı olmak için dozaj formlarına dahil edilmiştir. Farmakolojik olarak inert olduğu düşünülse de, ilaç aktif bileşiği etkinliği bozabilir. Gereç ve Yöntem: Çalışmada DSC, TGA ve FTIR sistemleri kullanılmıştır. Askorbik asit, butile hidroksianisol, kalsiyum fosfat dibazik, selüloz, magnezyum stearat, mannitol, sodyum karboksimetil selüloz, sukroz, talk, nişasta, primojel ve sitrik asidin Tadalafil ile etkileşimi incelenmiştir. İkili ilaç karışımları: eksipiyan analiz edilmiştir. Sonuçlar: Spektroskopik ve termal sonuçlara göre; Tadalafil magnezyum stearat, mannitol, sukroz ve askorbik asit ile geçimsizdir. Sonuç: İlaç-eksipiyan uyumluluğunu araştıran çalışmalar, ilaç geliştirme çalışmalarında önemli bir adımdır. Bu tür çalışmalarda termal ve spektroskopik teknikler yaygın olarak kullanılmaktadır.

Anahtar Kelimeler

• Tadalafil
• Geçimlilik
• Yardımcı madde
• Fourier Dönüşümü Kızılötesi Spektroskopisi
• Diferansiyel tarama kalorimetrisi

Drug-Excipient Compatibility Studies In Binary Mixtures of Tadalafil by Using DSC, TGA and FTIR

Öz

Objective: During drug preformulation studies, thermal analysis and spectroscopic techniques are used to detect physical or chemical incompatibilities between the active compound and the excipients in the formulation, and to demonstrate the safety and/or efficacy of the final product. It has revolutionized erectile dysfunction with the development of a selective cyclic guanosine monophosphate-specific PDE-5 inhibitors. Tadalafil is one of these inhibitors. Excipients are included in dosage forms to assist in manufacture, absorption or application. Although considered to be pharmacologically inert, the drug active compound may impair effectiveness. Material and Method: DSC, TGA, and FTIR, were used in the work. Ascorbic acid, butylated hydroxyanisole, calcium phosphate dibasic, cellulose, magnesium stearate, mannitol, sodium carboxymethyl cellulose, sucrose, talc, starch, primojel, and citric acid exhibit interaction with Tadalafil. Binary mixtures of drug:excipient have been analyzed. Results: Based on spectroscopic and thermal results; Tadalafil is incompatible with magnesium stearate, mannitol, sucrose, and ascorbic acid. Conclusion: Studies to investigate drug-excipient compatibility are an important step in drug development studies. Thermal and spectroscopic techniques are widely used in such studies.

Anahtar Kelimeler

• Tadalafil
• Compatibility
• Excipient; Fourier Transform Infrared Spectroscopy
• Differential Scanning Calorimetry

Kaynakça

1. [1] Giuseppe, G. P., Capron, F., Stewart, S., Leone, O., Humbert, M., Robbins, I. M., Reid, L. M., Tuder, R. M. 2004. Pathologic assessment of vasculopathies in pulmonary hypertension. Journal of the American College of Cardiology, 43(12), 25-32.
2. [2] Rich, S. E. Primary pulmonary hypertension: executive summary from the World Symposium—primary pulmonary hypertension. http:// www.who.int/ncd/cvd/pph.html.
3. [3] Tanaka, S., Uchida, A., Hakamata, A., Miyakawa, S., Odagari, N., Inui, N., Watanabe, H., Namıkı, N. 2020. Simultaneous LC-MS analysis of plasma concentrations of sildenafil, tadalafil, bosentan, ambrisentan, and macitentan in patients with pulmonary arterial hypertension. Pharmazie, 75, 236-239.
4. [4] Giaid, A., Yanagisawa, M., Langleben, D., Michel, R. P., Levy, R., Shennib, H., Kimura, S., Masaki, T., Duguid, W. P., Stewart, D. J. 1993. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. New England Journal of Medicine, 328, 1732–1739.
5. [5] Galie, N., Ghofrani, H. A., Torbicki, A., Barst, R. J., Rubin, L. J., Badesch, D., Fleming, T., Parpia, T., Burgess, G., Branzi, A., Grimminger, F., Kurzyna, M., Simonneau, G. 2005. Sildenafil citrate therapy for pulmonary arterial hypertension. New England Journal of Medicine, 353, 2148–2157.
6. [6] Galie, N., Olschewski, H., Oudiz, R. J., Torres, F., Frost, A., Ghofrani, H. A., Badesch, D. B., McGoon, M. D., McLaughlin, V. V., Roecker, E. B., Gerber, M. J., Dufton, C., Wiens, B. L., Rubin, L. J. 2008. Ambrisentan for the treatment of pulmonary arterial hypertension results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation, 117(23), 3010–3019.
7. [7] Galie, N., Brundage, B. H., Ghofrani, H. A., Oudiz, R. J., Simonneau, G., Safdar, Z., Shapiro, S., White, R. J., Chan, M., Beardsworth, A., Frumkin, L., Barst, R. J. 2009. Tadalafil therapy for pulmonary arterial hypertension. Circulation, 119(22), 2894–2903.
8. [8] Galie, N., Barbera, J. A., Frost, A. E., Ghofrani, H. A., Hoeper, M. M., McLaughlin, V. V., Peacock, A. J., Simonneau, G., Vachiery, J. L., Grunig, E., Oudiz, R. J., Vonk-Noordegraaf, A., White, R. J., Blair, C., Gillies, H., Miller, K. L., Harris, J. H., Langley, J., Rubin, L. J. 2015. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. New England Journal of Medicine, 373, 834–844.

9. [9] Sastry, B. K., Narasimhan, C., Reddy, N. K., Raju, B. S. 2004. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, doubleblind, crossover study. Journal of the American College of Cardiology, 43 (7), 1149–1153.
10. [10] Stewart, D. J., Levy, R. D., Cernacek, P., Langleben, D. 1991. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Annals of Internal Medicine, 114(6); 464–469.
11. [11] Channick, R. N., Simonneau, G., Sitbon, O., Robbins, I. M., Frost, A., Tapson, V. F., Badesch, D. B., Roux, S., Rainisio, M., Bodin, F., Rubin, L. J. 2001. Effects of the dual endothelinreceptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet, 358(9288), 1119–1123.
12. [12] Coward, R. M., Carson, C. C. 2008. Tadalafi l in the treatment of erectile dysfunction. Therapeutics and Clinical Risk Management, 4(6), 1315–1329.
13. [13] Dave, V. S., Haware, R. V., Sangave, N. A., Sayles, M., Popielarczyk, M. 2015. Drug-excipient compatibility studies in formulation development: Current trends and techniques. St. John Fisher College Fisher Digital Publications,1, 8-15.
14. [14] Chidambaram, M., Krishnasamy, K. 2014. Drug-drug/drug-excipient compatibility studies on curcumin using non-thermal methods. Advanced Pharmaceutical Bulletin, 4(3), 309-312.
15. [15] McDaid, F. M., Barker, S. A., Fitzpatrick, S., Petts, C. R., Craig, D. Q. M. 2003. Further investigations into the use of high sensitivity differential scanning calorimetry as a means of predicting drug–excipient interactions. International Journal of Pharmaceutics, 252(1), 235-240.
16. [16] Thomas, V. H., Naath, M. 2008. Design and utilization of the drug–excipient chemical compatibility automated system. International Journal of Pharmaceutics, 359(1),150-157.
17. [17] Brown, M. E., Antunes, E. M., Glass, B. D., Lebete, M., Walker, R. B. 1999. DSC screening of potential prochlorperazine-excipient interactions in preformulation studies. Journal of Thermal Analysis and Calorimetry, 56, 1317–1322.
18. [18] Pyramides, G., Robinson, J. W., Zito, S. W. 1995. The combined use of DSC and TGA for the thermal analysis of atenolol tablets. Journal of Pharmaceutical and Biomedical Analysis, 13(2), 103–110.
19. [19] Giron, D. 1998. Contribution of thermal methods and related techniques to the rational development of pharmaceuticals—Part I. Pharmaceutical Science & Technology Today, 1(5), 191–199.
20. [20] Phipps, M. A., Winnike, R. A., Viscomi, F., Long, S. T. 1998. Excipient compatibility assessment by isothermal microcalorimetry. Journal of Pharmacy and Pharmacology, 50(59), 9.
21. [21] Newman, A. W., Byrn, S. R. 2003. Solid-state analysis of the active pharmaceutical ingredient in drug products. Drug Discovery Today, 8(19), 898–905.
22. [22] Qi, L., Harding, S., Hill, G., Reading, M., Craig, D. Q. M. 2008. The developmentof microthermal analysis and photothermal microspectroscopy as novel approaches to drug–excipient compatibility studies. International Journal of Pharmaceutics, 354(1–2), 149–157.
23. [23] Aigner, Z., Heinrich, R., Sipos, E., Farkas, G., Ciurba, A., Berkesi, O., Szabó-Révész, P. 2011. Compatibility studies of aceclofenac with retard tablet excipients by means of thermal and FT-IR spectroscopic methods. Journal of Thermal Analysis and Calorimetry, 104, 265–271.
24. [24] Mura, P., Faucci, M. T., Manderioli, A., Bramanti, G., Ceccarelli, L. 1998. Compatibility study between ibuproxam and pharmaceutical excipients using differential scanning calorimetry, hot-stage microscopy and scanning electron microscopy. Journal of Pharmaceutical and Biomedical Analysis, 18(1-2), 151–163.
25. [25] Botha, S. A., Lotter, A. P. 1990. Compatibility study between Naproxen and tablet excipients using differential scanning calorimetry. Drug Development and Industrial Pharmacy, 16(9), 673–683.
26. [26] Chadha, R., Bhandari, S. 2014. Drug–excipient compatibility screening—role of thermoanalytical and spectroscopic techniques. Journal of Pharmaceutical and Biomedical Analysis, 87, 82– 97.
27. [27] Uzunović, A., Vranic, E. 2007. Effect of Magnesium stearate concentration on dissoluiton properties of ranitidine hydrochloride coated tablets. Bosnian Journal of Basic Medical Sciences 7(3), 279-283.
28. [28] Boge, L., Västberg, A., Umerska, A., Bysell, H., Eriksson, J., Edwards, K., Millqvist-Fureby, A., Andersson, M. 2018. Freeze-dried and re-hydrated liquid crystalline nanoparticles stabilized with disaccharides for drug-delivery of the plectasin derivative AP114 antimicrobial peptide. Journal of Colloid and Interface Science 522, 126–135.
29. [29] Thakral, S., Sonje, J., Munjal, B., Bhatnagar, B., Suryanarayanan, R. 2023. Mannitol as an excipient for lyophilized injectable formulations. Journal of Pharmaceutical Sciences 112; 19−35.
30. [30] Madejová, J. 2003. FTIR techniques in clay mineral studies. Vibrational Spectroscopy, 31(1), 1-10.
31. [31] Wakasawa, T., Sano, K., Hirakura, Y., Toyooka, T., Kitamura, S. 2008. Solid-state compatibility studies using a high-throughput and automated forced degradation system. International Journal of Pharmaceutics, 355(1-2), 164–173.
32. [32] Monajjemzadeh, F., Hassanzadeh, D., Valizadeh, H., Siahi-Shadbad, M. R., Mojarrad, J.S., Robertson, T.A., Roberts, M. S. 2009. Compatibility studies of acyclovir and lactose in physical mixtures and commercial tablets. European Journal of Pharmaceutics and Biopharmaceutics, 73(3), 404–413.
33. [33] Wesolowski, M., Rojek, B. J. 2013. Thermogravimetric detection of incompatibilities between atenolol and excipients using multivariate techniques. Journal of Thermal Analysis and Calorimetry, 113, 169-117.
34. [34] Yathirajan, H. S., Nagaraj, B., Nagaraja, P., Bolte, M. 2005. Sildenafil citrate monohydrate. Acta Crystallographica Section E, 2005(E61), O489-O491.
35. [35] Sawatdee, S., Pakawatchai, C., Nitichai, K., Srichana, T., Phetmung, H. 2015. Why sildenafil and sildenafil citrate monohydrate crystals are not stable? Saudi Pharmaceutical Journal, 23(5), 504-514.
36. [36] Wizel, S., Krochmal, B., Givant A., Diller, D. 2006. U.S. Patent 20060111571 A1 2006.
37. [37] Mura, P., Manderioli, A., Bramanti, G., Furlanetto, S., Pinzauti, S. 1995. Utilization of differential scanning calorimetry as a screening technique to determine the compatibility of ketoprofen with excipients. International Journal of Pharmaceutics, 119, 71-79.
38. [38] Lu, M., Xing, H., Yang, T., Yu, J., Yang, Z., Sun, Y., Ding, P. 2017. Dissolution enhancement of tadalafil by liqui solid technique. Pharmaceutical Development and Technology 22(1), 77–89
39. [39] Wei, Y., Ling, Y., Su, M., Qin, L., Zhang, J., Gao, Y., Qian, S. 2018. Characterization and stability of amorphous tadalafil and four crystalline polymorphs. Chemical & Pharmaceutical Bulletin 66, 1114–1121.
40. [40] Pani, N. R., Nath, L. K, Acharya, S. 2011. Compatibility studies of nateglinide with excipients in immediate release tablets. Acta Pharmaceutica, 61(2), 237-247.
41. [41] Manikandan, M., Kannan, K., Manavalan, R. 2013. Compatibility studies of camptothecin with various pharmaceutical excipients used in the development of nanoparticle formulation. International Journal of Pharmacy and Pharmaceutical Sciences, 5(4), 315-321.