# Evidence: polymer chain disentanglement

Parent: — · class: transport and absorption · names merged here: polymer chain disentanglement

14 papers measured or used it, 0 only mentioned it (of 207 kept papers). Papers in year order; each section heading ends with the paper's category / subcategory. Generated by tools/build_evidence.py from registry/concepts.csv and the cards; do not edit.

## 2020 Saboo — Congruent release of drug and polymer from amorphous solid dispersions: insights into the role of drug-polymer hydrogen bonding, surface crystallization and glass transition · Dissolution / A. Release mechanism and LoC

[2020-saboo-congruent-release-hbond-crystallization-tg-pvpva-asd](../../../cards/2020-saboo-congruent-release-hbond-crystallization-tg-pvpva-asd/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: polymer chain disentanglement

| id | kind | content | locator |
|---|---|---|---|
| C54 | claim, prior hypothesis, authors: asserted | Polymer dissolution involves solvent diffusion and chain disentanglement; disentanglement is faster above Tg (rubbery, with a gel layer), while below Tg the gel layer thins and dissolution changes from disentanglement to cracking [rests on: cited: refs 35, 36] | p.33 |
| C55 | claim, mechanism, authors: "is expected to depend"; "may explain" | For ASDs, polymer dissolution rate is expected to depend on the water absorbed to form the gel layer, which falls with DL and may explain polymer-controlled dissolution at low DL, and on the Tg of the hydrated matrix or gel layer relative to the temperature; lowering the temperature impedes chain mobility and disentanglement, which may explain the lower IND LoC at lower temperatures [rests on: R29; cited: ref 37] | p.33 |

## 2021 Que — Impact of Drug−Polymer Intermolecular Interactions on Dissolution Performance of Copovidone-Based Amorphous Solid Dispersions · Dissolution / A. Release mechanism and LoC

[2021-que-drug-polymer-interactions-loc-copovidone-asd](../../../cards/2021-que-drug-polymer-interactions-loc-copovidone-asd/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: polymer chain disentanglement

| id | kind | content | locator |
|---|---|---|---|
| C42 | claim, mechanism, authors: asserted | (Literature) A glassy polymer such as PVPVA dissolves by solvent penetration into a plasticized gel and chain disentanglement followed by diffusion; solvent quality (Flory−Huggins χ) matters; neat PVPVA sorbs much water at high water activity, its Tg falls below room temperature, and it gels and dissolves rapidly. [rests on: cited: refs 15, 43, 45−47] | Section 5, p.3505−3506 |
| C44 | claim, mechanism, authors: "We can rationalize"; "if"; "anticipated"; "could explain" | Proposed rationale: a drug−polymer interaction that persists in water occupies a polymer solvation site and lowers the solvent fraction (as in vapour sorption of hydrogen-bonded ASDs); if this holds in the medium, lower water uptake would reduce plasticization (slower solvent penetration) and disentanglement, lowering polymer dissolution and hence drug release, which could explain the lower LoCs of PHPH/PVPVA and TIPP/PVPVA. [rests on: argument only; cited: refs 44−47] | Section 5, p.3506 |

## 2021 Saboo — Exploring the Role of Surfactants in Enhancing Drug Release from Amorphous Solid Dispersions at Higher Drug Loadings · Dissolution / A. Release mechanism and LoC

[2021-saboo-tpgs-felodipine-pvpva-asd-release-high-loading](../../../cards/2021-saboo-tpgs-felodipine-pvpva-asd-release-high-loading/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: polymer chain disentanglement

| id | kind | content | locator |
|---|---|---|---|
| C37 | claim, mechanism, authors: "We propose" | Proposed release model (Fig. 14), extending the group's binary model (ref 17): a transient gel layer forms where water plasticizes polymer chains, which disentangle before release; at high DL whether release is drug- or polymer-controlled depends largely on the architecture of the drug-rich phase formed by phase separation in the hydrated matrix [rests on: R19, R21, R23; cited: refs 17, 47] | p.16-17 |
| C43 | claim, mechanism, authors: "could be related"; "should theoretically"; "may compete"; conclusions: "may also play a role" | TPGS acts as a plasticizer that lowers Tg and raises molecular mobility; a lower Tg should let polymer disentanglement start with less water, favour polymer dissolution, and so compete with phase separation and prevent the drug-rich surface layer; conclusions: higher mobility may also play a role in the higher LoC [rests on: R5; cited: refs 47, 49] | p.17, p.19 |

## 2022 Correasoto — Role of surfactants in improving release from higher drug loading amorphous solid dispersions · Dissolution / A. Release mechanism and LoC

[2022-correa-soto-surfactants-higher-drug-loading-atazanavir-pvpva-asds](../../../cards/2022-correa-soto-surfactants-higher-drug-loading-atazanavir-pvpva-asds/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: polymer chain disentanglement

| id | kind | content | locator |
|---|---|---|---|
| C33 | claim, prior hypothesis, authors: asserted; "typically" | Glassy polymers dissolve by solvent ingress, swelling, plasticization and gel-layer formation, chain disentanglement by reptation over a characteristic time, then diffusion of free chains; for high-MW neutral polymers such as PVPVA under stirring, solvent ingress or disentanglement is typically rate-limiting [rests on: cited: Devotta 1995; Miller-Chou and Koenig 2003; Papanu 1989] | p.8 |
| C36 | claim, mechanism, authors: "would be anticipated" | A system with higher initial Tg needs more solvent to plasticize it enough for chain disentanglement, so it would have lower mobility at a given time and slower disentanglement; system Tg and the plasticizing ability of the solvent govern polymer release rate through free volume and mobility [rests on: cited: Devotta 1995; Devotta and Mashelkar 1996] | p.8 |
| C40 | claim, mechanism, authors: abstract: "We speculate"; "may facilitate"; "possible explanation"; discussion: "Our supposition"; "at least in part"; conclusions: "it is postulated"; "still not completely clear" | Improved release with surfactants or VP is due, at least in part, to plasticization raising polymer-chain mobility, which improves polymer release in the presence of the drug and hence drug release; surfactants also enhance water penetration into the matrix; polymer dissolution is necessary for drug release; the mechanism is not completely clear [rests on: R2, R3, R13, R20, R10, R11] | p.1, p.9, p.10 |

## 2022 Hiew — Combining drug salt formation with amorphous solid dispersions – a double edged sword · Dissolution / A. Release mechanism and LoC

[2022-hiew-combining-drug-salt-formation-asd-double-edged-sword](../../../cards/2022-hiew-combining-drug-salt-formation-asd-double-edged-sword/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: polymer chain disentanglement

| id | kind | content | locator |
|---|---|---|---|
| E2 | equation | polymer chain disentanglement rate (Narasimhan-Peppas): k_d = B / (1 − v_p)^1.9 | p.58 |
| C38 | claim, prior hypothesis, authors: asserted ("Studies have shown") | Polymer dissolution is controlled by water diffusion into the matrix, chain disentanglement from the plasticized gel and chain diffusion in the boundary layer; modelling is complicated by non-Fickian diffusion, with separate models for glassy and rubbery polymers; for polymers with Tg above the experimental temperature a critical polymer volume fraction must be reached before disentanglement [rests on: cited: refs 43-45] | p.57 |
| C39 | claim, prior hypothesis, authors: "is expected" | A larger difference between T and Tg means more solvent is needed to plasticize the polymer; without it relaxation and disentanglement are slow and dissolution slows, as shown for several polymers [rests on: E1; cited: ref 45] | p.58 |

## 2022 Hiew — Balancing Solid-State Stability and Dissolution Performance of Lumefantrine Amorphous Solid Dispersions: The Role of Polymer Choice and Drug−Polymer Interactions · Solid state stability / Miscibility and drug-polymer interactions

[2022-hiew-lumefantrine-asd-stability-dissolution-polymer-choice](../../../cards/2022-hiew-lumefantrine-asd-stability-dissolution-polymer-choice/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · used · as: polymer chain disentanglement

| id | kind | content | locator |
|---|---|---|---|
| C46 | claim, prior hypothesis, authors: asserted; "could be" | Polymer dissolution is governed by solvent diffusion and chain disentanglement (swollen gel, reptation); enteric polymers also need carboxylic acid ionization; proton diffusion away from the interface or disentanglement could be rate-limiting [rests on: cited: refs 45, 50] | p.408, p.410 |
| C49 | claim, mechanism, authors: "is expected"; "would be expected"; "provide an explanation" | Interaction of the hydrophobic drug with the polymer is expected to retard polymer dissolution by reducing the rate and extent of chain hydration and hence disentanglement, and persistent association with the lumefantrine ion would reduce polymer solubility; these factors explain the fall of enteric polymer dissolution with DL [rests on: argument only] | p.408 |
| C59 | claim, mechanism, authors: "is consistent with"; "likely"; "may also" | PVPVA release does not depend on ionization and stays constant with DL, consistent with no drug−polymer interaction; above a critical DL, dilution by the hydrophobic drug likely prevents enough water uptake for chain disentanglement, and a drug-rich interfacial layer may also hinder polymer release [rests on: R13.a–j, R17] | p.410-411 |

## 2022 Qi — Improved dissolution of an enteric polymer and its amorphous solid dispersions by polymer salt formation · Dissolution / A. Release mechanism and LoC

[2022-qi-enteric-polymer-salt-hp50-miconazole-asd-dissolution](../../../cards/2022-qi-enteric-polymer-salt-hp50-miconazole-asd-dissolution/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: polymer chain disentanglement

| id | kind | content | locator |
|---|---|---|---|
| C10 | claim, prior hypothesis, authors: asserted | Polymer dissolution involves water ingress, chain disentanglement, and release and diffusion across the boundary layer; enteric polymers also need ionization, which increases hydration and chain mobility and enables reptative disentanglement [rests on: cited: refs 10, 11] | p.2 |
| C30 | claim, mechanism, authors: asserted ("will also be affected") | Surface pH also affects gel-layer hydration, with less hydration at lower ionization, and the gel-layer solvent fraction determines the polymer disentanglement rate [rests on: cited: ref 28] | p.8 |
| C35 | claim, mechanism, authors: "somewhat surprising"; "is likely a key contributor" | That the counterion barely affects salt dissolution is somewhat surprising given the higher water uptake of the Na salt than the ammonium salts; all salts take up much more water than HP-50, which aids water ingress, the gel-layer solvent fraction and chain disentanglement; the higher hydration on salt formation is likely a key contributor to faster dissolution [rests on: R11, R10; cited: ref 28] | p.8 |
| C40 | claim, mechanism, authors: "It is likely" | The higher hydration of the polymer salts likely helps mitigate the harmful effect of a lipophilic drug on the water solvent fraction of the gel layer, which is crucial for chain disentanglement and release [rests on: R11, R14] | p.9 |

## 2022 Yang — Release mechanisms of amorphous solid dispersions: Role of drug-polymer phase separation and morphology · Dissolution / A. Release mechanism and LoC

[2022-yang-release-mechanisms-rtv-pvpva-asd-phase-separation-morphology](../../../cards/2022-yang-release-mechanisms-rtv-pvpva-asd-phase-separation-morphology/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: polymer chain disentanglement

| id | kind | content | locator |
|---|---|---|---|
| C32 | claim, mechanism, authors: asserted | A neat PVPVA compact first swells because polymer chains have not had time to disentangle, diffuse and dissolve, and later shrinks once chains disentangle and dissolve [rests on: R9; cited: ref 34] | pdf p.15 |
| C41 | claim, prior hypothesis, authors: asserted ("well understood"; "typically") | Polymer dissolution proceeds by solvent penetration and chain disentanglement: plasticization turns the glassy matrix into a rubbery gel layer with a sharp glass-gel interface; chains disentangle at the solvent-gel interface and diffuse away; when disentanglement is slower than water penetration the gel layer grows and becomes a barrier to water, until a steady state at equal rates; steady-state gel layers range from hundreds of microns to millimeters [rests on: cited: refs 34, 36-46; R20] | pdf p.22 |

## 2023 Bapat — Does Media Choice Matter When Evaluating the Performance of Hydroxypropyl Methylcellulose Acetate Succinate-Based Amorphous Solid Dispersions? · Dissolution / A. Release mechanism and LoC

[2023-bapat-hpmcas-asd-media-choice-buffer-capacity-release](../../../cards/2023-bapat-hpmcas-asd-media-choice-buffer-capacity-release/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: polymer chain disentanglement

| id | kind | content | locator |
|---|---|---|---|
| C45 | claim, mechanism, authors: "unlikely"; "likely"; "consistent with"; "further support"; "certainly for the case of the neat polymer" | HPMCAS-MF, although it forms a thin removable gel layer in some media, is unlikely to form molecular entanglements: its MW (∼18,000 Da) is below estimated critical values of other polysaccharides, and no plateau appears in rate versus rotation speed^0.5 even for the pre-ionized salt, so dissolution is diffusion- rather than disentanglement-controlled, certainly for neat polymer [rests on: R14, R18, R19, R27; cited: ref 69] | p.5724 |
| C30 | claim, mechanism, authors: results: "consistent with"; discussion: "in line with the supposition" | Relative release enhancement is similar for all systems and linear in the square root of rotation speed, so HPMCAS dissolution is predominantly diffusion-controlled (diffusion across the boundary layer rather than disentanglement) for the conditions studied [rests on: R19, R18; cited: ref 51] | p.5720; p.5724 |
| R25 | record, cited | dissolution of Eudragit L and S (Nguyen and Fogler) — rotating disc, laminar flow (ref 51) — when diffusion-limited, dissolution rate proportional to polymer solubility at the dissolving interface, varying with the inverse of the interfacial hydrogen ion concentration; buffer facilitation depended on buffer species concentration, buffer pKa and bulk pH; at high buffer concentration and high rotation speed the rate reached a plateau versus rotation speed, read by ref 51 as a switch to disentanglement control | p.5721; p.5723 |

## 2023 Correasoto — Release Enhancement by Plasticizer Inclusion for Amorphous Solid Dispersions Containing High Tg Drugs · Dissolution / A. Release mechanism and LoC

[2023-correa-soto-plasticizer-release-enhancement-high-tg-pvpva-asds](../../../cards/2023-correa-soto-plasticizer-release-enhancement-high-tg-pvpva-asds/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: polymer chain disentanglement

| id | kind | content | locator |
|---|---|---|---|
| C33 | claim, prior hypothesis, authors: "most likely"; "realistically, it is difficult" | Polymer-controlled release is desirable because PVPVA dissolves much faster than neat lipophilic amorphous drugs, also in low-DL ASDs; polymer dissolution proceeds by solvent ingress, chain reptation and disengagement, and diffusion away from the interface; for glassy high-molecular-weight PVPVA under stirring it is most likely controlled by chain disengagement, which is hard to deconvolute from solvent ingress [rests on: cited: refs 12, 15, 16, 50, 51] | p.787 |
| C39 | claim, mechanism, authors: "it is reasonable to suggest"; conclusion: "The suggested mechanism" | It is reasonable to suggest that one mechanism by which plasticizers enhance drug dissolution rate and the LoC of high Tg API ASDs is increased polymer chain mobility, i.e. a faster disentanglement rate; conclusion: the suggested mechanism is enhanced polymer disentanglement [rests on: R13, R6, R12, R23] | p.788 |
| E2 | equation | free-volume (Doolittle-type) maximum chain mobility, Devotta model: m_p,∞ = A_d exp −(B_d/f_g) | p.788 |
| E3 | equation | disengagement rate proportional to chain mobility: k_d ∝ m_p | p.788 |

## 2023 Deac — Dissolution Mechanisms of Amorphous Solid Dispersions: A Close Look at the Dissolution Interface · Dissolution / A. Release mechanism and LoC

[2023-deac-asd-dissolution-interface](../../../cards/2023-deac-asd-dissolution-interface/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: polymer chain disentanglement

| id | kind | content | locator |
|---|---|---|---|
| C42 | claim, prior hypothesis, authors: asserted | Linear, nonionic, glassy polymers above the entanglement molecular weight, such as PVPVA, dissolve through a rubbery gel layer: solvent plasticizes the glass at the glass/gel interface; entangled chains there diffuse slowly while segments are mobile; the gel grows and swells as solvent enters and its viscosity falls; at a critical solvent concentration the chains disentangle and leave at the gel/solution interface [rests on: cited: refs 30-38] | p.2227-2228 |
| C51 | claim, mechanism, authors: "A possible explanation" | Polymer release increased faster than water penetration, as the gel thinned; a possible explanation is faster initial water entry from drug plasticization plus phase separation moving most water into the hydrophilic phase, diluting the chains so they reach the disentanglement point sooner [rests on: R4] | p.2230 |
| C52 | claim, conclusion, authors: "it can be inferred"; "This is expected" | The water-polymer ratio implies that low-DL ASD gels need about as much water per polymer to disentangle as neat PVPVA, as expected because the hydrophilic phase controls gel erosion and is compositionally practically the same as the neat PVPVA gel (Fig. 16) [rests on: R4] | p.2230-2231 |
| C73 | claim, mechanism, authors: "it was proposed" | The congruent release rate is controlled by the rate of water penetration into the ASD and by disentanglement of polymer chains from the gel/solution surface [rests on: R4; C50, C51] | p.2233 |

## 2023 Deac — Dissolution Mechanisms of Amorphous Solid Dispersions: Role of Drug Load and Molecular Interactions · Dissolution / A. Release mechanism and LoC

[2023-deac-asd-drug-load-molecular-interactions-loc](../../../cards/2023-deac-asd-drug-load-molecular-interactions-loc/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: polymer chain disentanglement

| id | kind | content | locator |
|---|---|---|---|
| C32 | claim, assumption, authors: asserted; "is expected to remain" | During hydration the ASD keeps a constant drug/polymer ratio until phase separation, because solvent penetrates polymer matrices with negligible chain diffusion until chains disentangle, and the hydrophobic drug stays trapped in the matrix until then [rests on: cited: refs 47, 48, 50] | p.730 |

## 2024 Deac — Dissolution Mechanisms of Amorphous Solid Dispersions: Application of Ternary Phase Diagrams To Explain Release Behavior · Dissolution / A. Release mechanism and LoC

[2024-deac-asd-ternary-phase-diagrams-release](../../../cards/2024-deac-asd-ternary-phase-diagrams-release/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: polymer chain disentanglement

| id | kind | content | locator |
|---|---|---|---|
| C39 | claim, mechanism, authors: "may be explained"; "is not expected"; "may impact" | The gel-solution boundary marks the polymer concentration at which chains disentangle; weakly interacting MePHPH is not expected to change this (boundary as for neat PVPVA, R27), whereas strongly interacting PHPH may affect disentanglement so less polymer is needed at higher PHPH [rests on: R27] | p.1911 |
| C46 | claim, prior hypothesis, authors: asserted; "often, although not always" | Gel-layer phase-separation morphology versus DL explains polymer- versus drug-controlled release; water-induced phase separation is often triggered inside the gel layer and arises from drug-water incompatibility; polymer chains trapped by entanglement escape once diluted enough to disentangle; the LoC of drug-PVPVA ASDs is dictated by domain morphology toward the gel-solution interface [rests on: cited: refs 4-6, 24, 54, 55] | p.1912 |
| C47 | claim, mechanism, authors: asserted | Below the LoC the hydrophobic phase is present as nanodroplets in a continuous hydrophilic phase that absorbs water until chains disentangle and the droplets are released; above the LoC the interconnected hydrophobic phase (and hydrophilic regions inside it) cannot be released and forms a surface barrier [rests on: cited: ref 4] | p.1913 |

## 2025 Benson — Dissolution of copovidone-based amorphous solid dispersions: Influence of atomic layer coating, hydration kinetics, and formulation · ASD process / ASD process

[2025-benson-alc-coated-rtv-pvpva-asd-hydration-release](../../../cards/2025-benson-alc-coated-rtv-pvpva-asd-hydration-release/paper.html) · ASD process / ASD process · used · as: polymer chain disentanglement

| id | kind | content | locator |
|---|---|---|---|
| C5 | claim, prior hypothesis, authors: "typically"; "possibly" | For neutral polymers such as PVPVA, release is polymer-controlled (the optimal regime) below the LoC and drug-controlled, slower and possibly incomplete, above it; the drug-controlled regime typically occurs when the hydrophobic drug has phase separated into a continuous amorphous layer that blocks further hydration; adequate hydration is needed for the polymer to swell, disentangle and dissolve [rests on: cited: refs 22, 26, 27, 30, 31] | p.324 |
| C28 | claim, conclusion, authors: asserted ("as expected") | In uncoated tablets the drug segregates into small discrete nanodroplets in the gel layer that move into bulk solution as the polymer disentangles and dissolves, as expected below the LoC at 37 °C [rests on: R14.a, R20] | p.327 |
| C61 | claim, prior hypothesis, authors: asserted; "typically" | PVPVA dissolves by forming a gel layer of entangled chains that disentangle once a critical water concentration is reached at the gel-solution interface, at a steady state between water penetration and disentanglement; in drug-PVPVA ASDs the gel typically separates into drug-rich and polymer/water-rich phases because of a miscibility gap; below the LoC the drug-rich phase forms nanodroplets released with the polymer, above it drug-rich regions grow, interconnect over time, hinder hydration and slow release [rests on: cited: refs 22-24, 27, 35, 39, 41, 45-52] | p.330 |