Crosslinking: An avenue to develop stable amorphous solid dispersion with high drug loading and tailored physical stability

Sahoo, Anasuya; Kumar, N.S. Krishna; Suryanarayanan, Raj

doi:10.1016/j.jconrel.2019.09.007

Cited by 40 publications

(45 citation statements)

References 46 publications

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“…Furthermore, increasing cross-linking temperatures led to increasing ASD’s T g , indicating that the degree of cross-linking is clearly increasing with cross-linking temperature (although it seems that this effect is less pronounced in temperatures above 150 °C). Finally, it should be pointed out that the T g ’s shift to higher temperatures with the progressive increase in cross-linker concentration observed in the present work was less pronounced compared to previous studies using KTZ . Keeping in mind that both APIs (i.e., KTZ and IND) possess rather similar thermal properties (KTZ has a T g value of ∼45 °C and a T m of ∼150 °C) and that both are considered to be strong glass formers, this finding adds to our previous hypothesis that probably intermolecular interactions formed between the API and the polymeric matrices are significantly affecting the cross-linking process.…”

Section: Resultssupporting

confidence: 56%

“…Nonetheless, and despite their unique features (such as good biocompatibility and highly tunable physicochemical and thermomechanical properties), the extremely low aqueous solubility of cross-linked polymeric hydrogels makes them inappropriate for the preparation of per os ASD formulations, especially in the case of APIs exhibiting low aqueous solubility . As a result, the rather limited attempts made in this direction (i.e., preparation of per os hydrogel-based ASDs for low-aqueous-solubility APIs) are focusing exclusively on the in vitro evaluation of API’s sustained supersaturation properties, ,,− while, only recently, the use of in situ thermal polymeric cross-linking was suggested as a new, novel technique for the preparation of HDL ASDs …”

Section: Introductionmentioning

confidence: 99%

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High-Drug-Loading Amorphous Solid Dispersions via In Situ Thermal Cross-Linking: Unraveling the Mechanisms of Stabilization

et al. 2021

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This article takes a step forward in understanding the mechanisms involved during the preparation and performance of cross-linked high-drug-loading (HDL) amorphous solid dispersions (ASDs). Specifically, ASDs, having 90 wt % poorly water-soluble drug indomethacin (IND), were prepared via in situ thermal cross-linking of poly(acrylic acid) (PAA) and poly(vinyl alcohol) (PVA) and thoroughly evaluated in terms of physical stability and in vitro supersaturation. Results showed that HDL ASDs having excellent active pharmaceutical ingredient (API) amorphous stability and prolonged in vitro supersaturation were prepared by fine tuning the cross-linking procedure. Unraveling of the processes involved during ASD’s formation shed light on the significant role of the cross-linking conditions (i.e., temperature and time), the physicochemical properties of the API, and the hydrolysis level of the cross-linker as key factors in modulating ASD’s stability. In-depth analysis of the prepared systems revealed the (1) reduction of API’s molecular motions within the cross-linked polymeric networks (through API’s strong spatial confinement), (2) the structural changes in the prepared cross-linked matrices (induced by the high API drug loading), and (3) the tuning of the cross-linking density via utilization of low-hydrolyzed PVA as the major mechanisms responsible for ASD’s exceptional performance. Complementary analysis by means of molecular dynamics simulations also highlighted the vital role of strong drug–polymer intermolecular interactions evolving among the ASD components. Overall, the impression of the complexity of in situ cross-linked ASDs has been reinforced with the excessive variation of parameters investigated in the current study, offering thus insights up to the submolecular level to lay the groundwork and foundations for the comprehensive assessment of a new emerging class of HDL amorphous API formulations.

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Section: Resultssupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

High-Drug-Loading Amorphous Solid Dispersions via In Situ Thermal Cross-Linking: Unraveling the Mechanisms of Stabilization

et al. 2021

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“…In addition to the above-mentioned techniques, several classical characterization techniques have also been widely used in the field of pharmaceuticals for several decades such as FT-IR, Raman spectroscopy, powder X-ray diffraction (PXRD), differential scanning calorimeter (DSC), etc. [92][93][94][95]. These classical characterization techniques have found new applications and they are integrated with other techniques [96,97].…”

Section: Other Characterization Techniquesmentioning

confidence: 99%

Recent Advances in the Application of Characterization Techniques for Studying Physical Stability of Amorphous Pharmaceutical Solids

Wang

Cheng

et al. 2021

Crystals

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The amorphous form of a drug usually exhibits higher solubility, faster dissolution rate, and improved oral bioavailability in comparison to its crystalline forms. However, the amorphous forms are thermodynamically unstable and tend to transform into a more stable crystalline form, thus losing their advantages. In order to investigate and suppress the crystallization, it is vital to closely monitor the drug solids during the preparation, storage, and application processes. A list of advanced techniques—including optical microscopy, surface grating decay, solid-state nuclear magnetic resonance, broadband dielectric spectroscopy—have been applied to characterize the physicochemical properties of amorphous pharmaceutical solids, to provide in-depth understanding on the crystallization mechanism. This review briefly summarizes these characterization techniques and highlights their recent advances, so as to provide an up-to-date reference to the available tools in the development of amorphous drugs.

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“…It is well known that temperature is one of the major factors that affect drug stability. [ 33,34 ] Without exception, an increase of 10 ℃ led to at least two‐fold elevated k obs of ZL006 in pH 7 or 9 buffers with a fixed buffer concentration of 0.05 m and ionic strength of 0.5 m , and the temperature dependence of the degradation rate followed the Arrhenius equation between 40 and 60 ℃ (Figure S1E, Supporting Information). [ 34 ] As shown in Figure 1E,F, ZL006 was degraded faster in the presence of the oxidant hydrogen peroxide (H 2 O 2 ) ( k obs = 0.1857 ± 0.0077 h –1 ) compared to the control group without external oxidants ( k obs = 0.0888 ± 0.0022 h –1 ), which may be attributed to the easily oxidized phenolic hydroxyl groups of ZL006.…”

Section: Resultsmentioning

confidence: 99%

An Injectable Hydrogel for Treatment of Chronic Neuropathic Pain

Zeng

et al. 2022

Macromolecular Bioscience

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Current treatments for chronic neuropathic pain often fall short. A small‐molecular compound ZL006 can suppress N‐Methyl‐d‐aspartate receptor (NMDAR)‐mediated neuropathic pain behaviors without blocking essential NMDAR function and brings new hope for neuropathic pain therapy. The persistent nature of neuropathic pain mandates the long‐term treatment. However, similar to existing analgesics, ZL006 has only a short duration of action. To unleash the therapeutic potential of ZL006, the stability of ZL006 in aqueous solutions is investigated, and a ZL006‐incorporated P407‐based thermoresponsive injectable hydrogel is developed. The computational analysis is performed to help achieve the desired ZL006‐loaded hydrogel system and elucidate the gelation mechanism. The hydrogel matrix can be loaded with ZL006 in an aqueous phase at room temperature without costly specialized equipment and no organic solvent, where the sol is formed and injectable. On subcutaneous administration and subsequent rapid warming to physiological temperature, the sol is converted to a gel. The thermoresponsive hydrogel at body temperature enables the extended release of encapsulated ZL006, and therefore a single subcutaneous injection of ZL006‐hydrogel produces a prolonged and stable analgesic action in mice with spinal nerve ligation. The study provides a practical chronic neuropathic pain therapy and a new perspective on future applications of ZL006.

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Crosslinking: An avenue to develop stable amorphous solid dispersion with high drug loading and tailored physical stability

Cited by 40 publications

References 46 publications

High-Drug-Loading Amorphous Solid Dispersions via In Situ Thermal Cross-Linking: Unraveling the Mechanisms of Stabilization

High-Drug-Loading Amorphous Solid Dispersions via In Situ Thermal Cross-Linking: Unraveling the Mechanisms of Stabilization

Recent Advances in the Application of Characterization Techniques for Studying Physical Stability of Amorphous Pharmaceutical Solids

An Injectable Hydrogel for Treatment of Chronic Neuropathic Pain

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