Effect of Polymer Species on Maximum Aqueous Phase Supersaturation Revealed by Quantitative Nuclear Magnetic Resonance Spectroscopy

Ueda, Keisuke; Moseson, Dana E.; Pathak, Vaibhav; Taylor, Lynne S.

doi:10.1021/acs.molpharmaceut.0c01174

Cited by 24 publications

(41 citation statements)

References 59 publications

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“…The mixing of the polymer with the IBP-rich phase caused these peak shifts. , Indeed, the polymer peak intensity in the aqueous phase decreased in the presence of the IBP-rich phase (Figure S3). The 1 H peaks of the polymer present in the IBP-rich phase cannot be detected in the solution-state NMR spectrum due to the long re-orientational correlation time of the polymer in this phase . The mixing of polymer with the IBP-rich phase also resulted in mobility suppression of IBP in the drug-rich phase, together with changes in the chemical environment of IBP molecules in this phase.…”

Section: Resultssupporting

confidence: 91%

“…Thus, these polymers at a concentration of 1000 μg/mL showed a minimal solubilization effect on IBP. This result is in agreement with a previous study which reported that the molecular state of aqueous phase dissolved IBP was unchanged by adding PVP, PVP–VA, or HPMC at 1000 μg/mL …”

Section: Resultsmentioning

confidence: 99%

“…Figure shows the solution-state 1 H NMR spectra of IBP-supersaturated solutions recorded at different temperatures. Since an IBP dose concentration of 400 μg/mL exceeds the amorphous solubility of IBP across the measurement temperature range, IBP underwent LLPS and formed a colloidal IBP-rich phase. , Although IBP-rich droplets were generally well dispersed in the polymer solutions at 15–60 °C, the HPMC solution containing an IBP-rich phase formed gel-like aggregates at 60 °C (Figure S2). It has been reported that HPMC formed aggregates due to hydrophobic interactions of methoxy and hydroxypropyl residues in HPMC when the temperature increased to a certain point. − A further increase in the temperature induces gelation of the HPMC solution.…”

Section: Resultsmentioning

confidence: 99%

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Variable-Temperature NMR Analysis of the Thermodynamics of Polymer Partitioning between Aqueous and Drug-Rich Phases and Its Significance for Amorphous Formulations

et al. 2021

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We previously reported that the polymers used in amorphous solid dispersion (ASD) formulations, such as polyvinylpyrrolidone (PVP), polyvinylpyrrolidone/vinyl acetate (PVP–VA), and hypromellose (HPMC), distribute into the drug-rich phase of ibuprofen (IBP) formed by liquid–liquid phase separation, resulting in a reduction in the maximum drug supersaturation in the aqueous phase. Herein, the mechanism underlying the partitioning of the polymer into the drug-rich phase was investigated from a thermodynamic perspective. The dissolved IBP concentration in the aqueous phase and the amount of polymer distributed into the IBP-rich phase were quantitatively analyzed in IBP-supersaturated solutions containing different polymers using variable-temperature solution-state nuclear magnetic resonance (NMR) spectroscopy. The polymer weight ratio in the IBP-rich phase increased at higher temperatures, leading to a more notable reduction of IBP amorphous solubility. Among the polymers, the amorphous solubility reduction was the greatest for the PVP–VA solution at lower temperatures, while HPMC reduced the amorphous solubility to the greatest extent at higher temperatures. The change in the order of polymer impact on the amorphous solubility resulted from the differences in the temperature dependency of polymer partitioning. The van’t Hoff plot of the polymer partition coefficient revealed that both enthalpy and entropy changes for polymer transfer into the IBP-rich phase from the aqueous phase (ΔH aqueous→IBP‑rich and ΔS aqueous→IBP‑rich) gave positive values for most of the measured temperature range, indicating that polymer partitioning into the IBP-rich phase was an endothermic but entropically favorable process. The polymer transfer into the IBP-rich phase was more endothermic for HPMC than for PVP and PVP–VA. The solid-state NMR analysis of the IBP/polymer ASD implied that the newly formed IBP/polymer interactions in the IBP-rich phase upon polymer incorporation were weaker for HPMC, providing a rationale for the larger positive transfer enthalpy for HPMC. The change in Gibbs free energy for polymer transfer (ΔG aqueous→IBP‑rich) showed negative values across the experimental temperature range, decreasing with an increase in temperature, indicating that the distribution of the polymer into the IBP-rich phase is favored at higher temperatures. Moreover, ΔG aqueous→IBP‑rich for HPMC showed the greatest decrease with the temperature, likely reflecting the temperature-induced dehydration of HPMC in the aqueous phase. This study contributes fundamental insights into the phenomenon of polymer partitioning into drug-rich phases, furthering the understanding of achievable supersaturation levels and ultimately providing information on polymer selection for ASD formulations.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Variable-Temperature NMR Analysis of the Thermodynamics of Polymer Partitioning between Aqueous and Drug-Rich Phases and Its Significance for Amorphous Formulations

et al. 2021

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“…Solubilities of amorphous acalabrutinib dosed as the 50/50 ( w/w ) acalabrutinib/HPMCAS-H ASD were determined in different HCl molarities (pH 4.0, 4.5, 5.0, and 6.0) containing 34 mM NaCl. This approach was used rather than measuring amorphous solubility in the absence of polymer, since polymer has been shown to impact the apparent amorphous solubility [ 13 , 31 ]. After dosing the 50/50 ( w/w ) acalabrutinib/HPMCAS-H ASD to each medium, HCl was automatically titrated to maintain the target starting pH during dissolution using a Metrohm Titrado apparatus (Metohm, Tampa, FL, USA).…”

Section: Methodsmentioning

confidence: 99%

In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets

et al. 2021

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Amorphous solid dispersion (ASD) dosage forms can improve the oral bioavailability of poorly water-soluble drugs, enabling the commercialization of new chemical entities and improving the efficacy and patient compliance of existing drugs. However, the development of robust, high-performing ASD dosage forms can be challenging, often requiring multiple formulation iterations, long timelines, and high cost. In a previous study, acalabrutinib/hydroxypropyl methylcellulose acetate succinate (HPMCAS)-H grade ASD tablets were shown to overcome the pH effect of commercially marketed Calquence in beagle dogs. This study describes the streamlined in vitro and in silico approach used to develop those ASD tablets. HPMCAS-H and -M grade polymers provided the longest acalabrutinib supersaturation sustainment in an initial screening study, and HPMCAS-H grade ASDs provided the highest in vitro area under the curve (AUC) in gastric to intestinal transfer dissolution tests at elevated gastric pH. In silico simulations of the HPMCAS-H ASD tablet and Calquence capsule provided good in vivo study prediction accuracy using a bottom–up approach (absolute average fold error of AUC0-inf < 2 except for Calquence + famotidine ≈ 3). This streamlined approach combined an understanding of key drug, polymer, and gastrointestinal properties with in vitro and in silico tools to overcome the acalabrutinib pH effect without the need for reformulation or multiple studies, showing promise for reducing time and costs to develop ASD drug products.

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“…58,59 Furthermore, a previous study has shown that polymer partitioning from the aqueous phase into the drug-rich phase formed in drug-supersaturated solutions varies depending on the molecular weight of the polymer; higher molecular weights of PVP and HPMC resulted in greater polymer partitioning into the drug-rich phase. 60 Similarly, the distribution of additives in CLT self-associates can increase with an increase in the molecular weight of NEP and PVP. Thus, an increase in the molecular weight of the additives resulted in a stronger mobility suppression of CLT self-associates.…”

Section: ■ Discussionmentioning

confidence: 99%

NMR-Based Mechanistic Study of Crystal Nucleation Inhibition in a Supersaturated Drug Solution by Polyvinylpyrrolidone

Ueda

Yamamoto

Higashi

et al. 2022

Crystal Growth & Design

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In this study, the molecular states of supersaturated drugs and crystallization inhibitors in aqueous solutions were characterized using NMR to elucidate the inhibition mechanism of drug crystal nucleation in drug-supersaturated solutions. Polyvinylpyrrolidone (PVP) K12, PVP K25, and 1-ethyl-2-pyrrolidone (NEP) were used as additives to evaluate their ability to inhibit chlorthalidone (CLT) crystal nucleation. Although an inhibitory effect of NEP on the crystal nucleation of CLT was not observed, PVP effectively inhibited CLT crystallization and maintained CLT in a supersaturated state in the long term. In the 1D 1 H NMR spectra, the aromatic proton peaks of CLT showed an upfield shift with increasing CLT concentration, reflected by the self-association of CLT in aqueous solution; the number of self-associates increased with increasing supersaturation level. The presence of the additives in the aqueous solution induced downfield shifts of the CLT peaks, which were the largest in the PVP K25 solution and the smallest in the NEP solution. Nuclear Overhauser effect spectroscopy (NOESY) measurements revealed that the PVP formed a hydrophobic interaction with CLT via the carbon chain of PVP. Furthermore, the spin−spin relaxation rate of the supersaturated CLT was significantly increased by the addition of PVP K25, indicating the mobility suppression of supersaturated CLT by PVP K25, which can be caused by the intermolecular interactions between CLT and PVP K25. Furthermore, CLT mobility suppression by PVP K25 became more significant with increasing CLT supersaturation levels. This implies that PVP K25 interacted particularly with CLT self-associates formed in the supersaturated solution and suppressed their molecular mobility, thereby inhibiting the reorientation from the CLT self-associates to the crystal nucleus. The present study highlights the importance of the molecular weight of crystallization inhibitors on the ability of mobility suppression of a self-associated drug due to the nucleation inhibition effect.

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Effect of Polymer Species on Maximum Aqueous Phase Supersaturation Revealed by Quantitative Nuclear Magnetic Resonance Spectroscopy

Cited by 24 publications

References 59 publications

Variable-Temperature NMR Analysis of the Thermodynamics of Polymer Partitioning between Aqueous and Drug-Rich Phases and Its Significance for Amorphous Formulations

Variable-Temperature NMR Analysis of the Thermodynamics of Polymer Partitioning between Aqueous and Drug-Rich Phases and Its Significance for Amorphous Formulations

In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets

NMR-Based Mechanistic Study of Crystal Nucleation Inhibition in a Supersaturated Drug Solution by Polyvinylpyrrolidone

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