Dataset Information

Spray-Dried Amorphous Solid Dispersions of Atorvastatin Calcium for Improved Supersaturation and Oral Bioavailability.

ABSTRACT: Over the past few decades, the amorphous solid dispersions (ASDs) technique has emerged as a promising strategy to enhance the in vitro/in vivo characteristic of hydrophobic drugs. The low aqueous solubility and poor bioavailability of atorvastatin calcium (ATO), a lipid-lowering drug, present challenges for effective drug delivery. The objective of this work was to improve the aqueous solubility, in vitro dissolution, and oral absorption of ATO with amorphous solid dispersion technique prepared by spray-drying method. The optimized ternary formulation comprising of ATO; hydroxypropyl methylcellulose (HPMC), as a hydrophilic polymer; and sodium lauryl sulfate (SLS), as a surfactant, at a weight ratio of 1/1/0.1, showed significant improvement in aqueous solubility by ~18-fold compared to that of the free drug, and a cumulative release of 94.09% compared to a release of 59.32% of the free drug. Further, physicochemical studies via scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffraction revealed a change from the crystalline state of the free drug to its amorphous state in the ASD. Pharmacokinetic analysis in rats demonstrated 1.68- and 2.39-fold increments in AUC and Cmax, respectively, in the ASD over the free drug. Altogether, hydrophilic carrier-based ASDs prepared by the spray-drying technique represent a promising strategy to improve the biopharmaceutical performance of poorly soluble drugs.

SUBMITTER: Kwon J

PROVIDER: S-EPMC6781288 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Spray-Dried Amorphous Solid Dispersions of Atorvastatin Calcium for Improved Supersaturation and Oral Bioavailability.

Kwon Jaewook J Giri Bhupendra Raj BR Song Eon Soo ES Bae Jinju J Lee Junseong J Kim Dong Wuk DW

Pharmaceutics 20190906 9

Over the past few decades, the amorphous solid dispersions (ASDs) technique has emerged as a promising strategy to enhance the in vitro/in vivo characteristic of hydrophobic drugs. The low aqueous solubility and poor bioavailability of atorvastatin calcium (ATO), a lipid-lowering drug, present challenges for effective drug delivery. The objective of this work was to improve the aqueous solubility, in vitro dissolution, and oral absorption of ATO with amorphous solid dispersion technique prepared ...[more]

PMID: 31500147

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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:The maximum achievable concentration of a drug in solution is dictated by the chemical potential of the solid form. Because an amorphous solid has a higher chemical potential than the corresponding crystal form, in the absence of phase transformations, a higher transient solubility is expected. However, the chemical potential of an amorphous drug can be reduced by mixing with another component. Therefore, upon mixing with a polymer to form an amorphous solid dispersion (ASD), the maximum solution concentration achieved can be potentially altered, in particular if the polymer is poorly soluble in the dissolution medium. Such changes in the chemical potential of the drug may be a critical factor in determining the maximum achievable solution concentration, and could alter the crystallization driving force of the drug. Therefore, the aim of this study was to gain insights into the impact of poorly soluble polymers on the "amorphous solubility" of drugs formulated as amorphous solid dispersions. Lopinavir was selected as a model drug with a low crystallization tendency, enabling determination of the amorphous solubility as a function of ASD composition. Model polymers included cellulose acetate (CA), CA phthalate (CAP), ethylcellulose (EC), Eudragit® RL PO (EUD), hydroxypropylmethylcellulose (HPMC), HPMC acetate succinate (HPMCAS), and HPMC phthalate (HPMCP). The "amorphous solubility" of the drug alone was determined and then the changes in maximum achievable concentration were measured as a function of drug loading. Drug-polymer interactions were characterized using infrared spectroscopy (IR), differential scanning calorimetry (DSC) and moisture sorption analysis. The results showed that the maximum achievable concentration ("amorphous solubility") of lopinavir varied with the extent of drug-polymer interactions, as well as the drug weight fraction in the ASD. This information is of great value when evaluating the maximum achievable concentration of amorphous systems formulated with pH responsive polymers, and should contribute to a broader understanding of drug phase behavior in the context of ASDs.

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

Spray-Dried Amorphous Solid Dispersions of Atorvastatin Calcium for Improved Supersaturation and Oral Bioavailability.

Publications

Spray-Dried Amorphous Solid Dispersions of Atorvastatin Calcium for Improved Supersaturation and Oral Bioavailability.

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