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

Abstract

Engineering of pharmaceutical cocrystals is an advantageous alternative to salt formation for improving the aqueous solubility of hydrophobic drugs. Although, spray drying is a well-established scale-up technique in the production of cocrystals, several issues can arise such as sublimation or stickiness due to low glass transition temperatures of some organic molecules, making the process very challenging. Even though, fluidised bed spray coating has been successfully employed in the production of amorphous drug-coated particles, to the best of our knowledge, it has never been employed in the production of cocrystals. The feasibility of this technique was proven using three model cocrystals: sulfadimidine (SDM)/4-aminosalicylic acid (4ASA), sulfadimidine/nicotinic acid (NA) and ibuprofen (IBU)/ nicotinamide (NAM). Design of experiments were performed to understand the critical formulation and process parameters that determine the formation of either cocrystal or coamorphous systems for SDM/4ASA. The amount and type of binder played a key role in the overall solid state and in vitro performance characteristics of the cocrystals. The optimal balance between high loading efficiencies and high degree of crystallinity was achieved only when a binder: cocrystal weight ratio of 5:95 or 10:90 was used. The cocrystal coated beads showed an improved in vitro-in vivo performance characterised by: (i) no tendency to aggregate in aqueous media compared to spray dried formulations, (ii) enhanced in vitro activity (1.8-fold greater) against S. aureus, (iii) larger oral absorption and bioavailability (2.2-fold higher C), (iv) greater flow properties and (v) improved chemical stability than cocrystals produced by other methods derived from the morphology and solid nature of the starter cores.

Personalised 3D Printed Medicines: Optimising Material Properties for Successful Passive Diffusion Loading of Filaments for Fused Deposition Modelling of Solid Dosage Forms

“…The sample mass was allowed to reach equilibrium, defined as dm/dt ≤ 0.002 mg/min over 10 min, before the RH was changed [30].…”

“…where k is the degradation rate (% remaining drug/day), T is the temperature in Kelvin degrees, a is the collision factor, B is the humidity factor, RH is the relative humidity, Ea is the activation energy in kcal mol −1 , and R is the gas constant (0.00198 kcal K −1 mol −1 ) [30]. In order to calculate the degradation rate, the amount degraded at different time points was fitted at each condition to the following kinetic models: zero-order, first-order, second order, Avrami and diffusion using the following equations (Equations (12)-(16)) [39]:…”

Improved Solubility and Dissolution Rates in Novel Multicomponent Crystals of Piperine with Succinic Acid

“…In general, a multicomponent crystal phase includes a salt, cocrystal, hydrate, and solvate [32,33]. Numerous studies have demonstrated that the formation of a multicomponent crystal phase of API with a suitable excipient could enhance its physicochemical properties, such as solubility and dissolution rate, permeability, bioavailability, physical stability, compressibility, and pharmacological efficacy [34][35][36][37][38][39]. To the best of our knowledge, only two studies on the multicomponent crystal phase of piperine have been reported: a cocrystal with resveratrol, and a salt with a halide [40,41].…”

Cocrystal of Ibuprofen–Nicotinamide: Solid-State Characterization and In Vivo Analgesic Activity Evaluation

“…The preparation of the cocrystalline phase of ibuprofen with certain coformers has improved the drug’s solubility, intrinsic dissolution rate, and overall performance. The drug shows no likelihood to agglomerate in aqueous media, and can improve its chemical stability [ 7 ]. In addition, the mechanical properties and hygroscopicity of the compound are also reported to have improved simultaneously.…”