# Evidence: drug-polymer interactions

Parent: — · class: molecular interaction · names merged here: drug-polymer interaction; drug-polymer interactions; drug-polymer intermolecular interactions; drug–polymer interactions; polymer-drug interactions; specific drug-polymer interactions

65 papers measured or used it, 13 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 · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R10 | record, measured | IR carbonyl region of physical mixes — amorphous indomethacin + PVP, 5-70 wt% PVP (P4, P8) — doublet of amorphous indomethacin (≈1710 and ≈1684 cm−1) retained at every composition with the PVP band superimposed and growing with PVP content (read from Fig. 5); no band at 1636 cm−1 | Fig. 5, p.1695; text p.1696 |
| R11 | record, measured | IR acid carbonyl bands of solid dispersions — P3 dispersions, 5-70 wt% PVP (P8) — cyclic dimer carbonyl peak decreases in intensity while the non-hydrogen bonded carbonyl peak increases between 5 and 20% PVP; at 20% PVP and above a single broad peak at 1726 cm−1, which becomes a shoulder as indomethacin content decreases further and the PVP carbonyl absorption dominates | Fig. 5, p.1695; text p.1696 |
| R12 | record, measured | IR band at 1636 cm−1 — P3 dispersions versus P4 physical mixes — absent in physical mixes; present in dispersions with 5-50% PVP; at 60-70% PVP merged with the non-hydrogen bonded carbonyl peak and apparent only as a shoulder; overall band considerably broader than in the physical mix | Fig. 5, p.1695; text p.1696 |
| R13 | record, measured | PVP C-N stretch — PVP dispersed with indomethacin, IR and Raman — no changes observed (spectra not shown) | p.1695 |
| C26 | claim, conclusion, authors: asserted ("Clearly") | Solid dispersion spectra are clearly different from those of physical mixes of the same composition; no such interactions were observed in physical mixes [rests on: R10, R11, R12] | p.1695, p.1697 |
| C35 | claim, conclusion, authors: discussion: "Spectral data support the fact"; abstract results: "indicating hydrogen bonding"; abstract conclusions and summary: asserted | Indomethacin forms hydrogen bonds with PVP, between the drug hydroxyl and the polymer carbonyl, at the expense of dimer formation [rests on: R11, R12, R14, R15, R16] | p.1691, p.1696, p.1697 |

## 2006 Konno — Influence of Different Polymers on the Crystallization Tendency of Molecularly Dispersed Amorphous Felodipine · Solid state stability / Physical stability

[2006-konno-felodipine-polymer-crystallization-nucleation-solid-dispersions](../../../cards/2006-konno-felodipine-polymer-crystallization-nucleation-solid-dispersions/paper.html) · Solid state stability / Physical stability · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R16 | record, measured | NH peak position by hydrogen-bond pattern (cm⁻¹) — amorphous felodipine; dispersions at 70% w/w polymer (table footnote) — sub-table below (Table 2 transcribed in full) | Table 2, p.2701 |
| C21 | claim, mechanism, authors: "strongly suggests" | An unchanged NH position with HPMC could mean no interaction or one of similar strength; the rise of the free carbonyl peak (1701 relative to 1682 cm⁻¹) with HPMCAS and HPMC points to disruption of felodipine NH-carbonyl hydrogen bonds by new bonds from the felodipine NH to polymer acceptor groups, increasing with polymer content [rests on: R13, R14, R15] | p.2700-2701 |
| C29 | claim, conclusion, authors: asserted ("was found to be") | Felodipine-polymer hydrogen-bond strength ranks PVP > HPMC > HPMCAS: stronger than in amorphous felodipine with PVP, similar with HPMC, slightly weaker with HPMCAS; abstract: hydrogen bonds formed with each polymer, stronger with PVP than with the others [rests on: R16, R11, R13, R14] | p.2692, p.2702 |
| C31 | claim, conclusion, authors: asserted ("it is clear") | Drug-polymer interaction strength varies between the polymers but does not correlate with their effect on the nucleation rate; this differs from Miyazaki et al. [R21] [rests on: R4, R16] | p.2702, p.2703 |

## 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 interactions

| id | kind | content | locator |
|---|---|---|---|
| R13 | record, measured | NH-stretch features of felodipine with PVP — felodipine films with increasing PVP (P6) — shoulder at 3,420 cm⁻¹; peak at 3,345 cm⁻¹; with increasing PVP a shoulder, then a peak, appears at 3,288 cm⁻¹; the same development is reported for nifedipine | p.2311-2312 |
| R15 | record, measured | NH peak height ratio, drug-drug band (3,345 cm⁻¹) over drug-PVP band (3,288 cm⁻¹), versus PVP acceptor:drug donor ratio (error bars one SD) — nifedipine-PVP and felodipine-PVP dispersions (P6) — sub-table below; text: peak positions and breadths of the drug-PVP bands very similar for the two drugs | Fig. 12, p.2313; text p.2312 |
| C29 | claim, conclusion, authors: asserted ("very similar") | The interactions of the two drugs with PVP are very similar in strength (peak position) and extent (peak breadth), as the peak height ratio versus acceptor:donor ratio shows; for a given number of donors and acceptors the drug-polymer interaction is very similar [rests on: R12, R14, R15] | p.2312 |
| C30 | claim, conclusion, authors: "would" | Because nifedipine has the lower molecular weight, at a given weight percent of PVP it would hydrogen bond to PVP to a greater extent than felodipine; drug-polymer interactions are slightly higher for nifedipine-PVP at a given weight fraction [rests on: R15; argument only] | p.2312, p.2314 |

## 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 · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R10 | record, measured | FTIR NH and carbonyl bands after exposure and drying — 25% PVP films (P1), 75% RH at 25 °C for 0 (initial), 1, 3, 4, 5, 6, 7 weeks, dried before measurement (P5) — NH region: band maximum ≈3333 cm⁻¹ (initial) to ≈3339 cm⁻¹ (7 weeks), second band ≈3231-3234 cm⁻¹ (read from Fig. 7a); the lower-wavenumber shoulder (text: 3,291 cm⁻¹, arrow in Fig. 7a) loses intensity relative to the higher-wavenumber component (text: around 3345 cm⁻¹) as exposure time increases; carbonyl region: the shoulder at around 1,655 cm⁻¹ decreases in intensity after exposure and drying; no peak at 3,373 cm⁻¹ | Fig. 7, p.974; text p.974-975 |
| R11 | record, measured | FTIR NH and carbonyl bands after exposure and drying — 25% HPMCAS films and 25% HPMC films, same protocol as R10 (P5) — no notable differences between spectra (initial to 7 weeks) in the NH or the C=O region (text; Figs. 8, 9) | Figs. 8, 9, p.975; text p.975 |
| R17 | record, cited | FTIR band assignments used — felodipine dispersions — NH stretch: ≈3345 cm⁻¹ felodipine-felodipine and 3,291 cm⁻¹ felodipine-PVP hydrogen bonding (ref 11); C=O shoulder at around 1,655 cm⁻¹: PVP carbonyl hydrogen bonded with the drug (ref 19); 3,373 cm⁻¹: NH stretch of crystalline felodipine (no reference given) | p.974-975 |
| C21 | claim, mechanism, authors: results: "These results suggest"; "consistent with"; discussion: "appears to undergo"; abstract: "appeared to undergo" | In 25% PVP dispersions absorbed moisture disrupts felodipine-PVP hydrogen bonds, giving more drug-drug interactions, and the disruption persists after the water is removed (NH shoulder at 3,291 cm⁻¹ and C=O shoulder at 1,655 cm⁻¹ decrease); the dispersion appears to undergo molecular-level changes [rests on: R10, R17] | p.969, p.974-975, p.977 |
| C32 | claim, mechanism, authors: "it is unlikely" | The stabilizing ability of the polymers in the presence of absorbed moisture is unlikely to come from any specific drug-polymer interaction; the same conclusion was reached without moisture (ref 11) [rests on: R14; cited: ref 11] | p.977 |

## 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 interactions

| id | kind | content | locator |
|---|---|---|---|
| R7 | record, measured | PCA loadings — felodipine-PVP (R6) — PC1 loading has the same features as the IR absorbance of PVP subtracted from that of amorphous felodipine (caption); the regions of largest PC2 loading are the NH region (boxed in Fig. 3b) and the carbonyl region (text); NH-region spectra of dispersions with 70, 50 and 30% PVP shown below the loadings | Fig. 3b, p.2527; text p.2527 |
| R9 | record, measured | PCA loadings — nifedipine-PVP (R8) — PC1 loading has the same features as the IR absorbance of PVP subtracted from that of amorphous nifedipine (caption); PC2 loading highlights the boxed NH region (caption) and has large features in the carbonyl region (read from Fig. 4b); NH-region spectra of dispersions with 70, 50 and 25% PVP shown | Fig. 4b, p.2528 |
| R10 | record, measured | carbonyl-region IR spectra (≈1500-1750 cm−1), dispersion versus calculated physical mixture — ketoconazole-PVP dispersions with 30 and 70% PVP (P3, P4), with amorphous ketoconazole and pure PVP — carbonyl peaks of the dispersions at the same wavenumbers as in the pure components; the ketoconazole carbonyl peak is slightly lower in the dispersion than in the calculated mixture, in all dispersions (text) and at 30 and 70% PVP (Fig. 5); no other significant spectral change on visual examination; dispersion spectra closely resemble the calculated mixtures | Fig. 5, p.2528; text p.2528 |
| C19 | claim, conclusion, authors: asserted ("it is obvious"); "indicating" | For felodipine-PVP, PC1 alone describes the calculated physical mixtures, the dispersions are spectroscopically different from them, and a second PC is needed for the dispersions [rests on: R6] | p.2527 |
| C20 | claim, mechanism, authors: "is thought to"; "presumably" | The PC1 loading reflects composition; the PC2 loading is thought to arise from specific drug-polymer interactions, its largest NH and carbonyl features presumably reflecting drug-polymer hydrogen bonding [rests on: R7] | p.2527 |
| C24 | claim, conclusion, authors: "indicates"; "not possible" | These interactions mean that at least some ketoconazole and PVP molecules experience a different chemical environment from molecular-level mixing, but the extent of miscibility cannot be judged from the very limited spectral changes [rests on: R10] | p.2528 |

## 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 · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R9 | record, measured | felodipine NH stretching peak position (cm⁻¹) — amorphous felodipine and spin-coated dispersions with 50% w/w polymer (P6, P7) — sub-table below | Table 2, p.2394 |
| 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 |
| C38 | claim, conclusion, authors: discussion: "corresponds well", "further supported"; conclusions: "appeared to correlate well" | The polymers with the strongest drug–polymer interactions, PVP and PVP/VA, are the best growth inhibitors, and the IR order corresponds well with the inhibition order; PVP/VA, in which 40% of the pyrrolidone groups are replaced by weakly interacting acetate, is less effective than an equal amount of PVP, and PVAc has essentially no effect [rests on: R9, R6, R8, R5] | p.2396, p.2397 |
| C40 | claim, generalisation, authors: discussion: "strongly suggest"; abstract: "appear"; conclusions: "appeared to correlate well" | Drug–polymer specific interactions play a key role in a polymer's effectiveness as a crystal growth inhibitor; polymers that form stronger or more extensive hydrogen bonds with the drug appear to be better crystallization inhibitors [rests on: R6, R8, R9, C38] | p.2390, p.2396, p.2397 |

## 2010 Kestur — Effects of the Molecular Weight and Concentration of Polymer Additives, and Temperature on the Melt Crystallization Kinetics of a Small Drug Molecule · Solid state stability / Physical stability

[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 · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R9 | record, measured | IR NH stretching band of amorphous felodipine — pure felodipine and 20 wt% PVP K-12, K-29/32, K-90 films, 25 °C (P7) — pure felodipine 3341 cm⁻¹; with PVP shifted to 3337 cm⁻¹ and broadened; extent of shift and broadening the same for the three PVP grades | p.3589; Fig. S3, SI p.3 |
| C13 | claim, conclusion, authors: "indicate"; "indicating"; abstract: "indicate" | The NH shift and broadening with PVP mean stronger and/or more numerous drug-polymer than drug-drug interactions, and the felodipine-PVP interaction does not depend on PVP molecular weight in the range studied [rests on: R9] | p.3585, p.3589; SI p.3 |
| C36 | claim, prior hypothesis, authors: asserted ("has been shown") | PVP is miscible with felodipine and hydrogen bonds with it over the whole concentration range and up to the felodipine melting temperature; the extent of hydrogen bonding increases with concentration, and its strength for PVP-felodipine decreases with increasing temperature [rests on: cited: refs 14, 37-41] | p.3593 |

## 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: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R14 | record, cited | felodipine-polymer dispersions at low RH — ref 30 (with ref 12 for HPMCAS interactions) — nucleation rate: no significant difference between PVP and HPMCAS at a given concentration, lower than for the pure drug; HPMCAS at low levels does not raise the calorimetric Tg of felodipine; PVP forms stronger specific interactions with felodipine than HPMCAS; specific felodipine-HPMCAS interactions present (refs 12, 30) | p.752 |
| C37 | claim, mechanism, authors: "may" | Specific felodipine-HPMCAS interactions may couple the motions of drug and polymer side chains, and water may barely affect this coupling because HPMCAS has multiple hydrogen-bond donors and acceptors per repeat unit that can bind water and keep the drug-polymer interaction intact [rests on: R14; cited: refs 12, 30, 31] | p.752 |
| C40 | claim, mechanism, authors: discussion: "may arise"; conclusions: asserted ("Thus at low RH, PVP forms stronger interactions"), under "It is speculated" | PVP is the better inhibitor at low RH because it forms stronger specific interactions with felodipine than HPMCAS [rests on: R3, R5, R14] | p.752, p.753 |
| C42 | claim, mechanism, authors: discussion: "may result in disruption"; conclusions: asserted, under "It is speculated" | PVP has a very strong affinity for water, so at higher RH absorbed water may disrupt felodipine-PVP interactions and weaken growth inhibition; moisture disrupts drug-polymer interactions in PVP systems more than in HPMCAS systems [rests on: R5, R17; cited: refs 12, 34] | p.752-753 |
| C44 | claim, generalisation, authors: "It is speculated"; "may play a role" | The strength of drug-polymer interactions may help determine how effective a polymer is as a crystal growth inhibitor [rests on: R3, R5, R14] | p.753 |

## 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 interactions

| id | kind | content | locator |
|---|---|---|---|
| C11 | claim, prior hypothesis, authors: "suggested"; "hypothesized" | Crowley and Zografi suggested the size of the discrepancy relates to specific drug–polymer interactions and hypothesized the largest difference at about a 1:1 molar ratio of drug hydrogen bond donors to the PVP repeat-unit acceptor [rests on: cited: ref 10] | p.1057-1058 |
| C14 | claim, mechanism, authors: "it has been suggested"; "If ... indeed"; "it is intuitive" | HPMC and HPMCAS, unlike PVP, have multiple hydrogen bond donors and acceptors per repeat unit and have been suggested to interact more weakly with felodipine (ref 17); if specific drug–polymer interaction causes the reduction in uptake, blends with these cellulose polymers would be less affected [rests on: R7, R8, R9; cited: ref 17] | p.1058-1059 |
| C15 | claim, generalisation, authors: "reasonable to speculate" | The magnitude of the gap between measured and predicted uptake is related to the nature of the drug–polymer interactions and to how they affect the ability of water to interact with the individual components [rests on: R7, R8, R9; argument only] | p.1059 |
| C27 | claim, mechanism, authors: "it is unlikely"; "most likely" | These assumptions are unlikely to hold: drug–polymer interactions would most likely change the ability of water to interact with the drug or the polymer, and water will change the drug–polymer interactions [rests on: R22; cited: refs 22-25] | p.1061-1062 |

## 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 interactions

| 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 |
| 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 |
| R13 | record, measured | IR carbonyl region after humid storage — indomethacin-50% PVPVA films, as prepared, after 1 day at 75% RH and 7 days at 94% RH, dried — 1640 cm⁻¹ band (vinylpyrrolidone C=O H-bonded to drug) and 1683 cm⁻¹ band at the same relative intensity before and after storage | Fig. 7a, p.486; text p.485-486 |
| R20 | record, derived (relation named, not printed) | red shift of the vinylpyrrolidone carbonyl band of PVPVA on H-bonding to the drug — dry 50 wt% PVPVA dispersions (R1) — indomethacin-PVPVA: 42-44 cm⁻¹; other PVPVA dispersions studied: 19-22 cm⁻¹ | text p.489 |
| C28 | claim, mechanism, authors: "This supposition is supported"; "would result" | Indomethacin forms stronger interactions with PVPVA than felodipine, quinidine and pimozide do, judged by the larger carbonyl red shift; its COOH group is a better hydrogen-bond donor than NH or OH; stronger interactions give a lower χDP and a more favourable ΔHmix, consistent with the absence of demixing in indomethacin-PVPVA, as reported with PVP [rests on: R20, R13, R3.h; cited: ref 10] | p.489 |

## 2010 Eerdenbrugh — Small Scale Screening To Determine the Ability of Different Polymers To Inhibit Drug Crystallization upon Rapid Solvent Evaporation · Solid state stability / Miscibility and drug-polymer interactions

[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 · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C33 | claim, mechanism, authors: results: "it is reasonable to speculate"; conclusions: "was ascribed to" | Drug-polymer intermolecular interactions underlie the differences in crystallization inhibition; polymer performance is ascribed to the synergy, or lack of it, between drug and polymer chemistry [rests on: R3, C22, C32] | p.1335; p.1337 |
| C34 | claim, prior hypothesis, authors: "have been reported"; "have also been suggested" | Drug-polymer interactions influence drug-polymer miscibility and have been suggested to be important for inhibiting crystallization in solid dispersions [rests on: cited: refs 18-20] | p.1335 |
| C35 | claim, generalisation, authors: "strongly suggests" | The patterns in polymer performance for different classes of drug chemistry make drug-polymer interactions extremely important in preventing crystallization [rests on: R3, C33] | p.1335 |

## 2011 Baird — Evaluation and modeling of the eutectic composition of various drug-polyethylene glycol solid dispersions · Solid state stability / PEG dispersions

[2011-baird-drug-peg-eutectic-composition-modeling-solid-dispersions](../../../cards/2011-baird-drug-peg-eutectic-composition-modeling-solid-dispersions/paper.html) · Solid state stability / PEG dispersions · measured · as: specific drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R9 | record, measured and derived per column | solubility in PEG 400, mole fraction, activity coefficient and Flory–Huggins parameter — P5 (25 °C, PEG 400); x drug derived (conversion not printed, X4); γ drug derived (E7); χdp derived (E8 with R1 interaction energies) — sub-table below | Table 3, p.208 |
| R10 | record, measured | IR band positions, measured versus calculated (additive) spectrum — 25:75 drug-PEG 3350 melts (P4) — sub-table below | Fig. 5, p.209; text p.209-210 |
| C31 | claim, conclusion, authors: asserted ("confirm") | For chlorpropamide and aceclofenac the IR spectra confirm specific interactions with PEG 3350 and, with the solubility results, explain the model's inaccuracy [rests on: R10, R9, R1] | p.209 |
| C36 | claim, generalisation, authors: conclusions: "For the systems investigated"; abstract: asserted ("confirmed", "demonstrated") | For the systems investigated, the accuracy of the model is delineated by the presence or absence of specific drug-polymer interactions, specific interactions giving inaccurate predictions; the abstract states that the deviations were confirmed to be due to specific interactions, as demonstrated by IR [rests on: R1, R9, R10] | p.201, p.210 |

## 2011 Kestur — Influence of polymer chemistry on crystal growth inhibition of two chemically diverse organic molecules · Solid state stability / Miscibility and drug-polymer interactions

[2011-kestur-polymer-chemistry-crystal-growth-bifonazole-nimesulide](../../../cards/2011-kestur-polymer-chemistry-crystal-growth-bifonazole-nimesulide/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R13 | record, measured | NH region of nimesulide with 30 wt% polymer (Fig. 7 caption; data in the image printed above the Fig. 8 caption) — solvent-cast films (P10): no polymer (solid), PVP K12 (dashed), PVP/VA (dotted), PVAc (dash-dotted) — text: small changes in the NH region with polymer; figure: maximum ≈3281 cm−1 without polymer and ≈3258-3265 cm−1 with each polymer (≈16-23 cm−1 lower); intensity at 3150-3200 cm−1 highest for PVP, then PVP/VA, then PVAc, lowest without polymer | Fig. 7, p.6717 (image above Fig. 8 caption); text p.6717 |
| R14 | record, measured | PVP carbonyl region (Fig. 8 caption; data in the image printed above the Fig. 7 caption) — pure PVP K12 (dash-dotted) and nimesulide-PVP films with 20, 30, 40 and 50 wt% PVP (solid lines) (P10); nimesulide alone (dashed) — text: changes observed; a shoulder (arrow) associated with drug-polymer interactions; figure: pure PVP maximum ≈1684 cm−1, dispersions ≈1680 cm−1 (≈4 cm−1 lower) with a shoulder at ≈1657 cm−1 whose height differs among the four compositions; nimesulide alone shows no band in 1720-1630 cm−1 | Fig. 8, p.6717 (image above Fig. 7 caption); text p.6717 |
| R15 | record, measured | PVP/VA acetate and vinylpyrrolidone carbonyl regions — pure PVP/VA (dotted) and PVP/VA-nimesulide with 20, 30, 40 and 50 wt% polymer (solid) (P10) — text: changes to the vinylpyrrolidone carbonyl similar to PVP; figure: carbonyl maximum ≈1684 cm−1 (pure) and ≈1679-1680 cm−1 (dispersions) with a shoulder near ≈1660 cm−1; acetate maximum ≈1737 cm−1 (pure) and ≈1735 cm−1 (dispersions) | Fig. S3, SI pdf p.3; text p.6717 |
| R16 | record, measured | PVAc acetate carbonyl region — pure PVAc (dash-dotted) and PVAc-nimesulide with 20, 30, 40 and 50 wt% polymer (solid) (P10) — text: changes to the PVAc carbonyl peak minimal; figure: maximum ≈1739 cm−1 (pure) and ≈1738 cm−1 (dispersions); dispersion bands narrower on the high-wavenumber side and with slightly more intensity at ≈1705-1720 cm−1 | Fig. S2, SI pdf p.2; text p.6717 |
| C23 | claim, conclusion, authors: "suggesting some extent"; "confirming"; abstract: "did occur" | Small NH-region changes with polymer suggest some drug-polymer interaction, and changes in the PVP carbonyl region confirm drug-polymer interactions in nimesulide-PVP dispersions [rests on: R13, R14] | p.6712, p.6717 |
| C24 | claim, conclusion, authors: asserted ("much smaller") | The shifts of the drug NH peak and the PVP carbonyl peak are much smaller than in systems with similar groups such as felodipine-PVP [rests on: R13, R14, R20] | p.6717 |
| C27 | claim, mechanism, authors: discussion: "it appears"; "lend support"; "most likely explain"; abstract: asserted ("was hampered") | Involvement of the nimesulide NH in an intramolecular hydrogen bond considerably diminishes drug-polymer hydrogen bonding, supported by minimal NH changes on adding 1-ethyl-2-pyrrolidinone or acetic acid in solution; this most likely explains why the differences between polymers are smaller than anticipated [rests on: R17, R13, R14, R10-R12] | p.6712, p.6717 |

## 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 interactions

| id | kind | content | locator |
|---|---|---|---|
| R15 | record, cited, calculated and measured per column and row | molecular properties, PVP carbonyl shift and phase-behaviour class of 20 binary ASD systems — five systems of this work (rows e, f, g, s, t: carbonyl shift and class measured here, R2-R6, R14) and 15 systems from earlier studies (row sources not stated) — sub-table below | Table II, p.1216 |
| R17 | record, derived (P7) | loadings of the predictive component with error bars (meaning of error bars not stated) — OPLS-DA model of R16 — sub-table below | Fig. 11, p.1218 |
| C30 | claim, assumption, authors: "would be expected"; "can be expected" | API–polymer interaction strength is represented by the API pKa (a lower pKa means a stronger acid, expected to be a better hydrogen-bond donor) and by the PVP carbonyl red shift (a stronger donor gives a larger shift); donor strength is set by the electronegativity of the bonding atom and electron-withdrawing substituents [rests on: cited: refs 7, 20, 21] | p.1215, p.1217 |
| C32 | claim, conclusion, authors: asserted ("excellent correlation") | Except for indoprofen, the extent of the PVP carbonyl red shift correlates excellently with the tendency to undergo AAPS [rests on: R15] | p.1217 |
| C40 | claim, conclusion, authors: asserted | In the predictive component a lower API pKa and a larger PVP carbonyl red shift lead to systems without moisture-induced miscibility change; a COOH donor marks systems that stay miscible, NH and OH donors a tendency to AAPS, and a lone CO acceptor a non-separating system [rests on: R17] | p.1217; Fig. 11 caption, p.1218 |

## 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 interactions

| 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 |
| R20 | record, measured | ATR-FTIR spectra, 1800-1000 cm⁻¹, measured (solid line) versus calculated physical mixture (dashed) — drug/PEG 20/80, molten (P8) — KET/PEG: measured and calculated nearly superimposed, carbonyl band ≈1650 cm⁻¹ in both; BZC/PEG: carbonyl band ≈1700 cm⁻¹ (measured, split) versus ≈1686 cm⁻¹ (calculated), further differences near 1600, 1270 and 1170 cm⁻¹; IBP/PEG: carbonyl band ≈1735 (measured) versus ≈1703 cm⁻¹ (calculated); NLU/PEG: carbonyl band ≈1733 versus ≈1721 cm⁻¹, differences at 1350-1280 cm⁻¹ (all read from Fig. S2); CPM/PEG and HLP/PEG spectra not shown | Fig. S2, SI pdf p.3; text SI pdf p.2 |
| C10 | claim, conclusion, authors: main text: asserted ("confirmed"); SI: "show evidence" | Drug-polymer interactions in these systems were confirmed by FTIR; in the SI, the BZC/PEG, IBP/PEG and NLU/PEG spectra are not well modelled by the calculated physical mixture, whereas the KET/PEG spectrum is [rests on: R20] | p.934; SI pdf p.2 |
| C32 | claim, generalisation, authors: abstract: asserted ("were incorporated"; rapidly crystallizing, weakly interacting drugs "tended to be excluded"); p.938: "This suggests"; conclusions: asserted | Drugs that interact favourably with PEG are incorporated into the interlamellar regions until they crystallize, whereas weakly interacting drugs are excluded: with BZC, CPM, IBP or NLU the long period is much larger than with KET before the drug crystallizes; drugs with higher solubility in and strong interaction with PEG give a larger increase of L than weakly interacting drugs [rests on: R18, R5] | p.932, p.938 |

## 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 interactions

| id | kind | content | locator |
|---|---|---|---|
| R14 | record, measured | NH stretch peak position (cm−1; unit not printed in the table) — flutamide and 1:1 molar mixtures (P4) — sub-table below; text: largest shift 28 cm−1, with PVP | Table 3, p.3226 |
| R15 | record, measured | FTIR C=O region with PVP — flutamide-PVP 1:1 (P4) — PVP carbonyl band moves from 1679 cm−1 (neat PVP) to 1658 cm−1 in the mixture; figure: mixture peaks at ≈1683 and ≈1658 cm−1 with a shoulder near ≈1710 cm−1 | Fig. 8, p.3226; text p.3226 |
| R16 | record, measured | FTIR C=O region with PDMA — flutamide-PDMA 1:1 (P4) — PDMA carbonyl band moves from 1641 to 1620 cm−1; relative intensity of the higher-wavenumber flutamide C=O shoulder (≈1710 cm−1) increases | Fig. 9, p.3226; text p.3226 |
| C39 | claim, conclusion, authors: asserted ("clearly showed") | FTIR clearly showed interactions of flutamide with the polymer acceptor groups (downward NH and polymer C=O shifts); for the carbonyl polymers, larger NH decreases go with greater growth inhibition; the computed carbonyl oxygen charges also match the extent of growth reduction [rests on: R14, R15, R16, R25, R3] | p.3228 |
| C40 | claim, generalisation, authors: asserted ("strongly support") | Both pieces of evidence strongly support the hypothesis that specific drug-polymer interactions are extremely important in determining the extent of crystal growth inhibition [rests on: R14, R25, R3] | 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 · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R16 | record, measured | FTIR of APAP with PAA — 30% w/w PAA film (P8) — combined NH/OH peak 3301 → 3320 cm−1; PAA acid C=O 1705 → 1714 cm−1; increased intensity of the 1636 cm−1 shoulder | Fig. 10, p.5194; text p.5194 |
| R17 | record, measured | FTIR of APAP with PVP — 30% w/w PVP film (P8) — NH/OH peak 3301 → 3283 cm−1; pyrrolidone C=O 1679 → 1657 cm−1 | Fig. 11, p.5194; text p.5194 |
| R18 | record, measured | FTIR of APAP with PVPVA — 30% w/w PVPVA film (P8); data not shown — NH/OH peak 3301 → 3294 cm−1; pyrrolidone C=O 1682 → 1657 cm−1 | p.5194 |
| R19 | record, measured | FTIR of APAP with PVPh — 30% w/w PVPh film (P8); data not shown — NH/OH peak shifted slightly to higher wavenumber (value not printed); no change in the C=O stretching region | p.5194 |
| R20 | record, measured | FTIR of APAP with the other polymers — 30% w/w films (P8) of the polymers not named above (by elimination HPMC, HPMCAS, E100); data not shown — no noticeable shifts in peak positions | p.5194 |
| C31 | claim, conclusion, authors: results: "found to correlate well"; discussion: asserted; conclusions: "could be correlated" | More favourable drug-polymer hydrogen bonding correlates well with growth inhibition: the polymers with the greatest inhibitory effect (PAA, PVP, PVPVA) show the greatest FTIR changes, with the vinylpyrrolidone carbonyl bonding the APAP phenol and the PAA acidic OH bonding the APAP amide carbonyl (abstract: PAA and PVP observed to hydrogen-bond with APAP; conclusions: growth inhibition "could be correlated" to hydrogen bonding) [rests on: R6, R16, R17, R18, R19, R20] | p.5188, p.5194, p.5195, p.5196 |

## 2012 Zhu — Modification of Crystallization Behavior in Drug/Polyethylene Glycol Solid Dispersions · Solid state stability / PEG dispersions

[2012-zhu-api-peg-solid-dispersion-crystallization-behavior](../../../cards/2012-zhu-api-peg-solid-dispersion-crystallization-behavior/paper.html) · Solid state stability / PEG dispersions · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C13 | claim, prior hypothesis, authors: "The hypothesis to be tested" | Hypothesis tested: the crystallization tendency of the pure API, combined with its ability to interact with the polymer, will affect API crystallization in the dispersion [rests on: argument only] | p.546 |
| C20 | claim, prior hypothesis, authors: "suggested"; "can potentially impact" | The model APIs differ in estimated solubility in supercooled liquid PEG, interaction parameters and crystallization tendency; infrared studies suggest that HLP and FNB do not hydrogen-bond with PEG whereas BZC and IBP can; earlier reports suggest that such differences can affect crystallization [rests on: R25; cited: refs 10, 12, 13, 23, 25] | p.548 |
| C38 | claim, generalisation, authors: "suggest" | Both the crystallization tendency of the drug and its ability to interact with PEG influence crystallization kinetics in the dispersion, with heterogeneous nucleation by PEG as an additional factor for some compounds [rests on: C1, C2, C3, C4, R23] | p.552 |
| C39 | claim, generalisation, authors: asserted ("Hence") | If the pure API crystallizes fast relative to PEG and has no favourable interaction with PEG (HLP), PEG has negligible effect on API crystallization; if it crystallizes fast but interacts favourably (BZC), onset is delayed and rate reduced [rests on: R1, R7, R9, R11, R23] | p.552 |

## 2013 Ilevbare — Maintaining Supersaturation in Aqueous Drug Solutions: Impact of Different Polymers on Induction Times · Dissolution / D. Crystallization from solution

[2013-ilevbare-polymers-supersaturation-induction-times](../../../cards/2013-ilevbare-polymers-supersaturation-induction-times/paper.html) · Dissolution / D. Crystallization from solution · used · as: polymer-drug interactions

| id | kind | content | locator |
|---|---|---|---|
| C4 | claim, mechanism, authors: abstract: "most likely influences"; discussion: "would be expected", "is likely to interact" | Relative hydrophobicity sets the affinity of polymer segments for the drug, and so the polymer's ability to form polymer-solute interactions (and to mix with drug prenucleation aggregates) against polymer-solvent and polymer-polymer interactions: a very hydrophilic polymer prefers water, a too-hydrophobic polymer prefers other polymer molecules [rests on: argument only; cited: ref 17] | p.740, p.749 |
| C12 | claim, prior hypothesis, authors: "It is hypothesized" | The ability of a polymer to inhibit crystal nucleation depends on the strength of its interaction with the crystallizing solute molecules [rests on: argument only] | p.741 |
| C35 | claim, mechanism, authors: "should" | An effective nucleation inhibitor should interact favourably with the solute: a strong affinity of the polymer for the solute, relative to the solvent and other polymer molecules, makes it interact with solute aggregates and disrupts their reorganization [rests on: cited: ref 17] | p.749 |
| C36 | claim, recommendation, authors: "it is apparent"; "should"; "These expectations are in general supported" | To be an effective nucleation inhibitor, a polymer should have a hydrophobicity similar to the solute's (to maximize nonspecific interactions) or form highly favourable specific interactions with the drug [rests on: R9, R13] | p.749 |

## 2013 Kestur — Evaluation of the crystal growth rate of felodipine polymorphs in the presence and absence of additives as a function of temperature · Solid state stability / Physical stability

[2013-kestur-felodipine-polymorph-crystal-growth-pvp-additives](../../../cards/2013-kestur-felodipine-polymorph-crystal-growth-pvp-additives/paper.html) · Solid state stability / Physical stability · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C6 | claim, mechanism, authors: abstract: "most likely"; discussion: "suggest", "suggesting" | The similar growth-rate ratios of the two polymorphs at 60-100 °C indicate that PVP inhibits felodipine growth through an effect on the amorphous material rather than at the crystal surface: the PVP-felodipine interacting environment is similar for both polymorphs, and the polymer's impact on growth originates in its impact on the properties of the liquid phase [rests on: R15, C14] | p.2, p.13 |
| C8 | claim, prior hypothesis, authors: "mainly attributed"; "it is not clear" | PVP delays felodipine crystal growth, an effect mainly attributed to specific PVP-felodipine interaction; whether the interaction acts at the crystal surface or in the amorphous region was not clear [rests on: cited: refs 8, 9] | p.4 |

## 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 · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R2 | record, measured | polyphenol OH stretching peak position (cm-1) at 30% (w/w) polyphenol — P4; 30% (w/w) was the highest polyphenol content that gave a thin amorphous film with every polymer; PAA not listed (R11) — sub-table below | Table 1, p.5; text p.4 |
| R4 | record, measured; shift derived (polymer peak minus dispersion peak, relation not printed) | C=O stretching peak positions of the pure polymers and of dispersions with 30% (w/w) flavonoid, and the shifts (cm-1) — P4; HPMC not listed (no carbonyl, R11) — sub-table below | Table 2, p.6; text p.5 |
| R6 | record, measured | IR 3600-2400 cm-1 region of quercetin-E100 films — P4; 0 (100% E100), 10, 30, 50% (w/w) quercetin — text: the E100 bands at 2820 and 2770 cm-1 diminish as quercetin increases and are absent at 50% (w/w) quercetin; naringenin-E100 spectra were described as similar (not shown). Figure: both bands sharp at 0 and 10%, smaller at 30%, absent at 50%; a broad band near ≈3400 cm-1 grows with quercetin content (read from Fig. 6) | Fig. 6, p.6; text p.5 |
| C18 | claim, conclusion, authors: p.5: "can be suggested"; abstract: "suggested" | From the IR analysis and the relative strength of ionic and hydrogen bonding, the predicted order of crystallization-inhibiting performance is E100 (ionic interactions) > PVP > HPMCAS > HPMC ≥ CMCAB > PAA [rests on: R2, R4, R5, R6, C16] | p.1, p.5, p.9 |
| C36 | claim, assumption, authors: asserted | When drug and polymer interact, the IR spectrum shows peaks shifted relative to the physical mixture of amorphous drug and polymer; the shifts come from specific interactions, usually hydrogen bonding, that differ from self-association [rests on: cited: refs 31, 43, 44] | p.9 |

## 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 · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R5 | record, measured | IR bands of resveratrol-PVP K29/32 films (0, 10, 30% resveratrol) — P5 — OH region: resveratrol OH maximum at around 3193 cm−1 at 30%, against 3238 cm−1 for crystalline resveratrol (text); lowest OH position of all resveratrol-polymer systems; broadening more pronounced than with E100. C=O region: pure PVP 1682 cm−1; at 30% bands at 1680 cm−1 and a new shoulder at 1656 cm−1 (26 cm−1 below 1682); shoulder weaker at 10% than at 30%; crystalline resveratrol trace flat in this region | Fig. 3, p.176; text p.175 |
| R6 | record, measured | IR bands of resveratrol-E100 films — P5 — sub-table below; text: OH at 3391 cm−1 with 60% polymer; slight broadening, less than with PVP K29/32; new C=O band at 1701 cm−1 (Table 1 value at 30%); ratio of the 1730 cm−1 band to the new band higher at higher polymer content | Fig. 4, p.177; text p.175 |
| R7 | record, measured | E100 bands at 2820 and 2770 cm−1 (reported in ref 32 as non-ionized dimethylamino groups) — P5, E100 films 0-60% resveratrol — present in neat E100; intensity decreased quickly as resveratrol increased; absent at 50% resveratrol (text) | Fig. 4 (OH-region panel), p.177; text p.175 |
| R11 | record, measured | resveratrol OH peak position at 40% (w/w) resveratrol — P5 — sub-table below | Table 2, p.178 |
| C45 | claim, generalisation, authors: abstract: "could be correlated", "suggested", "it is rationalized"; conclusions: asserted ("strongly related") | Manufacturability and physical stability of resveratrol dispersions are strongly related to the specific resveratrol-polymer interactions, polymers forming weaker hydrogen bonds being less effective inhibitors; abstract: polymer influence could be correlated with polymer structure, polymers with good acceptor groups performing better, stability was suggested to be linked to the type and strength of interactions, and inhibitor effectiveness is rationalized by them [rests on: R2, R11, R12, R17] | p.171, p.183 |

## 2014 Trasi — Nucleation and crystal growth of amorphous nilutamide – unusual low temperature behavior · Solid state stability / Crystallization tendency

[2014-trasi-taylor-amorphous-nilutamide-low-temperature-nucleation](../../../cards/2014-trasi-taylor-amorphous-nilutamide-low-temperature-nucleation/paper.html) · Solid state stability / Crystallization tendency · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R11 | record, measured | FTIR NH and C=O positions with PAA — 1:1 molar nilutamide-PAA spin-coated film (P4) — little change in the nilutamide NH or C=O peak positions relative to pure amorphous nilutamide (spectrum not shown) | p.7190 |
| R12 | record, measured | FTIR NH and C=O positions with PVP — 1:1 molar nilutamide-PVP spin-coated film (P4) — text: drug NH and polymer C=O shifted to lower wavenumbers. Figure: NH band maximum ≈3313 (nilutamide) versus a broad band ≈3300–3230 with maximum ≈3130 (mixture); PVP C=O ≈1678 (PVP alone) versus ≈1662 (mixture); nilutamide C=O ≈1788 and ≈1728 in both (read from Fig. 7) | Fig. 7, p.7190; text p.7190 |
| C17 | claim, conclusion, authors: "indicating" | With PAA, any drug-polymer hydrogen bonding is comparable in strength to the hydrogen bonding in pure amorphous nilutamide [rests on: R11] | p.7190 |
| C18 | claim, mechanism, authors: "indicating"; "this is possible because" | The NH and PVP C=O shifts mean nilutamide-PVP hydrogen bonds stronger than those in nilutamide alone, possible because PVP has a better acceptor group than nilutamide [rests on: R12] | p.7190 |
| C19 | claim, generalisation, authors: asserted ("correlates well"); "in general agreement" | The nilutamide-polymer interaction strength correlates with the relative impact of each polymer on crystal growth, in general agreement with other studies [rests on: R3, R11, R12] | p.7190 |

## 2014 Wegiel — Curcumin amorphous solid dispersions: the influence of intra and intermolecular bonding on physical stability · Solid state stability / Physical stability

[2014-wegiel-curcumin-asd-intramolecular-bonding-physical-stability](../../../cards/2014-wegiel-curcumin-asd-intramolecular-bonding-physical-stability/paper.html) · Solid state stability / Physical stability · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R3 | record, measured | OH peak position (cm-1) — spin-coated films at 80% w/w curcumin (P1, P4) — sub-table below | Table 1, p.979 |
| R4 | record, measured | polymer C=O stretching peak position (cm-1) — neat polymer and spin-coated film with 80% w/w curcumin (P1, P4) — sub-table below | Table 2, p.979 |
| R6 | record, measured | IR spectra of PVP dispersions versus curcumin content — PVP films, 20, 40, 60, 80 wt% curcumin (P1, P4) — OH region, text: curcumin OH peak maximum around 3187 cm-1 at 80% curcumin (R3.f), the lowest of all dispersions; figure: broad band without a sharp maximum at 80% (plateau ≈3380 to ≈3190) and maximum ≈3185 at 60% (read from Fig. 7a). Carbonyl region, text: new shoulder at 1655 cm-1 at 80% curcumin, 27 cm-1 below the non-hydrogen-bonded PVP carbonyl at 1682 cm-1 (R4.a); ratio of free to hydrogen-bonded carbonyl rises with polymer content; figure: maximum ≈1681 at 20 and 40 wt% curcumin (40%: shoulder ≈1660), broad maximum ≈1662 at 60%, shoulder ≈1655 beside the curcumin bands at 80% (read from Fig. 7b) | Fig. 7, p.980-981 |
| R7 | record, measured | E100 bands at 2820 and 2770 cm-1 (assigned to non-ionized dimethylamino groups, cited ref 32) versus curcumin content — E100 films, 20, 40, 60, 80 wt% curcumin (P1, P4) — text: both bands decrease quickly in intensity as curcumin rises and are fully eradicated at 60% curcumin; figure: both bands clear in neat E100 and at 20%, weak at 40%, at most a faint shoulder near ≈2770 at 60%, absent at 80% (read from Fig. 8, upper panel) | Fig. 8, p.981 |
| C13 | claim, conclusion, authors: "appeared to be minor"; "it can be inferred"; "confirmed"; "indicate" | Curcumin interactions with the cellulosic polymers were minor: from the OH shift curcumin hydrogen-bonded most weakly with CMCAB and most strongly with HPMC; the carbonyl shifts (4 versus 8 cm-1) confirmed CMCAB weaker than HPMCAS; overall the cellulosic polymers hydrogen-bond weakly with curcumin [rests on: R3.b-d, R4.c-d, R5] | p.979-981 |
| C14 | claim, conclusion, authors: "suggests"; "confirms"; "provides further evidence" | PVP, whose amide carbonyl is a strong acceptor, formed the strongest and most extensive hydrogen bonds with curcumin: the lowest OH maximum (3187 cm-1), and a new hydrogen-bonded carbonyl shoulder at 1655 cm-1 (27 cm-1 shift) that confirms curcumin-PVP hydrogen bonding [rests on: R3.f, R4.a, R6] | p.980-981 |
| C15 | claim, conclusion, authors: "indicating"; "little to no evidence" | Curcumin-E100 hydrogen bonding is limited or weak: OH shift about 4 cm-1 and the smallest carbonyl shift (2 cm-1) [rests on: R3.e, R4.e] | p.981 |

## 2015 Sato — Chiral discrimination by a cellulose polymer: differential crystallization inhibition of enantiomers in amorphous dispersions · Solid state stability / Physical stability

[2015-sato-cellulose-polymer-chiral-crystallization-inhibition-enantiomers](../../../cards/2015-sato-cellulose-polymer-chiral-crystallization-inhibition-enantiomers/paper.html) · Solid state stability / Physical stability · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R12 | record, measured | IR of dispersions with HPMCP — ATP(S) and ATP(R) with 30% HPMCP (P5) — NH/OH region: OH peak at slightly higher wavenumber; larger change in the NH peaks with a new peak at 3253 cm−1 (Fig. 12); carbonyl region: pure HPMCP carbonyl at 1727 cm−1, a new peak at 1699 cm−1 in the dispersions (Fig. S1); spectra with ATP(R) and ATP(S) identical | p.5050; Fig. 12, p.5051; Fig. S1, SI p.1 |
| R13 | record, measured | IR NH/OH region of dispersions with HPMCAS LF — ATP(S) and ATP(R) with 30% HPMCAS LF (P5) — new NH peak at 3290 cm−1; OH peak slightly higher in wavenumber; changes larger for ATP(S); the 3390 cm−1 asymmetric NH2 band drastically reduced in the ATP(S) dispersion and present to a greater extent in the ATP(R) dispersion | p.5050-5051; Fig. 13, p.5051 |
| R14 | record, measured | IR NH/OH region of dispersions with HPMCAS HF — ATP(S) and ATP(R) with 20% HPMCAS HF (P5) — new peak at 3290 cm−1 in both; the 3390 cm−1 band more intense in the ATP(S) dispersion than in the ATP(R) dispersion | p.5051; Fig. 14 |
| C24 | claim, conclusion, authors: "strongly suggests" | The IR data show that both HPMCAS and HPMCP interact with ATP by hydrogen bonding between polymer carbonyl groups and the ATP amino group [rests on: R12, R13, R14] | p.5052 |
| C27 | claim, generalisation, authors: "strongly supports" | Because the systems differ only in chirality, the result supports earlier reports that compound-polymer intermolecular interactions are critical determinants of a polymer's effectiveness as a crystal growth inhibitor [rests on: R7, R8, R13, R14; cited: refs 11, 22, 23] | p.5052 |

## 2015 Trasi — Evaluating the influence of polymers on nucleation and growth in supersaturated solutions of acetaminophen · Dissolution / D. Crystallization from solution

[2015-trasi-polymers-nucleation-growth-supersaturated-acetaminophen](../../../cards/2015-trasi-polymers-nucleation-growth-supersaturated-acetaminophen/paper.html) · Dissolution / D. Crystallization from solution · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C4 | claim, prior hypothesis, authors: "highly dependent" | Polymer effectiveness depends highly on the interaction with the particular compound; the polymer must inhibit crystallization in the solid during storage and in the aqueous environment during dissolution; polymers are also the most common inhibitors in supersaturated transdermal systems [rests on: cited: ref 11; argument only] | p.1242 |
| C31 | claim, mechanism, authors: "presumably required"; "likely to be important" | For nucleation inhibition the polymer must interact with the drug during embryo formation and disrupt self-assembly; unlike small molecules it cannot be incorporated into the nucleus, so drug-polymer interactions are presumably required, and those that can compete with solvent-drug interactions are likely important [rests on: argument only; cited: ref 20] | p.1247 |

## 2015 Wegiel — Phase Behavior of Resveratrol Solid Dispersions Upon Addition to Aqueous media · Dissolution / B. Supersaturation from ASD dissolution

[2015-wegiel-resveratrol-solid-dispersions-aqueous-phase-behavior](../../../cards/2015-wegiel-resveratrol-solid-dispersions-aqueous-phase-behavior/paper.html) · Dissolution / B. Supersaturation from ASD dissolution · used · as: drug-polymer intermolecular interactions

| id | kind | content | locator |
|---|---|---|---|
| R21 | record, cited (7) | earlier storage study of the same resveratrol dispersions — powdered dispersions at high RH and temperature — PVP (strong hydrogen bonds) and E100 (ionic interaction with resveratrol) were effective crystallization inhibitors; HPMC, HPMCAS and CMCAB (much weaker hydrogen bonds) crystallized rapidly at high RH | Introduction, pdf p.2; Discussion, pdf p.10 |
| C35 | claim, generalisation, authors: may | Strong compound–polymer interactions in the matrix may favour stability against crystallization during storage but may harm compound release on dissolution. [rests on: R21, R11, R12] | Discussion, pdf p.11 |
| C36 | claim, mechanism, authors: is thought to be | Crystallization from cellulosic dispersions is thought to come from insufficiently strong resveratrol–polymer intermolecular interactions. [rests on: R21] | Discussion, pdf p.11 |
| C37 | claim, mechanism, authors: most probably | The dependence of crystallization extent on polymer amount most probably reflects the limited number of polymer functional groups (e.g., hydroxyls) available to hydrogen bond with resveratrol, which falls as polymer content falls. [rests on: R13, R21] | Discussion, pdf p.11 |

## 2016 Li — Leaching of Lopinavir Amorphous Solid Dispersions in Acidic Media · Dissolution / B. Supersaturation from ASD dissolution

[2016-li-lopinavir-asd-leaching-acidic-media](../../../cards/2016-li-lopinavir-asd-leaching-acidic-media/paper.html) · Dissolution / B. Supersaturation from ASD dissolution · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C34 | claim, generalisation, authors: "might be expected" | In an intimately mixed drug–polymer system, drug solubility might be expected to depend on the drug's amorphous solubility, the drug loading and the drug–polymer interactions [rests on: argument only; cited: refs 20–23] | pdf p.8-9 |
| C36 | claim, mechanism, authors: "would be expected" | LPV–polymer interactions would be expected to be similar across the HPMCAS grades, consistent with LPV leaching not changing between them [rests on: R4] | pdf p.9 |
| C37 | claim, mechanism, authors: "might suggest" | The stronger suppression of LPV leaching by HPMCP might reflect more favourable LPV–HPMCP intermolecular interactions or a higher water content of the spray-dried particles [rests on: R4.d, R19.d] | pdf p.9 |

## 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 · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C32 | claim, mechanism, authors: "readily explainable"; "may be caused" | In 30:70 TPV-PVPVA both phases soften over a similar range, explained by the similar PVPVA and TPV Tgs; the continuous phase softening above pure PVPVA may be caused by drug-polymer intermolecular interactions [rests on: R16.i-j, R16.d, M1, M4; cited: ref 39] | p.20-21 |

## 2016 Sato — Acceleration of the crystal growth rate of low molecular weight organic compounds in supercooled liquids in the presence of polyhydroxybutylate · Solid state stability / Physical stability

[2016-sato-phb-crystal-growth-supercooled-organic-compounds](../../../cards/2016-sato-phb-crystal-growth-supercooled-organic-compounds/paper.html) · Solid state stability / Physical stability · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R9 | record, measured | FTIR spectra, 2800-3600 and 1550-1800 cm−1 (band positions ≈, read from Figs. 7-10) — DPB with 10% and 20% PHB, pure amorphous DPB and semicrystalline pure PHB (Fig. 7); FLU with 10% PHB and pure FLU (Fig. 8); GRI with 5% and 20% PHB, 5% PVAc and pure GRI (Fig. 9); CEL with 5% and 20% PHB and pure CEL (Fig. 10) (P4) — text: no change in NH peak positions; C=O region of each dispersion matches the sum of the two pure-component spectra; the PHB spectrum changes considerably in the dispersions. Figures: pure PHB C=O maximum ≈1722 cm−1 with shoulder ≈1744 and a sharp band ≈3435 cm−1; DPB-PHB 10% and 20% C=O band ≈1741 cm−1; DPB N-H ≈3315 and amide ≈1644 cm−1 in pure and both dispersions; FLU N-H ≈3317 cm−1 and bands ≈1714, ≈1681, ≈1618, ≈1596 cm−1 in pure and 10% PHB, extra band ≈1743 cm−1 with PHB; GRI bands ≈1711, ≈1669, ≈1615, ≈1590 cm−1 in all four, extra band ≈1742 cm−1 with 20% PHB and with 5% PVAc, weak shoulder with 5% PHB; CEL N-H ≈3356 and ≈3270 cm−1 and band ≈1600 cm−1 in all three, extra band ≈1738 cm−1 (strong at 20%, weak at 5% PHB). No IR shown for ATP or APAP mixtures | Figs. 7-10, p.5; text p.5-6 |
| C11 | claim, conclusion, authors: "there seems to be no significant" | NH peak positions do not change and the C=O region of the dispersions is the sum of the pure spectra, so there seems to be no significant drug-polymer interaction [rests on: R9] | p.6 |
| C2 | claim, prior hypothesis, authors: "poorly understood"; "suggested to be important" | Polymers are added to reduce the crystallization rate and improve physical stability; the stabilizing mechanism is poorly understood, and raising Tg to reduce mobility, dilution lowering the drug chemical potential, and specific drug-polymer interactions restricting local mobility have been suggested [rests on: cited: refs 1, 6-11] | p.1 |
| C16 | claim, prior hypothesis, authors: "are also considered" | Drug-polymer specific interactions are also considered to set how well a polymer inhibits crystal growth; small amounts of polymer with no significant effect on Tg or viscosity have been found to considerably delay growth [rests on: cited: refs 26-29] | p.6 |

## 2016 Schram — Polymer Inhibition of Crystal Growth by Surface Poisoning · Dissolution / D. Crystallization from solution

[2016-schram-polymer-inhibition-crystal-growth-surface-poisoning](../../../cards/2016-schram-polymer-inhibition-crystal-growth-surface-poisoning/paper.html) · Dissolution / D. Crystallization from solution · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C28 | claim, mechanism, authors: "is likely due to"; Table 5: asserted ("due to") | Such effective poisoning is likely because an ASD is an intimate mixture of API and polymer; effective ASD stabilisers form strong specific interactions with the API (refs 33, 34), and such interactions disrupt crystal evolution more than polymer present only in solution; Table 5: smaller features of ASD-grown crystals due to more intimate API-polymer interaction [rests on: R2.f, R2.g, R10; cited: refs 33, 34] | p.24, 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 interactions

| id | kind | content | locator |
|---|---|---|---|
| R10 | record, measured | IR carbonyl region, normalized — IDM-HPMC films 5-95% DL and amorphous IDM (100%) (P1, P5) — amorphous IDM peaks at 1733, 1709 and 1683 cm-1; 5% DL: relative intensity of 1733 cm-1 increased and 1709 cm-1 peak absent; spectra did not change significantly until 50% DL; at 60% DL the 1709 cm-1 peak becomes apparent and its relative intensity increases with DL. Figure: 5-30% traces deepest minimum at ≈1705 cm-1; 40% and 50% traces intermediate there; 60-95% traces with a band at ≈1709 cm-1 growing with DL; 100% trace strongest at ≈1709 cm-1 with the ≈1733 cm-1 band reduced to a shoulder | Fig. 9, p.14; text p.13-14 |
| R12 | record, measured | IR of IDM-PVP films — P1, P5; data not shown (spectra reported in ref 32) — 5-80% DL: peaks at 1733 and 1709 cm-1 absent, new peaks at 1724 and 1640 cm-1; higher DL: spectra similar to pure amorphous IDM | p.14 |
| C28 | claim, conclusion, authors: "indicating"; "was estimated to be at least" | In IDM-PVP films at 5-80% DL the new 1724 and 1640 cm-1 bands show strong IDM-PVP interaction; at higher DL drug-drug interactions dominate; the IR miscibility limit is at least 80% DL [rests on: R12] | p.14 |
| C29 | claim, mechanism, authors: "can be attributed" | The high IDM-PVP miscibility limit can be attributed to the strong drug-polymer interactions [rests on: R12; cited: ref 32] | p.14 |

## 2017 Tian — Impact of Polymers on the Melt Crystal Growth Rate of Indomethacin Polymorphs · Solid state stability / Physical stability

[2017-tian-polymers-melt-crystal-growth-indomethacin-polymorphs](../../../cards/2017-tian-polymers-melt-crystal-growth-indomethacin-polymorphs/paper.html) · Solid state stability / Physical stability · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R16 | record, cited | strength of drug-polymer interaction — IDM with PVP, HPMC, HPMCAS (ref 33) — decreasing in the order IDM-PVP > IDM-HPMC > IDM-HPMCAS | p.17 |
| C31 | claim, mechanism, authors: "most likely" | The better inhibition by PVP at low temperature is most likely explained by both reduced molecular mobility and a smaller thermodynamic driving force [rests on: R13, R16, R12] | p.17 |
| C32 | claim, mechanism, authors: "perhaps" | The lower effectiveness of HPMCAS compared with HPMC over the same temperature range can perhaps be attributed to weaker drug-polymer interactions [rests on: R16, R12] | p.17 |

## 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 interactions

| id | kind | content | locator |
|---|---|---|---|
| C3 | claim, prior hypothesis, authors: asserted | Storage far below Tg reduces mobility; polymers mixed at the molecular level stabilize amorphous drugs through intermolecular hydrogen bonds that must be broken before crystallization, antiplasticization and a lower chemical potential; both nucleation and growth must be slowed, and the best polymer depends on drug and process (for acetaminophen HPMCAS inhibited nucleation best, polyacrylic acid and PVP growth) [rests on: cited: refs 2-7] | pdf p.2 |
| 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 — Impact of Eudragit EPO and Hydroxypropyl Methylcellulose on Drug Release Rate, Supersaturation, Precipitation Outcome and Redissolution Rate of Indomethacin Amorphous Solid Dispersions · Dissolution / B. Supersaturation from ASD dissolution

[2017-xie-eudragit-epo-hpmc-indomethacin-asd-supersaturation-redissolution](../../../cards/2017-xie-eudragit-epo-hpmc-indomethacin-asd-supersaturation-redissolution/paper.html) · Dissolution / B. Supersaturation from ASD dissolution · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C49 | claim, mechanism, authors: cited fact asserted; "is expected" | EPO forms a salt with IND through ionic interaction of its cationic nitrogen with the drug's carboxylic acid, so EPO is expected to inhibit IND dimer formation and crystallization better than HPMC, which lacks such an interaction [rests on: cited: ref 23; R26] | pdf p.18 |
| C55 | claim, mechanism, authors: "presumably" | EPO's effect on IND crystalline and amorphous solubility is presumably due to intermolecular drug-polymer interactions in solution [rests on: R1, R2, R3] | 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: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R3 | record, measured | IR of CEX:PVP films versus ratio — 9:1, 7:3, 5:5, 3:7, 1:9 with neat amorphous CEX and neat PVP (P2); PVP grade not named in the caption — new N-H band at 3196 cm−1 grows at the expense of the 3268 cm−1 band as polymer loading increases; PVP C=O at 1682 cm−1 develops a shoulder at 1661 cm−1 (CEX has no absorbance there) that grows as the drug:polymer ratio increases; figure: 1661 cm−1 arrow on the 9:1 trace, 3196 cm−1 arrow on the 1:9 trace | Fig. 2a, p.4; text p.3 |
| R4 | record, measured | IR of CEX:PVP/VA films — P2; ratios not printed — pyrrolidone C=O at 1684 cm−1 develops a shoulder at 1662 cm−1; acetate C=O shows minimal change except at the highest drug loadings; CEX N-H shifts from 3268 to approximately 3198 cm−1 | text p.3; Fig. S2 (not supplied) |
| R5 | record, measured | IR of CEX:HPMCAS films versus ratio — 9:1 to 1:9 (P2) — CEX N-H band at 3268 cm−1 shifts gradually toward 3237 cm−1 as polymer loading increases; HPMCAS ester carbonyl shifts from 1743 to 1734 cm−1 as drug loading increases | Fig. 2b, p.4; text p.3 |
| R6 | record, measured | IR of CEX:HPMC films — P2; ratios not printed — no clear spectral evidence of intermolecular interaction; relatively minor changes in the N-H stretching region between neat amorphous CEX and dispersion | text p.3; Fig. S3 (not supplied) |
| C1 | claim, conclusion, authors: abstract: asserted ("It was found"); conclusions: asserted | PVP and PVP/VA form stronger or more extensive hydrogen bonds with CEX than the cellulose-based polymers [rests on: R3, R4, R5, R6] | p.1, p.10 |
| C4 | claim, conclusion, authors: abstract: asserted ("strongly affected"); conclusions: asserted ("were found") | On exposure to moisture, stability of CEX ASDs is strongly affected by both hygroscopicity and strength of drug-polymer interactions; ASDs with stronger interaction and lower hygroscopicity were less susceptible to moisture-induced AAPS and crystallization [rests on: R13, R17, R18, R23, R24] | p.1, p.10 |

## 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 · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C42 | claim, mechanism, authors: "suggests"; "could result"; "appears" | Since no sodium signal was found, ionic chloride contamination is unlikely, and the 197 eV Cl 2p component suggests ITZ chlorine in an altered electronic environment, which could result from changed drug-drug or drug-polymer interactions; water raises this component, ITZ then appearing to sit in a more polymer-rich environment, and the drug-enriched n-hexane surface shows less of it [rests on: R21, R20] | p.24-25 |

## 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 interactions

| id | kind | content | locator |
|---|---|---|---|
| R10 | record, measured | IR carbonyl region (1590-1710 cm−1) — spin-coated films (P11): LPV-CAP, LPV-HPMCAS, LPV-HPMCP (panel D labelled "LPV-P"), 15-85% DL — amorphous LPV doublet at 1648 and 1674 cm−1; amorphous CAP, HPMCAS and HPMCP no significant peaks in this region; LPV-CAP: 1648 cm−1 peak decreases in intensity with increasing polymer content and the doublet becomes one broad peak at 1660 cm−1; LPV-HPMCAS and LPV-HPMCP: with decreasing DL the 1674 cm−1 peak becomes more intense than the 1648 cm−1 peak; LPV-EC: no shift in the carbonyl region | Fig. 6A, 6C, 6D, p.121; text p.119 |
| R11 | record, measured | IR OH-stretch region (3380-3540 cm−1) and other systems — LPV-EC films (P11); LPV-CA and LPV-EUD films — amorphous EC peak at 3481 cm−1, amorphous LPV no peak in 3440-3540 cm−1; with LPV the EC peak at 3470 cm−1; no IR peak shifts for LPV-CA and LPV-EUD (data not shown) | Fig. 6B, p.121; text p.119 |
| R12 | record, measured and derived (E1) | water uptake at 90% RH (weight gain %; endpoint of isotherms) — amorphous LPV, polymer and 50% DL ASD powders (P12); additive prediction by E1 — sub-table below (all values ≈, read from Fig. 7); text: CA, EUD and CAP ASD isotherms close to the additive prediction; HPMCAS and HPMCP ASDs below it; EC: drug and polymer sorb similar amounts | Fig. 7, p.121; text p.119 |
| R13 | record, measured (exp) and derived (predicted, E1) | water uptake at 90% RH versus DL (weight gain %) — ASD powders (P12); 0% DL = polymer, 100% DL = LPV (≈4.2) — sub-table below (all values ≈, read from Fig. 8); text: CAP below 50% DL similar to prediction, above 50% significantly lower; HPMCAS and HPMCP lower than predicted | Fig. 8, p.122; text p.119 |
| C35 | claim, conclusion, authors: "suggest"; "suggesting" | Together with two Tgs, the additive sorption points to negligible drug-polymer interaction in 50% DL CA and EUD ASDs; the reduced sorption of HPMCAS and HPMCP ASDs points to molecular interactions [rests on: R12, R8] | p.119 |
| C39 | claim, conclusion, authors: "suggests" | HPMCAS and HPMCP ASDs sorb less than predicted at 90% RH, pointing to stronger interactions with LPV than CA and EUD [rests on: R13.i-l] | p.119 |
| C54 | claim, conclusion, authors: "approximate"; "consistent with" | The hydrogen-bonded ASDs show composition-dependent suppression with the approximate order HPMCP > EC > HPMCAS, in line with HPMCP forming stronger or more extensive interactions [rests on: R3] | p.123 |

## 2018 Mosqueragiraldo — Crystallization Inhibition Properties of Cellulose Esters and Ethers for a Group of Chemically Diverse Drugs - Experimental and Computational Insight · Dissolution / D. Crystallization from solution

[2018-mosquera-giraldo-cellulose-esters-ethers-crystallization-inhibition-computational-insight](../../../cards/2018-mosquera-giraldo-cellulose-esters-ethers-crystallization-inhibition-computational-insight/paper.html) · Dissolution / D. Crystallization from solution · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R9 | record, simulated | radial distribution function between all polymer atoms and the drug molecules: main peak height and position — 10 ns production of chain plus 25-molecule aggregate (P9, P11); distance axis 0-9 nm — sub-table below | Fig. 9, p.21; text p.21, p.25-27 |
| R12 | record, simulated (E1) | estimated free energy of interaction relative to the ideal gas state (kcal/mol), printed bar labels — polymer-drug energy groups over the 10 ns production trajectory, 310 K (P10) — sub-table below; text: A5b-drug interaction insignificant; ECD-TPV marginal | Fig. 12, p.24; text p.23-24, p.29 |
| C25 | claim, conclusion, authors: asserted; "appears to be stronger"; "appears to interact more weakly" | Free energies of interaction: A5b interaction with TPV and ATZ insignificant; A5a interacts with both, more strongly with ATZ; ECA and ECB attract TPV, ECB more strongly; ECD interacts marginally with TPV; ATZ attracts ECA, ECB and ECD, more strongly ECA and ECB [rests on: R12] | p.23-24, p.29 |
| C43 | claim, generalisation, authors: discussion: "agree"; "may give valuable information"; abstract: "were supported" | The free energies agree with the induction times of Figs. 4 and 5, so the estimated drug-polymer free energy of interaction may give valuable information about a polymer's tendency to interact with the drug and prevent crystallization; abstract: the effective materials had a higher probability of close contacts and more negative estimated free energies [rests on: R12, R9, R1, R2] | p.2, p.29 |

## 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 interactions

| id | kind | content | locator |
|---|---|---|---|
| C34 | claim, mechanism, authors: "It is likely" | Key RTV-PVPVA interactions in the presence of water are likely saturated around 25-30% DL, leaving RTV above this DL susceptible to phase separation from PVPVA [rests on: argument only] | p.16 |
| C36 | claim, mechanism, authors: "suggests" | Congruent release of the low-DL ASDs suggests a drug-polymer interaction that persists during hydration and release, at least over the dissolution timescale, hindering AAPS [rests on: R3.a-f, R18] | p.16 |

## 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: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R16 | record, measured | F 1s components by XPS — P7; neat amorphous ledipasvir and ASDs 5, 10, 20, 50% DL before dissolution — neat amorphous ledipasvir: one peak at 687.1 ± 0.1 eV; ASDs: an additional peak at 684.0 ± 0.2 eV (about 3 eV lower); share of F 1s at 684.0 eV 77, 73, 42, 18% at 5, 10, 20, 50% DL (text); Fig. 8: ≈77.5, ≈73.5, ≈41.5, ≈17.5%, neat ledipasvir 0%; Fig. 3S: neat drug single peak ≈687 eV, 20% DL ASD two fitted components ≈684 and ≈687 eV | text p.22; Fig. 8, p.24; Fig. 3S, SI p.4 |
| R22 | record, measured | 19F spectra with added polymer — P8; 2 mg/mL ledipasvir in toluene-d8 alone, with 2 mg/mL PVPVA, with 2 mg/mL PVA — text: with PVPVA the chemical shift difference between F peaks reduced; PVA had no impact; with PVP 19F NMR could not be measured (minimal solubility in toluene) | Fig. 12, p.29; text p.26 |
| R25 | record, derived (P10; E2, E3, E4) | 19F chemical shift difference between the two F atoms vs equivalent DL (NMR) and molar amount of F at the lower BE vs DL (XPS) — NMR: ledipasvir with VP in toluene-d8 (R23); XPS: 100 mg compacts (R16) — sub-table below (all values ≈, read from Fig. 16); figure: shaded "Congruent Release" band from ≈3 to ≈10% DL; text: the lower-BE F amount reached a plateau for DLs exceeding 10% | Fig. 16, p.37; text p.36; SI p.8 |
| C43 | claim, conclusion, authors: "suggest" | The lower-BE F amount plateaus above 10% DL and the polymer disrupts drug-drug interactions effectively only below 7% DL; ledipasvir-PVPVA interactions saturate at a fairly low DL (< 10%), above which drug-drug interactions predominate [rests on: R25] | p.36 |
| C45 | claim, generalisation, authors: abstract: asserted ("Evidence is provided ... play a central role"); discussion: "this may be coincidental", "clearly deserve further investigation"; conclusions: "may play a role" | The DL at which ledipasvir-PVPVA interactions saturate lies close to the DL where release switched from polymer- to drug-controlled, so drug-polymer interactions as a function of DL influence release [rests on: R25, R3, R4] | p.2, p.36, 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 · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C4 | claim, prior hypothesis, authors: "likely to be oversimplified" | Dissolution has been polymer-controlled at low DL and drug-controlled at high DL; this picture is likely oversimplified and the DL of the switch is poorly understood; polymer type and drug-polymer interactions or phase behaviour influence ASD dissolution in a drug-specific way [rests on: cited: refs 12-23] | pdf p.5 |
| C7 | claim, assumption, authors: asserted | Nil and Cil are structural analogues of the same therapeutic class with high chemical similarity, non-ionizing, of relatively low crystallization tendency, and with similar ability to hydrogen bond with the polymer, differing in log P by 2.5 units [rests on: M1, M2; argument only] | pdf p.5, p.34 |
| C13 | claim, mechanism, authors: "most likely" | Polymer release from ASDs is slightly slower than from polymer alone even at low DL, as seen before, most likely from the higher hydrophobicity of the formulation or drug-polymer interactions [rests on: R5, R6, R8; cited: refs 2, 20] | pdf p.18 |

## 2020 Moseson — Application and Limitations of Thermogravimetric Analysis to Delineate the Hot Melt Extrusion Chemical Stability Processing Window · ASD process / ASD process

[2020-moseson-tga-hme-chemical-stability-processing-window](../../../cards/2020-moseson-tga-hme-chemical-stability-processing-window/paper.html) · ASD process / ASD process · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C32 | claim, prior hypothesis, authors: "may stabilize"; "have been reported"; "may similarly destabilize" | Polymers may stabilize the melt against recrystallization and have been reported to protect drugs from thermal degradation (or to destabilize them); testing the ASD lets drug-polymer interactions that cause chemical degradation show up [rests on: cited: refs 11, 12, 37, 65, 67] | p.21 |
| C38 | claim, mechanism, authors: "an interesting insight"; "may be more protective" | The different PCZ onset ranges with the two polymers suggest that PVPVA may protect PCZ better than HPMCAS [rests on: R5, R14] | p.24 |
| C39 | claim, mechanism, authors: "This suggests"; "some protection" | The delayed onset of IDM/PVPVA compared with neat IDM suggests that PVPVA gives some protection against thermal degradation of IDM, as Vyazovkin and colleagues found with PVP, whose effect (stabilizing or destabilizing) depends on intermolecular interactions and drug-polymer ratio; the stabilization mechanism is complex [rests on: R5, R14; cited: refs 11, 37] | p.24 |

## 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 · measured · as: drug–polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R7 | record, measured | halogen core-level BE, neat compound and new low-BE peaks in polymer — P5; ASDs (P4); DL and n behind each value not stated — sub-table R7 | Table 1, p. 18; p. 15 |
| R10 | record, measured | O 1s BE of PVP carbonyl — neat PVP vs clotrimazole/PVP 50/50 wt% (P5) — text: O 1s shifted to higher BE by 0.2 eV in the dispersion; peak maxima ≈530.8 eV (PVP) and ≈531.0 eV (dispersion), peak heights ≈1400 and ≈2300 CPS (read from Fig. 6S) | p. 28; Fig. 6S, SI p. 10 |
| R11 | record, measured | IR carbonyl band positions — P7 films; 10-90% DL — pure PVPVA: VP C=O "around" 1684 cm-1, VA C=O 1736 cm-1; clotrimazole-PVPVA and brotrimazole-PVPVA: VP C=O maximum 1684 → 1682 cm-1 from 10% to 90% DL, VA C=O position unchanged; Me-DIBF-PVPVA: VP C=O downshift 6 cm-1; Me-DIBF films: absorbance above ≈1750 cm-1 rises with DL and the 90% VP band is broader (read from Fig. 5c) | p. 25; Fig. 5, pp. 25-26 |
| C2 | claim, generalisation, authors: abstract: "may", "potentially"; p. 31: asserted ("common, but long-neglected") | Halogen bonding may be a common but neglected interaction in drug-polymer amorphous blends and potentially important for their properties and performance [rests on: argument only; R7, R11, R12] | pp. 2, 31 |
| C35 | claim, generalisation, authors: asserted | Non-covalent interactions affect solubility, solid-form landscape and phase transformations of pharmaceutical systems [rests on: argument only] | p. 27 |

## 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: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R24 | record, measured | NH stretch peak position (cm⁻¹) — amorphous felodipine and 30% DL ASD films (P11) — sub-table below (Table 3); figure: maxima at ≈3342 (felodipine), ≈3292 (PVP and PVPVA, which also show a second band near ≈3225), ≈3362 (EUDS, magenta) and ≈3355 (HPMCAS, orange); HPMC shows no distinct maximum, only a shoulder near ≈3350 (read from Fig. 13); polymers show no significant peaks in this region (data not shown); a shoulder or second peak at 3342 cm⁻¹ remains for most ASDs | Table 3, p.12; Fig. 13, p.12; text p.8, p.10 |
| R25 | record, measured | IR carbonyl stretching region — amorphous felodipine and Fel:HPMC 30:70 film (P11) — amorphous felodipine: doublet at 1701 and 1682 cm⁻¹; Fel-HPMC: 1682 cm⁻¹ peak not discernible, single slightly broader peak at 1699 cm⁻¹ | Fig. S8, SI p.10 |
| C25 | claim, conclusion, authors: "consistent with"; "suggesting"; "appears to be the case" | The NH downshift with PVP and PVPVA is consistent with stronger drug-polymer hydrogen bonds than in amorphous felodipine; the upshift with EUDS and HPMCAS suggests weaker interactions; with HPMC there is no NH shift and carbonyl changes indicate an interaction of similar strength to neat drug; the hydrogen-bonding order is PVP ≅ PVPVA > HPMC > HPMCAS > EUDS; residual drug-drug bonding means the extent of drug-polymer bonding cannot be quantified [rests on: R24, R25] | p.8, p.10 |
| C48 | claim, conclusion, authors: asserted; "appear"; "if any"; "clearly needs further evaluation" | There is no positive correlation between drug-polymer hydrogen-bond strength and the LoC: PVP and PVPVA bond more strongly and have low LoCs, HPMCAS and EUDS appear to bond more weakly and give more consistent rates; the role of drug-polymer interactions, if any, needs further evaluation [rests on: R24, R15, R14] | p.13 |

## 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 · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R9 | record, measured | ATR-FTIR carbonyl band position, neat polymer versus 4:6 dispersion (cm−1) — P6 — sub-table below; new band at around 1560 cm−1 in the CAP, HPMCP and L100 dispersions; acid donor region: broad peaks; lumefantrine has no carbonyl group, amorphous lumefantrine bands at ≈1635, ≈1590 and ≈1565 cm−1 (read from Fig. 5a) | Fig. 5, p.7; text p.5-6 |
| R10 | record, measured | XPS N 1s spectra — lumefantrine and 4:6 ASDs with L100, HPMCAS, CAP, HPMCP (P15) — lumefantrine: single N 1s peak at 399 eV; with the acidic polymers a second component at 402 eV; the polymers contain no nitrogen; fitted 402 eV component small for HPMCAS and L100, about equal to the 399 eV component for HPMCP and larger than it for CAP (figure) | Fig. 6, p.8; text p.6 |
| R11 | record, derived (E2) | percentage protonation of lumefantrine (value with deviation in parentheses; n not stated) — 4:6 ASDs (P15) — sub-table below | Table 2, p.8 |
| C11 | claim, mechanism, authors: "anticipated"; "suggests"; "indicating" | The polymer carbonyls, anticipated to self-hydrogen-bond with the polymer carboxylic acid donors, shift to higher wavenumbers with lumefantrine, which reflects a change in hydrogen bonding; the small HPMCP shift reflects some drug-polymer interaction [rests on: R9] | p.5-6 |
| C14 | claim, conclusion, authors: asserted ("clearly different") | The 402 eV N 1s component is protonated lumefantrine nitrogen (assignment from ref 37; a positive charge raises the binding energy), so the basic drug undergoes partial salt formation with the acidic polymers, to clearly different extents, small for HPMCAS and largest for CAP [rests on: R10, R11; cited: ref 37] | p.6 |
| C32 | claim, mechanism, authors: "can"; "expected" | Polymers bearing acidic groups can interact more strongly with the weakly basic tertiary amine of lumefantrine, to an extent expected to depend on the amount of acid groups [rests on: argument only] | p.10 |

## 2020 Ueda — Polymer type impacts amorphous solubility and drug-rich phase colloidal stability: A mechanistic study using nuclear magnetic resonance spectroscopy · Dissolution / C. Amorphous solubility and LLPS

[2020-ueda-polymer-type-amorphous-solubility-drug-rich-phase-colloidal-stability](../../../cards/2020-ueda-polymer-type-amorphous-solubility-drug-rich-phase-colloidal-stability/paper.html) · Dissolution / C. Amorphous solubility and LLPS · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R4 | record, measured | ¹H NMR of IBP and polymer below S_a,IBP, EUD-E — as R3, EUD-E 300 µg/mL — IBP peaks shifted relative to buffer (aromatic pair ≈7.29 and ≈7.21 ppm against ≈7.29 and ≈7.24 ppm in buffer, read from Fig. 2); EUD-E resonances changed in shape and chemical shift when IBP was present (for example the ≈2.95 ppm peak and the ≈0.9-1.0 ppm band, read from Fig. 2) | Fig. 2, p.16; text p.15 |
| R11 | record, measured | ¹H NMR aromatic region above S_a,IBP, EUD-E — as R9, EUD-E 300 µg/mL — aqueous-phase IBP peaks up-field of buffer, ≈7.24 and ≈7.13 ppm at + 100 against ≈7.29 and ≈7.25 ppm (read from Fig. 5); IBP-rich peaks at ≈6.97 and ≈6.80 (+ 100) to ≈6.95 and ≈6.78 ppm (+ 300), close to buffer, and much sharper than in HPMC and PVP-VA | Fig. 5, p.26; text p.25 |
| C12 | claim, mechanism, authors: "consistent with" | The shifts of IBP and EUD-E resonances in EUD-E solution are consistent with intermolecular interactions between EUD-E and IBP in aqueous solution that lead to IBP solubilization, as reported for mefenamic acid with EUD-E (hydrogen bonding and hydrophobic interaction) [rests on: R4; cited: refs 38, 39] | p.15 |
| C25 | claim, mechanism, authors: asserted | In EUD-E solution, complex formation between IBP and EUD-E in the aqueous phase induced the up-field shift of the aqueous IBP peaks, as below S_a,IBP [rests on: R11, R4] | p.25 |

## 2020 Wilson — Amorphous solid dispersions of enzalutamide and novel polysaccharide derivatives: investigation of relationships between polymer structure and performance · Bioperformance / Bioperformance

[2020-wilson-enzalutamide-polysaccharide-asd-polymer-performance](../../../cards/2020-wilson-enzalutamide-polysaccharide-asd-polymer-performance/paper.html) · Bioperformance / Bioperformance · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C5 | claim, prior hypothesis, authors: asserted; "It is to be expected" | To inhibit crystallization the polymer must interact with the drug through specific interactions (van der Waals, ionic, hydrogen bonding), whose relative importance is expected to differ between dry and hydrated states [rests on: cited: refs 9, 17, 18] | p.2 |
| C41 | claim, mechanism, authors: "can be attributed" | Since no crystallization was observed, the low free-drug concentration from the CA Sub ASD can be attributed to low polymer solubility combined with strong drug-polymer interactions in the matrix [rests on: R7, R8; cited: ref 21] | p.6 |

## 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 · measured · as: drug–polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R6 | record, measured | carbonyl band positions, FTIR — 4:6 CAP and 4:6 EL100 ASDs versus neat polymers (P5) — CAP: neat main carbonyl 1675 cm−1 with a shoulder at higher wavenumber; ASD dominant carbonyl 1733 cm−1; EL100: neat 1707 cm−1, ASD 1725 cm−1; the 4:6 EL100 ASD trace also has a band at ≈1600 cm−1 of height comparable to its carbonyl band (read from Fig. 5) | Fig. 5, p.2427; text p.2426 |
| R7 | record, measured | carbonyl region, FTIR — 2:8, 3:7, 4:6 HPMCP and HPMCAS ASDs versus neat polymers (P5) — minor changes relative to neat polymer; spectra at 20% and 30% drug loading similar to 40%; two carbonyl peaks not resolved in neat HPMCP, HPMCAS, EL100 | Fig. 5, p.2427; text p.2426 |
| C18 | claim, conclusion, authors: asserted ("most remarkable") | A polymer carbonyl peak shifts to higher wavenumber on forming a dispersion with lumefantrine; the shift is largest for CAP, similar for EL100 and minor for HPMCP and HPMCAS; 20% and 30% loading spectra resemble 40% [rests on: R6, R7] | p.2426 |
| C19 | claim, mechanism, authors: "further suggests"; "again suggest" | Neat CAP has two chemically distinct carbonyl groups (ester and acid); the changed peak ratio in the ASD suggests an interaction that changes one carbonyl environment; subtle peak-shape changes in the other polymers again suggest changed carbonyl environments [rests on: R6, R7] | p.2426 |
| C20 | claim, caveat, authors: "is warranted" | Because the polymers are acidic, lumefantrine is basic and the IR changes, the nature of the interaction needs further probing, which XPS was used for [rests on: R6, R7] | p.2426−2427 |

## 2021 Moseson — Amorphous Solid Dispersions Containing Residual Crystallinity: Competition Between Dissolution and Matrix Crystallization · ASD process / ASD process

[2021-moseson-residual-crystallinity-dissolution-matrix-crystallization](../../../cards/2021-moseson-residual-crystallinity-dissolution-matrix-crystallization/paper.html) · ASD process / ASD process · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C53 | claim, generalisation, authors: "likely" | The crystallization tendency of the amorphous hydrated drug and the lack of persistent drug-polymer interactions likely play a role in the dominance of matrix crystallization [rests on: argument only] | p.14 |
| C56 | claim, mechanism, authors: asserted ("therefore"); "may have" | This mobility lets drug molecules reorganize into crystals or join nearby crystals, and rapid polymer depletion disrupts drug-polymer interactions that may have stabilized the ASD under ambient conditions [rests on: argument only] | p.14 |

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

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

| id | kind | content | locator |
|---|---|---|---|
| R7 | record, measured (rows a, c, d, e); cited ref 17 (row b) | VP carbonyl band of PVPVA vs DL — ASD films at 10−90% DL (P2) — see sub-table R7 | Section 4.2.1, p.3500−3501; Section 5, p.3503; Fig. 2, p.3500 |
| R9 | record, measured | I 3d binding energies (P3) — neat amorphous compounds (as printed) and TIPP/PVPVA, Me-TIPP/PVPVA ASD compacts — neat: one doublet, 620.7 ± 0.01 eV (I 3d5/2) and 632.2 ± 0.04 eV (printed "I 3d1/2"); ASDs: additional doublet at lower BE, 618.1 ± 0.05 and 629.6 ± 0.05 eV; doublet components in ratio 3:2 | Section 4.2.2, p.3501; SI Fig. 4S |
| C19 | claim, conclusion, authors: asserted ("there is evidence"); abstract: "confirmed" | In the solid state there is evidence of halogen bonding only (Me-TIPP), hydrogen bonding only (PHPH), both (TIPP) and no specific interactions (Me-PHPH); the abstract states the interactions were studied and confirmed by XPS and IR. [rests on: R7, R8, R9, R11, R12] | Abstract, p.3496; Section 5, p.3504 |
| C45 | claim, generalisation, authors: "it is suggested"; "may depend"; "substantial evidence" | The LoC of PVPVA-based ASDs may depend on the strength and extent of specific compound−polymer interactions, with substantial evidence that lacking specific interactions improves release at higher DLs. [rests on: R19, R20, R7, R12] | Conclusions, p.3506 |
| C47 | claim, generalisation, authors: "may be" | Drug−polymer interactions may be a dominant factor in how drug and polymer release from ASDs in aqueous solution. [rests on: R19, R20, R21] | Conclusions, p.3506; Abstract, p.3496 |

## 2021 Ueda — Effect of Polymer Species on Maximum Aqueous Phase Supersaturation Revealed by Quantitative Nuclear Magnetic Resonance Spectroscopy · Dissolution / C. Amorphous solubility and LLPS

[2021-ueda-polymer-species-maximum-aqueous-supersaturation-nmr](../../../cards/2021-ueda-polymer-species-maximum-aqueous-supersaturation-nmr/paper.html) · Dissolution / C. Amorphous solubility and LLPS · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C40 | claim, mechanism, authors: abstract: asserted ("as a result of more extensive drug−polymer interactions"); discussion: "consistent with"; "would, in turn, be consistent with" | IBP interacts more strongly with PVP-VA (pyrrolidone carbonyl acceptor) than with HPMC 603 (weak OH and ether acceptors): the larger downfield shift with PVP-VA despite less polymer in the drug-rich phase fits stronger interaction, which would in turn fit the larger drop in dissolved IBP with PVP-VA [rests on: R3, R5, R14, R19; cited: refs 50-53] | p.1344, p.1353 |
| R14 | record, cited | Flory-Huggins χ between IBP and PVP-VA — 1/1 IBP/PVP-VA blend in an ASD (ref 50) — ca. −1; IBP-PVP-VA hydrogen bonding reported, giving a negative χ; pyrrolidone carbonyl of vinylpyrrolidone as hydrogen bond acceptor for the carboxylic acid (refs 51, 52) | p.1352 |
| R19 | record, cited | IBP-polymer interaction strength by molecular dynamics simulation — ref 53 — IBP-PVP-VA interactions much stronger than IBP-HPMC interactions | p.1353 |
| X5 | extractor note | claim-data gap — The abstract states that the larger IBP drop with PVP-VA than HPMC is "a result of more extensive drug−polymer interactions" (C40), but no interaction was measured in the hydrated IBP-rich phase: the support is the larger downfield shift (R3), a cited MD simulation (R19) and a cited χ for a 1/1 blend (R14); the authors themselves note that χ may change with water (C39, C41) — C40, C39, C41, R3, R14, R19 — treat drug-polymer interaction as the authors' proposed explanation, not a measured result |  |

## 2021 Wilson — Interaction of Polymers with Enzalutamide Nanodroplets—Impact on Droplet Properties and Induction Times · Dissolution / D. Crystallization from solution

[2021-wilson-enzalutamide-nanodroplets-polymer-interactions-induction-times](../../../cards/2021-wilson-enzalutamide-nanodroplets-polymer-interactions-induction-times/paper.html) · Dissolution / D. Crystallization from solution · measured · as: drug-polymer interaction

| id | kind | content | locator |
|---|---|---|---|
| R17 | record, measured | d-HPMCAS emission with enzalutamide — P9; d-HPMCAS 50 (a) and 100 (b) μg/mL with enzalutamide 20, 30, 40, 45, 70, 90, 120 μg/mL — text: peak near 437 nm in all spectra; broad peak near 535 nm in buffer and near 528 nm at low enzalutamide; above 42 μg/mL new peaks at 469 and 487 nm, higher intensity, overall maximum at lower wavelength, the 535 nm peak a shoulder. Figure: 469/487 nm peaks distinct at 70, 90 and 120 μg/mL, not at 20-45 μg/mL; 120 μg/mL reaches ≈590 (a) and ≈650 (b) near 470-487 nm; intensity at 400 nm rises from ≈90-130 (20-30 μg/mL) to ≈950-1000 (120 μg/mL) (read from Fig. 11) | Fig. 11, p.844; text p.844 |
| R20 | record, simulated | RDF between all polymer atoms and all drug atoms — P11, 15 ns trajectories — both curves peak at ≈29-30 near ≈1.0-1.1 nm and fall to ≈0 by ≈3-3.5 nm; the HPMCAS curve rises earlier (≈25 near ≈0.5 nm) (read from Fig. 13) | Fig. 13, p.844 |
| R21 | record, simulated | estimated free energy of interaction (kcal/mol) — P11 — Eud EPO + ENZ ≈-28; HPMCAS + ENZ ≈-43 (read from Fig. 14) | Fig. 14, p.845 |
| C34 | claim, conclusion, authors: "indicate" | In MD enzalutamide interacts with both polymers; the similar RDFs mean comparable polymer-drug distances; Eud EPO is globular and HPMCAS extended [rests on: R19, R20] | p.844 |
| C57 | claim, mechanism, authors: "may be mediated"; "may be critical" | Stabilization against crystallization in enzalutamide droplet solutions may be mediated by drug-polymer interactions at the droplet-water interface, and MD shows that polymer conformation at that interface may be critical [rests on: R19, R21, R22, C43] | p.846-847 |

## 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 · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R20 | record, measured | FT-IR spectra of RTV-ASDs compared with neat RTV and polymers — 20% DL HPMC, HPMCAS LF and MF ASDs (Fig. S14); 20% DL PVP and PVP/VA grade ASDs and 10−50% DL PVP K-30 and PVP/VA 64 ASDs (Fig. 9) — RTV-HPMCAS MF and LF: no shifts and no new bands; RTV-HPMC: bands at 1639 and 1722 cm⁻¹ (RTV 1633 and 1716 cm⁻¹); RTV-PVP K-30: shoulder at 1720 cm⁻¹ at all DLs (Fig. 9A); RTV-PVP/VA 64: band at 1681 cm⁻¹ slightly shifted and broadened relative to neat PVP/VA 64 (Fig. 9C); text: no notable changes in the ASD spectra overall | Fig. 9, p.339; Fig. S14, SI p.15; text p.339-341 |
| C28 | claim, conclusion, authors: "might indicate" | FT-IR detected no notable changes in the ASD spectra; the HPMCAS ASDs showed no shifts or new bands; the slight shifts in RTV-HPMC (1639 and 1722 cm⁻¹) might reflect drug-polymer interactions that disrupt RTV self-interactions [rests on: R19, R20] | p.339-340 |
| C29 | claim, conclusion, authors: "might indicate"; "may suggest" | The 1720 cm⁻¹ shoulder of RTV-PVP K-30 might reflect changed hydrogen bonding from ASD formation or a simple overlap of RTV and PVP bands; the shifted and broadened 1681 cm⁻¹ band of RTV-PVP/VA 64, seen before (ref 27), may mean that RTV interacts preferentially with the C=O of vinyl pyrrole [rests on: R20; cited: ref 27] | p.340-341 |
| C35 | claim, mechanism, authors: "may offer some support"; "may"; "perhaps"; "possibly"; "further suggesting" | Intermolecular interactions may help explain the protection by PVP and PVP/VA: most degradants form by intramolecular attack during hydrolysis, so interactions may protect RTV; FT-IR shifts, perhaps from hydrogen bonding, lie in regions of the more reactive groups; the PVP over PVP/VA order is possibly from more interactions with the vinyl pyrrole carbonyl; the absence of interaction evidence with HPMCAS or HPMC further supports this [rests on: R20, R10] | p.342 |
| C36 | claim, caveat, authors: "somewhat tenuous" | The spectral evidence for drug-polymer interactions is somewhat tenuous [rests on: R20] | p.342 |

## 2022 Duong — Combining enabling formulation strategies to generate supersaturated solutions of delamanid: In situ salt formation during amorphous solid dispersion fabrication for more robust release profiles · Dissolution / B. Supersaturation from ASD dissolution

[2022-duong-delamanid-in-situ-salt-asd-release](../../../cards/2022-duong-delamanid-in-situ-salt-asd-release/paper.html) · Dissolution / B. Supersaturation from ASD dissolution · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R11 | record, measured | drug-polymer interactions by IR — free-base ASDs with HPMCAS and HPMCP (P11) — no specific intermolecular interactions detected (Fig. S2) | p.135 |
| C11 | claim, prior hypothesis, authors: asserted ("have been demonstrated") | Some polymers inhibit drug crystallization in solution, attributed to drug-polymer intermolecular interactions, and polymers can also stabilize drug-rich droplets formed above the amorphous solubility [rests on: cited: refs 35-37] | p.134-135 |
| C51 | claim, prior hypothesis, authors: "are thought to" | ASD polymers kinetically stabilize the supersaturated solution and are thought to inhibit crystallization through non-specific drug-polymer interactions; not all polymers are equally effective [rests on: cited: refs 35, 36, 51, 52] | p.141 |

## 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: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R18 | record, measured | carbonyl-region FTIR (1800-1550 cm−1) of ASD films — spin-coated films (P10): free base 10, 25%; PEG 250 diacid (1:1) 25, 30%; benzoate 20, 25, 30%; PEG 250 diacid (2:1) 25, 30%; besylate, tosylate, camsylate 10, 15, 30%; HCl 10, 20, 30%; sulfate 5, 30% DL; with neat PVPVA, amorphous lumefantrine and each neat salt — PVPVA vinyl acetate C=O at 1736 cm−1 and vinylpyrrolidone C=O at 1684 cm−1; no shift of either peak at any DL except in the tosylate ASDs; peak height ratios changed with DL for several ASDs (Fig. S4, SI not supplied), most visibly for the PEG 250 diacid (1:1) salt with excess acid groups (Fig. 12b) | Fig. 12, p.56; text p.55-56 |
| C24 | claim, conclusion, authors: "suggests"; "there might be" | Changes in FTIR peak height ratios with DL point to a minor extent of interaction between some lumefantrine salts and PVPVA carbonyls, most visible for the non-stoichiometric salt with excess acid groups [rests on: R18] | p.55-56 |
| C30 | claim, conclusion, authors: "indicated"; "appear" | FTIR shows that the lumefantrine salts generally have a very low tendency to interact with PVPVA; only the PEG 250 diacid/sulfate salts with an unreacted acid group showed some sign of hydrogen bonding, and specific interactions of the stoichiometric salts with PVPVA appear less extensive than in systems studied before [rests on: R18] | p.57 |
| C31 | claim, conclusion, authors: "appears" | Neither the sulfate (2:1) ASD nor the free base ASD shows compelling evidence of specific interactions, yet their LoCs are 2 and 35% with drug Tg of 101 and 20 °C, so Tg appears to play an important role in release [rests on: R18, R20.a, R20.i, R2] | p.57 |

## 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 · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C48 | claim, recommendation, authors: "may be a strategy" | Congruent release may be a strategy to avoid matrix crystallization: drug and polymer stay in the solid at the formulated ratio where interactions inhibit crystallization, and release finishes before the nucleation induction time; 5% and 10% DL and their processing variants showed no evidence of crystallization [rests on: R6, R8] | p.32 |
| C63 | claim, mechanism, authors: "can be speculated upon"; "may also play a role" | Not all ASDs are susceptible to matrix crystallization; speculated reasons from BCL: BCL-PVP-family hydrogen bonds, found here with PVPVA, are rapidly disrupted on hydration leaving the drug unprotected; drugs above their wet Tg are more mobile; amorphous BCL crystallizes rapidly above Tg despite high glass forming ability; amorphous BCL can be mechanically activated [rests on: R19, R25, R26; cited: refs 14, 62] | p.35 |
| 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 Ueda — Variable-Temperature NMR Analysis of the Thermodynamics of Polymer Partitioning between Aqueous and Drug-Rich Phases and Its Significance for Amorphous Formulations · Dissolution / C. Amorphous solubility and LLPS

[2022-ueda-polymer-partitioning-ibuprofen-drug-rich-phase-nmr](../../../cards/2022-ueda-polymer-partitioning-ibuprofen-drug-rich-phase-nmr/paper.html) · Dissolution / C. Amorphous solubility and LLPS · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R11 | record, measured | solid-state 1H MAS spectra — P5, P6; crystalline IBP, amorphous IBP, ASDs with polymer weight ratio 40%; 40 °C — sub-table below; text: crystalline IBP broad peaks around 1, 7 and 12.5 ppm (aliphatic, aromatic, carboxylic); amorphous IBP highly resolved sharp peaks; IBP peaks broader in ASDs than in amorphous IBP; polymer peaks at higher field overlap aliphatic IBP peaks; aliphatic and aromatic IBP peaks of ASDs slightly down-field of amorphous IBP; carboxylic proton a single peak at 9−10 ppm in every ASD, at the highest field for IBP/HPMC | Fig. 6, p.105; text p.105-106 |
| R12 | record, measured | solid-state 13C spectra — P5, P7; crystalline IBP (CP/MAS), amorphous IBP and ASDs with polymer weight ratio 40% (PST/MAS); 40 °C — carbonyl carbon (C1) ≈183.5 ppm crystalline, ≈181.9 amorphous, ≈176.8 IBP/PVP, ≈177.3 IBP/PVP−VA, ≈179.2 IBP/HPMC (all read from Fig. 7); text: chemical shift changes between crystalline and amorphous IBP; IBP peaks of ASDs shifted further, most for the carbonyl carbon; one carbonyl peak in each ASD; carbonyl up-field of IBP/HPMC by a larger amount for IBP/PVP and IBP/PVP−VA; in PST spectra IBP peaks stronger than polymer peaks | Fig. 7, p.106; text p.106 |
| R13 | record, measured | carboxylic proton peak versus temperature — P6; ASDs with polymer weight ratio 40%; 25, 40, 55 °C — up-field shift with increasing temperature in all three ASDs; printed 25 → 55 °C differences: IBP/HPMC 0.717 ppm, IBP/PVP−VA 0.271 ppm, IBP/PVP 0.279 ppm; peak positions at 25, 40, 55 °C ≈9.7, ≈9.3, ≈9.0 (HPMC), ≈9.9, ≈9.8, ≈9.6 (PVP−VA), ≈9.7 (broad), ≈9.6, ≈9.5 ppm (PVP) (read from Fig. 8) | Fig. 8, p.107 |
| R15 | record, derived (E9) | chemical shift temperature coefficient TC of IBP carboxylic acid proton — R13 — around −9 × 10−3 ppm/K for IBP/PVP and IBP/PVP−VA ASDs; −24 × 10−3 ppm/K for IBP/HPMC ASD | p.107 |
| C31 | claim, conclusion, authors: asserted ("revealed") | Solid-state NMR shows that polymer mixing disrupts IBP-IBP carboxylic acid hydrogen bonding; the IBP carboxylic proton interacts strongly with PVP and PVP−VA and weakly with HPMC, while HPMC interacts with the IBP C=O and PVP and PVP−VA do so minimally [rests on: R11, R12] | p.106 |
| C32 | claim, conclusion, authors: "indicates"; "implying"; "reflecting" | The TC of about −9 × 10−3 ppm/K indicates intermolecular hydrogen bonding of the IBP carboxylic proton with PVP and PVP−VA; the larger TC for IBP/HPMC implies that this bond with HPMC is disrupted more easily on heating, and the up-field carbonyl shift reflects reduced C=O hydrogen bonding, so the IBP-HPMC interaction is highly temperature-dependent while that with PVP or PVP−VA is less so [rests on: R13, R14, R15; cited: refs 73-79] | p.107 |

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

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

| id | kind | content | locator |
|---|---|---|---|
| C8 | claim, prior hypothesis, authors: "suggested" | Factors suggested to influence the LoC are adhesive drug-polymer interaction strength, drug Tg and additives; PHPH and MePHPH copovidone ASDs are known to have low and high LoCs (R14) [rests on: cited: refs 10, 13, 23-27; R14] | p.2218 |
| C64 | claim, prior hypothesis, authors: asserted | Strong drug-polymer interactions, especially hydrogen bonding, improve physical stability but can harm release, especially in PVPVA ASDs; the low LoC of PHPH-PVPVA was attributed to adhesive hydrogen bonding, and similar effects were noted for other compounds [rests on: cited: refs 13, 23, 47-49] | p.2231 |
| C65 | claim, mechanism, authors: abstract: "This was due to"; discussion: asserted (cited ref 22); conclusions: "was due to" | Hydrogen bonding increases PVPVA distribution into the hydrophobic phase, making it volumetrically larger (associative separation; segregative when the polymer prefers the hydrophilic phase); this incorporation of polymer is why the continuous hydrophobic phase formed at lower DL for PHPH, a high polymer content giving a low LoC [rests on: R6, R7, R12; cited: refs 22, 50] | p.2217, p.2231-2232, p.2233 |
| C74 | claim, generalisation, authors: "highlights"; "provides" | The study highlights the importance of drug-polymer interactions for release as a function of DL and gives a thermodynamic argument for qualitatively predicting release from drug-polymer interactions [rests on: R6, R7, R12; C68] | p.2217, p.2233 |

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

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

| id | kind | content | locator |
|---|---|---|---|
| C2 | claim, prior hypothesis, authors: asserted ("As demonstrated by spectroscopic methods") | The LoC correlates with drug-polymer interaction strength, lower for stronger interactions: for the four analogues (PHPH hydrogen bonds, TIPP hydrogen and halogen bonds, MeTIPP halogen bonds, MePHPH none) hydrogen-bonding systems had significantly lower LoCs, the LoC falling with the cumulative strength/extent of specific interactions; indomethacin versus its ester showed the same in PVPVA [rests on: cited: refs 14, 31, 34; R8, R17] | p.722, p.724, p.729 |
| C26 | claim, conclusion, authors: "Interestingly"; "Overall ... trends with" | The amount of PVPVA associated with the drug nanoparticles correlates with, and trends with, the strength/extent of drug-polymer interactions [rests on: R3, R8] | p.729, p.732 |
| C46 | claim, mechanism, authors: "it is reasonable to infer" | It is reasonable to infer that the phenol-containing compounds take up much PVPVA into the insoluble phase because of favourable drug-polymer interactions, whereas for the methoxy derivatives the lack of hydrogen bonds makes extensive polymer distribution into that phase energetically less favourable [rests on: R3, R8; cited: ref 69] | p.732 |
| C63 | claim, mechanism, authors: discussion: "are hypothesized"; conclusions: "It is suggested"; "It is speculated herein"; "may be closely related" | Strong drug-polymer interactions lower the LoC by shifting the plait point to a lower drug/polymer ratio, which raises the polymer content of the hydrophobic binode and so the hydrophobic-phase volume at a given drug load, favouring an interconnected barrier; associative ASDs therefore need less drug than segregative ones to reach the minimum hydrophobic volume for a barrier, and barrier formation may be closely related to the plait-point position, partly governed by drug-polymer interactions [rests on: R3, R8; argument only] | p.734 |

## 2023 Nguyen — Impact of Gastric pH Variations on the Release of Amorphous Solid Dispersion Formulations Containing a Weakly Basic Drug and Enteric Polymers · Dissolution / B. Supersaturation from ASD dissolution

[2023-nguyen-gastric-ph-variations-delamanid-enteric-polymer-asd](../../../cards/2023-nguyen-gastric-ph-variations-delamanid-enteric-polymer-asd/paper.html) · Dissolution / B. Supersaturation from ASD dissolution · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C41 | claim, prior hypothesis, authors: "is expected"; "are expected" | Where the polymer is essentially insoluble, drug release is expected to depend on the drug's chemical potential in the ASD (drug loading, water content, drug-polymer interactions); weakly interacting, poorly miscible systems release most, strongly interacting systems least [rests on: cited: refs 6, 26, 71] | p.1691 |
| C42 | claim, mechanism, authors: "it is inferred"; "may form" | HPMCP-55, with higher phthalyl content, molecular weight and acid resistance than HPMCP-50, may form stronger or more extensive interactions with DLM, reducing release at pH where the polymer is insoluble [rests on: R11.b, R11.f; M5] | p.1691 |

## 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 · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C2 | claim, prior hypothesis, authors: abstract: asserted; introduction: "can influence" | Drug-polymer interactions and drug Tg have been reported to affect the LoC; the effect of polymer molecular weight had not been explored [rests on: cited: refs 18-20] | p.1, p.2 |
| C10 | claim, assumption, authors: asserted; "could have implications" | Polymer molecular weight strongly influences gel-layer properties and so could affect the LoC; PVP was used for its many grades; clotrimazole was chosen because it does not form strong interactions with PVP, minimizing confounding by drug-polymer interaction, and because it crystallizes slowly [rests on: cited: ref 28; argument only] | p.2 |
| C53 | claim, recommendation, authors: asserted ("always"); "should" | Failure Mode II needs a distinctly different approach: phase inversion will always occur in unionized conditions as DL rises, but its DL can be raised; it is primarily driven by thermodynamics, so drug-polymer-water interactions set its DL and different polymer and additive chemistries should be evaluated; strong drug-polymer interactions trigger it at lower DL yet favour physical stability, so the ASD must be balanced [rests on: cited: refs 21, 26; argument only] | p.10 |

## 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: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R31 | record, measured or cited per row | midpoint Tg of dry ASDs (K, n = 3); pure-component rows of Table S2 are in B1 — P15 — sub-table below | Table S2, SI p.10-11 |
| R36 | record, simulated (P21) | drug thermodynamic activity in dry ASD, drug volume fraction 0.05, 37 °C — PVPVA ASDs of four drugs — MePHPH ≈0.06; MeTIPP ≈2 × 10⁻³; TIPP ≈1 × 10⁻⁹; PHPH ≈1 × 10⁻¹³ (read from log axis of Fig. 17); rank of activity PHPH < TIPP < MeTIPP < MePHPH | Fig. 17, p.1915 |
| R50 | record, derived | PC-SAFT binary interaction parameters kij (drug-PVPVA fitted to a dilute tie line) — P19 — sub-table below | Table S6, SI p.20 |
| C55 | claim, generalisation, authors: "appear" | Drug-polymer-water interactions dictate the shape of the phase envelope, and drug-polymer interactions appear to strongly influence the distribution of PVPVA [rests on: R15, R17] | p.1915 |
| C58 | claim, conclusion, authors: asserted ("confirm") | PC-SAFT drug activities in the dry ASDs confirm the interaction rank PHPH > TIPP > MeTIPP > MePHPH, low activity meaning strong drug-polymer interaction [rests on: R36, R39] | p.1915 |
| C67 | claim, generalisation, authors: asserted ("were shown") | Strong drug-polymer interactions shift the critical point and trigger phase inversion and the falling-off-the-cliff effect at lower DL than weak interactions, which results in drastically different release and ultimately bioavailability [rests on: R36, R37] | p.1917 |

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

[2024-polyzois-praziquantel-racemic-enantiopure-asd-release](../../../cards/2024-polyzois-praziquantel-racemic-enantiopure-asd-release/paper.html) · Dissolution / B. Supersaturation from ASD dissolution · used · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| C5 | claim, prior hypothesis, authors: "are known to" | Polymers inhibit drug crystallization in solution through drug-polymer interactions that suppress nucleation and/or crystal growth, and crystallization inhibition is a key criterion for choosing an ASD polymer [rests on: cited: refs 51, 52] | p.5288, p.5291 |
| C26 | claim, mechanism, authors: "may be attributed"; "could" | The weaker inhibition of R-PZQ may be attributed to structural differences: RS-PZQ crystallizes in its stable commercial form as a triclinic anhydrate with all molecules in syn conformation, R-PZQ only as hydrates (monoclinic C2) with anti conformation, and these conformational differences could change how the polymers interact with the drug [rests on: R4; cited: refs 3, 12, 64] | p.5291 |
| C27 | claim, mechanism, authors: "may" | Alternatively, interaction of one carbonyl group of each R-PZQ molecule with water may reduce drug-polymer interaction and therefore crystallization inhibition [rests on: argument only] | p.5291 |
| C28 | claim, mechanism, authors: "it is not unreasonable to speculate" | Chiral polymers such as HPMCAS and HPMC interact stereoselectively with enantiomers (refs 65, 66), so the polymers may interact more with S-PZQ and better inhibit crystallization of the racemate than of R-PZQ [rests on: R4; cited: refs 65, 66] | p.5291 |

## 2025 Shah — Chemistry and ionization of HPMCAS influences the dissolution and solution-mediated crystallization of posaconazole amorphous solid dispersions · Dissolution / D. Crystallization from solution

[2025-shah-hpmcas-ionization-posaconazole-asd-crystallization](../../../cards/2025-shah-hpmcas-ionization-posaconazole-asd-crystallization/paper.html) · Dissolution / D. Crystallization from solution · measured · as: drug-polymer interactions

| id | kind | content | locator |
|---|---|---|---|
| R8 | record, measured | emission spectra at 8 µg/mL PCZ — buffer pH 6.5 alone or with 900 µg/mL HPMCAS L, M, H (P7) — maximum intensity ≈59 (buffer), ≈66 (L), ≈71 (M), ≈86 (H) a.u.; main peak near 380 nm for buffer and ≈373-375 nm with polymer; a shoulder at ≈356 nm in all spectra (read from Fig. 5C) | Fig. 5C, p.228 |
| R9 | record, measured | λmax of PCZ emission vs PCZ concentration (nm) — buffer pH 6.5 alone or with 900 µg/mL HPMCAS (P7) — sub-table below (read from Fig. 5D, values fall on whole nm); text: λmax 380 nm in buffer and 379 nm with L below LLPS | Fig. 5D, p.228; text p.228 |
| C22 | claim, mechanism, authors: results: "suggesting"; discussion: "signifies"; abstract: "suggested" (greater interaction with increasing A/S ratio) | Below the LLPS concentration the emission maximum blue-shifts in the order no polymer, L, M, H, so posaconazole sits in a more hydrophobic environment with the polymer even when molecularly dissolved; this signifies drug-polymer interactions in bulk solution; the 1 nm difference between buffer (380 nm) and L (379 nm) is within method variability [rests on: R8, R9] | p.223, p.228, p.231 |
| C48 | claim, mechanism, authors: "can be rationalized"; asserted | The pairwise interactions of posaconazole, HPMCAS and water and their distribution between the two phases can be rationalized by chemistry and ionization: posaconazole (log P 4.6) has low affinity for water and phase separates at about 10 µg/mL; amphiphilic HPMCAS interacts with drug and water; its affinity for posaconazole rises with A/S ratio and with lower pH while its affinity for water does the opposite, so H interacts more with posaconazole in solution and partitions more into the drug-rich phase than L [rests on: R2, R16; argument only] | p.231-232 |

## Mentioned only

- 2008 Konno — [2008-konno-polymer-type-felodipine-asd-dissolution](../../../cards/2008-konno-polymer-type-felodipine-asd-dissolution/paper.html) · Dissolution / B. Supersaturation from ASD dissolution (ref 11)
- 2009 Rumondor — [2009-rumondor-polymer-rh-felodipine-crystallization-kinetics](../../../cards/2009-rumondor-polymer-rh-felodipine-crystallization-kinetics/paper.html) · Solid state stability / Physical stability (ref C18)
- 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 20)
- 2017 Elkhabaz — [2017-elkhabaz-ezetimibe-asd-phase-behavior-biorelevant-media](../../../cards/2017-elkhabaz-ezetimibe-asd-phase-behavior-biorelevant-media/paper.html) · Bioperformance / Bioperformance (ref 46)
- 2017 Indulkar — [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 (ref 42)
- 2017 Mugheirbi — [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 (ref C55)
- 2017 Saboo — [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 (ref C4)
- 2018 Moseson — [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 (ref C42)
- 2019 Elkhabaz — [2019-elkhabaz-posaconazole-asd-phase-transformations-biorelevant-media](../../../cards/2019-elkhabaz-posaconazole-asd-phase-transformations-biorelevant-media/paper.html) · Dissolution / B. Supersaturation from ASD dissolution (ref 69)
- 2019 Li — [2019-li-lopinavir-hpmc-asd-microstructure-dissolution](../../../cards/2019-li-lopinavir-hpmc-asd-microstructure-dissolution/paper.html) · ASD process / ASD process (ref 13)
- 2023 Hiew — [2023-hiew-grazoprevir-hierarchical-cpad-surface-drug-release](../../../cards/2023-hiew-grazoprevir-hierarchical-cpad-surface-drug-release/paper.html) · Dissolution / A. Release mechanism and LoC (ref C35)
- 2023 Nguyen — [2023-nguyen-enteric-coating-delamanid-hpmcp-asd-release](../../../cards/2023-nguyen-enteric-coating-delamanid-hpmcp-asd-release/paper.html) · Dissolution / B. Supersaturation from ASD dissolution (ref 16)
- 2025 Hiew — [2025-hiew-surface-composition-wettability-high-drug-loading-asd](../../../cards/2025-hiew-surface-composition-wettability-high-drug-loading-asd/paper.html) · Dissolution / A. Release mechanism and LoC (ref 25)