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Molecular Origin of the Distinct Tabletability of Loratadine and Desloratadine: Role of the Bonding Area – Bonding Strength Interplay

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Abstract

Purpose

To explain the different tabletability of two structurally similar H1-receptor antihistamine drugs, loratadine (LOR) and desloratadine (DES), based on the molecular basis of bonding area and bonding strength.

Methods

LOR and DES were characterized by powder X-ray diffractometry, thermal analysis, and dynamic water sorption. The compressibility, tabletability, compactibility, and Heckel analysis of their bulk powders and formulations were evaluated. A combined energy framework and topological analysis was used to characterize the crystal structure – mechanical property relationship. Surface energy of bulk powder was assessed by contact angle measurement using the Owens/Wendt theory.

Results

Both LOR and DES bulk powders are phase pure and stable under compaction. The superior tabletability of LOR is attributed to both larger bonding area (BA) and higher interparticle bonding strength (BS). The larger BA of LOR results from its experimentally established higher plasticity, which is explained by the presence of more densely packed molecular layers with smooth surface topology. The higher BS of LOR corresponded to its significantly higher dispersive component of the surface energy.

Conclusions

This work provides new insights into the molecular origins of BA and BS, which can be applied to improve mechanical properties and tableting performance of drugs through appropriate crystal engineering.

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Abbreviations

BA:

Bonding area

BS:

Bonding strength

DES:

Desloratadine

DSC:

Differential scanning calorimetry

LOR:

Loratadine

MCC:

Microcrystalline cellulose

OTC:

Over-the-counter

PXRD:

Powder X-ray diffractometry

RH:

Relative humidity

TGA:

Thermogravimetric analysis

P y :

Mean yield pressure

ε:

Tablet porosity

ρ:

Tablet density

ρt :

Powder true density

σ0 :

Tensile strength of the tablet at zero porosity

References

  1. Sun CC. Microstructure of tablet—pharmaceutical significance, assessment, and engineering. Pharm Res. 2017;34(5):918–28.

    CAS  PubMed  Google Scholar 

  2. Sun CC. Decoding powder tabletability: roles of particle adhesion and plasticity. J Adhes Sci Technol. 2011;25(4–5):483–99.

    CAS  Google Scholar 

  3. Ambros MC, Podczeck F, Podczeck H, Newton JM. The characterization of the mechanical strength of chewable tablets. Pharm Dev Technol. 1998;3(4):509–15.

    CAS  PubMed  Google Scholar 

  4. Bi Y, Sunada H, Yonezawa Y, Danjo K, Otsuka A, Iida K. Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity. Chem Pharm Bull. 1996;44(11):2121–7.

    CAS  PubMed  Google Scholar 

  5. Simons FE, Simons KJ. Histamine and h1-antihistamines: Celebrating a century of progress. J Allergy Clin Immunol. 2011;128(6):1139–1150.e1134.

    CAS  PubMed  Google Scholar 

  6. Simons FE. Advances in h1-antihistamines. N Engl J Med. 2004;351(21):2203–17.

    CAS  PubMed  Google Scholar 

  7. Lieberman P, Hernandez-Trujillo V, Lieberman J, Frew AJ. Antihistamines. In: Rich RR, Fleisher TA, Shearer WT, Schroeder HW, Frew AJ, Weyand CM, editors. Clinical immunology. third ed. Edinburgh: Mosby; 2008. p. 1317–29.

  8. Lemke TL, Williams DA. Foye's principles of medicinal chemistry: Wolters Kluwer health/Lippincott Williams & Wilkins; 2012.

  9. Hilbert J, Radwanski E, Weglein R, Luc V, Perentesis G, Symchowicz S, et al. Pharmacokinetics and dose proportionality of loratadine. J Clin Pharmacol. 1987;27(9):694–8.

    CAS  PubMed  Google Scholar 

  10. Ramanathan R, Reyderman L, Kulmatycki K, Su AD, Alvarez N, Chowdhury SK, et al. Disposition of loratadine in healthy volunteers. Xenobiotica. 2007;37(7):753–69.

    CAS  PubMed  Google Scholar 

  11. Clark MJ, Million RP. Allergic rhinitis: market evolution. Nat Rev Drug Discov. 2009;8(4):271–2.

    CAS  PubMed  Google Scholar 

  12. Trygstad TK, Hansen RA, Wegner SE. Evaluation of product switching after a state medicaid program began covering loratadine otc 1 year after market availability. J Manag Care Pharm. 2006;12(2):108–20.

    PubMed  Google Scholar 

  13. Glass DJ, Harper AS. Assessing satisfaction with desloratadine and fexofenadine in allergy patients who report dissatisfaction with loratadine. BMC Fam Pract. 2003;4:10.

    PubMed  PubMed Central  Google Scholar 

  14. Geha RS, Meltzer EO. Desloratadine: a new, nonsedating, oral antihistamine. J Allergy Clin Immunol. 2001;107(4):751–62.

    CAS  PubMed  Google Scholar 

  15. Molimard M, Diquet B, Benedetti MS. Comparison of pharmacokinetics and metabolism of desloratadine, fexofenadine, levocetirizine and mizolastine in humans. Fundam Clin Pharmacol. 2004;18(4):399–411.

    CAS  PubMed  Google Scholar 

  16. Ramanathan R, Reyderman L, Su AD, Alvarez N, Chowdhury SK, Alton KB, et al. Disposition of desloratadine in healthy volunteers. Xenobiotica. 2007;37(7):770–87.

    CAS  PubMed  Google Scholar 

  17. Osei-Yeboah F, Chang SY, Sun CC. A critical examination of the phenomenon of bonding area - bonding strength interplay in powder tableting. Pharm Res. 2016;33(5):1126–32.

    CAS  PubMed  Google Scholar 

  18. Reutzel-Edens SM, Bush JK, Magee PA, Stephenson GA, Byrn SR. Anhydrates and hydrates of olanzapine: crystallization, solid-state characterization, and structural relationships. Cryst Growth Des. 2003;3(6):897–907.

    CAS  Google Scholar 

  19. Roy S, Quiñones R, Matzger AJ. Structural and physicochemical aspects of dasatinib hydrate and anhydrate phases. Cryst Growth Des. 2012;12(4):2122–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sun C, Grant DJW. Improved tableting properties of p-hydroxybenzoic acid by water of crystallization: a molecular insight. Pharm Res. 2004;21(2):382–6.

    PubMed  Google Scholar 

  21. Chang S-Y, Sun CC. Superior plasticity and tabletability of theophylline monohydrate. Mol Pharm. 2017;14(6):2047–55.

    CAS  PubMed  Google Scholar 

  22. Grzesiak AL, Lang M, Kim K, Matzger AJ. Comparison of the four anhydrous polymorphs of carbamazepine and the crystal structure of form i. J Pharm Sci. 2003;92(11):2260–71.

    CAS  PubMed  Google Scholar 

  23. Sun C, Grant DJ. Influence of crystal structure on the tableting properties of sulfamerazine polymorphs. Pharm Res. 2001;18(3):274–80.

    CAS  PubMed  Google Scholar 

  24. Bag PP, Chen M, Sun CC, Reddy CM. Direct correlation among crystal structure, mechanical behaviour and tabletability in a trimorphic molecular compound. CrystEngComm. 2012;14(11):3865–7.

    CAS  Google Scholar 

  25. Aitipamula S, Wong ABH, Chow PS, Tan RBH. Cocrystallization with flufenamic acid: comparison of physicochemical properties of two pharmaceutical cocrystals. CrystEngComm. 2014;16(26):5793–801.

    CAS  Google Scholar 

  26. Liu L, Wang C, Dun J, Chow AHL, Sun CC. Lack of dependence of mechanical properties of baicalein cocrystals on those of the constituent components. CrystEngComm. 2018;20(37):5486–9.

    CAS  Google Scholar 

  27. Krishna GR, Shi L, Bag PP, Sun CC, Reddy CM. Correlation among crystal structure, mechanical behavior, and tabletability in the co-crystals of vanillin isomers. Cryst Growth Des. 2015;15(4):1827–32.

    CAS  Google Scholar 

  28. Sun CC, Hou H. Improving mechanical properties of caffeine and methyl gallate crystals by cocrystallization. Cryst Growth Des. 2008;8(5):1575–9.

    CAS  Google Scholar 

  29. Mannava MKC, Suresh K, Nangia A. Enhanced bioavailability in the oxalate salt of the anti-tuberculosis drug ethionamide. Cryst Growth Des. 2016;16(3):1591–8.

    CAS  Google Scholar 

  30. Suresh K, Nangia A. Lornoxicam salts: crystal structures, conformations, and solubility. Cryst Growth Des. 2014;14(6):2945–53.

    CAS  Google Scholar 

  31. Fell JT, Newton JM. Determination of tablet strength by the diametral-compression test. J Pharm Sci. 1970;59(5):688–91.

    CAS  PubMed  Google Scholar 

  32. Joiris E, Martino PD, Berneron C, Guyot-Hermann A-M, Guyot J-C. Compression behavior of orthorhombic paracetamol. Pharm Res. 1998;15(7):1122–30.

    CAS  PubMed  Google Scholar 

  33. Khomane KS, More PK, Raghavendra G, Bansal AK. Molecular understanding of the compaction behavior of indomethacin polymorphs. Mol Pharm. 2013;10(2):631–9.

    CAS  PubMed  Google Scholar 

  34. Yadav JPA, Bansal AK, Jain S. Molecular understanding and implication of structural integrity in the deformation behavior of binary drug–drug eutectic systems. Mol Pharm. 2018;15(5):1917–27.

    CAS  PubMed  Google Scholar 

  35. Heckel RW. An analysis of powder compaction phenomena. Trans Metall Soc AIME. 1961;221:1001–8.

    Google Scholar 

  36. Heckel RW. Density-pressure relationships in powder compaction. Trans Metall Soc AIME. 1961;221:671–5.

    CAS  Google Scholar 

  37. Kuentz M, Leuenberger H. Pressure susceptibility of polymer tablets as a critical property: a modified heckel equation. J Pharm Sci. 1999;88(2):174–9.

    CAS  PubMed  Google Scholar 

  38. Paul S, Sun CC. The suitability of common compressibility equations for characterizing plasticity of diverse powders. Int J Pharm. 2017;532(1):124–30.

    CAS  PubMed  Google Scholar 

  39. Owens DK, Wendt RC. Estimation of the surface free energy of polymers. J Appl Polym. 1969;13(8):1741–7.

    CAS  Google Scholar 

  40. Srirambhatla VK, Guo R, Dawson DM, Price SL, Florence AJ. Reversible, two-step single-crystal to single-crystal phase transitions between desloratadine forms I, II, and III. Cryst Growth Des. 2020;20(3):1800–10.

    CAS  Google Scholar 

  41. Woollam GR, Neumann MA, Wagner T, Davey RJ. The importance of configurational disorder in crystal structure prediction: the case of loratadine. Faraday Discuss. 2018;211(0):209–34.

    CAS  PubMed  Google Scholar 

  42. Bryant MJ, Maloney AGP, Sykes RA. Predicting mechanical properties of crystalline materials through topological analysis. CrystEngComm. 2018;20(19):2698–704.

    CAS  Google Scholar 

  43. Turner MJ, McKinnon JJ, Wolff SK, Grimwood DJ, Spackman PR, Jayatilaka D and Spackman MA. Crystalexplorer17. In: University of Western Australia; 2017.

  44. Turner MJ, Grabowsky S, Jayatilaka D, Spackman MA. Accurate and efficient model energies for exploring intermolecular interactions in molecular crystals. J Phys Chem Lett. 2014;5(24):4249–55.

    CAS  PubMed  Google Scholar 

  45. Turner MJ, Thomas SP, Shi MW, Jayatilaka D, Spackman MA. Energy frameworks: insights into interaction anisotropy and the mechanical properties of molecular crystals. Chem Commun. 2015;51(18):3735–8.

    CAS  Google Scholar 

  46. Bhatt PM, Desiraju GR. Form i of desloratadine, a tricyclic antihistamine. Acta Crystallogr C. 2006;62(6):o362–3.

    PubMed  Google Scholar 

  47. Kaminski JJ, Carruthers NI, Wong S-C, Chan T-M, Motassim Billah M, Tozzi S, et al. Conformational considerations in the design of dual antagonists of platelet-activating factor (paf) and histamine. Bioorg Med Chem. 1999;7(7):1413–23.

    CAS  PubMed  Google Scholar 

  48. Popovic G, Cakar M, Agbaba D. Acid-base equilibria and solubility of loratadine and desloratadine in water and micellar media. J Pharm Biomed Anal. 2009;49(1):42–7.

    CAS  PubMed  Google Scholar 

  49. Sun CC. A material-sparing method for simultaneous determination of true density and powder compaction properties--aspartame as an example. Int J Pharm. 2006;326(1–2):94–9.

    CAS  PubMed  Google Scholar 

  50. Wang C, Sun CC. Identifying slip planes in organic polymorphs by combined energy framework calculations and topology analysis. Cryst Growth Des. 2018;18(3):1909–16.

    CAS  Google Scholar 

  51. Singaraju AB, Nguyen K, Gawedzki P, Herald F, Meyer G, Wentworth D, et al. Combining crystal structure and interaction topology for interpreting functional molecular solids: a study of theophylline cocrystals. Cryst Growth Des. 2017;17(12):6741–51.

    CAS  Google Scholar 

  52. Joshi TV, Singaraju AB, Shah HS, Morris KR, Stevens LL, Haware RV. Structure–mechanics and compressibility profile study of flufenamic acid:Nicotinamide cocrystal. Cryst Growth Des. 2018;18(10):5853–65.

    CAS  Google Scholar 

  53. Wang C, Sun CC. Computational techniques for predicting mechanical properties of organic crystals: a systematic evaluation. Mol Pharm. 2019;16(4):1732–41.

    CAS  PubMed  Google Scholar 

  54. Fichtner F, Mahlin D, Welch K, Gaisford S, Alderborn G. Effect of surface energy on powder compactibility. Pharm Res. 2008;25(12):2750–9.

    CAS  PubMed  Google Scholar 

  55. Sun CC. Role of surface free energy in powder behavior and tablet strength. In: Mittal K, Etzler F, editors. Adhesion science: Applications to pharmaceutical, medical and dental fields: Scrivener Publishing /John Wiley & Sons; 2017. p. 75–88.

  56. Du Y, Xu J, Sakizadeh JD, Weiblen DG, McCormick AV, Francis LF. Modulus- and surface-energy-tunable thiol–ene for uv micromolding of coatings. ACS Appl Mater Interfaces. 2017;9(29):24976–86.

    CAS  PubMed  Google Scholar 

  57. Hiestand EN. Dispersion forces and plastic deformation in tablet bond. J Pharm Sci. 1985;74(7):768–70.

    CAS  PubMed  Google Scholar 

  58. Steiner T. R. Desiraju G. distinction between the weak hydrogen bond and the van der waals interaction. Chem Commun. 1998;8:891–2.

    Google Scholar 

  59. Luangtana-Anan M, Fell JT. Bonding mechanisms in tabletting. Int J Pharm. 1990;60(3):197–202.

    CAS  Google Scholar 

  60. Aakeröy CB, Seddon KR. The hydrogen bond and crystal engineering. Chem Soc Rev. 1993;22(6):397–407.

    Google Scholar 

  61. Desiraju GR. Crystal engineering: from molecule to crystal. J Am Chem Soc. 2013;135(27):9952–67.

    CAS  PubMed  Google Scholar 

  62. Vishweshwar P, McMahon JA, Bis JA, Zaworotko MJ. Pharmaceutical co-crystals. J Pharm Sci. 2006;95(3):499–516.

    CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

We thank the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing the resources that contributed to the research results reported within this paper (http://www.msi.umn.edu).

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Author notes

  1. Zhongyang Shi and Chenguang Wang contributed equally to this work.

Authors and Affiliations

  1. Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, University of Minnesota, 9-127B Weaver-Densford Hall 308 Harvard Street S.E, Minneapolis, Minnesota, 55455, USA

    Zhongyang Shi, Chenguang Wang & Changquan Calvin Sun

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  1. Zhongyang Shi
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Correspondence to Changquan Calvin Sun.

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Shi, Z., Wang, C. & Sun, C.C. Molecular Origin of the Distinct Tabletability of Loratadine and Desloratadine: Role of the Bonding Area – Bonding Strength Interplay. Pharm Res 37, 133 (2020). https://doi.org/10.1007/s11095-020-02856-2

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