Physical Instability: A Key Problem of Amorphous Drugs

Rams-Baron, Marzena; Jachowicz, Renata; Болдырева, Е. В.; Zhou, Deliang; Jamróz, Witold; Paluch, Marian

doi:10.1007/978-3-319-72002-9_5

Cited by 13 publications

(11 citation statements)

References 158 publications

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“…Most amorphous drugs were found to have this T gβ at very low temperatures and this implies that when they are stored at room temperature (RT), they will revert from the amorphous form to their respective lower energy crystalline states [8,9]. Physical stability is therefore the main problem facing the development of amorphous drugs into solid dosage forms, such as capsules and tablets [10].…”

Section: Introductionmentioning

confidence: 99%

Determination of Stable Co-Amorphous Drug–Drug Ratios from the Eutectic Behavior of Crystalline Physical Mixtures

2019

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Co-amorphous drug–drug systems have been developed with the overall aim of improving the physical stability of two or more amorphous drugs. Co-amorphous systems often show good physical stability, and higher solubility and dissolution rates compared to their crystalline counterparts. The aim of this study is to determine if eutectic mixtures of two drugs can form stable co-amorphous systems. Three drug–drug mixtures, indomethacin–naproxen (IND−NAP), nifedipine–paracetamol (NIF−PAR), and paracetamol–celecoxib (PAR−CCX), were investigated for their eutectic and co-amorphization behavior as well as their physical stability in the co-amorphous form. The phase diagrams of the crystalline mixtures and the thermal behavior of the co-amorphous systems were analyzed by differential scanning calorimetry. The solid-state form and physical stability of the co-amorphous systems were analyzed using X-ray powder diffractometry during storage at room temperature at dry conditions. Initial eutectic screening using nifedipine (NIF), paracetamol (PAR), and celecoxib (CCX) indicated that IND−NAP, NIF−PAR, and PAR−CCX can form eutectic mixtures. Phase diagrams were then constructed using theoretical and experimental values. These systems, at different drug-to-drug ratios, were melted and cooled to form binary mixtures. Most mixtures were found to be co-amorphous systems, as they were amorphous and exhibited a single glass transition temperature. The stability study of the co-amorphous systems indicated differences in their physical stability. Comparing the phase diagrams with the physical stability of the co-amorphous mixtures, it was evident that the respective drug–drug ratio that forms the eutectic point also forms the most stable co-amorphous system. The eutectic behavior of drug–drug systems can thus be used to predict drug ratios that form the most stable co-amorphous systems.

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Section: Introductionmentioning

confidence: 99%

Determination of Stable Co-Amorphous Drug–Drug Ratios from the Eutectic Behavior of Crystalline Physical Mixtures

2019

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“…To improve the aqueous solubility of APIs, different formulation methods have been designed including amorphous forms, which have no long-range crystallographic order and higher internal energy compared with their respective crystalline forms (Berry and Steed, 2017;Healy et al, 2017;Khodadadi and Meesters, 2018;Williams et al, 2013). However, pure amorphous APIs are often physically unstable and can crystallise as a result of increased molecular mobility, especially when stored above their glass transition temperature or in humid environments (Kissi et al, 2018;Rams-Baron et al, 2018;Sun et al, 2012). Methods to improve the stability of amorphous APIs include the formation of amorphous solid dispersions and co-amorphous (COAM) materials (Karagianni et al, 2018;Ma and Williams, 2019;Van Den Mooter, 2012;Wu et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Predictive identification of co-formers in co-amorphous systems

Chambers

Grohganz

Palmelund

et al. 2021

European Journal of Pharmaceutical Sciences

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“…These manufacturing methods will often produce drugs in the amorphous form [ 10 , 11 ], which could offer benefits such as increased apparent solubility of poorly soluble drugs, and thereby increase their bioavailability [ 12 ]. For an amorphous drug, however, the drawback is their physical stability [ 13 ], and products from new manufacturing techniques such as 3D printing will not be immune to this. 3D printing based on FDM (combined with HME) involves heating and, therefore, mainly follows the thermodynamic pathway of producing amorphous drugs [ 14 , 15 ] and not the kinetic pathway involving mechanical disruption of crystals.…”

Section: Introductionmentioning

confidence: 99%

Influence of Drug Load on the Printability and Solid-State Properties of 3D-Printed Naproxen-Based Amorphous Solid Dispersion

et al. 2021

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Fused deposition modelling-based 3D printing of pharmaceutical products is facing challenges like brittleness and printability of the drug-loaded hot-melt extruded filament feedstock and stabilization of the solid-state form of the drug in the final product. The aim of this study was to investigate the influence of the drug load on printability and physical stability. The poor glass former naproxen (NAP) was hot-melt extruded with Kollidon® VA 64 at 10–30% w/w drug load. The extrudates (filaments) were characterised using differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and thermogravimetric analysis (TGA). It was confirmed that an amorphous solid dispersion was formed. A temperature profile was developed based on the results from TGA, DSC, and DMA and temperatures used for 3D printing were selected from the profile. The 3D-printed tablets were characterised using DSC, X-ray computer microtomography (XµCT), and X-ray powder diffraction (XRPD). From the DSC and XRPD analysis, it was found that the drug in the 3D-printed tablets (20 and 30% NAP) was amorphous and remained amorphous after 23 weeks of storage (room temperature (RT), 37% relative humidity (RH)). This shows that adjusting the drug ratio can modulate the brittleness and improve printability without compromising the physical stability of the amorphous solid dispersion.

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Physical Instability: A Key Problem of Amorphous Drugs

Cited by 13 publications

References 158 publications

Determination of Stable Co-Amorphous Drug–Drug Ratios from the Eutectic Behavior of Crystalline Physical Mixtures

Determination of Stable Co-Amorphous Drug–Drug Ratios from the Eutectic Behavior of Crystalline Physical Mixtures

Predictive identification of co-formers in co-amorphous systems

Influence of Drug Load on the Printability and Solid-State Properties of 3D-Printed Naproxen-Based Amorphous Solid Dispersion

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