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

Abstract

Purpose: The aim of this work was to evaluate the influence of crystal habit on the dissolution and in vitro antibacterial and anitiprotozoal activity of sulfadimidine:4-aminosalicylic acid cocrystals.Methods: Cocrystals were produced via milling or solvent mediated processes. In vitro dissolution was carried out in the flow-through apparatus, with shadowgraph imaging and mechanistic mathematical models used to observe and simulate particle dissolution. In vitro activity was tested using agar diffusion assays.Results: Cocrystallisation via milling produced small polyhedral crystals with antimicrobial activity significantly higher than sulfadimidine alone, consistent with a fast dissolution rate which was matched only by cocrystals which were milled following solvent evaporation.Cocrystallisation by solvent evaporation (ethanol, acetone) or spray drying produced flattened, plate-like or quasi-spherical cocrystals, respectively, with more hydrophobic surfaces and greater tendency to form aggregates in aqueous media, limiting both the dissolution rate and in vitro activity. Deviation from predicted dissolution profiles was attributable to aggregation behaviour, supported by observations from shadowgraph imaging. Conclusions: Aggregation behaviour during dissolution of cocrystals with different habitsaffected the dissolution rate, consistent with in vitro activity. Combining mechanistic models with shadowgraph imaging is a valuable approach for dissolution process analysis.

Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals

“…Grossjohann et al used liquidassisted milling and spray drying to generate two different polymorphic forms of sulfadimidine:4-aminosalicylic acid cocrystals (1:1) where spray drying from ethanol led to the formation of the metastable form II of the cocrystal and liquid (ethanol)-assisted milling led to the formation of the thermodynamically stable form I of the cocrystal. Spray drying was determined, by PXRD and DVS to lead to partial amorphisation, which was not observed for form II cocrystals prepared by liquidassisted milling or solvent evaporation from ethanol or acetone [147]. Alhalaweh and Velaga showed that spray drying of incongruently saturating systems can lead to the formation of pure cocrystals.…”

“…DVS is important for studying the relationship between sorbed vapors and different solid forms [202]. Sorption-desorption isotherms in dynamic vapor sorption may be used to quantify the equilibrium amount of vapor sorbed or desorbed as a function of the amount of vapor present, at isothermal/ isobaric conditions [147]. The vapors can be from water or any volatile solvent.…”

Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating

“…The coformer should be a GRAS (generally regarded as safe) listed molecule with high solubility, but it can be also be another active molecule that enhances the activity of the API. Several examples are described in the literature where the coformer improves API activity such as the sulfadimidine (SDM) -4 aminosalicylic acid (4ASA) cocrystal for infectious diseases [6,7] or the celecoxib -tramadol (hydrochloride) cocrystal which is used for the treatment of pain, and was recently approved and commercialized by Esteve S.A [8,9].…”

Characterization and Simulation of Hydrodynamics in the Paddle, Basket and Flow-Through Dissolution Testing Apparatuses - A Review

“…In a hypothetical situation, a change in flow rate should not impact the relative fluid velocity, however, the effect of flow rate on dispersion of the powder bed and particle interactions with the cell surfaces will be affected by flow rate. Shadowgraph imaging has proven useful for exploring particle behavior within the FTC apparatus in terms of particle velocities, sizes, and particle agglomeration tendencies (4,14).…”

“…Shadowgraph imaging is a noninvasive optical technique which, in addition to quantifying the size and shape of particles at a point in time, can also quantify their absolute velocity ( Figure 1) (4,14). Digital images of particle-laden fluid are captured against a background of pulsed light.…”