# Evidence: moisture-induced crystallization

Parent: — · class: kinetics · names merged here: humidity-induced crystallization; moisture-induced crystallization

10 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.

## 2008 Konno — Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine · Dissolution / B. Supersaturation from ASD dissolution

[2008-konno-polymer-type-felodipine-asd-dissolution](../../../cards/2008-konno-polymer-type-felodipine-asd-dissolution/paper.html) · Dissolution / B. Supersaturation from ASD dissolution · used · as: moisture-induced crystallization

| id | kind | content | locator |
|---|---|---|---|
| R18 | record, cited | solid-state crystallization of felodipine dispersions with the same three polymers — refs 21, 22 — dry (ref 21): nucleation rate of felodipine in the dispersions did not vary with polymer type; no difference in stabilizing ability. With atmospheric moisture (ref 22): diverse inhibitory effects, correlated with both the amount of polymer and the amount of moisture; HPMCAS and HPMC superior to PVP at high relative humidity and similar to each other | p.494, p.498 |
| C34 | claim, generalisation, authors: "It thus appears"; "may vary" | Different crystallization inhibition mechanisms are important and may vary with the amount of water in the system [rests on: R18, R10] | p.498 |

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

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

| id | kind | content | locator |
|---|---|---|---|
| R12 | record, measured | time course of moisture-induced spectral change and crystallization — dispersions stored at high RH (P7, P16) — NH-region changes of R11 type seen after 2–24 h; after longer storage the spectra changed in a way the authors assign to crystallization, and crystals were seen by polarized light microscopy; storage times not printed | p.175 |
| R19 | record, measured | AFM topography and phase of films after humid storage — 50% (w/w) PVP films on glass, 94% RH, vacuum-dried at least 24 h before imaging; 5 µm × 5 µm (P3, P14) — sub-table below | Fig. 13, p.179; text p.178, p.180 |
| R20 | record, measured | TEM micrographs and electron diffraction — (a) amorphous felodipine, (b) PVP, (c) "30% PVP-Felodipine" at 0% RH, (d) the same at 94% RH, spin coated on grids, vacuum-dried overnight (P4, P15); scale bars 100 nm — (a), (b) no distinct features; (c) uniform, no distinct regions; (d) two distinct regions (darker domains in a lighter matrix) and no diffraction rings in the inset; after longer storage at 94% RH diffraction rings were seen (data not shown) | Fig. 14, p.180 |
| C24 | claim, conclusion, authors: 4 h: "indicating"; 16 h: "presumably" | The birefringence after 4 h at 94% RH shows crystals, and the 220–440 nm shapes after 16 h are surface drug crystallization [rests on: R19.d-e] | p.178, p.180 |
| C25 | claim, mechanism, authors: "it appears" | The dispersion first separates into two amorphous phases, and the drug-rich regions then crystallize [rests on: R19, R20, R12] | p.180 |

## 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 · measured · as: moisture-induced crystallization

| id | kind | content | locator |
|---|---|---|---|
| R1 | record, measured | crystal growth rate (mm/min) versus storage RH, mean and error bar, n = 3 — felodipine alone (M1), spin-coated films (P1), humidity stage at 25 °C (P3), growth rate by P5 — sub-table below; text: growth rate increased approximately 2-fold over 13-80% RH and 40-fold when RH was further increased to 87% (results); "15−40-fold" increase above 80% RH (abstract) and at 87% RH (conclusions) | Fig. 1, p.748; text p.747, p.748-749, p.753 |
| C4 | claim, prior hypothesis, authors: "In general" | Absorbed water generally promotes crystallization of amorphous pharmaceutical systems (indomethacin; sucrose-PVP and sucrose-PVP/VA dispersions) [rests on: cited: refs 9-11] | p.747 |
| C9 | claim, conclusion, authors: asserted | Above 80% RH the growth rate rises abruptly (results: 40-fold at 87% RH; abstract and conclusions: 15-40-fold) and the crystals change from spherulitic to needle-like [rests on: R1, R2] | p.747, p.748-749, p.753 |
| C24 | claim, mechanism, authors: "is expected"; "indeed observed" | Because crystal growth rate depends on molecular mobility, water uptake by amorphous felodipine should raise its growth rate, and this trend was observed for drug alone up to 80% RH [rests on: R1, R10, R19] | p.749-750 |

## 2010 Eerdenbrugh — Crystallization Tendency of Active Pharmaceutical Ingredients Following Rapid Solvent Evaporation—Classification and Comparison with Crystallization Tendency from Undercooled Melts · Solid state stability / Crystallization tendency

[2010-van-eerdenbrugh-api-crystallization-tendency-rapid-solvent-evaporation](../../../cards/2010-van-eerdenbrugh-api-crystallization-tendency-rapid-solvent-evaporation/paper.html) · Solid state stability / Crystallization tendency · used · as: moisture-induced crystallization

| id | kind | content | locator |
|---|---|---|---|
| P4 | method | humidity-induced crystallization of films | p.3828, Fig. 2 |
| R3 | record, measured | crystal coverage after 2 days at 94% RH, room temperature (PLM) — felodipine films from DCM, 0.03-1.30 M (P4) — crystals cover the whole surface at 0.26, 0.52, 0.78, 1.04 and 1.30 M; below 0.26 M coverage incomplete: 0.20 and 0.13 M mostly non-birefringent with local crystalline patches, 0.07 and 0.03 M no visible crystals; text: similar behavior with the other solvent systems (data not shown) | Fig. 2, p.3832; text p.3831 |

## 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: moisture-induced crystallization

| id | kind | content | locator |
|---|---|---|---|
| R11 | record, measured and calculated | IR carbonyl region after storage and drying, indoprofen–PVP — 50% PVP shown (Fig. 8) with calculated 50% physical mixture; 30, 10, 70, 90% not shown; 54-94% RH (P3) — 50% PVP: slight increase in relative intensity of the 1,682 cm⁻¹ peak after 54 and 75% RH, no sign of crystallization at 75% RH or lower, shifted 1,641 cm⁻¹ band still present; after 84 and 94% RH abrupt decrease of the 1,641 cm⁻¹ peak and a sharp peak at 738 cm⁻¹ (not shown); the plotted 84 and 94% RH spectra also lack the ≈1,727 cm⁻¹ band of the initial film (read from Fig. 8). 30% PVP: similar trend, crystallization detected after 75% RH. 10% PVP: crystallization detected after 54% RH, the lowest RH used. 70 and 90% PVP: AAPS pattern, no crystallization up to 94% RH | Fig. 8, p.1214; p.1218 |
| R14 | record, derived (P3) | phase behaviour after storage at increasing RH, classified from the IR spectra (R9-R13) — five API–PVP systems, 22 °C, up to 94% RH — sub-table below | Table I, p.1213 |
| C22 | claim, conclusion, authors: "indicating"; "suggesting"; "can be explained by" | Indoprofen 50% PVP: the increase at 1,682 cm⁻¹ after 54 and 75% RH means more free PVP carbonyls and, without crystallization, AAPS; the abrupt loss of the 1,641 cm⁻¹ peak at 84 and 94% RH is explained by API crystallization (738 cm⁻¹ peak); 30% PVP behaved alike with crystallization from 75% RH; 70 and 90% PVP showed AAPS without crystallization [rests on: R11] | p.1214 |
| C4 | claim, prior hypothesis, authors: asserted ("has been shown") | Absorbed moisture accelerates crystallization of amorphous APIs in pure form and mixed with other ingredients [rests on: cited: refs 2-4] | p.1209 |

## 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: moisture-induced crystallization

| id | kind | content | locator |
|---|---|---|---|
| R12 | record, measured | days before crystallization was observed by XRPD — P3, P4; polymer content of each dispersion in parentheses — sub-table below | Table 3, p.179 |
| R14 | record, measured | crystallization of 40% resveratrol-60% HPMC — P3, P4 — 84% RH, 25 °C: crystalline material after 1 day, crystallinity increasing until fully crystallized after 126 days (text); Fig. 7a traces at initial, 1, 5, 36 and 124 days, peaks growing to near the physical mixture by 36 days. 0% RH at 50, 90 and 120 °C: crystalline after 1 day; approximately 5%, 20% and 100% crystallized after 275 days, no further crystallization after 25 days (text); Fig. 7b (caption: after 100 days) traces labelled 0 °C, 50 °C, 90 °C and 120 °C: halo at 0 and 50 °C, small peaks at 90 °C, peaks close to the physical mixture at 120 °C | Fig. 7, p.180; text p.180 |
| R16 | record, measured | PAA dispersion in storage — P3, P4; 85% polymer — at 84% RH, 25 °C: some crystallinity after 1 day, almost the entire sample crystalline by day 275; at 0% RH, 120 °C: fully crystallized after 1 day | text p.180 |
| C39 | claim, conclusion, authors: discussion: "in general"; conclusions: asserted ("much greater extent") | The other dispersions were in general much less stable to moisture than to elevated temperature: moisture induced rapid and complete crystallization, heating only partial crystallization followed by long periods at constant crystalline fraction; conclusions: high RH promoted crystallization to a much greater extent than elevated temperatures [rests on: R12, R13, R14, R16] | p.183 |

## 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: moisture-induced crystallization

| 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 |
| C1 | claim, prior hypothesis, authors: introduction: asserted ("The hypothesis tested herein"); discussion: it was anticipated | Dispersions whose drug–polymer interactions gave stability at elevated RH were expected also to resist crystallization during dissolution and to give higher resveratrol concentrations than rapidly crystallizing dispersions. [rests on: R21] | Introduction, pdf p.2; Discussion, pdf p.10 |

## 2017 Correasoto — Second harmonic generation microscopy as a tool for the early detection of crystallization in spray dried dispersions · Characterization methods / Solid-state methods

[2017-correa-soto-shg-early-crystallization-spray-dried-asds](../../../cards/2017-correa-soto-shg-early-crystallization-spray-dried-asds/paper.html) · Characterization methods / Solid-state methods · measured · as: moisture-induced crystallization

| id | kind | content | locator |
|---|---|---|---|
| R1 | record, measured | first storage time at which crystallinity was detected, by method — FTM 15% and EZT 30% HPMCAS SDDs, open dish, 40 °C (P2) — sub-table below | abstract p.86; p.88-91; Figs. 1-3, 5, 9-12 |
| R4 | record, measured | SHG images — FTM 15% ASD, 82% RH, 40 °C (P3) — 8 days: a few spots; at equivalent times considerably more crystals than at 75% RH (text); from 26 days dense fields of elongated regions; 60 days: nearly continuous bright field (read from Fig. 3) | Fig. 3, p.90; text p.89 |
| C15 | claim, conclusion, authors: asserted ("Unsurprisingly") | At 82% RH FTM crystallization is faster, with clear evidence of crystals after 8 days and considerably more crystals than at 75% RH at equivalent storage times [rests on: R4, R2, R1.c] | p.89 |

## 2019 Purohit — Assessing the impact of endogenously derived crystalline drug on the in vivo performance of amorphous formulations · Bioperformance / Bioperformance

[2019-purohit-endogenous-crystallinity-in-vivo-amorphous-tacrolimus](../../../cards/2019-purohit-endogenous-crystallinity-in-vivo-amorphous-tacrolimus/paper.html) · Bioperformance / Bioperformance · measured · as: humidity-induced crystallization

| id | kind | content | locator |
|---|---|---|---|
| R1 | record, measured | % crystallized tacrolimus versus storage time (values read from Fig. 1; error bars drawn, type and n not stated) — Accord capsules in open vials at 40 °C/75% RH (P1); XRPD (P2) — text: maximally crystalline after 4 weeks; caption: maximum extent by the end of 28 d, plateau at 35 d; figure: sub-table below | Fig. 1, p.18; text p.8-9 |
| R2 | record, measured | tacrolimus crystallization in the innovator product — Prograf capsules, 35 days at 40 °C/75% RH (P1) — no tacrolimus crystallization (data not shown) | p.9 |
| C33 | claim, conclusion, authors: asserted | The Accord product undergoes rapid crystallization of tacrolimus in the powder blend at 40 °C/75% RH [rests on: R1] | p.12 |

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

[2021-bhujbal-lumefantrine-asd-spray-antisolvent-precipitation](../../../cards/2021-bhujbal-lumefantrine-asd-spray-antisolvent-precipitation/paper.html) · Solid state stability / Physical stability · used · as: moisture-induced crystallization

| id | kind | content | locator |
|---|---|---|---|
| C11 | claim, prior hypothesis, authors: "may cause" | In anti-solvent precipitation the ASD is in contact with water longer; moisture accelerates crystallization and may destabilize the ASD, so residual moisture must be removed rapidly [rests on: cited: refs 30, 31] | p.2424 |
| C27 | claim, mechanism, authors: results: "could also be responsible"; discussion: "could be a reason" | The higher water content of the CAP ASD could explain its rapid crystallization within a day of accelerated storage [rests on: R10.h, R4.a, R5] | p.2427, p.2429 |
| C43 | claim, mechanism, authors: asserted; "is known to" (ref 46) | EL100 ASDs did not have a high moisture content but took 4 days to dry against ~12 h; prolonged contact of the amorphous drug with water is known to raise crystallization risk [rests on: R11; cited: ref 46] | p.2429 |
| C51 | claim, mechanism, authors: "could have been a cause" | The more protonated CAP and EL100 ASDs had higher moisture or longer water exposure, and were stable for >30 days when made without aqueous solvent, so high or prolonged moisture could have caused their instability [rests on: R10, R11, R20] | p.2430 |
| C56 | claim, generalisation, authors: discussion: "negatively affects"; conclusions: asserted | ASD stability was reduced by moisture during manufacturing or storage [rests on: R10, R11, R4] | p.2430 |