Myth or Truth: The Glass Forming Ability Class III Drugs Will Always Form Single-Phase Homogenous Amorphous Solid Dispersion Formulations

Panini, Piyush; Rampazzo, Massimiliano; Singh, Abhishek; Vanhoutte, Filip; Mooter, Guy Van den

doi:10.3390/pharmaceutics11100529

Cited by 15 publications

(11 citation statements)

References 47 publications

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“…It was reported that the glass-forming ability (GFA) has an influence on the physical stability of drug [ 49 ]. The GFA class III drugs have a strong tendency to transform into its amorphous state, resulting in the highest physical stability compared to class I and class II active pharmaceutical ingredients [ 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

Sahakijpijarn

Moon

Koleng³

et al. 2020

Pharmaceutics

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Remdesivir exhibits in vitro activity against SARS-CoV-2 and was granted approval for emergency use. To maximize delivery to the lungs, we formulated remdesivir as a dry powder for inhalation using thin film freezing (TFF). TFF produces brittle matrix nanostructured aggregates that are sheared into respirable low-density microparticles upon aerosolization from a passive dry powder inhaler. In vitro aerodynamic testing demonstrated that drug loading and excipient type affected the aerosol performance of remdesivir. Remdesivir combined with optimal excipients exhibited desirable aerosol performance (up to 93.0% FPF< 5 µm; 0.82 µm mass median aerodynamic diameter). Remdesivir was amorphous after the TFF process, which benefitted drug dissolution in simulated lung fluid. TFF remdesivir formulations are stable after one month of storage at 25 °C/60% relative humidity. An in vivo pharmacokinetic evaluation showed that TFF remdesivir–leucine was poorly absorbed into systemic circulation while TFF remdesivir-Captisol® demonstrated increased systemic uptake compared to leucine. Remdesivir was hydrolyzed to the nucleoside analog GS-441524 in the lung, and levels of GS-441524 were greater in the lung with leucine formulation compared to Captisol®. In conclusion, TFF technology produces high-potency remdesivir dry powder formulations for inhalation that are suitable to treat patients with COVID-19 on an outpatient basis and earlier in the disease course where effective antiviral therapy can reduce related morbidity and mortality.

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Section: Discussionmentioning

confidence: 99%

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

Sahakijpijarn

Moon

Koleng³

et al. 2020

Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…It was reported that the glass forming ability (GFA) has an influence on the physical stability of drug [44]. The GFA class III drugs have a strong tendency to transform into its amorphous state, resulting in the highest physical stability compared to class I and class II APIs [44,45].…”

Section: Physical and Chemical Stability Of Remdesivir Dry Powder Promentioning

confidence: 99%

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

Sahakijpijarn

Moon

Koleng³

et al. 2020

Preprint

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Remdesivir, an investigational broad-spectrum antiviral agent, has shown in vitro activity against SARS-CoV-2. To maximize direct delivery to the target site, the lungs, we aim to develop remdesivir as a dry powder for inhalation using thin film freezing (TFF). TFF produces a brittle matrix of nanostructured aggregates that can be sheared into respirable low-density microparticles upon aerosolization from a passive dry powder inhaler. In vitro aerodynamic testing demonstrated that drug loading and excipient type affected the aerosol performance of remdesivir. Remdesivir combined with optimal excipients (e.g. Captisol®, mannitol, lactose, leucine) exhibited suitable aerosol performance (up to 92.4% FPF and 0.86 µm MMAD). Remdesivir was amorphous after the TFF process, which we hypothesize will provide a benefit for drug dissolution once administered to the lungs. Neither the organic/water processing cosolvent or the rapid freezing rate used during the TFF process affected the chemical stability of remdesivir during processing. In conclusion, TFF is a suitable technology for producing remdesivir dry powder formulations suitable for pulmonary administration.

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“…Solid dispersion, defined as the dispersion of one or more active ingredient in a carrier or matrix at solid state, is an established platform technology to enhance the dissolution rate and improve the apparent solubility of a drug and, hence, increase the bioavailability of a range of poorly water soluble drugs [ 1 , 2 , 3 ]. Several classes of hydrophilic polymers have been used as carriers to prepare solid dispersions, including PVP [ 4 , 5 , 6 ] and its derivatives [ 7 , 8 , 9 ], polyethylene glycols [ 10 , 11 ], cellulose ethers [ 12 , 13 ] and poloxamers [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Mutual Effects of Hydrogen Bonding and Polymer Hydrophobicity on Ibuprofen Crystal Inhibition in Solid Dispersions with Poly(N-vinyl pyrrolidone) and Poly(2-oxazolines)

et al. 2021

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Poly(N-vinyl pyrrolidone) (PVP), poly(2-methyl-2-oxazoline) (PMOZ), poly(2-ethyl-2-oxazoline) (PEOZ), poly(2-n-propyl-2-oxazoline) (PnPOZ), and poly(2-isopropyl-2-oxazoline) (PiPOZ) were used to prepare solid dispersions with ibuprofen (IB), a model poorly-water soluble drug. Dispersions, prepared by solvent evaporation, were investigated using powder X-ray diffractometry, differential scanning calorimetry, and FTIR spectroscopy; hydrogen bonds formed between IB and all polymers in solid dispersions. PMOZ, the most hydrophilic polymer, showed the poorest ability to reduce or inhibit the crystallinity of IB. In contrast, the more hydrophobic polymers PVP, PEOZ, PnPOZ, and PiPOZ provided greater but similar abilities to reduce IB crystallinity, despite the differing polymer hydrophobicity and that PiPOZ is semi-crystalline. These results indicate that crystallinity disruption is predominantly due to hydrogen bonding between the drug molecules and the polymer. However, carrier properties affected drug dissolution, where PnPOZ exhibited lower critical solution temperature that inhibited the release of IB, whereas drug release from other systems was consistent with the degree of ibuprofen crystallinity within the dispersions.

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Myth or Truth: The Glass Forming Ability Class III Drugs Will Always Form Single-Phase Homogenous Amorphous Solid Dispersion Formulations

Cited by 15 publications

References 47 publications

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing

Mutual Effects of Hydrogen Bonding and Polymer Hydrophobicity on Ibuprofen Crystal Inhibition in Solid Dispersions with Poly(N-vinyl pyrrolidone) and Poly(2-oxazolines)

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