(740a) Comparative Assessment of Spray-Dried Hybrid Nanocrystal–Amorphous Solid Dispersions (HyNASDs) and ASDs

With an increasing number of poorly water-soluble drugs, aqueous solubility has become a critical issue in the pharmaceutical industry. Slow and incomplete release of the poorly water-soluble drugs in the gastrointestinal tract (GI) results in slow absorption and ultimately limited bioavailability. To resolve this issue, among various formulation approaches, drug nanocrystal-based solid dosage forms (nanocomposites) and amorphous solid dispersions (ASDs) have achieved substantial popularity (1–3). In a nanocomposite, drug nanocrystals are usually dispersed in the polymeric matrix as a secondary phase (3), whereas in an ASD, drug is molecularly dispersed in a miscible, amorphous polymer to form a single phase (2). While offering several advantages such as dissolution rate enhancement, improved bioavailability, elimination of food effects, etc., drug nanoparticles have been used in several marketed products (4). However, limited improvement in the bioavailability was observed for drugs with very low aqueous solubility and high drug dose (5). On the other hand, owing to the high apparent (kinetic) solubility, ASDs can generate high extent of supersaturation along with enhanced dissolution rate, which results in bioavailability enhancement of poorly soluble drugs with high therapeutic doses (6). Consequently, drug nanocomposites appear to have limited supersaturation capability, which is the greatest impediment to the bioavailability enhancement and their competitiveness to ASDs.

Being motivated by the use of high polymer concentration, i.e., low drug:polymer mass ratios from 1:1 to 1:9 in drug ASDs (7) unlike the high drug:polymer ratios in drug nanocomposites (3), Rahman et al. (8) have produced nanocomposites with a high polymer concentration (>100% with respect to frug). They used 1:1 to 1:5 drug:polymer mass ratios with/without SDS in the production of griseofulvin (GF) nanocomposites, which is a fast crystallizing poorly soluble drug (9). This approach led to formation of a special class of nanocomposites with notable amorphous drug content (>10%), i.e., hybrid nanocrystal–amorphous solution dispersions (HyNASDs), which showed significant relative supersaturation (~300%) during dissolution. Judicious choice of polymers that have relatively low aqueous viscosities even at high concentrations allowed for preparation of drug nanosuspensions and their spray-drying without any processing issues. To generalize the applicability of HyNASDs, further investigation is required with other drugs and polymer systems.

Being motivated by the earlier work in Rahman et al. (8,10), the main objective of this study is to boost the supersaturation capability of drug nanocomposites in dissolution tests significantly by using low drug:polymer mass ratio (high polymer loading), thus, producing HyNASDs. Unlike Rahman et al. (8,10), HyNASDs were produced using a slow crystallizing poorly water-soluble drug, Itraconazole (ITZ). Additionally, the dissolution performance of HyNASDs and ASDs w/o an anionic surfactant (SDS) was compared in a head-to-head fashion. To this end, a wet media milled ITZ suspension and an ITZ solution, containing the same polymer (HPC: hydroxypropylcellulose, Sol: Soluplus, VA64: Kollidon VA6) in deionized water and in dichloromethane (DCM) were spray-dried to prepare ITZ HyNASDs and ITZ ASDs, respectively (see Fig. 1, left and middle panels). To elucidate the impact of SDS during in vitro drug release from the HyNASDs, ITZ suspensions with 0.125% SDS and w/o SDS were used. The solid-state characterization of the spray-dried powders as well as physical mixtures (PMs) prepared by blending formulation components without spray drying was performed by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). Release of ITZ from the spray-dried powders was studied using a USP II apparatus coupled with UV-spectroscopy.

Similar XRPD diffractograms (not shown for brevity) to those of the physical mixtures (PMs) were observed for the spray-dried powders produced from aqueous suspension(W)-based feeds confirming that spray-drying of the aqueous milled suspensions led to formation of nanocomposites that are largely crystalline in nature. Interestingly, the diffractograms of the spray-dried powders show significantly reduced peak intensities as compared with their respective PMs, beyond the dilution effect of the polymers. Wet media milling followed by spray drying led to reduction of crystallinity and formation of notable amorphous (~5–30%) ITZ. In the presence of high polymer loading in the suspensions, amorphization of ITZ seemed to have taken place during the spray drying. Reduction in peak intensity was more pronounced in the case of Sol confirming more amorphous ITZ formation in the Sol formulations than HPC and VA64 formulations. On the other hand, XRPD diffractograms of the spray-dried powders produced from solution-based (S) feeds showed a halo pattern, confirming that ITZ dispersed molecularly into the polymer matrices forming amorphous solid dispersions (ASDs). DSC results confirm the XRPD findings (not shown for brevity).

A Distek 2100C USP II (paddle apparatus) dissolution tester (North Brunswick, NJ, USA) was used to determine ITZ release from the as-received ITZ, spray-dried powders, and the physical mixtures (PMs) with 100 mg equivalent ITZ in 1000 mL 0.1 N HCl solution at 37 °C stirred at 50 rpm paddle speed. Fig. 1 (right panel) illustrates ITZ release from as-received ITZ crystalline powder, aqueous spray-dried 1:5 ITZ powder:Sol without wet-media milling (W-AR-Sol-1:5) and with aqueous wet media milling prior to spray drying (W-Sol-1:5 and W-Sol-1:5-SDS, latter including SDS), a traditional nanocomposite prepared with 5:1 mass ratio of ITZ:Sol (W-Sol-5:1), and the spray dried solution of 1:5 ITZ-Sol in dichloromethane (S-Sol-1:5). Considering the ITZ solubility as a baseline, we see from Fig. 1 that the spray drying of aqueous as-received ITZ microcrystals–Sol suspension (W-AR-Sol-1:5) slightly increased the dissolution rate and extent of relative supersaturation of ITZ. Despite having a much higher ITZ:Sol ratio (W-Sol-5:1), a traditional nanocomposite with wet-milled ITZ exhibited a higher supersaturation than W-AR-Sol-1:5. On the other hand, upon use of higher Sol in the wet-milled ITZ suspension (W-Sol:1:5), a HyNASD was formed, which exhibited a notably higher supersaturation. The addition of SDS (W-Sol:1:5-SDS) slightly helped to raise the supersaturation. The ASD (S-Sol-1:5) was superior to the identical HyNASD formulation (W-Sol:1:5) in terms of ITZ supersaturation.

Other results from our dissolution study can be summarized as follows: without SDS in the formulation, 360%, 320%, and 790% ITZ relative supersaturation was achieved from HPC, VA64, and Sol-based HyNASDs, respectively, in the dissolution tests whereas the presence of SDS resulted in 480%, 360%, and 850% supersaturation from HPC, VA64, and Sol-based HyNASDs, respectively. These level of supersaturation generation capability of HyNASDs could be attributed to the slow recrystallization of ITZ in the dissolution medium, interactions/miscibility of ITZ–polymers as well as the size of the drug (nano)crystals in the polymeric matrix. Higher supersaturation from Sol-based HyNASDs compared to HPC/VA64-based HyNASDs could be explained by the greater miscibility of Sol–ITZ and micellar solubilization of ITZ by Sol. Presence of SDS in the formulation enhanced the relative wetting effectiveness of the polymers and resulted higher extent of supersaturation during dissolution due to the finer ITZ particles in the milled suspensions and higher amorphous content in the spray-dried powders compared to the formulation w/o SDS.

Overall, the most striking finding from this study is that despite having ~70–80% nanocrystals, HyNASDs provided very high extent of ITZ supersaturation (~800% within 210 min) unlike traditional nanocomposites (50%), which could render nanoparticle formulations more attractive in bioavailability enhancement of poorly soluble drugs. On the other hand, ITZ release comparison of the ASD and the HyNASD with identical formulation suggests that the ASD generated higher extent of supersaturation (up to 1670%) than HyNASDs (up to 790%). However, this extent of high relative supersaturation from a largely nanocrystalline drug formulation is an interesting and exciting finding, which could render HyNASDs competitive to ASDs upon further formulation–process optimization.

References

1. Müller RH, Gohla S, Keck CM. State of the art of nanocrystals–special features, production, nanotoxicology aspects and intracellular delivery. Eur J Pharm Biopharm. 2011;78(1):1–9.

2. Brough C, Williams R. Amorphous solid dispersions and nano-crystal technologies for poorly water-soluble drug delivery. Int J Pharm. 2013;453(1):157–66.

3. Bhakay A, Rahman M, Dave RN, Bilgili E. Bioavailability enhancement of poorly water-soluble drugs via nanocomposites: Formulation processing aspects and challenges. Pharmaceutics. 2018;10(3):86.

4. Junghanns J-UA, Müller RH. Nanocrystal technology, drug delivery and clinical applications. Int J Nanomed. 2008;3(3):295–309.

5. Müller R, Jacobs C, Kayser O. Nanosuspensions as particulate drug formulations in therapy: rationale for development and what we can expect for the future. Adv Drug Delivery Rev. 2001;47(1):3–19.

6. Hancock BC, Parks M. What is the true solubility advantage for amorphous pharmaceuticals? Pharm Res. 2000;17(4):397–404.

7. Baghel S, Cathcart H, O'Reilly NJ. Polymeric amorphous solid dispersions: a review of amorphization, crystallization, stabilization, solid-state characterization, and aqueous solubilization of biopharmaceutical classification system class II drugs. J Pharm Sci. 2016;105(9):2527–44.

8. Rahman M, Ahmad S, Tarabokija J, Bilgili E. Roles of surfactant and polymer in drug release from spray-dried hybrid nanocrystal-amorphous solid dispersions (HyNASDs). Powder Technol. 2020;361:663–78.

9. Baird JA, Van Eerdenbrugh B, Taylor LS. A classification system to assess the crystallization tendency of organic molecules from undercooled melts. J Pharm Sci. 2010;99(9):3787–806.

10. Rahman M, Arevalo F, Coelho A, Bilgili E. Hybrid nanocrystal–amorphous solid dispersions (HyNASDs) as alternative to ASDs for enhanced release of BCS Class II drugs. Eur J Pharm Biopharm. 2019;145:12–26.