Understanding Dissolution and Crystallization with Imaging: A Surface Point of View

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Kuvaus

The tendency for crystallization during storage and administration is the most considerable hurdle for poorly water-soluble drugs formulated in the amorphous form. There is a need to better detect often subtle and complex surface crystallization phenomena and understand their influence on the critical quality attribute of dissolution. In this study, the interplay between surface crystallization of the amorphous form during storage and dissolution testing, and its influence on dissolution behavior, is analyzed for the first time with multimodal nonlinear optical imaging (coherent anti-Stokes Raman scattering (CARS) and sum frequency generation (SFG)). Complementary analyses are provided with scanning electron microscopy, X-ray diffraction and infrared and Raman spectroscopies. Amorphous indomethacin tablets were prepared and subjected to two different storage conditions (30 °C/23% RH and 30 °C/75% RH) for various durations and then dissolution testing using a channel flow-through device. Trace levels of surface crystallinity previously imaged with nonlinear optics after 1 or 2 days of storage did not significantly decrease dissolution and supersaturation compared to the freshly prepared amorphous tablets while more extensive crystallization after longer storage times did. Multimodal nonlinear optical imaging of the tablet surfaces after 15 min of dissolution revealed complex crystallization behavior that was affected by both storage condition and time, with up to four crystalline polymorphs simultaneously observed. In addition to the well-known α- and γ-forms, the less reported metastable ε- and η-forms were also observed, with the ε-form being widely observed in samples that had retained significant surface amorphousness during storage. This form was also prepared in the pure form and further characterized. Overall, this study demonstrates the potential value of nonlinear optical imaging, together with more established solid-state analysis methods, to understand complex surface crystallization behavior and its influence on drug dissolution during the development of amorphous drugs and dosage forms.
Alkuperäiskielienglanti
LehtiMolecular Pharmaceutics
Vuosikerta15
Numero11
Sivut5361-5373
Sivumäärä13
ISSN1543-8384
DOI - pysyväislinkit
TilaJulkaistu - marraskuuta 2018
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 317 Farmasia

Lainaa tätä

@article{3eb1aca70886400caf930116e615a52f,
title = "Understanding Dissolution and Crystallization with Imaging: A Surface Point of View",
abstract = "The tendency for crystallization during storage and administration is the most considerable hurdle for poorly water-soluble drugs formulated in the amorphous form. There is a need to better detect often subtle and complex surface crystallization phenomena and understand their influence on the critical quality attribute of dissolution. In this study, the interplay between surface crystallization of the amorphous form during storage and dissolution testing, and its influence on dissolution behavior, is analyzed for the first time with multimodal nonlinear optical imaging (coherent anti-Stokes Raman scattering (CARS) and sum frequency generation (SFG)). Complementary analyses are provided with scanning electron microscopy, X-ray diffraction and infrared and Raman spectroscopies. Amorphous indomethacin tablets were prepared and subjected to two different storage conditions (30 °C/23{\%} RH and 30 °C/75{\%} RH) for various durations and then dissolution testing using a channel flow-through device. Trace levels of surface crystallinity previously imaged with nonlinear optics after 1 or 2 days of storage did not significantly decrease dissolution and supersaturation compared to the freshly prepared amorphous tablets while more extensive crystallization after longer storage times did. Multimodal nonlinear optical imaging of the tablet surfaces after 15 min of dissolution revealed complex crystallization behavior that was affected by both storage condition and time, with up to four crystalline polymorphs simultaneously observed. In addition to the well-known α- and γ-forms, the less reported metastable ε- and η-forms were also observed, with the ε-form being widely observed in samples that had retained significant surface amorphousness during storage. This form was also prepared in the pure form and further characterized. Overall, this study demonstrates the potential value of nonlinear optical imaging, together with more established solid-state analysis methods, to understand complex surface crystallization behavior and its influence on drug dissolution during the development of amorphous drugs and dosage forms.",
keywords = "AMORPHOUS SOLID DISPERSIONS, BEHAVIOR, DOSAGE FORMS, INDOMETHACIN POLYMORPHS, PHARMACEUTICALS, PHASE-TRANSFORMATIONS, POORLY SOLUBLE DRUG, SENSITIVE DETECTION, SOLUBILITY ADVANTAGE, SUPERSATURATION, amorphous, dissolution, indomethacin, nonlinear optics, polymorphism, surface crystallization, 317 Pharmacy",
author = "Dunja Novakovic and Antti Isom{\"a}ki and Bibi Pleunis and Fraser-Miller, {Sara J.} and Peltonen, {Leena Johanna} and Timo Laaksonen and Strachan, {Clare Joanna}",
year = "2018",
month = "11",
doi = "10.1021/acs.molpharmaceut.8b00840",
language = "English",
volume = "15",
pages = "5361--5373",
journal = "Molecular Pharmaceutics",
issn = "1543-8384",
publisher = "American Chemical Society",
number = "11",

}

Understanding Dissolution and Crystallization with Imaging: A Surface Point of View. / Novakovic, Dunja; Isomäki, Antti; Pleunis, Bibi; Fraser-Miller, Sara J.; Peltonen, Leena Johanna; Laaksonen, Timo ; Strachan, Clare Joanna.

julkaisussa: Molecular Pharmaceutics, Vuosikerta 15, Nro 11, 11.2018, s. 5361-5373.

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

TY - JOUR

T1 - Understanding Dissolution and Crystallization with Imaging: A Surface Point of View

AU - Novakovic, Dunja

AU - Isomäki, Antti

AU - Pleunis, Bibi

AU - Fraser-Miller, Sara J.

AU - Peltonen, Leena Johanna

AU - Laaksonen, Timo

AU - Strachan, Clare Joanna

PY - 2018/11

Y1 - 2018/11

N2 - The tendency for crystallization during storage and administration is the most considerable hurdle for poorly water-soluble drugs formulated in the amorphous form. There is a need to better detect often subtle and complex surface crystallization phenomena and understand their influence on the critical quality attribute of dissolution. In this study, the interplay between surface crystallization of the amorphous form during storage and dissolution testing, and its influence on dissolution behavior, is analyzed for the first time with multimodal nonlinear optical imaging (coherent anti-Stokes Raman scattering (CARS) and sum frequency generation (SFG)). Complementary analyses are provided with scanning electron microscopy, X-ray diffraction and infrared and Raman spectroscopies. Amorphous indomethacin tablets were prepared and subjected to two different storage conditions (30 °C/23% RH and 30 °C/75% RH) for various durations and then dissolution testing using a channel flow-through device. Trace levels of surface crystallinity previously imaged with nonlinear optics after 1 or 2 days of storage did not significantly decrease dissolution and supersaturation compared to the freshly prepared amorphous tablets while more extensive crystallization after longer storage times did. Multimodal nonlinear optical imaging of the tablet surfaces after 15 min of dissolution revealed complex crystallization behavior that was affected by both storage condition and time, with up to four crystalline polymorphs simultaneously observed. In addition to the well-known α- and γ-forms, the less reported metastable ε- and η-forms were also observed, with the ε-form being widely observed in samples that had retained significant surface amorphousness during storage. This form was also prepared in the pure form and further characterized. Overall, this study demonstrates the potential value of nonlinear optical imaging, together with more established solid-state analysis methods, to understand complex surface crystallization behavior and its influence on drug dissolution during the development of amorphous drugs and dosage forms.

AB - The tendency for crystallization during storage and administration is the most considerable hurdle for poorly water-soluble drugs formulated in the amorphous form. There is a need to better detect often subtle and complex surface crystallization phenomena and understand their influence on the critical quality attribute of dissolution. In this study, the interplay between surface crystallization of the amorphous form during storage and dissolution testing, and its influence on dissolution behavior, is analyzed for the first time with multimodal nonlinear optical imaging (coherent anti-Stokes Raman scattering (CARS) and sum frequency generation (SFG)). Complementary analyses are provided with scanning electron microscopy, X-ray diffraction and infrared and Raman spectroscopies. Amorphous indomethacin tablets were prepared and subjected to two different storage conditions (30 °C/23% RH and 30 °C/75% RH) for various durations and then dissolution testing using a channel flow-through device. Trace levels of surface crystallinity previously imaged with nonlinear optics after 1 or 2 days of storage did not significantly decrease dissolution and supersaturation compared to the freshly prepared amorphous tablets while more extensive crystallization after longer storage times did. Multimodal nonlinear optical imaging of the tablet surfaces after 15 min of dissolution revealed complex crystallization behavior that was affected by both storage condition and time, with up to four crystalline polymorphs simultaneously observed. In addition to the well-known α- and γ-forms, the less reported metastable ε- and η-forms were also observed, with the ε-form being widely observed in samples that had retained significant surface amorphousness during storage. This form was also prepared in the pure form and further characterized. Overall, this study demonstrates the potential value of nonlinear optical imaging, together with more established solid-state analysis methods, to understand complex surface crystallization behavior and its influence on drug dissolution during the development of amorphous drugs and dosage forms.

KW - AMORPHOUS SOLID DISPERSIONS

KW - BEHAVIOR

KW - DOSAGE FORMS

KW - INDOMETHACIN POLYMORPHS

KW - PHARMACEUTICALS

KW - PHASE-TRANSFORMATIONS

KW - POORLY SOLUBLE DRUG

KW - SENSITIVE DETECTION

KW - SOLUBILITY ADVANTAGE

KW - SUPERSATURATION

KW - amorphous

KW - dissolution

KW - indomethacin

KW - nonlinear optics

KW - polymorphism

KW - surface crystallization

KW - 317 Pharmacy

U2 - 10.1021/acs.molpharmaceut.8b00840

DO - 10.1021/acs.molpharmaceut.8b00840

M3 - Article

VL - 15

SP - 5361

EP - 5373

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 11

ER -