The effect of HPMCAS functional groups on drug crystallization from the supersaturated state and dissolution improvement

Ueda, Keisuke; Higashi, Kenjirou; Yamamoto, Keiji; Moribe, Kunikazu

doi:10.1016/j.ijpharm.2014.01.005

Cited by 105 publications

(107 citation statements)

References 31 publications

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“…A comparative study using compounds with similar structures is effective to reveal the intermolecular interactions . The inhibition of drug crystallization by a polymer has been studied and compared with that of other polymers containing different substituents . Ilevbare et al reported that the inhibition efficiency of drug crystallization changes depending on the hydrophobic/hydrophilic balance of each polymer and drug couple.…”

Section: Introductionmentioning

confidence: 99%

An Insight into Different Stabilization Mechanisms of Phenytoin Derivatives Supersaturation by HPMC and PVP

Otsuka

Ueda

Ohyagi

et al. 2015

Journal of Pharmaceutical Sciences

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Section: Introductionmentioning

confidence: 99%

An Insight into Different Stabilization Mechanisms of Phenytoin Derivatives Supersaturation by HPMC and PVP

Otsuka

Ueda

Ohyagi

et al. 2015

Journal of Pharmaceutical Sciences

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“…Additionally, the estimation of δ can vary greatly in the case of hypromellose polymers. The properties of hypromellose polymers are defined by a large range of molecular weight and percentage levels of methoxyl, hydroxyl, and hydroxypropyl group substitutions on the cellulose chain [ 39 ]. This results in δ values being inaccurate when using the group contribution methods.…”

Section: Resultsmentioning

confidence: 99%

Prediction of Phase Behavior of Spray-Dried Amorphous Solid Dispersions: Assessment of Thermodynamic Models, Standard Screening Methods and a Novel Atomization Screening Device with Regard to Prediction Accuracy

et al. 2018

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The evaluation of drug–polymer miscibility in the early phase of drug development is essential to ensure successful amorphous solid dispersion (ASD) manufacturing. This work investigates the comparison of thermodynamic models, conventional experimental screening methods (solvent casting, quench cooling), and a novel atomization screening device based on their ability to predict drug–polymer miscibility, solid state properties (Tg value and width), and adequate polymer selection during the development of spray-dried amorphous solid dispersions (SDASDs). Binary ASDs of four drugs and seven polymers were produced at 20:80, 40:60, 60:40, and 80:20 (w/w). Samples were systematically analyzed using modulated differential scanning calorimetry (mDSC) and X-ray powder diffraction (XRPD). Principal component analysis (PCA) was used to qualitatively assess the predictability of screening methods with regards to SDASD development. Poor correlation was found between theoretical models and experimentally-obtained results. Additionally, the limited ability of usual screening methods to predict the miscibility of SDASDs did not guarantee the appropriate selection of lead excipient for the manufacturing of robust SDASDs. Contrary to standard approaches, our novel screening device allowed the selection of optimal polymer and drug loading and established insight into the final properties and performance of SDASDs at an early stage, therefore enabling the optimization of the scaled-up late-stage development.

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“…Its relatively higher substitution with hydrophobic methoxy and acetate groups can interact with the hydrophobic regions of abiraterone and prevent further recrystallization [63]. It has been reported that HPMCAS maintains drug supersaturation and prevents drug precipitation by reducing molecular mobility for nucleation, thus prolonging the time required for nucleation and re-dissolving precipitated aggregates by interacting with the hydrophobic groups on the surface of the drug, hence interfering with drug crystallization [64][65][66]. So, it was determined that HPMCAS 126 G was a suitable secondary polymer for the development of a ternary abiraterone KSD.…”

Section: Selection Of a Suitable Ternary Component For Ksdsmentioning

confidence: 99%

Improved Dissolution and Pharmacokinetics of Abiraterone through KinetiSol® Enabled Amorphous Solid Dispersions

Gala

Miller²,

Williams

2020

Pharmaceutics

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Abiraterone is a poorly water-soluble drug. It has a high melting point and limited solubility in organic solvents, making it difficult to formulate as an amorphous solid dispersion (ASD) with conventional technologies. KinetiSol® is a high-energy, fusion-based, solvent-free technology that can produce ASDs. The aim of this study was to evaluate the application of KinetiSol to make abiraterone ASDs. We developed binary KinetiSol ASDs (KSDs) using both polymers and oligomers. For the first time, we reported that KinetiSol can process hydroxypropyl-β-cyclodextrin (HPBCD), a low molecular-weight oligomer. Upon X-ray diffractometry and modulated differential scanning calorimetry analysis, we found the KSDs to be amorphous. In vitro dissolution analysis revealed that maximum abiraterone dissolution enhancement was achieved using a HPBCD binary KSD. However, the KSD showed significant abiraterone precipitation in fasted state simulated intestinal fluid (FaSSIF) media. Hence, hypromellose acetate succinate (HPMCAS126G) was selected as an abiraterone precipitation inhibitor and an optimized ternary KSD was developed. A pharmacokinetic study revealed that HPBCD based binary and ternary KSDs enhanced abiraterone bioavailability by 12.4-fold and 13.8-fold, respectively, compared to a generic abiraterone acetate tablet. Thus, this study is the first to demonstrate the successful production of an abiraterone ASD that exhibited enhanced dissolution and bioavailability.

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The effect of HPMCAS functional groups on drug crystallization from the supersaturated state and dissolution improvement

Cited by 105 publications

References 31 publications

An Insight into Different Stabilization Mechanisms of Phenytoin Derivatives Supersaturation by HPMC and PVP

An Insight into Different Stabilization Mechanisms of Phenytoin Derivatives Supersaturation by HPMC and PVP

Prediction of Phase Behavior of Spray-Dried Amorphous Solid Dispersions: Assessment of Thermodynamic Models, Standard Screening Methods and a Novel Atomization Screening Device with Regard to Prediction Accuracy

Improved Dissolution and Pharmacokinetics of Abiraterone through KinetiSol® Enabled Amorphous Solid Dispersions

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