Dataset Information

Long-Term Physical (In)Stability of Spray-Dried Amorphous Drugs: Relationship with Glass-Forming Ability and Physicochemical Properties.

ABSTRACT: This study shows the importance of the chosen method for assessing the glass-forming ability (GFA) and glass stability (GS) of a drug compound. Traditionally, GFA and GS are established using in situ melt-quenching in a differential scanning calorimeter. In this study, we included 26 structurally diverse glass-forming drugs (i) to compare the GFA class when the model drugs were produced by spray-drying with that when melt-quenching was used, (ii) to investigate the long-term physical stability of the resulting amorphous solids, and (iii) to investigate the relationship between physicochemical properties and the GFA of spray-dried solids and their long-term physical stability. The spray-dried solids were exposed to dry (<5% RH) and humid (75% RH) conditions for six months at 25 °C. The crystallization of the spray-dried solids under these conditions was monitored using a combination of solid-state characterization techniques including differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. The GFA/GS class assignment for 85% of the model compounds was method-dependent, with significant differences between spray-drying and melt-quenching methods. The long-term physical stability under dry condition of the compounds was predictable from GFA/GS classification and glass transition and crystallization temperatures. However, the stability upon storage at 75% RH could not be predicted from the same data. There was no strong correlation between the physicochemical properties explored and the GFA class or long-term physical stability. However, there was a slight tendency for compounds with a relatively larger molecular weight, higher glass transition temperature, higher crystallization temperature, higher melting point and higher reduced glass transition temperature to have better GFA and better physical stability. In contrast, a high heat of fusion and entropy of fusion seemed to have a negative impact on the GFA and physical stability of our dataset.

SUBMITTER: Edueng K

PROVIDER: S-EPMC6781026 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Long-Term Physical (In)Stability of Spray-Dried Amorphous Drugs: Relationship with Glass-Forming Ability and Physicochemical Properties.

Edueng Khadijah K Bergström Christel A S CAS Gråsjö Johan J Mahlin Denny D

Pharmaceutics 20190821 9

This study shows the importance of the chosen method for assessing the glass-forming ability (GFA) and glass stability (GS) of a drug compound. Traditionally, GFA and GS are established using in situ melt-quenching in a differential scanning calorimeter. In this study, we included 26 structurally diverse glass-forming drugs (i) to compare the GFA class when the model drugs were produced by spray-drying with that when melt-quenching was used, (ii) to investigate the long-term physical stability o ...[more]

PMID: 31438566

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Project description:Spray drying is widely used in the manufacturing of amorphous solid dispersion (ASD) systems due to its fast drying rate, enabling kinetic trapping of the drug in amorphous form. Spray-drying conditions, such as solvent composition, can have a profound impact on the properties of spray-dried dispersions. In this study, the phase behavior of spray-dried dispersions from methanol and methanol-water mixtures was assessed using ritonavir and copovidone [poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA)] as dispersion components. The resultant ASDs were characterized using differential scanning calorimetry (DSC), fluorescence spectroscopy, X-ray photoelectron spectroscopy (XPS), as well as surface-normalized dissolution rate (SNDR) measurements. Quaternary phase diagrams were calculated using a four-component Flory-Huggins model. It was found that the addition of water to the solvent system can lead to phase separation during the spray-drying process. A 10:90 H2O/MeOH solvent system caused a minor extent of phase separation. Phase heterogeneity in the 50 and 75% drug loading ASDs prepared from this spray solvent can be detected using DSC but not with other techniques used. The 25% drug loading system did not show phase heterogeneity in solid-state characterization but exhibited a compromised dissolution rate compared to that of the miscible ASD prepared from H2O-free solvent. This is possibly due to the formation of slow-releasing drug-rich phases upon phase separation. ASDs prepared with a 60:40 H2O/MeOH solvent mixture showed phase heterogeneity with all analytical methods used. The surface composition of dispersion particles as measured by fluorescence spectroscopy and XPS showed good agreement, suggesting surface drug enrichment of the spray-dried ASD particles prepared from this solvent system. Calculated phase diagrams and drying trajectories were consistent with experimental observations, suggesting that small variations in solvent composition may cause significant changes in ASD phase behavior during drying. These findings should aid in spray-drying process development for ASD manufacturing and can be applied broadly to assess the risk of phase separation for spray-drying systems using mixed organic solvents or other solvent-based processes.

Project description:In a spray drying operation, a two-fluid nozzle (2FN) with a single channel is commonly used for atomizing the feed solution. However, the less commonly used three-fluid nozzle (3FN) has two separate channels, which allow spray drying of materials in two incompatible solution systems. Although amorphous solid dispersions (ASDs) prepared using a 3FN have been reported to deliver comparable drug dissolution performance relative to those prepared using a 2FN, few studies have systematically examined the effect of 3FN on the physical stability. Therefore, the goal of this work is to systematically study the physical stability of ASDs that are spray-dried using a 3FN compared to those prepared using the traditional 2FN. For the 2FN, a single solution of naproxen and polyvinylpyrrolidone (PVP) was prepared in a mixture of acetone and water at a 1:1 volume ratio because 2FN allows for only one solution inlet. For the 3FN, naproxen and PVP were dissolved individually in acetone and water, respectively, because 3FN allows simultaneous entry of two solutions. Upon storage of the formulated ASDs at different humidity levels (25%, 55% and 75% RH), naproxen crystallized more quickly from the 3FN ASDs as compared with the 2FN ASDs. 3FN ASDs crystallized after 5 days of storage at all conditions, whereas 2FN ASDs did not crystallize even at 55% RH for two months. This relatively higher crystallization tendency of 3FN ASDs was attributed to the inhomogeneity of drug and polymers as identified by the solid-state Nuclear Magnetic Resonance findings, specifically due to poor mixing of water- and acetone-based solutions at the 3FN nozzle. When only acetone was used as a solvent to prepare drug-polymer solutions for 3FN, the formulated ASD was found to be stable for >3 months of storage (at 75% RH), which suggests that instability of the 3FN ASD was due to the insufficient mixing of water and acetone solutions. This study provides insights into the effects of solvent and nozzle choices on the physical stability of spray-dried ASDs.

Dataset Information

Long-Term Physical (In)Stability of Spray-Dried Amorphous Drugs: Relationship with Glass-Forming Ability and Physicochemical Properties.

Publications

Long-Term Physical (In)Stability of Spray-Dried Amorphous Drugs: Relationship with Glass-Forming Ability and Physicochemical Properties.

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