Controlled Recrystallization of Tubular Vinpocetine Crystals with Increased Aqueous Dissolution Rate and In Vivo Bioavailability

Abstract

Vinpocetine was a BCS II drug, whose clinical applications had suffered from low oral bioavailability because of its inefficient dissolution in the GI tract. As the dissolution rate depended on the surface area of the drug crystals, we herein explored shape-controlled recrystallization via antisolvent process as an excipient-free strategy to improve the bioavailability of VIN. By adjusting the water/ethanol ratio, initial VIN concentration, and temperatures, morphologies of the crystalline products could be finely tuned from three-dimensional cubes and tubes, to twodimensional frizzled plates, and finally to zero-dimensional microparticle clusters. Morphology analysis and in situ FBRM surveillance of the growing process suggested that a diffusion-limited crystal growth mechanism was responsible for the shape variation of VIN products. Finally, we tested the in vitro dissolution efficiency as well as the in vivo bioavailability of recrystallized VIN crystals. Results manifested that the tubular crystal showed a faster dissolution behavior as compared with the raw VIN, achieving an increased AUC 0-t of 484.0 ± 24.6 ng/mL•h, which was 1.3-fold that of the raw VIN product (386.6 ± 22.8 ng/mL•h). To the best of our knowledge, this was one in vitro to in vivo report for bioavailability improvement of BCS II drug by applying the shape-controlled recrystallization strategy.

Impact of Affecting the Formation Defects in Vinpocetine Crystals

“…The crystal surface condition of the VIP crystal and the presence of cavities could be obtained by scanning electron microscopy (SEM) analysis. A crystal habit regulation scheme for hollow tubular VIP crystal has been reported by Sun et al 15 The SEM photographs shown in Figure 6 revealed a cubic VIP crystal with multiple types of cavities on the surface of the crystal. These features shared by Figure 6a,b suggested that the isolated cavities on the crystal plane usually appear at the junction of the crystal face, and the scanning electron microscope image shows that the size of the exposed cavities entrance reached 10−20 μm.…”

“…12−14 It is known that VIP crystalline products contained several crystal habits and extraordinary crystal defects. Sun et al 15 designed a specific antisolvent crystallization protocol to obtain a tubular VIP crystal and proposed the theoretical mechanisms for its formation. However, studies on the formation mechanism of VIP crystal defects and the regulation of key influencing factors have not been reported.…”

Two anhydrous forms and one monohydrate of a cocrystal of axitinib and glutaric acid: characterization, property evaluation and phase transition study

“…Based on the literature, it is known that the polymorphism, morphology, and particle size can work together to affect the dissolution behavior of a solid drug. 51,52 As the particle size was controlled to the same level for all the samples by sieving before the dissolution testing, the different polymorphic forms and different morphologies are possible reasons for the better dissolution behavior of AXI-GA·H 2 O than AXI-GA I .…”

Membrane-Assisted Antisolvent Crystallization: Interfacial Mass-Transfer Simulation and Multistage Process Control

“…Antisolvent crystallization is an essential separation and purification technology in the manufacturing of fine chemicals , and pharmaceutical crystals. − By avoiding high-temperature operations, antisolvent crystallization is suitable for heat-sensitive materials with low energy consumption. − Also, the final product can be easily regulated by adjusting the operating parameters − and solution/antisolvent system. , While the traditional approach of antisolvent crystallization usually involves batch droplets and mixing of the antisolvent, this operation commonly induces a local high supersaturation degree and explosive nucleation, which easily result in broad crystal size distribution and undesired particle morphology. − The mixing rate and supersaturation distribution cannot meet the stable nucleation requirement of the scale-up operation . Thus, the accurate mass transfer and supersaturation control at the antisolvent–solvent mixing interface are the eternal concerns to hinder the exceeding local supersaturated concentration and explosive nucleation. − …”