Dual Functionality of Bile Acid: Physical Stabilization of Drugs in the Amorphous Form and Solubility Enhancement in Solution

Rahul Lalge; Navpreet Kaur; Naga Kiran Duggirala; Raj Suryanarayanan

doi:10.1021/acs.molpharmaceut.2c00294

Dual Functionality of Bile Acid: Physical Stabilization of Drugs in the Amorphous Form and Solubility Enhancement in Solution

Rahul Lalge, Navpreet Kaur, Naga Kiran Duggirala, Raj Suryanarayanan

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

9 Scopus citations

Abstract

Drugs containing an amino aromatic nitrogen moiety were stabilized in the amorphous form by the surfactant cholic acid (CA). Coamorphous systems of lamotrigine (LAM), pyrimethamine (PYR), and trimethoprim (TRI) were each prepared with CA. Drug-CA interactions, investigated by IR and solid-sate NMR spectroscopy, revealed deprotonation of the carboxylic acid group in CA and the protonation of the most basic nitrogen of the drug. The coamorphous systems exhibited exceptional physical stability and resisted crystallization at (i) elevated temperatures (>100 °C) and (ii) accelerated storage conditions, 40 °C/75% relative humidity for 15 months. The dissolution performance of each coamorphous system was compared with the respective crystalline drug based on the area under the curve (AUC) of the concentration-time profiles. A 25-fold increase in AUC was observed in the PYR-CA coamorphous system. The solubility enhancement is attributed not only due to drug amorphization but also due to solubilization by CA. The supramolecular synthon approach, through a drug-CA interaction, yielded physically stable coamorphous systems with enhanced aqueous drug solubility.

Original language	English (US)
Pages (from-to)	2595-2606
Number of pages	12
Journal	Molecular pharmaceutics
Volume	19
Issue number	7
DOIs	https://doi.org/10.1021/acs.molpharmaceut.2c00294
State	Published - Jul 4 2022

Bibliographical note

Funding Information:
The project was partially supported by the William and Mildred Peters endowment fund. 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 ). We thank (i) Dr. Lorraine Francis for providing access to the Coating Process Laboratory (Department of Chemical Engineering, University of Minnesota), (ii) Tata Gopinath for helping with the solid-state NMR experiments at the Minnesota NMR Center, University of Minnesota, (iii) Dr. Timothy Wiedmann and Dr. N. S. Krishna Kumar for the helpful discussions and comments, (iv) Jinghan Li for the helpful discussions and carrying out dynamic light scattering experiments at Bio-Techne, MN, and (v) Shihao Liu and Iaroslav Makhnenko for helping with the surface tension measurements.

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

Keywords

bile salts
cholic acid
coamorphous
crystallization
micelle
physical stability
solubilization
ssNMR

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.2c00294

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title = "Dual Functionality of Bile Acid: Physical Stabilization of Drugs in the Amorphous Form and Solubility Enhancement in Solution",

abstract = "Drugs containing an amino aromatic nitrogen moiety were stabilized in the amorphous form by the surfactant cholic acid (CA). Coamorphous systems of lamotrigine (LAM), pyrimethamine (PYR), and trimethoprim (TRI) were each prepared with CA. Drug-CA interactions, investigated by IR and solid-sate NMR spectroscopy, revealed deprotonation of the carboxylic acid group in CA and the protonation of the most basic nitrogen of the drug. The coamorphous systems exhibited exceptional physical stability and resisted crystallization at (i) elevated temperatures (>100 °C) and (ii) accelerated storage conditions, 40 °C/75% relative humidity for 15 months. The dissolution performance of each coamorphous system was compared with the respective crystalline drug based on the area under the curve (AUC) of the concentration-time profiles. A 25-fold increase in AUC was observed in the PYR-CA coamorphous system. The solubility enhancement is attributed not only due to drug amorphization but also due to solubilization by CA. The supramolecular synthon approach, through a drug-CA interaction, yielded physically stable coamorphous systems with enhanced aqueous drug solubility.",

keywords = "bile salts, cholic acid, coamorphous, crystallization, micelle, physical stability, solubilization, ssNMR",

author = "Rahul Lalge and Navpreet Kaur and Duggirala, {Naga Kiran} and Raj Suryanarayanan",

note = "Funding Information: The project was partially supported by the William and Mildred Peters endowment fund. 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 ). We thank (i) Dr. Lorraine Francis for providing access to the Coating Process Laboratory (Department of Chemical Engineering, University of Minnesota), (ii) Tata Gopinath for helping with the solid-state NMR experiments at the Minnesota NMR Center, University of Minnesota, (iii) Dr. Timothy Wiedmann and Dr. N. S. Krishna Kumar for the helpful discussions and comments, (iv) Jinghan Li for the helpful discussions and carrying out dynamic light scattering experiments at Bio-Techne, MN, and (v) Shihao Liu and Iaroslav Makhnenko for helping with the surface tension measurements. Publisher Copyright: {\textcopyright} 2022 American Chemical Society. All rights reserved.",

year = "2022",

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doi = "10.1021/acs.molpharmaceut.2c00294",

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AU - Lalge, Rahul

AU - Kaur, Navpreet

AU - Duggirala, Naga Kiran

AU - Suryanarayanan, Raj

N1 - Funding Information: The project was partially supported by the William and Mildred Peters endowment fund. 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 ). We thank (i) Dr. Lorraine Francis for providing access to the Coating Process Laboratory (Department of Chemical Engineering, University of Minnesota), (ii) Tata Gopinath for helping with the solid-state NMR experiments at the Minnesota NMR Center, University of Minnesota, (iii) Dr. Timothy Wiedmann and Dr. N. S. Krishna Kumar for the helpful discussions and comments, (iv) Jinghan Li for the helpful discussions and carrying out dynamic light scattering experiments at Bio-Techne, MN, and (v) Shihao Liu and Iaroslav Makhnenko for helping with the surface tension measurements. Publisher Copyright: © 2022 American Chemical Society. All rights reserved.

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N2 - Drugs containing an amino aromatic nitrogen moiety were stabilized in the amorphous form by the surfactant cholic acid (CA). Coamorphous systems of lamotrigine (LAM), pyrimethamine (PYR), and trimethoprim (TRI) were each prepared with CA. Drug-CA interactions, investigated by IR and solid-sate NMR spectroscopy, revealed deprotonation of the carboxylic acid group in CA and the protonation of the most basic nitrogen of the drug. The coamorphous systems exhibited exceptional physical stability and resisted crystallization at (i) elevated temperatures (>100 °C) and (ii) accelerated storage conditions, 40 °C/75% relative humidity for 15 months. The dissolution performance of each coamorphous system was compared with the respective crystalline drug based on the area under the curve (AUC) of the concentration-time profiles. A 25-fold increase in AUC was observed in the PYR-CA coamorphous system. The solubility enhancement is attributed not only due to drug amorphization but also due to solubilization by CA. The supramolecular synthon approach, through a drug-CA interaction, yielded physically stable coamorphous systems with enhanced aqueous drug solubility.

AB - Drugs containing an amino aromatic nitrogen moiety were stabilized in the amorphous form by the surfactant cholic acid (CA). Coamorphous systems of lamotrigine (LAM), pyrimethamine (PYR), and trimethoprim (TRI) were each prepared with CA. Drug-CA interactions, investigated by IR and solid-sate NMR spectroscopy, revealed deprotonation of the carboxylic acid group in CA and the protonation of the most basic nitrogen of the drug. The coamorphous systems exhibited exceptional physical stability and resisted crystallization at (i) elevated temperatures (>100 °C) and (ii) accelerated storage conditions, 40 °C/75% relative humidity for 15 months. The dissolution performance of each coamorphous system was compared with the respective crystalline drug based on the area under the curve (AUC) of the concentration-time profiles. A 25-fold increase in AUC was observed in the PYR-CA coamorphous system. The solubility enhancement is attributed not only due to drug amorphization but also due to solubilization by CA. The supramolecular synthon approach, through a drug-CA interaction, yielded physically stable coamorphous systems with enhanced aqueous drug solubility.

KW - bile salts

KW - cholic acid

KW - coamorphous

KW - crystallization

KW - micelle

KW - physical stability

KW - solubilization

KW - ssNMR

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SN - 1543-8384

VL - 19

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EP - 2606

JO - Molecular pharmaceutics

JF - Molecular pharmaceutics

IS - 7

ER -

Dual Functionality of Bile Acid: Physical Stabilization of Drugs in the Amorphous Form and Solubility Enhancement in Solution

Abstract

Bibliographical note

Keywords

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