Assessment of formulation robustness for nano-crystalline suspensions using failure mode analysis or derisking approach.
The small particle size of nano-crystalline suspensions can be responsible for their physical instability during drug product preparation (downstream processing), storage and administration. For that purpose, the commercial formulation needs to be sufficiently robust to various triggering conditions, such as ionic strength, shear rate, wetting/dispersing agent desorption by dilution, temperature and pH variation. In our previous work we described a systematic approach to select the suitable wetting/dispersant agent for the stabilization of nano-crystalline suspension. In this paper, we described the assessment of the formulation robustness (stabilized using a mixture of sodium dodecyl sulfate (SDS) and polyvinylpyrrolidone (PVP) and) by measuring the rate of perikinetic (diffusion-controlled) and orthokinetic (shear-induced) aggregation as a function of ionic strength, temperature, pH and dilution. The results showed that, using the SDS/PVP system, the critical coagulation concentration is about five times higher than that observed in the literature for suspension colloidaly stable at high concentration. The nano-suspension was also found to be very stable at ambient temperature and at different pH conditions. Desorption test confirmed the high affinity between API and wetting/dispersing agent. However, the suspension undergoes aggregation at high temperature due to the desorption of the wetting/dispersing agent and disaggregation of SDS micelles. Furthermore, aggregation occurs at very high shear rate (orhokinetic aggregation) by overcoming the energy barrier responsible for colloidal stability of the system.
Sanofi R&D, 13, quai Jules Guesde, 94403 Vitry sur Seine, France. Electronic address: mostafa.nakach@sanofi.com.
Mostafa
M
Nakach
Sanofi R&D, 13, quai Jules Guesde, 94403 Vitry sur Seine, France. Electronic address: Jean-Rene.Authelin@sanofi.com.
Jean-René
JR
Authelin
Ecole des Mines d'Albi, Campus Jarlard, Route de Teillet 83013 Albi France, France. Electronic address: cecile.voignier@mines-albi.fr.
Cecile
C
Voignier
89 Nash Grove Lane, Wokingham, Berkshire RG40 4HE, UK. Electronic address: tharwat@tadros.fsnet.co.uk.
Tharwat
T
Tadros
Ecole des Mines d'Albi, Campus Jarlard, Route de Teillet 83013 Albi France, France. Electronic address: laurence.Galet@mines-albi.fr.
Laurence
L
Galet
Ecole des Mines d'Albi, Campus Jarlard, Route de Teillet 83013 Albi France, France. Electronic address: alain.chamayou@mines-albi.fr.
Alain
A
Chamayou
D002626:Chemistry, Pharmaceutical / Q000379:methods; D003460:Crystallization; D004355:Drug Stability; D004356:Drug Storage; D005079:Excipients / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008823:Micelles; D053758:Nanoparticles; D009994:Osmolar Concentration; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry; D011205:Povidone / Q000737:chemistry*; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry*; D013535:Suspensions; D013696:Temperature
D005079:Excipients; D008823:Micelles; D004364:Pharmaceutical Preparations; D013535:Suspensions; D012967:Sodium Dodecyl Sulfate; D011205:Povidone
Aggregation; Dispersing agent; Flocculation; Nano-crystalline suspension; Shear rate; Wetting agent