<p>Engineering of solidified glyburide nanocrystals for tablet formulation via loading of carriers: downstream processing, characterization, and bioavailability</p>

Abstract

Introduction: Presenting poorly water-soluble drugs as nanoparticles has shown to be an effective technique in enhancing drug dissolution rate, intrinsic solubility, and thus oral bioavailability. Nevertheless, working with nanoparticles introduces many challenges, one of which is their physical instability. Formulating nanoparticles into a solid dosage form may overcome such challenges and thus unlock the potential benefits of nanosizing. Methods: The current work investigates the possibility of developing a novel solid dosage form, with enhanced dissolution rate, whereby nanocrystals (~400 nm) of the class II Biopharmaceutical Classification System drug, glyburide (GBD) were fabricated through combined precipitation and homogenization procedures. Using a novel, but scalable, spraying technique, GBD nanocrystals were loaded onto commonly used tablet fillers, water-soluble lactose monohydrate (LAC), and water insoluble microcrystalline cellulose (MCC). Conventional tableting processes were then used to convert the powders generated into a tablet dosage form. Results: Studies of redispersibility showed considerable preservation of size characteristics of GBD nanocrystals during downstream processing with redispersibility indices of 105 and 118 for GBD-LAC and GBD-MCC, respectively. Characterization by differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy showed that the powders generated powders contained nanosized crystals of GBD which adhered to carrier surfaces. Powder flowability was characterized using Hausner ratio (HR) and Carr's index (CI). GBD-LAC-loaded particles exhibited poor flowability with CI and HR of 37.5% and 1.60, respectively, whilst GBD-MCC particles showed a slightly improved flowability with CI and HR of 26.47% and 1.36, respectively. The novel tablet dosage form met US Pharmacopeia specifications, including drug content, hardness, and friability. Conclusion: Higher dissolution rates were observed from the nanocrystal-based tablets compared to the microsized and commercial drug formulations. Moreover, the novel nanocrystal tablet dosage forms showed enhanced in vivo performance with area under the plasma concentrationtime curve in the first 24 hours values 1.97 and 2.24 times greater than that of marketed tablets.

The Rat Continuous Intestine Model Predicts the Impact of Particle Size and Transporters on the Oral Absorption of Glyburide

“…Table 2 also lists the observed AUC, observed and predicted C max and t max , and EOCs for the digitized datasets from the literature. 33,34 Again, as expected, the extent of absorption as seen by the relative AUC increase increased with a smaller API particle size. Model-predicted C−t profiles for the formulation datasets from Yang et al and Ali et al are depicted in Figure 3.…”

“…In addition to the in-house data, two publications have recently described in detail the collection of PK datasets from GLY formulations with a defined particle size in the rat. , Animal study details in the present as well as the published studies are listed in Table . Rat PK datasets were digitized from these publications with PlotDigitizer version 2.6.8.…”

“…Specifically, glyburide (GLY) formulations with two different mean particle sizes were prepared, and oral dosing studies were conducted in the rat. In addition to the in-house pharmacokinetic datasets, two recently published glyburide datasets by other laboratories were used to test model predictions. , Finally, we simulated C – t profiles for different particle sizes and different transporter activities for GLY in the rat.…”

Advanced modification of drug nanocrystals by using novel fabrication and downstream approaches for tailor-made drug delivery

“…For example, nanosuspension could be used as wet agent to mix with other excipients such as starch for granulation and then was applied for tabletting (Liu et al., 2018). In one study, glyburide nanocrystals were loaded in lactose monohydrate and microcrystalline cellulose for tabletting, which was finally observed highly improved in vivo AUC value compared to the marketed tablets (Ali et al., 2019).…”

Comparison of Downstream Processing of Nanocrystalline Solid Dispersion and Nanosuspension of Diclofenac Acid to Develop Solid Oral Dosage Form

“…On the other hand, the oral solid products are more patient compliant, relatively stable and hold a large market share [ 1 , 7 ]. Thus, incorporation of nanocrystals to oral solid dosage forms (OSDs) is essential for their commercial development [ 2 , 15 , 18 ].…”