Influence of Polymer Molecular Weight on Drug–polymer Solubility: A Comparison between Experimentally Determined Solubility in PVP and Prediction Derived from Solubility in Monomer

Knopp, Matthias Manne; Olesen, Niels Erik; Holm, Per; Langguth, Peter; Holm, René; Rades, Thomas

doi:10.1002/jps.24410

Cited by 90 publications

(75 citation statements)

References 38 publications

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“…In this study, the solubility of a drug-polymer dispersion was determined from the drug-polymer interaction and has been concluded that better solubility and higher drug-polymer interaction leads to improved physical stability of amorphous solid dispersion 37 Piroxicam…”

Section: Spray Drying/film Castingmentioning

confidence: 99%

Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs

Baghel

Cathcart

O’Reilly

2016

Journal of Pharmaceutical Sciences

727

431

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Poor water solubility of many drugs has emerged as one of the major challenges in the pharmaceutical world. Polymer-based amorphous solid dispersions have been considered as the major advancement in overcoming limited aqueous solubility and oral absorption issues. The principle drawback of this approach is that they can lack necessary stability and revert to the crystalline form on storage. Significant upfront development is, therefore, required to generate stable amorphous formulations. A thorough understanding of the processes occurring at a molecular level is imperative for the rational design of amorphous solid dispersion products. This review attempts to address the critical molecular and thermodynamic aspects governing the physicochemical properties of such systems. A brief introduction to Biopharmaceutical Classification System, solid dispersions, glass transition, and solubility advantage of amorphous drugs is provided. The objective of this review is to weigh the current understanding of solid dispersion chemistry and to critically review the theoretical, technical, and molecular aspects of solid dispersions (amorphization and crystallization) and potential advantage of polymers (stabilization and solubilization) as inert, hydrophilic, pharmaceutical carrier matrices. In addition, different preformulation tools for the rational selection of polymers, state-of-the-art techniques for preparation and characterization of polymeric amorphous solid dispersions, and drug supersaturation in gastric media are also discussed.

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Section: Spray Drying/film Castingmentioning

confidence: 99%

Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs

Baghel

Cathcart

O’Reilly

2016

Journal of Pharmaceutical Sciences

727

431

View full text Add to dashboard Cite

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“…It is noteworthy that Knopp et al., have suggested that modeling the entire polymer is unnecessary to obtain reliable miscibility data and instead, there is a threshold number of repeat units beyond which the

χ

‐parameter effectively converges and provides consistent miscibility behavior, even with an extension of the molecular chain . This suggests that we can obtain appreciably accurate results with relatively small molecules in well‐established simulation procedure.…”

Section: Resultsmentioning

confidence: 83%

“…Knopp et al. reported that using the monomer species to estimate polymer miscibility may be flawed in cases where the chemistry is changed upon polymerization . Thus, in order to more accurately capture the chemistry of PEG, the trimer form was used instead of the monomer, whereas only the monomer was considered for PMMA.…”

Section: Resultsmentioning

confidence: 99%

“…Previous work related to the χ‐parameter has highlighted the large spread of values generated by experimental measurements (e. g., by inverse gas chromatography, differential scanning calorimetry, or small‐angle neutron scattering), necessitating very precise control of experimental conditions. To compound all of these difficulties, even when such precision is possible, there is no guarantee that the requisite data (Hildebrand or Hansen solubility parameters, cohesive energy densities, etc.)…”

Section: Introductionmentioning

confidence: 99%

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Molecular Modeling Approach to Determine the Flory‐Huggins Interaction Parameter for Polymer Miscibility Analysis

et al. 2018

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In this work, we present a thorough procedure for estimating the Flory-Huggins χ-parameter for use in atomistic and mesoscale molecular simulations in computational materials science. In particular, we propose improvements upon traditional Flory-Huggins theory by implementing a Connolly volume normalization (CVN). We apply this technique to several test systems, including a blend of poly (epichlorohydrin) and poly (methyl acrylate), a blend of polyethylene glycol and poly (methyl methacrylate), a blend of polystyrene and deuterated polystyrene, and three molecular-weight variants (monomer, dimer, and trimer) of a triblock copolymer for use in multicompartment micelle applications. Our results demonstrate that the newly developed procedure offers high accuracy and efficiency in predicting the Flory-Huggins χ-parameter for miscibility analysis compared to traditional experimental and computational methods. There are still several factors that cause the magnitude of the χ-parameter to vary between simulations performed on molecular species with the same identity but different degrees of polymerization; although we discuss possible explanations for these factors, this is nonetheless a primary focus for further exploration into this new methodology.

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“…Also, the larger the percentage of binder, the higher the depression of the melting point of the cocrystal and the lower the degree of crystallinity due to the formation of an amorphous solid dispersion ( Figure 4A). The glass transitions for amorphous SDM and PVP K90 were reported to be 78 ˚C and 173 ˚C, respectively [31,32]. No experimental glass transition has been reported for 4ASA due to its high tendency for crystallisation.…”

Section: Investigation Of Other Formulation and Process Parameters Inmentioning

confidence: 99%

Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating

Serrano

Walsh

O’Connell

et al. 2018

European Journal of Pharmaceutics and Biopharmaceutics

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Engineering of pharmaceutical cocrystals is an advantageous alternative to salt formation for improving the aqueous solubility of hydrophobic drugs. Although, spray drying is a well-established scale-up technique in the production of cocrystals, several issues can arise such as sublimation or stickiness due to low glass transition temperatures of some organic molecules, making the process very challenging. Even though, fluidised bed spray coating has been successfully employed in the production of amorphous drug-coated particles, to the best of our knowledge, it has never been employed in the production of cocrystals. The feasibility of this technique was proven using three model cocrystals: sulfadimidine (SDM)/4-aminosalicylic acid (4ASA), sulfadimidine/nicotinic acid (NA) and ibuprofen (IBU)/ nicotinamide (NAM). Design of experiments were performed to understand the critical formulation and process parameters that determine the formation of either cocrystal or coamorphous systems for SDM/4ASA. The amount and type of binder played a key role in the overall solid state and in vitro performance characteristics of the cocrystals. The optimal balance between high loading efficiencies and high degree of crystallinity was achieved only when a binder: cocrystal weight ratio of 5:95 or 10:90 was used. The cocrystal coated beads showed an improved in vitro-in vivo performance characterised by: (i) no tendency to aggregate in aqueous media compared to spray dried formulations, (ii) enhanced in vitro activity (1.8-fold greater) against S. aureus, (iii) larger oral absorption and bioavailability (2.2-fold higher C), (iv) greater flow properties and (v) improved chemical stability than cocrystals produced by other methods derived from the morphology and solid nature of the starter cores.

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Influence of Polymer Molecular Weight on Drug–polymer Solubility: A Comparison between Experimentally Determined Solubility in PVP and Prediction Derived from Solubility in Monomer

Cited by 90 publications

References 38 publications

Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs

Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs

Molecular Modeling Approach to Determine the Flory‐Huggins Interaction Parameter for Polymer Miscibility Analysis

Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating

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