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

The AAPS Journal
H de WaardH W Frijlink

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 dissolu...Continue Reading

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Citations

Jul 24, 2013·International Journal of Pharmaceutics·Baoyan ZuoZhonggui He
May 13, 2014·Journal of Pharmaceutical and Biomedical Analysis·Juan G RosasMarcel Blanco
May 25, 2011·Pharmaceutical Research·Hans de WaardHenderik W Frijlink
Dec 19, 2015·Critical Reviews in Clinical Laboratory Sciences·Menuka Pallebage-GamarallageJohn Mamo
Aug 8, 2014·Journal of Pharmaceutical Sciences·William Wei Lim ChinRajeev Gokhale
Dec 21, 2010·International Journal of Pharmaceutics·T De BeerC Vervaet
Apr 15, 2015·Advanced Drug Delivery Reviews·Amrit PaudelJukka Rantanen
Jun 9, 2016·Expert Opinion on Drug Delivery·Carin Ru Shan SiowLai Wah Chan
Sep 3, 2016·Pharmaceutics·Manasi M ChogaleVandana B Patravale
Feb 14, 2018·Bioengineering·Bhavesh D KevadiyaChandrabhanu Tripathi
May 26, 2021·Drug Development and Industrial Pharmacy·Maja PreskarMirjana Gašperlin

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Methods Mentioned

BETA
Raman
differential scanning calorimetry
X-ray

Software Mentioned

HoloREACT
PLSplusIQ
Grams
AI
Matlab

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