An example of how to handle amorphous fractions in API during early pharmaceutical development: SAR114137--a successful approach.
The so-called pharmaceutical solid chain, which encompasses drug substance micronisation to the final tablet production, at pilot plant scale is presented as a case study for a novel, highly potent, pharmaceutical compound: SAR114137. Various solid-state analytical methods, such as solid-state Nuclear Magnetic Resonance (ssNMR), Differential Scanning Calorimetry (DSC), Dynamic Water Vapour Sorption Gravimetry (DWVSG), hot-stage Raman spectroscopy and X-ray Powder Diffraction (XRPD) were applied and evaluated to characterise and quantify amorphous content during the course of the physical treatment of crystalline active pharmaceutical ingredient (API). DSC was successfully used to monitor the changes in amorphous content during micronisation of the API, as well as during stability studies. (19)F solid-state NMR was found to be the method of choice for the detection and quantification of low levels of amorphous API, even in the final drug product (DP), since compaction during tablet manufacture was identified as a further source for the formation of amorphous API. The application of different jet milling techniques was a critical factor with respect to amorphous content formation. In the present case, the change from spiral jet milling to loop jet milling led to a decrease in amorphous API content from 20-30 w/w% to nearly 0 w/w% respectively. The use of loop jet milling also improved the processability of the API. Stability investigations on both the milled API and the DP showed a marked tendency for recrystallisation of the amorphous API content on exposure to elevated levels of relative humidity. No significant impact of amorphous API on either the chemical stability or the dissolution rate of the API in drug formulation was observed. Therefore, the presence of amorphous content in the oral formulation was of no consequence for the clinical trial phases I and II.
Sanofi-Aventis Deutschland GmbH, Chemical and Biotechnological Development (C&BD) Frankfurt Chemistry, Frankfurt, Germany. Electronic address: Christine.petzoldt@sanofi.com.
Christine
C
Petzoldt
Sanofi-Aventis Deutschland GmbH, R&D, LGCR, Pharmaceutical Operations, Frankfurt, Germany.
Oliver
O
Bley
Covance Laboratories, Alnwick, Northumberland, United Kingdom. Electronic address: Stephen.Byard@covance.com.
Stephen J
SJ
Byard
Sanofi-Aventis Deutschland GmbH, R&D, LGCR, Analytical Development, Frankfurt, Germany.
Doris
D
Andert
Sanofi-Aventis Deutschland GmbH, R&D, LGCR, Analytical Development, Frankfurt, Germany.
Bruno
B
Baumgartner
Sanofi-Aventis Deutschland GmbH, R&D, LGCR, Analytical Development, Frankfurt, Germany.
Norbert
N
Nagel
Sanofi-Aventis Deutschland GmbH, Chemical and Biotechnological Development (C&BD) Frankfurt Chemistry, Frankfurt, Germany.
Christoph
C
Tappertzhofen
Sanofi-Aventis Deutschland GmbH, Chemical and Biotechnological Development (C&BD) Frankfurt Chemistry, Frankfurt, Germany. Electronic address: Martinphilipp.feth@sanofi.com.
Martin Philipp
MP
Feth
D000700:Analgesics / Q000138:chemical synthesis*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D055808:Drug Discovery / Q000379:methods*; D013059:Spectrum Analysis, Raman / Q000379:methods*; D014961:X-Ray Diffraction / Q000379:methods*
D000700:Analgesics
Amorphous content; Differential Scanning Calorimetry (DSC); Jet milling; Micronisation; Pharmaceutical solid chain; Solid-state Nuclear Magnetic Resonance (ssNMR)