Characterization of the Solid Physical State of API and Its Distribution in Pharmaceutical Hot Melt Extrudates Using Terahertz Raman Imaging

Abstract

In this study, a method employing THz Raman imaging to characterize the solid state of acetaminophen within a solid dispersion prepared by hot melt extrusion was reported. The peak at 89 cm−1 originating from the crystalline lattice vibrations provides unambiguous discrimination between crystalline and amorphous N-acetyl-para-aminophenol (APAP; acetaminophen) contents in the hot melt extrusion (HME) extrudates. Extrudates from four different HME processes (two different temperatures and two levels of screw speeds) were analyzed and compared. The results show that both high process temperature and high screw speed favor the formation of amorphous APAP solid dispersions. Finally, the high spatial resolution (~ 1 μm) Raman images of the extrudates prepared at 170°C and 200 rpm show a near-complete amorphous APAP dispersion in an HPMC matrix, confirming an efficient HME process. The study demonstrates that THz Raman imaging is ideally suited for the identification of different solid physical states of the APIs in a polymer matrix, and provides direct visualization of their distribution in HME extrudates.

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References

  1. 1.

    Repka MA, Bandari S, Kallakunta VR, Vo AQ, McFall H, Pimparade MB, et al. Melt extrusion with poorly soluble drugs—an integrated review. Int J Pharm. 2018;535:68–85. https://doi.org/10.1016/j.ijpharm.2017.10.056.

  2. 2.

    Censi R, Gigliobianco MR, Casadidio C, Di Martino P. Hot melt extrusion: highlighting physicochemical factors to be investigated while designing and optimizing a hot melt extrusion process. Pharmaceutics. 2018;10:89. https://doi.org/10.3390/pharmaceutics10030089.

  3. 3.

    Baghel S, Cathcart H, O’Reilly NJ. Polymeric amorphous solid dispersions: a review of amorphization, crystallization, stabilization, solid-state characterization, and aqueous solubilization of biopharmaceutical classification system class II drugs. J Pharm Sci. 2016;105:2527–44. https://doi.org/10.1016/j.xphs.2015.10.008.

    CAS  Article  Google Scholar 

  4. 4.

    Hitzer P, Bäuerle T, Drieschner T, Ostertag E, Paulsen K, van Lishaut H, et al. Process analytical techniques for hot-melt extrusion and their application to amorphous solid dispersions. Anal Bioanal Chem. 2017;409:4321–33. https://doi.org/10.1007/s00216-017-0292-z.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Furuyama N, Hasegawa S, Hamaura T, Yada S, Nakagami H, Yonemochi E, et al. Evaluation of solid dispersions on a molecular level by the Raman mapping technique. Int J Pharm. 2008;361:12–8. https://doi.org/10.1016/j.ijpharm.2008.05.009.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Parrott EPJ, Zeitler JA. Terahertz time-domain and low-frequency Raman spectroscopy of organic materials. Appl Spectrosc. 2015;69:1–25. https://doi.org/10.1366/14-07707.

  7. 7.

    Paudel A, Raijada D, Rantanen J. Raman spectroscopy in pharmaceutical product design. Adv Drug Deliv Rev. 2015;89:3–20. https://doi.org/10.1016/j.addr.2015.04.003.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Tres F, Treacher K, Booth J, Hughes LP, Wren SAC, Aylott JW, et al. Real time Raman imaging to understand dissolution performance of amorphous solid dispersions. J Control Release. 2014;188:53–60. https://doi.org/10.1016/j.jconrel.2014.05.061.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Nanubolu JB, Burley JC. Investigating the recrystallization behavior of amorphous paracetamol by variable temperature Raman studies and surface Raman mapping. Mol Pharm. 2012;9:1544–58. https://doi.org/10.1021/mp300035g.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Kauffman JF, Batykefer LM, Tuschel DD. Raman detected differential scanning calorimetry of polymorphic transformations in acetaminophen. J Pharm Biomed Anal. 2008;48:1310–5. https://doi.org/10.1016/j.jpba.2008.09.008.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Roy S, Chamberlin B, Matzger AJ. Polymorph discrimination using low wavenumber Raman spectroscopy. Org Process Res Dev. 2013;17:976–80. https://doi.org/10.1021/op400102e.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Li S, Tian Y, Jones DS, Andrews GP. Optimizing drug solubilization in amorphous polymer dispersions: rational selection of hot-melt extrusion processing parameters. AAPS Pharm SciTech. 2016;17:200–13. https://doi.org/10.1208/s12249-015-0450-6.

    CAS  Article  Google Scholar 

  13. 13.

    Li Y, Pang H, Guo Z, Lin L, Dong Y, Li G, et al. Interactions between drugs and polymers influencing hot melt extrusion. J Pharm Pharmacol. 2014;66:148–66. https://doi.org/10.1111/jphp.12183.

    CAS  Article  PubMed  Google Scholar 

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Correspondence to Michael Repka or Rui Chen.

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Ibrahim, M., Zhang, J., Repka, M. et al. Characterization of the Solid Physical State of API and Its Distribution in Pharmaceutical Hot Melt Extrudates Using Terahertz Raman Imaging. AAPS PharmSciTech 20, 62 (2019). https://doi.org/10.1208/s12249-018-1282-y

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Keywords

  • hot melt extrusion
  • terahertz raman imaging
  • acetaminophen
  • solid physical state
  • amorphous solid dispersion
  • spatial resolution