# Evidence: drug-polymer miscibility

Parent: — · class: phase behaviour · names merged here: drug-polymer miscibility; drug–polymer miscibility; homogeneous molecular dispersion

48 papers measured or used it, 8 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.

## 1997 Taylor — Spectroscopic Characterization of Interactions Between PVP and Indomethacin in Amorphous Molecular Dispersions · Solid state stability / Miscibility and drug-polymer interactions

[1997-taylor-pvp-indomethacin-amorphous-molecular-dispersions](../../../cards/1997-taylor-pvp-indomethacin-amorphous-molecular-dispersions/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · used · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| C39 | claim, generalisation, authors: asserted ("in no way indicates"; "This picture is supported") | The coexistence of several species does not indicate more than one phase; they are distributed so that a single phase forms, supported by the single Tg of these dispersions, generally considered indicative of one phase, and by their similarity to the liquid indomethacin-methylpyrrolidone system [rests on: R17, C31; cited: refs 7, 34] | p.1697 |
| R17 | record, cited | glass transition of indomethacin-PVP solid dispersions — ref 7 — single glass transition temperature over all composition ranges | p.1697 |
| X9 | extractor note | claim-data gap — C39 (single phase) rests on the cited single Tg (R17) and on spectral similarity to a liquid solution; XRPD (R1) shows the absence of crystals but cannot distinguish one amorphous phase from two — C39, R17, R1 — take miscibility from ref 7, not from this paper's data |  |

## 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 · measured · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R4 | record, measured | DSC thermal events (°C) and Raman form of probucol in the dispersions — Table 1 compositions; code 1) solvent method (P4), 2) compression moulding (P3); DSC P2, Raman P1 — sub-table below | Table 2, p.145 |
| C14 | claim, conclusion, authors: "seemed"; "can often be used as an indication of miscibility" | Probucol seemed to form a single-phase amorphous system with PVP by the solvent method; a Tg between those of the components can often indicate miscibility [rests on: R4.a, R9; cited: Bosma et al. 1988] | p.143 |
| C32 | claim, conclusion, authors: "to some extent"; "indicate" | Molecular-level mixing of probucol and PVP occurred to some extent: Raman shows some hydrogen bonding and the dispersion Tg lies between those of probucol (26 °C) and PVP (163 °C) [rests on: R4.a, R5; M1, M2] | p.147 |
| 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 |

## 2006 Marsac — Theoretical and Practical Approaches for Prediction of Drug–Polymer Miscibility and Solubility · Solid state stability / Miscibility and drug-polymer interactions

[2006-marsac-drug-polymer-miscibility-solubility](../../../cards/2006-marsac-drug-polymer-miscibility-solubility/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · measured · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R2 | record, simulated (E1) | ΔGmix/RT versus Φ_polymer; no ordinate scale — nifedipine–PVP K29/32 (caption: "k29/30"); χ = −4.2 (a), −3.8 (b), 0.5 (c), 1.0 (d), 2.0 (e) — (e) above the end-point baseline at all compositions (maximum near Φ ≈0.37); (c) and (d) shallow and below the baseline, (c) lower than (d); (a) and (b) deep with one minimum near Φ ≈0.54, (a) deeper than (b) (read from Fig. 2); text: large positive χ gives positive ΔGmix, small χ gives negative ΔGmix with one minimum | Fig. 2, p.2420; text p.2420 |
| R3 | record, simulated (E1) | χ required for miscibility over the entire composition range — nifedipine–PVP (K29/32), from the Fig. 2 simulations — approximately 0.6 or less | p.2420 |
| R13 | record, cited (ref 28) | miscibility of felodipine and nifedipine with PVP — experiments in ref 28 — both miscible with PVP over all concentrations | p.2420 |
| C33 | claim, conclusion, authors: asserted | The melting-point χ of −3.8 predicts nifedipine–PVP miscibility (Fig. 2), consistent with experiment; abstract: with these χ values miscibility was predicted for all compositions, in agreement with experimental data [rests on: R9, R2, R13] | p.2417, p.2422 |
| X9 | extractor note | claim-data gap — The abstract and C33 state that miscibility was predicted for all compositions in agreement with experiment; Fig. 2 computes only nifedipine–PVP K29/32, and felodipine's χ (−4.2) appears only as curve (a) on that nifedipine system; the χ values refer to temperatures near the melting points (C32), while the temperature of the Fig. 2 simulation is not stated; the experimental miscibility is cited (R13) — C33, C32, R2, R9, R13 — treat felodipine–PVP miscibility as not separately computed and the prediction temperature as unstated |  |

## 2006 Marsac — A Comparison of the Physical Stability of Amorphous Felodipine and Nifedipine Systems · Solid state stability / Physical stability

[2006-marsac-physical-stability-amorphous-felodipine-nifedipine](../../../cards/2006-marsac-physical-stability-amorphous-felodipine-nifedipine/paper.html) · Solid state stability / Physical stability · measured · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R17 | record, measured | Tg versus PVP content (°C; error bars one SD), with Gordon-Taylor (solid) and Couchman-Karasz (dashed) curves — nifedipine-PVP (a) and felodipine-PVP (b) dispersions (P3, P7); fit parameters not printed — sub-table below; text: a single Tg at every composition; Tg of felodipine with 10 wt% PVP 40.5 (±0.5) °C, slightly below pure felodipine; Tgs of the two drug-PVP systems virtually identical at every concentration | Fig. 10, p.2312; text p.2311 |
| C23 | claim, conclusion, authors: "indicates" | A single Tg at every composition shows that both drug-polymer systems are miscible across the entire concentration range [rests on: R17] | p.2311 |
| C44 | claim, conclusion, authors: "demonstrate"; "potential changes" | A single Tg and drug-polymer interactions at all compositions demonstrate miscibility, so the molecular environment of the drug is altered, with potential changes in ΔGv, ΔGs and ΔE [rests on: R17, R13, R14] | p.2314 |

## 2009 Marsac — Estimation of Drug–Polymer Miscibility and Solubility in Amorphous Solid Dispersions Using Experimentally Determined Interaction Parameters · Solid state stability / Miscibility and drug-polymer interactions

[2009-marsac-drug-polymer-miscibility-solubility-asd-interaction-parameters](../../../cards/2009-marsac-drug-polymer-miscibility-solubility-asd-interaction-parameters/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · measured · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R1 | record, cited or measured per row | miscibility class and the evidence for it — nine small molecule–polymer pairs — sub-table below | Table I, p.144 |
| R7 | record, derived (E2) | Flory–Huggins χ from offset melting temperatures (lattice volume = EP volume) — P1, P6 — sub-table below | Table II, p.146 |
| C12 | claim, conclusion, authors: asserted | Pairs reported as miscible (Table I) show melting point depression, to various degrees, while immiscible or partially miscible pairs show little or none [rests on: R1, R2, R3, R4, R5] | p.139, p.144 |
| C29 | claim, conclusion, authors: "indicating"; "These results indicate"; "suggesting" | Most miscible systems have χ close to or below zero, indicating athermal or slightly exothermic mixing, so miscibility in these systems is largely driven by entropy; indomethacin's lowest χ suggests more exothermic mixing; immiscible systems yield large positive χ [rests on: R7, R9] | p.146-147 |
| C44 | claim, mechanism, authors: "it can be predicted"; "consistent with" | Itraconazole–Eudragit E100 (ref 65) combines a polymer with strong ionic self-interactions and an API with mainly dispersive interactions; adhesive interactions are predicted to be unfavourable relative to cohesive ones, giving the reported miscibility gap, and the lack of melting point depression is consistent with substantial immiscibility [rests on: R1.i, R4, R7.i] | p.149 |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R6 | record, measured | PCA of IR spectra: scores on PC1 and PC2 — felodipine-PVP spin-coated dispersions (P3) and calculated physical mixtures (P4), PCA as P5 — text: PC1 alone describes the trend of the calculated physical mixtures, which vary little along PC2; dispersion scores lie apart from the physical-mixture scores; a second PC is needed for the trend of the dispersions. Sub-table below (all values ≈, read from Fig. 3a) | Fig. 3a, p.2527; text p.2527 |
| R8 | record, measured | PCA of IR spectra: scores on PC1 and PC2 — nifedipine-PVP spin-coated dispersions (P3) and calculated physical mixtures (P4) — text: the dispersions have scores different from the calculated physical-mixture scores. Sub-table below (all values ≈, read from Fig. 4a) | Fig. 4a, p.2528; text p.2528 |
| 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 |
| C38 | claim, conclusion, authors: abstract: "was verified" (complete range); discussion: "clearly established" (range of compositions studied); conclusions: asserted (complete range) | Nifedipine-PVP and felodipine-PVP are miscible, forming one amorphous phase across the drug-polymer concentration range [rests on: R6-R9, R16.a-d, R17, R19, R20, R5] | p.2523, p.2532, p.2533 |
| C40 | claim, conclusion, authors: discussion: "seemed to suggest"; abstract: partial miscibility "suspected", one phase "could only be unambiguously verified at higher concentrations of polymer"; conclusions: "suspected to be miscible at higher PVP loading, but not at lower" | Ketoconazole-PVP shows some drug-polymer interaction by IR, and PXRD shows significant molecular-level change at 70% PVP but not at 30% PVP, so the system appears partially miscible, with a single amorphous phase only at higher PVP [rests on: R10, R16.e-f, R21] | p.2523, p.2533 |
| 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 |

## 2009 Rumondor — Effects of Polymer Type and Storage Relative Humidity on the Kinetics of Felodipine Crystallization from Amorphous Solid Dispersions · Solid state stability / Physical stability

[2009-rumondor-polymer-rh-felodipine-crystallization-kinetics](../../../cards/2009-rumondor-polymer-rh-felodipine-crystallization-kinetics/paper.html) · Solid state stability / Physical stability · used · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| C22 | claim, mechanism, authors: abstract: "It is hypothesized"; discussion: "supporting the supposition", "can be explained in part", "can be explained by"; conclusions: "can be attributed" | The rapid and PVP-level-independent crystallization of PVP dispersions at high RH, and their faster crystallization than HPMCAS dispersions, are explained by the greater moisture sorption of PVP dispersions, which causes moisture-induced drug-polymer immiscibility (amorphous-amorphous phase separation) in addition to raising molecular mobility (lowering Tg) [rests on: R6-R9, R21, R23, R24, R25] | p.2599, p.2604, p.2605 |
| C33 | claim, recommendation, authors: "highlight the importance" | The effects of storage conditions on the miscibility of amorphous solid dispersions need to be considered when interpreting drug crystallization data [rests on: R9, C22] | p.2605 |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R3 | record, measured | IR of dry, freshly prepared dispersions — all five drug-PVP systems (P1, P2) — spectra differ from the calculated amorphous physical-mixture spectra and from the crystalline reference spectra; band positions in R4 | p.1495, p.1497, p.1498 |
| R5 | record, measured | number of Tg events of dry rotary-evaporated dispersions — droperidol-PVP and pimozide-PVP, polymer up to 50% dry weight basis (P8) — one Tg event, located between the Tgs of the pure amorphous drug and the pure polymer; compositions and values not printed except for pimozide-PVP (R17, R18) | p.1495 |
| C1 | claim, conclusion, authors: abstract: asserted ("confirmed"); discussion: asserted | Immediately after preparation, drug and polymer were completely miscible in all five dispersions, shown by specific drug-polymer interactions and a single Tg [rests on: R3, R4, R5, R6] | p.1492, p.1501 |
| C14 | claim, conclusion, authors: "support" | The single Tg of droperidol- and pimozide-PVP supports the IR conclusion that the dry systems are miscible over the composition range studied [rests on: R5] | p.1495 |

## 2010 Kestur — Role of polymer chemistry in influencing crystal growth rates from amorphous felodipine · Solid state stability / Miscibility and drug-polymer interactions

[2010-kestur-polymer-chemistry-felodipine-crystal-growth-inhibition](../../../cards/2010-kestur-polymer-chemistry-felodipine-crystal-growth-inhibition/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · used · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| C2 | claim, prior hypothesis, authors: "it is generally accepted"; abstract: asserted | Polymers are effective crystallization inhibitors for many organic glasses and supercooled liquids; to be effective they are generally accepted to need molecular mixing with the drug in one amorphous phase (an ASD), so readily crystallizing polymers are generally not effective [rests on: cited: refs 8-12] | p.2390 |
| C5 | claim, assumption, authors: asserted; "potentially" | The two-step route gives uniform drug–polymer mixing at the molecular level; rotary evaporation below 5% w/w would partially crystallize felodipine and give a potentially non-uniform mixture [rests on: argument only] | p.2391 |
| C37 | claim, conclusion, authors: asserted ("clearly demonstrate") | IR shows that each polymer forms intermolecular interactions with felodipine, as expected for a molecular dispersion, to different extents [rests on: R9, R11-R14] | p.2396 |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R2 | record, measured | NH-region spectra from 0 °C (bottom) to as high as 180 °C (top) — dispersions with (a) 0, (b) 30, (c) 37, (d) 46, (e) 74 wt% PVP; 5–15 °C steps (P6) — (a) one main band, maximum ≈3340 cm−1 in the lowest and ≈3350 cm−1 in the highest spectrum, shoulder ≈3420 cm−1; (b) maximum ≈3345 cm−1 with shoulder ≈3300 and band ≈3230 cm−1; (c) broad maximum ≈3300–3340 cm−1 and band ≈3230 cm−1; (d) and (e) maximum ≈3297 cm−1, band ≈3225 cm−1 and the ≈3340 cm−1 band as a shoulder; in (b)–(e) the band near 3290–3300 cm−1 is present in every spectrum up to the highest temperature (read from Fig. 1); text: at high PVP content the drug–polymer band dominates and the drug–drug band appears as a shoulder | Fig. 1, p.173 |
| R3 | record, measured | drug–drug NH peak position vs temperature (cm−1, n = 3 trials) — 0, 30, 54 wt% PVP films (P6) — sub-table below; text: pure amorphous felodipine 3337 cm−1 at 5 °C to 3350 cm−1 at 160 °C (see X1) | Fig. 2a, p.174; text p.172 |
| R4 | record, measured | drug–polymer NH peak position vs temperature (cm−1, n = 3 trials) — 30 and 54 wt% PVP films (P6) — sub-table below; text: 30 wt% PVP 3288 cm−1 at 5 °C to 3296 cm−1 at 160 °C | Fig. 2b, p.174; text p.172 |
| R6 | record, measured | NH peak positions on heating (▲) and cooling (●) — 37 wt% PVP film, 0–160 °C (P6) — heating and cooling points superimpose (text: no hysteresis); drug–drug ≈3344 cm−1 at 0 °C to ≈3351–3353 cm−1 at 160 °C; drug–polymer ≈3291.5 cm−1 at 0 °C to ≈3298 cm−1 at 160 °C (read from Fig. 3) | Fig. 3, p.174; text p.173 |
| C33 | claim, conclusion, authors: asserted ("clearly demonstrate") | The variable-temperature spectra demonstrate that felodipine–PVP miscibility is maintained up to the drug's melting point, shown by the persisting drug–polymer hydrogen bonds [rests on: R2, R3, R4] | p.181 |
| C35 | claim, conclusion, authors: "quite remarkable and indicates"; "suggesting"; "good agreement" | The reversibility of the drug–polymer interactions with temperature (cited as Figure 8; see X2) shows the system is well mixed at all temperatures explored; no upper or lower critical solution temperature was seen over the timescales and temperatures studied, so this is a region of miscibility, in good agreement with the miscibility predicted from Tg and mixing thermodynamics (ref 25) [rests on: R6, R23] | p.181 |
| C47 | claim, conclusion, authors: "supports the supposition" | At 125 °C, well above the Tg of felodipine and of the one-phase dispersion (about 80 °C), remixing takes place over several hours, which supports miscibility of amorphous felodipine and PVP in the absence of moisture [rests on: R16, R17, R21] | p.182 |

## 2010 Rumondor — Analysis of the Moisture Sorption Behavior of Amorphous Drug–Polymer Blends · Solid state stability / Physical stability

[2010-rumondor-moisture-sorption-amorphous-drug-polymer-blends](../../../cards/2010-rumondor-moisture-sorption-amorphous-drug-polymer-blends/paper.html) · Solid state stability / Physical stability · used · as: drug–polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| C5 | claim, assumption, authors: asserted ("have been previously demonstrated") | Blends prepared by P1 are miscible with a single Tg, as demonstrated previously [rests on: cited: refs 8, 10, 15-17] | p.1056 |
| C38 | claim, assumption, authors: "seems more appropriate" | Treating the blend as a new solid matrix with its own combined interactions with water is more appropriate for blends with intimate molecular-level mixing, as shown for these model systems (ref 16) [rests on: cited: ref 16] | p.1063 |
| R20 | record, cited | indomethacin–PVP miscibility and interaction strength — single Tg (ref 11), infrared spectroscopy (ref 12), powder X-ray diffraction (ref 13); later interaction-parameter estimate (ref 14) — miscible; interaction parameter much lower than 1.27-1.49 | p.1056 |

## 2010 Rumondor — Application of Partial Least-Squares (PLS) modeling in quantifying drug crystallinity in amorphous solid dispersions · Characterization methods / Solid-state methods

[2010-rumondor-pls-quantifying-crystallinity-amorphous-solid-dispersions](../../../cards/2010-rumondor-pls-quantifying-crystallinity-amorphous-solid-dispersions/paper.html) · Characterization methods / Solid-state methods · used · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| C7 | claim, prior hypothesis, authors: "is known to" | FEL and PVP form an intimately mixed amorphous solid dispersion [rests on: cited: Marsac et al. 2006a, 2006b, 2008, 2010; Konno and Taylor 2006] | p.156 |
| C8 | claim, assumption, authors: "It is recognized"; "may occur" | The X-ray pattern of a molecular-level ASD is not a linear combination of the pure amorphous patterns, and intimate mixing may change the halo shape; calibration samples must therefore be ASD mixed with crystalline FEL rather than amorphous FEL, crystalline FEL and polymer [rests on: cited: Rumondor et al. 2009a; Newman et al. 2008] | p.156 |
| C26 | claim, mechanism, authors: "Several potential explanations can be offered" | The shifts may reflect intimate drug-polymer mixing in the amorphous solid dispersion samples [rests on: R16; cited: Rumondor et al. 2009a; Newman et al. 2008] | p.158-159 |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R1 | record, measured | IR band positions (cm⁻¹) with the authors' assignments — spin-coated films (P1, P2), dry: polymers, amorphous drugs, 50 wt% polymer dispersions — sub-table below (sh = shoulder, w = weak); assignments copied as printed | Table 1, p.481 |
| R2 | record, measured | IR of dry dispersions immediately after preparation — all dispersions studied (P1, P2) — bands assigned by the authors to drug-polymer interactions (R1) present in every dry dispersion; spectra differ from the amorphous drug and polymer references | p.480 |
| 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 |
| C9 | claim, conclusion, authors: "support the conclusion" | In the absence of water all drug-polymer systems studied were mixed at the molecular level as one-phase amorphous dispersions; felodipine-HPMCAS is confirmed miscible as reported earlier [rests on: R1, R2, R3] | p.480 |
| C16 | claim, conclusion, authors: "it can be concluded" | Felodipine-HPMCAS, quinidine-HPMCAS, indomethacin-PVPVA and indomethacin-HPMCAS: exposure up to 94% RH did not disrupt drug-polymer interactions and the dispersions stayed one phase at all times [rests on: R13-R17, R3.f-i] | p.485, p.487 |

## 2011 Alonzo — Dissolution and Precipitation Behavior of Amorphous Solid Dispersions · Dissolution / B. Supersaturation from ASD dissolution

[2011-alonzo-asd-dissolution-precipitation-nanoparticles](../../../cards/2011-alonzo-asd-dissolution-precipitation-nanoparticles/paper.html) · Dissolution / B. Supersaturation from ASD dissolution · used · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| C8 | claim, assumption, authors: asserted ("previously confirmed"; "known molecular level miscibility") | All API–polymer combinations studied are miscible at the molecular level [rests on: cited: refs 21-23] | p.3318, p.3328 |
| C36 | claim, caveat, authors: "cannot be entirely ruled out but seems unlikely" | Particles formed by crystallization of nanometre-scale amorphous drug regions in the polymer matrix cannot be entirely ruled out but are unlikely given the high polymer concentration and known molecular miscibility [rests on: cited: refs 21-23] | p.3328 |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R1 | record, measured | appearance and PXRD of dry dispersions — spin-coated films of all systems (P1); bulk 50:50 powders immediately after production (P6) — films transparent; PXRD halo pattern (data not shown) | p.1211 |
| R2 | record, measured | IR carbonyl region and OH band, dry clofoctol–PVP — films at 100, 90, 70, 50, 30, 10% PVP (P1, P2) — PVP carbonyl peak at 1,682 cm⁻¹ in pure PVP; a new peak at 1,663 cm⁻¹ grows as PVP content falls (Fig. 2, arrow): maximum ≈1,684 with shoulder ≈1,663 at 50% PVP, maximum ≈1,663 with shoulder ≈1,684 at 30% PVP, single maximum ≈1,663 at 10% PVP (read from Fig. 2); clofoctol free OH peak at 3,365 cm⁻¹ moves to 3,263 cm⁻¹ and broadens in the binary films (not shown); pure clofoctol has no significant absorption in the carbonyl region | Fig. 2, p.1211 |
| R4 | record, measured and calculated | IR carbonyl region, dry indoprofen–PVP — films at 100, 90, 70, 50, 30, 0% PVP (P1, P2); calculated 50% physical mixture (P5) — from 100 to 70% PVP the free PVP carbonyl peak at 1,682 cm⁻¹ loses relative intensity and a shoulder develops at 1,641 cm⁻¹ (Fig. 3, arrow); the 50% PVP film spectrum differs from the calculated 50% physical-mixture spectrum, which has no band near 1,641 cm⁻¹; pure amorphous indoprofen: shoulder ≈1,734, maxima ≈1,699 and ≈1,611 cm⁻¹ (read from Fig. 3) | Fig. 3, p.1211-1212 |
| R6 | record, measured and calculated | IR carbonyl region, dry loratadine–PVP — films at 100-0% PVP (P1, P2); calculated 50% physical mixture (P5) — amorphous loratadine carbonyl peak at 1,698 cm⁻¹, pure PVP at 1,682 cm⁻¹; in the dispersions one broad merged peak lies between them; its shape differs from the calculated physical-mixture spectrum, which has a maximum ≈1,695 and a shoulder ≈1,673 cm⁻¹ (arrows, read from Fig. 5) | Fig. 5, p.1212-1213 |
| C9 | claim, conclusion, authors: "suggesting" | Transparent films point to amorphous films; the PXRD halo of bulk dispersions is typical of amorphous systems [rests on: R1] | p.1211 |
| C13 | claim, conclusion, authors: asserted ("clearly show") | Indoprofen–PVP dispersion spectra cannot be constructed from the spectra of the pure amorphous components; 1,682 cm⁻¹ is non-hydrogen-bonded PVP carbonyl and 1,641 cm⁻¹ PVP carbonyl hydrogen bonded to the indoprofen COOH, as reported for indomethacin–PVP and ketoprofen–PVP [rests on: R4; cited: refs 7, 13] | p.1211-1212 |
| C15 | claim, conclusion, authors: "are anticipated"; "indicated" | No hydrogen bonds are anticipated between loratadine and PVP, giving subtler spectral changes; the merged peak differing from the calculated physical mixture indicated intimate mixing [rests on: R6, R7] | p.1212-1213 |

## 2011 Zhu — Time-Resolved SAXS/WAXS Study of the Phase Behavior and Microstructural Evolution of Drug/PEG Solid Dispersions · Solid state stability / PEG dispersions

[2011-zhu-time-resolved-saxs-waxs-drug-peg-solid-dispersions](../../../cards/2011-zhu-time-resolved-saxs-waxs-drug-peg-solid-dispersions/paper.html) · Solid state stability / PEG dispersions · measured · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R5 | record, derived (χ by E1 and E2; solubility by E3); eutectic columns measured (Figs. 2-4); HLP and CPM rows from cited phase diagrams (ref 19) | interaction parameter, solubility in PEG at 25 °C, eutectic composition and temperature — six APIs with PEG 3350; footnote a: calculated from melting point depression data with 50-80% API loading; footnote b (HLP, CPM): calculated from the phase diagrams taken from the literature (ref 19) — sub-table below; text: CPM/PEG eutectic composition 35% with a minimum melting point of 55 °C | Table 1, p.935; text p.934 |
| E1 | equation | Flory-Huggins melting point depression: (1/T_M^mix − 1/T_M^pure) = −(R/ΔH_fus)[ln φ_API + (1 − 1/m)φ_polymer + χφ_polymer²] | p.934 |
| C6 | claim, assumption, authors: "consistent with" | More negative interaction parameters are consistent with a negative enthalpy of mixing, reflecting favourable drug-polymer interactions [rests on: argument only] | p.934 |

## 2012 Trasi — Effect of Additives on Crystal Growth and Nucleation of Amorphous Flutamide · Solid state stability / Physical stability

[2012-trasi-flutamide-additives-growth-nucleation](../../../cards/2012-trasi-flutamide-additives-growth-nucleation/paper.html) · Solid state stability / Physical stability · measured · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R18 | record, measured | FTIR NH and C=O regions with PAA — flutamide-PAA 1:1 (P4) — no change in the position of any hydrogen-bonding band; mixture spectrum matches the sum of the two pure-component spectra | Fig. 11, p.3227 |
| R21 | record, measured | miscibility of flutamide-PAA at higher polymer content — flutamide-PAA blends at higher drug-polymer ratios (IR, P4); 50 wt% blend (DSC, P5) — IR spectrum equals the summation of the component spectra; Tg of the 50 wt% blend identical to that of flutamide (value not printed) | p.3228 |
| C29 | claim, conclusion, authors: asserted ("clearly was not the case") | PAA, which lacks a good acceptor but has a strong donor expected to bind the flutamide amide carbonyl, does not interact with flutamide, unlike acetaminophen with PAA; the mixture spectrum is a simple summation, typical of immiscible systems [rests on: R18, R27; cited: refs 17, 18] | p.3227 |
| C38 | claim, conclusion, authors: "it appears" | At higher drug-polymer ratios flutamide-PAA blends appear immiscible [rests on: R21] | p.3228 |

## 2012 Trasi — Effect of polymers on nucleation and crystal growth of amorphous acetaminophen · Solid state stability / Physical stability

[2012-trasi-taylor-polymers-nucleation-growth-amorphous-acetaminophen](../../../cards/2012-trasi-taylor-polymers-nucleation-growth-amorphous-acetaminophen/paper.html) · Solid state stability / Physical stability · used · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| C17 | claim, conclusion, authors: results: "confirms"; discussion: "indicating" | The slight increase in Tg confirms (results) or indicates (discussion) that the drug is miscible with each polymer [rests on: R9] | p.5192, p.5195 |
| R9 | record, measured | onset Tg, onset Tm and ΔHf at 10 °C/min — Tg: amorphous dispersions with 10% polymer (P4); Tm and ΔHf: physical mixtures with 10% w/w polymer (P5); standard deviation for Tg and Tm below 1 °C; values in parentheses for ΔHf not defined — sub-table below; text: Tg rises by at most 4 °C (PAA and PVP), by 2-3 °C for the other dispersions | Table 1, p.5191; text p.5191 |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R1 | record, cited (ref 30) | miscibility of felodipine–PAA blends — earlier study with a variety of experimental techniques — partially miscible: miscible at low and at high polymer concentrations, phase separated at intermediate compositions; 90:10 (w/w) felodipine–PAA miscible; 30:70 (w/w) starts to show phase separation | p.2067, p.2068, p.2071 |
| R2 | record, measured | AFM topography, 25:75 felodipine–PAA — P1 film on ZnSe; P5; 5 × 3 µm², colour range 250 nm — text: smooth surface with few topographical features and a uniform interaction with the tip; figure: uniform height over the whole area, no domains | Fig. 2a, p.2068; text p.2068 |
| 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 |
| C20 | claim, conclusion, authors: "can always be inferred"; "in line with" | In both phases the other component can always be detected from its characteristic peaks, in line with a partially miscible system [rests on: R9, R10; cited: ref 30] | p.2070 |
| C21 | claim, conclusion, authors: "is to be expected"; "one would expect"; "have suggested" | Partial miscibility is expected: from the AFM result the PAA-rich phase should hold at least 25% felodipine, and earlier work found a 90:10 felodipine–PAA dispersion miscible [rests on: R2, R1] | p.2070-2071 |
| C30 | claim, conclusion, authors: "suggested" | Standard AFM across compositions showed limited miscibility, in line with previous findings [rests on: R2, R3, R4; cited: ref 30] | p.2066 |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| C8 | claim, assumption, authors: asserted; "often used" | Peak shifts in the IR spectrum of a miscible dispersion relative to the physical mixture come from specific drug-polymer interactions, usually hydrogen bonding, and the presence of specific interactions is often used to infer miscibility [rests on: cited: refs 12, 30, 31] | p.174-175 |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R1 | record, measured | prodan emission maximum and pyrene I/III ratio in films (SD below 2 nm and below 0.02; n not stated) — spin-coated films (P2), fluorescence spectroscopy (P3); heating 2 min at 165 °C (P5) — sub-table below | Table 1, p.31; text p.9, p.11 |
| 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 |
| R13 | record, measured | local softening (transition) temperature by nanoTA — 40:60 film (P10), probe heated at 2 °C/s; one curve on a discrete domain (green), two on the continuous phase (purple); topography 20.01 × 20.01 µm, height -125 to 125 nm — ITZ-rich domain: 71 °C (text; plot marker 71.26 °C, -5.6374 V); continuous phase: 108 °C (text; plot marker 108.94 °C, -5.0332 V). Domain curve rises from ≈-5.93 V at ≈35 °C to the marker, then falls until it stops near ≈80 °C; continuous-phase curves rise to the marker and then continue at a lower slope to ≈120 and ≈150 °C (read from Fig. 8) | Fig. 8, p.28; text p.14 |
| 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 |
| C1 | claim, prior hypothesis, authors: abstract: "is considered"; introduction: "It is commonly thought" | Molecular-level drug-polymer miscibility is considered a prerequisite for an optimally performing ASD [rests on: cited: refs 3, 7] | p.2; p.3 |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| 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 |
| C7 | claim, conclusion, authors: "consistent with" | The initial prodan value of the 50:50 PB–PVP film lies between those of PVP and amorphous probucol, consistent with a miscible film [rests on: R4] | p.11 |
| C17 | claim, conclusion, authors: "This is indicative of"; "correlates well" | In 80:20 RTV–PVP the new 1654 cm-1 band is a hydrogen bond between the PVP carbonyl and RTV donors; after 97% RH the interactions are disrupted by AAPS, cohesive interactions re-form (1630 and 1717 cm-1 for an RTV-rich phase, 1681 cm-1 for a PVP-rich phase); this indicates AAPS and correlates well with the fluorescence data; together with DSC it confirms initial miscibility [rests on: R17; abstract] | p.2, p.14-15 |
| C19 | claim, conclusion, authors: "consistent with"; "suggesting"; "indicating"; "either ... or" | PB–PVP DSC: one Tg before exposure means a molecularly mixed dispersion; two Tg events after 6 h mean phase separation, before crystallization starts at 21 h; at 30 h the Tg at 25 °C is that of amorphous PB and the endotherm near the PB melting point shows the drug-rich domains have started to crystallize, either during continued moisture exposure or during the DSC heating [rests on: R19, R5] | p.15 |

## 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: drug-polymer miscibility

| 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 |
| R5 | record, measured | topography versus DL — TPV-HPMCAS films 1:9 to 5:5 (P1, P2); 4 x 2 µm (1:9, 2:8), 5 x 2.51 µm (3:7, 5:5), 3 x 1.5 µm (4:6); colour scale ±25 nm — text: below 40% DL irregular height variations like those of the pure HPMCAS film; at 40% DL very small, regularly shaped circular domains about 120 nm in diameter and 50 nm in height; features more obvious at 50% DL | Fig. 3B, 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 |
| R9 | record, measured | local AFM-IR spectra of continuous and dispersed phases — 80:20 TPV-HPMCAS (P4), n = 5 per phase; height image ±50 nm — 1525 cm-1 bands of similar intensity in both phases; 1236 cm-1 HPMCAS band clearly more intense in the continuous phase | Fig. 4B, p.38; text p.16 |
| R10 | record, measured | local AFM-IR spectra of continuous and dispersed phases — 50:50 TPV-PVPVA (P4), n = 5 per phase; height image ±50 nm — continuous phase: 1244 cm-1 PVPVA band stronger than the 1525 cm-1 TPV band; dispersed phase: 1244 cm-1 band weaker than the 1525 cm-1 band; bands of both components in both phases | Fig. 4C, p.38; text p.16 |
| C17 | claim, conclusion, authors: results: "appeared to occur when the drug loading exceeded 30%"; abstract: "a smaller miscibility gap was observed", "higher than ~30-40%"; discussion: "exceeded 30- 40%" | TPV-HPMCAS phase separation begins above about 30% DL, so this pair is more miscible than TPV-HPMC and its phases are harder to tell apart chemically, both containing much TPV [rests on: R5, R9, R11] | p.3, p.16, p.25 |
| C52 | claim, conclusion, authors: discussion: "indicate", "appears to be the most miscible"; abstract: "Phase separation was observed" | TPV-HPMCAS is the most miscible pair, phase separated above 30% DL in films spin-coated under ambient conditions, while HPMC and PVPVA separate at lower DL (abstract: above 10%); the marketed TPV product (Incivek) is a spray-dried HPMCAS ASD [rests on: R4-R6, R9, R11] | p.3, p.28 |

## 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: drug-polymer miscibility

| 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 |
| R3 | record, measured | normalized emission spectra and emission maximum versus DL (mean, n = 3) — IDM-HPMCAS films 5-95% DL, fresh (P1, P3) — text: a new blue-shifted emission peak at 30% DL relative to the 20% DL spectrum. Fig. 4A: 5, 10 and 20% DL one band with maximum ≈510-515 nm; 30-95% DL maximum ≈478-485 nm. Fig. 4B: sub-table below | Fig. 4, p.10; text p.8 |
| R4 | record, measured | normalized emission spectra and emission maximum versus DL (mean, n = 3) — IDM-PVP films 5-95% DL, fresh (P1, P3) — text: the emission peak at ~480 nm is not observed until the DL reaches 80%. Fig. 5A: 5-70% DL one band with maximum ≈505-515 nm; 80, 90 and 95% DL maximum ≈478 nm. Fig. 5B: sub-table below | Fig. 5, p.10; text p.8 |
| R21 | record, derived (P3-P6) | miscibility by method, as tabulated by the authors — films (fluorescence, IR) and bulk ASDs (DSC) — sub-table below | Table 2, p.23 |
| C17 | claim, conclusion, authors: "suggest"; "appears to be" | IDM-HPMC is miscible up to 50% DL and phase separates at 60% and above; the miscibility limit lies between 50% and 60% DL [rests on: R2] | p.8 |
| C18 | claim, conclusion, authors: "suggests"; "appears" | IDM-HPMCAS forms a new drug-rich phase at 30% DL; the miscibility limit lies between 20% and 30% DL [rests on: R3] | p.8 |
| C56 | claim, conclusion, authors: asserted ("experimentally determined") | IDM is miscible only at relatively low DL with HPMCAS, more with HPMC, and over the largest range with PVP (abstract: miscibility limits 50%~60%, 20%~30% and 70%~80% DL for HPMC, HPMCAS and PVP) [rests on: R21] | p.2, p.25 |

## 2016 Xie — Improved Release of Celecoxib from High Drug Loading Amorphous Solid Dispersions Formulated with Polyacrylic Acid and Cellulose Derivatives · Dissolution / B. Supersaturation from ASD dissolution

[2016-xie-celecoxib-high-drug-loading-asd-paa-cellulose-derivatives](../../../cards/2016-xie-celecoxib-high-drug-loading-asd-paa-cellulose-derivatives/paper.html) · Dissolution / B. Supersaturation from ASD dissolution · measured · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R19 | record, measured | Tg of 1:1 binary ASDs (onset, second heating; unit not printed in Table 3) — P9 — CEX:HPMCAS 1:1 67±1; CEX:HPMC 1:1 71±6; CEX:PAA 1:1 83±2; pure components in B1 | Table 3, p.29 |
| C55 | claim, conclusion, authors: "indicates" | Each 1:1 binary ASD has a Tg between those of its components, so the drug has some miscibility with each polymer [rests on: R19; M1-M4] | p.29 |

## 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: drug-polymer miscibility

| 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 |
| 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 |
| C8 | claim, conclusion, authors: "consistent with"; "appear to be miscible" | ECP-HPMC films spun at 18% RH are miscible for 10-90% DL, at least at the 40 nm spatial resolution of the AFM settings [rests on: R3.a] | p.14 |
| C30 | claim, conclusion, authors: "consistent with" | Freshly prepared bulk ECP-PVPVA ASDs show one Tg, consistent with miscibility over 10-90% DL when prepared under low RH; Tg falls with DL because ECP has a lower Tg than PVPVA [rests on: R24, M1] | p.28 |
| C33 | claim, conclusion, authors: asserted | ECP-polymer ASDs prepared under dry conditions or heated are fully miscible over 10-90% DL; trace water during preparation makes them phase separated; originally miscible ASDs became phase separated over 10-80% DL after 7 days at high RH (TEM) [rests on: R3.a, R10, R12, R19] | p.31 |
| C51 | claim, conclusion, authors: asserted ("confirming") | Rigorously excluding water during film formation gives miscible films, confirming the role of water in inducing phase separation [rests on: R3.a, R12.f] | p.40 |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R10 | record, measured | BF TEM of 30:70 E3 film made at 7% RH — P1.c, P9 — very homogeneous micrograph, no discrete domains (200 nm scale bar) | Fig. 3c, p.4392; text p.4393 |
| R24 | record, measured | UV absorption peaks vs drug loading — P1.l, P7, 20% RH — sub-table R24; text: systematic red shift with increasing loading, shift above 20% loading | Fig. 10a, p.4396; text p.4395−4396 |
| R25 | record, measured | emission vs drug loading, excitation 330 nm — P1.l, P5, 20% RH — sub-table R25; text: emission peak at around 386 nm in the 30−50% films | Fig. 10b, p.4396; text p.4396 |
| R26 | record, measured | BF TEM of spray-dried particles — P3 batches, ultrathin grids — sub-table R26; text: size of the dark spots increases with water in the stock solution (no sizes given) | Fig. 11, p.4397; text p.4396−4397 |
| C6 | claim, conclusion, authors: FLOM: asserted ("yielded a fully miscible film"); TEM: "indicating" | Films made at 7% RH are miscible: fully miscible at FLOM resolution, and homogeneous by TEM in agreement with FLOM and AFM. [rests on: R1.c, R3.h, R10] | p.4392; p.4393 |
| C33 | claim, conclusion, authors: "This indicates" | When spin coating at 20% RH, phase separation occurs above 20% drug loading. [rests on: R24, R25] | p.4396 |
| C39 | claim, mechanism, authors: "Our results therefore suggest" | ITZ–HPMC is thermodynamically miscible as a dry binary ASD but becomes kinetically trapped in a phase-separated state when made from a water-containing solvent; the phase separation has thermodynamic and kinetic components. [rests on: R1, R3, R10, R26] | p.4397−4398 |

## 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: drug-polymer miscibility

| 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 |
| 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 |
| C20 | claim, conclusion, authors: Results: suggests; Discussion: it can be inferred; Table II, Abstract, Conclusions: asserted | SD ASD: near-identical T1 but distinct T1rho are read as ITZ and HPMC being miscible on the 30–130 nm scale but immiscible at 2–8 nm (immiscible at 10 nm or lower, miscible above 30 nm); classed partially miscible; SD domains are smaller than 10 nm. [rests on: R21.a] | Results, pdf p.9; Table II, pdf p.9; Discussion, pdf p.12; Abstract, pdf p.1; Conclusions, pdf p.12 |
| C21 | claim, conclusion, authors: Results: suggesting; Discussion: indicates; Table II, Conclusions: asserted | Film-cast ASD: larger API–polymer differences in both T1 and T1rho are read as the slowly dried dispersion being phase separated (immiscible), at a length scale above 30 nm, supporting the fluorescence and confocal results. [rests on: R21.b] | Results, pdf p.9; Table II, pdf p.9; Discussion, pdf p.12; Conclusions, pdf p.12 |
| C26 | claim, conclusion, authors: asserted | In this study DSC gave a single, broad Tg for all ASDs studied (miscible by DSC criteria), whereas the fluorescence techniques detected phase separation in all samples. [rests on: R3, R7, R16, R17] | Discussion, pdf p.10; Conclusions, pdf p.12 |

## 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: drug-polymer miscibility

| 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 |
| 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 |
| C23 | claim, conclusion, authors: results: "suggesting"; discussion: "This suggests" | The nearly constant I/III of RTV-HPMCAS films means these systems resist phase separation and stay miscible for up to 96 h at 97% RH [rests on: R2] | pdf p.7, p.15 |
| C29 | claim, conclusion, authors: results: "consistent with", "indicates"; discussion: "in some", "supports the supposition", "appears", "suggesting" | Two Tgs in moisture-exposed RTV-PVP and RTV-PVPVA ASDs are consistent with moisture-induced AAPS; with the lower Tg near that of amorphous RTV (45 °C), phase separation appears extensive; the single, unchanged Tg of RTV-HPMCAS ASDs means they stay miscible, at least within DSC resolution [rests on: R6] | pdf p.10, p.16 |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R5 | record, measured | AFM topography and nano-IR spectra at five marked points — 50:50 w/w mico:PVPVA film spin-coated at 20% RH (P1), 5 x 5 µm — smooth topography (colour scale -20 to 20 nm); the five spectra (1524-1800 cm⁻¹) overlap, with the PVPVA band near 1679 cm⁻¹ and the broad drug band near 1590 cm⁻¹ in each; text: identical spectra at each analysis point, peaks of both drug and polymer | Fig. 4, pdf p.27; text pdf p.12-13 |
| R12 | record, measured | CFM with prodan and R6G — 50:50 film prepared at 20% RH (P1, P9) — uniform fluorescence intensity: blue at 407 nm excitation, red at 561 nm, purple when combined | Fig. 9, pdf p.30; text pdf p.15 |
| R14 | record, measured | modulated DSC midpoint Tg — 50:50 rotary-evaporated ASD powder, vacuum-dried (P10, P12) — single Tg at 26 °C | pdf p.16 |
| C10 | claim, conclusion, authors: "suggesting"; "indicating"; "suggest"; abstract: "confirmed" | The smooth topography of the 20% RH film suggests that drug and polymer are miscible, since phase-separated systems typically show topographic features; identical spectra across the film indicate chemical homogeneity at the about 100 nm resolution of nano-IR, so films prepared at low RH are miscible [rests on: R5, R27] | pdf p.3, p.12-13 |
| C41 | claim, conclusion, authors: "further confirmed"; "do not appear" | Water's ability to induce phase separation is further confirmed by high-RH exposure of a miscible film; miconazole and PVPVA as a binary system do not appear to be inherently immiscible [rests on: R15, R16, R5, R12] | pdf p.19 |

## 2017 Trasi — Evaluation of the Crystallization Tendency of Commercially Available Amorphous Tacrolimus Formulations Exposed to Different Stress Conditions · Solid state stability / Physical stability

[2017-trasi-commercial-amorphous-tacrolimus-crystallization-stress](../../../cards/2017-trasi-commercial-amorphous-tacrolimus-crystallization-stress/paper.html) · Solid state stability / Physical stability · used · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| C47 | claim, mechanism, authors: discussion and conclusions: "we believe"; abstract: "It seems probable" | Accord does not contain an ASD with molecular-level mixing of drug and polymer; the drug is present as a coating (shell) of amorphous tacrolimus on lactose (water-soluble excipient) particles, and in this state it is more susceptible to crystallization [rests on: R18, R21, R16] | pdf p.1, p.13 |
| C49 | claim, mechanism, authors: "We thus speculate" | Accord was made by ethanol wet granulation with solvent removal at elevated temperature and HPMC physically mixed in after amorphization, so no solid dispersion forms and tacrolimus and HPMC have no intermolecular interactions [rests on: R18.i, R25, R21] | pdf p.13 |
| C50 | claim, generalisation, authors: "are considered to be essential" | Molecular-level mixing and drug-polymer interactions are essential for stabilization of the amorphous form [rests on: cited: ref 36] | pdf p.13 |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R14 | record, measured | dry Tg (onset, °C) of binary ASDs versus polymer content — P6; neat-component Tg in B1; error bars on some points, n not stated — sub-table below; text: a single Tg for each composition, intermediate between the neat components | Fig. 6, p.6; text p.5-6 |
| C26 | claim, conclusion, authors: "suggesting" | A single Tg intermediate between the components suggests that CEX is miscible with each polymer [rests on: R14] | p.5-6 |

## 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: drug-polymer miscibility

| 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 |
| R9 | record, measured | Tg events after humidity exposure — ASD powders at 97% RH, 25 °C, 48 h (P10); data in supplementary Fig. A (not supplied) — text: trends similar to the dry state; EC, HPMCAS and HPMCP ASDs one Tg, lower than dry; CA ASDs two Tgs at all DLs; LPV and EUD similar Tg with water, only one Tg distinguished; CAP ASDs one Tg above 15% DL | p.119-120 |
| 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 |
| C29 | claim, conclusion, authors: "indicating possible" | LPV-CAP gave two Tgs at 15 and 33% DL and one from 50% DL, pointing to possibly increased miscibility with increasing DL [rests on: R8.c] | p.119 |
| C30 | claim, conclusion, authors: "suggesting" | A single Tg at all DLs for EC, HPMCAS and HPMCP ASDs points to drug-polymer miscibility [rests on: R8.d-f] | p.119 |

## 2018 Moseson — Nanometer-Scale Residual Crystals in a Hot Melt Extruded Amorphous Solid Dispersion: Characterization by Transmission Electron Microscopy · ASD process / ASD process

[2018-moseson-nanometer-residual-crystals-hme-asd-tem](../../../cards/2018-moseson-nanometer-residual-crystals-hme-asd-tem/paper.html) · ASD process / ASD process · used · as: homogeneous molecular dispersion

| id | kind | content | locator |
|---|---|---|---|
| R2 | record, cited | formulation critical temperature Tc (solubility temperature: lowest temperature at which a homogeneous molecular dispersion could theoretically be prepared) — 1:1 IDM:PVPVA; temperature-composition phase diagram of ref 6 — 131 °C | p.4, p.9-10 |
| C1 | claim, prior hypothesis, authors: "may"; "should" | If the crystalline-to-amorphous transformation during HME is incomplete, residual crystals may contribute to stability or dissolution performance issues; with sufficient thermal input and mixing a homogeneous molecular dispersion free of residual crystallinity should result [rests on: cited: refs 5-9] | p.3 |

## 2018 Moseson — The application of temperature-composition phase diagrams for hot melt extrusion processing of amorphous solid dispersions to prevent residual crystallinity · ASD process / ASD process

[2018-moseson-temperature-composition-phase-diagrams-hme-asd-residual-crystallinity](../../../cards/2018-moseson-temperature-composition-phase-diagrams-hme-asd-residual-crystallinity/paper.html) · ASD process / ASD process · used · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| C8 | claim, prior hypothesis, authors: asserted | Miscible drug-polymer systems show melting point depression because exothermic mixing plus favourable mixing entropy lowers the drug's chemical potential; immiscible systems show none [rests on: cited: refs 41, 42] | p.7-8 |
| C15 | claim, conclusion, authors: asserted ("confirming") | IDM showed melting point depression across the composition range, confirming drug-polymer miscibility at elevated temperatures [rests on: R2, R5, R6] | p.15 |
| C20 | claim, conclusion, authors: asserted | χ = -1.97 is comparable with values reported for the same system in other studies, and all studies conclude that IDM-PVPVA is miscible on the basis of a negative χ [rests on: R4, R7] | p.17 |

## 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: drug-polymer miscibility

| 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 |
| 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 |
| C29 | claim, generalisation, authors: discussion: "indicate", "can be"; conclusions: "can be" | Small amounts of water present as a contaminant in the solvent can be a "double-edged sword" for drug-polymer miscibility [rests on: R1, R4] | p.38; p.44 |

## 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 · used · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R21 | record, cited | dry-state miscibility of RTV-PVPVA ASDs — ref 14 — demonstrated previously | p.16 |
| C27 | claim, prior hypothesis, authors: "potentially" | A binary ASD stays miscible while drug-polymer adhesive interactions are favourable relative to drug-drug and polymer-polymer cohesion, allowing for mixing entropy; water interacts with the hydrophilic polymer, potentially disrupting drug-polymer interactions, so drug self-associates into nano- to micron-sized drug-rich domains (water-induced AAPS); water also lowers Tg and raises mobility [rests on: cited: refs 14, 28-31, 43-48] | p.14 |
| C35 | claim, conclusion, authors: "in agreement with" | The observations agree with an initially miscible system, consistent with the previously shown dry-state miscibility [rests on: R21, R18] | p.16 |

## 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 · used · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| P2 | method | rotary-evaporated ASD film in vial | p.8; Fig. 2 caption, p.36–37 |
| R13 | record, measured | nanoTA local Tg of miscible films versus DL (calibration) — rotary-evaporated miscible films 0–100% DL (P10) — sub-table below; Gordon–Taylor fit with K = 0.628 (text), curve from ≈209 °C at 0% to ≈94 °C at 100% DL; text: nanoTA softening temperatures of pure HPMC and LPV films 20–60 °C above DSC Tg; Tg of homogeneous films rose with polymer content | Fig. 6B, p.41; text p.18 |
| C7 | claim, assumption, authors: asserted | LPV was chosen as a poorly soluble drug with low crystallization propensity, and HPMC because it has one of the highest Tgs among common ASD polymers, which allows local compositions to be estimated from local thermal properties [rests on: cited: refs 47, 32] | p.6-7 |

## 2019 Moseson — Dissolution of Indomethacin Crystals into a Polymer Melt: Role of Diffusion and Fragmentation · ASD process / ASD process

[2019-moseson-indomethacin-copovidone-melt-dissolution-fragmentation](../../../cards/2019-moseson-indomethacin-copovidone-melt-dissolution-fragmentation/paper.html) · ASD process / ASD process · used · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R26 | record, cited | IDM-copovidone interactions and miscibility (refs 32, 87-91) — IDM-copovidone — favourable specific interactions; miscible at high temperatures | pdf p.10 |
| C38 | claim, assumption, authors: asserted; "would be able" | Miscible drug-polymer systems show melting point depression, so the drug can dissolve into the polymer below its melting point; with favourable IDM-copovidone interactions and a solubility temperature of about 78 °C at 1:5 (R21, R26), all of the drug could dissolve at 130 °C if taken to completion [rests on: R21, R26; cited: refs 32, 85-91] | pdf p.10 |

## 2020 Que — Evidence for Halogen Bonding in Amorphous Solid Dispersions · Solid state stability / Miscibility and drug-polymer interactions

[2020-que-halogen-bonding-amorphous-solid-dispersions](../../../cards/2020-que-halogen-bonding-amorphous-solid-dispersions/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · used · as: drug–polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| C8 | claim, conclusion, authors: asserted | For every compound, additional lower-BE halogen peaks appear when the compound is molecularly mixed with PVPVA or PVP [rests on: R7, R8] | pp. 15-16 |
| X10 | extractor note | claim-data gap — No XRPD, DSC or other test of amorphous, single-phase state is reported for any ASD (up to 50 wt%) or IR film (up to 90 wt%); "molecularly mixed/dispersed" is assumed — C1, C8, P4, P7 — treat amorphous, miscible state as unverified, especially at 40-50 wt% (XPS) and 60-90 wt% (IR) |  |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| 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 |
| C29 | claim, mechanism, authors: asserted | Wet granulation dries much more slowly than spray drying, which makes crystallization more likely; faster solvent evaporation favours drug-polymer miscibility [rests on: argument only] | p.9 |

## 2021 Bhujbal — Physical Stability and Dissolution of Lumefantrine Amorphous Solid Dispersions Produced by Spray Anti-Solvent Precipitation · Solid state stability / Physical stability

[2021-bhujbal-lumefantrine-asd-spray-antisolvent-precipitation](../../../cards/2021-bhujbal-lumefantrine-asd-spray-antisolvent-precipitation/paper.html) · Solid state stability / Physical stability · used · as: drug–polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| C25 | claim, conclusion, authors: asserted | At 4:6, the Tg of HPMCP and HPMCAS ASDs lies between the Tg of neat amorphous drug and neat polymer [rests on: R10.c, R10.f] | p.2427 |
| C47 | claim, prior hypothesis, authors: "Theoretically"; "could decrease" | A miscible ASD should have a Tg between those of neat drug and polymer, and water can lower Tg [rests on: cited: refs 40−43] | p.2429 |

## 2022 Jr — Impact of Polymer Type on Thermal Degradation of Amorphous Solid Dispersions Containing Ritonavir · ASD process / ASD process

[2022-alvarenga-polymer-type-thermal-degradation-ritonavir-asd](../../../cards/2022-alvarenga-polymer-type-thermal-degradation-ritonavir-asd/paper.html) · ASD process / ASD process · used · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| C10 | claim, conclusion, authors: "indicating"; "confirmed" | A single Tg for each 20% DL ASD (54−135 °C) shows a single-phase amorphous system, and XRPD confirmed amorphous ASDs from both solvent evaporation and HME [rests on: R3, R5] | p.334 |
| R3 | record, measured | Tg of 20% DL RTV-ASDs (°C, mean ± SD, n = 3) — solvent evaporation (P1), DSC (P4) — sub-table below; text: a single Tg of 54−135 °C for each system | Table 1, p.335; text p.334 |
| R5 | record, measured | DSC and XRPD phase state — 20% DL ASDs with all ten polymers and 10−50% DL PVP K-30 and PVP/VA 64 ASDs (P1); HME extrudates at 130−160 °C (P2) — one Tg step in each ASD thermogram (Fig. S3A-C); crystalline RTV melting endotherm near 126 °C (Fig. S3D); neat RTV XRPD with sharp peaks between ≈8 and 30° 2θ; all solvent-evaporated ASDs and all extrudates show broad halos without sharp peaks | Figs. S3-S5, SI p.5-7; text p.334 |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R4 | record, measured | number of glass transitions and melting events in ASDs — P7; all ASDs of Table 1 — single Tg and no melting event in all ASDs except 50% DL HPMCAS, which showed a melting peak at 126.3 ± 0.3 °C after heating above its Tg | p.397; Table 1 footnote c, p.397 |
| C9 | claim, conclusion, authors: "indicating"; "suggests" | A single Tg without melting indicates a molecularly dispersed amorphous state in all ASDs except 50% DL HPMCAS, whose melting endotherm suggests some recrystallization during DSC heating [rests on: R4, R5] | p.397 |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R18 | record, measured | Tg of dry ASDs before dissolution (°C) — P10 — each ASD a single Tg; sub-table below | Fig. 8A, p.391; text p.387 |
| C18 | claim, conclusion, authors: "suggesting" | A single Tg in every dry ASD suggests miscibility [rests on: R18] | p.387 |

## 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: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R18 | record, measured | amorphous state and glass transition of the ASDs — all formulations; P6, P7 — all amorphous by XRPD (data not shown); a single Tg for every sample (Table S1, Fig. S7, SI not supplied) | text p.26-27 |
| R20 | record, measured | 1H T1 and T1ρ relaxation times of BCL and PVPVA signals (mean ± SD as printed) — P9 — sub-table below; text: miscible on a ~150 nm length scale for each sample (T1); 30-SE/MP more homogeneous on the ~10 nm length scale than 30-SE/CM5m and 30-HME/CM30s (T1ρ) | Table 2, p.28; text p.27 |
| C35 | claim, conclusion, authors: asserted; "indicated" | By T1 every ASD was miscible on a ~150 nm scale, consistent with a single Tg (homogeneity at >30 nm); by T1ρ 30-SE/MP was more homogeneous on a ~10 nm scale than 30-SE/CM5m and 30-HME/CM30s [rests on: R20, R18] | p.27 |

## 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: drug–polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| R15 | record, measured | PVPVA remaining in the aqueous phase after centrifugation — PVPVA 800 µg/ml, RTV nanodroplets 200 µg/ml, 37 °C, 300 rpm; 21100 g 30 min; initial and 0, 1, 2, 3 h — text: unchanged after 3 h in all media; values in the sub-table below | Fig. 8, p.9; §4.5, p.8 |
| R22 | record, measured | phase assignment and cross-contamination of spectra, all five films — Fig. 9 films — drug-rich phase continuous with Span 85 and discrete with SDS, Tween 80 and Span 20; binary film bicontinuous; in all systems no drug bands in polymer-rich spectra and no polymer bands in drug-rich spectra | §4.6, p.8 |
| C32 | claim, conclusion, authors: §4.6: "indicates"; §5.2: "indicate"; §6: asserted | The spectra and depletion data point to a high extent of phase separation of RTV and PVPVA in the presence of water (large miscibility gap, very low mutual miscibility). [rests on: R15, R22] | §4.6, p.8; §5.2, p.13; §6, p.15 |

## 2024 Shah — Orthogonal Analytical Methods to Elucidate How Low Levels of Residual Crystallinity in Posaconazole Amorphous Solid Dispersions Impact Phase Behavior during Release · ASD process / ASD process

[2024-shah-posaconazole-asd-residual-crystallinity-release-phase-behavior](../../../cards/2024-shah-posaconazole-asd-residual-crystallinity-release-phase-behavior/paper.html) · ASD process / ASD process · used · as: drug-polymer miscibility

| id | kind | content | locator |
|---|---|---|---|
| C17 | claim, conclusion, authors: "is consistent with" | The increase of Tg with polymer weight fraction is consistent with the formation of a single-phase ASD [rests on: R6] | p.444 |
| C41 | claim, mechanism, authors: "The likely reason" | The likely reason for the lower gastric release of the fully amorphous samples is molecular-level mixing with HPMCAS (single Tg, Fig. S9), which is effectively insoluble at gastric pH, in line with a thermodynamic explanation by Li and Taylor for enteric-polymer ASDs; crystalline PCZ is phase-separated from the polymer and far below its solubility, which drives its dissolution [rests on: R7, R12, R15, R18; cited: ref 50] | p.450 |
| R7 | record, measured | DSC thermograms (exo up) — amorphous PCZ, HPMCAS MF and ASDs made at 175 °C (P4) — text: each ASD has a single glass transition and no crystalline PCZ melting peak; labelled Tg (I): trace "10% - 175 °C" 79.82 °C, "25% - 175 °C" 97.78 °C, "50% - 175 °C" 110.72 °C, HPMCAS MF 122.15 °C, amorphous PCZ 61.46 °C; amorphous PCZ trace also has a broad exotherm at ≈145-165 °C and a sharp endotherm at ≈172 °C (read from Fig. S9) | Fig. S9, SI pdf p.11 |

## Mentioned only

- 2008 Marsac — [2008-marsac-nifedipine-felodipine-pvp-sorbed-water-recrystallization](../../../cards/2008-marsac-nifedipine-felodipine-pvp-sorbed-water-recrystallization/paper.html) · Solid state stability / Physical stability (ref C24)
- 2010 Kestur — [2010-kestur-pvp-mw-concentration-temperature-felodipine-melt-crystallization](../../../cards/2010-kestur-pvp-mw-concentration-temperature-felodipine-melt-crystallization/paper.html) · Solid state stability / Physical stability (ref 37)
- 2010 Eerdenbrugh — [2010-van-eerdenbrugh-polymer-crystallization-inhibition-spin-coating-screen](../../../cards/2010-van-eerdenbrugh-polymer-crystallization-inhibition-spin-coating-screen/paper.html) · Solid state stability / Miscibility and drug-polymer interactions (ref 18)
- 2011 Eerdenbrugh — [2011-van-eerdenbrugh-ab-initio-polymer-selection-asd-crystallization](../../../cards/2011-van-eerdenbrugh-ab-initio-polymer-selection-asd-crystallization/paper.html) · Solid state stability / Miscibility and drug-polymer interactions (ref 38)
- 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 31)
- 2014 Raina — [2014-raina-polymers-nifedipine-crystallization-phase-transition-dissolution](../../../cards/2014-raina-polymers-nifedipine-crystallization-phase-transition-dissolution/paper.html) · Dissolution / B. Supersaturation from ASD dissolution (ref C2)
- 2018 Tres — [2018-tres-asd-phase-behavior-fluorescence-lifetime-ritonavir-lopinavir](../../../cards/2018-tres-asd-phase-behavior-fluorescence-lifetime-ritonavir-lopinavir/paper.html) · Characterization methods / Solution methods (ref M3 C10)
- 2021 Que — [2021-que-drug-polymer-interactions-loc-copovidone-asd](../../../cards/2021-que-drug-polymer-interactions-loc-copovidone-asd/paper.html) · Dissolution / A. Release mechanism and LoC (ref 9)