Physical Stability and Dissolution Behavior of Ketoconazole–Organic Acid Coamorphous Systems

Fung, Michelle H.; Bērziņš, Kārlis; Suryanarayanan, Raj

doi:10.1021/acs.molpharmaceut.8b00035

Cited by 57 publications

(67 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[16][17][18] For example, ionic interactions in indomethacinarginine co-amorphous system remarkably enhanced the intrinsic dissolution rate and physical stability relative to amorphous indomethacin. 19 Tryptophan bound to carbamazepine via hydrogen bonding and p-p interaction. 20 Meanwhile, co-amorphous can improve the drug release properties through the precipitation of drug rich phase of nano/micro dimensions.…”

Section: Introductionmentioning

confidence: 99%

Co-amorphous palbociclib–organic acid systems with increased dissolution rate, enhanced physical stability and equivalent biosafety

et al. 2019

View full text Add to dashboard Cite

The preparation of co-amorphous drug systems by adding a small molecular excipient is a promising formulation in the modern pharmaceutical industry to improve the solubility, dissolution rate, and bioavailability of poorly soluble drugs. In this study, palbociclib co-amorphous systems with organic acids (succinic, tartaric, citric, and malic acid) at molar ratios of 1 : 1 were prepared by co-milling and characterized by differential scanning calorimetry (DSC), fourier transform infrared spectroscopy (FTIR) and solid-state nuclear magnetic resonance (SS-NMR). These solid-state investigations have confirmed the formation of co-amorphous salts between PAL and organic acids. The solubility, dissolution rate and stability of the four co-amorphous drug systems were significantly improved compared with these of crystalline and amorphous palbociclib. The biosafety of the coamorphous drug systems was the same as that of palbociclib without affecting the efficacy of the drug and eliciting toxic side effects. These comprehensive approaches for the palbociclib-acid co-amorphous drug systems provided a theoretical basis for its clinical applications.

show abstract

Section: Introductionmentioning

confidence: 99%

Co-amorphous palbociclib–organic acid systems with increased dissolution rate, enhanced physical stability and equivalent biosafety

et al. 2019

View full text Add to dashboard Cite

show abstract

“…However, ketoconazole-succinic acid and ketoconazole-oxalic acid coamorphous systems crystallized more readily than pure amorphous ketoconazole did upon contact with water vapor or aqueous phosphate buffer 40 . The dissolution enhancement of the ketoconazole-organic acid coamorphous systems may be explained by an increase in particle surface areas upon particle size reduction and improved solubility of ketoconazole in the diffusion layer due to the decrease in pH 40 . It is noteworthy that a higher strength of acid yields a more pronounced dissolution enhancement 40 .…”

Section: In Vitro and In Vivo Performancementioning

confidence: 92%

“…Nevertheless, the role of co-former to effectively maintain the amorphous state of API in aqueous environment is not always a prerequisite for the dissolution improvement of co-amorphous systems. For instance, the spray dried ketoconazole-organic acid coamorphous solids has been reported to exhibit higher dissolution rates than the crystalline counterpart, amorphous ketoconazole and their physical mixtures 40 . However, ketoconazole-succinic acid and ketoconazole-oxalic acid coamorphous systems crystallized more readily than pure amorphous ketoconazole did upon contact with water vapor or aqueous phosphate buffer 40 .…”

Section: In Vitro and In Vivo Performancementioning

confidence: 99%

“…For instance, the spray dried ketoconazole-organic acid coamorphous solids has been reported to exhibit higher dissolution rates than the crystalline counterpart, amorphous ketoconazole and their physical mixtures 40 . However, ketoconazole-succinic acid and ketoconazole-oxalic acid coamorphous systems crystallized more readily than pure amorphous ketoconazole did upon contact with water vapor or aqueous phosphate buffer 40 . The dissolution enhancement of the ketoconazole-organic acid coamorphous systems may be explained by an increase in particle surface areas upon particle size reduction and improved solubility of ketoconazole in the diffusion layer due to the decrease in pH 40 .…”

Section: In Vitro and In Vivo Performancementioning

confidence: 99%

See 1 more Smart Citation

Advances in coamorphous drug delivery systems

Shi

Moinuddin

Cai

2019

Acta Pharmaceutica Sinica B

139

View full text Add to dashboard Cite

In recent years, the coamorphous drug delivery system has been established as a promising formulation approach for delivering poorly water-soluble drugs. The coamorphous solid is a single-phase system containing an active pharmaceutical ingredient (API) and other low molecular weight molecules that might be pharmacologically relevant APIs or excipients. These formulations exhibit considerable advantages over neat crystalline or amorphous material, including improved physical stability, dissolution profiles, and potentially enhanced therapeutic efficacy. This review provides a comprehensive overview of coamorphous drug delivery systems from the perspectives of preparation, physicochemical characteristics, physical stability, in vitro and in vivo performance. Furthermore, the challenges and strategies in developing robust coamorphous drug products of high quality and performance are briefly discussed.

show abstract

“…The extent of dissolution enhancement was quantified from the AUC ratio ([AUC 0– t ,sample ]/[AUC 0– t ,IIIM-290 ]). 35 …”

Section: Methodsmentioning

confidence: 99%

Selection of a Water-Soluble Salt Form of a Preclinical Candidate, IIIM-290: Multiwell-Plate Salt Screening and Characterization

et al. 2018

View full text Add to dashboard Cite

IIIM-290, a semisynthetic derivative of natural product rohitukine, is an orally bioavailable Cdk inhibitor, efficacious in the xenograft models of colon, pancreatic, and leukemia cancer. Its low aqueous solubility (∼8.6 μg/mL) could be one of the reasons for achieving optimal in vivo efficacy relatively at a higher dose. Being a nitrogenous compound, salt formation was envisaged as one of the ideal approaches to enhance its solubility and dissolution profile. Thus, herein, a solubility-guided miniaturized 96-well plate salt screening protocol was devised for identification of the suitable salt form of this preclinical candidate. The solubility-guided strategy has resulted in the identification of hydrochloride as the most favorable counterion, resulting in 45-fold improvement in aqueous solubility. The HCl salt was then scaled up at a gram size and characterized using 1H and 13C NMR, scanning electron microscopy, powder X-ray diffraction, Fourier-transform infrared, and differential scanning calorimetry studies. The HCl salt displayed enhancement in the in vitro dissolution profile as well as improved plasma exposure in the pharmacokinetic study. The oral administration of the IIIM-290·HCl salt in BALB/c mice resulted in >1.5-fold improvement in areas under the curve, Cmax, and half-life. The prepared salt also did not alter its cyclin-dependent kinase (Cdk)-2 and Cdk-9 inhibition activity. This biopharmaceutically improved lead has a potential to investigate further in preclinical studies. The solubility-guided salt screening strategy implemented herein could be utilized for other preclinical leads.

show abstract

Physical Stability and Dissolution Behavior of Ketoconazole–Organic Acid Coamorphous Systems

Cited by 57 publications

References 14 publications

Co-amorphous palbociclib–organic acid systems with increased dissolution rate, enhanced physical stability and equivalent biosafety

Co-amorphous palbociclib–organic acid systems with increased dissolution rate, enhanced physical stability and equivalent biosafety

Advances in coamorphous drug delivery systems

Selection of a Water-Soluble Salt Form of a Preclinical Candidate, IIIM-290: Multiwell-Plate Salt Screening and Characterization

Contact Info

Product

Resources

About