Pharmaceutical Research

, Volume 25, Issue 12, pp 2835–2844 | Cite as

Ultrasound Assisted Engineering of Lactose Crystals

  • Ravindra S. Dhumal
  • Shailesh V. Biradar
  • Anant R. Paradkar
  • Peter York
Research Paper



To engineer lactose crystals of desired size, shape, surface and particle size distribution (PSD) as a carrier for dry powder inhalers (DPI) by ultrasound assisted in-situ seeding.


Lactose crystals were obtained from solution by ultrasound assisted in-situ seeding, followed by growth in viscous glycerin solution. The crystals were characterized for physical properties and 63–90 μm size fractions of different batches were mixed with salbutamol sulphate (SS) and compared for in-vitro deposition.


Cooling crystallization with stirring for 10–20 h resulted in crystals with wide PSD and varied shape. Application of ultrasound resulted in rapid and complete crystallization in 5 min with rod-shaped fine crystals (15–30 μm) and narrow PSD. In-situ seeded batches yielded micro-fine rod-shaped seed crystals. Seeding followed by growth in glycerin showed desirable size, high elongation ratio, smooth surface and narrow PSD, while growth under stirring showed high elongation ratio with rough surface. Crystals grown in glycerin showed highest dispersibility and fine particle fraction (FPF) of SS.


Ultrasound assisted in-situ seeding, followed by ordered growth in glycerin offers rapid technique for separation of nuclei induction from crystal growth yielding desirable characteristics for better dispersion and in-vitro deposition when employed as DPI carrier.


dry powder inhaler particle engineering ultrasound assisted crystallization α-lactose monohydrate 





bulk density


cooling crystallization from lactose solution 30% w/w


cooling crystallization from lactose solution 40% w/w


cooling crystallization from lactose solution 50% w/w


Carr’s index


dry powder inhaler


differential scanning calorimetry


emitted dose


fine particle dose


fine particle fraction


enthalpy of dehydration of lactose obtained from the dehydration endotherm (J/g)


enthalpy of vaporization of water, 2,261 J/g




α-lactose monohydrate




particle size distribution


recovered dose


molecular mass of anhydrous lactose (340.3)


molecular mass of water (18.0)


scanning electron microscopy


crystallization of 30% w/w lactose solution with sonication for 5 min


crystallization of 40% w/w lactose solution with sonication for 5 min


crystallization of 50% w/w lactose solution with sonication for 5 min


crystallization of 30% w/w lactose solution with sonication for 45 s followed by growth in glycerin


crystallization of 40% w/w lactose solution with sonication for 45 s followed by growth in glycerin


crystallization of 50% w/w lactose solution with sonication for 45 s followed by growth in glycerin


crystallization of 30% w/w lactose solution with sonication for 45 s followed by stirring


crystallization of 40% w/w lactose solution with sonication for 45 s followed by stirring


crystallization of 50% w/w lactose solution with sonication for 45 s followed by stirring


salbutamol sulphate


tap density


thermogravimetric analysis




X-ray powder diffractometry



Anant R. Paradkar is thankful to British Council for UK-India Education and Research Initiative (UKERI) Fellowship, Bharati Vidyapeeth University, Pune for the sabbatical leave and AICTE (New Delhi, India) for grant in the form of Research Promotion Scheme. Ravindra S. Dhumal and Shailesh V. Biradar are thankful to CSIR (New Delhi, India) for providing financial support in the form of Senior Research Fellowship (SRF). Authors acknowledge the support of Cipla Ltd, (Mumbai, India), DMV International (The Netherlands) and Universal Capsules (Mumbai, India) for providing gift samples of salbutamol sulphate, lactose monohydrate and hard gelatin capsules, respectively. Authors are thankful to Dr. P. K. Khanna, Head, Nano Science group, Centre for Materials for Electronic Technology (C-MET), Pune, India for providing the facilities at C-MET.


  1. 1.
    V. Kapil, A. K. Dodeja, and S. C. Sharma. Manufacture of lactose—Effect of processing parameters on yield and purity. J. Food Sci. Tech. 28:167–170 (1991).Google Scholar
  2. 2.
    T. A. Nickerson. Lactose chemistry. J. Agri. Food Chem. 27:672–677 (1979) doi: 10.1021/jf60224a038.CrossRefGoogle Scholar
  3. 3.
    B. Elvers, S. Hawkins, and G. Schulz. Ullmann’s encyclopedia of industrial chemistry. Vol. A, 15. VCH, Germany, 1990, pp. 107–114.Google Scholar
  4. 4.
    H. G. Brittain, S. J. Bogdanowich, D. F. Bugay, J. DeVincentis, G. Lewen, and A. W. Newman. Physical characterization of pharmaceutical solids. Pharm. Res. 8:963–973 (1991) doi: 10.1023/A:1015888520352.PubMedCrossRefGoogle Scholar
  5. 5.
    A. H. Kibbe (Ed). Lactose. In Handbook of pharmaceutical excipients, 3rd Edn. London Pharmaceutical, London, 2000, pp. 276–285.Google Scholar
  6. 6.
    S. L. Raghavan, R. I. Ristic, D. B. Sheen, and J. N. Sherwood. The bulk crystallization of lactose monohydrate from aqueous solution. J. Pharm. Sci. 90:823–832 (2000) doi: 10.1002/jps.1036.CrossRefGoogle Scholar
  7. 7.
    Y. Shi, B. Liang, and R.W. Hartel. Crystallization kinetics of alpha-lactose in a continuous cooling crystallizer. J. Food Sci. 55:817–820 (1990) doi: 10.1111/j.1365-2621.1990.tb05238.x.CrossRefGoogle Scholar
  8. 8.
    B. Liang, Y. Shi, and R. W. Hartel. Growth rate dispersion effects on lactose crystal size distributions from a continuous cooling crystallizer. J. Food Sci. 56:848–854 (1991) doi: 10.1111/j.1365-2621.1991.tb05397.x.CrossRefGoogle Scholar
  9. 9.
    R. K. Bund, and A. B. Pandit. Rapid lactose recovery from buffalo whey by use of ‘anti-solvent, ethanol’. J. Food Eng. 82:333–341 (2007) doi: 10.1016/j.jfoodeng.2007.02.045.CrossRefGoogle Scholar
  10. 10.
    H. Larhrib, G. P. Martin, C. Marriot, and D. Prime. The use of engineered lactose crystals as a carrier for aerosolized salbutamol sulphate from dry powder inhalers. Proceedings of drug delivery to the lungs, London. 10:155–159 (1999).Google Scholar
  11. 11.
    A. Leviton. Methanol extraction of lactose and soluble proteins from skim milk powder. Ind. Eng. Chem. 41:1351–1357 (1949) doi: 10.1021/ie50475a013.CrossRefGoogle Scholar
  12. 12.
    T. D. Dincer, G. M. Parkinson, A. L. Rohl, and M. I. Ogden. Crystallization of a-lactose monohydrate from dimethyl sufoxide (DMSO) solution: influence of b-lactose. J. Cryst. Growth. 205:368–374 (1999) doi: 10.1016/S0022-0248(99)00238-9.CrossRefGoogle Scholar
  13. 13.
    H. Larhrib, G. P. Martin, D. Prime, and C. Marriot. Characterization and deposition studies of engineered lactose crystals with potential for use as a carrier for aerosolized salbutamol sulphate from dry powder inhalers. Eur. J. Pharm. Sci. 19:211–221 (2003) doi: 10.1016/S0928-0987(03)00105-2.PubMedCrossRefGoogle Scholar
  14. 14.
    R. K. Bund, and A. B. Pandit. Sonocrystallization: effect on lactose recovery and crystal habit. Ultrason. Sonochem. 14:143–152 (2007) doi: 10.1016/j.ultsonch.2006.06.003.PubMedCrossRefGoogle Scholar
  15. 15.
    T. Bergfors. Seeds to crystals. J. Struct. Biol. 142:66–76 (2003) doi: 10.1016/S1047-8477(03)00039-X.PubMedCrossRefGoogle Scholar
  16. 16.
    M. Louhi-Kultanen, M. Karjalainen, J. Rantanen, M. Huhtanen, and J. Kallas. Crystallization of glycine with ultrasound. Int. J. Pharm. 320:23–29 (2006) doi: 10.1016/j.ijpharm.2006.03.054.PubMedCrossRefGoogle Scholar
  17. 17.
    H. Li, J. Wang, Y. Bao, Z. Guo, and M. Zhang. Rapid sonocrystallization in the salting-out process. J. Cryst. Growth. 247:192–198 (2003) doi: 10.1016/S0022-0248(02)01941-3.CrossRefGoogle Scholar
  18. 18.
    H. Steckel, P. Markefka, H. teWierik, and R. Kammelar. Functionality testing of inhalation grade lactose. Eur. J. Pharm. Biopharm. 57:495–505 (2004) doi: 10.1016/j.ejpb.2003.12.003.PubMedCrossRefGoogle Scholar
  19. 19.
    X. M. Zeng, G. P. Martin, S. K. Tee, A. A. Ghoush, and C. Marriott. Effect of particle size and adding sequence of fine lactose on the deposition of salbutamol sulphate from dry powder formulation. Int. J. Pharm. 182:133–144 (1999) doi: 10.1016/S0378-5173(99)00021-6.PubMedCrossRefGoogle Scholar
  20. 20.
    H. Larhrib, G. P. Martin, C. Marriot, and D. Prime. The influence of carrier and drug morphology on the drug delivery from dry powder formulation. Int. J. Pharm. 25:283–296 (2003) doi:  10.1016/S0378-5173(03)00156-X.CrossRefGoogle Scholar
  21. 21.
    J. N. Staniforth. Improvement in dry powder inhaler performance: surface passivation effects. Proceedings of Drug Delivery to Lung. 8:85–86 (1997).Google Scholar
  22. 22.
    X. M. Zeng, G. P. Martin, C. Marriott, and J. Pritchard. Crystallization of lactose from carbopol gels. Pharm. Res. 17:879–886 (2001) doi: 10.1023/A:1007572612308.CrossRefGoogle Scholar
  23. 23.
    X. M. Zeng, G. P. Martin, C. Marriott, and J. Pritchard. The use of lactose recrystallised from carbopol gels as a carrier for aerosolised salbutamol sulphate. Eur. J. Pharm. Biopharm. 51:55–62 (2001) doi: 10.1016/S0939-6411(00)00142-9.CrossRefGoogle Scholar
  24. 24.
    X. M. Zeng, G. P. Martin, C. Marriott, and J. Pritchard. The influence of crystallization conditions on the morphology of lactose intended for use as a carrier for dry powder aerosols. J. Pharm. Pharmacol. 52:633–643 (2000) doi: 10.1211/0022357001774462.PubMedCrossRefGoogle Scholar
  25. 25.
    M. D. Luque de Castro, and F. Priego-Capote. Ultrasound-assisted crystallization (sonocrystallization). Ultrason. Sonochem. 14:717–724 (2007) doi: 10.1016/j.ultsonch.2006.12.004.PubMedCrossRefGoogle Scholar
  26. 26.
    M. N. Patil, G. M. Gore, and A. B. Pandit. Ultrasonically controlled particle size distribution of explosives: a safe method. Ultrason. Sonochem. 15:177–187 (2008) doi: 10.1016/j.ultsonch.2007.03.011.PubMedCrossRefGoogle Scholar
  27. 27.
    M. Maheshwari, H. Jahagidar, and A. R. Paradkar. Melt sonocrystallization of ibuprofen: effect on crystal properties. Eur. J. Pharm. Sci. 25:41–48 (2005) doi: 10.1016/j.ejps.2005.01.013.CrossRefGoogle Scholar
  28. 28.
    A. R. Paradkar, M. Maheshwari, R. Kamble, I. Grimsey, and P. York. Design and Evaluation of celecoxib porous particles using melt sonocrystallization. Pharm. Res. 23:1395–1400 (2006) doi: 10.1007/s11095-006-0020-4.PubMedCrossRefGoogle Scholar
  29. 29.
    A. R. Paradkar, M. Maheshwari, A. R. Ketkar, and B. Chauhan. Preparation and evaluation of ibuprofen beads by melt solidification technique. Int. J. Pharm. 255:33–42 (2003) doi: 10.1016/S0378-5173(03)00081-4.PubMedCrossRefGoogle Scholar
  30. 30.
    Z. Guo, A. G. Jones, and N. Li. The effect of ultrasound on the homogeneous nucleation of BaSO4 during reactive crystallization. Chem. Eng. Sci. 61:1617–1626 (2006) doi: 10.1016/j.ces.2005.09.009.CrossRefGoogle Scholar
  31. 31.
    Z. Guo, A. M. Zhang, and H. Li. The effect of ultrasound on anti-solvent crystallization process. J. Cryst. Growth. 273:555–563 (2005) doi: 10.1016/j.jcrysgro.2004.09.049.CrossRefGoogle Scholar
  32. 32.
    P. W. Cains, P. D. Martin, and C. J. Price. The use of ultrasound in industrial chemical synthesis and crystallization. 1. Application to synthetic chemistry. Org. Process Res. Dev. 2:34–48 (1998) doi: 10.1021/op9700340.CrossRefGoogle Scholar
  33. 33.
    A. van Kreveld, and A. S. Michaels. Measurement of crystal growth rates in lactose crystals. J. Dairy Sci. 38:107–133 (1965).Google Scholar
  34. 34.
    R. S. Dhumal, S. V. Biradar, S. Yamamura, A. R. Paradkar and P. York. Preparation of amorphous cefuroxime axetil nanoparticles by sonoprecipitation for enhancement of bioavailability. Eur. J. Pharm. Biopharm. (2008) doi: 10.1016/j.ejpb.2008.04.001.
  35. 35.
    R. K. Khankari, D. Law, and D. J. W. Grant. Determination of water content in pharmaceutical hydrates by differential scanning calorimetry. Int. J. Pharm. 89:117–127 (1992) doi: 10.1016/0378-5173(92)90080-L.CrossRefGoogle Scholar
  36. 36.
    J. G. Stark and H. G. Wallace. In: Chemistry data book, SI Edn. John Murry, London, 1976, pp. 122.Google Scholar
  37. 37.
    G. Buckton, O. C. Chidavaenzi, and F. Koosha. The effect of spray drying feed temperature and subsequent crystallization conditions on the physical form of lactose. AAPS PharmSciTech. 3:1–6 (2002) doi: 10.1208/pt0304.CrossRefGoogle Scholar
  38. 38.
    P. R. Bryon, E. L. Kelly, and M. J. Kontny. Recommendations of the USP Advisory Panel on aerosols on the USP general chapters on aerosols <601> and uniformity of dosage units <905>. Pharm. Forum. 20:7477–7505 (1994).Google Scholar
  39. 39.
    X. M. Zeng, G. P. Martin, S. K. Tee, and C. Marriott. The role of fine lactose on the dispersion and deaggregation of salbutamol sulphate in an air stream in vitro. Int. J. Pharm. 176:99–110 (1998) doi: 10.1016/S0378-5173(98)00300-7.CrossRefGoogle Scholar
  40. 40.
    W. C. Hinds. Aerosol technology: properties, behavior and measurement of airborne particles. Wiley Interscience, New York, 1982.Google Scholar
  41. 41.
    K. Ikegami, Y. Kawashima, H. Takeuchi, H. Yamamoto, N. Isshiki, D. Momose, and K. Ouchi. Improved inhalation behavior of steroid KSR-592 in vitro with JethalerÒ by polymorphic transformation to needle-like crystals (b-form). Pharm. Res. 19:1439–1445 (2002) doi: 10.1023/A:1020492213172.PubMedCrossRefGoogle Scholar
  42. 42.
    A. J. Hickey, K. A. Fults, and R. S. Pillai. Use of particle morphology to influence the delivery of drugs from dry powder aerosols. J. Biopharm. Sci. 3:107–113 (1992).Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Ravindra S. Dhumal
    • 1
  • Shailesh V. Biradar
    • 1
  • Anant R. Paradkar
    • 1
    • 2
  • Peter York
    • 2
  1. 1.Department of PharmaceuticsBharati Vidyapeeth University, Poona College of Pharmacy and Research CentrePuneIndia
  2. 2.Institute of Pharmaceutical InnovationsUniversity of BradfordBradfordUK

Personalised recommendations