In-situ crystallization of sildenafil during ionic crosslinking of alginate granules
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pISSN: 0256-1115 eISSN: 1975-7220
INVITED REVIEW PAPER
INVITED REVIEW PAPER
In-situ crystallization of sildenafil during ionic crosslinking of alginate granules Seungvin Cho*, Jeong Won Kang**, and Jonghwi Lee*,† *Department of Chemical Engineering and Materials Science, Chung-Ang University, 221 Heukseok-dong, Dongjak-gu, Seoul 06974, Korea **Department of Chemical and Biological Engineering, Korea University, 145 Anam-ro, Sungbuk-gu, Seoul 02841, Korea (Received 28 February 2020 • Revised 9 May 2020 • Accepted 13 May 2020)
AbstractHydrogel particles containing drug crystals were investigated for the development of drug formulations with improved processability, bioavailability, and physical stability. However, crystal engineering inside hydrogel particles has been limited due to various difficulties involved in the preparation processes and their control. This study demonstrates the crosslinking of alginate granules and the simultaneous crystallization of a drug, sildenafil, inside the granules by using a simple and scalable preparation technique. The particle size of the drug crystals was successfully decreased to the submicron range while their crystallinity could be controlled by the processing parameters. Moreover, these results are shown to be due to the strong interactions between the polymer chains and the drug as well as the diffusion-limited processes of solvent, antisolvent, sildenafil, alginate, and crosslinking ions (Ca2+). This simple crystallization technique will be useful for the development of novel drug delivery systems based on hydrogels and drug crystallites. Keywords: Drug Delivery, Hydrogel, Alginate, Sildenafil, Polymer-directed Crystallization, Granule
an antisolvent [10]. Unfortunately, the crystal size was not analyzed either and only the conventional X-ray powder diffraction (XRD) results, similar to those obtained from the regular antisolvent crystallization, were reported. Moreover, no interactions between the alginate and the drugs were reported in this study. Alginate microparticles were also utilized as additives (heteronucleants) to control the nucleation of drug crystals formed during cooling crystallization [11,12]. In this case, loading of the drug into the microparticles was only controlled through bulk nucleation and equilibrium partitioning, which are intrinsically difficult to control. Still, these previous studies did elucidate some details on the confinement effect and diffusion-limited crystallization. However, the structures of engineered particle and crystals were not investigated properly and, to the best of our knowledge, no attempt to uncrosslink the networks for the analysis of the loaded crystals has been made. In this study, a convenient and scalable process that can produce hydrogel granules containing drug crystals was developed. These hydrogel granules are large enough for post-unit operations such as blending, milling, compaction, and tableting [13], while the drug crystals are small enough to show improved dissolution characteristics [14-16]. In this s
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