Cocrystalization and Simultaneous Agglomeration Using Hot Melt Extrusion

Dhumal, Ravindra S.; Kelly, Adrian L.; York, Peter; Coates, Phil; Paradkar, Anant

doi:10.1007/s11095-010-0273-9

Cited by 194 publications

(128 citation statements)

References 34 publications

(33 reference statements)

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“…Enhancement in percent drug release could be due to better maintenance of micro-environmental pH, which results in higher solubility by inclusion of tartaric acid or formation of an in situ compound Xtartaric acid co-crystal solid dispersion. Similar results of dissolution enhancement due to formation of in situ co-crystals during hot melt extrusion of mixture of either API and coformer or API, coformer, and polymer carrier have been reported by other researchers (23,24). In the present study, however, much higher levels of impurities (∼10%) were observed for tartaric acid containing ternary ASD (formulation 5b), which could be related to degradation of tartaric acid as the tartaric acid degradation temperature of 175°C was close to the extrusion temperature of 165-170°C.…”

Section: Pvp Va64 Containing Amorphous Solid Dispersionssupporting

confidence: 89%

Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale

2015

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Abstract. The objective of the study was to develop an amorphous solid dispersion (ASD) for an insoluble compound X by hot melt extrusion (HME) process. The focus was to identify material-sparing approaches to develop bioavailable and stable ASD including scale up of HME process using minimal drug. Mixtures of compound X and polymers with and without surfactants or pH modifiers were evaluated by hot stage microscopy (HSM), polarized light microscopy (PLM), and modulated differential scanning calorimetry (mDSC), which enabled systematic selection of ASD components. Formulation blends of compound X with PVP K12 and PVP VA64 polymers were extruded through a 9-mm twin screw mini-extruder. Physical characterization of extrudates by PLM, XRPD, and mDSC indicated formation of single-phase ASD's. Accelerated stability testing was performed that allowed rapid selection of stable ASD's and suitable packaging configurations. Dissolution testing by a discriminating two-step non-sink dissolution method showed 70-80% drug release from prototype ASD's, which was around twofold higher compared to crystalline tablet formulations. The in vivo pharmacokinetic study in dogs showed that bioavailability from ASD of compound X with PVP VA64 was four times higher compared to crystalline tablet formulations. The HME process was scaled up from lab scale to clinical scale using volumetric scale up approach and scale-independent-specific energy parameter. The present study demonstrated systematic development of ASD dosage form and scale up of HME process to clinical scale using minimal drug (∼500 g), which allowed successful clinical batch manufacture of enabled formulation within 7 months.

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Section: Pvp Va64 Containing Amorphous Solid Dispersionssupporting

confidence: 89%

Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale

2015

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“…100) Several modified procedures, such as the addition of matrix polymers (e.g., polyvinyl caprolactam-polyvinyl acetate-polyethylene glycolgraft-copolymer), 101,102) have been reported. Applying process analytical technologies, such as Raman and near-IR spectroscopies, that enables in situ monitoring of product changes provides valuable information for controlling the mechanical manufacturing methods.…”

Section: Manufacturing Of Cocrystalsmentioning

confidence: 99%

Characterization and Quality Control of Pharmaceutical Cocrystals

Izutsu¹,

Koide²,

Takata

et al. 2016

Chem. Pharm. Bull.

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Recent active research and new regulatory guidance on pharmaceutical cocrystals have increased the rate of their development as promising approaches to improve handling, storage stability, and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, their complex structure and the limited amount of available information related to their performance may require development strategies that differ from those of single-component crystals to ensure their clinical safety and efficacy. This article highlights current methods of characterizing pharmaceutical cocrystals and approaches to controlling their quality. Different cocrystal regulatory approaches between regions are also discussed. The physical characterization of cocrystals should include elucidating the structure of their objective crystal form as well as their possible variations (e.g., polymorphs, hydrates). Some solids may also contain crystals of individual components. Multiple processes to prepare pharmaceutical cocrystals (e.g., crystallization from solutions, grinding) vary in their applicable ingredients, scalability, and characteristics of resulting solids. The choice of the manufacturing method affects the quality control of particular cocrystals and their formulations. In vitro evaluation of the properties that govern clinical performance is attracting increasing attention in the development of pharmaceutical cocrystals. Understanding and mitigating possible factors perturbing the dissolution and/ or dissolved states, including solution-mediated phase transformation (SMPT) and precipitation from supersaturated solutions, are important to ensure the bioavailability of orally administrated lower-solubility APIs. The effect of polymer excipients on the performance of APIs emphasizes the relevance of formulation design for appropriate use.

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“…These non-ionic interactions such as hydrogen bounds are very robust, so cocyrstal forms exhibit a high thermal stability and they are also very stable at high relative humidity, where salts are known to be unstable [11]. Although cocrystals can be formed by various methods such as solution crystallization [12,13], slurry conversions [14], ultrasonication [15,16] and melt processes [17,18], (wet or dry) grinding methods [19][20][21] are often preferred preparation methods based on their simplicity, eco-friendliness and high productivity [22]. Since wet-milling (i.e.…”

Section: Introductionmentioning

confidence: 99%

Formulation of itraconazole nanococrystals and evaluation of their bioavailability in dogs

Smet¹,

Saerens²,

Beer³

et al. 2014

European Journal of Pharmaceutics and Biopharmaceutics

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The aim of the study was to increase the bioavailability of itraconazole (ITRA) using nanosized cocrystals prepared via wet milling of ITRA in combination with dicarboxylic acids. Wet milling was used in order to create a nanosuspension of ITRA in combination with dicarboxylic acids. After spraydrying and bead layering, solid state was characterized by MDSC, XRD, Raman and FT-IR. The release profiles and bioavailability of the nanococrystalline suspension, the spray-dried and bead layered formulation were evaluated. A monodispers nanosuspension (549 ± 51 nm) of ITRA was developed using adipic acid and Tween®80. Solid state characterization indicated the formation of nanococrystals by hydrogen bounds between the triazole group of ITRA and the carboxyl group of adipic acid. A bioavailability study was performed in dogs. The faster drug release from the nanocrystal-based formulation was reflected in the in-vivo results since T max of mean profile after administration of the formulations was observed 3h after administration, while T max of mean profile after administration of the reference formulation was observed only 6h after administration. This fast release of ITRA was obtained by a dual concept: manufacturing of nanosized cocrystals of ITRA and adipic acid via wet milling. Formation of stable nanosized cocrystals via this approach seems a good alternative for amorphous systems to increase the solubility and obtain a fast drug release of BCS class II drugs.

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Cocrystalization and Simultaneous Agglomeration Using Hot Melt Extrusion

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Cited by 194 publications

References 34 publications

Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale

Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale

Characterization and Quality Control of Pharmaceutical Cocrystals

Formulation of itraconazole nanococrystals and evaluation of their bioavailability in dogs

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