Impact of Hydroxypropyl Methylcellulose Acetate Succinate Critical Aggregation Concentration on Celecoxib Supersaturation

Bristol, Ashleigh N.; Lamm, Matthew S.; Li, Yongjun

doi:10.1021/acs.molpharmaceut.1c00372

Cited by 12 publications

(12 citation statements)

References 54 publications

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“…We also tried to pause the titration when the LLPS onset point was detected. The UV extinction value remained stable for at least 20 min, suggesting the number and size of the metastable particles were stable within the individual test . Additional experiments were also conducted to highlight the differences in UV extinction values caused by the crystalline CXB and LLPS (Figure S3).…”

Section: Resultsmentioning

confidence: 99%

Kinetic and Thermodynamic Interplay of Polymer-Mediated Liquid–Liquid Phase Separation for Poorly Water-Soluble Drugs

Qian,

Stella,

Liu

et al. 2024

Mol. Pharmaceutics

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Understanding the interplay between kinetics and thermodynamics of polymer-mediated liquid−liquid phase separation is crucial for designing and implementing an amorphous solid dispersion formulation strategy for poorly water-soluble drugs. This work investigates the phase behaviors of a poorly water-soluble model drug, celecoxib (CXB), in a supersaturated aqueous solution with and without polymeric additives (PVP, PVPVA, HPMCAS, and HPMCP). Drug−polymer−water ternary phase diagrams were also constructed to estimate the thermodynamic behaviors of the mixtures at room temperature. The liquid− liquid phase separation onset point for CXB was detected using an inline UV/vis spectrometer equipped with a fiber optic probe. Varying CXB concentrations were achieved using an accurate syringe pump throughout this study. The appearance of the transient nanodroplets was verified by cryo-EM and total internal reflection fluoresence microscopic techniques. The impacts of various factors, such as polymer composition, drug stock solution pumping rates, and the types of drug−polymer interactions, are tested against the onset points of the CXB liquid−liquid phase separation (LLPS). It was found that the types of drug−polymer interactions, i.e., hydrogen bonding and hydrophobic interactions, are vital to the position and shapes of LLPS in the supersaturation drug solution. A relation between the behaviors of LLPS and its location in the CXB−polymer−water ternary phase diagram was drawn from the findings.

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Section: Resultsmentioning

confidence: 99%

Kinetic and Thermodynamic Interplay of Polymer-Mediated Liquid–Liquid Phase Separation for Poorly Water-Soluble Drugs

Qian,

Stella,

Liu

et al. 2024

Mol. Pharmaceutics

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“…However, the supersaturation state was not easy to capture even for the RT-annealed CEL, presumably due to fast crystallization. HPMC-AS, which effectively suppresses the crystallization of a wide range of pharmaceutical glasses, − including CEL, , was added to maintain supersaturation. As shown in Figure c, RT-annealed CEL achieved a maximum concentration of 5 μg/mL in about 8–10 h, which was 29-folds of the equilibrium solubility, and then slowly desupersaturated.…”

Section: Resultsmentioning

confidence: 99%

Nucleation During Storage Impeded Supersaturation in the Dissolution Process of Amorphous Celecoxib

Song

Kawakami

2023

Mol. Pharmaceutics

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The aqueous solubility of active pharmaceutical ingredients (APIs) is one of the most critical factors in determining the absorption of orally administered drugs. Amorphization of API may offer better drug absorption than the crystalline state owing to enhanced solubility. However, if crystal nuclei are formed during storage, they may develop into crystals upon contact with water, thus limiting the dissolution advantage. In an earlier study, we found that the nuclei of amorphous celecoxib (CEL) could be formed at freezing temperatures (FT) without further crystal growth. Following this finding, we compared the dissolution performances of amorphous CEL annealed at room temperature (RT, 25 °C) or FT (−20 °C). We found that only the RT-annealed CEL could achieve a supersaturated state effectively during the dissolution process, which could be explained by the fast conversion of the FTannealed amorphous CEL to a crystalline state owing to the presence of nuclei. Investigation of the residual solids revealed that supersaturation could be maintained for a while after the appearance of the crystals, which could be explained by heterogeneous nucleation and competition between the dissolution of amorphous parts and crystallization. In addition, a new crystalline form of CEL was observed during dissolution.

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“…The distribution of HPMCAS into a drug-rich phase did not agree between different grades, resulting in dissolution performance [ 38 ]. Structural conformation of HPMCAS with random-coil or aggregation affected the supersaturation state of the drug; change in the conformation between grades of HPMCAS impacted the supersaturation of celecoxib [ 39 ]. These findings suggest that both grades of HPMCAS used in this study formed similar interactions with IMC in a supersaturated solution, resulting in comparable results for the initial dissolution rate and concentration at a plateau between 420 and 480 min.…”

Section: Resultsmentioning

confidence: 99%

Dissolution-permeation of hot-melt extruded amorphous solid dispersion comprising an experimental grade of HPMCAS

Tanaka¹,

Miyano²,

Ueda³

2023

ADMET DMPK

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Background and purpose: Physicochemical properties of an amorphous solid dispersion (ASD) comprising an experimental grade of hydroxypropyl methylcellulose acetate succinate (HPMCAS-MX) with lower glass transition temperature have been previously investigated. This study aimed to evaluate applicability of HPMCAS-MX to hot-melt extrusion (HME) and dissolution-permeation performance of prepared ASDs using MicroFLUX. Review approach: A physical mixture of indomethacin (IMC) and HPMCAS-MX or -MG (a commercial grade with higher transition temperature) at 20:80 weight ratio was hot-melt extruded to prepare an ASD (IMC-MX and IMC-MG, respectively). The dissolution-permeation performance and the stability of the ASDs were measured. Key results: A torque reduction at 120 °C implied that IMC-MX transformed into an amorphous state at this temperature, but IMC-MG required around 170 °C. This result was supported by Raman mapping of the the HME samples. IMC-MG and IMC-MX remained in an amorphous state at 40 °C for three months. The initial dissolution rate and solubility of the ASDs were higher than that of crystalline IMC. The apparent permeability of IMC from IMC-MX and IMC-MG was comparable but was approximately two-fold higher than that from crystalline IMC. Conclusion: HPMCAS-MX enabled HME process at a lower temperature and improved the dissolution-permeation performance of indomethacin.

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Impact of Hydroxypropyl Methylcellulose Acetate Succinate Critical Aggregation Concentration on Celecoxib Supersaturation

Cited by 12 publications

References 54 publications

Kinetic and Thermodynamic Interplay of Polymer-Mediated Liquid–Liquid Phase Separation for Poorly Water-Soluble Drugs

Kinetic and Thermodynamic Interplay of Polymer-Mediated Liquid–Liquid Phase Separation for Poorly Water-Soluble Drugs

Nucleation During Storage Impeded Supersaturation in the Dissolution Process of Amorphous Celecoxib

Dissolution-permeation of hot-melt extruded amorphous solid dispersion comprising an experimental grade of HPMCAS

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