Physical Stability of Amorphous Solid Dispersions: a Physicochemical Perspective with Thermodynamic, Kinetic and Environmental Aspects

Xia, Lin; Hu, Yang; Liu, Lei; Su, Lili; Li, Na; Yu, Jing; Tang, Bo; Yang, Ziyi

doi:10.1007/s11095-018-2408-3

Cited by 97 publications

(50 citation statements)

References 140 publications

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“…Similar T g values were obtained for all tested drug-polymer combinations. Assessment of T g properties during ASD screening is known to provide useful information regarding the physical stability of amorphous system [44]. Again, this confirms the robustness of our miniaturized equipment to gain insight into final properties of SDSDs.…”

Section: :60 (W/w) Asdssupporting

confidence: 69%

Comparison of a Novel Miniaturized Screening Device with Büchi B290 Mini Spray-Dryer for the Development of Spray-Dried Solid Dispersions (SDSDs)

et al. 2018

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Spray-drying is an increasingly popular technology for the production of amorphous solid dispersions (ASDs) in the pharmaceutical industry that is used in the early evaluation and industrial production of formulations. Efficient screening of ASD in the earliest phase of drug development is therefore critical. A novel miniaturized atomization equipment for screening spray-dried solid dispersions (SDSDs) in early formulation and process development was developed. An in-depth comparison between the equipment/process parameters and performance of our novel screening device and a laboratory Büchi B290 mini spray-dryer was performed. Equipment qualification was conducted by comparing the particle/powder attributes, i.e., miscibility/solid state, residual solvent, and morphological properties of binary SDSDs of itraconazole prepared at both screening and laboratory scales. The operating mode of the miniaturized device was able to reproduce similar process conditions/parameters (e.g., outlet temperature (Tout)) and to provide particles with similar drug–polymer miscibility and morphology as laboratory-scale SDSDs. These findings confirm that the design and operation of this novel screening equipment mimic the microscale evaporation mechanism of a larger spray-dryer. The miniaturized spray-dryer was therefore able to provide a rational prediction of adequate polymer and drug loading (DL) for SDSD development while reducing active pharmaceutical ingredient (API) consumption by a factor of 120 and cycle time by a factor of 4.

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Section: :60 (W/w) Asdssupporting

confidence: 69%

Comparison of a Novel Miniaturized Screening Device with Büchi B290 Mini Spray-Dryer for the Development of Spray-Dried Solid Dispersions (SDSDs)

et al. 2018

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“…9) To prevent this, solid dispersions in which drug molecules are dispersed in a water-soluble polymer matrix in the amorphous state have been used. 10) Amorphous drugs in solid dispersions are stabilized by homogeneous mixing with a polymer. 11) This effect allows for the production of practical solid formulations which are highly stable even under stressed conditions such as heat and humidity.…”

Section: Introductionmentioning

confidence: 99%

Intermolecular Interactions between Drugs and Aminoalkyl Methacrylate Copolymer in Solution to Enhance the Concentration of Poorly Water-Soluble Drugs

Higashi

Ueda

Moribe

2019

CHEMICAL & PHARMACEUTICAL BULLETIN

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An aminoalkyl methacrylate copolymer, Eudragit ® E (EUD-E), has gained tremendous attention as a solid dispersion carrier because it efficiently stabilizes drugs in the amorphous state. Furthermore, EUD-E remarkably enhances drug dissolution in water. This review focuses on the interaction between drugs and EUD-E in solution, which contributes to the enhancement of drug concentration. Studies examining interactions between acidic drugs and EUD-E in organic solvents have revealed that the interaction occurs predominantly by electrostatic interaction, including hydrogen bonding and dipolar interactions. Other studies on interactions in aqueous solution found evidence for strong electrostatic interactions between acidic drugs and EUD-E in ion exchange experiments. 1 H-NMR studies using high-resolution magic-angle spinning, nuclear Overhauser effect spectroscopy, diffusion, and relaxation time measurements successfully identified the interaction site and strength in aqueous solution. Hydrophobic and ionic interactions occurred between drugs and EUD-E. The conformation of EUD-E, which was affected by the ionic strength and pH of the aqueous media, also influenced the interaction. The knowledge discussed in this review will be helpful in designing solid dispersion formulations with EUD-E, which will efficiently enhance drug concentration and subsequent absorption into the body.

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“…This observation correlates well with the relatively high T g value obtained for 40:60 ( w / w ) CDP146 SDSDs, detailed in Table 3 . Solid dispersion with high T g generate anti-plasticization effect that reduces the molecular mobility and therefore contributes to the drug stabilization in the amorphous state [ 37 ]. At this stage, the assessment of carrier’s potential to maintain amorphous state upon storage did not allow discriminating the four carriers.…”

Section: Resultsmentioning

confidence: 99%

A Novel Protocol Using Small-Scale Spray-Drying for the Efficient Screening of Solid Dispersions in Early Drug Development and Formulation, as a Straight Pathway from Screening to Manufacturing Stages

et al. 2018

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This work describes a novel screening strategy that implements small-scale spray-drying in early development of binary amorphous solid dispersions (ASDs). The proposed methodology consists of a three-stage decision protocol in which small batches (20–100 mg) of spray-dried solid dispersions (SDSDs) are evaluated in terms of drug–polymer miscibility, physical stability and dissolution performance in bio-predictive conditions. The objectives are to select the adequate carrier and drug-loading (DL) for the manufacturing of robust SDSD; and the appropriate stabilizer dissolved in the liquid vehicle of SDSD suspensions, which constitutes the common dosage form used during non-clinical studies. This methodology was verified with CDP146, a poorly water soluble (<2 µg/mL) API combined with four enteric polymers and four stabilizers. CDP146/HPMCAS-LF 40:60 (w/w) and 10% (w/v) PVPVA were identified as the lead SDSD and the best performing stabilizer, respectively. Lead SDSD suspensions (1–50 mg/mL) were found to preserve complete amorphous state during 8 h and maintain supersaturation in simulated rat intestinal fluids during the absorption window. Therefore, the implementation of spray-drying as a small-scale screening approach allowed maximizing screening effectiveness with respect to very limited API amounts (735 mg) and time resources (9 days), while removing transfer steps between screening and manufacturing phases.

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Physical Stability of Amorphous Solid Dispersions: a Physicochemical Perspective with Thermodynamic, Kinetic and Environmental Aspects

Abstract: When designing amorphous solid dispersions, it isrecommended that these thermodynamic, kinetic and environmental aspects should be completely investigatedand compared to establish rationale formulations for amorphous solid dispersions with high physical stability.

Cited by 97 publications

References 140 publications

Comparison of a Novel Miniaturized Screening Device with Büchi B290 Mini Spray-Dryer for the Development of Spray-Dried Solid Dispersions (SDSDs)

Comparison of a Novel Miniaturized Screening Device with Büchi B290 Mini Spray-Dryer for the Development of Spray-Dried Solid Dispersions (SDSDs)

Intermolecular Interactions between Drugs and Aminoalkyl Methacrylate Copolymer in Solution to Enhance the Concentration of Poorly Water-Soluble Drugs

A Novel Protocol Using Small-Scale Spray-Drying for the Efficient Screening of Solid Dispersions in Early Drug Development and Formulation, as a Straight Pathway from Screening to Manufacturing Stages

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