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pH-Dependent supersaturation from amorphous solid dispersions of weakly basic drugs

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Abstract

Purpose

In amorphous solid dispersions (ASDs), the chemical potential of a drug can be reduced due to mixing with the polymer in the solid matrix, and this can lead to reduced drug release when the polymer is insoluble in the dissolution media. If both the drug and the polymer composing an ASD are ionizable, drug release from the ASD becomes pH-dependent. The goal of this study was to gain insights into the pH-dependent solubility suppression from ASD formulations.

Methods

The maximum release of clotrimazole, a weakly basic drug, from ASDs formulated with insoluble and pH-responsive polymers, was determined as a function of solution pH. Drug-polymer interactions in ASDs were probed using melting point depression, moisture sorption, and solid-state Nuclear Magnetic Resonance spectroscopy (SSNMR) measurements.

Results

The extent of solubility suppression was dependent on polymer type and drug loading. The strength of drug-polymer interactions was found to correlate well with the degree of solubility suppression. For the same ASD, the degree of solubility suppression was nearly constant across the solution pH range studied, suggesting that polymer-drug interactions in residual ASD solids was independent of solution pH. The total drug release agrees with the Henderson-Hasselbalch relationship if the suppressed amorphous solubility of the free drug is independent of solution pH.

Conclusions

The mechanism of solubility suppression at different solution pHs appeared to be drug-polymer interactions in the solid-state, where the concentration of the free drug remains the same at variable pHs and the total drug concentration follows the Henderson-Hasselbalch relationship.

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Abbreviations

ASD:

Amorphous solid dispersion

CA:

Cellulose acetate

CTZ:

Clotrimazole

CPMAS:

Cross polarization and magic-angle spinning

DL:

Drug loading

DSC:

Differential scanning calorimetry

EC:

Ethylcellulose

EUD EPO:

Eudragit® E PO

EUD L100:

Eudragit® L100

EUD RLPO:

Eudragit® RL PO

HPLC:

High performance liquid chromatography

HPMC:

Hydroxypropyl methylcellulose

HPMCAS:

Hydroxypropyl methylcellulose acetate succinate

HPMCP:

Hydroxypropyl methylcellulose phthalate

RH:

Relative humidity

SSNMR:

Solid-state nuclear magnetic resonance

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors gratefully thank Crystal Pharmatech Inc. for supporting this study. We also express thanks to the University of Connecticut for providing startup funding to support AN. The authors declare no competing financial interest.

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Authors and Affiliations

  1. Pharmaceutical Development, Biogen, 115 Broadway, Cambridge, Massachusetts, 02142, USA

    Bo Wang

  2. Kansas Analytical Services LLC, Fort Collins, 4921 Eagle Lake Drive, Ft. Collins, Colorado, 80524, USA

    Matthew J. Nethercott & Michael Hanrahan

  3. Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road Unit 3092, Storrs, Connecticut, 06269, USA

    Akshay Narula & Na Li

  4. Center for Pharma Crystallization, J-Star Research, 6 Cedarbrook Dr., Cranbury, New Jersey, 08512, USA

    Shanming Kuang

  5. Research and Development, Crystal Pharmatech Inc., 3000 Eastpark Blvd Suite 500B, Cranbury, New Jersey, 08512, USA

    Robert M. Wenslow

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  1. Bo Wang
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Wang, B., Nethercott, M.J., Narula, A. et al. pH-Dependent supersaturation from amorphous solid dispersions of weakly basic drugs. Pharm Res 39, 2919–2936 (2022). https://doi.org/10.1007/s11095-021-03147-0

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