Skip to main content

Advertisement

SpringerLink
Log in

Thermodynamic and Kinetic Investigation on the Crucial Factors Affecting Adefovir Dipivoxil-Saccharin Cocrystallization

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

The aim of this study was to perform a thermodynamic and kinetic investigation on the crucial factors affecting the cocrystallization between adefovir dipivoxil (AD) and saccharin (SAC).

Methods

Phase solubility diagrams and ternary phase diagrams were constructed based on the solubility data of AD, SAC and their cocrystals in ethanol, isopropanol and ethyl acetate at different temperatures. The conductimetric method was used to determine the induction time. A quantitative and intuitive technique modified from dissolution testing was employed to investigate the cocrystallization kinetics.

Results

AD-SAC cocrystals exhibited different crystal habits but only one cocrystal polymorph was confirmed. The effects of several crucial factors, including the input amounts of two components, AD/SAC ratio, solvent and temperature, on the crystallization of single-component alone, cocrystal formation, cocrystal stability, supersaturation, nucleation, crystal growth and cocrystal yield were determined. Thermodynamic and kinetic parameters provided the rationale for this spontaneous cocrystallization system without the need of solvent evaporation and temperature change.

Conclusions

This systemic investigation enriched the present understanding of thermodynamics and kinetics of cocrystals and built the groundwork for AD-SAC cocrystal scale-up.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

AD:

Adefovir dipivoxil

API:

Active pharmaceutical ingredient

CBZ:

Carbamazepine

CCF:

Cocrystal former

IND:

Indomethacin

K 11 :

Complexation constant

K sp :

Solubility product

NCT:

Nicotinamide

PSD:

Phase solubility diagram

PTFE:

Polytetrafluoroethylene

SAC:

Saccharin

SEM:

Scanning electron microscopy

TPD:

Ternary phase diagram

XRPD:

X-ray powder diffraction

References

  1. Miroshnyk I, Mirza S, Sandler N. Pharmaceutical co-crystals-an opportunity for drug product enhancement. Expert Opin Drug Del. 2009;6(4):333–41.

    Article  CAS  Google Scholar 

  2. Shayanfar A, Asadpour-Zeynali K, Jouyban A. Solubility and dissolution rate of a carbamazepine–cinnamic acid cocrystal. J Mol Liq. 2013;187:171–6.

    Article  CAS  Google Scholar 

  3. Gao Y, Zu H, Zhang J. Enhanced dissolution and stability of adefovir dipivoxil by cocrystal formation. J Pharm Pharmacol. 2011;63(4):483–90.

    Article  CAS  PubMed  Google Scholar 

  4. Trask AV, Motherwell WD, Jones W. Physical stability enhancement of theophylline via cocrystallization. Int J Pharm. 2006;320(1):114–23.

    Article  CAS  PubMed  Google Scholar 

  5. Karki S, Friščić T, Fábián L, Laity PR, Day GM, Jones W. Improving mechanical properties of crystalline solids by cocrystal formation: new compressible forms of paracetamol. Adv Mater. 2009;21(38–9):3905–9.

    Article  CAS  Google Scholar 

  6. Jung MS, Kim JS, Kim MS, Alhalaweh A, Cho W, Hwang SJ, et al. Bioavailability of indomethacin-saccharin cocrystals. J Pharm Pharmacol. 2010;62(11):1560–8.

    Article  CAS  PubMed  Google Scholar 

  7. Chow SF, Chen M, Shi L, Chow AH, Sun CC. Simultaneously improving the mechanical properties, dissolution performance, and hygroscopicity of ibuprofen and flurbiprofen by cocrystallization with nicotinamide. Pharm Res. 2012;29(7):1854–65.

    Article  CAS  PubMed  Google Scholar 

  8. Ainouz A, Authelin JR, Billot P, Lieberman H. Modeling and prediction of cocrystal phase diagrams. Int J Pharm. 2009;374(1):82–9.

    Article  CAS  PubMed  Google Scholar 

  9. Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties. Cryst Growth Des. 2009;9(6):2950–67.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Padrela L, Rodrigues MA, Velaga SP, Fernandes AC, Matos HA, De Azevedo EG. Screening for pharmaceutical cocrystals using the supercritical fluid enhanced atomization process. J Supercrit Fluid. 2010;53(1):156–64.

    Article  CAS  Google Scholar 

  11. Nehm SJ, Rodríguez-Spong B, Rodriguez-Hornedo N. Phase solubility diagrams of cocrystals are explained by solubility product and solution complexation. Cryst Growth Des. 2006;6(2):592–600.

    Article  CAS  Google Scholar 

  12. Chiarella RA, Davey RJ, Peterson ML. Making co-crystals the utility of the ternary phase diagram. Cryst Growth Des. 2007;7(7):1223–6.

    Article  CAS  Google Scholar 

  13. Gagniere E, Mangin D, Puel F, Bebon C, Klein JP, Monnier O, et al. Cocrystal formation in solution: in situ solute concentration monitoring of the two components and kinetic pathways. Cryst Growth Des. 2009;9(8):3376–83.

    Article  CAS  Google Scholar 

  14. Derdour L, Fevotte G, Puel F, Carvin P. Real-time evaluation of the concentration of impurities during organic solution crystallization. Powder Technol. 2003;129(1):1–7.

    Article  CAS  Google Scholar 

  15. Gagniere E, Mangin D, Puel F, Rivoire A, Monnier O, Garcia E, et al. Formation of co-crystals: kinetic and thermodynamic aspects. J Cryst Growth. 2009;311(9):2689–95.

    Article  CAS  Google Scholar 

  16. Starrett JEJ, Tortolani DR, Russell J, Hitchcock MJ, Whiterock V, Martin JC, et al. Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy) ethyl] adenine (PMEA). J Med Chem. 1994;37(12):1857–64.

    Article  CAS  PubMed  Google Scholar 

  17. Gao Y, Gao J, Liu Z, Kan H, Zu H, Sun W, et al. Coformer selection based on degradation pathway of drugs: a case study of adefovir dipivoxil-saccharin and adefovir dipivoxil-nicotinamide cocrystals. Int J Pharm. 2012;438(1–2):327–35.

    Article  CAS  PubMed  Google Scholar 

  18. Hickey MB, Peterson ML, Scoppettuolo LA, Morrisette SL, Vetter A, Guzmán H, et al. Performance comparison of a co-crystal of carbamazepine with marketed product. Eur J Pharm Biopharm. 2007;67(1):112–9.

    Article  CAS  PubMed  Google Scholar 

  19. Nokhodchi A, Bolourtchian N, Dinarvand R. Crystal modification of phenytoin using different solvents and crystallization conditions. Int J Pharm. 2003;250(1):85–97.

    Article  CAS  PubMed  Google Scholar 

  20. Zhang J, Zu H, Gao Y. Formation thermodynamics of adefovir dipivoxil-saccharin co-crystals. Acta Phys-Chim Sin. 2011;27(3):547–52.

    Google Scholar 

  21. Good DJ, Rodríguez-Hornedo N. Solubility advantage of pharmaceutical cocrystals. Cryst Growth Des. 2009;9(5):2252–64.

    Article  CAS  Google Scholar 

  22. Schartman RR. On the thermodynamics of cocrystal formation. Int J Pharm. 2009;365(1):77–80.

    Article  CAS  PubMed  Google Scholar 

  23. Crosio MP, Jullien M. Fluorescence study of precrystallization of ribonuclease A: effect of salts. J Cryst Growth. 1992;122(1):66–70.

    Article  CAS  Google Scholar 

  24. Michinomae M, Mochizuki M, Ataka M. Electron microscopic studies on the initial process of lysozyme crystal growth. J Cryst Growth. 1999;197(1):257–62.

    Article  CAS  Google Scholar 

  25. Kozlovskii MI, Wakita H, Masuda I. Analyses of precipitation processes of bis (dimethylglyoximato) Ni (II) and related complexes. J Cryst Growth. 1983;61(2):377–82.

    Article  Google Scholar 

  26. Kuldipkumar A, Kwon GS, Zhang GG. Determining the growth mechanism of tolazamide by induction time measurement. Cryst Growth Des. 2007;7(2):234–42.

    Article  CAS  Google Scholar 

  27. Van der Leeden MC, Kashchiev D, Van Rosmalen GM. Precipitation of barium sulfate: Induction time and the effect of an additive on nucleation and growth. J Colloid Interf Sci. 1992;152(2):338–50.

    Article  Google Scholar 

  28. Söhnel O, Mullin JW. A method for the determination of precipitation induction periods. J Cryst Growth. 1978;44(4):377–82.

    Article  Google Scholar 

  29. Childs SL, Rodríguez-Hornedo N, Reddy LS, Jayasankar A, Maheshwari C, McCausland L, et al. Screening strategies based on solubility and solution composition generate pharmaceutically acceptable cocrystals of carbamazepine. CrystEngComm. 2008;10(7):856–64.

    Article  CAS  Google Scholar 

  30. Alhalaweh A, Sokolowski A, Rodríguez-Hornedo N, Velaga SP. Solubility behavior and solution chemistry of indomethacin cocrystals in organic solvents. Cryst Growth Des. 2011;11(9):3923–9.

    Article  CAS  Google Scholar 

  31. Higuchi T, Connors KA. Phase-solubility techniques. Adv Anal Chem Instrum. 1965;4(2):117–212.

    CAS  Google Scholar 

  32. Alhalaweh A, Velaga SP. Formation of cocrystals from stoichiometric solutions of incongruently saturating systems by spray drying. Cryst Growth Des. 2010;10(8):3302–5.

    Article  CAS  Google Scholar 

  33. Rahman Z, Agarabi C, Zidan AS, Khan SR, Khan MA. Physico-mechanical and stability evaluation of carbamazepine cocrystal with nicotinamide. AAPS PharmSciTech. 2011;12(2):693–704.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Lee KC, Kim KJ. Effect of supersaturation and thermodynamics on co-crystal formation. Chem Eng Technol. 2011;34(4):619–23.

    Article  CAS  Google Scholar 

  35. Rodríguez-Hornedo N, Nehm SJ, Seefeldt KF, Pagán-Torres Y, Falkiewicz CJ. Reaction crystallization of pharmaceutical molecular complexes. Mol Pharmaceut. 2006;3(3):362–7.

    Article  Google Scholar 

  36. Yi WT, Yan CY, Ma PH. Crystallization kinetics of Li2CO3 from LiHCO3 solutions. J Cryst Growth. 2010;312(16):2345–50.

    Article  CAS  Google Scholar 

  37. Tung HH, Paul EL, Midler M, McCauley JA. Crystallization of organic compounds: an industrial perspective. New Jersey: Wiley-AIChE; 2009.

    Book  Google Scholar 

  38. Selvaraju K, Valluvan R, Kumararaman S. Experimental determination of metastable zone width, induction period, interfacial energy and growth of nonlinear optical Hippuric acid single crystal. Mater Lett. 2006;60(12):1549–53.

    Article  CAS  Google Scholar 

  39. Liu X, Wang Z, Duan A, Zhang G, Wang X, Sun Z, et al. Measurement of l-arginine trifluoroacetate crystal nucleation kinetics. J Cryst Growth. 2008;310(10):2590–2.

    Article  CAS  Google Scholar 

  40. Nielsen AE, Sarig S. Homogeneous nucleation of droplets and interfacial tension in the liquid system methanol-water-tribromomethane. J Cryst Growth. 1971;8(1):1–7.

    Article  CAS  Google Scholar 

  41. Storey RA, Ymén I. Solid state characterization of pharmaceuticals. Chichester: Wiley-Blackwell; 2011.

    Book  Google Scholar 

  42. Desikan S, Anderson SR, Meenan PA, Toma PH. Crystallization challenges in drug development: scale-up from laboratory to pilot plant and beyond. Curr Opin Drug Discov Dev. 2000;3(6):723–33.

    CAS  Google Scholar 

  43. Beckmann W. Crystallization- basic concepts and industrial applications. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA; 2013.

    Book  Google Scholar 

Download references

Acknowledgments

This research was supported by the Important National Science & Technology Specific Projects (NO. 2011ZX09201-101-02), The National Natural Science Fund (NO. 81202988) and the Fundamental Research Funds for the Central Universities (Program No. JKP2011006).

Author information

Authors and Affiliations

  1. School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China

    Kun Ma, Ying Zhang, Hongliang Kan, Ling Luo, Qing Su & Jianjun Zhang

  2. School of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, 210009, China

    Linfeng Cheng, Jing Gao & Yuan Gao

  3. Center for Drug Evaluation, State Food and Drug Administration, Beijing, 100038, China

    Kun Ma

Authors
  1. Kun Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongliang Kan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Linfeng Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ling Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qing Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jing Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuan Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jianjun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jianjun Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ma, K., Zhang, Y., Kan, H. et al. Thermodynamic and Kinetic Investigation on the Crucial Factors Affecting Adefovir Dipivoxil-Saccharin Cocrystallization. Pharm Res 31, 1766–1778 (2014). https://doi.org/10.1007/s11095-013-1281-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-013-1281-3

KEY WORDS

Search

Navigation