# Evidence: self-association

Parent: — · class: molecular interaction · names merged here: drug self-association; drug-drug interactions; molecular self-assembly; self-association

12 papers measured or used it, 0 only mentioned it (of 207 kept papers). Papers in year order; each section heading ends with the paper's category / subcategory. Generated by tools/build_evidence.py from registry/concepts.csv and the cards; do not edit.

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

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

| id | kind | content | locator |
|---|---|---|---|
| C45 | claim, generalisation, authors: abstract: "may influence"; summary: "offers an explanation" | PVP may influence crystallisation kinetics by preventing the self-association of indomethacin; the hydrogen bond offers an explanation of how PVP inhibits crystallisation from the amorphous phase at levels where its antiplasticising effect is minimal [rests on: C35, C5; cited: ref 7] | p.1691, p.1697 |
| C38 | claim, mechanism, authors: asserted; dimers: "may still be present" | At low PVP, indomethacin is present as dimers and PVP-indomethacin species with some free PVP; as PVP increases free PVP increases, and dimers may still be present depending on the equilibrium constant; the ratios of the species (Fig. 7) vary with PVP content [rests on: R11, R12, R18] | p.1696 |

## 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 · used · as: self-association

| id | kind | content | locator |
|---|---|---|---|
| R18 | record, cited | hydrogen bonding in the bifonazole crystal — crystal structure (ref 15) — weak C-H···N hydrogen bonded chains parallel to the b axis | p.6716 |
| R19 | record, cited | hydrogen bonding in the nimesulide crystal — crystal structure (ref 19); motif frequency (ref 20) — intramolecular NH···O and intermolecular NH···NO2 hydrogen bonds formed by the same NH donor; the intramolecular pattern described as a common motif occurring in crystals with high probability | p.6716 |
| R22 | record, cited | self-association of carboxylic acids — PAA (ref 17); carboxylic acids in crystals (ref 18) — PAA forms a variety of self-associations including dimers; carboxylic acid self-association can be disrupted relatively easily | p.6716 |
| C15 | claim, mechanism, authors: discussion: "should be capable"; "should be preferred"; abstract: "This may be related to" | Any polymer with a donor stronger than the bifonazole C-H should form more favourable hydrogen bonds with the imidazole nitrogen than the drug-drug C-H···N contacts, disrupting drug-drug interactions and delaying crystallization; this is the case for PAA, whose COOH O-H is a much stronger donor [rests on: R18, R7; cited: ref 16] | p.6712, p.6716 |
| C16 | claim, mechanism, authors: "would be expected"; "should disrupt" | The bifonazole imidazole nitrogen should be a better acceptor than the PAA carbonyl and so disrupt PAA self-association [rests on: R22] | p.6716 |

## 2011 Eerdenbrugh — An ab initio polymer selection methodology to prevent crystallization in amorphous solid dispersions by application of crystal engineering principles · Solid state stability / Miscibility and drug-polymer interactions

[2011-van-eerdenbrugh-ab-initio-polymer-selection-asd-crystallization](../../../cards/2011-van-eerdenbrugh-ab-initio-polymer-selection-asd-crystallization/paper.html) · Solid state stability / Miscibility and drug-polymer interactions · measured · as: self-association

| id | kind | content | locator |
|---|---|---|---|
| R7 | record, cited (published crystal structures, CSD reference codes; refs 29-31) | hydrogen-bond motifs in carboxylic acid crystals — flurbiprofen, flufenamic acid, 4-biphenylcarboxylic acid, 4-biphenylacetic acid, anthranilic acid polymorphs — carboxylic acid dimers in flurbiprofen (FLUBIP/FLUBIP01/FLUBIP02), flufenamic acid (FPAMCA/FPAMCA11), 4-biphenylcarboxylic acid (BOPSEE10/BOPSEE11), 4-biphenylacetic acid (ref 29) and anthranilic acid AMBACO03/AMBACO05/AMBACO06/AMBACO08/AMBACO09; in AMBACO01/AMBACO07 the aniline nitrogen bonds to the carboxylic acid, with a neutral and a zwitterionic molecule in the asymmetric unit (refs 30, 31); in flufenamic and anthranilic acid crystals intramolecular N–H···O=C bonds close 6-membered rings | p.6173-6174 |
| R13 | record, cited (CSD reference codes) | hydrogen-bond motifs in amide crystals — benzamide (BZAMID/BZAMID01/BZAMID05/BZAMID06); phenacetin (PYRAZB10/PYRAZB21) — benzamide: dimers through one N–H and one oxygen lone pair, the other hydrogens and lone pairs bonded to neighbouring dimers, all donors and acceptors used; phenacetin: one hydrogen bond per molecule to an adjacent amide oxygen, forming chains; ether oxygen not hydrogen-bonded | p.6176 |
| R14 | record, derived (E2) | probabilities (%) of hydrogen-bond classes in CSD structures containing an amide fragment A and a fragment B — CSD survey (P5); B = the drug's own amide fragment, a COOH fragment (labelled PAA) or a C(O)NC2 fragment (labelled PVP) — sub-table below; footnote a: for drug-drug pairs all hydrogen-bonded cases were classed A-A | Table 3, p.6177 |
| C17 | claim, prior hypothesis, authors: asserted | Carboxylic acids self-associate in crystals, typically as dimers, with 100% frequency when no competing groups are present, but other acceptors that compete for the strong carboxyl donor can disrupt this pattern [rests on: cited: refs 27, 28; R7] | p.6173 |
| C30 | claim, prior hypothesis, authors: asserted | Self-association of hydrogen-bearing amide groups occurs with extremely high frequency [rests on: cited: ref 27; R13] | p.6176 |

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

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

| id | kind | content | locator |
|---|---|---|---|
| C10 | claim, assumption, authors: asserted | The PVP carbonyl band (a mixed carbonyl and N-C stretching mode) is a useful probe of intermolecular hydrogen bonding with a donor, since the carbonyl is an acceptor and PVP has no donors; the DEX OH bands were not analysed to the same extent, since DEX hydrogen bonds with itself and bonds to PVP form at the expense of DEX-DEX bonds, which complicates their interpretation [rests on: cited: refs 29, 31-33] | p.2757-2758 |
| C18 | claim, mechanism, authors: "This suggests"; "can be rationalized"; "probably" | The composition-dependent PVP-rich Tg and the near-pure-DEX DEX-rich Tg suggest that PVP is less miscible in DEX than DEX in PVP: PVP gains hydrogen bonds on mixing, whereas DEX replaces DEX-DEX bonds by DEX-PVP bonds, which probably lowers the overall extent of hydrogen bonding; so the PVP-rich phase holds more DEX than the DEX-rich phase holds PVP [rests on: R4, R6; cited: ref 28] | p.2758-2759 |
| C36 | claim, mechanism, authors: "it is clear"; "can be considered"; "may stem from" | Since many systems phase separate, the enthalpic part of the free energy of mixing has to be positive and phase separation occurs where the entropy cannot counterbalance it; DEX-DEX interactions are energetically more favourable than DEX-PVP interactions, which may stem from DEX-DEX hydrogen bonds being stronger and/or more numerous [rests on: R13; argument only] | p.2764 |
| C37 | claim, conclusion, authors: "Support for this is provided"; "indicating" | The blue shift of the DEX OH peak maximum with increasing PVP (lower DEX fraction) in the fully miscible DEX1-PVP12 system indicates an overall decrease of DEX-DEX hydrogen bonding as DEX-PVP hydrogen bonding increases, supporting C36 [rests on: R16] | p.2764 |
| R16 | record, measured | peak maximum of the DEX OH stretching band versus DEX1 weight fraction — DEX1-PVP12 films (P4) — sub-table below | Fig. 8, p.2763 |

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

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

| id | kind | content | locator |
|---|---|---|---|
| C5 | claim, prior hypothesis, authors: "the hypothesis" | Hypothesis tested: disrupting resveratrol self-assembly by drug-polymer intermolecular interactions is critical both to form an amorphous solid dispersion and to keep it physically stable [rests on: argument only] | p.172 |
| C29 | claim, mechanism, authors: "it is reasonable to expect" | Polymers that offer a better hydrogen-bonding alternative to resveratrol-resveratrol interactions can reasonably be expected to be good crystallization inhibitors [rests on: argument only] | p.181 |
| C47 | claim, recommendation, authors: "It thus appears" | For a compound with a high inherent crystallization tendency such as resveratrol, rational selection of a polymer that disrupts molecular self-assembly through drug-polymer interactions appears necessary to obtain a dispersion stable toward crystallization [rests on: R2, R12, R17] | p.183 |

## 2016 Li — A Comparison of the Crystallization Inhibition Properties of Bile Salts · Dissolution / D. Crystallization from solution

[2016-li-crystallization-inhibition-properties-bile-salts](../../../cards/2016-li-crystallization-inhibition-properties-bile-salts/paper.html) · Dissolution / D. Crystallization from solution · measured · as: self-association

| id | kind | content | locator |
|---|---|---|---|
| R26 | record, simulated | bile salt-bile salt clustering in tetramers (frequency; 1 = interacting, 2 = separated) — P9, P10 — SDC-SDC ≈95 (1), ≈1905 (2); SUDC-SUDC ≈1475 (1), ≈530 (2) (read from Fig. 9E); text: SUDC-SUDC clusters during 73% and SDC-SDC during 5% of the trajectory | Fig. 9E, p.40; text p.21, p.28 |
| C38 | claim, conclusion, authors: asserted ("Accordingly") | SUDC molecules tend to self-interact strongly as well as build complexes with NVP, whereas SDC molecules tend to stay separated; NVP self-interacts about half the time in both systems [rests on: R25, R26] | p.21 |
| C60 | claim, mechanism, authors: "may indicate" | SUDC self-aggregates even with NVP present while SDC remains monomeric, which may indicate a lower tendency of SUDC to interact with a nevirapine nucleus [rests on: R26] | p.28 |

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

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

| id | kind | content | locator |
|---|---|---|---|
| R18 | record, measured | normalized UV absorption peaks of films — P7; same ITZ concentration in all films — sub-table R18 | Fig. 7, p.4395; text p.4394 |
| R19 | record, measured | emission of an evaporating ITZ solution — P6; 3 mg/mL ITZ in DCM–MeOH; excitation 330 nm — sub-table R19; solution slightly turbid at 120 min; features at 450−475 nm in the 120 and 180 min spectra | Fig. 8, p.4396; text p.4395 |
| R22 | record, measured | emission spectra of films, excitation 330 nm — P5; P1 samples — sub-table R22 | Fig. 9, p.4396; Fig. SI.6, SI p.4; text p.4395 |
| R24 | record, measured | UV absorption peaks vs drug loading — P1.l, P7, 20% RH — sub-table R24; text: systematic red shift with increasing loading, shift above 20% loading | Fig. 10a, p.4396; text p.4395−4396 |
| R25 | record, measured | emission vs drug loading, excitation 330 nm — P1.l, P5, 20% RH — sub-table R25; text: emission peak at around 386 nm in the 30−50% films | Fig. 10b, p.4396; text p.4396 |
| R27 | record, measured | emission spectra of spray-dried particles and HPMC "as is", excitation 330 nm — P3 batches, P5 — sub-table R27; text: intensity of the 373 nm peak increases with water content | Fig. 12, p.4397; text p.4397 |
| C31 | claim, mechanism, authors: results: "indicating"; discussion: asserted ("supporting the presence") | The extra emission peak comes from self-associated ITZ and is absent when ITZ is molecularly mixed with the polymer; these aggregates produce the extra peaks in the evaporating solution, phase-separated films and spray-dried particles. [rests on: R19, R22, R27] | p.4395; p.4399 |
| C32 | claim, conclusion, authors: "is indicative of"; "appears to be characteristic" | The UV red shift above 20% loading reflects ITZ aggregation, and the 386 nm emission peak is characteristic of ITZ–ITZ interactions. [rests on: R24, R25] | p.4396 |
| C50 | claim, mechanism, authors: abstract: "suggested"; discussion: "can be attributed" | The spectroscopic changes arise from molecular aggregation and/or local polarity; in the drug domains, nematic assembly of ITZ couples the optical transitions of ITZ monomers in supramolecular aggregates. [rests on: R18, R22, R24, R25] | p.4387; p.4398 |

## 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 · used · as: drug self-association

| id | kind | content | locator |
|---|---|---|---|
| C44 | claim, mechanism, authors: "perhaps, at least intuitively, consistent"; "may restrict" | The stronger CEX hydrogen bonds with PVP and PVP/VA may restrict diffusive motion and hence self-association of drug molecules, in line with literature examples linking interactions to physical stability [rests on: R3, R4, R5, R6, R29; cited: refs 7, 44] | p.8 |

## 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-drug interactions

| id | kind | content | locator |
|---|---|---|---|
| R20 | record, measured | 19F peak splitting vs ledipasvir concentration — P8; toluene-d8, 0.5, 2, 4 mg/mL, 298 K — text: chemical shift difference between the two F atoms larger at higher concentration from 0.5 to 4 mg/mL; outer satellite peaks ≈1.31, ≈1.40, ≈1.46 ppm apart at 0.5, 2, 4 mg/mL (read from Fig. 11) | Fig. 11, p.28; text p.25 |
| R21 | record, measured | 19F peak splitting vs temperature — P8; 2 mg/mL ledipasvir in toluene-d8, 278, 298, 318 K — text: chemical shift difference between the two F atoms decreased with increasing temperature; outer satellite peaks ≈1.59, ≈1.41, ≈1.28 ppm apart at 278, 298, 318 K (read from Fig. 5S) | Fig. 5S, SI p.6; text p.25 |
| C23 | claim, mechanism, authors: "confirmed"; "This is because"; "due to" | The concentration dependence shows the 19F splitting comes from intermolecular (drug-drug) interactions, which are more probable at higher concentration; the smaller splitting at higher temperature comes from increased bond rotation [rests on: R20, R21] | p.25 |
| C38 | claim, mechanism, authors: "appears"; "lend the support to this conjecture" | Amorphous ledipasvir forms cohesive intermolecular hydrogen bonds between its secondary amine groups and fluorine, F acting as an acceptor [rests on: R20; cited: ref 36] | p.34 |

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

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

| id | kind | content | locator |
|---|---|---|---|
| C11 | claim, mechanism, authors: "We rationalized" | Proposed rationale: at low DL drug molecules are further apart and mostly interact with polymer; at high DL they are closer and tend to self-interact [rests on: R9] | p. 18 |
| C27 | claim, mechanism, authors: "can perhaps be rationalized"; "may" | Cl ≈ Br may arise because brotrimazole self-interacts more (Br...phenyl or imidazole contact in its crystal, absent in clotrimazole), competing with the brotrimazole-PVPVA interaction [rests on: R5, R6] | p. 29 |

## 2022 Duong — Phase Behavior and Crystallization Kinetics of a Poorly Water-Soluble Weakly Basic Drug as a Function of Supersaturation and Media Composition · Dissolution / D. Crystallization from solution

[2022-duong-posaconazole-phase-behavior-crystallization-kinetics-media](../../../cards/2022-duong-posaconazole-phase-behavior-crystallization-kinetics-media/paper.html) · Dissolution / D. Crystallization from solution · used · as: drug self-association

| id | kind | content | locator |
|---|---|---|---|
| C13 | claim, mechanism, authors: "probably" | Below pH 2.5 the measured crystalline solubility was consistently above the calculated values, probably from self-complexation or self-aggregation of highly ionized molecules [rests on: R1, R3; cited: refs 42, 45, 46] | p.1149 |
| C16 | claim, mechanism, authors: "might play a role"; "may result" | Above-calculated amorphous solubility below pH 2.5 may reflect self-complexation and the large DMSO volume needed (up to 8% of the medium at pH 1.0) [rests on: R1, R3] | p.1150 |

## 2025 Bapat — Modification of Peptide and Permeation Enhancer In Vitro Release Rates by Dispersion with a Gel-Forming Polymer · Peptide permeability / Peptide permeability

[2025-bapat-peptide-permeation-enhancer-pvpva-synchronous-release](../../../cards/2025-bapat-peptide-permeation-enhancer-pvpva-synchronous-release/paper.html) · Peptide permeability / Peptide permeability · measured · as: self-association

| id | kind | content | locator |
|---|---|---|---|
| R24 | record, measured | SNAC fluorescence intensity at 414 nm versus SNAC concentration — SNAC 0–2 mg/mL in 50 mM pH 6.8 phosphate buffer, without and with 1 mg/mL PVPVA (P9) — text: intensity rises, reaches a maximum and then falls; maximum around 0.1 mg/mL with and without polymer; sub-table below | Fig. 10, p.1016; text p.1012 |
| C34 | claim, mechanism, authors: "suggesting" | The fall of SNAC fluorescence above a maximum suggests quenching by self-association; aggregation starts around 0.1 mg/mL, unaffected by PVPVA [rests on: R24] | p.1012 |