# Evidence: amorphous-amorphous phase separation

Parent: — · class: phase behaviour · names merged here: amorphous-amorphous phase separation; amorphous–amorphous phase separation; drug-polymer phase separation

51 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.

## 2001 Broman — A comparison of alternative polymer excipients and processing methods for making solid dispersions of a poorly water soluble drug · ASD process / ASD process

[2001-broman-polymer-excipients-processing-probucol-solid-dispersions](../../../cards/2001-broman-polymer-excipients-processing-probucol-solid-dispersions/paper.html) · ASD process / ASD process · used · as: drug-polymer phase separation

| id | kind | content | locator |
|---|---|---|---|
| C16 | claim, mechanism, authors: "suggests"; "perhaps"; "indicating" | In the compression-moulded PVP sample the higher Tg means probucol and PVP did not fully mix during the melt, perhaps because the moulding time was short; the Tg reflects a PVP-rich phase with an interphase, and the smaller carbonyl shift means less interaction [rests on: R4.b, R5, R9] | p.144 |
| C33 | claim, mechanism, authors: "Presumably" | Neither PAA nor PEO stabilised amorphous probucol, after melting or after solvent evaporation; probably neither forms a single-phase system with probucol at room temperature [rests on: R4.c, R4.d, R4.e, R4.f, R3] | p.147-148 |
| C45 | claim, mechanism, authors: "It is suspected"; "We hypothesis"; "possibly" | The controlled high pressure together with high local temperature in compression moulding is suspected to give intimate contact and mixing of the molten components; on cooling the drug crystallises but stays in intimate contact with the polymer, possibly as a fine precipitate dispersed in it [rests on: argument only; cited: Chiou & Reigelman 1971] | p.149-150 |

## 2008 Konno — Ability of Different Polymers to Inhibit the Crystallization of Amorphous Felodipine in the Presence of Moisture · Solid state stability / Physical stability

[2008-konno-polymers-inhibit-amorphous-felodipine-moisture-crystallization](../../../cards/2008-konno-polymers-inhibit-amorphous-felodipine-moisture-crystallization/paper.html) · Solid state stability / Physical stability · used · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| C34 | claim, mechanism, authors: discussion: "These results suggest", "maybe"; abstract: "may be indicative of phase separation"; conclusions: "showed evidence of a tendency to phase separate" | The 25% PVP dispersion may be undergoing partial phase separation induced by absorbed moisture [rests on: R10] | p.969, p.977 |
| C35 | claim, mechanism, authors: "indicating" | After the moisture is removed the dispersion does not remix at room temperature, so it is kinetically trapped as a partially phase-separated system [rests on: R10] | p.977 |
| C36 | claim, mechanism, authors: "may" | PVP systems may be more susceptible to moisture-induced phase separation either simply because they absorb more water or for more complex reasons involving the relative polarities of the three components [rests on: R9; argument only] | p.977 |
| X14 | extractor note | claim-data gap — C34 (partial phase separation of the 25% PVP dispersion) rests on IR band changes measured after drying (R10); Figs. 3a and 4 report one Tg per sample, and whether a second transition was looked for in the humidified PVP dispersions is not stated — C34, C35, R10, R5, R7 — treat phase separation as a proposed reading of the IR data, not an observation |  |

## 2009 Rumondor — Evaluation of Drug-Polymer Miscibility in Amorphous Solid Dispersion Systems · Solid state stability / Miscibility and drug-polymer interactions

[2009-rumondor-drug-polymer-miscibility-asd-dsc-ir-pxrd](../../../cards/2009-rumondor-drug-polymer-miscibility-asd-dsc-ir-pxrd/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R1 | record, measured (Tg columns); derived, E1 (Couchman-Karasz column) | midpoint Tg of felodipine-PAA dispersions; where two glass transition events were detected both are given as Tg1 / Tg2 (table footnote a) — felodipine-PAA bulk powders (P1); "Experiment 1" = heating to 180 °C, "Experiment 2" = heating to 146 °C with 30 s hold (P2; mapping by the 50% row, p.2526) — sub-table below | Table I, p.2526 |
| R13 | record, measured | PCA of IR spectra: number of PCs, loading correlation, scores — felodipine-PAA dispersions (P3) and calculated physical mixtures (P4) — calculated physical mixtures: one PC; dispersions: three PCs; PC1 loading of the dispersions versus that of the physical mixtures: Pearson's ρ >0.99; dispersions with 30, 50 and 70% PAA have scores close to the matching physical mixtures with little variation along PC2; the 90% PAA dispersion is described only when PC2 is included; the 10% PAA dispersion varies along PC3; the 10 and 90% PAA dispersions lie off the PC1 composition trend (caption). Sub-table below (all values ≈, read from Fig. 7a) | Fig. 7a, p.2529; text pp.2528-2529 |
| R16 | record, derived (P8) | polymer concentration (% polymer, dry weight basis, per the table title) from PDF reconstruction using pure components, versus actual — four systems at 30 and 70% polymer (P6-P8) — sub-table below | Table II, p.2531 |
| C13 | claim, conclusion, authors: "These results suggest"; "as indicated by" | Two Tgs at 70 and 90% felodipine in both heating regimens show that felodipine and PAA are at least partially immiscible [rests on: R1.b-c] | p.2526 |
| C44 | claim, conclusion, authors: discussion: "was detected with all three"; "suggesting"; abstract: immiscibility "was verified" for 30 to 70% polymer; conclusions: "practically immiscible between 30 and 70% polymer concentration" | Felodipine-PAA has limited miscibility by all three techniques: between 30 and 70% polymer neither IR nor PDF/PCRM detects a change in chemical environment, pointing to a drug-rich and a polymer-rich phase each holding only a small fraction of the other component [rests on: R1, R12, R13, R16.g-h, R18, R22] | p.2523, p.2533 |
| C46 | claim, mechanism, authors: "suggest"; "It is speculated" | At 10 and 90% PAA, IR points to some mixing while "more than one Tg for samples containing 90% PAA" points to more than one phase; some mixing is speculated to occur with an excess of one pure component left as a separate phase [rests on: R13, R1] | p.2533 |

## 2009 Rumondor — Phase Behavior of Poly(vinylpyrrolidone) Containing Amorphous Solid Dispersions in the Presence of Moisture · Solid state stability / Physical stability

[2009-rumondor-pvp-asd-moisture-induced-immiscibility](../../../cards/2009-rumondor-pvp-asd-moisture-induced-immiscibility/paper.html) · Solid state stability / Physical stability · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R7 | record, measured | IR νNH region after storage and drying (band maxima ≈, read from Fig. 2) — nifedipine-PVP 50% PVP, 94% RH (P4.a) — Fig. 2: initial main band ≈3293 with a second band ≈3225; 24 h and 4 days: main band ≈3343, matching the physical-mixture and amorphous traces (≈3345); crystalline reference ≈3317, with no separate band at that position in the 24 h and 4 day traces. Text: 3288 band lower in relative intensity after 1 h, with a concurrent rise at 3345; band at ~1660 lower (data not shown); no 3317 band; IR bands of crystalline nifedipine developed after 48 h | Fig. 2, p.1497; text p.1497-1498 |
| R9 | record, measured | IR carbonyl region after storage at 94% RH and drying (band maxima ≈, read from Fig. 3) — pimozide-PVP 30% PVP (P4.c) — Fig. 3: initial bands ≈1709 and ≈1685 with a shoulder ≈1660; 1 h: main band ≈1691 with a shoulder ≈1712; 6 days: main band ≈1692; physical mixture main band ≈1692; amorphous pimozide ≈1696; crystalline ≈1693. Text: 1709 band (free drug C=O) and 1661 band (PVP C=O H-bonded to drug) lower in relative intensity; after 6 days at 22 °C/94% RH the band centred at 1690 began to shift to 1693 | Fig. 3, p.1497; text p.1498 |
| R10 | record, measured | IR carbonyl region after storage at different RH and drying — pimozide-PVP 30% PVP: 3 days at 54% RH, 2 days at 75% RH, 2 days at 84% RH, 1 h at 94% RH (P4.d) — caption and text: intensity of the 1709 and 1661 bands lower with increasing storage RH, spectra progressively closer to the calculated physical mixture; changes present after 54% RH. Figure (≈, read from Fig. 4): 54% RH keeps the two-band profile of the initial film (≈1711, ≈1687) with a weaker ≈1660 shoulder; from 75% RH ≈1711 is a shoulder and the main band is at ≈1691; 94% RH (1 h) is closest to the physical mixture (≈1693) | Fig. 4, p.1498; text p.1498 |
| R12 | record, measured | IR carbonyl region after storage at 94% RH and drying (band maxima ≈, read from Fig. 5) — droperidol-PVP 30% PVP (P4.e) — Fig. 5: initial bands ≈1717 and ≈1682 with a shoulder ≈1657; 1 h: ≈1717 reduced to a shoulder, main band ≈1684; 22 h: broad ≈1698 and ≈1682; 6 days: ≈1697 and ≈1683; physical mixture: shoulder ≈1700, main band ≈1685; amorphous droperidol ≈1706 and ≈1685; crystalline ≈1682. Text: free drug C=O band at 1717 lower in relative intensity; band at 1685 shifted to 1683 after 22 h at 94% RH, more so after 6 days | Fig. 5, p.1498 |
| R17 | record, measured | DSC midpoint Tg — pimozide-PVP 50:50 (P9), 42 h at room temperature/94% RH; pure amorphous pimozide — pure amorphous pimozide 60 °C; dry dispersion 94 °C; after 94% RH (wet): two Tg events at −21 and 44 °C; after 94% RH and drying: two Tg events at 61 and 112 °C | Fig. 8, p.1499 |
| R18 | record, measured | DSC midpoint Tg (no figure) — pimozide-PVP 70:30, i.e. 30% PVP (P9) — dry 81 °C; wet: two Tg events at 13 and 48 °C; dried: two Tg events at 59 and 109 °C | p.1499 |
| C2 | claim, conclusion, authors: abstract: asserted; discussion: "it appears" | After storage at elevated RH (75-94%), nifedipine-, droperidol- and pimozide-PVP dispersions formed drug-rich and polymer-rich amorphous phases before the drug crystallized; indomethacin- and ketoprofen-PVP did not [rests on: R7-R13, R14-R16, R17, R18, R22] | p.1492, p.1501 |

## 2010 Marsac — Effect of Temperature and Moisture on the Miscibility of Amorphous Dispersions of Felodipine and Poly(vinyl pyrrolidone) · Solid state stability / Physical stability

[2010-marsac-temperature-moisture-miscibility-felodipine-pvp-asd](../../../cards/2010-marsac-temperature-moisture-miscibility-felodipine-pvp-asd/paper.html) · Solid state stability / Physical stability · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R7 | record, measured | NH and OH region measured in the humid cell — 69.7 wt% felodipine / 30.3 wt% PVP films after 1 week at 33, 58, 75% RH, 25 °C (P7, P8) — broad OH band at ≈3450–3650 cm−1 rises in the order initial < 33 < 58 < 75% RH; drug–polymer NH bands fall in intensity relative to drug–drug NH bands; changes small at 33 and 58% RH and distinct at 75% RH | Fig. 4, p.174 |
| R8 | record, measured | NH region after re-drying — the R7 films after 0, 33, 58, 75% RH for 1 week at 25 °C, then 1 week at 0% RH over phosphorus pentoxide (P7) — the NH-region changes seen in the humid state remain after drying; absorbance near ≈3335 cm−1 relative to the ≈3300 cm−1 maximum rises in the order 0 < 33 < 58 < 75% RH (arrow, read from Fig. 5) | Fig. 5, p.175; text p.174 |
| R11 | record, measured | NH region after 1 day at high RH and drying, with felodipine reference spectra — (a) 30.3 wt% PVP and (b) 46.4 wt% PVP, as prepared and after 75, 84, 94% RH for 1 day (P1, P7) — (a) 75% and 84% RH spectra close to the initial broad ≈3300–3340 cm−1 maximum, with less absorbance near 3290 cm−1; 94% RH spectrum peaks at ≈3340 cm−1 and falls steeply toward 3250 cm−1, close in shape to amorphous felodipine. (b) initial and 75% RH spectra peak at ≈3297 cm−1 with a band at ≈3230 cm−1; 84% and 94% RH spectra peak at ≈3340 cm−1, the 94% spectrum with less residual absorbance at ≈3300–3230 cm−1. References: crystalline felodipine NH band ≈3362 cm−1, amorphous felodipine ≈3340 cm−1 (all read from Fig. 7). Text: changes larger than in Fig. 5; dried spectra increasingly resemble amorphous felodipine; no significant crystallization in the spectra | Fig. 7, p.176; text p.175 |
| R13 | record, measured | NH region of films cast with and without water in the solvent — 30 wt% (upper pair, read as panel a) and 50 wt% PVP (lower pair, read as panel b); dashed = water added, solid = no water (P1, P2) — without water: upper maximum ≈3300 cm−1 with shoulder ≈3340 cm−1, lower maximum ≈3293 cm−1, both with a band at ≈3228 cm−1; with water: both maxima at ≈3340 cm−1 with only a weak band at ≈3230 cm−1 (read from Fig. 8). Text: the 3290 cm−1 band is reduced relative to the 3345 cm−1 band when water was in the solution; the spectra resemble those of dry-cast dispersions after elevated RH | Fig. 8, p.176 |
| R14 | record, measured | DSC first and second heating scans after humid storage — 46.5 wt% PVP powder; (a) 75%, (b) 84%, (c) and (d) 94% RH for about 12 h; (a)–(c) vacuum-dried overnight and N2-purged 1 h; (d) also dried 17 h in the DSC (P9, P11) — text: every first scan shows a glass transition-like event at about 45–50 °C; (d) also shows an event with onset at ~124 °C; no recrystallization exotherm; every second scan shows a single Tg at around 80 °C. Figure: (a), (b) first scans step near ≈50–60 °C and a larger step near ≈80–100 °C; (c) sharp endotherm ≈50 °C and broad endotherm ≈95–130 °C; (d) sharp endotherm ≈54 °C and endotherm with minimum ≈129 °C; second scans one step near ≈80–100 °C (read from Fig. 9; scans not labelled, see X6) | Fig. 9, p.177; text p.176 |
| R19 | record, measured | AFM topography and phase of films after humid storage — 50% (w/w) PVP films on glass, 94% RH, vacuum-dried at least 24 h before imaging; 5 µm × 5 µm (P3, P14) — sub-table below | Fig. 13, p.179; text p.178, p.180 |
| R20 | record, measured | TEM micrographs and electron diffraction — (a) amorphous felodipine, (b) PVP, (c) "30% PVP-Felodipine" at 0% RH, (d) the same at 94% RH, spin coated on grids, vacuum-dried overnight (P4, P15); scale bars 100 nm — (a), (b) no distinct features; (c) uniform, no distinct regions; (d) two distinct regions (darker domains in a lighter matrix) and no diffraction rings in the inset; after longer storage at 94% RH diffraction rings were seen (data not shown) | Fig. 14, p.180 |
| C14 | claim, conclusion, authors: "strongly suggest" | The rise of drug–drug relative to drug–polymer hydrogen bonding means the dispersions undergo amorphous–amorphous phase separation into a drug-rich and a polymer-rich amorphous phase [rests on: R7, R8, R11] | p.175 |
| C27 | claim, conclusion, authors: "appears to have undergone" | The 94% RH TEM sample, with two distinct regions and no diffraction rings, has undergone amorphous–amorphous phase separation; longer storage gave crystals [rests on: R20] | p.180 |
| C39 | claim, conclusion, authors: "suggest"; "suggesting"; "must be" | At 75% or 84% RH (4.8 and 9.9 wt% water, from Table 1) phase separation is far from complete and drug–polymer interactions persist at a reduced level; after 94% RH (40.3 wt% water) the NH band resembles that of pure amorphous drug, so the drug-rich phase holds little polymer and the polymer-rich phase "must be" drug poor [rests on: R11, R10.b] | p.181-182 |

## 2010 Rumondor — Effects of Moisture on the Growth Rate of Felodipine Crystals in the Presence and Absence of Polymers · Solid state stability / Physical stability

[2010-rumondor-moisture-felodipine-crystal-growth-pvp-hpmcas](../../../cards/2010-rumondor-moisture-felodipine-crystal-growth-pvp-hpmcas/paper.html) · Solid state stability / Physical stability · used · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R18 | record, cited | moisture-induced amorphous-amorphous phase separation — refs 6, 8, 34 — at sufficiently high RH sorbed water induces amorphous-amorphous phase separation; known for felodipine-PVP dispersions exposed to high RH | p.753 |
| C43 | claim, mechanism, authors: abstract: "probably"; discussion: "would explain"; "would be expected"; conclusions: "may result from" | At high RH sorbed water induces amorphous-amorphous phase separation into drug-rich and polymer-rich domains whose composition is independent of the starting composition, so growth rates from films with different PVP contents merge [rests on: R5, R18] | p.747, p.753 |

## 2010 Rumondor — Effect of Polymer Hygroscopicity on the Phase Behavior of Amorphous Solid Dispersions in the Presence of Moisture · Solid state stability / Physical stability

[2010-rumondor-polymer-hygroscopicity-moisture-phase-separation-asd](../../../cards/2010-rumondor-polymer-hygroscopicity-moisture-phase-separation-asd/paper.html) · Solid state stability / Physical stability · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R3 | record, measured | Tg (midpoint) and ΔCp of dispersions before and after humidity exposure (P7) — 50 wt% polymer powders (P5); after: 25 °C/94% RH 24 h, dried to plateau, hermetically sealed — sub-table below; n and uncertainty not stated | Table 3, p.483 |
| R4 | record, measured | IR NH region after humid storage — felodipine-50% PVPVA films, as prepared and after 1 day at 54% and at 84% RH, dried (P4) — spectra: main band ≈3300 cm⁻¹ with a shoulder at ≈3340 cm⁻¹ that is highest after 84% RH (read from Fig. 2a); text: relative intensity of the 3341 cm⁻¹ band increased with storage RH; at 84% RH a 17% reduction in intensity of the drug-polymer H-bond band relative to the drug-drug H-bond band | Fig. 2a, p.483; text p.481, p.489 |
| R6 | record, measured | IR carbonyl region after humid storage — quinidine-50% PVP films, as prepared and after 1 day at 54% and at 84% RH, dried — 1681 cm⁻¹ band with 1662 cm⁻¹ shoulder in dispersions (absent in PVP alone); shoulder decreased after 54% RH and was virtually eliminated after 84% RH; at 84% RH a 47% reduction in intensity of the drug-polymer H-bond band relative to the free vinylpyrrolidone carbonyl band | Fig. 3a, p.484; text p.482, p.489 |
| R7 | record, measured | IR carbonyl region after humid storage — quinidine-50% PVPVA films, as prepared and after 1 day at 84% and at 94% RH, dried — three bands between 1650 and 1800 cm⁻¹; 1665 cm⁻¹ band (absent in pure polymer and pure drug) decreased slightly in relative intensity after storage, less than the 1662 cm⁻¹ shoulder of quinidine-PVP (R6); at 84% RH an 11% reduction | Fig. 4a, p.484; text p.482-483, p.489-490 |
| R8 | record, measured | IR carbonyl region after humid storage — pimozide-50% PVPVA films, as prepared and after 1 day at 54% and at 84% RH, dried — four carbonyl bands; the 1661 cm⁻¹ shoulder and the 1709 cm⁻¹ band decreased in intensity with increasing RH | Fig. 5a, p.485; text p.483 |
| R11 | record, measured | IR carbonyl region after humid storage — pimozide-50% HPMCAS films, as prepared and after increasing RH (Fig. 6a: as prepared and after 1 day at 94% RH), dried — broad 1704 cm⁻¹ band split into a peak at 1709 cm⁻¹ and a shoulder at 1698 cm⁻¹; the 1698 cm⁻¹ shoulder stays lower than the 1709 cm⁻¹ peak; in Fig. 6a the after-94% RH spectrum differs only slightly from the as-prepared spectrum in the 1690-1720 cm⁻¹ region | Fig. 6a, p.485; text p.483-484 |
| C10 | claim, conclusion, authors: "The results suggest" | For felodipine-PVPVA, quinidine-PVP, quinidine-PVPVA, pimozide-PVPVA and pimozide-HPMCAS, storage at the specified RH formed drug-rich and polymer-rich amorphous phases [rests on: R3.a-e, R4, R6-R8, R11] | p.481 |
| C36 | claim, conclusion, authors: asserted ("were found") | Felodipine-PVPVA, quinidine-PVP, quinidine-PVPVA, pimozide-PVPVA and pimozide-HPMCAS underwent amorphous-amorphous phase separation on exposure to RHs as low as 54% and as high as 94%; felodipine-HPMCAS, quinidine-HPMCAS, indomethacin-PVPVA and indomethacin-HPMCAS stayed miscible after 94% RH [rests on: R3, R4-R17] | p.477, p.490 |

## 2011 Rumondor — Understanding the Tendency of Amorphous Solid Dispersions to Undergo Amorphous–Amorphous Phase Separation in the Presence of Absorbed Moisture · Solid state stability / Physical stability

[2011-rumondor-asd-moisture-aaps-pvp-opls](../../../cards/2011-rumondor-asd-moisture-aaps-pvp-opls/paper.html) · Solid state stability / Physical stability · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R9 | record, measured | IR carbonyl region after storage and drying, clofoctol–PVP — 30, 50, 70% PVP shown (Fig. 6), 10 and 90% not shown; 54, 75, 84, 94% RH (P3) — 50% PVP: after 54% RH the 1,663 cm⁻¹ peak lost intensity relative to the 1,682 cm⁻¹ peak; text: at 75, 84 and 94% RH its intensity kept decreasing while overlap with the pure PVP peak shifted the band toward 1,682 cm⁻¹; figure: shoulder ≈1,663 lowest after 54% RH, intermediate after 75%, near the initial height with a broadened band after 84 and 94% (read from Fig. 6). 70% PVP: shoulder near 1,660 cm⁻¹ lower after 54% RH (only 54% plotted). 90% PVP: similar changes (not shown). 30% and 10% PVP: spectra after storage up to 94% RH and drying identical to the initial spectra (30%: initial and 94% plotted, maximum ≈1,662). No crystalline clofoctol peaks at 854 and 1,238 cm⁻¹; no crystals seen visually | Fig. 6, p.1213 |
| R10 | record, measured | IR carbonyl region after storage and drying, probucol–PVP — 50% PVP shown (Fig. 7); 70, 90, 30, 10% not shown; 54-94% RH (P3) — 50% PVP: the shoulder at 1,663 cm⁻¹ falls gradually in relative intensity against the 1,682 cm⁻¹ peak from the initial spectrum to 94% RH (plotted maximum ≈1,686, read from Fig. 7); 70 and 90% PVP: similar changes; 30% PVP: much smaller change; 10% PVP: no change | Fig. 7, p.1213-1214 |
| R11 | record, measured and calculated | IR carbonyl region after storage and drying, indoprofen–PVP — 50% PVP shown (Fig. 8) with calculated 50% physical mixture; 30, 10, 70, 90% not shown; 54-94% RH (P3) — 50% PVP: slight increase in relative intensity of the 1,682 cm⁻¹ peak after 54 and 75% RH, no sign of crystallization at 75% RH or lower, shifted 1,641 cm⁻¹ band still present; after 84 and 94% RH abrupt decrease of the 1,641 cm⁻¹ peak and a sharp peak at 738 cm⁻¹ (not shown); the plotted 84 and 94% RH spectra also lack the ≈1,727 cm⁻¹ band of the initial film (read from Fig. 8). 30% PVP: similar trend, crystallization detected after 75% RH. 10% PVP: crystallization detected after 54% RH, the lowest RH used. 70 and 90% PVP: AAPS pattern, no crystallization up to 94% RH | Fig. 8, p.1214; p.1218 |
| R12 | record, measured and calculated | IR carbonyl region after storage and drying, nilutamide–PVP — 50% PVP shown (Fig. 9) with calculated physical mixture; 10, 30, 70, 90% not shown; 54-94% RH (P3) — 50% PVP: gradual decrease in relative intensity at 1,663 cm⁻¹ and gradual increase at 1,682 cm⁻¹ with increasing RH; the same changes at 10, 30, 70 and 90% PVP; no crystalline nilutamide in any sample | Fig. 9, p.1214-1215 |
| R13 | record, measured and calculated | IR carbonyl region after storage and drying, loratadine–PVP — 50% PVP shown (Fig. 10) with calculated physical mixture; 10, 30, 70, 90% not shown; 54-94% RH (P3) — 50% PVP: single peak initially at 1,686 cm⁻¹ separates gradually into a peak at 1,692 cm⁻¹ and a shoulder at 1,675 cm⁻¹; after 94% RH and drying the spectrum resembles the calculated 50% physical-mixture spectrum (maximum ≈1,693, shoulder ≈1,672 cm⁻¹, arrows, read from Fig. 10); 10, 30, 70, 90% PVP: similar behaviour | Fig. 10, p.1215 |
| R14 | record, derived (P3) | phase behaviour after storage at increasing RH, classified from the IR spectra (R9-R13) — five API–PVP systems, 22 °C, up to 94% RH — sub-table below | Table I, p.1213 |
| C16 | claim, assumption, authors: asserted | If AAPS occurs, polymer-rich and API-rich amorphous domains form, and the IR spectra show stronger pure-API or pure-PVP features at the expense of interaction features [rests on: cited: refs 5-7] | p.1213 |

## 2012 Eerdenbrugh — Molecular Weight Effects on the Miscibility Behavior of Dextran and Maltodextrin with Poly(vinylpyrrolidone) · Solid state stability / Miscibility and drug-polymer interactions

[2012-van-eerdenbrugh-dextran-maltodextrin-pvp-molecular-weight-miscibility](../../../cards/2012-van-eerdenbrugh-dextran-maltodextrin-pvp-molecular-weight-miscibility/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R4 | record, measured | Tg versus DEX6 weight fraction — DEX6-PVP25 (P2, P3, second heating) — sub-table below; text: two Tg events at DEX weight fractions between 0.5 and 0.8 | Fig. 3a, p.2759; text p.2758 |
| R7 | record, measured | Tg versus DEX40 weight fraction — DEX40-PVP25 (P2, P3) — sub-table below | Fig. 4a, p.2759 |
| R10 | record, measured | Tg versus DEX450 weight fraction — DEX450-PVP25 (P2, P3) — sub-table below | Fig. 5a, p.2760 |
| R13 | record, measured, or inferred per cell | miscibility map from DSC Tg events — 20 DEX-PVP systems at DEX weight fraction 0.1-0.9 (P3) — sub-table below | Table III, p.2761 |
| C6 | claim, assumption, authors: asserted | Both polymers are amorphous, so their blends are fully amorphous, crystallization cannot occur, and interpretation is limited to amorphous-amorphous phase separation versus miscible blends [rests on: argument only] | p.2756 |
| C16 | claim, conclusion, authors: "indicating"; "tends to" | Two Tg events at 0.5-0.8 DEX in DEX6-PVP25 indicate a miscibility gap; DEX6-PVP30 and DEX6-PVP90 behave similarly; with lower-MW PVP the gap becomes smaller (PVP17) or disappears (PVP12); the gap tends to occur at high DEX weight fractions [rests on: R4, R6, R13] | p.2758 |

## 2012 Eerdenbrugh — Nanoscale Mid-Infrared Imaging of Phase Separation in a Drug–Polymer Blend · Characterization methods / Solid-state methods

[2012-van-eerdenbrugh-felodipine-paa-nanoscale-mid-ir-phase-separation](../../../cards/2012-van-eerdenbrugh-felodipine-paa-nanoscale-mid-ir-phase-separation/paper.html) · Characterization methods / Solid-state methods · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R3 | record, measured | AFM topography, 50:50 felodipine–PAA — as R2 — text: more heterogeneous; discrete domains in a continuous phase, the domains raised above it; domains submicrometre, the smallest about 100 nm in diameter, range about 100 nm to a few hundreds of nanometres; figure: many rounded domains of similar size, mostly separate from each other | Fig. 2b, p.2068; text p.2069 |
| R4 | record, measured | AFM topography, 75:25 felodipine–PAA — as R2 — text: domains much more variable in size, from about 100 nm to several micrometres, dominating the image and often (almost) touching each other; figure: several of the largest domains have a lower centre than their rim | Fig. 2c, p.2068; text p.2069 |
| R9 | record, measured | local AFM-IR spectra at eight marked positions — 50:50 film on ZnSe (P1), P6 at 137 kHz; positions 1–4 on discrete domains (red), 5–8 on the continuous phase (green); 1.5 × 2.5 µm² topography, colour scale 100 nm — text: continuous phase, the peak near 1700 cm−1 is the dominant peak of the 1200–1800 cm−1 region and the 1500 cm−1 peak is relatively weak; discrete domains, the 1500 cm−1 peak is somewhat higher than the 1700 cm−1 peak; in both phases the characteristic peaks of the other component are present; figure: the same pattern in each of the four spectra of each group | Fig. 4a-b, p.2071; text p.2070 |
| R10 | record, measured | average spectrum of each phase (n = 4, normalized, offset) — as R9 — 1500 cm−1 peak height relative to the 1700 cm−1 peak: discrete domains ≈1.1; continuous phase ≈0.6 (read from Fig. 4c, heights above the minimum near 1550–1600 cm−1); both averages also show bands near 1450 and 1290 cm−1 | Fig. 4c, p.2071 |
| C8 | claim, conclusion, authors: "strongly suggest"; 75:25 "apparently" | The AFM images point to a phase-separated system evolving with increasing felodipine content; the 75:25 film appears phase separated [rests on: R2, R3, R4] | p.2069 |
| C19 | claim, conclusion, authors: results: asserted ("we can now unambiguously conclude"); abstract: "revealed", continuous phase "tended to be rich in PAA" | The discrete domains are an amorphous felodipine-rich phase, identified by the relative intensity of the 1500 cm−1 peak (characteristic of felodipine, absent in PAA), embedded in a PAA-rich continuous phase [rests on: R9, R10, R6] | p.2066, p.2070 |

## 2012 Eerdenbrugh — Nanoscale Mid-Infrared Evaluation of the Miscibility Behavior of Blends of Dextran or Maltodextrin with Poly(vinylpyrrolidone) · Characterization methods / Solid-state methods

[2012-van-eerdenbrugh-nanoscale-mid-ir-dextran-maltodextrin-pvp-miscibility](../../../cards/2012-van-eerdenbrugh-nanoscale-mid-ir-dextran-maltodextrin-pvp-miscibility/paper.html) · Characterization methods / Solid-state methods · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R9 | record, measured | topography — DEX450-PVP90 film, colour scale 0-500 nm, scale bar 10 µm — domain running horizontally through the centre higher (thicker) than the domains above and below; smaller domains of the other phase within both large domains, most visible in the thinner top and bottom domains (arrow); 20 marked positions about 2.5 µm apart: 7 in the thinner domains (4 top, 3 bottom), 13 in the central thicker domain (counted on Fig. 3A) | Fig. 3A, p.1463; text p.1463-1464 |
| R12 | record, measured | topography — DEX450-PVP25 film, colour scale 0-750 nm, scale bar 10 µm — thickest domain runs centrally, thinner domains above and below; smaller domains within both phases, less distinct than in DEX450-PVP90; 10 marked positions about 4 µm apart: 6 in the thinner domains (2 top, 4 bottom), 4 in the central thicker domain (counted on Fig. 4A) | Fig. 4A, p.1463; text p.1464 |
| R14 | record, measured | topography — DEX450-PVP12 film; Fig. 5A 50 × 30 µm area, colour scale 0-200 nm; Fig. 5B 5 × 3 µm area, 0-100 nm — submicrometer-sized discrete domains, lower (thinner), dispersed in a thicker continuous phase; domain diameters in Fig. 5B ≈0.2-0.7 µm (read against the 1 µm scale bar) | Fig. 5A-B, p.1464; text p.1464 |
| R16 | record, measured | topography — DEX40-PVP90 film, colour scales 0-250 nm, scale bars 10, 5 and 1 µm — discrete domains of about 5 to 10 µm diameter, higher (thicker), in a thinner continuous phase (Fig. 6A-B); smaller discrete domains of about a few hundred nanometers to a few micrometers in the continuous phase (Fig. 6B-C); 10 marked positions about 2.5 µm apart: 6 in the continuous phase, 4 on discrete domains (counted on Fig. 6B) | Fig. 6A-C, p.1465; text p.1465 |
| R19 | record, measured | topography — DEX6-PVP90 film, colour scales 0-75 nm, scale bars 10 and 1 µm — discrete domains (higher) distributed in a thinner continuous phase; domain diameters ≈0.3-0.6 µm (read from Fig. 8B); features in the centre and lower right-hand corner of Fig. 8B are artifacts from sample damage by the cantilever (caption) | Fig. 8A-B, p.1466; text p.1465, p.1467 |
| R22 | record, measured | topography — DEX40-PVP12 film; Fig. 9A colour scale 0-750 nm, scale bar 10 µm; Fig. 9B 0-500 nm, 1 µm — discrete domains (lower, thinner) dispersed in a thicker continuous phase; the domain in Fig. 9B ≈1.5-2 µm across, dark domains in Fig. 9A ≈0.4-1.8 µm (read against the scale bars); 10 marked positions about 0.5 µm apart: 4 in the domain, 6 in the continuous phase (counted on Fig. 9B) | Fig. 9A-B, p.1467; text p.1467 |
| C35 | claim, conclusion, authors: DSC: "appears"; AFM: "suggesting" | DEX6-PVP90 is more miscible and appears completely miscible at 50/50 by DSC, but AFM contradicts this and suggests some immiscibility at this composition [rests on: R1.c, R19] | p.1465, p.1467 |

## 2013 Wegiel — Mid-infrared spectroscopy as a polymer selection tool for formulating amorphous solid dispersions · Solid state stability / Miscibility and drug-polymer interactions

[2013-wegiel-mid-ir-polymer-selection-polyphenol-asd-stability](../../../cards/2013-wegiel-mid-ir-polymer-selection-polyphenol-asd-stability/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · used · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| C42 | claim, mechanism, authors: "Possible explanations" | Possible explanations for the unexpectedly good high-humidity stability of the polyphenol-PVP dispersions are suppression of moisture sorption by strong polyphenol-polymer hydrogen bonds, or absence of amorphous-amorphous phase separation because the flavonoids are more hydrophilic; strong hydrogen bonding suppressed moisture uptake for resveratrol [rests on: R9.b, R9.h, R16; cited: refs 49, 50] | p.10 |

## 2013 Wegiel — Crystallization of Amorphous Solid Dispersions of Resveratrol during Preparation and Storage—Impact of Different Polymers · Solid state stability / Physical stability

[2013-wegiel-resveratrol-asd-polymer-crystallization-stability](../../../cards/2013-wegiel-resveratrol-asd-polymer-crystallization-stability/paper.html) · Solid state stability / Physical stability · used · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| C36 | claim, mechanism, authors: "Possible explanations" | Possible explanations for the high-humidity stability of the PVP dispersions are suppression of moisture sorption by strong drug-polymer hydrogen bonds or absence of amorphous-amorphous phase separation owing to the greater hydrophilicity of resveratrol [rests on: cited: refs 40, 41] | p.182-183 |

## 2015 Purohit — Miscibility of Itraconazole-Hydroxypropyl Methylcellulose Blends- Insights with High Resolution Analytical Methodologies · Solid state stability / Miscibility and drug-polymer interactions

[2015-purohit-itraconazole-hpmc-miscibility-high-resolution-methods](../../../cards/2015-purohit-itraconazole-hpmc-miscibility-high-resolution-methods/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R6 | record, measured | fluorescence micrographs of pyrene-containing films — 10:90 film shown (Fig. 3); excitation 330-380 nm, emission from 420 nm (P4) — before heating: discrete bright domains of ≈1 µm (read from Fig. 3a, scale bar 20 µm) on a darker continuous phase; text: similar images for all ratios. After heating at 165 °C: more uniform intensity with faint residual spots (Fig. 3b) | Fig. 3, p.21; text p.11-12 |
| R10 | record, measured | AFM topography of films before heating; domain size — films 10:90 to 50:50 on ZnSe (P9); 40:60 film for nanoTA (P10) — text: phase-separated domains at all ratios; discrete domains of 500-1000 nm in a continuous phase. Figure readings: round raised domains (bright) in a darker continuous matrix; diameters ≈0.4-1.0 µm in 10:90 to 30:70 (Fig. 6a-c), ≈0.5-1.4 µm in 40:60 (Fig. 6d), ≈0.7-1.0 µm in 50:50 (Fig. 6e, 2.5 µm scan), ≈0.5-1.5 µm in the 20 µm scan of 40:60 (Fig. 8) (read from scale bars) | Figs. 6, 8, p.24-25, p.28; text p.13-14 |
| R11 | record, measured | nanoIR spectra (1600-1800 cm⁻¹) at marked points before heating — blue markers on domains, red markers on the continuous phase (P9) — sub-table below; text: domain spectra show the ITZ carbonyl peak; continuous-phase spectra lack it or show a very low signal | Fig. 6, p.24-25; text p.13 |
| R14 | record, measured | AFM topography and nanoIR chemical image at 1700 cm⁻¹ — 30:70 film, 10 × 10 µm; height scale -500 to 500 nm; chemical image -0.1 to 0.1 V — red ITZ-rich round domains of ≈1.5-2.5 µm (read from the graphic) in a blue ITZ-lean continuous phase; raised domains in topography coincide with the red regions | TOC graphic, p.39 |
| C36 | claim, conclusion, authors: discussion: asserted ("clearly indicate"); abstract: "phase separation was observed"; conclusions: DSC "provided ambiguous results" | ITZ and HPMC are phase separated over 10-50% drug loading when prepared by solvent removal and examined by fluorescence spectroscopy or AFM-IR, while DSC did not show clear evidence of phase separation [rests on: R1, R6, R10, R11, R7] | p.2; p.14; p.19 |
| C37 | claim, conclusion, authors: discussion: asserted ("reveals"); abstract: "indicated" (sub-micron scale); conclusions: asserted | The lower-viscosity component ITZ forms discrete drug-rich domains of 500-1000 nm in a drug-lean (HPMC) continuous phase; a lower-viscosity phase forming discrete domains was reported before [rests on: R10, R11, R13; cited: ref 40] | p.2; p.14; p.19 |

## 2015 Purohit — Phase Separation Kinetics in Amorphous Solid Dispersions Upon Exposure to Water · Characterization methods / Solid-state methods

[2015-purohit-phase-separation-kinetics-asd-water](../../../cards/2015-purohit-phase-separation-kinetics-asd-water/paper.html) · Characterization methods / Solid-state methods · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R4 | record, measured | prodan emission maximum versus time at 97% RH (error bars shown; n not stated) — 50:50 and 20:80 PB–PVP spin-coated films with prodan (P1, P5); references at time 0: amorphous PB ≈418 nm, PVP ≈451 nm (read from Fig. 3) — sub-table below; text: 50:50 starts at 437 nm (PVP 451 nm, amorphous probucol 418 nm), falls to a minimum of 425 nm, rises sharply after 21 h to a final 435 nm; 20:80 follows a similar course from a higher start; time axis is categorical (unequal spacing) | Fig. 3, p.23; text p.11-12 |
| R6 | record, measured | pyrene I/III versus time at 97% RH (error bars shown; n not stated) — 20:80, 50:50 and 80:20 RTV–PVP films with pyrene (P1, P5); references at time 0: amorphous RTV ≈1.30, PVP ≈1.81 (read from Fig. 5) — sub-table below; text: 50:50 starts between the pure-component values, drops at the shortest exposure times and plateaus at 1.30, very close to pure ritonavir; no crystallization seen during the experiment; same trend at all three ratios with different extent; pyrene chosen for RTV–PVP as it gave a greater response than other dyes (data not shown) | Fig. 5, p.24; text p.12 |
| R7 | record, measured | fluorescence micrographs (40X objective) — 80:20 RTV–PVP film with pyrene before and after 97% RH (P9); exposure time not stated — before: uniform, low signal over the whole field; after: many bright, roughly round domains of a few micrometres (≈5 µm, read against the 100 µm scale bar) with dark domain-free areas; text: probe concentrated in certain regions of the film | Fig. 6, p.25; text p.12-13 |
| R10 | record, measured | prodan emission maximum of the undissolved film versus immersion time (error bars shown; n not stated) — 50:50 PB–PVP film in 100 mM pH 6.8 phosphate buffer (P6); references: amorphous PB ≈418 nm, PVP ≈451 nm (read from Fig. 8a) — 0: ≈437; 10 s: ≈428 (error bar ≈424 to ≈431); 1 min: ≈424; 2 min: ≈424; 3 min: ≈422.5; 5 min: ≈422; 7 min: ≈421.5; 10 min: ≈421.5; 15 min: ≈423; 20 min: ≈423; 30 min: ≈424.5 nm (all read from Fig. 8a); text: immediate decrease after immersion, shifts to lower values until most of the film has dissolved and the probe signal disappears; final peak around 425 nm, the same as after 97% RH | Fig. 8a, p.27; text p.13 |
| R11 | record, measured | pyrene I/III of the undissolved film versus immersion time (error bars shown except at 2 and 30 min; n not stated) — 50:50 RTV–PVP film in 100 mM pH 6.8 phosphate buffer (P6); references: amorphous RTV ≈1.29, PVP ≈1.81 (read from Fig. 8b) — 0: ≈1.565; 10 s: ≈1.49; 1 min: ≈1.51; 2 min: ≈1.50; 3 min: ≈1.485; 5 min: ≈1.47; 7 min: ≈1.51; 10 min: ≈1.455; 15 min: ≈1.445; 20 min: ≈1.405; 30 min: ≈1.29 (all read from Fig. 8b); text: final pyrene peak ratio 1.3 | Fig. 8b, p.27; text p.13 |
| R17 | record, measured | carbonyl-region IR spectra — 80:20 RTV–PVP film on KRS-5 before and after 97% RH, dried before measurement (P10); amorphous RTV and PVP references; exposure time not stated — text: dry amorphous RTV carbonyl peaks at 1630 and 1717 cm-1; dry PVP carbonyl at 1681 cm-1; unexposed ASD shows a new peak at 1654 cm-1 (arrow); after exposure the 1654 cm-1 feature is absent and peaks at 1630 and 1717 cm-1 and at 1681 cm-1 are present. Figure: exposed ASD spectrum has maxima at ≈1678 and ≈1632 cm-1 with a shoulder near ≈1705 cm-1 and a minimum near ≈1652 cm-1 (read from Fig. 11) | Fig. 11, p.30; text p.14-15 |
| R19 | record, measured | reversing heat flow (modulated DSC) — amorphous PB (melt-quenched), PB–PVP K90 bulk ASD (ratio not stated) before and after 6 h and 30 h at 97% RH, dried under nitrogen (P3, P12) — text: single Tg before exposure; two Tg events after 6 h; after 30 h a Tg at 25 °C matching amorphous PB and an endotherm close to the melting point of crystalline PB. Figure (read from Fig. 13): amorphous PB step ≈23-32 °C (midpoint ≈27 °C); dry ASD one step ≈130-150 °C; 6 h steps near ≈40 °C and ≈100 °C; 30 h step ≈23-32 °C (inset 4a), a maximum near ≈114 °C and a large endotherm running off scale between ≈122 and ≈145 °C | Fig. 13, p.32; text p.15 |
| R20 | record, measured | reversing heat flow (modulated DSC) — amorphous RTV (melt-quenched), RTV–PVP K90 bulk ASD (ratio not stated) before and after moisture exposure (time not stated) (P3, P12) — text: single Tg before exposure; after exposure two Tgs with midpoints of 50 °C and 140 °C; no crystallization over the experiments. Figure (read from Fig. 14): amorphous RTV step ≈41-54 °C (midpoint ≈48 °C); dry ASD one step ≈79-104 °C (midpoint ≈94 °C); exposed ASD steps ≈40-54 °C and ≈120-150 °C | Fig. 14, p.33; text p.15-16 |
| C25 | claim, conclusion, authors: "strongly suggest"; "It is reasonable to expect"; "would be expected" | The immersion results strongly suggest that PB–PVP and RTV–PVP undergo AAPS in the film as it hydrates during dissolution; this is reasonable to expect because both separate at high RH by fluorescence, IR and DSC, and bulk water would be expected to induce the same changes with faster kinetics, as observed [rests on: R10, R11, R16, R4, R6, R17, R19, R20] | p.17-18 |
| C35 | claim, conclusion, authors: asserted ("were found"; "in good agreement") | Environment-sensitive probes are a new approach to monitor phase transformations in an ASD matrix during hydration from atmospheric or bulk water; they were found sensitive to hydration, moisture-induced AAPS and drug crystallization; the fluorescence results agree well with the complementary techniques [rests on: R4, R6, R10, R11, R13, R14, R17-R22] | p.2, p.20 |

## 2016 Li — Nanoscale Infrared, Thermal, and Mechanical Characterization of Telaprevir-Polymer Miscibility in Amorphous Solid Dispersions Prepared by Solvent Evaporation · Solid state stability / Miscibility and drug-polymer interactions

[2016-li-telaprevir-polymer-miscibility-nanoscale-afm-ir](../../../cards/2016-li-telaprevir-polymer-miscibility-nanoscale-afm-ir/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R4 | record, measured | topography versus DL — TPV-HPMC films 1:9 to 5:5 (P1, P2), contact mode, 4 x 2 µm — text: discrete domains present at 10% DL; height features larger as DL increases; from 40% to 50% DL domains more irregular in shape and less uniform in size; domain height about 30 nm at 50% DL. Figure colour scales ±10 nm (1:9), ±25 nm (2:8 to 4:6), ±50 nm (5:5) | Fig. 3A, p.37; text p.13 |
| R6 | record, measured | topography versus DL — TPV-PVPVA films 1:9 to 5:5 (P1, P2); contact mode at 10-20% DL, tapping mode at 30-50% DL; 5 x 2.51 µm (1:9, 2:8), 4 x 2 µm (3:7 to 5:5) — text: discrete domains present at 10% DL; spacing between domains decreases as DL increases; surface rougher; domain diameter about 280 nm at 10% DL and 380 nm at 50% DL; domain height about 20 nm at 10% DL and 100 nm at 50% DL. Figure colour scales ±25, ±50, ±100, ±200 and ±100 nm for 1:9 to 5:5 | Fig. 3C, p.37; text p.13-14 |
| R8 | record, measured | local AFM-IR spectra of continuous and dispersed phases — 60:40 TPV-HPMC (P4), n = 4 per phase; the discrete domains are the higher regions of the height image (±25 nm, 4 x 2 µm) — continuous phase: 1450 cm-1 band of comparable intensity to the 1525 cm-1 band; dispersed phase: 1450 cm-1 band considerably weaker than the 1525 cm-1 band; characteristic TPV and HPMC bands present in both phases | Fig. 4A, p.38; text p.15 |
| R13 | record, measured | AFM-IR, ratio and contact-resonance frequency images — 60:40 TPV-HPMC (P5); 4 x 4.01 µm; scales: height ±50 nm, IR ±0.2 V, ratio ±0.5, frequency ±7.5 kHz — 1525 cm-1 image matches the topography, with higher TPV signal on the raised discrete domains; 1457/1525 cm-1 ratio image higher in the continuous phase; frequency image: discrete drug-rich domains red (higher frequency), surrounding polymer blue | Fig. 6A, p.40; text p.18-19 |
| R16 | record, measured | nanoTA softening temperature (°C, mean ± SD) — pure-component films and phase-separated films (P7) — sub-table below | Table 2, p.46; Fig. 7, p.41; text p.19-21 |
| R19 | record, measured | LCR images at two frequencies — 60:40 TPV-HPMC (P8); 4 x 4.01 µm; height ±50 nm; LCR ±0.4 V (128 kHz), ±0.1 V (123 kHz) — at 128 kHz the discrete domains give the stronger signal (more yellow); at 123 kHz the continuous phase gives the stronger signal; some small discrete regions (red circles) give the polymer-type LCR response and weak 1525 cm-1 absorbance in Fig. 6A; smallest height feature discriminated (blue circles) around 98 nm in diameter | Fig. 9A, p.43; text p.22, p.26 |
| R22 | record, measured | pyrene fluorescence images — films on quartz (P9); scale bars 100 µm (A-C), 50 µm (D) — pure HPMCAS film: even fluorescence, no heterogeneity; 60:40 TPV-HPMC, 80:20 TPV-HPMCAS and 50:50 TPV-PVPVA: dispersed phase brighter than the continuous phase; lower-DL films not imaged (domains below the optical diffraction limit) | Fig. 10, p.44; text p.23 |
| C23 | claim, conclusion, authors: asserted ("confirming") | The ratio images match the topography, confirming phase separation, and the continuous phase is polymer-rich [rests on: R13-R15] | p.18 |
| C54 | claim, conclusion, authors: asserted | The drug-rich phase forms discrete domains from below 50 nm to a few hundred nanometres, depending on the system, in a polymer-rich continuous phase; such information is essential to relate microstructure to product performance [rests on: R4-R10, R13-R15, R22] | p.3, p.29 |

## 2016 Tian — Investigating the Correlation between Miscibility and Physical Stability of Amorphous Solid Dispersions Using Fluorescence-based Techniques · Solid state stability / Physical stability

[2016-tian-indomethacin-polymer-miscibility-physical-stability-fluorescence](../../../cards/2016-tian-indomethacin-polymer-miscibility-physical-stability-fluorescence/paper.html) · Solid state stability / Physical stability · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R2 | record, measured | normalized emission spectra and emission maximum versus DL (mean, n = 3) — IDM-HPMC films 5-95% DL, fresh (P1, P3) — text: for 5%~50% DL the emission maximum (~515 nm) did not change significantly, with a slight decrease with increasing DL; between 50 and 60% DL a new peak appears around 480 nm, similar to that of pure IDM, and a shoulder remains at ~515 nm. Fig. 3A: 5-50% DL one band with maximum ≈510-515 nm; 60, 70 and 80% DL maximum ≈480-485 nm with a shoulder near ≈510 nm; 90 and 95% DL maximum ≈478 nm. Fig. 3B: sub-table below | Fig. 3, p.9; text p.7-8 |
| R7 | record, measured | fluorescence images of fresh films — IDM-HPMC films 5-95% DL (P1, P4); scale bar 20.0 µm — text: intensity homogeneous at 5%~50% DL; heterogeneous at 60% DL or higher, with green and dark domains. Figure: 5% uniform blue; 10% uniform teal; 20% and 50% uniform green; 30% and 40% green with sparse small dark irregular spots; 60% fine bright speckle; 70% clusters of dark spots; 80% large dark domains a few tens of µm across; 90% dense dark domains separated by green bands; 95% fine dark pits over the whole field | Fig. 6, p.11-12; text p.10-11 |
| R8 | record, measured | fluorescence images of fresh films — IDM-HPMCAS films 5-95% DL (P1, P4); scale bar 20.0 µm — text: 5% and 10% homogeneous; 20% reasonably homogeneous; some heterogeneity at 30%; phase separation obvious at higher DL. Figure: 5% blue and 10% teal, uniform; 20% green with dark branched features along lines in part of the field; 30% extensive dark branched network; 40% and 50% dark speckled bands; 60% and 70% dark domains tens of µm across in a green matrix; 80% and 90% interconnected green and dark pattern; 95% finer interconnected pattern | Fig. 7, p.12; text p.11 |
| R9 | record, measured | fluorescence images of fresh films — IDM-PVP films 5-95% DL (P1, P4); scale bar 20.0 µm — text: obvious heterogeneity at 70% DL and higher. Figure: 5% and 10% uniform blue; 20-50% uniform green; 60% uniform green crossed by a network of thin dark lines; 70% dark specks and streaks; 80-95% mottled green and dark texture, finer at higher DL | Fig. 8, p.13; text p.11 |
| C16 | claim, conclusion, authors: "suggests"; "indicating"; "is attributed to" | The ~480 nm peak appearing at 60% DL in HPMC resembles pure IDM and places part of the IDM in an IDM-rich environment, while the ~515 nm shoulder shows a population still in the polymer environment; the new peak is attributed to phase separation and an IDM-rich, less polar phase [rests on: R2, R1] | p.8 |
| C21 | claim, conclusion, authors: "indicating"; "are expected to be"; "are thought to be"; "suggest"; "appears" | IDM-HPMC films are homogeneous at 5-50% DL (IDM uniformly dispersed); at 60% and above green domains are an IDM-rich phase and dark domains an HPMC-rich phase, so phase separation has occurred; miscibility is exceeded at around 60% DL [rests on: R7] | p.10-11 |
| C22 | claim, conclusion, authors: "indicating"; "reasonably"; "obvious"; "appears" | IDM-HPMCAS films are miscible at 5% and 10%, reasonably homogeneous at 20%, somewhat heterogeneous at 30% and clearly phase separated above; miscibility is limited to around 20% DL [rests on: R8] | p.11 |
| C23 | claim, conclusion, authors: "indicating" | IDM-PVP films show obvious heterogeneity, read as phase separation, at 70% DL and above [rests on: R9] | p.11 |

## 2017 Indulkar — Origin of Nanodroplet Formation upon Dissolution of an Amorphous Solid Dispersion: A Mechanistic Isotope Scrambling Study · Dissolution / A. Release mechanism and LoC

[2017-indulkar-origin-nanodroplet-formation-asd-isotope-scrambling](../../../cards/2017-indulkar-origin-nanodroplet-formation-asd-isotope-scrambling/paper.html) · Dissolution / A. Release mechanism and LoC · used · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| C7 | claim, prior hypothesis, authors: asserted | Two mutually exclusive mechanisms have been proposed (Fig. 1). Mechanism I (refs 12, 19, 20): drug and polymer leave the ASD congruently or nearly so, dissociate in the stagnant layer or bulk, and drug above the amorphous solubility precipitates as amorphous nanodroplets. Mechanism II (ref 21): water ingress causes AAPS in the hydrated matrix, giving nano-sized drug-rich domains in a continuous polymer phase; polymer dissolves faster than drug and the domains are released as nanodroplets, some of which dissolve until the amorphous solubility is reached. Both end with nanodroplets in equilibrium with a solution at the amorphous solubility [rests on: cited: refs 12, 19-21] | pdf p.6-7 |
| C33 | claim, mechanism, authors: asserted ("will") | If a drug-rich layer forms at the interface, for example by AAPS in the hydrated matrix, the drug controls release, release slows because the polymer carrier effect is lost, the drug concentration can reach only the amorphous solubility and an equilibrium with undissolved amorphous drug eventually results; nanodroplets via mechanism I form only when the amorphous solubility is exceeded [rests on: argument only] | pdf p.17-18 |
| C38 | claim, generalisation, authors: "are expected" | AAPS depends on drug–polymer miscibility in the presence of water, set by the balance of drug, polymer and water interactions, and varies with drug, polymer type and composition; drug–PVPVA ASDs that dissolve rapidly while staying miscible in water are expected to form nanospecies via mechanism I [rests on: cited: refs 46-48; argument only] | pdf p.20 |

## 2017 Li — Understanding the impact of water on the miscibility and microstructure of amorphous solid dispersions – An AFM/LCR and TEM/EDX study · ASD process / ASD process

[2017-li-water-miscibility-microstructure-asd-afm-tem-edx](../../../cards/2017-li-water-miscibility-microstructure-asd-afm-tem-edx/paper.html) · ASD process / ASD process · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R3 | record, measured | AFM surface topography, 5 µm × 5 µm images — ECP-HPMC films from 50:50 MeOH:DCM, 50 mg/mL (P4), spun at 18, 35 or 50% RH (P5), 10-90% DL — sub-table below; text: no surface features at 18% RH for 10-90% DL; at 35% RH small round discrete domains at 30% DL and above, larger and taller with DL, height about 50 nm at 50% DL to 120 nm at 90% DL; at 50% RH discrete round domains at all DL, diameter and height increasing with DL from 10 to 90% | Fig. 2, p.16-17; text p.14 |
| R12 | record, measured | AFM topography of films from water-spiked stock — ECP-HPMC, binary solvent, 50 mg/mL, water added into 1 mL stock, spun at 18% RH; 10% and 50% ECP — sub-table below; text: all stock solutions transparent after water addition, no precipitate before spin coating; phase separation at 20 µL water for 50% DL; domain size larger with more water and, at constant water, with higher DL | Fig. 4, p.21; text p.19 |
| R18 | record, measured | TEM microstructure, films phase separated during preparation — ECP-PVPVA spun at 50% RH from methanol at 5 mg/mL, 10-90% DL — sub-table below; text: spherical discrete domains, size increasing with DL; at 80 and 90% DL three features: dark spherical particles, a dark net-like shade in the background and light holes in the background | Fig. 8A, p.29; text p.26 |
| R19 | record, measured | TEM microstructure, initially miscible films after humid storage — ECP-PVPVA spun at 18% RH, stored at 97% RH for 7 days, vacuum dried 2 days, 10-90% DL — sub-table below; text: net-like structures at 10-80% DL, 90% DL homogeneous; irregular domains at 10-30%; regular round discrete features homogeneously distributed at 40-80%, holes smaller with higher DL | Fig. 8B, p.29; text p.26 |
| R24 | record, measured | glass transition temperature (°C) by modulated DSC versus DL — bulk ECP-PVPVA ASDs (P12): fresh, and after 24 h at 97% RH then 2 days vacuum drying (P13); n and error-bar meaning not stated — sub-table below; text: all fresh ASDs one Tg, decreasing with DL; after storage two Tgs at 10-50% DL, one Tg at 60-90% DL; representative stored traces in Fig. S8 | Fig. 10A, p.31; Fig. S8, SI p.11; text p.28 |
| C32 | claim, conclusion, authors: abstract: asserted ("It was found"); discussion: "clearly indicate" | The phase behaviour of ECP-HPMC and ECP-PVPVA is very susceptible to water, an anti-solvent for ECP, which causes phase separation by two routes: solution-state separation during preparation and solid-state separation during storage at high RH [rests on: R3, R12, R18, R19, R24] | p.3, p.31 |

## 2017 Mugheirbi — Insights into Water-Induced Phase Separation in Itraconazole–Hydroxypropylmethyl Cellulose Spin Coated and Spray Dried Dispersions · ASD process / ASD process

[2017-mugheirbi-water-induced-phase-separation-itz-hpmc-asd](../../../cards/2017-mugheirbi-water-induced-phase-separation-itz-hpmc-asd/paper.html) · ASD process / ASD process · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R5 | record, measured | BF TEM of 30:70 E3 film made at 40% RH — P1.a, P9 — discrete domains around 250 nm in diameter (text) embedded in an inhomogeneous continuous phase; each domain surrounded by a ring (donut-like appearance) | Fig. 3a, p.4392; text p.4393 |
| R7 | record, measured | HAADF STEM of the R5 film — P1.a, P9 — continuous phase shows an interconnected network of bright and dark regions (200 nm scale bar) | Fig. 3b, p.4392; text p.4393 |
| R8 | record, measured | EDX N and O content (% w/w) of dark and light HAADF regions — R7 film; ≥3 areas per region type, each ≥100 nm; remainder reported as carbon; error-bar type not printed — sub-table R8; text: N relatively abundant in light HAADF (dark BF) regions, O relatively abundant in dark HAADF (light BF) regions | Fig. 3b inset, p.4392; text p.4393 |
| R17 | record, measured | topography and LCR image of the 7% RH E3 film after storage — P1.c film, P13, then 24 h vacuum, imaged at 19% RH; 10 × 10 μm; LCR at 140 kHz — not flat; no discrete spherical domains; irregular network-like structure with submicron surface corrugations (height colour scale ±100 nm); LCR amplitude shows two interpenetrating levels, red labelled ITZ-rich and blue labelled HPMC-rich; polymer-rich areas topographically higher than drug-rich areas | Fig. 6b,c, p.4395; text p.4394 |
| C13 | claim, conclusion, authors: "seem to be encapsulated"; "supporting the above supposition" | The discrete drug-rich domains are encapsulated by polymer in a donut-like structure; the thinner ring of the 50:50 film, with less polymer, supports this. [rests on: R5, R6] | p.4393 |
| C15 | claim, conclusion, authors: "suggesting"; "consistent with" | Light HAADF (dark BF) regions are richer in drug and dark HAADF (light BF) regions richer in polymer, so the continuous phase shows biphasic drug–polymer segregation rather than thickness variation alone; this inhomogeneity was not seen before in this system. [rests on: R7, R8, R9] | p.4393 |
| C26 | claim, conclusion, authors: asserted ("was found to phase separate") | The film made miscible at 7% RH phase separated after 24 h storage at elevated humidity, with ITZ-rich and HPMC-rich regions. [rests on: R17] | p.4394; p.4399 |

## 2017 Purohit — Insights into Nano- and Micron-Scale Phase Separation in Amorphous Solid Dispersions Using Fluorescence-Based Techniques in Combination with Solid State Nuclear Magnetic Resonance Spectroscopy · Characterization methods / Solid-state methods

[2017-purohit-itraconazole-hpmc-asd-phase-separation-fluorescence-ssnmr](../../../cards/2017-purohit-itraconazole-hpmc-asd-phase-separation-fluorescence-ssnmr/paper.html) · Characterization methods / Solid-state methods · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R7 | record, measured | pyrene I1/I3 peak ratio (Table I, sub-table below) — ITZ alone, HPMC alone and 40:60 ASDs, excitation 332 nm (P9) — rows a–e below; standard deviations ≤0.02 for all samples; n not printed | Table I, pdf p.6; Results, pdf p.6 |
| R16 | record, measured | confocal distribution of probes, slow-evaporation film — 40:60 film cast on quartz, prodan + R6G, excitation 407 and 561 nm (P3, P10) — R6G signal mainly in the continuous phase, with dark unstained areas; prodan signal in discrete circular domains, large areas unstained; drug-rich (prodan) domains around 5 μm (text pdf p.7) and ~3–5 μm (text pdf p.11); larger prodan regions made of smaller aggregates (circled in Fig. 8); scale bar 20 μm | Fig. 8, pdf p.8; Results, pdf p.7; Discussion, pdf p.11 |
| R17 | record, measured | confocal distribution of probes, spin-coated film — 40:60 spin-coated film, prodan + R6G (P2, P10) — same distribution as R16 (prodan in discrete domains, R6G in continuous phase); drug-rich domains 1 μm (text pdf p.7) and ~400 nm–1 μm (text pdf p.11) | Fig. 8, pdf p.8; Results, pdf p.7; Discussion, pdf p.11 |
| R21 | record, measured (T1, T1rho); derived (Δ by subtraction; domain size by E2) | 1H T1 and T1rho of ITZ and HPMC with spin-diffusion domain-size ranges (Table II, sub-table below) — SD ASD and film-cast ASD (P11, P12) — rows a–b below; averages of a few resolved peaks; standard errors in parentheses; the Miscibility column is given as claims C20 and C21 | Table II, pdf p.9 |
| C8 | claim, conclusion, authors: Results: indicates; Conclusions: asserted ("demonstrated") | All ASD samples are phase separated regardless of the evaporation rate used; solvent-evaporated ITZ–HPMC ASDs form discrete drug-rich domains. [rests on: R7, R9, R16, R17] | Results, pdf p.6; Conclusions, pdf p.12 |
| C13 | claim, conclusion, authors: Results: "Thus it is clear"; Discussion: asserted ("clearly demonstrate") | In the films, the discrete phase is drug-rich (prodan) and the continuous phase is polymer-rich (R6G), in both cast and spin-coated films. [rests on: R16, R17, R19] | Results, pdf p.7; Discussion, pdf p.11; Fig. 8, pdf p.8 |

## 2017 Purohit — Phase Behavior of Ritonavir Amorphous Solid Dispersions during Hydration and Dissolution · Dissolution / A. Release mechanism and LoC

[2017-purohit-ritonavir-asd-hydration-dissolution-phase-behavior](../../../cards/2017-purohit-ritonavir-asd-hydration-dissolution-phase-behavior/paper.html) · Dissolution / A. Release mechanism and LoC · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R2 | record, measured | pyrene I/III ratio in films versus time at 97% RH — spin-coated films with pyrene (P6, P8), 10:90 to 50:50 RTV:polymer, and pure amorphous RTV and pure polymer films — sub-table below; text: I/III of fresh ASD films lies between pure drug and pure polymer and varies with DL; PVP and PVPVA ratios fall with time toward the pure amorphous RTV value; ~1.30 at the end of day 3 in all PVP and PVPVA films except 10% DL; HPMCAS ratios without significant change | Fig. 2, pdf p.7; text pdf p.7, p.15 |
| R3 | record, measured | confocal fluorescence of films after 97% RH (nile red, excitation 561 nm) — 10:90 and 50:50 films of each polymer (P6, P9); time at 97% RH not printed — caption: fresh films uniformly fluorescent before exposure. After exposure: PVP 10:90 densely packed bright domains about 1 µm across with a few dark holes several µm wide; PVP 50:50 bright interconnected domains with dark gaps; PVPVA 10:90 discrete bright round domains about 1-3 µm on a dark background; PVPVA 50:50 dense bright interconnected domains with dark gaps; HPMCAS 10:90 and 50:50 uniform red without discernible domains (domain sizes read against the 5 µm scale bars) | Fig. 3, pdf p.8; text pdf p.8 |
| R4 | record, measured | confocal fluorescence of films after 10 s in dissolution medium, dried — RTV-PVP 10:90 and 50:50 films (P9) — 10:90 uniformly fluorescent; 50:50 bright continuous phase with many dark domains of about 1-3 µm (read against the 5 µm scale bar). Text: similar behaviour for PVPVA ASDs; HPMCAS 10% and 50% DL films uniform after exposure (images not shown) | Fig. 4, pdf p.9; text pdf p.8 |
| R5 | record, measured | AFM topography before and after 97% RH for 4 days — 10:90 films on ZnS (P10) — PVP before: featureless, 5 x 5 µm scan, height scale ±10 nm; PVP after: raised discrete domains in a 20 x 20 µm scan, height scale ±150 nm; PVPVA before: featureless, 5 x 5 µm, ±7.5 nm; PVPVA after: larger raised domains in a 20 x 20 µm scan, ±150 nm; HPMCAS before: mottled, 5 x 5 µm, ±50 nm; HPMCAS after: fine texture, 5 x 5 µm, ±7.5 nm. Text: discrete domain sizes of 5-10 µm in PVP and PVPVA films | Fig. 5, pdf p.9; text pdf p.16 |
| R6 | record, measured | glass transitions in reversing heat flow after 97% RH for 24 h and drying — bulk ASD powders 10:90 to 50:50 (P4, P11) — sub-table below; text: two Tgs in RTV-PVP and RTV-PVPVA ASDs (RTV-rich and polymer-rich phase); one Tg in RTV-HPMCAS ASDs, unchanged after moisture exposure; all freshly prepared ASDs showed a single Tg (data in SI, not supplied) | Fig. 6, pdf p.10; text pdf p.10, p.16 |
| R9 | record, measured | SEM of film surfaces after 10 s in dissolution medium, dried — 50:50 and 10:90 films of each polymer (P13) — PVP 50:50 rough porous network texture; PVPVA 50:50 granular surface with many sub-µm to µm features; PVP 10:90 smooth; PVPVA 10:90 smooth with two isolated spheres under 1 µm; HPMCAS 50:50 smooth; HPMCAS 10:90 smooth with scattered small particles. Text: phase separation or inhomogeneity in 50% DL RTV-PVP and RTV-PVPVA; all 10% DL ASDs and 50% DL RTV-HPMCAS uniform | Fig. 8, pdf p.12; text pdf p.10, p.18 |
| C1 | claim, conclusion, authors: abstract: asserted; discussion: "multiple orthogonal analytical approaches suggest" | All RTV-PVP and RTV-PVPVA ASDs underwent moisture-induced AAPS on high-RH storage, whereas RTV-HPMCAS ASDs remained miscible [rests on: R2, R3, R5, R6] | pdf p.1, p.16 |
| C22 | claim, mechanism, authors: results: "can be interpreted as follows", "indicates"; discussion: "clearly apparent", "indicating" | Fig. 2 means that PVP and PVPVA ASDs phase separate rapidly after absorbing water at 97% RH: hydrophobic pyrene sits in the drug-rich AAPS domains, whose lower local polymer content lowers I/III; I/III ~1.30 by day 3 (except 10% DL) means pyrene is surrounded mainly by RTV and AAPS is extensive; discussion: all PVP and PVPVA ASDs start AAPS as early as 1 h [rests on: R2] | pdf p.7, p.15 |

## 2017 Saboo — Water-induced phase separation of miconazole-poly (vinylpyrrolidone-co-vinyl acetate) amorphous solid dispersions: Insights with confocal fluorescence microscopy · Solid state stability / Physical stability

[2017-saboo-water-induced-miconazole-pvpva-asd-phase-separation](../../../cards/2017-saboo-water-induced-miconazole-pvpva-asd-phase-separation/paper.html) · Solid state stability / Physical stability · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R6 | record, measured | AFM topography — 50:50 film spin-coated at 60% RH (P1), 5 x 5 µm — discrete, circular domains forming pits in a continuous phase; pit depth around 200-400 nm (text); colour scale -200 to 200 nm; pits ≈0.3-0.7 µm across, merged pit regions up to ≈1.5 µm (read from Fig. 5A) | Fig. 5A, pdf p.28; text pdf p.13 |
| R13 | record, measured | CFM with prodan and R6G — 50:50 film prepared at 60% RH (P1, P9) — approximately circular domains stained blue by prodan; continuous phase stained red by R6G; text (pdf p.19): domains from submicron to few microns after film formation at moderate RH; figure: domains from <1 to ≈15 µm across (read from Fig. 10A scale bar) | Fig. 10, pdf p.30; text pdf p.15, p.19 |
| R15 | record, measured | CFM after 75% RH storage — initially miscible 50:50 film prepared at low RH, stored at 75% RH, RT (P2) — after 7 days: discrete domains stained blue by prodan in a red R6G-stained continuous phase; domains ≈1-3 µm (read from Fig. 11A scale bar); text: no further morphology change for storage up to 4 weeks; results at 1, 2 and 3 days not reported | Fig. 11, pdf p.31; text pdf p.16 |
| R16 | record, measured | AFM topography and AFM-IR maps after 75% RH storage — film of R15 after 1 week, 10 x 10 µm — discrete pits ≈1.5-3 µm across (read from Fig. 12A) in a continuous phase, colour scale -200 to 200 nm; pit regions higher absorption at 1590 cm⁻¹ and lower at 1679 cm⁻¹ (map scales -0.1 to 0.1 V) | Fig. 12, pdf p.31; text pdf p.16 |
| R18 | record, measured | CFM after buffer immersion — initially miscible 50:50 films in pH 6.8 phosphate buffer, then dried (P3); images at 5, 20 and 30 min (10 min not shown) — 5 min: R6G-bright discrete domains ≈4-8 µm (read from Fig. 13) in a prodan-stained matrix; 20 min: large prodan-stained regions, tens of µm, holding small R6G-bright inclusions and separated by R6G-stained continuous regions; 30 min: prodan-stained domains ≈10-25 µm separated by an interconnected R6G-stained network; text: at first the polymer forms a discrete phase in a drug-rich matrix, with time the phases appear more bi-continuous | Fig. 13, pdf p.32; text pdf p.16-17 |
| C42 | claim, mechanism, authors: asserted | The phase separation is induced by water, an antisolvent for hydrophobic miconazole [rests on: R5, R6, R15] | pdf p.19 |

## 2017 Xie — Effect of Temperature and Moisture on the Physical Stability of Binary and Ternary Amorphous Solid Dispersions of Celecoxib · Solid state stability / Physical stability

[2017-xie-temperature-moisture-celecoxib-binary-ternary-asd-stability](../../../cards/2017-xie-temperature-moisture-celecoxib-binary-ternary-asd-stability/paper.html) · Solid state stability / Physical stability · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R18 | record, measured | DSC thermograms of 6:4 ASDs after 3 days at 94% RH, RT, hermetically sealed — P7 — sub-table below; text: in the first heating CEX:PVP/VA, CEX:HPMCAS and CEX:HPMC show a single Tg and the PVP ASDs two distinct Tg values; on reheating a single Tg in all binary dispersions including CEX:PVP | Fig. 7a, p.7; text p.6-7 |
| R19 | record, measured | DSC thermograms of 6:4 ASDs after 3 days at 75% RH, RT, hermetically sealed — P7 — text: water uptake of PVP ASDs substantially lower than at 94% RH; two-Tg evidence less pronounced in CEX:PVP-K12; no two-Tg evidence in CEX:PVP-K29/32 or the other binaries; figure: no arrows; first heating endothermic peaks ≈58 °C (PVP-K12), ≈66 °C (PVP/VA), ≈61 °C (HPMC), ≈61 °C (HPMCAS), a step ≈60-68 °C for PVP-K29/32, a faint change near ≈85 °C in the PVP-K12 trace; second heating one step per trace (read from Fig. 7b) | Fig. 7b, p.7; text p.7 |
| R9 | record, measured | IR of CEX:PVP-K29/32 films after exposure to 94% RH at RT — P4; 3:7 shown (Fig. 4: unexposed, 1 day, 18 days); trends stated as similar for other ratios — text: 3196 cm−1 band decreases and 3268 cm−1 band increases; slight decrease of the 1661 cm−1 C=O shoulder; after 18 days crystallization in the 7:3 CEX:PVP film by spectral change and loss of film transparency on visual inspection; Fig. 4 caption: crystallization observed after 18 days of storage; figure: after 1 and 18 days the strongest N-H feature lies near ≈3335 cm−1 (read from Fig. 4) | text p.4; Fig. 4, p.5 |
| C5 | claim, conclusion, authors: abstract: "appeared to" | Binary and ternary ASDs containing PVP appeared to undergo partial AAPS at 94% RH followed by crystallization, whereas the other binary ASDs crystallized directly without AAPS [rests on: R9, R11, R18, R23] | p.1 |
| C32 | claim, conclusion, authors: "implying"; "suggesting" | After 94% RH the single Tg of CEX:PVP/VA, CEX:HPMCAS and CEX:HPMC implies that water uptake did not cause AAPS, whereas the two Tg values of the PVP ASDs, consistent with IR, suggest that absorbed water partially demixed drug and PVP [rests on: R18, R9] | p.6-7 |
| C35 | claim, conclusion, authors: "appeared less pronounced" | At 75% RH PVP ASDs take up much less water than at 94% RH; moisture-induced AAPS appeared less pronounced in the PVP-K12 ASD and absent in PVP-K29/32 and the other binaries [rests on: R19, R13] | p.7 |

## 2018 Bhardwaj — Surface area normalized dissolution to study differences in itraconazole-copovidone solid dispersions prepared by spray-drying and hot melt extrusion · Dissolution / A. Release mechanism and LoC

[2018-bhardwaj-surface-area-normalized-dissolution-itraconazole-pvpva-asd](../../../cards/2018-bhardwaj-surface-area-normalized-dissolution-itraconazole-pvpva-asd/paper.html) · Dissolution / A. Release mechanism and LoC · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R15 | record, measured | pyrene fluorescence intensity ratio of peak I (373 nm) to peak III (383 nm), average (av) and standard deviation (sd); n not stated — spray-dried samples containing pyrene (P8) — sub-table below | Table 5, p.18-19 |
| R16 | record, measured | TEM appearance of spray-dried particles — (a) ITZ from MeOH-DCM; ITZ-PVPVA 20-80 from (b) MeOH-DCM, (c) MeOH-DCM-water, (d) n-hexane-DCM, (e) n-hexane-DCM at 70 °C outlet, (f) cyclohexane-DCM (P9) — (a)-(c): uniform contrast across the particle, no darker or lighter domains discerned; (d)-(f): small, lighter globular structures that occupy a high volume fraction by eye; scale bars 100 nm (a), 20 nm (b), 50 nm (c), 50 nm (d), 100 nm (e), 0.2 µm (f) | Fig. 9, p.19-20 |
| C35 | claim, conclusion, authors: "indicating"; "suggests" | Similar pyrene I/III ratios across the spray-dried dispersions indicate that pyrene sits in a similar average environment, which suggests that discrete drug-rich and polymer-rich phases are not formed [rests on: R15] | p.19 |
| C37 | claim, conclusion, authors: "suggests"; "can cause" | TEM particles of the reference dispersion look homogeneous with no evidence of phase separation; adding water (which can produce drug-rich domains during evaporation) gave similarly homogeneous particles, which suggests that water did not separate drug and polymer into regions detectable by TEM [rests on: R16.a-c; cited: Li et al., 2017] | p.19 |

## 2018 Li — Tailoring supersaturation from amorphous solid dispersions · Dissolution / B. Supersaturation from ASD dissolution

[2018-li-tailoring-supersaturation-lopinavir-insoluble-polymer-asd](../../../cards/2018-li-tailoring-supersaturation-lopinavir-insoluble-polymer-asd/paper.html) · Dissolution / B. Supersaturation from ASD dissolution · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R8 | record, measured | Tg of fresh dry ASDs (°C; error bars on some points; pure-component Tgs in B1) — solvent-evaporated ASDs (P9) — sub-table below (all values ≈, read from Fig. 5; two values = two Tg events); text: two Tgs close to the pure components at 15-85% DL for CA; two Tgs at 15-50% DL and one at 70 and 85% for EUD; two Tgs at 15 and 33% and one from 50% for CAP; one Tg at all DLs for EC, HPMCAS, HPMCP | Fig. 5, p.120; text p.118-119 |
| R14 | record, measured | LPV concentration from LPV-HPMCAS ASD versus physical mixture (μg/mL, mean with error bars) — pH 3, 48 h (P5, P14); 100% DL point at 17.4 — sub-table below (all values ≈, read from Fig. 9); text: no solubility suppression for the physical mixtures; composition-dependent suppression for the miscible ASDs | Fig. 9, p.123; text p.123 |
| C27 | claim, conclusion, authors: "indicating" | Two Tgs close to the pure components at 15-85% DL show that LPV is largely immiscible with CA at all compositions studied [rests on: R8.a] | p.118-119 |
| C49 | claim, mechanism, authors: asserted | In phase-separated ASDs the components are not intimately mixed and behave independently during solution equilibration, so Eqs. 4 and 6 do not apply [rests on: argument only; R14] | p.123 |
| C56 | claim, conclusion, authors: "suggest"; "as supported by" | The Fig. 2 data mark CA and EUD ASDs as phase separated, supported by DSC, IR and moisture sorption (water gain predicted by the additive model) [rests on: R3.b-c, R8.a-b, R11, R12.a-b] | p.123 |

## 2018 Mosqueragiraldo — Influence of Polymer and Drug Loading on the Release Profile and Membrane Transport of Telaprevir · Bioperformance / Bioperformance

[2018-mosquera-giraldo-telaprevir-asd-polymer-loading-release-membrane-transport](../../../cards/2018-mosquera-giraldo-telaprevir-asd-polymer-loading-release-membrane-transport/paper.html) · Bioperformance / Bioperformance · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R23 | record, measured | modulated DSC (reversing heat flow) and XRPD before dissolution — 50% PVPVA: 50% TPV and 70% PVPVA: 30% TPV ASDs (P2, P3) — XRPD: halo patterns, broad maxima at ≈9-10 and ≈19° 2θ, no sharp peaks; DSC: one step for 50% PVPVA (arrow at ≈108 °C) and two overlapping steps for 70% PVPVA (arrows at ≈110 and ≈127 °C) (read from Fig. 12a; Tg values not printed) | Fig. 12, p.27; text p.25 |
| C53 | claim, conclusion, authors: "indicate"; "suggests"; "may have undergone" | Both PVPVA ASDs are amorphous within XRPD detection limits; the 50% PVPVA ASD has one Tg and the 70% PVPVA ASD two overlapping Tgs, so the 70% PVPVA: 30% TPV ASD may have partially phase separated [rests on: R23] | p.25-26 |
| C54 | claim, prior hypothesis, authors: "can"; "probably" | Polymer-drug miscibility can affect dissolution; PVPVA ASDs are more prone to phase separation because of polymer hygroscopicity; TPV-PVPVA ASDs tend to phase separate, probably through water taken up during preparation and storage [rests on: cited: refs 19, 31, 37] | p.26 |
| C55 | claim, mechanism, authors: "can be attributed"; "possible" | The poor performance of the PVPVA ASDs is attributed to possible solid-state phase separation between polymer and drug and to PVPVA being a weak solution crystallization inhibitor because its hydrophilicity favours interaction with water rather than with hydrophobic TPV [rests on: R22, R23, R24] | p.26 |

## 2018 Mugheirbi — Phase Behavior of Drug-Hydroxypropyl Methylcellulose Amorphous Solid Dispersions Produced from Various Solvent Systems: Mechanistic Understanding of the Role of Polymer using Experimental and Theoretical Methods · ASD process / ASD process

[2018-mugheirbi-itz-hpmc-asd-solvent-phase-behavior](../../../cards/2018-mugheirbi-itz-hpmc-asd-solvent-phase-behavior/paper.html) · ASD process / ASD process · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R1 | record, measured | film phase state by FLOM versus spin-coating temperature — ITZ:HPMC 30:70 films from each alcohol:DCM solution (P1, P2), 50% RH, 21-50 °C (P6); scale bar 20 µm — sub-table below (panel descriptions are the extractor's reading of the micrographs); text: at 21 °C (± 0.5) films from MeOH, EtOH and IPA show regions of high fluorescence intensity, films from n-PrOH and n-BuOH a homogeneous fluorescence; with rising temperature the phase-separated domains of MeOH and EtOH films become smaller; IPA films prepared above 30 °C show no discrete domains but an inhomogeneous fluorescence with a microstructure similar to that of spinodal decomposition (ref 12); spin-coating temperature does not change the FLOM appearance of PrOH and BuOH films. Figure annotations: "Decrease in domain size" and "Increase in evaporation rate" from 21 to 50 °C; "Increase in alcohol's viscosity" and "Increase in miscibility" from MeOH to n-BuOH | Fig. 2, p.17; text p.16-17 |
| R2 | record, measured | film texture by BF TEM — films spin coated at 50% RH (P2, P7); scale bars 0.5 µm; samples chosen as those with the clearest FLOM evidence of phase separation, plus BuOH — sub-table below; no TEM image shown for PrOH films at 50% RH | Fig. 3, p.19; text p.18 |
| R4 | record, measured | film phase state by FLOM and BF TEM at low RH — films spin coated at 21 °C (P4): 20% RH (panels a-e), 7% RH (panels f-h); TEM scale bars without a value — sub-table below | Fig. 4, p.21; text p.19-20 |
| C8 | claim, conclusion, authors: "indicating"; "as inferred" | At 21 °C and 50% RH, films from MeOH, EtOH and IPA were phase separated with a non-uniform drug distribution, while films from PrOH and BuOH were miscible, inferred from their homogeneous fluorescence [rests on: R1] | p.16 |
| C12 | claim, conclusion, authors: "indicated"; "somewhat surprisingly"; "counterintuitive" | At 20% RH, MeOH films stayed phase separated (agreeing with ref 12) and EtOH films were miscible; IPA films were heterogeneous without discrete domains; PrOH and BuOH films were, "somewhat surprisingly", phase separated, and remained so at 7% RH together with IPA, which the authors call counterintuitive given miscible MeOH films at 7% RH [rests on: R4, R5] | p.19-20 |

## 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: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R18 | record, measured | Nile red fluorescence of films before and after water exposure — 20, 30, 40% DL films (P9) — before water: uniform, homogeneous films for all three DLs; after water: 20% DL film remains uniform; 30% and 40% DL films show discrete domains of intense emission; figure: at 30% DL sparse bright spots of a few µm, denser in part of the field; at 40% DL dense bright spots across the field (read from Fig. 7) | p.11; Fig. 7, p.32 |
| C8 | claim, conclusion, authors: abstract: "suggested" | Thin films at or below the LoC stay homogeneous after water exposure, whereas films above the LoC undergo water-induced AAPS to various extents [rests on: R18] | p.2 |
| C20 | claim, conclusion, authors: "indicates" | The discrete bright domains in 30% and 40% DL films after water exposure indicate water-induced AAPS forming hydrophobic drug-rich domains, into which the hydrophobic probe partitions and emits more intensely [rests on: R18; cited: refs 30, 34] | p.11 |
| C33 | claim, mechanism, authors: "can be attributed" | The drastic drop in release over a small DL increase can be attributed to a faster rate of AAPS relative to dissolution at high DL [rests on: R16, R17, R18] | p.16 |
| X6 | extractor note | claim-data gap — Water-induced AAPS (C8, C9, C33, C39, C56) was observed only in spin-coated films dipped in water for a few seconds and imaged once, at 20, 30 and 40% DL, although films at 10-50% DL were prepared; AAPS was not observed in the dissolving tablets, and neither the rate of AAPS nor that of dissolution was measured — C9, C33, C39, C47, C56, R18, P9 — treat the competition between AAPS and dissolution as the authors' inference from films plus release data |  |

## 2019 Li — Microstructure Formation for Improved Dissolution Performance of Lopinavir Amorphous Solid Dispersions · ASD process / ASD process

[2019-li-lopinavir-hpmc-asd-microstructure-dissolution](../../../cards/2019-li-lopinavir-hpmc-asd-microstructure-dissolution/paper.html) · ASD process / ASD process · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R8 | record, measured | AFM height images of films by route and DL — films P4 (and P3), dry, 15–85% DL — sub-table below; text: miscible films smooth with very few surface structures; water-prepared films spherical discrete domains at all DL, larger at higher DL, domain height ≈50 nm at 15% DL and ≈500 nm at 70% DL; 97% RH films irregular discrete and semi-continuous domains at all DL, sizes 100 nm to a few µm | Fig. 4, p.39; text p.16 |
| R14 | record, measured | local Tg of discrete and continuous regions by phase-separation route — 33% DL films (P4, P10): 4% water, or miscible film stored at 97% RH for 7 days — text (value ± SD): 97% RH continuous 173 ± 13 °C, discrete 83 ± 16 °C; 4% water continuous 191 ± 20 °C, discrete 141 ± 34 °C. Figure boxes: 4% water discrete median ≈146 °C (whiskers ≈85–187), continuous median ≈197 °C (whiskers ≈140–216); 97% RH discrete ≈64–92 °C, continuous median ≈167 °C (whiskers ≈163–198); miscible 33% DL band ≈144–153 °C (read from Fig. 6C) | Fig. 6C, p.41; text p.19 |
| R15 | record, measured | local Tg of discrete and continuous regions versus water-to-solvent ratio — 33% DL films (P4, P10), 2–100% water; n = 5–30 scans per phase, at least 10 per phase for ≤50% water — sub-table below; text: discrete-phase medians below 110 °C; continuous-phase medians above 180 °C at 2–40% water; continuous phase 142 ± 11, 116 ± 16 and 124 ± 7 °C at 50, 70 and 100% water | Fig. 6D, p.41; text p.19 |
| R18 | record, measured | local Tg grouped into phases — 33% DL films with 2–40% water (P11); purple polymer-richest, green polymer-rich, red intermediate, blue drug-rich — sub-table below; four groups at 2, 4, 8% water, three groups at 10–40% water; miscible 33% DL band ≈144–153 °C | Fig. 7A, p.43; text p.20 |
| C14 | claim, conclusion, authors: results: asserted ("improved significantly"); abstract: "was found to improve" | Compared with miscible ASDs, both phase-separated systems improved release at 33–85% DL, in rate and in degree of supersaturation (abstract: heterogeneous domains improve release for DL "above 33% w/w") [rests on: R2] | p.2, p.14-15 |
| C29 | claim, conclusion, authors: "suggested"; "appears to be insufficient" | Local Tgs at 2–40% water cluster into 3–4 composition groups (drug-rich, intermediate, polymer-rich); topography alone appears insufficient to describe the compositional variation, which exists within both continuous and discrete regions [rests on: R18] | p.20 |

## 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 · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R14 | record, measured | Nile red fluorescence of films (scale bar 50 µm) — P6; (a) 50% DL before exposure; (b) 5%, (c) 10%, (d) 50% DL after 100% RH, 37 °C, 3 days — (a) smooth, homogeneous intensity (text: all films before exposure); (b) mostly homogeneous; (c) small domains differing in intensity; (d) large domains differing in intensity, ≈10-20 µm across (read from Fig. 6d scale bar) | Fig. 6, p.21; text p.20 |
| C16 | claim, conclusion, authors: unexposed: "confirms"; exposed: "suggesting" | Unexposed films show no phase separation at microscope resolution; after moisture exposure the 5% DL film shows minimal or no, the 10% DL film some, and the 50% DL film more extensive phase separation [rests on: R14] | p.20 |
| C33 | claim, conclusion, authors: "lend support to the contention" | The film images support water-induced phase separation of ledipasvir from PVPVA into drug-rich regions, more discernible at 10 and 50% than at 5% DL [rests on: R14] | p.33 |
| C35 | claim, mechanism, authors: discussion: "may"; "can result"; "a reasonable explanation"; conclusions: "It appears"; "may depend" | Release depends on the race between dissolution and amorphous-amorphous phase separation: at low DL dissolution may outrun phase separation (or separation is not favourable), giving congruent release; at higher DL faster separation at the dissolution front lets polymer-rich domains dissolve and leaves a drug-rich layer that stops release of the interior polymer, which explains the 7.5 and 10% DL results [rests on: R3, R4, R14, R15] | p.33-34, p.39 |

## 2019 Saboo — Congruent release of drug and polymer: A “sweet spot” in the dissolution of amorphous solid dispersions · Dissolution / A. Release mechanism and LoC

[2019-saboo-congruent-drug-polymer-release-asd-sweet-spot](../../../cards/2019-saboo-congruent-drug-polymer-release-asd-sweet-spot/paper.html) · Dissolution / A. Release mechanism and LoC · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R9 | record, measured | % release of Nil and PVPVA in the first 15 min (mean ± SD, n = 3) — Nil:PVPVA 10:90 compact held in the die at 97% RH for 12 h versus unexposed control (P13, P9) — sub-table below; text: exposed compact released drug slowly and at a much lower rate than polymer for 15 min; polymer also slower than in the control; between 15 and 20 min the surface layer appeared to peel off and drug release was much faster afterwards (Fig. S1, not supplied) | Fig. 3, pdf p.20; text pdf p.19-20 |
| R17 | record, measured | surface topography after humidity exposure (SEM) — Nil:PVPVA 10:90 compact (P13, P15) — before exposure smooth (Fig. 11a); after 97% RH for 12 h rough, wrinkled topography (Fig. 11b); an exposed compact after 15 min of dissolution no longer showed these features (image not shown) | Fig. 11, pdf p.27 |
| R19 | record, measured | film morphology by CFM (prodan blue, R6G red; scale bar 50 µm) — Nil:PVPVA 10:90 films before and after 97% RH for 12 h (P8, P13, P18) — before exposure: both probes homogeneous, purple overlay; after exposure: blue drug-rich domains as filled circles or as rings, red polymer-rich phase continuous and also inside the rings (arrows); circular domains roughly 5-15 µm across (read from the Fig. 12 scale bar) | Fig. 12, pdf p.29-30 |
| C24 | claim, mechanism, authors: "most likely"; "indicating" | The rough topography after 97% RH most likely arises from water-induced AAPS at the exposed surface, and its disappearance after 15 min of dissolution indicates that this AAPS is superficial, not in the bulk [rests on: R17] | pdf p.27 |
| C41 | claim, conclusion, authors: "Further evidence" | Converting a congruently releasing system into an incongruent one by high RH is further evidence of the role of matrix phase separation [rests on: R9, R17] | pdf p.35 |

## 2020 Li — Water-induced phase separation of spray dried amorphous solid dispersions · ASD process / ASD process

[2020-li-water-induced-phase-separation-spray-dried-asd-ritonavir-pvpva](../../../cards/2020-li-water-induced-phase-separation-spray-dried-asd-ritonavir-pvpva/paper.html) · ASD process / ASD process · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R2 | record, measured | glass transition events, unaged mDSC reversing heat flow — SDDs at 25, 50, 75% DL from MeOH and from 10:90 H2O:MeOH (P4) — sub-table below; text: single Tg at all DL for methanol SDDs, Tg lower at higher DL; single Tg at 25% and 50% DL from 10:90; transition of the 50% DL 10:90 SDD slightly broader than the methanol one; multiple glass transitions at 75% DL from 10:90; unaged DSC of the four 50% DL SDDs (0:100 to 40:60) gave broad, ambiguous transitions (data not shown) | Fig. 3, p.16; text p.14-16 |
| R3 | record, measured | reversing heat flow after aging — 50% DL SDDs from 0:100, 10:90, 20:80, 40:60 H2O:MeOH, aged 72 h at 40 °C (P5) — sub-table below; text: gradual broadening of the glass transition with increasing water in the spray solvent, two clear transitions for 40:60 | Fig. 4A, p.17; text p.17 |
| R4 | record, measured | non-reversing heat flow after aging — as R3 — sub-table below; text: two distinct peaks for 10:90, 20:80 and 40:60, one for MeOH | Fig. 4B, p.18; text p.17 |
| R6 | record, measured | pyrene peak 1/3 ratio — SDD series by DL (P6); error bars shown, n not printed — sub-table below; text: methanol SDDs decrease linearly with DL; 10:90 nearly identical to methanol; 60:40 significantly lower at 25, 50 and 75% DL; methanol SDDs stored at 75% RH also lower | Fig. 6, p.20; text p.19 |
| R7 | record, measured | surface drug content by XPS (% RTV on surface, mean ± SD over at least 4 spots) — nine SDDs (P8) — sub-table below; text: for 60:40, surface composition 59% to 70% RTV at 25% DL and 85% to 91% at 50% DL | Table S1, SI p.2; Fig. 7, p.21; text p.20 |
| C2 | claim, conclusion, authors: abstract: asserted ("It was found"); discussion: asserted ("clearly demonstrate"); conclusions: asserted | Water added to the spray solvent can lead to phase separation of ASDs during spray drying, even from an initially one-phase stock solution [rests on: R3, R4, R6, R7, R10] | p.3, p.27, p.37 |
| C23 | claim, conclusion, authors: results: "confirming"; discussion: "it was possible ... to confirm phase separation" | After aging, the reversing transition of 50% DL SDDs broadens with solvent water and splits in two at 40:60, and two non-reversing peaks at 10:90, 20:80 and 40:60 show a second phase [rests on: R3, R4] | p.17, p.34-35 |

## 2020 Saboo — Patterns of drug release as a function of drug loading from amorphous solid dispersions: A comparison of five different polymers. · Dissolution / A. Release mechanism and LoC

[2020-saboo-asd-drug-loading-polymer-hydrophobicity-release](../../../cards/2020-saboo-asd-drug-loading-polymer-hydrophobicity-release/paper.html) · Dissolution / A. Release mechanism and LoC · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R23 | record, measured | confocal fluorescence of prodan-containing films — 30% DL films before and after 24 h at 97% RH (P10) — before: homogeneous blue fluorescence (data not shown); after: PVP, PVPVA and HPMC films show discrete domains of intense blue (scale bars 5, 3 and 20 µm); HPMCAS and EUDS films uniform at high (Fig. 12, 5 µm bars) and low magnification (Fig. S7, 20 µm bars) | Fig. 12, p.12; Fig. S7, SI p.9; text p.8 |
| C23 | claim, conclusion, authors: "indicating"; "consistent with"; "suggesting" | Films are initially miscible; after 24 h at high RH the discrete domains in 30% DL PVP, PVPVA and HPMC films are consistent with phase separation, while uniform HPMCAS and EUDS films suggest minimal or no phase separation [rests on: R23] | p.8 |
| C43 | claim, mechanism, authors: discussion and conclusion: "likely"; abstract: "was attributed to" | Water-induced AAPS is likely the cause of the LoC and the loss of dissolution performance of high-DL PVP, PVPVA and HPMC ASDs [rests on: R23, R19, R21, R22] | p.1, p.12, p.13-14 |
| C41 | claim, mechanism, authors: "may be key"; "thought to be the case" | Competition between AAPS and dissolution may decide the regime: if dissolution is faster (thought to be so for the ≤10% DL ASDs here, whatever the polymer), drug and polymer release congruently and the surface keeps its composition; if AAPS is faster, drug- and polymer-rich domains dissolve at rates set by their composition, the polymer leaves first, the surface turns drug-rich and drug release slows [rests on: argument only; R14] | p.12 |

## 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: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| 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 |
| C41 | claim, mechanism, authors: "would be expected"; "likely explains" | AAPS would release polymer faster, depleting it at the interface; drug release would then follow the drug-rich phase, slower as neat polymer dissolves 3 orders of magnitude faster than neat amorphous drug; by mass balance the surface becomes drug-enriched and forms a barrier for polymer diffusion, which likely explains the non-linear, slowing polymer release [rests on: R3, R6] | p.28-29 |
| C42 | claim, conclusion, authors: "more supportive"; "would not be anticipated" | Differential polymer loss without AAPS is the alternative; the change in surface roughness over a length scale of ~500 nm in incongruent IND ASDs is more supportive of phase separation, as polymer loss alone would not be anticipated to change topography so much [rests on: R19, R24] | p.29 |
| X8 | extractor note | claim-data gap — AAPS at the dissolving IND interface (C40, C41, C42) is inferred, not observed: the paper shows surface drug enrichment (R17, R21, R28) and roughening (R19, R24) but no direct evidence of two amorphous phases at the interface; the authors weigh the alternative of polymer loss without phase separation on topography alone (C42) — C41, C42, C40, R19, R24 — treat AAPS at the interface as the authors' interpretation |  |

## 2020 Trasi — Physical stability and release properties of lumefantrine amorphous solid dispersion granules prepared by a simple solvent evaporation approach · Solid state stability / Physical stability

[2020-trasi-lumefantrine-asd-granules-solvent-evaporation](../../../cards/2020-trasi-lumefantrine-asd-granules-solvent-evaporation/paper.html) · Solid state stability / Physical stability · used · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| C31 | claim, mechanism, authors: "clearly not effective"; "most likely" | PVPVA, commonly used for melt-extruded ASDs (the route of the Jain et al. formulations), is clearly not effective at inhibiting lumefantrine crystallization, especially under stress storage; its limited specific interactions with lumefantrine, together with its hygroscopicity and the high log P of lumefantrine, most likely make the dispersion prone to amorphous phase separation and then crystallization [rests on: R2, R3.a; cited: refs 32, 33] | p.9-10 |
| C2 | claim, prior hypothesis, authors: asserted; "can still occur" | Polymers stabilise ASDs: they should be miscible and interact with the drug, a high-Tg polymer raises the dispersion Tg and lowers mobility, and mixing lowers the drug chemical potential; phase separation into drug-rich and polymer-rich regions can still occur and lead to crystallization in drug-rich domains [rests on: cited: refs 16, 27, 29, 43] | p.1-2 |

## 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 · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R21 | record, measured | AFM topography and deflection after 12 h at ≈100% RH — 30% DL films at 0, 2, 5, 10% TPGS (P12-P14); 10 µm × 10 µm — sub-table below | Fig. 11, p.13; text p.13 |
| R23 | record, measured | AFM-nanoIR images after 12 h at ≈100% RH — 30% DL films at 0 and 10% TPGS (P16); 10 µm × 10 µm — 0% TPGS: height scale −90 to 90 nm; ratio image shows contiguous, elongated drug-rich (red) regions interleaved with drug-lean (blue) regions. 10% TPGS: height scale −35 to 35 nm; round, separated drug-rich domains in a continuous drug-lean phase. Text: elevated height features are drug-rich; surrounding continuous phase polymer-rich or drug-lean. IR image scale −0.1 to 0.1 V; ratio scale −1.5 to 1.5 | Fig. 13, p.14; text p.14 |
| C24 | claim, conclusion, authors: "suggested"; z: "indicated" | After high RH all films were inhomogeneous or phase separated: irregular semi-continuous domains at 0% and 2% TPGS, circular discrete domains at 5% and 10%; domain sizes in z did not differ significantly (comparable height variations); fresh films were homogeneous [rests on: R21, R20] | p.13 |
| C25 | claim, conclusion, authors: asserted ("confirming"; "A clear contrast") | nanoIR confirms phase separation of the initially miscible films: elevated features are drug-rich, the surrounding continuous phase polymer-rich or drug-lean; drug-rich domains are contiguous in the 30% DL binary film and spherical and well segregated in the ternary film [rests on: R22, R23] | p.14 |

## 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 · used · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| C6 | claim, prior hypothesis, authors: intro: "we hypothesized"; discussion: "It was thus anticipated" | High log P drugs were expected to make the ASD more hydrophobic and to undergo AAPS in the wet matrix more readily, impairing release [rests on: argument only; cited: ref 22] | Introduction p.2068; Discussion p.2076 |
| C17 | claim, mechanism, authors: "It has been suggested" | Release decline at a given DL has been linked to water-induced AAPS at the dissolving interface: when AAPS outpaces dissolution a drug-rich layer forms and controls slower release [rests on: cited: ref 22] | Discussion p.2076 |
| C21 | claim, mechanism, authors: "can be better explained" | Log P depends on many factors (molecular size the largest); AAPS tendency is better explained by the solvent Δχ effect (E2), i.e., the relative strength of water–polymer and water–drug interactions, with drugs having much larger χ with water than polymers, plus drug–polymer specific interactions [rests on: E2; cited: refs 44–46, 20, 22] | Discussion p.2076–2077 |
| C33 | claim, mechanism, authors: "most likely" | Rapid polymer release despite very low drug release in miconazole–PVPVA ASDs most likely reflects water-induced AAPS: the polymer-rich phase dissolves with little hindrance from the mobile supercooled-liquid drug-rich phase [rests on: R13; R28] | Discussion p.2078 |

## 2022 Soto — Impact of Surfactants on the Performance of Clopidogrel-Copovidone Amorphous Solid Dispersions: Increased Drug Loading and Stabilization of Nanodroplets · Dissolution / A. Release mechanism and LoC

[2022-correa-soto-surfactants-clopidogrel-copovidone-asd-nanodroplets](../../../cards/2022-correa-soto-surfactants-clopidogrel-copovidone-asd-nanodroplets/paper.html) · Dissolution / A. Release mechanism and LoC · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R20 | record, measured | film morphology, binary CPD-PVPVA ASDs — 40, 50, 60 DL films before and after 5 min at 100% RH (P17); red = Nile red (561 nm), green = Alexa 488 (488 nm) — before exposure all three films uniform; after exposure: 40 DL unchanged and uniform; 50 DL bicontinuous structure of Nile red-rich and Alexa 488-rich domains; 60 DL continuous Nile red-rich (drug) phase with discrete Alexa 488-rich (polymer) domains | Fig. 11, p.180; text p.177 |
| R21 | record, measured | film morphology with SDS — as R20 with 5 g SDS per 100 g (P17) — 40 DL uniform after exposure; 50 DL after exposure: results text "a small extent of heterogeneity in fluorescence intensity", discussion text "remains homogeneous (within the detection limit of the measurement which is ~500 nm)"; 60 DL after exposure: continuous CPD-rich phase with polymer-rich discrete domains smaller than in the binary 60 DL film | Fig. 12, p.181; text p.180, p.185 |
| R22 | record, measured | film morphology with TPGS — as R20 with 5 g TPGS per 100 g (P17) — 40 DL uniform after exposure; 50 DL bicontinuous after exposure; 60 DL large irregular structures after exposure | Fig. 13, p.181; text p.180 |
| R23 | record, measured | film morphology with TWN — as R20 with 5 g TWN per 100 g (P17) — 40 DL uniform after exposure; 50 and 60 DL fine-scale heterogeneous pattern after exposure; text: bicontinuous morphology "for DLs above 50%" | Fig. 14, p.182; text p.180 |
| C52 | claim, mechanism, authors: "suggest" | CPD-PVPVA ASDs tend to undergo water-induced AAPS because PVPVA has a much higher affinity for water than lipophilic CPD (cLogP 3.8), and drug-rich domains reduce unfavourable drug-water contact; 50 and 60 DL films form bicontinuous domains while 40 DL stays homogeneous over a short time [rests on: R20, M1] | p.184 |
| C53 | claim, mechanism, authors: "is linked to"; "support a link"; "is proposed" | Phase separation that leaves enough drug-rich phase to form a continuous or semi-continuous barrier at the ASD surface degrades release; for CPD, extensive separation at 50 DL and above goes with poor release, and at high DL rapid AAPS, a continuous drug-rich phase, fast polymer loss and surface drug enrichment give very low drug release [rests on: R20, R17, R18; cited: refs 12, 77, 81] | p.184 |

## 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 · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R9 | record, measured | phase separation in wet film (confocal, 561 and 488 nm channels) — binary ATZ-PVPVA 10% DL film, 100% RH, 37 °C, 0 min and 3 h (P8) — no phase separation within the resolution of the method for at least 3 h; both channels uniform at 0 min and 3 h | Fig. 8, p.7; text p.4 |
| R10 | record, measured | phase separation in wet films (confocal) — 10% DL films with SDS, CTAB or TPGS, 100% RH, 37 °C, 0 and 10 min (P8) — uniform at 0 min; phase separation within 10 min; 561 nm images: more intense small discrete red domains in a lower-intensity red background (low contrast), least contrast for SDS; 488 nm images: green continuous background; figure: CTAB 10 min shows the most distinct red domain network, TPGS fine domains, SDS faint texture | Fig. 9, p.7; text p.4, p.6 |
| R11 | record, measured | phase separation in wet films (confocal) — 10% DL films with Tween®80, Span®20, Span®80 or Span®85, 100% RH, 37 °C, 0 and 10 min (P8) — phase separation within 10 min with greater contrast: small red domains in a black background (561 nm); green background with black pits (488 nm); regions intense in Nile red lack Alexa 488 signal; figure: Span®20 discrete round red droplets, Tween®80 and Span®85 irregular connected red domains, Span®80 10 min image with a large four-pointed feature in a textured field; Span®20 0 min 488 nm image shows scattered bright dots | Fig. 10, p.8; text p.6 |
| R12 | record, measured | phase separation in wet film at higher temperature — binary ATZ-PVPVA 10% DL film, 100% RH, 50 °C, 10 min (P8) — text: phase separation within 10 min; figure: fine granular texture in the 561 nm channel, 488 nm channel nearly uniform | Fig. 11, p.8; text p.6 |
| C18 | claim, conclusion, authors: asserted | Binary 10% DL films showed no phase separation within the method's resolution after at least 3 h at 100% RH and 37 °C, whereas all ternary films phase separated within 10 min [rests on: R9, R10, R11] | p.4 |

## 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: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R19 | record, measured | water-induced phase separation of ASD films at high RH — Nile red-stained ASD films (P15) imaged at 37 °C and high RH (P16); DL, RH and exposure time not stated in the main text; Figs. S6-S8 (SI not supplied) — free base ASD phase separated (Figs. S6-S8); benzoate salt ASD phase separated (Fig. S7); sulfate salt ASD remained visually homogeneous, no obvious phase separation (Fig. S8) | p.57, p.58 |
| C35 | claim, mechanism, authors: asserted ("predisposed") | Lack of specific drug-polymer interactions and the high lipophilicity of lumefantrine (log P 8.34) predisposed the free base-PVPVA system to water-induced phase separation at high humidity [rests on: R19; cited: refs 40-42] | p.57 |
| C36 | claim, mechanism, authors: asserted | Once phase separated, the low Tg of lumefantrine and some of its salts increased the risk of recrystallization because the polymer no longer protects the drug; ASDs with higher DL and low-Tg salts were especially susceptible, with crystalline peaks as soon as 3 days [rests on: R8, R19] | p.57 |

## 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: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| C41 | claim, prior hypothesis, authors: asserted ("has been attributed") | The cliff in PVPVA ASDs has been attributed to water-induced AAPS during hydration: the PVPVA-rich phase dissolves first and leaves a drug-enriched surface that blocks further release of drug and sometimes polymer [rests on: cited: refs 24, 26, 40, 41] | p.408 |
| C43 | claim, conclusion, authors: "appeared" | HPMCP and CAP also appeared effective in minimizing AAPS during dissolution [rests on: R18, R21] | p.408 |
| C61 | claim, mechanism, authors: "can be rationalized"; "if this interaction persists"; "predispose" | The instability of PVPVA ASDs can be rationalized by weak drug−polymer interaction: the lumefantrine OH is held in an intramolecular hydrogen bond (R33), which, if it persists in the ASD, leaves little specific interaction; with hygroscopic PVPVA and lipophilic drug, this predisposes the ASDs to AAPS and crystallization [rests on: R17, R6.a–d, R33; cited: ref 56] | p.411 |

## 2022 Indulkar — Role of Surfactants on Release Performance of Amorphous Solid Dispersions of Ritonavir and Copovidone · Dissolution / A. Release mechanism and LoC

[2022-indulkar-surfactants-ritonavir-copovidone-asd-release-performance](../../../cards/2022-indulkar-surfactants-ritonavir-copovidone-asd-release-performance/paper.html) · Dissolution / A. Release mechanism and LoC · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R19 | record, measured | Tg onset before and after dissolution (°C) — P10; Span 20 and Tween 80 ASDs; post-dissolution material scraped from the exposed tablet surface — sub-table below; text: Tg decreased after dissolution, to a value "very close" to the reported Tg of ritonavir (ref 35, value not printed); only one Tg labelled per trace; after-dissolution traces also show unlabelled events above ≈100 °C (Fig. 8B: small exotherm near ≈110 °C followed by a noisy endotherm; Fig. 8C: large endotherm from ≈100 to ≈150 °C) | Figs. 8B-C, p.391-392; text p.387 |
| C19 | claim, conclusion, authors: results: "This indicates"; "has likely occurred"; discussion: "suggest"; abstract: asserted | The post-dissolution Tg of Span 20 and Tween 80 ASDs fell to a value very close to the reported Tg of ritonavir, so ritonavir likely phase separated on contact with water, with loss of PVPVA and enrichment of RTV on the surface; the DSC data suggest these ASDs underwent AAPS giving a separate ritonavir-rich phase [rests on: R19] | p.381, p.387, p.394 |
| C44 | claim, mechanism, authors: "This suggests"; "may" | Tween 80 and Span 20 may improve initial wetting and dissolution, removing the lag time, but are ineffective at preventing AAPS [rests on: R6, R7, R19] | p.394 |
| C45 | claim, mechanism, authors: "may"; general comments: asserted | Unlike SDS, Tween 80 and Span 20 do not raise the dissolution rate over polymer alone, so the dissolution rate may be lower than the rate of AAPS and of drug-rich phase formation at the surface; these ASDs do not fare better than the binary ASD at 30% DL; release from them was compromised by AAPS [rests on: R20, R19, R6, R7] | p.394, p.395 |
| X10 | extractor note | alternative explanation — The AAPS assignment for the Span 20 and Tween 80 ASDs (C19) rests on one lowered Tg onset (42.18 and 40.25 °C, R19.b, R19.d) of material scraped from the wet surface and run in open pans after a 5 h nitrogen purge (P10). No second, polymer-rich Tg is reported, the ritonavir Tg used for comparison is not printed, the post-dissolution traces show large unassigned events above ≈100 °C (R19), and the water content of the scraped samples is not reported; residual water in a still-mixed matrix would also lower the Tg — C19, R19, P10 — treat AAPS in the Span 20 and Tween 80 ASDs as inferred from a Tg shift only |  |

## 2022 Moseson — Formulation and processing strategies which underpin susceptibility to matrix crystallization in amorphous solid dispersions · ASD process / ASD process

[2022-moseson-processing-strategies-matrix-crystallization-bcl-pvpva-asd](../../../cards/2022-moseson-processing-strategies-matrix-crystallization-bcl-pvpva-asd/paper.html) · ASD process / ASD process · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R16 | record, measured | confocal cross-section of 30% DL SE compacts vs exposure time — P14, P15, P18; 0, 5, 30, 60 min — drug-rich (red) surface layer 55 ± 6 µm (n = 10) at 5 min and 103 ± 9 µm (n = 10) at 30 min; gel layer 440 ± 6 µm (n = 10) between drug-rich layer and dry core at 5 min, thicker at 30 min; compact thickness 2092 ± 24 µm (n = 10) to 2696 ± 50 µm (n = 10) after 60 min; surface highly irregular at 60 min | Fig. 11a-d, p.26; text p.25 |
| R17 | record, measured | confocal cross-section of 50% DL SE compacts vs exposure time — P14, P15, P18; 0, 5, 30, 60 min — 5 min: red regions scattered across the surface, 8 ± 2 µm (n = 10), morphology similar to the surface crystals in Fig. 10b inset; 30 min: more continuous thin red drug layer 1.9 ± 0.3 µm (n = 10); 60 min: no disordered drug-rich (red) layer at the surface; compact thickness 1988 ± 11 µm to 2441 ± 12 µm after 60 min; gel layer not distinguishable from the unwetted compact | Fig. 11e-h, p.26; text p.25 |
| C32 | claim, mechanism, authors: "suggest"; "indicating"; "consistent with"; "suggests" | In 50% DL compacts the red surface regions at 5 min are disordered drug-rich domains without polymer; their crystal-like morphology means surface crystallization had begun before full dye expulsion (or the dye was trapped); the thinner drug-rich layer at 30 min is consistent with more complete crystallization, and its absence at 60 min suggests the layer had fully crystallized [rests on: R17, R15] | p.25 |
| C70 | claim, caveat, authors: "may" | Other factors not evaluated may affect susceptibility on hydration: Tg of the drug and/or ASD, persistence of drug-polymer interactions, and kinetics of amorphous-amorphous phase separation [rests on: argument only] | p.36 |

## 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: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R4 | record, measured | surface morphology of partially dissolved compacts, Nile red channel (scale bar 50 µm) — dye-containing compacts, P2, P5, P6 — sub-table below; text: black areas present in several images | Fig. 3, pdf p.9-10; text pdf p.8-9 |
| 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 |
| R10 | record, measured | time-lapse morphology, 10% DL (scale bars 100 µm) — P7; images at 0, 1, 2, 5, 10, 15 min, enlargement of 15 min — before medium: homogeneous orange; immediately after medium (1 min): orange-green boundary as for neat PVPVA and small red droplets close to the gel-solution interface; gel-solution interface ambiguous (gradient of water/solid content); with time the waterfront moves into the compact and red droplets keep forming near the gel-solution interface and enter the bulk solution (1-15 min); droplets mainly near the gel-solution interface, not throughout the hydrated gel (enlargement, Fig. 8g) | Fig. 8, pdf p.17; text pdf p.15-16 |
| R11 | record, measured | time-lapse morphology, 20% DL (scale bars 100 µm) — P7; images at 0, 1, 2, 5, 10, 15 min, enlargement of 15 min — small red droplets formed near the gel-solution boundary and released into bulk solution as at 10% DL; at the same time point droplet formation deeper into the gel layer than at 10% DL; homogeneous region between the waterfront and the start of droplet formation shorter than at 10% DL | Fig. 9, pdf p.18; text pdf p.16 |
| R12 | record, measured | time-lapse morphology, 30% DL (scale bars 100 µm) — P7; images at 0, 1, 2, 5, 10, 20, 30 min — after medium addition a darker green hydrated region; a continuous but porous red layer formed immediately at the gel-solution interface (1 min); air bubbles escaping through the layer at 1 min (arrows) and at 2, 5 and 30 min; pores and channels at the compact-solution interface; green colour beyond the red layer; waterfront position less deep than at lower DLs at the same time points | Fig. 10, pdf p.20; text pdf p.18-19 |
| 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 |
| C8 | claim, prior hypothesis, authors: "It has been reported" | Water-induced AAPS is the separation of an initially miscible ASD into an insoluble amorphous drug-rich phase and a soluble polymer-rich phase on addition of water; both its kinetics and its phase morphology depend on DL [rests on: cited: refs 8, 27-30] | pdf p.4 |
| C44 | claim, conclusion, authors: "is possible"; "is expected"; "It is apparent" | The gel layer replaces a sharp solid-liquid interface with a solids gradient; its high water content makes water-induced AAPS possible, depending on DL and water content; phase separation is favoured close to the solution where water content is highest, as seen in the cross-sections and time-lapse images [rests on: R6, R10-R13] | pdf p.23 |

## 2022 Yang — Phase separation in surfactant-containing amorphous solid dispersions: Orthogonal analytical methods to probe the effects of surfactants on morphology and phase composition · Solid state stability / Physical stability

[2022-yang-surfactant-containing-rtv-pvpva-asd-phase-separation](../../../cards/2022-yang-surfactant-containing-rtv-pvpva-asd-phase-separation/paper.html) · Solid state stability / Physical stability · measured · as: amorphous–amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R3 | record, measured | AAPS time-lapse, binary 20% DL — RTV-PVPVA 20-80 film; high RH, 37 °C; 0, 5, 10, 30 min; scale bar 50 µm — phase separation barely discernible; fine bicontinuous texture visible only at the longest exposure (30 min) | Fig. 3a, p.6; §4.1, p.5 |
| R4 | record, measured | AAPS time-lapse, binary 30% DL — RTV-PVPVA 30-70 film; same conditions; scale bar 50 µm — homogeneous at 0 min; bicontinuous red/green structure at 5 min; coarser red drug-rich network at 10 and 30 min | Fig. 3b, p.6; §4.1, p.5 |
| R5 | record, measured | AAPS time-lapse, SDS film — RTV-PVPVA-SDS 30-70-5; same conditions; scale bar 10 µm — homogeneous at 0 and 5 min; fine texture at 10 min; discrete circular red drug-rich domains at 30 min, larger than those with Tween 80 | Fig. 3c, p.6; §4.1, p.5 |
| R6 | record, measured | AAPS time-lapse, Tween 80 film — RTV-PVPVA-Tween 80 30-70-5; same conditions; scale bar 10 µm — homogeneous at 0 and 5 min; dense, very small discrete red domains at 10 and 30 min | Fig. 3d, p.6; §4.1, p.5 |
| R7 | record, measured | AAPS time-lapse, Span 20 film — RTV-PVPVA-Span 20 30-70-5; same conditions; scale bar 50 µm — homogeneous at 0 min; irregular red drug-rich domains with bicontinuous regions at 5 min; at 10 and 30 min large green polymer-rich areas next to regions of discrete and continuous red drug-rich domains | Fig. 3e, p.6; §4.1, p.5 |
| R8 | record, measured | AAPS time-lapse, Span 85 film — RTV-PVPVA-Span 85 30-70-5; same conditions; scale bar 50 µm — homogeneous at 0 min; bicontinuous structure at 5 min; coarsened continuous red drug-rich regions beside large green areas at 10 and 30 min | Fig. 3f, p.6; §4.1, p.5 |
| C1 | claim, conclusion, authors: abstract: asserted ("notably"); §4.1: asserted ("Drastic"); §5.4: asserted ("drastically") | Adding surfactants changed both the kinetics and the morphology of water-induced AAPS in 30% DL RTV-PVPVA films. [rests on: R4, R5, R6, R7, R8] | Abstract, p.1; §4.1, p.5; §5.4, p.14 |
| C7 | claim, conclusion, authors: §4.1: asserted ("Therefore"); §5.4, §5.5, §6: asserted | SDS and Tween 80 retarded AAPS kinetics (films homogeneous at 5 min, or domains not yet ripened to visible size), whereas the binary, Span 20 and Span 85 films had phase separated by 5 min and ripened rapidly. [rests on: R4, R5, R6, R7, R8] | §4.1, p.5; §5.4, p.14; §5.5, p.14; §6, p.15 |

## 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: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R6 | record, measured | in situ morphology of dissolving MePHPH-PVPVA compacts (blue = prodan, red = R6G, magenta = both) — P7; 37 °C pH 6.8 buffer, manual pipette mixing — sub-table below; text: all compacts formed a gel layer; all MePHPH-PVPVA ASDs showed separation of blue and red colours somewhere in the gel layer; the onset distance from the glass/gel boundary decreased with DL; light-signal loss in the gel in Figs. 5b, 6b-g and 7b,d | Figs. S2, S3 (SI p.3-4), Figs. 5-7 (p.2223-2225); text p.2222, p.2223, p.2231 |
| R7 | record, measured | in situ morphology of dissolving PHPH-PVPVA compacts — P7 — sub-table below; text: both dyes partitioned into the hydrophobic phase after phase separation, which stayed magenta, while the hydrophilic phase was depleted of both dyes and appeared black; the distance between onset and glass/gel boundary visually decreased with DL | Figs. 8-10, p.2226-2228; text p.2222-2223 |
| C5 | claim, prior hypothesis, authors: asserted | Water-induced AAPS is thermodynamically the same phenomenon as LLPS in a different concentration regime; it has been studied for processing and storage and proposed at the dissolving ASD/solution interface, but is not typically studied in situ [rests on: cited: refs 11, 17-19] | p.2218 |
| C25 | claim, conclusion, authors: "This indicates" | The separation of blue and red colours in all MePHPH-PVPVA gels indicates segregative phase separation into a hydrophobic and a hydrophilic phase [rests on: R6; cited: ref 22] | p.2222 |
| C71 | claim, conclusion, authors: asserted ("successfully") | In situ fluorescence confocal microscopy captured the phase-separation morphologies at the ASD/solution interface for both systems; phase separation was detected in the gel layer for most of the ASDs [rests on: R6, R7] | p.2217, p.2232-2233 |

## 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: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| C8 | claim, prior hypothesis, authors: "is thought to be largely responsible"; "It was proposed"; "It has been suggested" | A drug-rich surface layer is thought to cause the catastrophic drop in drug and polymer release above the LoC; its origin was proposed to be rapid water-induced AAPS at the surface; Han et al. argued the same mechanism generates the nanoparticles and suggested that the hydrophobic phase releases as nanoparticles below the percolation threshold but forms a continuous insoluble barrier above it [rests on: cited: refs 4, 5, 12, 31-33] | p.723 |
| C28 | claim, prior hypothesis, authors: asserted; "may form" | ASDs undergo water-induced AAPS when water brings them into the two-phase region; polymers form a rubbery, viscous gel layer at the dissolution interface, also seen for ASDs; Han et al. proposed that the barrier may form through AAPS in the gel layer [rests on: cited: refs 32, 43-53] | p.730 |
| C67 | claim, conclusion, authors: "was found to trend with"; "were reported" | For the four analogues the LoC trends with the association of PVPVA in the hydrophobic phase formed by water-induced LLPS/AAPS, which in turn relates to interaction strength; the associative systems were reported to have lower LoCs than the segregative ones [rests on: R8, R3; cited: ref 14] | 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: amorphous–amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R6 | record, measured | phase morphology, Span 20 30–70–10 — P7 at 5, 10, 20 min; P8 at 0, 1, 2, 3, 5 min — compact surfaces: discrete red domains in a continuous green phase at all times; cross sections: three layers — bottom glassy compact with particle boundaries (orange), homogeneous orange gel layer, top layer with separated red and green domains; discrete red domains at the dissolving interface at 5, 10, 20 min; in situ: water front advancing into the compact from 1 min, discrete red droplets formed at the gel–solution interface and leaving into the bulk, green colour in the bulk beyond the interface; large red circle at right of the 5 min image | Fig. 4a–k, p.2825–2826; text p.2823–2824 |
| R13 | record, measured | phase morphology, SDS 40–60–10 (30% DL stated similar; not shown) — P7 at 5, 10, 20 min; P8 at 0, 0.5, 1, 2, 5 min — surfaces: small discrete red droplets, agglomerated, at all times; cross sections: homogeneous gel layer with no visible phase separation; red domains only at the gel–solution interface; in situ: homogeneous hydrated gel; red nanodroplets formed only at the gel–solution boundary | Fig. 9a–k, p.2835–2836; text p.2829 |
| R21 | record, measured (RH); derived (P11, water content) | minimum RH and water content (% of dry solid mass) at which phase separation was observed — 30% DL films, 12 h storage (P12) — see R21 sub-table | Table II, p.2840; text p.2834 |
| C8 | claim, mechanism, authors: asserted | Surfactant incorporation affected both kinetic and thermodynamic factors governing RTV–PVPVA–water phase separation, modifying phase morphology during dissolution. [rests on: R6–R14, R21, R22] | Abstract, p.2817 |

## 2024 Deac — Dissolution mechanisms of amorphous solid dispersions: Role of polymer molecular weight and identification of a new failure mode · Dissolution / A. Release mechanism and LoC

[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 · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R7 | record, measured | film morphology after 3 and 11 h at 100% RH, 37 °C (blue = prodan, drug-rich hydrophobic phase; red = Alexa Fluor 488, water/polymer-rich hydrophilic phase) — 10% DL K12 and 10% DL K29/32 films (P10) — sub-table below; text: phase separation seen after 3 h; in both films the drug-rich phase appeared as droplets and the hydrophilic phase was continuous; in the K12 film the drug-rich domains appeared to agglomerate extensively into strands, especially after 11 h; in the K29/32 film the droplets stayed separate (no agglomeration into strands) | Fig. 3, p.6; text p.6 |
| R8 | record, measured | film morphology after 1 h at 100% RH, 37 °C, versus DL — K12 films 20, 30, 40% DL; K29/32 films 30, 40% DL (P10) — sub-table below; text: the drug-rich phase formed droplet domains up to 30% DL; at 40% DL it was a continuous phase and the hydrophilic phase formed dispersed droplets within it; phase inversion between 30 and 40% DL for both K12 and K29/32 (p.9) | Fig. 4, p.7; text p.6, p.9 |
| R10 | record, measured | morphology at the dissolution front by in situ confocal microscopy (green-circled regions: 1 dry ASD, 2 gel layer, 3 solution; water entering from right to left; scale bar 25 µm) — 10% DL K12 compact after 2 min; 10% DL K29/32 compact after more than 7 min; pH 8.0 buffer, 37 °C (P8) — sub-table below | Fig. 5, p.7; text p.6-9 |
| R11 | record, measured | composition of the hydrophilic (solution) and hydrophobic (nanodroplet) phases, wt%, mean ± SD, n = 4 — 10% DL K12 and 10% DL K29/32 ASDs mixed with buffer at ASD:water 40:60, heated to about 90 °C and cooled, centrifuged at 37 °C (P9); x-axis of Fig. 6 labels the polymer "PVPVA" (X2) — sub-table below; text: compositions statistically similar for the two grades; hydrophobic phase about ~80 wt% clotrimazole; hydrophilic phase ~40 wt% PVP, ~60 wt% water and trace clotrimazole | Fig. 6, p.8; text p.8 |
| C28 | claim, conclusion, authors: asserted | PVP segregates from clotrimazole during water-induced phase separation (segregative phase separation): a drug-rich hydrophobic phase and a PVP- and water-rich hydrophilic phase with trace drug [rests on: R11] | p.8 |

## 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 · measured · as: amorphous-amorphous phase separation

| id | kind | content | locator |
|---|---|---|---|
| R1 | record, measured | film phase state by transmission microscopy — MePHPH-PVPVA films 10-50% DL (P2), 62-97% RH at 37 °C (P8), up to 12 days — text: all DL transparent and homogeneous at 62 and 75% RH; heterogeneous domains at and above 80% RH. Figure: 50% DL network-like domains at 80% RH, droplets and large domains at 83-97%; 40% DL faint texture at 80%, droplets at 83-97%; 30% DL droplets at 80-97%; 20% DL sparse faint domains at 80 and 83%, droplets at 92 and 97%; 10% DL sparse faint domains at 80-92%, droplets at 97%; neat PVPVA at 97% RH homogeneous | Fig. 2, p.1906; text p.1905 |
| R2 | record, measured | composition of ASD powder after RH equilibration (wt%, mean ± SD, n = 3) — MePHPH-PVPVA powder (P9), 7-14 days, 37 °C — sub-table below | Table 4, p.1906 |
| R15 | record, measured | total composition and equilibrium binode compositions (wt%, SD from n = 4 "except where noted"; no row is marked) — all equilibrated nondilute (P4) and dilute (P5) mixtures, 37 °C — sub-table below (rows are not labelled with the mixture in the source; see X12) | Table S1, SI p.6 |
| R18 | record, measured | morphology evolution by confocal fluorescence (red hydrophilic, blue hydrophobic) — MePHPH-PVPVA films 10-60% DL (P3), 100% RH, 37 °C (P11) — sub-table below; text: all films initially homogeneous; onset morphology co-continuous at every DL including the lowest; morphology after 1 h persisted at least 6 h for DLs below and above 40% | Fig. 7, p.1908; text p.1909 |
| R19 | record, measured | morphology evolution by confocal fluorescence — PHPH-PVPVA films 5-20% DL (P3), 100% RH, 37 °C (P11) — sub-table below; text: earliest detected morphology already had one phase dispersed and persisted | Fig. 8, p.1909 |
| C13 | claim, conclusion, authors: "indicated"; "in agreement with" | Heterogeneous domains indicate that MePHPH-PVPVA films phase separated at 80% RH and above; the binodal lies between the 75% and 80% RH film compositions; the water content needed to induce phase separation is below 15 wt%, in agreement with the earlier finding of phase separation below the average gel-layer water content [rests on: R1, R2, R40] | p.1905-1906 |

## Mentioned only

- 2013 Harrison — [2013-harrison-afm-ir-griseofulvin-nanocrystals-hpmc](../../../cards/2013-harrison-afm-ir-griseofulvin-nanocrystals-hpmc/paper.html) · Characterization methods / Solid-state methods (ref 8)
- 2017 Trasi — [2017-trasi-commercial-amorphous-tacrolimus-crystallization-stress](../../../cards/2017-trasi-commercial-amorphous-tacrolimus-crystallization-stress/paper.html) · Solid state stability / Physical stability (ref 14)