Abstract
The conventional “top-down”, “bottom-up” and “combination” approaches of generating drug nanocrystals produce a “nanosuspension” (NS). It requires significant downstream processing for drying the liquid by suitable means followed by its granulation to develop an oral solid dosage form (OSD). In this paper, we used a novel, spray drying-based NanoCrySP technology for the generation of drug nanocrystals in the form of nanocrystalline solid dispersion (NCSD). We hypothesized that the NCSD would require minimal downstream processing since the nanocrystals are obtained in powder form during spray drying. We further compared downstream processing of NS and NCSD of diclofenac acid (DCF) prepared by wet media milling and NanoCrySP technology, respectively. The NS and NCSD were characterized for crystallinity, crystal size, assay and dissolution. The NCSD was physically mixed with 0.3% Aerosil® 200, 1.76% croscarmellose sodium (CCS) and 0.4% sodium stearyl fumarate (SSF) and filled into size 0 hard gelatin capsules. The NS was first wet granulated using Pearlitol® SD 200 (G1 granules) and Celphere® 203 (G2 granules) in a fluidized bed processor, and the resulting granules were mixed using the same extra granular excipients as NCSD and filled into capsules. A discriminatory dissolution method was developed to monitor changes in dissolution behavior due to crystal growth during processing. Cost analysis and comparison of process efficiency was performed using an innovation radar tool. The NS and NCSD were successfully fabricated with a crystal size of 363 ± 21.87 and 361.61 ± 11.78, respectively. In comparison to NCSD-based capsules (65.13%), the G1 and G2 granules showed crystal growth and decrease in dissolution to 52.68% and 48.37%, respectively, in 120 min. The overall cost for downstream processing of NCSD was up to 80% lower than that of NS. An innovation radar tool also concluded that the one-step NanoCrySP technology was more efficient and required less downstream processing than the two-step wet media milling approach for conversion of nanocrystals to OSD.
Highlights
Poor aqueous solubility profoundly affects oral bioavailability of drugs belonging to Class II and IV of Biopharmaceutical Classification System (BCS)
MAN assisted in generation of diclofenac acid (DCF) nanocrystals in nanocrystalline solid dispersion (NCSD) by providing sites for heterogeneous nucleation during spray drying
The comparison of bottom-up spray drying-based NanoCrySP technology and the top-down wet media milling method followed by granulation using fluidized bed processor (FBP) was executed to identify an efficient process for the generation of nanocrystal-based oral solid dosage form (OSD)
Summary
Poor aqueous solubility profoundly affects oral bioavailability of drugs belonging to Class II and IV of Biopharmaceutical Classification System (BCS). A plethora of strategies such as particle size reduction, salt formation, solvent mixtures, inclusion compounds and complexation have been employed to improve solubility [1]. Amongst these approaches, particle size reduction to nano range is a promising strategy to tackle solubility as well as dissolution rate limited oral bioavailability [2,3]. The product obtained using these approaches is a liquid dispersion of nanocrystals—i.e., a nanosuspension [1,12,13] It possesses inherent physical and chemical instability issues such as sedimentation, crystal growth due to Ostwald ripening, solid-state transformation and hydrolysis. Incorporation of nanocrystals to oral solid dosage forms (OSDs) is essential for their commercial development [2,15,18]
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