# Evidence: drug-rich barrier layer

Parent: drug-rich surface layer · class: transport and absorption · names merged here: barrier layer; drug-rich barrier; drug-rich barrier layer; drug-rich surface barrier; surface barrier

7 papers measured or used it, 1 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.

## 2019 Que — Insights into the Dissolution Behavior of Ledipasvir-Copovidone Amorphous Solid Dispersions: Role of Drug Loading and Intermolecular Interactions · Dissolution / A. Release mechanism and LoC

[2019-que-ledipasvir-copovidone-asd-loc-interactions](../../../cards/2019-que-ledipasvir-copovidone-asd-loc-interactions/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: barrier layer

| id | kind | content | locator |
|---|---|---|---|
| C5 | claim, prior hypothesis, authors: asserted | Studies of polyphase mixtures relate each component's dissolution rate to composition, solute-solvent interactions and phase segregation at the dissolution front forming a barrier layer; interface composition has not been widely studied for ASDs [rests on: cited: refs 18, 19] | p.4 |
| C32 | claim, mechanism, authors: discussion: "it appears"; abstract: asserted ("physically hindered"); conclusions: asserted | The drug-rich surface layer is a physical barrier that stops further release of drug and even of water-soluble PVPVA, leading to swelling [rests on: R13, R15, R4] | p.2, p.33, p.39 |

## 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: drug-rich barrier layer

| id | kind | content | locator |
|---|---|---|---|
| C16 | claim, mechanism, authors: "could be attributed"; "often observed" | The release plateau at ~30 min after rapid initial release could come from water-induced phase separation during dissolution forming a drug-rich layer on the compact surface that blocks further release; such a drug-rich barrier is often seen with higher-DL ASDs [rests on: R10.i, R10.j, R10.q; cited: refs 10, 13, 36] | p.52 |
| C27 | claim, prior hypothesis, authors: "has been attributed"; "is thought to contribute" | Above a critical DL specific to each drug-PVPVA ASD, drug release falls off a cliff; this has been ascribed to a barrier drug-rich layer on the compact surface that makes release drug-controlled, and amorphous-amorphous phase separation is thought to contribute to this contiguous layer [rests on: cited: refs 10, 36, 37] | p.56-57 |

## 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 · measured · as: drug-rich barrier layer

| id | kind | content | locator |
|---|---|---|---|
| R5 | record, measured | layer structure of a compact cross-section, Nile red channel (scale bar 100 µm) — 30% DL (30-70) compact after 5 min dissolution, top side only in contact with medium (P2, P5) — three layers: bottom glassy core with irregular particle arrangement, clear grain boundaries and cracks; top thin (5-10 µm) drug-rich layer, continuous at the water-facing side and more porous just below the surface; between them a homogeneous gel layer without obvious particle boundaries, containing circular voids (labels in figure: "Drug-rich layer at surface", "Gel layer", "Void", "Glassy core") | Fig. 4, pdf p.11; text pdf p.10 |
| R6 | record, measured | cross-section morphology, Nile red plus Alexa Fluor 488 (scale bars 50 µm) — dye-containing compacts, P2, P5, P6 — sub-table below | Fig. 5, pdf p.12-13; text pdf p.11-12, p.24 |
| R13 | record, measured | time-lapse morphology, 40% DL (scale bars 100 µm) — P7; images at 0, 1, 2, 5, 10, 20, 30 min — red and green regions at the compact-solution interface immediately after medium addition (1 min); a thin continuous red layer covering the compact-solution interface with all green regions under it; layer swelled and grew in thickness with time; layer appeared more rigid and non-porous than at 30% DL; no green beyond the red layer; phase-separated region extending 50-100 µm into the ASD matrix | Fig. 11, pdf p.21; text pdf p.19, p.24 |
| C3 | claim, mechanism, authors: abstract: asserted ("was the cause"); conclusion: "can be rationalized" | Formation of discrete drug-rich droplets at lower DL leads to rapid, congruent release of drug and polymer (droplets in the polymer gel phase are carried into solution by polymer dissolution), whereas a continuous drug-rich phase at the matrix-solution interface causes poor drug and polymer release and delayed water ingress; release rate and extent versus DL can be rationalized by the phase separation morphology at this interface [rests on: R2, R4, R6, R8, R10-R13] | pdf p.3, p.26 |
| C55 | claim, mechanism, authors: "can act"; "may serve"; "This explains" | The drug-rich coating impedes polymer dissolution by acting as a barrier to water penetration and may act as a physical barrier to polymer release even when water penetrates; this explains why poor drug release is often accompanied by poor polymer release [rests on: R8, R2.e-h, R14] | pdf p.25 |

## 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: drug-rich barrier

| id | kind | content | locator |
|---|---|---|---|
| C31 | claim, mechanism, authors: "can be broadly rationalized"; "at a simplistic level"; "may" | The release gains can be broadly rationalized by trends between poor release and API Tg and by the Tg reduction from the plasticizer: at a simplistic level a plasticizer may increase mobility of the ASD components, promoting polymer dissolution, and may affect formation of the drug-rich barrier postulated above the LoC [rests on: R16, R17, R18; cited: refs 12, 16, 17] | p.787 |
| C32 | claim, caveat, authors: "will be needed"; "may be important" | A more in-depth evaluation is needed to elucidate any correlation with drug-rich barrier formation, which may be important in explaining differences among the plasticizers [rests on: argument only] | p.787 |

## 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 · measured · as: surface barrier

| id | kind | content | locator |
|---|---|---|---|
| R9 | record, measured | morphology of the compact surface after partial dissolution — MePHPH-PVPVA compacts 30, 40, 50% DL; P8 — sub-table below | Fig. 11, p.2229; text p.2223-2224, p.2231 |
| R10 | record, measured | morphology of the compact surface after partial dissolution, PHPH series and controls — PHPH-PVPVA compacts 5, 10, 20% DL at 2 min (P8); controls of neat PHPH and neat MePHPH (2 min), neat PVPVA and 20% DL MePHPH (10 min) — sub-table below | Fig. 12, p.2229; Fig. S4, SI p.5; text p.2224-2225 |
| R11 | record, measured | cross-sectional morphology of partially dissolved compacts (gel layer marked by a green bar) — MePHPH-PVPVA compacts 30, 40, 50% DL after 2, 10 or 20 min (P9); PHPH-PVPVA compacts — sub-table below | Fig. 13, p.2230; text p.2225 |
| C54 | claim, prior hypothesis, authors: asserted | The sharp decline above the LoC, seen for PVPVA-, PVP- and HPMC-based ASDs, has been attributed to an insoluble barrier on the ASD surface [rests on: cited: refs 8, 10, 11, 14, 16, 22; R17] | p.2231 |
| C56 | claim, mechanism, authors: "it is expected"; asserted | The water-poor hydrophobic phase is expected to become more viscous; once connected it adds structure and mechanical strength to the gel layer and, anchored to it, persists at the interface as an insoluble barrier [rests on: R6, R9, R11] | p.2231 |
| C57 | claim, conclusion, authors: asserted ("reveals") | In top view the barrier is porous (Fig. 11j,k; Fig. 12c), as reported for other ASDs (R16) [rests on: R9.c, R10.c, R16] | p.2231 |

## 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 · measured · as: drug-rich surface barrier

| id | kind | content | locator |
|---|---|---|---|
| R6 | record, measured | PHPH on the compact surface (%) by ATR-FTIR (E3) before and after exposure — PHPH-PVPVA ASD compacts at 5% (a), 15% (b) and 50% DL (c, d) (P4, P12); medium pH 6.8 buffer spiked with 40 µg/mL PHPH, in (d) also 1 mg/mL PVPVA; 37 °C, 100 rpm; compacts dried before analysis — sub-table below; text: 15% DL surface rose to "approximately 20%" drug after 30 min; 50% DL change "negligible"; in (d) surface PHPH "reduced" | Fig. 5, p.729; text p.728 |
| R7 | record, measured | MePHPH on the compact surface (%) by ATR-FTIR (E4) before and after exposure — MePHPH-PVPVA ASD compacts at 30% (a) and 50% DL (b) (P4, P12); pH 6.8 buffer without added drug; 37 °C, 100 rpm; compacts dried before analysis — sub-table below; text: at 30% DL the drug/polymer ratio "remained the same"; at 50% DL the surface rose to "90−100%" drug | Fig. 6, p.729; text p.728 |
| C3 | claim, conclusion, authors: asserted ("It was found") | ASD compacts with drug loads above the LoC formed an insoluble surface barrier that was in pseudo-equilibrium with the aqueous phase and prevented further release of drug and polymer during dissolution [rests on: R6, R7] | p.722 |
| C59 | claim, conclusion, authors: asserted ("very similar") | Above the LoC the compact surface composition evolves to be very similar to the hydrophobic binodal composition measured under dilute conditions [rests on: R6.b-d, R7.b, R8] | p.734 |
| C62 | claim, mechanism, authors: "is due to" (barrier); "is postulated" (gel-layer origin); "is reasoned" (plait point) | The LoC is due to a hydrophobic barrier on the ASD surface, postulated to form by phase separation in the gel layer next to the dry core when the hydrophobic phase outweighs the hydrophilic phase in volume and becomes an interconnected network; an ASD with a drug/polymer ratio above that of the plait point is reasoned to form the larger hydrophobic phase [rests on: R6, R7; argument only] | p.734 |

## 2023 Yang — Drug Release from Surfactant-Containing Amorphous Solid Dispersions: Mechanism and Role of Surfactant in Release Enhancement · Dissolution / A. Release mechanism and LoC

[2023-yang-surfactant-containing-asd-release-enhancement](../../../cards/2023-yang-surfactant-containing-asd-release-enhancement/paper.html) · Dissolution / A. Release mechanism and LoC · measured · as: drug-rich barrier layer

| id | kind | content | locator |
|---|---|---|---|
| R7 | record, measured | phase morphology, Span 20 40–60–10 — P7 at 5, 10, 20 min; P8 at 0, 0.5, 1, 2, 3, 5 min — surfaces: continuous red layer with green regions (scale bars 100 μm); cross sections: red drug-rich layer of about 50 to 100 μm at the dissolving interface from 5 min, with green pores connecting the solution to the gel layer at all times; in situ: red layer with pores at the interface at 0.5–2 min; at 3 and 5 min pores closed in the field of view | Fig. 5a–l, p.2827–2828; text p.2824–2825 |
| R9 | record, measured | phase morphology, Span 85 40% DL (text description of SI figure) — P7, P8 — continuous network of drug-rich domains evolving into a high-coverage, thick drug-rich layer across the compact surface at later times | Fig. S1 (not supplied); text p.2826–2827 |
| C15 | claim, mechanism, authors: asserted ("Therefore"); pores: suggesting, by inference | In the Span 20 40% DL ASD, the drug-rich barrier layer prevented drug release beyond its amorphous solubility, while polymer could leave through the pores in this layer. [rests on: R7, R2.d, R3.d] | Results, p.2824–2825 |
| C40 | claim, generalisation, authors: observation: asserted; mechanism: appears to be | Across the ternary ASDs, every releasing system lacked a persistent continuous drug-rich barrier and every system with such a barrier released minimal drug, so preventing or disrupting the barrier appears to be an important release-enhancing mechanism of surfactants. [rests on: R2, R6–R14] | Discussion, p.2837 |

## Mentioned only

- 2023 Hiew — [2023-hiew-grazoprevir-hierarchical-cpad-surface-drug-release](../../../cards/2023-hiew-grazoprevir-hierarchical-cpad-surface-drug-release/paper.html) · Dissolution / A. Release mechanism and LoC (ref C35)