Influence of Plasdone™ S630 Ultra—an Improved Copovidone on the Processability and Oxidative Degradation of Quetiapine Fumarate Amorphous Solid Dispersions Prepared via Hot-Melt Extrusion Technique

Butreddy, Arun; Sarabu, Sandeep; Bandari, Suresh; Batra, Amol; Lawal, Kamaru; Chen, Nick Ningyi; Bi, Vivian; Dürig, Thomas; Repka, Michael A.

doi:10.1208/s12249-021-02069-9

Cited by 15 publications

(9 citation statements)

References 42 publications

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“…These results suggest that selecting a larger particle size range can improve the processability of formulations using KinetiSol compounding. These results are in agreement with a recent study that describes a modest increase in the processability of a novel copovidone polymer (Plasdone™ S630 Ultra) during the hot melt extrusion of quetiapine ASDs, which was attributed to improved flowability compared to another copovidone [40].…”

Section: Increased Particle Size Of Polymers During Kinetisol Compoun...supporting

confidence: 93%

Pre-Processing a Polymer Blend into a Polymer Alloy by KinetiSol Enables Increased Ivacaftor Amorphous Solid Dispersion Drug Loading and Dissolution

Thompson

Davis²,

Miller³

et al. 2023

Biomedicines

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This study compares the effects of pre-processing multiple polymers together to form a single-phase polymer alloy prior to amorphous solid dispersion formulation. KinetiSol compounding was used to pre-process a 1:1 (w/w) ratio of hypromellose acetate succinate and povidone to form a single-phase polymer alloy with unique properties. Ivacaftor amorphous solid dispersions comprising either a polymer, an unprocessed polymer blend, or the polymer alloy were processed by KinetiSol and examined for amorphicity, dissolution performance, physical stability, and molecular interactions. A polymer alloy ivacaftor solid dispersion with a drug loading of 50% w/w was feasible versus 40% for the other compositions. Dissolution in fasted simulated intestinal fluid revealed that the 40% ivacaftor polymer alloy solid dispersion reached a concentration of 595 µg/mL after 6 h, 33% greater than the equivalent polymer blend dispersion. Fourier transform infrared spectroscopy and solid-state nuclear magnetic resonance revealed changes in the ability of the povidone contained in the polymer alloy to hydrogen bond with the ivacaftor phenolic moiety, explaining the differences in the dissolution performance. This work demonstrates that the creation of polymer alloys from polymer blends is a promising technique that provides the ability to tailor properties of a polymer alloy to maximize the drug loading, dissolution performance, and stability of an ASD.

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Section: Increased Particle Size Of Polymers During Kinetisol Compoun...supporting

confidence: 93%

Pre-Processing a Polymer Blend into a Polymer Alloy by KinetiSol Enables Increased Ivacaftor Amorphous Solid Dispersion Drug Loading and Dissolution

Thompson

Davis²,

Miller³

et al. 2023

Biomedicines

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“…Also, the PVPVA was dried before every use to remove the residual moisture sorbed by PVPVA during subsequent usages. Moreover, PVPVA has also proven to be a useful polymer in generating hot-melt extrusion formulation of a poorly water-soluble drug . Previous research from our lab has shown that milling solid povidones can generate free radicals, primarily due to the cleavage and scission of polymeric chains, as also mentioned elsewhere .…”

Section: Discussionsupporting

confidence: 57%

“…Moreover, PVPVA has also proven to be a useful polymer in generating hot-melt extrusion formulation of a poorly water-soluble drug. 57 Previous research from our lab has shown that milling solid povidones can generate free radicals, 38 primarily due to the cleavage and scission of polymeric chains, as also mentioned elsewhere. 58 Furthermore, several reports highlight the degradation of polymers such as povidones during milling by mechanoactivation.…”

Section: Autoxidation Of Amorphous Drugs By Comillingmentioning

confidence: 68%

Mechanoactivation as a Tool to Assess the Autoxidation Propensity of Amorphous Drugs

et al. 2023

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Mechanoactivation has attracted considerable attention in the pharmaceutical sciences due to its ability to generate amorphous materials and solid-state synthetic products without the use of solvent. Although some studies have reported drug degradation during milling, no studies have systematically investigated the use of mechanoactivation in predicting drug degradation in the solid state. Thus, this work explores the autoxidation of drugs in the solid state by comilling amorphous mifepristone (MFP):polyvinylpyrrolidone vinyl acetate (PVPVA) and amorphous olanzapine (OLA):PVPVA. MFP was amorphized by ball milling and OLA by quench cooling techniques. Subsequently, comilling the amorphous drugs in the presence of a 10-fold weight ratio of PVPVA (the excipient containing reactive free radicals) was performed at several milling frequencies to identify the kinetics of mechano-autoxidation over milling durations. Overall, milling led to the degradation of up to 5% drug in the solid state. The autoxidation mechanism was confirmed by performing a stress study in the solution at 50 °C for 5 h, by using a 10 mM azo-bis(isobutyronitrile) (AIBN) as a stressing agent. By deconvoluting the effect of milling frequency and the energy on the extent and kinetics of milling-induced autoxidation of amorphous drugs, it was possible to fit an extended Arrhenius model that allowed extrapolation of mechanoactivated degradation rates (K m) to zero milling frequencies. Further, the autoxidation rates of drugs stored at high temperatures were observed to follow an Arrhenius behavior. A good degree of agreement was observed between the model predictions obtained by mechanoactivation (K m) to the reaction rates observed under accelerated temperatures. Additionally, the impact of adding an antioxidant (e.g., butylated hydroxytoluene) to the mixture during comilling was also examined. This study can be helpful in evaluating the stability of amorphous solids stored in accelerated (non-hermetic) conditions, in screening solid-state autoxidation propensity of drugs, and for the rational selection of antioxidants.

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“…Excess Cur raw drug, the physical mixture, and the SD were added to a hydrochloric acid solution with pH 1.2, containing 0.5% Tween-80, and the equilibrium solubility is shown in Table 2. The solubility of the Cur-EPO SD was five times higher than that of Cur, indicating that the SD preparation can effectively improve Cur solubility [47,48].…”

Section: Equilibrium Solubility Studiesmentioning

confidence: 95%

Preparation of Curcumin-Eudragit® E PO Solid Dispersions with Gradient Temperature through Hot-Melt Extrusion

Zhang

Zhu

et al. 2021

Molecules

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Hot-melt extrusion (HME) has great advantages for the preparation of solid dispersion (SD), for instance, it does not require any organic solvents. Nevertheless, its application to high-melting-point and thermosensitive drugs has been rarely reported. In this study, thermally unstable curcumin (Cur) was used as a drug model. The HME process was systematically studied by adjusting the gradient temperature mode and residence time, with the content, crystallinity and dissolution of Cur as the investigated factors. The effects of barrel temperature, screw speed and cooling rate on HME were also examined. Solubility parameters and the Flory–Huggins method were used to evaluate the miscibility between Cur and carriers. Differential scanning calorimetry, X-ray diffraction, Fourier transform infrared spectroscopy, equilibrium solubility and in vitro and in vivo experiments were used to characterize and evaluate the results. An amorphous Cur SD was successfully obtained, increasing the solubility and release of Cur. In the optimal process, the mass ratio of Cur to Eudragit® E PO (EPO) was 1:4 and the barrel temperature was set at a gradient heating mode (130 °C–135 °C–140 °C–145 °C–150 °C–155 °C–160 °C) at 100 rpm. Related pharmacokinetic test results also showed the improved bioavailability of the drug in rats. In a pharmacodynamic analysis of Sprague–Dawley rats, the Cmax and the bioavailability of the Cur-EPO SD were 2.6 and 1.5 times higher than those of Cur, respectively. The preparation of the amorphous SD not only provided more solubility but also improved the bioavailability of Cur, which provides an effective way to improve the bioavailability of BCS II drugs.

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Influence of Plasdone™ S630 Ultra—an Improved Copovidone on the Processability and Oxidative Degradation of Quetiapine Fumarate Amorphous Solid Dispersions Prepared via Hot-Melt Extrusion Technique

Cited by 15 publications

References 42 publications

Pre-Processing a Polymer Blend into a Polymer Alloy by KinetiSol Enables Increased Ivacaftor Amorphous Solid Dispersion Drug Loading and Dissolution

Pre-Processing a Polymer Blend into a Polymer Alloy by KinetiSol Enables Increased Ivacaftor Amorphous Solid Dispersion Drug Loading and Dissolution

Mechanoactivation as a Tool to Assess the Autoxidation Propensity of Amorphous Drugs

Preparation of Curcumin-Eudragit® E PO Solid Dispersions with Gradient Temperature through Hot-Melt Extrusion

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