Understanding the Effect of Nucleation in Amorphous Solid Dispersions through Time-Temperature Transformation

Rahul Lalge; N. S.Krishna Kumar; Raj Suryanarayanan

doi:10.1021/acs.molpharmaceut.3c00313

Understanding the Effect of Nucleation in Amorphous Solid Dispersions through Time-Temperature Transformation

Rahul Lalge, N. S.Krishna Kumar, Raj Suryanarayanan

Pharmaceutics

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

In an earlier investigation, the critical cooling rate to prevent drug crystallization (CR_crit) during the preparation of nifedipine (NIF) amorphous solid dispersions (ASDs) was determined through a time-temperature transformation (TTT) diagram (Lalge et al. Mol. Pharmaceutics 2023, 20 (3), 1806-1817). The current study aims to use the TTT diagram to determine the critical cooling rate to prevent drug nucleation (CR_{crit N}) during the preparation of ASDs. ASDs were prepared with each polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). The dispersions were first stored under conditions promoting nucleation and then heated to the temperature that favors crystallization. The crystallization onset time (t_C) was determined by differential scanning calorimetry and synchrotron X-ray diffractometry. TTT diagrams for nucleation were generated, which provided the critical nucleation temperature (50 °C) and the critical cooling rate to avoid nucleation (CR_{crit N}). The strength of the drug-polymer interactions as well as the polymer concentration affected the CR_{crit N}, with PVP having a stronger interaction than HPMCAS. The CR_crit of amorphous NIF was ∼17.5 °C/min. The addition of a 20% w/w polymer resulted in CR_crit of ∼0.05 and 0.2 °C/min and CR_{crit N} of ∼4.1 and 8.1 °C/min for the dispersions prepared with PVP and HPMCAS, respectively.

Original language	English (US)
Pages (from-to)	4196-4209
Number of pages	14
Journal	Molecular pharmaceutics
Volume	20
Issue number	8
DOIs	https://doi.org/10.1021/acs.molpharmaceut.3c00313
State	Published - Aug 7 2023

Bibliographical note

Funding Information:
The project was partially supported by the William and Mildred Peters endowment fund (1701-11392-20662-UMF0003766-2108004). Parts of this work were carried out at the Characterization Facility, University of Minnesota, a member of the National Science Foundation-funded Materials Research Facilities Network (www.mrfn.org). This work used resources of the Advanced Photon Source, a U. S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by the Argonne National Laboratory under contract no. DEAC02-06CH11357. We thank Dr. Andrey Yakovenko and Dr. Wenqian Xu for their help with the use of the 17BM beamline. We thank Dr. Bhushan Munjal for proofreading the manuscript.

Funding Information:
The project was partially supported by the William and Mildred Peters endowment fund (1701-11392-20662-UMF0003766-2108004). Parts of this work were carried out at the Characterization Facility, University of Minnesota, a member of the National Science Foundation-funded Materials Research Facilities Network ( www.mrfn.org ). This work used resources of the Advanced Photon Source, a U. S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by the Argonne National Laboratory under contract no. DEAC02-06CH11357. We thank Dr. Andrey Yakovenko and Dr. Wenqian Xu for their help with the use of the 17BM beamline. We thank Dr. Bhushan Munjal for proofreading the manuscript.

Publisher Copyright:
© 2023 American Chemical Society.

Keywords

amorphous solid dispersion
crystallization
drug−polymer interactions
hot-melt extrusion
hydroxypropyl methylcellulose acetate succinate (HPMCAS)
nifedipine
nucleation
polyvinylpyrrolidone (PVP)
time−temperature transformation

PubMed: MeSH publication types

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

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10.1021/acs.molpharmaceut.3c00313

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title = "Understanding the Effect of Nucleation in Amorphous Solid Dispersions through Time-Temperature Transformation",

abstract = "In an earlier investigation, the critical cooling rate to prevent drug crystallization (CRcrit) during the preparation of nifedipine (NIF) amorphous solid dispersions (ASDs) was determined through a time-temperature transformation (TTT) diagram (Lalge et al. Mol. Pharmaceutics 2023, 20 (3), 1806-1817). The current study aims to use the TTT diagram to determine the critical cooling rate to prevent drug nucleation (CRcrit N) during the preparation of ASDs. ASDs were prepared with each polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). The dispersions were first stored under conditions promoting nucleation and then heated to the temperature that favors crystallization. The crystallization onset time (tC) was determined by differential scanning calorimetry and synchrotron X-ray diffractometry. TTT diagrams for nucleation were generated, which provided the critical nucleation temperature (50 °C) and the critical cooling rate to avoid nucleation (CRcrit N). The strength of the drug-polymer interactions as well as the polymer concentration affected the CRcrit N, with PVP having a stronger interaction than HPMCAS. The CRcrit of amorphous NIF was ∼17.5 °C/min. The addition of a 20% w/w polymer resulted in CRcrit of ∼0.05 and 0.2 °C/min and CRcrit N of ∼4.1 and 8.1 °C/min for the dispersions prepared with PVP and HPMCAS, respectively.",

keywords = "amorphous solid dispersion, crystallization, drug−polymer interactions, hot-melt extrusion, hydroxypropyl methylcellulose acetate succinate (HPMCAS), nifedipine, nucleation, polyvinylpyrrolidone (PVP), time−temperature transformation",

author = "Rahul Lalge and Kumar, {N. S.Krishna} and Raj Suryanarayanan",

note = "Funding Information: The project was partially supported by the William and Mildred Peters endowment fund (1701-11392-20662-UMF0003766-2108004). Parts of this work were carried out at the Characterization Facility, University of Minnesota, a member of the National Science Foundation-funded Materials Research Facilities Network (www.mrfn.org). This work used resources of the Advanced Photon Source, a U. S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by the Argonne National Laboratory under contract no. DEAC02-06CH11357. We thank Dr. Andrey Yakovenko and Dr. Wenqian Xu for their help with the use of the 17BM beamline. We thank Dr. Bhushan Munjal for proofreading the manuscript. Funding Information: The project was partially supported by the William and Mildred Peters endowment fund (1701-11392-20662-UMF0003766-2108004). Parts of this work were carried out at the Characterization Facility, University of Minnesota, a member of the National Science Foundation-funded Materials Research Facilities Network ( www.mrfn.org ). This work used resources of the Advanced Photon Source, a U. S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by the Argonne National Laboratory under contract no. DEAC02-06CH11357. We thank Dr. Andrey Yakovenko and Dr. Wenqian Xu for their help with the use of the 17BM beamline. We thank Dr. Bhushan Munjal for proofreading the manuscript. Publisher Copyright: {\textcopyright} 2023 American Chemical Society.",

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doi = "10.1021/acs.molpharmaceut.3c00313",

language = "English (US)",

volume = "20",

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N1 - Funding Information: The project was partially supported by the William and Mildred Peters endowment fund (1701-11392-20662-UMF0003766-2108004). Parts of this work were carried out at the Characterization Facility, University of Minnesota, a member of the National Science Foundation-funded Materials Research Facilities Network (www.mrfn.org). This work used resources of the Advanced Photon Source, a U. S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by the Argonne National Laboratory under contract no. DEAC02-06CH11357. We thank Dr. Andrey Yakovenko and Dr. Wenqian Xu for their help with the use of the 17BM beamline. We thank Dr. Bhushan Munjal for proofreading the manuscript. Funding Information: The project was partially supported by the William and Mildred Peters endowment fund (1701-11392-20662-UMF0003766-2108004). Parts of this work were carried out at the Characterization Facility, University of Minnesota, a member of the National Science Foundation-funded Materials Research Facilities Network ( www.mrfn.org ). This work used resources of the Advanced Photon Source, a U. S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by the Argonne National Laboratory under contract no. DEAC02-06CH11357. We thank Dr. Andrey Yakovenko and Dr. Wenqian Xu for their help with the use of the 17BM beamline. We thank Dr. Bhushan Munjal for proofreading the manuscript. Publisher Copyright: © 2023 American Chemical Society.

PY - 2023/8/7

Y1 - 2023/8/7

N2 - In an earlier investigation, the critical cooling rate to prevent drug crystallization (CRcrit) during the preparation of nifedipine (NIF) amorphous solid dispersions (ASDs) was determined through a time-temperature transformation (TTT) diagram (Lalge et al. Mol. Pharmaceutics 2023, 20 (3), 1806-1817). The current study aims to use the TTT diagram to determine the critical cooling rate to prevent drug nucleation (CRcrit N) during the preparation of ASDs. ASDs were prepared with each polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). The dispersions were first stored under conditions promoting nucleation and then heated to the temperature that favors crystallization. The crystallization onset time (tC) was determined by differential scanning calorimetry and synchrotron X-ray diffractometry. TTT diagrams for nucleation were generated, which provided the critical nucleation temperature (50 °C) and the critical cooling rate to avoid nucleation (CRcrit N). The strength of the drug-polymer interactions as well as the polymer concentration affected the CRcrit N, with PVP having a stronger interaction than HPMCAS. The CRcrit of amorphous NIF was ∼17.5 °C/min. The addition of a 20% w/w polymer resulted in CRcrit of ∼0.05 and 0.2 °C/min and CRcrit N of ∼4.1 and 8.1 °C/min for the dispersions prepared with PVP and HPMCAS, respectively.

AB - In an earlier investigation, the critical cooling rate to prevent drug crystallization (CRcrit) during the preparation of nifedipine (NIF) amorphous solid dispersions (ASDs) was determined through a time-temperature transformation (TTT) diagram (Lalge et al. Mol. Pharmaceutics 2023, 20 (3), 1806-1817). The current study aims to use the TTT diagram to determine the critical cooling rate to prevent drug nucleation (CRcrit N) during the preparation of ASDs. ASDs were prepared with each polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). The dispersions were first stored under conditions promoting nucleation and then heated to the temperature that favors crystallization. The crystallization onset time (tC) was determined by differential scanning calorimetry and synchrotron X-ray diffractometry. TTT diagrams for nucleation were generated, which provided the critical nucleation temperature (50 °C) and the critical cooling rate to avoid nucleation (CRcrit N). The strength of the drug-polymer interactions as well as the polymer concentration affected the CRcrit N, with PVP having a stronger interaction than HPMCAS. The CRcrit of amorphous NIF was ∼17.5 °C/min. The addition of a 20% w/w polymer resulted in CRcrit of ∼0.05 and 0.2 °C/min and CRcrit N of ∼4.1 and 8.1 °C/min for the dispersions prepared with PVP and HPMCAS, respectively.

KW - amorphous solid dispersion

KW - crystallization

KW - drug−polymer interactions

KW - hot-melt extrusion

KW - hydroxypropyl methylcellulose acetate succinate (HPMCAS)

KW - nifedipine

KW - nucleation

KW - polyvinylpyrrolidone (PVP)

KW - time−temperature transformation

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DO - 10.1021/acs.molpharmaceut.3c00313

M3 - Article

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SN - 1543-8384

VL - 20

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EP - 4209

JO - Molecular pharmaceutics

JF - Molecular pharmaceutics

IS - 8

ER -

Understanding the Effect of Nucleation in Amorphous Solid Dispersions through Time-Temperature Transformation

Abstract

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Keywords

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