# Evidence: falling-off-the-cliff effect

Parent: — · class: transport and absorption · names merged here: falling off a cliff; falling off a cliff effect; falling off the cliff; falling-off-the-cliff effect

6 papers measured or used it, 2 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 Indulkar — Insights into the dissolution mechanism of ritonavir-copovidone amorphous solid dispersions: importance of congruent release for enhanced performance · Dissolution / A. Release mechanism and LoC

[2019-indulkar-ritonavir-copovidone-asd-congruent-release-loc](../../../cards/2019-indulkar-ritonavir-copovidone-asd-congruent-release-loc/paper.html) · Dissolution / A. Release mechanism and LoC · measured · as: falling off a cliff effect

| id | kind | content | locator |
|---|---|---|---|
| R11 | record, measured | percentage of RTV and of PVPVA released at 60 min versus DL (mean, error bars SD; n not stated in caption) — P2 — sub-table below | Fig. 8, p.33 |
| C31 | claim, conclusion, authors: asserted ("obvious") | RTV-PVPVA ASD dissolution is fast at low DL and severely impaired at high DL, with a dramatic "falling off a cliff" drop in release above 25% DL [rests on: R11] | p.15-16, p.33 |
| C52 | claim, generalisation, authors: asserted ("Remarkably") | The DL range over which release switches from polymer- to drug-controlled is very narrow and the switch changes the drug release rate by orders of magnitude [rests on: R11, R1] | p.19 |

## 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 · measured · as: falling-off-the-cliff effect

| id | kind | content | locator |
|---|---|---|---|
| R3 | record, measured | surface-normalized release rate, 0-5 min (mg/min/cm², by E1; bars mean, error bars SD, n = 3) — ASD tablets 5-25% DL, neat PVPVA, amorphous drug; 37 °C, 100 rpm (P5); IND in M5, INDester in M6 — sub-table below (bar heights ≈, read from Fig. 2); text: amorphous IND alone 0.002 mg/min/cm²; amorphous INDester alone not determined (solution concentrations below HPLC detection limit); PVPVA alone ~3.5 mg/min/cm², around 1700 times faster than amorphous IND | Fig. 2, p.14; text p.13-14 |
| R29 | record, measured | limit of congruency (% DL by weight) versus dissolution temperature — IND:PVPVA ASD tablets, 0-5 min (P5, P7) — sub-table below; text: at 17 °C the 5% DL ASD released congruently; at 10 °C the 5% DL ASD released incongruently; no matrix crystallization by XRD and PLM on partially dissolved tablets | Fig. 11, p.27; text p.26 |
| C40 | claim, prior hypothesis, authors: "has been explained"; "appears to be the precursor" | The IND switch from fast, polymer-controlled release at 10% DL to almost no release at 15% DL ("falling off the cliff") has been seen for other systems and explained by a competition between drug release kinetics and AAPS in the matrix; AAPS appears to be the precursor of incongruent release at higher DL [rests on: R3; cited: refs 6, 7, 13] | p.28, p.31 |

## 2021 Yang — Drug Release and Nanodroplet Formation from Amorphous Solid Dispersions: Insight into the Roles of Drug Physicochemical Properties and Polymer Selection · Dissolution / A. Release mechanism and LoC

[2021-yang-asd-nanodroplet-release-drug-properties-polymer-selection](../../../cards/2021-yang-asd-nanodroplet-release-drug-properties-polymer-selection/paper.html) · Dissolution / A. Release mechanism and LoC · measured · as: falling-off-the-cliff effect

| id | kind | content | locator |
|---|---|---|---|
| R7 | record, measured | total released drug (μg/mL; 100 = complete) vs DL — loratadine ASDs, powder, 60 min (P12) — PVPVA: 10% ≈92; 20% ≈85; 25% ≈41; 30% ≈8; 35% ≈10; 40% ≈4. HPMCAS: 10% ≈97; 20% ≈93; 40% ≈86; 50% ≈46; 60% ≈20; 70% ≈12 (read from Fig. 3a). Text: PVPVA "falling-off-the-cliff" DL 25% | Fig. 3a, p.2071; text p.2073 |
| R8 | record, measured | total released drug vs DL — miconazole ASDs, powder, 60 min — PVPVA: 10% ≈100; 20% ≈103; 30% ≈100; 40% ≈93; 45% ≈42; 50% ≈3. HPMCAS: 10% ≈97; 20% ≈93; 30% ≈89; 40% ≈83; 50% ≈44; 60% ≈37; 65% ≈10; 70% ≈4 (read from Fig. 3b). Text: PVPVA cliff DL 40% | Fig. 3b, p.2071; text p.2073 |
| R9 | record, measured | total released drug vs DL — danazol ASDs, powder, 15 min (caption: API crystallization beyond 15 min) — PVPVA: ≈2% ≈91; ≈2.5% ≈96; 5% ≈78; 10% ≈9.5; 20% ≈9; 50% ≈8. HPMCAS: 5% ≈98; 10% ≈75; 20% ≈36; 30% ≈25; 50% ≈14; 70% ≈8 (read from Fig. 3c). Text: PVPVA cliff DL 5% | Fig. 3c, p.2071; text p.2073 |
| R10 | record, measured | total released drug vs DL — elbasvir ASDs, powder, 60 min — PVPVA: ≈2% ≈88; ≈2.5% ≈85; 5% ≈79; 10% ≈77; 20% ≈13; 50% ≈5. HPMCAS: ≈2.5% ≈95; 5% ≈97; 10% ≈57; 20% ≈9; 50% ≈11 (read from Fig. 3d). Text: PVPVA cliff DL 10% | Fig. 3d, p.2071; text p.2073 |
| R11 | record, measured | total released drug vs DL — paclitaxel ASDs, powder, 60 min — PVPVA: 5% ≈98; 10% ≈19; 15% ≈23; 20% ≈16. HPMCAS: 5% ≈102; 10% ≈82; 15% ≈37; 20% ≈32 (read from Fig. 4a) | Fig. 4a, p.2072 |
| R12 | record, measured | total released drug vs DL — ivacaftor ASDs, powder, 60 min — PVPVA: 5% ≈104; 10% ≈21; 15% ≈3; 20% ≈9. HPMCAS: 5% ≈104; 10% ≈99; 15% ≈44; 20% ≈7 (read from Fig. 4b) | Fig. 4b, p.2072 |
| C2 | claim, conclusion, authors: abstract: asserted; results: asserted ("No sudden decline"); discussion: "not always observed", "a more appropriate description" | PVPVA ASDs show a "falling-off-the-cliff" drop: near-complete to virtually no release within a 10% DL span in every PVPVA system (powder); HPMCAS ASDs instead decline gradually with DL (negative slope), forming some nanodroplets over a wider DL range even when release is incongruent; elbasvir ASDs of both polymers behaved alike [rests on: R7–R12] | Abstract p.2066; Results p.2073; Discussion p.2078; Conclusions p.2079 |
| C41 | claim, generalisation, authors: "This suggests" | Since earlier cliff reports used surface-normalized dissolution, the cliff seen here with powders implies PVPVA ASD behaviour does not depend on test type (powder vs non-disintegrating compact) [rests on: R7–R12, R19] | Discussion p.2078 |

## 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 · measured · as: falling off a cliff

| id | kind | content | locator |
|---|---|---|---|
| R10 | record, measured | drug released (% of total drug) versus time from ASD compacts (mean, error bars one SD, n = 3) — free base and salt ASDs (P2); 50 mM pH 6.8 phosphate buffer, 37 °C (P8) — sub-table below; text: free base rapid release up to 35% DL; benzoate 20 and 25% DL linear then plateau at ~30 min with ~60% and ~15% released at 30 min; benzoate 30% DL lag, release only after 20 min; PEG 250 diacid (2:1) 20 and 25% DL rapid; 30% DL lag for both drug:acid ratios; besylate and camsylate near complete at 10% DL, little or none at 15%; tosylate 10% DL plateau after 30 min at ~60%; HCl rapid at 5, 10, 15% DL, lower extent and rate at 20 and 25%, negligible at 25%; sulfate 2% DL rapid and near complete | Fig. 7, p.53; text p.52 |
| R12 | record, derived (relation named, not printed: slope of the linear portion of the concentration-time profile per exposed area) | surface-normalized drug release rate (mg·min−1·cm−2, mean, error bars one SD, n = 3) — ASDs of R10 with measurable release, 37 °C (P8); no bars for tosylate 15%, camsylate 15%, HCl 25% and sulfate 10-35% DL — sub-table below; text: all formulations with near complete drug release had rates higher than 3 mg·min−1·cm−2 | Fig. 8, p.54; text 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: falling-off-the-cliff effect

| id | kind | content | locator |
|---|---|---|---|
| R2 | record, measured | % released versus time (mean ± SD, n = 3) — RTV-PVPVA compacts and neat components, P2 — sub-table below | Fig. 2, pdf p.8 |
| C7 | claim, prior hypothesis, authors: "often observed"; "usually" | For PVPVA ASDs a "falling-off-the-cliff" effect is often seen: complete, congruent release only at relatively low DL, then a dramatic decline with incongruent release in which polymer usually releases faster than drug; the DL at which congruency is lost is the LoC; enteric polymer dispersions show a more gradual decrease with DL [rests on: cited: refs 5, 7, 8, 25, 26] | pdf p.3-4 |
| C10 | claim, prior hypothesis, authors: "We hypothesized" | Hypothesis: a continuous drug-rich barrier formed at the ASD surface is detrimental to drug release and coincides with the DL at which the cliff occurs [rests on: argument only] | pdf p.4 |

## 2024 Polyzois — Amorphous Solid Dispersion Formation for Enhanced Release Performance of Racemic and Enantiopure Praziquantel · Dissolution / B. Supersaturation from ASD dissolution

[2024-polyzois-praziquantel-racemic-enantiopure-asd-release](../../../cards/2024-polyzois-praziquantel-racemic-enantiopure-asd-release/paper.html) · Dissolution / B. Supersaturation from ASD dissolution · measured · as: falling-off-the-cliff effect

| id | kind | content | locator |
|---|---|---|---|
| R8 | record, measured | single-stage release versus time, SE RS-PZQ ASDs, target 667 µg/mL (mean of n = 3; error bars = SD) — 50 mL PBS pH 6.5, 37 °C, 100 rpm (P8) — text: HPMCAS-MF complete release at every DL (20-50%), complete within 10-21 min at 20 and 30% DL; HPMC E5 LV complete release up to 40% DL, within 28-53 min; HPMC E5 LV at 50% DL maximum 86% (p.5292: "∼86%"); figure readings in sub-table | Section 3.5.1, p.5290; Section 4.2.1, p.5292; Fig. 4a, p.5290 |
| R9 | record, measured | single-stage release versus time, SE RS-PZQ ASDs, target 1.5 mg/mL (mean of n = 3; error bars = SD) — 50 mL PBS pH 6.5, 37 °C, 100 rpm (P8) — text: HPMCAS-MF 20% DL complete release within 51 min; 30 and 40% DL dropped to 94 and 83% (p.5292: "∼83%"); the HPMC E5 LV series are not described in the text; figure readings in sub-table | Section 3.5.1, p.5290; Section 4.2.1, p.5292; Fig. 4b, p.5290 |
| C16 | claim, conclusion, authors: asserted | At 667 µg/mL no "falling-of-the-cliff" effect (ref 67) occurred: release never declined massively as DL increased for either polymer [rests on: R8; cited: ref 67] | p.5292 |
| C18 | claim, conclusion, authors: asserted ("No evidence") | For R-PZQ, overall release from HPMCAS-MF did not decrease with DL, although early release was slower at higher DL; no falling-off-the-cliff effect was seen with RS-PZQ or R-PZQ HPMCAS-MF ASDs [rests on: R9.a-c, R12.a, R13.a] | p.5292 |

## 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 C36)
- 2024 Deac — [2024-deac-asd-polymer-molecular-weight-failure-mode-loc](../../../cards/2024-deac-asd-polymer-molecular-weight-failure-mode-loc/paper.html) · Dissolution / A. Release mechanism and LoC (ref 9)