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Controlled crystallization of the lipophilic drug fenofibrate during freeze-drying: elucidation of the mechanism by in-line Raman spectroscopy

Hans de Waard, Thomas De Beer UGent, Wouter LJ Hinrichs, Chris Vervaet UGent, Jean Paul Remon UGent and Henderik W Frijlink (2010) AAPS JOURNAL. 12(4). p.569-575
abstract
We developed a novel process, “controlled crystallization during freeze-drying” to produce drug nanocrystals of poorly water soluble drugs. This process involves freeze-drying at a relatively high temperature of a drug and a matrix material from a mixture of tertiary butyl alcohol and water, resulting in drug nanocrystals incorporated in a matrix. The aim of this study was to elucidate the mechanisms that determine the size of the drug crystals. Fenofibrate was used as a model lipophilic drug. To monitor the crystallization during freeze-drying, a Raman probe was placed just above the sample in the freeze-dryer. These in-line Raman spectroscopy measurements clearly revealed when the different components crystallized during freeze-drying. The solvents crystallized only during the freezing step, while the solutes only crystallized after the temperature was increased, but before drying started. Although the solutes crystallized only after the freezing step, both the freezing rate and the shelf temperature were critical parameters that determined the final crystal size. At a higher freezing rate, smaller interstitial spaces containing the freeze-concentrated fraction were formed, resulting in smaller drug crystals (based on dissolution data). On the other hand, when the solutes crystallized at a lower shelf temperature, the degree of supersaturation is higher, resulting in a higher nucleation rate and consequently more and therefore smaller crystals. In conclusion, for the model drug fenofibrate, a high freezing rate and a relatively low crystallization temperature resulted in the smallest crystals and therefore the highest dissolution rate.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
fenofibrate, dissolution, nanocrystal, poorly water-soluble drug, raman spectroscopy, WATER-SOLUBLE DRUGS, PARTICLE-SIZE, DEVELOPMENT SETTINGS, DISSOLUTION RATES, NANOCRYSTALS, BIOAVAILABILITY, CLASSIFICATION, NANOPARTICLES, FORMULATION, TECHNOLOGY
journal title
AAPS JOURNAL
AAPS J.
volume
12
issue
4
pages
569 - 575
Web of Science type
Article
Web of Science id
000288426100009
JCR category
PHARMACOLOGY & PHARMACY
JCR impact factor
3.942 (2010)
JCR rank
42/249 (2010)
JCR quartile
1 (2010)
ISSN
1550-7416
DOI
10.1208/s12248-010-9215-z
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
978844
handle
http://hdl.handle.net/1854/LU-978844
date created
2010-06-16 09:17:48
date last changed
2011-07-08 12:25:41
@article{978844,
  abstract     = {We developed a novel process, {\textquotedblleft}controlled crystallization during freeze-drying{\textquotedblright} to produce drug nanocrystals of poorly water soluble drugs. This process involves freeze-drying at a relatively high temperature of a drug and a matrix material from a mixture of tertiary butyl alcohol and water, resulting in drug nanocrystals incorporated in a matrix. The aim of this study was to elucidate the mechanisms that determine the size of the drug crystals. Fenofibrate was used as a model lipophilic drug. To monitor the crystallization during freeze-drying, a Raman probe was placed just above the sample in the freeze-dryer. These in-line Raman spectroscopy measurements clearly revealed when the different components crystallized during freeze-drying. The solvents crystallized only during the freezing step, while the solutes only crystallized after the temperature was increased, but before drying started. Although the solutes crystallized only after the freezing step, both the freezing rate and the shelf temperature were critical parameters that determined the final crystal size. At a higher freezing rate, smaller interstitial spaces containing the freeze-concentrated fraction were formed, resulting in smaller drug crystals (based on dissolution data). On the other hand, when the solutes crystallized at a lower shelf temperature, the degree of supersaturation is higher, resulting in a higher nucleation rate and consequently more and therefore smaller crystals. In conclusion, for the model drug fenofibrate, a high freezing rate and a relatively low crystallization temperature resulted in the smallest crystals and therefore the highest dissolution rate.},
  author       = {de Waard, Hans and De Beer, Thomas and Hinrichs, Wouter LJ and Vervaet, Chris and Remon, Jean Paul and Frijlink, Henderik W},
  issn         = {1550-7416},
  journal      = {AAPS JOURNAL},
  keyword      = {fenofibrate,dissolution,nanocrystal,poorly water-soluble drug,raman spectroscopy,WATER-SOLUBLE DRUGS,PARTICLE-SIZE,DEVELOPMENT SETTINGS,DISSOLUTION RATES,NANOCRYSTALS,BIOAVAILABILITY,CLASSIFICATION,NANOPARTICLES,FORMULATION,TECHNOLOGY},
  language     = {eng},
  number       = {4},
  pages        = {569--575},
  title        = {Controlled crystallization of the lipophilic drug fenofibrate during freeze-drying: elucidation of the mechanism by in-line Raman spectroscopy},
  url          = {http://dx.doi.org/10.1208/s12248-010-9215-z},
  volume       = {12},
  year         = {2010},
}

Chicago
de Waard, Hans, Thomas De Beer, Wouter LJ Hinrichs, Chris Vervaet, Jean Paul Remon, and Henderik W Frijlink. 2010. “Controlled Crystallization of the Lipophilic Drug Fenofibrate During Freeze-drying: Elucidation of the Mechanism by In-line Raman Spectroscopy.” Aaps Journal 12 (4): 569–575.
APA
de Waard, H., De Beer, T., Hinrichs, W. L., Vervaet, C., Remon, J. P., & Frijlink, H. W. (2010). Controlled crystallization of the lipophilic drug fenofibrate during freeze-drying: elucidation of the mechanism by in-line Raman spectroscopy. AAPS JOURNAL, 12(4), 569–575.
Vancouver
1.
de Waard H, De Beer T, Hinrichs WL, Vervaet C, Remon JP, Frijlink HW. Controlled crystallization of the lipophilic drug fenofibrate during freeze-drying: elucidation of the mechanism by in-line Raman spectroscopy. AAPS JOURNAL. 2010;12(4):569–75.
MLA
de Waard, Hans, Thomas De Beer, Wouter LJ Hinrichs, et al. “Controlled Crystallization of the Lipophilic Drug Fenofibrate During Freeze-drying: Elucidation of the Mechanism by In-line Raman Spectroscopy.” AAPS JOURNAL 12.4 (2010): 569–575. Print.