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A Novel Strategy for Pharmaceutical Cocrystal Generation Without Knowledge of Stoichiometric Ratio: Myricetin Cocrystals and a Ternary Phase Diagram

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Abstract

Purpose

To develop a streamlined strategy for pharmaceutical cocrystal preparation without knowledge of the stoichiometric ratio by preparing and characterizing the cocrystals of myricetin (MYR) with four cocrystal coformers (CCF).

Methods

An approach based on the phase solubility diagram (PSD) was used for MYR cocrystals preparation and the solid-state properties were characterized by differential scanning calorimetry (DSC), fourier transform-infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The ternary phase diagram (TPD) was constructed by combining the PSD and nuclear magnetic resonance (NMR) data. After that, the TPD was verified by traditional methods. The dissolution of MYR in the four cocrystals and pure MYR within three different media were also evaluated.

Results

A simple research method for MYR cocrystal preparation was obtained as follows: first, the PSD of MYR and CCF was constructed and analyzed; second, by transforming the curve in the PSD to a TPD, a region of pure cocrystals formation was exhibited, and then MYR cocrystals were prepared and identified by DSC, FT-IR, PXRD, and SEM; third, with the composition of the prepared cocrystal from NMR, the TPD of the MYR-CCF-Solvent system was constructed. The powder dissolution data showed that the solubility and dissolution rate of MYR was significantly enhanced by the cocrystals.

Conclusions

A novel strategy for pharmaceutical cocrystals preparation without knowledge of the stoichiometric ratio based on the TPD was established and MYR cocrystals were successfully prepared. The present study provides a systematic approach for pharmaceutical cocrystal generation, which benefits the development and application of cocrystal technology in drug delivery.

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Abbreviations

API:

Active pharmaceutical ingredient

CAF:

Caffeine

CCF:

Cocrystal coformer

CYA:

4-Cyanopyridine

DSC:

Differential scanning calorimetry

FT-IR:

Fourier transform-infrared spectroscopy

HTS:

High throughput screening

INM:

Isonicotinamide

MYR:

Myricetin

NIC:

Nicotinamide

PSD:

Phase solubility diagram

PXRD:

Powder X-ray diffraction

SEM:

Scanning electron microscopy

TPD:

Ternary phase diagram

USP:

United states pharmacopeia

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Acknowledgments and Disclosures

This study was sponsored by the National Science Foundation of China (81303304), the Innovation Program of the Shanghai Municipal Education Commission (14YZ057), the Specialized Research Fund for the Doctoral Program of Higher Education (20133107120006), and the Nano-specific Project of the Shanghai Science and Technology Commission (12 nm0502400).

Author information

Authors and Affiliations

  1. Research Center for Health and Nutrition, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Chao Hong, Yan Xie, Yashu Yao, Xiurong Yuan & Hongyi Shen

  2. Pharmacy Department, Shanghai TCM-Integrated Hospital, Shanghai, 200082, China

    Guowen Li

  3. Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Yashu Yao

Authors
  1. Chao Hong
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  2. Yan Xie
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  3. Yashu Yao
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  4. Guowen Li
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  5. Xiurong Yuan
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Corresponding author

Correspondence to Yan Xie.

Electronic supplementary material

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SFig. 1

FTIR results of pure MYR. (GIF 323 kb)

High Resolution Image (TIFF 150 kb)

SFig. 2

FTIR results of pure CAF. (GIF 349 kb)

High Resolution Image (TIFF 159 kb)

SFig. 3

FTIR results of MYR-CAF cocrystal. (GIF 321 kb)

High Resolution Image (TIFF 147 kb)

SFig. 4

FTIR results of pure NIC. (GIF 349 kb)

High Resolution Image (TIFF 161 kb)

SFig. 5

FTIR results of MYR-NIC cocrystal. (GIF 122 kb)

High Resolution Image (TIFF 137 kb)

SFig. 6

FTIR results of pure INM. (GIF 329 kb)

High Resolution Image (TIFF 150 kb)

SFig. 7

FTIR results of MYR-INM cocrystal. (GIF 318 kb)

High Resolution Image (TIFF 145 kb)

SFig. 8

FTIR results of pure CYA. (GIF 384 kb)

High Resolution Image (TIFF 178 kb)

SFig. 9

FTIR results of MYR-CYA cocrystal. (GIF 378 kb)

High Resolution Image (TIFF 184 kb)

SFig. 10

PXRD patterns of pure MYR (a), MYR-CAF cocrystal (b), pure CAF (c). (GIF 532 kb)

High Resolution Image (TIFF 133 kb)

SFig. 11

PXRD patterns of pure MYR (a), MYR-NIC cocrystal (d), pure NIC (e). (GIF 529 kb)

High Resolution Image (TIFF 134 kb)

SFig. 12

PXRD patterns of pure MYR (a), MYR-INM cocrystal (f), pure INM (g). (GIF 542 kb)

High Resolution Image (TIFF 131 kb)

SFig. 13

PXRD patterns of pure MYR (a), MYR-CYA cocrystal (h), pure CYA (i). (GIF 500 kb)

High Resolution Image (TIFF 132 kb)

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Hong, C., Xie, Y., Yao, Y. et al. A Novel Strategy for Pharmaceutical Cocrystal Generation Without Knowledge of Stoichiometric Ratio: Myricetin Cocrystals and a Ternary Phase Diagram. Pharm Res 32, 47–60 (2015). https://doi.org/10.1007/s11095-014-1443-y

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  • DOI: https://doi.org/10.1007/s11095-014-1443-y

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