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Pharmaceutical Salts of Carvedilol: Polymorphism and Physicochemical Properties

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Abstract

We report novel pharmaceutical salts of an anti-hypertensive drug carvedilol (CVD) with pharmaceutically acceptable salt formers, including oxalic acid (OXA), fumaric acid (FUMA), benzoic acid (BZA), and mandelic acid (MDA) via conventional solvent evaporation technique. The pKa difference between CVD and selected acids was greater than 3, thus suggesting salt formation. Two polymorphic forms of CVD/MDA salts and one p-Dioxane solvate of CVD/FUMA salt were also reported in this paper. The salts were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). Stability of the salts was assessed by storage at 40°C/75% RH for 1 month. All CVD salts exhibited higher solubility in phosphate buffer solution pH 6.8 compared to the parent drug CVD and showed good stability in accelerated ICH conditions at 40°C/75% RH for 1 month. CVD/FUMA salt showed the highest solubility (1.78 times). Based on thermal analysis and slurry experiment, it was found that CVD/MDA polymorphs were related monotropically with Form 1 as the stable form. The results suggested that salt formation could be an alternative method to improve CVD solubility.

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Abbreviations

API:

Active pharmaceutical ingredient

BCS:

Biopharmaceutics Classification System

BZA:

Benzoic acid

CVD:

Carvedilol

DI:

De-ionized

DSC:

Differential scanning calorimetry

FTIR:

Fourier transform infrared spectroscopy

FUMA:

Fumaric acid

GRAS:

Generally recognized as safe

HPLC:

High performance liquid chromatography

MDA:

Mandelic acid

OPA:

Orthophosphoric acid

OXA:

Oxalic acid

PTFE:

Polytetrafluoroethylene

PXRD:

Powder X-ray diffraction

RH:

Relative humidity

SEDDS:

Self-emulsifying drug delivery systems

SEM:

Scanning electron microscopy

SMEDDS:

Self-microemulsifying drug delivery systems

TGA:

Thermogravimetric analysis

References

  1. Planinsek O, Kovaci B, Vrecer. Carvedilol dissolution improvement by preparation of solid dispersions with porous silica. Int J Pharm. 2011;406:41–8.

    Article  CAS  PubMed  Google Scholar 

  2. Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12:413–20.

    Article  CAS  PubMed  Google Scholar 

  3. Hamed R, Awadallah A, Sunoqrot S, Tarawneh O, Nazzal S, AlBaraghthi T, et al. pH-dependent solubility and dissolution behavior of carvedilol-case example of a weakly basic BCS class II drug. AAPS PharmSciTech. 2016;17:418–26.

    Article  CAS  PubMed  Google Scholar 

  4. Brook CS, Chen PY, Chen W, Dai Q, Dell’Orco PC, Labaw CS, et al. Carvedilol salts, corresponding compositions, methods of delivery and/or treatment. US Patent. 2010;7:750,036.

    Google Scholar 

  5. Kukec S, Dreu R, Vrbanec T, Srcic S, Vrecer F. Characterization of agglomerated carvedilol by hot-melt process in a fluid bed and high shear granulator. Int J Pharm. 2012;430:74–85.

    Article  CAS  PubMed  Google Scholar 

  6. Wei L, Sun P, Nie S, Pan W. Preparation and evaluation of SEDDS and SMEDDS containing carvedilol. Drug Dev Ind Pharm. 2005;31:785–94.

    Article  CAS  PubMed  Google Scholar 

  7. Mahmoud EA, Bendas ER, Mohamed MI. Preparation and evaluation of self nanoemulsifying tablets of carvedilol. AAPS PharmSciTech. 2009;10:183–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu D, Xu H, Tian B, Yuan K, Pan H, Ma S, et al. Fabrication of carvedilol nanosuspensions through the anti-solvent precipitation-ultrasonication method for the improvement of dissolution rate and oral bioavailability. AAPS PharmSciTech. 2012;13:295–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang Y, Zhi Z, Li X, Gao J, Song Y. Carboxylated mesoporous carbon microparticles as new approach to improve the oral bioavailability of poorly water-soluble carvedilol. Int J Pharm. 2013;454:403–11.

    Article  CAS  PubMed  Google Scholar 

  10. Hirlekar R, Kadam V. Preparation and characterization of inclusion complexes of carvedilol with methyl-β-cyclodextrin. J Incl Phenom Macrocyl Chem. 2009;63:219–24.

    Article  CAS  Google Scholar 

  11. Prado LD, Rocha HVA, Resende JALC, Ferreiraa GB, Teixeira AMRF. An insight into carvedilol solid forms: effect of supramolecular interactions on the dissolution profiles. CrystEngComm. 2014;16:3168–79.

    Article  CAS  Google Scholar 

  12. Domingos S, André V, Quaresma S, Martins ICB, Piedade MFM, Duarte MT. New forms of old drugs: improving without changing. J Pharm Pharmacol. 2015;67:830–46.

    Article  CAS  PubMed  Google Scholar 

  13. Serajuddin ATM. Salt formation to improve drug solubility. Adv Drug Deliv. 2007;1285:603–16.

    Article  Google Scholar 

  14. Mittapalli S, Mannava MKC, Khandavilli UBR, Allu S, Nangia A. Soluble salts and cocrystals of clotrimazole. Cryst Growth Des. 2015;15:2493–504.

    Article  CAS  Google Scholar 

  15. Aitipamula S, Chow PS, Tan RBH. Polymorphism in cocrystals: a review and assessment of its significance. CrystEngComm. 2016;16:3451–65.

    Article  Google Scholar 

  16. Brittain HG. Theory and principles of polymorphic systems. In: Brittain HG, editors. Polymorphism in Pharmaceutical Solids. New York: Marcel Dekker, Inc; 1999. p. 1–23.

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

    Article  CAS  Google Scholar 

  18. Grothe E, Meekes H, Vlieg E, Horst JH, de Gelder R. Solvates, salts, and cocrystal: a proposal for a feasible classification system. Cryst Growth Des. 2016;16:3237–43.

    Article  CAS  Google Scholar 

  19. Hiendrawan S, Veriansyah B, Widjojokusumo E, Soewandhi SN, Wikarsa S, Tjandrawinata RR. Physicochemical and mechanical properties of paracetamol cocrystal with 5-nitroisophthalic acid. Int J Pharm. 2016;497:106–13.

    Article  CAS  PubMed  Google Scholar 

  20. Aitipamula S, Chow PS, Tan RBH. The solvates of sulfamerazine: structural, thermochemical, and desolvation studies. CrystEngComm. 2012;14:691–9.

    Article  CAS  Google Scholar 

  21. Bhandaru JS, Malothu N, Akkinepally RR. Characterization and solubility studies of pharmaceutical cocrystals of eprosartan mesylate. Cryst Growth Des. 2015;15:1173–9.

    Article  CAS  Google Scholar 

  22. Hiendrawan S, Hartanti AW, Veriansyah B, Widjojokusumo E, Tjandrawinata RR. Solubility enhancement of ketoconazole via salt and cocrystal formation. Int J Pharm Pharm Sci. 2015;7:160–4.

    CAS  Google Scholar 

  23. Goud NR, Suresh K, Nangia A. Solubility and stability advantage of aceclofenac salts. Cryst Growth Des. 2013;13:1590–601.

    Article  CAS  Google Scholar 

  24. Yeo SD, Lee JC. Crystallization of sulfamethizole using the supercritical and liquid antisolvent processes. J Supercrit Fluids. 2004;30:315–23.

    Article  CAS  Google Scholar 

  25. Rahman Z, Agarabi C, Zidan AS, Khan SR, Khan MA. Physico-mechanical and stability evaluation of carbamazepine cocrystal with nicotinamide. AAPS PharmSciTech. 2011;12:693–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Aitipamula S, Chow PS, Tan RBH. Solvates and polymorphic phase transformations of 2-chloro-4-nitrobenzoic acid. CrystEngComm. 2011;13:1037–45.

    Article  CAS  Google Scholar 

  27. Aitipamula S, Chow PS, Tan RBH. Polymorphs and solvates of a cocrystal involving an analgesic drug, ethenzamide, and 3,5-dinitrobenzoic acid. Cryst Growth Des. 2010;10:2229–38.

    Article  CAS  Google Scholar 

  28. Burger A, Ramberger R. On the polymorphism of pharmaceuticals and other molecular crystals. I. Mikrochim Acta. 1979a;II:259–71.

  29. Burger A, Ramberger R. On the polymorphism of pharmaceuticals and other molecular crystals. II. Mikrochim Acta. 1979b;II:273–316.

  30. Cherukuvada S, Nangia A. Salts and ionic liquid of the antituberculosis drug S,S ethambutol. Cryst Growth Des. 2013;13:1752–60.

    Article  CAS  Google Scholar 

  31. Parmar VK, Shah SA. Hydrochloride salt co-crystals: preparation, characterization and physicochemical studies. Pharm Dev Technol. 2013;18:443–53.

    Article  CAS  PubMed  Google Scholar 

  32. Garcia JIA, Ruiz DH, Vasquez KM, Rojas HM, Hopfl H. Co-crystals of active pharmaceutical ingredients—acetazolamide. Cryst Growth Des. 2010;10:3732–42.

    Article  Google Scholar 

  33. Hiendrawan S, Veriansyah B, Widjojokusumo E, Soewandhi SN, Wikarsa S, Tjandrawinata RR. Simultaneous cocrystallization and micronization of paracetamol-dipicolinic acid cocrystal by supercritical antisolvent (SAS). Int J Pharm Pharm Sci. 2016;89–98.

  34. Aitipamula S, Wong ABH, Chow PS, Tan RBH. Pharmaceutical salts of haloperidol with some carboxylic acids and artificial sweeteners: hydrate formation, polymorphism, and physicochemical properties. Cryst Growth Des. 2014;14:2542–56.

    Article  CAS  Google Scholar 

  35. Swapna B, Maddileti D, Nangia A. Cocrystals of the tuberculosis drug isoniazid: polymorphism, isostructurality, and stability. Cryst Growth Des. 2014;14:5991–6005.

    Article  CAS  Google Scholar 

  36. Renuka, Singha SK, Gulati M, Kaur I. Characterization of solid state forms of glipizide. Powder Technol. 2014;264:365–76.

    Article  CAS  Google Scholar 

  37. Aucamp ME, Liebenberg W, Stieger N. Solvent-interactive transformations of pharmaceutical compounds. In: Mastai Y, editor. Advanced topics in crystallization. Croatia: InTech; 2015. p. 3–26.

    Google Scholar 

  38. Maher A, Croker DM, Rasmuson AC, Hodnett B. Solution mediated polymorphic transformation: form II to form III piracetam in ethanol. Cryst Growth Des. 2012;12:6151–7.

    Article  CAS  Google Scholar 

  39. Du W, Yin Q, Hao H, Bao Y, Zhang X, Huang J, et al. Solution-mediated polymorphic transformation of prasugrel hydrochloride from form II to form I. Ind Eng Chem Res. 2014;53:5652–9.

    Article  CAS  Google Scholar 

  40. Basavoju S, Bostrom D, Velaga SP. Pharmaceutical cocrystal and salts of norfloxacin. Cryst Growth Des. 2006;6:2699–708.

    Article  CAS  Google Scholar 

  41. Atkins P, de Paula J. Physical Chemistry. 7th ed. Oxford: OUP; 2002. p. 178.

    Google Scholar 

  42. Tao Q, Chen JM, Lu TB. Two polymorphs and one hydrate of a molecular salt involving phenazopyridine and salicylic acid. CrystEngComm. 2013;15:7852–5.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors acknowledge Dexa Laboratories of Biomolecular Sciences (DLBS)-PT Dexa Medica for financial support. The authors would like to thank Isabela Anjani for critical review on this manuscript.

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Authors and Affiliations

  1. Dexa Laboratories of Biomolecular Sciences (DLBS), PT Dexa Medica, Industri Selatan V, Block PP No. 7, Jababeka Industrial Estate II, Cikarang, 17550, West Java, Indonesia

    Stevanus Hiendrawan, Edward Widjojokusumo, Bambang Veriansyah & Raymond R. Tjandrawinata

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  1. Stevanus Hiendrawan
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  2. Edward Widjojokusumo
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  3. Bambang Veriansyah
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  4. Raymond R. Tjandrawinata
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Correspondence to Raymond R. Tjandrawinata.

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Hiendrawan, S., Widjojokusumo, E., Veriansyah, B. et al. Pharmaceutical Salts of Carvedilol: Polymorphism and Physicochemical Properties. AAPS PharmSciTech 18, 1417–1425 (2017). https://doi.org/10.1208/s12249-016-0616-x

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