Structured Development Approach for Amorphous Systems

Page, Susanne; Maurer, Reto; Wyttenbach, Nicole

doi:10.1007/978-3-319-42609-9_8

Cited by 5 publications

(6 citation statements)

References 126 publications

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“…is the inclusion of melt‐based amorphisation techniques. If only the subset of marketed drugs in amorphous products is considered, which are not included in Figure , a challenging T m /T g >1.4 was only observed with etravirine and vemurafenib . This can be compared to glass‐forming ability, which can be determined by means of a DSC method .…”

Section: Lipophilicity and Hydrophobicity Regarding Different Formulamentioning

confidence: 99%

Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches – a PEARRL review

Ditzinger

Price

Ilie

et al. 2018

Journal of Pharmacy and Pharmacology

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Current literature suggests that selection of formulation approaches in pharmaceutics is still highly dependent on the availability of technological expertise in a company or research group. Encouraging is that, recent advancements point to more structured and scientifically based development approaches. More research is still needed to better link physicochemical drug properties to pharmaceutical formulation design.

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Section: Lipophilicity and Hydrophobicity Regarding Different Formulamentioning

confidence: 99%

Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches – a PEARRL review

Ditzinger

Price

Ilie

et al. 2018

Journal of Pharmacy and Pharmacology

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“…Compounds which beneficially lower the melt viscosity and reduce the chemo-mechanical stress of the extrusion processes can impair the physical long-term stability of the product, modulate dissolution behaviour or worsen the downstream processability of a basically promising dispersion system [ 37 , 38 , 39 ]. Therefore, the selection of suitable plasticizers requires the same attention as more established polymer carrier systems [ 4 , 39 ]. In this context our prototyping device, MinEx applied in combination with torque rheometry, is a promising and elegant approach with predictive value.…”

Section: Discussionmentioning

confidence: 99%

“…Various assays have been established to screen for polymer carrier systems which combine best drug dissolution enhancement with excellent solid-state properties, such as high drug polymer miscibility and storage stability [ 4 , 5 ]. Quench-cooled melt mixtures (QCMMs) are an established preparative-explorative platform to assay molecular miscibility and physical stability of ASDs [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…The final performance of ASDs does not only depend on the intrinsic attributes of the components but also on the technical processes used to create the dispersion. Besides spray drying (SD) the process of hot melt extrusion (HME) is a key technology to enable ASDs [ 4 , 11 ]. Whereas SD gives micrometre-sized particles with low bulk density, the HME process produces dense ‘spaghetti’-shaped strands on the millimetre scale [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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A Miniaturized Extruder to Prototype Amorphous Solid Dispersions: Selection of Plasticizers for Hot Melt Extrusion

et al. 2018

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Hot-melt extrusion is an option to fabricate amorphous solid dispersions and to enhance oral bioavailability of poorly soluble compounds. The selection of suitable polymer carriers and processing aids determines the dissolution, homogeneity and stability performance of this solid dosage form. A miniaturized extrusion device (MinEx) was developed and Hypromellose acetate succinate type L (HPMCAS-L) based extrudates containing the model drugs neurokinin-1 (NK1) and cholesterylester transfer protein (CETP) were manufactured, plasticizers were added and their impact on dissolution and solid-state properties were assessed. Similar mixtures were manufactured with a lab-scale extruder, for face to face comparison. The properties of MinEx extrudates widely translated to those manufactured with a lab-scale extruder. Plasticizers, Polyethyleneglycol 4000 (PEG4000) and Poloxamer 188, were homogenously distributed but decreased the storage stability of the extrudates. Stearic acid was found condensed in ultrathin nanoplatelets which did not impact the storage stability of the system. Depending on their distribution and physicochemical properties, plasticizers can modulate storage stability and dissolution performance of extrudates. MinEx is a valuable prototyping-screening method and enables rational selection of plasticizers in a time and material sparing manner. In eight out of eight cases the properties of the extrudates translated to products manufactured in lab-scale extrusion trials.

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“…31,34,35 Hydroxypropyl methylcellulose (HPMC) is one of the most popular excipients for polymer-based solid dispersions used in numerous marketed products such as Certican, Intelence, Nivadil, Prograf, and the ITZ capsule formulation Sporanox. 36 Many researchers have already investigated solid dispersion systems of ITZ combined with HPMC as a stabilizing polymer using HME. 37−39 Therefore, ITZ-HPMC extrudate is utilized as a model of ASD.…”

Section: ■ Introductionmentioning

confidence: 99%

Formulating Amorphous Solid Dispersions: Impact of Inorganic Salts on Drug Release from Tablets Containing Itraconazole-HPMC Extrudate

et al. 2019

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Amorphous solid dispersions (ASD) are increasingly used to improve the oral bioavailability of poorly water-soluble compounds. However, hydrophilic polymers in ASD have high water-binding properties and, upon water contact, they often form a gel on the surface of the tablet, impacting the rate and extent of drug release. Most inorganic salts decrease water solubility of organic solutes, changing the gel properties of hydrophilic polymers. In this study, the effect of inorganic salts on drug release from a tablet formulation containing an itraconazole (ITZ)-hydroxypropyl methyl cellulose (HPMC) extrudate was investigated. The cloud point of a 1% HPMC solution with and without inorganic salts (KCl, KH2PO4, KHCO3, and potassium iodate (KI)) was determined to classify the salts according to their salting-out or salting-in effect. A kosmotropic effect on HPMC was observed for KCl, KH2PO4, and KHCO3, whereas KI exhibited a chaotropic effect. To prove the effect of these salts on drug release, tablets containing 66% of ITZ-HPMC extrudate (20:80 w/w %), 4% croscarmellose sodium, 30% microcrystalline cellulose, and different types and amounts of KHCO3, KH2PO4, KCl, and KI were compressed (same solid fraction of 0.83–0.85). Tablets without salts showed a slow release and low peak concentrations during dissolution in simulated gastric fluids. By adding the kosmotropic salts to the tablets, the rate and extent of drug release were increased, whereas the chaotropic anion iodide had no effect. The effect was pronounced even with the addition of as little as 2% of inorganic salts and tended to increase with the increasing amount of salt in the formulation. Tablets without salt stored under either dry or humid conditions exhibited a large difference in dissolution profiles, whereas little variation was observed for tablets with kosmotropic salts. In conclusion, the effect of inorganic salts was mechanistically clarified on ASD containing commonly used HPMC. This approach can be beneficial to successfully develop robust formulations containing ASD.

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Structured Development Approach for Amorphous Systems

Cited by 5 publications

References 126 publications

Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches – a PEARRL review

Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches – a PEARRL review

A Miniaturized Extruder to Prototype Amorphous Solid Dispersions: Selection of Plasticizers for Hot Melt Extrusion

Formulating Amorphous Solid Dispersions: Impact of Inorganic Salts on Drug Release from Tablets Containing Itraconazole-HPMC Extrudate

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