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A novel architecture for achieving high drug loading in amorphous spray dried dispersion tablets.

ABSTRACT: Although Amorphous Solid Dispersions (ASDs) effectively increase bioavailability, tablet mass can be high due to the large fraction of excipients needed to stabilize the amorphous drug in the solid state, extend drug supersaturation in solution and achieve robust manufacturability. The aim of this work was to reduce tablet mass of an ASD tablet comprising a low glass transition temperature (Tg), rapidly crystallizing drug without compromising these key attributes. In this approach, erlotinib (Tg = 42 °C, Tm/Tg = 1.4 K/K) was spray dried with the high Tg polymer poly(methyl methacrylate-co-methacrylic acid) (Eudragit® L100, Evonik) (Tg = 187 °C) to facilitate high drug loading while maintaining physical stability. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) (AQOAT® HF, Shin-Etsu) was granulated with the ASD to extend supersaturation in solution. For comparison, a benchmark ASD was spray dried at a lower drug loading with HPMCAS-H (Tg = 119 °C). This High Loaded Dosage Form (HLDF) approach reduced tablet mass by 40%, demonstrated similar physical stability and in vitro performance as the benchmark and exhibited excellent downstream manufacturability. Strategically combining two different polymers in a tablet to maintain physical stability and sustain supersaturation in solution can decrease tablet mass of some low Tg, rapidly crystallizing amorphous drugs.

SUBMITTER: Mudie DM

PROVIDER: S-EPMC7058468 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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A novel architecture for achieving high drug loading in amorphous spray dried dispersion tablets.

Mudie Deanna M DM Buchanan Stephanie S Stewart Aaron M AM Smith Adam A Shepard Kimberly B KB Biswas Nishant N Marshall Derrick D Ekdahl Alyssa A Pluntze Amanda A Craig Christopher D CD Morgen Michael M MM Baumann John M JM Vodak David T DT

International journal of pharmaceutics: X 20200219

Although Amorphous Solid Dispersions (ASDs) effectively increase bioavailability, tablet mass can be high due to the large fraction of excipients needed to stabilize the amorphous drug in the solid state, extend drug supersaturation in solution and achieve robust manufacturability. The aim of this work was to reduce tablet mass of an ASD tablet comprising a low glass transition temperature (T<sub>g</sub>), rapidly crystallizing drug without compromising these key attributes. In this approach, er ...[more]

PMID: 32154509

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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: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.

Dataset Information

A novel architecture for achieving high drug loading in amorphous spray dried dispersion tablets.

Publications

A novel architecture for achieving high drug loading in amorphous spray dried dispersion tablets.

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