Cocrystal habit engineering to improve drug dissolution and alter derived powder properties

Abstract

Objectives: Cocrystallization of sulfadimidine (SDM) with suitable coformers, such as 4-aminosalicylic acid (4-ASA), combined with changes in the crystal habit can favourably alter its physicochemical properties. The aim of this work was to engineer SDM:4-ASA cocrystals with different habits in order to investigate the effect on dissolution, and the derived powder properties of flow and compaction.Methods: Cocrystals were prepared in a 1:1 molar ratio by solvent evaporation using ethanol (habit I) or acetone (habit II), solvent evaporation followed by grinding (habit III) and spray-drying (habit IV).Key findings: Powder X-ray diffraction showed Bragg peak position was the same in all the solid products. The peak intensity varied, indicating different preferred crystal orientation confirmed by SEM micrographs: large prismatic crystals (habit I), large platelike crystals (habit II), small cube-like crystals (habit III) and microspheres (habit IV). The habit III exhibited the fasted dissolution rate; however, it underwent a polymorphic transition during dissolution. Habits I and IV exhibited the highest Carr's compressibility index, indicating poor flowability. However, habits II and III demonstrated improved flow. Spray drying resulted in cocrystals with improved compaction properties.Conclusions: Even for cocrystals with poor pharmaceutical characteristics, a habit can be engineered to alter the dissolution, flowability and compaction behavior.

Modelling and shadowgraph imaging of cocrystal dissolution and assessment of in vitro antimicrobial activity for sulfadimidine/4-aminosalicylic acid cocrystals

“…Experimental values were in good agreement with the simulated dissolution profile for PI and PII-IV. The faster cocrystal dissolution from PII-IV could be explained by the polymorphic transformation of PII-IV into PI in water during dissolution at very early time points, but also due to the engineered crystal habit as previously reported (Serrano et al, 2015b). The simulations for PII-HI, HII and HIII predicted the same rank-order of dissolution rates as experimental observations, but simulated dissolution rates were faster than experimental in each case.…”

“…However, this rapid drug release was followed by a levelling off in dissolution rate for the remainder of the dissolution time course, which resulted in an overestimation in the simulated dissolution profile. As previously described, the dissolution profile was incongruent, characterised by a larger and faster release of 4-ASA compared to SDM (Serrano et al, 2015b). Newer findings suggest that the in situ formation of the PI cocrystal could lead to a change in the initial release rate of SDM, contributing to the fast release observed up to 10 min.…”

“…Cocrystal Polymorph II-Habit III (PII-HIII) was obtained by spray-drying ethanolic solutions of SDM:4-ASA (1:1 molar ratio) using a Buchi B-290 Mini Spray Dryer (Buchi, Flawil, Switzerland) operating in the open-mode, as previously described [12]. Cocrystal Polymorph II-Habit IV (PII-HIV) was obtained from polymorph II-Habit I after dry milling in a planetary ball mill (Retsch PM100, Haan, Germany) as previously described (Serrano et al, 2015b). An equimolar physical mixture (PM) of 4-ASA and SDM was prepared by mixing the raw components in a mortar and pestle.…”

“…Cocrystal Polymorph II-Habit I (PII-HI) was obtained by crystallization from ethanol using a rotavapor (Buchi, Flawil, Switzerland) at 250 mbar pressure and 55 °C as previously described (Serrano et al, 2015b). Cocrystal Polymorph IIHabit II (PII-HII) was obtained by crystallization from acetone also using a rotavapor (Buchi, Flawil, Switzerland) at 250 mbar pressure and 55 °C as previously described (Serrano et al, 2015b). Cocrystal Polymorph II-Habit III (PII-HIII) was obtained by spray-drying ethanolic solutions of SDM:4-ASA (1:1 molar ratio) using a Buchi B-290 Mini Spray Dryer (Buchi, Flawil, Switzerland) operating in the open-mode, as previously described [12].…”

“…All cocrystals were prepared using a 1:1 molar ratio (SDM:4-ASA), as previously described (Serrano et al, 2015b).…”