An approach for chemical stability during melt extrusion of a drug substance with a high melting point

Haser, Abbe; Huang, Siyuan; Listro, Tony; White, David E.; Zhang, Feng

doi:10.1016/j.ijpharm.2017.03.070

Cited by 58 publications

(47 citation statements)

References 27 publications

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“…For example, it has been reported that drugs with a high melting point ≥200 • C, like abiraterone, are difficult to render amorphous using the HME technique, thus these drugs typically lie outside the formulation space of HME [32]. Also, since HME requires the application of external heat, attempts to formulate drugs with a high melting point can lead to drug and/or polymer degradation [32,33]. Alternatively, a prerequisite for solvent-based ASD manufacturing techniques (e.g., spray drying, thin film freezing) is that the drug and polymer must be co-soluble in organic solvents or in a mixture of organic and aqueous solvents [34].…”

Section: Introductionmentioning

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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Section: Introductionmentioning

confidence: 99%

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

Gala

Miller²,

Williams

2020

Pharmaceutics

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“…HPLC-MS identified two degradation pathways of meloxicam due to hydrolysis reactions when the drug extrusion was performed in presence of Kollidon ® VA64. The authors found that melting point suppression did not prevent meloxicam degradation; instead, they were able to increase the drug chemical stability through process parameter optimization, specifically, by establishing a minimum processing temperature (110 °C), and providing a basic pH environment during extrusion [ 59 ].…”

Section: Introductionmentioning

confidence: 99%

“…Another strategy is the injection of a supercritical fluid into the extruder barrel [ 59 ], because it acts as polymer plasticizer, decreasing polymer viscosity, melting temperature, and glass transition temperature [ 49 ].…”

Section: Introductionmentioning

confidence: 99%

“…In another pre-formulation study, HS-PLM revealed traces of crystalline meloxicam suspended in a glassy PVP/VA polymer, though X-ray beams could not sufficiently penetrate the sample to detect the crystals [ 59 ].…”

Section: Introductionmentioning

confidence: 99%

“…In one pre-formulation study, the Hansen solubility parameters for meloxicam and Kollidon ® VA64 were calculated, based on molecular structure and melting points, using a specific software. The results indicated differences in the solubility parameters for meloxicam and Kollidon ® VA64; this information made it possible to predict miscibility and melting point depression [ 59 ].…”

Section: Introductionmentioning

confidence: 99%

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Hot Melt Extrusion: Highlighting Physicochemical Factors to Be Investigated While Designing and Optimizing a Hot Melt Extrusion Process

et al. 2018

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Hot-melt extrusion (HME) is a well-accepted and extensively studied method for preparing numerous types of drug delivery systems and dosage forms. It offers several advantages: no solvents are required, it is easy to scale up and employ on the industrial level, and, in particular, it offers the possibility of improving drug bioavailability. HME involves the mixing of a drug with one or more excipients, in general polymers and even plasticizers, which can melt, often forming a solid dispersion of the drug in the polymer. The molten mass is extruded and cooled, giving rise to a solid material with designed properties. This process, which can be realized using different kinds of special equipment, may involve modifications in the drug physicochemical properties, such as chemical, thermal and mechanical characteristics thus affecting the drug physicochemical stability and bioavailability. During process optimization, the evaluation of the drug solid state and stability is thus of paramount importance to guarantee stable drug properties for the duration of the drug product shelf life. This manuscript reviews the most important physicochemical factors that should be investigated while designing and optimizing a hot melt extrusion process, and by extension, during the different pre-formulation, formulation and process, and post-formulation phases. It offers a comprehensive evaluation of the chemical and thermal stability of extrudates, the solid physical state of extrudates, possible drug-polymer interactions, the miscibility/solubility of the drug-polymer system, the rheological properties of extrudates, the physicomechanical properties of films produced by hot melt extrusion, and drug particle dissolution from extrudates. It draws upon the last ten years of research, extending inquiry as broadly as possible.

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Melt Extrusion

Thompson

Davis

DiNunzio

et al. 2022

Formulating Poorly Water Soluble Drugs

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An approach for chemical stability during melt extrusion of a drug substance with a high melting point

Cited by 58 publications

References 27 publications

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

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

Hot Melt Extrusion: Highlighting Physicochemical Factors to Be Investigated While Designing and Optimizing a Hot Melt Extrusion Process

Melt Extrusion

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