Freeze-drying of drug nanosuspension– study of formulation and processing factors for the optimization and characterization of redispersible cilostazol nanocrystals

The aim of this work was to systematically study the effect of freeze-drying of bottom-up processed cilostazol nanosuspension on the particle size after redispersion. Several different cryoprotectants and concentrations were compared and the influence of processing variables such as freezing temperature, cooling rate and primary drying temperature was systematically and thoroughly evaluated in combinations across the matrix former range and their concentrations to establish their impact on nanocrystal size. As a result, optimal settings for the lyophilization of cilostazol nanosuspensions were identified in terms of good redispersibility and acceptable cake appearance. Selected optimal formulations containing 10% trehalose, 5% maltodextrin or 10% PEG 1500 were further characterized with respect to sample morphology, solid state and residual content of moisture (0.4–1.0%) and DMSO (0–13%). The freeze-dried nanocrystals successfully preserved not only their original size (d50 = 0.366–0.453 μm and d90 = 1.68–2.82 μm, depending on the matrix former) and polymorphic form A of cilostazol, but also the improved dissolution rate (over 90% of the drug dissolved in 5 min vs. less than 30% dissolved from raw, untreated cilostazol in 60 min). Moreover, the study addressed the specific problems related to the presence of organic solvent (DMSO) when freeze-drying nanosuspensions developed with bottom-up precipitation methods.

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Materials

Cilostazol supplied by Glenmark (Mumbai, India) was kindly donated by Przedsiębiorstwo Farmaceutyczne Lek-Am Sp. z o.o. All other materials of p.a. grade were purchased from commercial sources, namely Chempur (Piekary Śląskie, Poland): dimethyl sulfoxide (DMSO), sucrose, glucose monohydrate, lactose monohydrate, d-fructose, glycine, gum arabic; Sigma Aldrich (Merck Life Science, Poznan, Poland): poly(vinyl alcohol) (PVA) MW 9–10 kDa 80% hydrolyzed, methanol for HPLC 99.9%; Pol-Aura (Dywity, Poland): trehalose dihydrate, polyethylene glycol (PEG) 1500 and 4000, maltose monohydrate, maltodextrin D.E. 9-15, inulin, xylitol; Alfa Aesar (Thermo Fisher Scientific, Waltham, MA, USA): D-mannitol.

Emilia Jakubowska, Michał Bielejewski, Bartłomiej Milanowski, Janina Lulek,
Freeze-drying of drug nanosuspension– study of formulation and processing factors for the optimization and characterization of redispersible cilostazol nanocrystals,
Journal of Drug Delivery Science and Technology,
Volume 74, 2022, 103528, ISSN 1773-2247,
https://doi.org/10.1016/j.jddst.2022.103528.